1.
Abdurahman, Samir, 1965-, et al.
(författare)
Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity
2008
Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 52:10, s. 3737-3744
Tidskriftsartikel (refereegranskat) abstract
Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH(2)), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.
2.
Saulo, Eleonor C., et al.
(författare)
Willingness and ability to pay for artemisinin-based combination therapy in rural Tanzania
2008
Ingår i: Malaria Journal. - London : BioMed Central. - 1475-2875 .- 1475-2875. ; 7, s. 227-
Tidskriftsartikel (refereegranskat) abstract
The aim of this study was to analyse willingness to pay (WTP) and ability to pay (ATP) for ACT for children below five years of age in a rural setting in Tanzania before the introduction of artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria. Socio-economic factors associated with WTP and expectations on anti-malaria drugs, including ACT, were also explored.MethodsStructured interviews and focus group discussions were held with mothers, household heads, health-care workers and village leaders in Ishozi, Gera and Ishunju wards in north-west Tanzania in 2004. Contingent valuation method (CVM) was used with "take-it-or-leave-it" as the eliciting method, expressed as WTP for a full course of ACT for a child and households' opportunity cost of ACT was used to assess ATP. The study included descriptive analyses with multivariate adjustment for potential confounding factors.ResultsAmong 265 mothers and household heads, 244 (92%, CI = 88%–95%) were willing to pay Tanzanian Shillings (TSh) 500 (US$ 0.46) for a child's dose of ACT, but only 55% (49%–61%) were willing to pay more than TSh 500. Mothers were more often willing to pay than male household heads (adjusted odds ratio = 2.1, CI = 1.2–3.6). Socio-economic status had no significant effect on WTP. The median annual non-subsidized ACT cost for clinical malaria episodes in an average household was calculated as US$ 6.0, which would represent 0.9% of the average total consumption expenditures as estimated from official data in 2001. The cost of non-subsidized ACT represented 7.0% of reported total annual expenditure on food and 33.0% of total annual expenditure on health care."Rapid effect," "no adverse effect" and "inexpensive" were the most desired features of an anti-malarial drug.ConclusionWTP for ACT in this study was less than its real cost and a subsidy is, therefore, needed to enable its equitable affordability. The decision taken in Tanzania to subsidize Coartem® fully at governmental health care facilities and at a consumer price of TSh 300–500 (US$ 0.28–0.46) at special designated shops through the programme of Accredited Drug Dispensing Outlets (ADDOs) appears to be well founded.
3.
Wettermark, Bjoern, et al.
(författare)
Secondary prevention in a large stroke population - A study of patients' purchase of recommended drugs
2008
Ingår i: Stroke. - New York : American Heart Association. - 0039-2499 .- 1524-4628. ; 39:10, s. 2880-2885
Tidskriftsartikel (refereegranskat) abstract
Background and Purpose - In this study, linked, anonymous data from The National Hospital Discharge Register and the Swedish Prescribed Drug Register were used for studying to what extent recommended drugs for secondary prevention after stroke and TIA were purchased by patients in the region of Stockholm, Sweden (2 million inhabitants). Methods - Data on purchased drugs for secondary stroke prevention during July 2005 to June 2006 by 17 902 patients > 18 years discharged after stroke or TIA during the period 1997 to June 2005 were analyzed by age, gender, and year of discharge. Results - Antiplatelets and warfarin were purchased by 87% of all stroke and 83% of all TIA patients, antihypertensives by 74% and 70%, and lipid lowering drugs by 41% and 39%, respectively. Conclusion - Time after discharge had only a minor influence on the proportion of patients purchasing the medicines.
4.
Karypidis, A.-H., et al.
(författare)
Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate
2008
Ingår i: The Pharmacogenomics Journal. - Avenet, NJ : Nature Pub. Group. - 1470-269X .- 1473-1150. ; 8:2, s. 147-151
Tidskriftsartikel (refereegranskat) abstract
Metabolism of androgens includes glucuronidation, the major pathway of steroid elimination in several steroid target tissues. Glucuronidation is catalysed by UDP-glucuronosyltransferases (UGTs). UGT2B17 has been shown to be particularly active against androgens and is highly abundant in the prostate. Recently, we discovered that deletion of the UGT2B17 gene is associated with low or undetectable urinary testosterone levels. Here, we determined the phenotypic outcome of the deletion by quantifying the UGT2B17 mRNA expression in normal prostate tissues in individuals with different genotypes. Additionally, the frequency of UGT2B17 deletion polymorphism was studied in a Swedish population-based case–control study including 176 patients diagnosed with prostate cancer and 161 controls. We found that the individuals homozygous for the insertion allele expressed 30 times more UGT2B17 mRNA in prostate tissue than the heterozygotes. Carriers of the deletion allele had a significantly increased risk of prostate cancer (OR=2.07; 95% CI=1.32–3.25). In conclusion, these results show the UGT2B17 deletion polymorphism is associated with prostate cancer risk.
5.
Fredin, Maria Fritsch, 1970, et al.
(författare)
The application and relevance of ex vivo culture systems for assessment of IBD treatment in murine models of colitis
2008
Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 58:3-4, s. 222-231
Tidskriftsartikel (refereegranskat) abstract
The aim of this study was to investigate the relevance of mouse ex vivo cultures as a first screening model for new therapeutic agents of Inflammatory Bowel Disease (IBD). Two murine models (dextran sodium sulphate (DSS)-induced colitis and Gαi2-deficient mice) and two anti-inflammatory agents (methyl-prednisolone and the proteasome inhibitor MG132) were evaluated. The in vivo effects of methyl-prednisolone were assessed in both models. Ex vivo colonic tissue from both mouse models were cultured in the presence or absence of the drugs and TaqMan Low-Density arrays were used to assess the regulation of inflammatory genes before and after drug treatment. Colitis induced a similar inflammatory gene profile in both mouse models in in vivo studies and in ex vivo cultures. The differences encountered reflected the different phases of colitis in the models, e.g. innate cytokine/chemokine profile in the DSS model and T cell related markers in Gαi2-deficient mice. After steroid treatment, a similar pattern of genes was suppressed in the two mouse models. We confirmed the suppression of inflammatory gene expression for IL-1β, IL-6 and iNOS in ex vivo and in vivo colons from both mouse models by quantitative RT-PCR. Importantly, the inflammatory responses in the murine ex vivo culture system reflected the in vivo response in the inflamed colonic tissue as assessed by changes in inflammatory gene expression, suggesting that the murine culture system can be used for validation of future IBD therapies.
6.
Gullberg, Elisabet, et al.
(författare)
Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis
2008
Ingår i: Laboratory investigation; a journal of technical methods and pathology. - New York, USA : Elsevier BV. - 1530-0307 .- 0023-6837. ; 88:11, s. 1215-26
Tidskriftsartikel (refereegranskat) abstract
Crohn's disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epithelium-derived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv+) or lacking (inv-) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of beta1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv+ Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, P<0.01) and ileal mucosa (268+/-47% of control; P<0.01), whereas inv bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size- and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of beta1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv+ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of beta1-integrin and stimulated uptake of nanoparticles via invasin-dependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.
7.
Kadi, Fawzi
(författare)
Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle : a basis for illegal performance enhancement
2008
Ingår i: British Journal of Pharmacology. - Basingstoke : Nature Publ. Group. - 0007-1188 .- 1476-5381. ; 154:3, s. 522-528
Tidskriftsartikel (refereegranskat) abstract
The popularity of testosterone among drug users is due to its powerful effects on muscle strength and mass. Important mechanisms behind the myotrophic effects of testosterone were uncovered both in athletes using steroids for several years and in short-term controlled studies. Both long-term and short-term steroid usage accentuates the degree of fibre hypertrophy in human skeletal muscle by enhancing protein synthesis. A mechanism by which testosterone facilitates the hypertrophy of muscle fibres is the activation of satellite cells and the promotion of myonuclear accretion when existing myonuclei become unable to sustain further enhancement of protein synthesis. Interestingly, long-term steroid usage also enhances the frequency of fibres with centrally located myonuclei, which implies the occurrence of a high regenerative activity. Under the action of testosterone, some daughter cells generated by satellite cell proliferation may escape differentiation and return to quiescence, which help to replenish the satellite cell reserve pool. However, whether long-term steroid usage induces adverse effects of satellite cells remains unknown. Testosterone might also favour the commitment of pluripotent precursor cells into myotubes and inhibit adipogenic differentiation. The effects of testosterone on skeletal muscle are thought to be mediated via androgen receptors expressed in myonuclei and satellite cells. Some evidence also suggests the existence of an androgen-receptor-independent pathway. Clearly, testosterone abuse is associated with an intense recruitment of multiple myogenic pathways. This provides an unfair advantage over non-drug users. The long-term consequences on the regenerative capacity of skeletal muscle are unknown.
8.
Hu, Baihua, et al.
(författare)
Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis
2006
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:21, s. 6151-6154
Tidskriftsartikel (refereegranskat) abstract
A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRâ and LXRR and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
9.
Ludvigsson, Jonas F., et al.
(författare)
A population-based study of coeliac disease, neurodegenerative and neuroinflammatory diseases
2007
Ingår i: Alimentary Pharmacology and Therapeutics. - : Wiley. - 0269-2813 .- 1365-2036. ; 25:11, s. 1317-1327
Tidskriftsartikel (refereegranskat) abstract
BackgroundIt has been suggested that coeliac disease (CD) is associated with several neurological diseases. However, the evidence of such an association is inconclusive as earlier research has often been based on small numbers with retrospective data collection.AimTo use Cox regression to examine the risk of neurological disease in individuals with CD.MethodsThrough Swedish national registers we identified some 14 000 individuals with a diagnosis of CD (1964–2003) and 70 000 reference individuals matched for age, sex, calendar year and county.ResultsCoeliac disease was associated with later polyneuropathy [hazard ratio (HR) = 3.4; 95% CI = 2.3–5.1]. We found no statistically significant association between CD and subsequent multiple sclerosis (HR = 0.9; 95% CI = 0.3–2.3), Parkinson’s disease (HR = 1.2; 95% CI = 0.8–1.9), Alzheimer’s disease (HR = 1.5; 95% CI = 0.9–2.6), hereditary ataxia (HR = 1.3; 95% CI = 0.5–3.6), the symptom ataxia (HR = 1.9; 95% CI = 0.6–6.2), Huntington’s disease (HR = 1.7; 95% CI = 0.3–8.6), myasthenia gravis (HR = 0.8; 95% CI = 0.2–3.8) or spinal muscular atrophy (HR = 0.5; 95% CI = 0.1–3.8). Prior polyneuropathy was associated with subsequent CD (odds ratio = 5.4; 95% CI = 3.6–8.2).ConclusionsThe association between CD and polyneuropathy indicates shared risks. We suggest that individuals with polyneuropathy routinely undergo screening for CD. There is no notable association between CD and other neurological outcomes investigated in this study.
10.
Ludvigsson, Jonas F., et al.
(författare)
Coeliac disease and the risk of fractures : a general population-based cohort study
2007
Ingår i: Alimentary Pharmacology and Therapeutics. - Oxford : Blackwell Scientific. - 0269-2813 .- 1365-2036. ; 25:3, s. 273-285
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt) abstract
Background: Earlier studies have suggested that untreated coeliac disease may be associated with osteoporosis, but results are contradictory for the risk of long-term fractures.Aim: To study the association between coeliac disease and fractures.Methods: We used Cox regresson to examine the future risk of hip fracture and fracture of any type in more than 13 000 individuals with coeliac disease and 65 000 age- and sex-matched reference individuals in a general population-based cohort.Results: During follow-up, 1365 first hip fractures and 4847 fractures of any type occurred. Coeliac disease was positively associated with subsequent hip fracture (hazard ratio = 2.1; 95% CI = 1.8-2.4) (in children: hazard ratio = 2.6; 95% CI = 1.1-6.2) and fractures of any type (hazard ratio = 1.4; 95% CI = 1.3-1.5) (in children: hazard ratio = 1.1; 95% CI = 1.0-1.2). The absolute excess risk of hip fractures in children with coeliac disease was 4/100 000 person-years. Incidence ratios for hip fracture in individuals with CD were around two both prior to diagnosis of coeliac disease and afterwards; this risk increase remained 20 years after diagnosis of coeliac disease.Conclusions: Individuals with coeliac disease, including children with coeliac disease, may be at increased risk of hip fracture and fracture of any type. Coeliac disease may be positively associated with long-term hip fracture risk.
