Characterization of a new muscarinic receptor antagonist PNU-171990 in guinea pig,cat and human smooth muscle

The present study was done to characterize a new compound, PNU-171990, 2-diisopropyl aminoethyl 1-phenylcyclopentane carboxylate hydrochloride, with functional smooth muscle selectivity at least as high as tolterodine. In vitro homogenates of guinea pig cerebral cortex, parotid gland, heart, urinary bladder, and Chinese hamster ovary (CHO) cells expressing human muscarinic m(1)-m(5) receptors PNU-171990 did not show selectivity for any subtype (pK(i), 7.72-8.64). PNU-171990 caused a parallel shift in the concentration-response curve for carbachol-induced contraction of smooth muscle from guinea pig bladder (pK(B), 7.65), guinea pig ileum (pK(B), 8.48), and human ileum (pK(B), 7.10). In vivo PNU-171990 inhibited urinary bladder contraction with a significantly lower ID(50) than on the salivary secretion (206 and 706 nmol/kg, respectively, P<0.05). In conclusion, PNU-171990 is a competitive and potent muscarinic receptor antagonist in vitro with a numerically better selectivity ratio for the bladder contraction over salivation in vivo than tolterodine.     

Interleukin-6 gene promoter -174G/C polymorphism and insulin resistance: a pilot study.

BACKGROUND: The aim of this pilot study was to evaluate the relationship between interleukin-6 promoter -174G/C (IL-6 -174G/C) polymorphism and insulin resistance (IR) in obese patients with coronary heart disease (CHD). METHODS: Twenty obese male patients with CHD were selected from a larger database of patients (n=606). IL-6 -174G/C genotype was previously analysed and only homozygotes with the CC genotype (n=10) or GG genotype (n=10) were selected. IR was measured using the homeostasis model assessment for IR (HOMA-IR) method. RESULTS: Differences in age, body mass index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), hypertension, IL-6, C-reactive protein and HOMA-IR were not significant between the genotypes (p>0.05), but analysis of a homogeneity-of-slopes model showed that genotype had a significant influence on HOMA-IR (p=0.037), and the interaction between genotype and HDL-C had a pronounced tendency to affect HOMA-IR (p=0.058). Using multiple regression analysis, we found that HDL-C had a significant effect on HOMA-IR (p=0.023), and TG had a tendency to affect HOMA-IR (p=0.066) only in the CC genotype. CONCLUSIONS: Our data show that IL-6 -174G/C polymorphism may have a significant effect on IR. A comparison between the effects of various cardiovascular risk factors showed that HDL-C may have a significant effect on HOMA-IR in the CC genotype but not in the GG genotype. Further research is needed to test the preliminary results.     

Possibilities of Useful Use of Glued Wooden Construction Residues

People have erected buildings with the use of timber structures for a long time. The uses of timber constructions are very diverse—it is used for the production of exterior wall and roof constructions, window frames and doors, and it is used for dry as well as wet premises. Scandinavian countries have extremely vast experience of using timber structures. Latvia has a rather extensive timber processing and timber structure manufacturing sector. Many companies are involved in timber processing, however, to enable even more extensive use of timber structures, environmental and technically economic requirements of contemporary building must be taken into consideration. Environmental requirements for timber structures provide certain advantages in comparison to other building materials, but technically economic requirements are very important as well. The development of manufacturing of glued constructions and research of production processes of these constructions allows one to find solutions for the reduction in the cost of timber structures, and the results of such research can ensure significant development of the use of timber structures in building, as well as reduce total construction costs. The basic objective of the study is to investigate the residual materials arising as a result of processing cross-laminated timber constructions (CLT panels), material generated as a result of high levels of construction production, and research of the opportunities to reprocess the residual materials generated as a result of laminated timber structure manufacturing into materials suitable for production of building constructions. The majority of CLT panels are manufactured using 20, 30 and 40 mm thick boards, and, during the panel manufacturing process, there are various standard thicknesses of panels, for example, 60, 80, 100, 120, 140, 160 mm, etc. Various layers are used for the creation of various thicknesses depending on the necessary technical properties. Various arrangements of the thickness of a single panel will cause different structural and physical behaviour (i.e., impact of changes in moisture, fire resistance, etc.). During the research and for the purposes of testing of CLT panels, only residues with equal types and thicknesses of lamellae were selected. Two main purposes were included in the panel testing process: (1) Comparison of technical performance of the residues of CLT panels with the classic CLT panel. Curve strength and tensile strength tests were performed in accordance with LVS EN standards (LVS EN 16351: 2016 and LVS EN 408 + A1: 2012). All the samples were prepared according to the LVS EN standards. (2) To assess the impact of two resins (melamine urea formaldehyde (MUF) and polyurethane (PU)), widely used in industry, on structural properties of recycled CLT material. Results of the research show that recycling residues of glued wooden constructions may lead to good results, and manufacturing residues of CLT panels may be successfully used in construction and for the reduction in CLT panel manufacturing costs.     

The influence of 8-Br 3′,5′-cyclic nucleotide analogs and of inhibitors of 3′,5′-cyclic nucleotide phosphodiesterase,on noradrenaline secretion and neuromuscular transmission in guinea-pig vas deferens

Summary The effects of 3,5-cyclic nucleotide phosphodiesterase (PDE) inhibitors and of 8-Br 3,5-cyclic nucleotide analogs on nerve-muscle transmission were studied in the guinea-pig vas deferens preincubated with ³H-noradrenaline.8-Br cyclic AMP and the PDE inhibitors 3-isobutyl-1-methylxanthine (IBMX) and 3-propionyl-4-hydrazinopyrazolopyridine (SQ 20006) enhanced the secretion of ³H-NA evoked by transmural nerve stimulation. 8-Br cyclic GMP was without effect in this respect.The muscle contraction evoked by transmural nerve stimulation, high potassium or by application of exogenous noradrenaline was depressed by IBMX and SQ 20006. The contraction evoked by transmural nerve stimulation was enhanced by 8-Br cyclic AMP and depressed by 8-Br cyclic GMP.These findings suggest differential involvement of 3,5-adenosine- and guanosine-cyclic nucleotides in excitation-secretion-coupling in the noradrenergic sympathetic nerves, and in excitation-contraction-coupling in the smooth muscle, of guinea-pig vas deferens.     

Assessment of patient capacity to consent to treatment

OBJECTIVE: To compare results of a specific capacity assessment administered by the treating clinician, and a Standardized Mini-Mental Status Examination (SMMSE), with the results of expert assessments of patient capacity to consent to treatment. DESIGN: Cross-sectional study with independent comparison to expert capacity assessments. SETTING: Inpatient medical wards at an academic secondary and tertiary referral hospital. PARTICIPANTS: One hundred consecutive inpatients facing a decision about a major medical treatment or an invasive medical procedure. Participants either were refusing treatment, or were accepting treatment but were not clearly capable according to the treating clinician. MEASUREMENTS AND MAIN RESULTS: The treating clinician (medical resident or student) conducted a specific capacity assessment on each participant, using a decisional aid called the Aid to Capacity Evaluation. A specific capacity assessment is a semistructured evaluation of the participant’s ability to understand relevant information and appreciate reasonably foreseeable consequences with regard to the specific treatment decision. Participants also received a SMMSE administered by a research nurse. Participants then had two independent expert assessments of capacity. If the two expert assessments disagreed, then an independent adjudication panel resolved the disagreement after reviewing videotapes of both expert assessments. Using the two expert assessments and the adjudication panel as the reference standard, we calculated areas under the receiver-operating characteristic curves and likelihood ratios. The areas under the receiver-operating characteristic curves were 0.90 for specific capacity assessment by treating clinician and 0.93 for SMMSE score (2p=.48). For the treating clinician’s specific capacity assessment, likelihood ratios for detecting incapacity were as follows: definitely incapable, 20 (95% confidence interval [CI] 3.6, 120); probably incapable, 6.1 (95% CI 2.6, 15); probably capable, 0.39 (95% CI 0.18, 0.81); and definitely capable, 0.05 (95% CI 0.01, 0.29). For the SMMSE, a score of 0 to 16 had a likelihood ratio of 15 (95% CI 5.3, 44), a score of 17 to 23 had a likelihood ratio of 0.68 (95% CI 0.35, 1.2), and a score of 24 to 30 had a likelihood ratio of 0.05 (95% CI 0.01, 0.26). CONCLUSIONS: Specific capacity assessments by the treating clinician and SMMSE scores agree closely with results of expert assessments of capacity. Clinicians can use these practical, flexible, and evaluated measures as the initial step in the assessment of patient capacity to consent to treatment. This project was supported by the physicians of Ontario through a grant (94–28) from Physicians’ Services Incorporated Foundation of Ontario. Dr. Naglie is partially supported by an Arthur Bond Fellowship from the Physicians’ Services Incorporated Foundation.