| 1. |
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| 2. |
- de Almeida, Rosa Maria M, et al.
(författare)
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Heightened aggression after chronic flunitrazepam in male rats: potential links to cortical and caudate-putamen-binding sites.
- 2008
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 197:2, s. 309-18
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Higher doses of benzodiazepines induce sedation. However, in low to moderate doses, benzodiazepines can increase aggressive behavior both after acute and chronic administration. The determinants for increasing aggression after chronic intake of flunitrazepam, a so-called date rape drug, in violence-prone individuals are incompletely understood. OBJECTIVES: The aim of this study is to assess the effects of acute and chronic treatment with flunitrazepam on male aggression in resident rats. We also examined possible changes in binding to benzodiazepine receptors throughout the brain of rats that display aggressive behavior after repeated flunitrazepam treatment using quantitative receptor autoradiography. MATERIALS AND METHODS: The behaviors of the male Wistar resident rats (n = 35) toward a male intruder were recorded for 10 min twice a week. The salient aggressive and non-aggressive elements in the resident rat's behavior were analyzed. Initially, the dose-dependent effects of flunitrazepam (0.01, 0.03, 0.1, 0.18, and 0.3 mg/kg) or vehicle were determined in all rats; subsequently, 0.3 mg/kg per day flunitrazepam was administered for 42 days (n = 15), and a parallel group was treated with vehicle (n = 20). After the chronic treatment, the flunitrazepam (0, 0.01, 0.03, 0.1, 0.18, and 0.3 mg/kg) effects were again assessed. RESULTS: The most significant finding is the escalation of aggression after chronic treatment with flunitrazepam. A previously sedative 0.3 mg/kg dose of flunitrazepam engendered very high levels of attack bites, sideways threats, and aggressive postures (total aggression) after 6 weeks of daily administration. Individual differences emerged, and these were associated with decreased binding to benzodiazepine receptors, mainly in the limbic structures such as the cingulate cortex (cingulate areas 1 and 2) and caudate-putamen (posterior part) of aggressive animals, suggesting that these areas are pivotal in the control of emotional and aggressive behavior. CONCLUSIONS: Chronic flunitrazepam produces changes in receptor binding in discrete areas of the cingulate cortex and caudate-putamen that are proposed to be part of the mechanisms for increased expression of aggressive behavior.
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| 3. |
- Jansen, Jurgen, et al.
(författare)
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Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 92:6, s. 2378-2381
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Tidskriftsartikel (refereegranskat)abstract
- Context: T-3 action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T-3 uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T-3 levels. Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T-3. Design: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T-3 uptake, 2) T-3 metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry. Results: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8. Conclusion: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T-3 levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T-3 in central neurons.
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| 4. |
- Kriström, Berit, et al.
(författare)
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Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature
- 2009
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 94:2, s. 483-490
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). OBJECTIVE: The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. SETTING: A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. INTERVENTION: The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. MAIN OUTCOME MEASURE: We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. RESULTS: The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. CONCLUSION: Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.
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| 5. |
- Larsson, Marie H, et al.
(författare)
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Pharmacological analysis of components of the change in transmural potential difference evoked by distension of rat proximal small intestine in vivo.
- 2008
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Ingår i: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 294:1
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Tidskriftsartikel (refereegranskat)abstract
- The reflex response to distension of the small intestine in vivo is complex and not well understood. The aim of this study was to characterize the neural mechanisms contributing to the complex time course of the intestinal secretory response to distension. Transmucosal potential difference (PD) was used as a marker for mucosal chloride secretion, which reflects the activity of the secretomotor neurons. Graded distensions (5, 10, and 20 mmHg) of distal rat duodenum with saline for 5 min induced a biphasic PD response with an initial peak (rapid response) followed by a plateau (sustained response). The rapid response was significantly reduced by the neural blockers tetrodotoxin and lidocaine (given serosally) and by intravenous (iv) administration of the ganglionic blocker hexamethonium and the NK(1) receptor antagonist SR-140333. Serosal TTX and iv SR-140333 significantly reduced the sustained response, which was also reduced by the NK(3) receptor antagonist talnetant and by the vasoactive intestinal polypeptide (VPAC) receptor antagonist [4Cl-d-Phe(6), Leu(17)]-VIP. Serosal lidocaine and iv hexamethonium had no significant effect on this component. Inhibition of nitric oxide synthase had no effect on any of the components of the PD response to distension. The PD response to distension thus seems to consist of two components, a rapidly activating and adapting component operating via nicotinic transmission and NK(1) receptors, and a slow component operating via VIP-ergic transmission and involving both NK(1) and NK(3) receptors.
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| 6. |
- Moore, Edward R.B. 1954, et al.
(författare)
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Considerations for Authenticating Bacterial Strains Coming Into and Going Out of Service Culture Collections
- 2008
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Ingår i: Proceedings of the XXVII ECCO Annual Meeting, June 10-11, Ghent, Belgium. ; , s. 22-24
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Konferensbidrag (refereegranskat)abstract
- Culture collections effectively provide important depositories of prokaryotic diversity, to be available for academic, biotechnological and commercial exploitation. Given the rationale for maintaining reference collections of bacterial strains, it is essential that the collections insure four important points: 1) the viability of strains; 2) the purity of strains; 3) the “authenticity” of strains, i.e., strains are what have been described and represented by the depositors; and 4) the accessibility of strains. Indeed, Rule 27(3) of the Code of Nomenclature of Prokaryotes states, “in the case of species or subspecies the culture collection numbers of at least two publicly accessible service collections in different countries where a subculture of the type strain has been deposited must be indicated”. Since 2002, proof of deposit and availability from culture collections has been required. Implicit in these requirements is the responsibility for the collection to provide proof of deposit to confirm the authenticity of the strain. However, culture collections should not consider themselves obligated to repeat the complete experimental procedures of depositors. The numbers of new taxonomic names included in categories covered by the rules of the Code of Nomenclature of Prokaryotes and validly published have risen an average of 14% each year for the last five years, to more than 900 in 2007 (www.bacterio.cict.fr/). The designated type strain for each of these new species and new combinations must be confirmed as available within culture collections. In principle, it is the responsibility of the respective culture collections to confirm the authenticity of these additions. In 2007, the CCUG issued 118 Certificates of Deposit (CoD) for type strains of newly proposed species. This represents 13% of the total number of new taxa described for that year and was an increase of 34% more than the number of CoD issued by the CCUG in 2006. In light of such increasing numbers of new taxa, culture collections must also respect the time, effort and expense required for “confirming” the authenticities of new deposits. The CCUG has assumed the responsibility for confirming authenticities of deposited strains, i.e., with respect to the protocols used to analyse the strains, and including the qualification: with a high degree of confidence. To this end, culture collections must consider carefully the methods they employ for analysing the authenticity of deposits. The methods to be used should necessarily be reproducible and elucidate the resolution adequate for recognising incorrect strains or contaminations. The CCUG employs phenotypic and cellular fatty acid (CFA) profiling as first- and second-phase analyses, with subsequent 16S rRNA gene sequencing as a tertiary-phase tool in cases wherein the phenotyping and CFA analyses prove to be inadequate. Phenotyping. CCUG “phenotyping” employs an initial screening of Gram-reaction, oxidase, catalase and cultivation on differential media. As has been pointed out before, if the results of simple, initial screening do not conform to the description of the organism, there is no need to carry on with more extensive analyses. Assuming that initial screening agrees with the description received from the depositor, phenotyping proceeds, employing taxon-specific customised and commercial (API, bioMérieux) tests (described in “CCUG Databases, Worksheets and Statistics”, www.ccug.se/default.cfm?navID=160). The resulting data are compared with the differential characteristics described by the depositors (i.e., the CCUG strongly recommends that depositors send the manuscript describing the strains, to be held in confidence). The CCUG carries out “phenotyping” analyses on most deposits. Thus, phenotypic authentications or identifications were performed on most of 1,715 strains deposited with the CCUG in 2007. Such analyses are reliable and useful for some taxa. Unfortunately, phenotyping also possesses well-known inherent problems. Firstly, the protocols require cultivation periods to allow the reactions to develop within the test panels. This generally takes 4 – 48 hours for most commercial systems, and some tests can require as long as six days. Secondly, reproducing phenotypic profiles in the culture collection lab that match those produced in the labs of depositors can be a challenge. Many reasons are responsible for inter-laboratory variability noted in phenotyping results. Additionally, it is recognised that some bacteria do not respond well to the substrates in commercial test panels (e.g., Stenotrophomonas spp., Sphingomonas spp.,), resulting in profiles of limited diversity. Deposits of such bacteria can not be reliably assessed, using phenotyping protocols. Furthermore, some bacteria do not present profiles that distinguish them from other species (e.g., Burkholderia cepacia complex spp., Streptococcus mitis complex spp., etc.). Thus, although bacteria belonging to closely related “species complexes” may be easily differentiated from organisms outside the respective species complex, the culture collection should be aware that inadvertent switches or contaminations with closely related species will most likely not be detected. For this reason, it is recommended that handling multiple samples of closely related and similar organisms on the bench should be done at different times. Chemotyping. CCUG “chemotyping”, may be applied, using cellular fatty acid (CFA) profiling and the protocols described in the MIDI Technical Note #101 (www.midi-inc.com). In 2007, the CCUG determined CFA profiles of 743 deposits (43%). In many cases, such analyses are able to confirm the authenticity of a deposited bacterial strain. Unfortunately, chemotyping faces some of the same limitations observed for phenotyping, in that some bacteria will produce CFA profiles of minimal diversity (e.g., Methylobacterium spp., etc.) or profiles that are not distinguishing (e.g., species of Enterobacteriaceae, etc.). The same risks associated with switching samples or contamination with closely related organisms must be acknowledged by culture collections. Furthermore, a minimal amount (100 mg) of biomass is necessary, which may be problematic to obtain from some fastidious organisms. Genotyping. It is clear that, just as phenotypic and chemotypic profiling may not be adequate for identifications of some bacteria, they also will prove less than perfect for reliable authentications of some bacteria. In such cases, 16S rRNA gene sequence determinations and comparative analyses may provide evidence supporting the authenticity of deposits. The CCUG employs partial 16S rRNA gene sequences for analysing the authenticities of deposited bacteria. The 16S rRNA genes are amplified by PCR, using universal primers. Amplification reactions are set up in duplicate, in order to minimise potential sequence mistakes caused by PCR error. The duplicate amplification products are combined prior to setting up sequence reactions. For purposes of authenticating deposited strains, the CCUG depends upon a single sequence reaction, resulting in determination of approximately 500 nucleotide positions (one third of the 16S rRNA gene) at the 5’-terminus of the 16S rRNA gene. Throughout the length of the 16S rRNA gene, five “hypervariable” regions have been observed to encompass the majority of nucleotide positions exhibiting variation. Three of the regions, comprising 71% of the variable positions in the five “hypervariable” regions, are located within the range of 500 nucleotide positions at the 5’-terminus of the gene. Thus, the probability is high that any deviation in sequence identity between sequences determined for deposited strains and the sequences determined for the strains by the depositors will be detected in this region. In order to provide a systematic assessment of deposited strains, using 16S rRNA gene sequence analysis, the exact region of sequence comparison must be specified, preferably with reference to the E. coli or other species 16S rRNA gene sequence. An extremely high, or perfect, correlation of sequence identities would be expected in order to confirm the deposited strains as being the same as described by the depositors. Of course, the limitations of using 16S rRNA gene sequence analysis as a tool for authenticating deposited strains can be the same as those faced by phenotyping and chemotyping, i.e., the problem of resolution between very closely related organisms. However, again, the question is whether the deposited strains can be considered to be the same organisms described by the depositors – with a high degree of confidence. In point of fact, the authentication process for strains coming into the CCUG is overly complex because information obtained from new organisms is, at the same time, incorporated into the CCUG identification databases. If the only issue were to confirm the authenticity of new strains deposited in the collection, a partial, single-reaction sequence of 16S rRNA genes could be recommended as adequate, in most cases. Such an approach would provide the necessary confidence in the authenticity of newly deposited strains and would help minimise the time, effort and expense of analyses. It is important to note that the 16S rRNA gene sequence is the only characteristic that is required in all cases of new bacterial species descriptions. Whereas phenotypic differential characteristics are required, the specific analyses are not defined. Chemotypic data may be recommended, but are not necessarily required. G+C% content and DNA-DNA similarities are required only in specific conditions. Thus, it is reasonable to assume that information certain to be included in the descriptions of new organisms would be used also by culture collections for authenticating new deposits. Although the methods described above may be considered to be “adequate” for authentication
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| 7. |
- Reuterskiold, Maria H, et al.
(författare)
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Diagnostic performance of computed tomography colonography in symptomatic patients and in patients with increased risk for colorectal disease
- 2006
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Ingår i: Acta Radiol. - : SAGE Publications. - 0284-1851. ; 47:9, s. 888-98
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate the diagnostic performance (colorectal lesions) of computed tomography (CT) colonography in 111 patients, a majority of whom were at high risk for colorectal neoplasia. MATERIAL AND METHODS: After bowel preparation, CT colonography was performed, immediately followed by conventional colonoscopy. The diagnostic performance of CT colonography was analyzed relative to lesion size, histological diagnosis, and diagnostic certainty. RESULTS: The sensitivity of CT colonography increased with lesion size (P<0.001), and was 91% (21/23) for lesions > or = 10 mm. All 10 carcinomas and 86% (19/22) of adenomas > or = 5 mm were detected. Unconfirmed or false-positive CT findings were generally small and/or reported with low diagnostic certainty. The specificity of CT colonography would be 45% (30/66; 95% CI 34% to 57%) if patients with findings of any size and any diagnostic certainty were selected for follow-up, and 92% (85/92; 95% CI 85% to 96%) if only patients with CT findings > or = 10 mm classified as certain were selected. CONCLUSION: CT colonography had a high sensitivity for lesions > or = 5 mm. The diagnostic performance increased with lesion size and degree of diagnostic certainty, and was higher for adenomas.
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| 8. |
- Skogvall, Staffan, et al.
(författare)
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Discovery of a potent and long-acting bronchorelaxing capsazepinoid, RESPIR 4-95
- 2008
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Ingår i: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1522-9629 .- 1094-5539. ; 21:1, s. 125-133
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Current drugs including beta-agonists have limited smooth muscle relaxant effects on human small airways. Yet this is a major site of obstruction in asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: This study explores human small airway relaxant effects of RESPIR 4-95, a novel chemical analogue (capsazepinoid) to capsazepine. Capsazepine was recently shown to relax small airways in a way which was independent of its TRPV(1) antagonism and independent of current bronchodilator drug mechanisms. METHOD: In vitro preparations of human small airways, 0.5-1.5mm in diameter and responding with reproducible contractions to leukotriene D(4) (LTD(4)) for 12h, were used. RESULTS: RESPIR 4-95 reversibly prevented LTD(4)-induced contractions as well as relaxed the established tonic contraction by LTD(4). RESPIR 4-95 exhibited marked improvements over the reference capsazepinoid, capsazepine, by being 10 times more potent, exhibiting twice as long duration of action after wash-out (9h), and inhibiting equally well LTD(4)-, histamine-, prostaglandin D(2) (PGD(2))-, and acetylcholine (ACh)-induced contractions. RESPIR 4-95 was distinguished from l-type calcium channel antagonist nifedipine by its greater efficacy and potency and by exhibiting increased relaxant effect by repeated exposures. Furthermore, RESPIR 4-95 was more efficacious and longer acting than the long-acting beta-agonist formoterol. CONCLUSION: Efficacy, potency, duration of action, and inexhaustibility of its relaxation of human small airways make RESPIR 4-95 an interesting lead compound for further developments aiming at drug treatment of small airway obstruction in asthma and COPD. Further work is warranted to unveil the molecular biology behind its relaxant actions.
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| 9. |
- Svensson, Per-Arne, 1969, et al.
(författare)
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Major role of HSP70 as a paracrine inducer of cytokine production in human oxidized LDL treated macrophages.
- 2006
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 185:1, s. 32-8
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Tidskriftsartikel (refereegranskat)abstract
- Lipid accumulation and inflammation are key hallmarks of the atherosclerotic plaque and macrophage uptake of oxidized low-density lipoprotein (oxLDL) is believed to drive these processes. Initial experiments show that supernatants from oxLDL treated macrophages could induce IL-1beta production in naïve macrophages. To search for potential paracrine mediators that could mediate this effect a DNA microarray scan of oxLDL treated human macrophages was performed. This analysis revealed that oxLDL induced activation of heat shock protein (HSP) expression. HSPs have been implicated in the development of atherosclerosis, but the exact mechanisms for this is unclear. Extracellular heat shock protein 70 (HSP70) has been shown to elicit a pro-inflammatory cytokine response in monocytes and could therefore be a potential paracrine pro-inflammatory mediator. After 24 h of oxLDL treatment there was a significant increase of HSP70 concentrations in supernatants from oxLDL treated macrophages (oxLDLsup) compared to untreated controls (P<0.05). OxLDLsup could induce both interleukin (IL)-1beta and IL-12 secretion in naïve macrophages. We also demonstrate that the effect of oxLDLsup on cytokine production and release could be blocked by inhibition of HSP70 transcription or secretion or by the use of HSP70 neutralizing antibodies. This suggests that extracellular HSP70 can mediate pro-inflammatory changes in macrophages in response to oxLDL.
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