Nitric oxide-an endogenous inhibitor of gastric acid secretion in isolated human gastric glands

BACKGROUND: Endothelial nitric oxide synthase (eNOS) has previously been detected in the glandular part of the human gastric mucosa. Furthermore, nitric oxide (NO) has been shown to influence gastric secretion in various animal models. The present study was conducted to investigate the influence of exogenously and endogenously derived NO on histamine- and cAMP-stimulated gastric acid secretion in isolated human oxyntic glands. METHODS: Oxyntic glands were isolated from human gastric biopsies and were subsequently pre-treated with NO donors and nitric oxide synthase inhibitors and then exposed to histamine or dibutyryl-cAMP (db-cAMP). The secretory response of the glands was determined as accumulation of [(14)C]aminopyrine. RESULTS: The histamine- or db-cAMP-induced acid secretion was attenuated by L-arginine, a known source of endogenous NO, and also by the NO-donors sodium nitroprusside (SNP) and S-nitroso-N-acetyl-penicillamine (SNAP). Pre-treatment with either of the NOS inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) or N(G)-nitro-L-arginine (L-NNA) enhanced the secretory response. CONCLUSION: Our results show that NO inhibits gastric acid secretion in isolated human gastric glands, and that there is endogenous formation of NO within the glandular epithelium in the vicinity of the parietal cells

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

[postcard] Lappar och Lappliv [klein formaat] /

Bijzondere collectiesPinxten, Ri

Differences in Whole-Blood Transcriptional Profiles in Inflammatory Bowel Disease Patients Responding to Vedolizumab Compared with Non-Responders

Vedolizumab is efficacious in the treatment of Crohns disease (CD) and ulcerative colitis (UC). However, a significant proportion of patients present with a non-response. To investigate whether differences in the clinical response to vedolizumab is reflected in changes in gene expression levels in whole blood, samples were collected at baseline before treatment, and at follow-up after 10-12 weeks. Whole genome transcriptional profiles were established by RNA sequencing. Before treatment, no differentially expressed genes were noted between responders (n = 9, UC 4, CD 5) and non-responders (n = 11, UC 3, CD 8). At follow-up, compared with baseline, responders displayed 201 differentially expressed genes, and 51 upregulated (e.g., translation initiation, mitochondrial translation, and peroxisomal membrane protein import) and 221 downregulated (e.g., Toll-like receptor activating cascades, and phagocytosis related) pathways. Twenty-two of the upregulated pathways in responders were instead downregulated in non-responders. The results correspond with a dampening of inflammatory activity in responders. Although considered a gut-specific drug, our study shows a considerable gene regulation in the blood of patients responding to vedolizumab. It also suggests that whole blood is not optimal for identifying predictive pre-treatment biomarkers based on individual genes. However, treatment outcomes may depend on several interacting genes, and our results indicate a possible potential of pathway analysis in predicting response to treatment, which merits further investigation

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-90198 Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease – Novel Clues to Drug Targets and Disease Mechanisms?

Background and Aims: Thiopurines are effective to induce and maintain remission in inflammatory bowel disease (IBD). The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. Here we explored the molecular basis of differences in metabolite profiles and in relation to disease activity. Methods: Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios.20, 10.0–14.0 and #4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with RT qPCR in an expanded patient cohort (n = 54). Additionally, 30 purine/thiopurine related genes were analysed separately. Results: Among 17 genes identified by microarray-screening, there were none with a known relationship to pathways of purines/thiopurines. For nine of them a correlation between expression level and the concentration of meTIMP, 6-TGN and

Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease : Novel Clues to Drug Targets and Disease Mechanisms?

Background and Aims Thiopurines are effective to induce and maintain remission in inflammatory bowel disease (IBD). The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. Here we explored the molecular basis of differences in metabolite profiles and in relation to disease activity. Methods Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios &gt;20, 10.0–14.0 and ≤4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with RT qPCR in an expanded patient cohort (n = 54). Additionally, 30 purine/thiopurine related genes were analysed separately. Results Among 17 genes identified by microarray-screening, there were none with a known relationship to pathways of purines/thiopurines. For nine of them a correlation between expression level and the concentration of meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio was confirmed in the expanded cohort. Nine of the purine/thiopurine related genes were identified in the expanded cohort to correlate with meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio. However, only small differences in gene expression levels were noticed over the three different metabolite profiles. The expression levels of four genes identified by microarray screening (PLCB2, HVCN1, CTSS, and DEF8) and one purine/thiopurine related gene (NME6) correlated significantly with the clinical activity of Crohn’s disease. Additionally, 16 of the genes from the expanded patient cohort interacted in networks with candidate IBD susceptibility genes. Conclusions Seventeen of the 18 genes which correlated with thiopurine metabolite levels also correlated with disease activity or participated in networks with candidate IBD susceptibility genes involved in processes such as purine metabolism, cytokine signaling, and functioning of invariant natural killer T cells, T cells and B cells. Therefore, we conclude that the identified genes to a large extent are related to drug targets and disease mechanisms of IBD.Funding Agencies|Futurum - the Academy for Healthcare||County Council Jonkoping||Medical Research Council of Southeast Sweden (FORSS)||Swedish Society of Medicine||County Council of Ostergotland||Swedish Cancer Society||Swedish Childhood Cancer Foundation||Rut and Richard Juhlins Foundation||Swedish Research Council||</p

Abnormally low offer in the Public Procurement Law.

Bakalaura darba tēma ir “Nepamatoti lēts piedāvājums Publisko iepirkumu likumā”. Temata aktualitāte ir saistīta ar to, ka publiskajos iepirkumos tiek iesniegti piedāvājumi, kas ir vērtējami kā nepamatoti lēti, kad piedāvātā cena neatbilst preces vai pakalpojumu reālajai vērtībai un attiecīgi tiek apšaubīta piegādāto preču un sniegto pakalpojumu kvalitāte vai noslēdzamā līguma izpilde. Piedāvājumu izvēlei un vērtēšanai publiskajos iepirkumos jābūt atbilstošai iepirkumā izvirzītajiem mērķiem, lai novēršot korupcijas riskus, sekmētu godīgu konkurenci pretendentu starpā, nodrošinātu vienlīdzīgu un taisnīgu attieksmi pret tiem, kā arī nodrošinātu pasūtītāja līdzekļu efektīvu izmantošanu. Bakalaura darba mērķis ir analizēt nepamatoti lēta piedāvājuma institūtu publisko iepirkumu jomā, konstatējot juridiskās problēmas, un izvirzīt priekšlikumus Publisko iepirkumu likuma pilnveidošanai. Veiktā pētījuma rezultātā secināts, ka tiesiskajā regulējumā nav nepamatoti lēta piedāvājuma definīcijas, bet ir noteikts pasūtītāja pienākums pieprasīt no pretendenta skaidrojumu, ja pasūtītājam rodās šaubas par iesniegto piedāvājumu. Savukārt pretendentam ir jāiesniedz pasūtītājam skaidrojums, pamatojoties uz pasūtītāja pieprasījumu, kam jābūt diezgan detalizētam, lai saņemtu to informāciju, kura ir nepieciešama lēmuma pieņemšanai par piedāvājuma akceptēšanu vai noraidīšanu. Papildus secināts, ka ir nepieciešams standartizēt iepirkuma dokumentāciju, noteikt pienākumu pieaicināt ekspertu komisijas sastāvā, izstrādāt kritērijus pretendenta skaidrojuma vērtēšanai. Atslēgas vārdi: Publiskie iepirkumi, nepamatoti lēts piedāvājums, konsultēšanās, kritēriji, tests.The topic of the bachelor’s thesis is “Abnormally low offer in the Public Procurement Law”. The actuality of the topic is related to the fact that there are cases when abnormally low tenders are submitted in public procurement, it means that the offered price does not correspond to the real value of the goods or services and accordingly the quality of delivered goods and services could be doubted. The selection and evaluation of tenders in public procurement must be in accordance with the objectives set in the procurement in order to prevent corruption risks, promote fair competition between tenderers, ensure equal and fair treatment of them, as well as ensure efficient use of contracting authority funds.. The aim of the bachelor’s thesis is to analyse the institute of abnormally low tender in the public procurement, which leads to identifying the legal problems and proposing the improvement of the Public Procurement Law. As a result of the research, it has been concluded that legal regulation does not contain a definition of abnormally low tender, but the contracting authority is obliged to request an explanation from the tenderer if the contracting authority has doubts about the submitted tender. In turn, the tenderer shall provide the contracting authority with an explanation based on the contracting authority’s request, which should be quite detailed in order to receive the information necessary to make a decision on accepting or rejecting the tender. In addition, it has been concluded that it is necessary to standardise the procurement documentation, to determine the obligation to invite expert to be part of the commission and to develop criteria for evaluating the tenderer’s explanation. Keywords: Public procurement, abnormally low offer, consultation, criteria, test