Acaricidal action of ozone on larvae and engorged females of Rhipicephalus microplus: a dose-dependent relationship.

The tick Rhipicephalus microplus is a vector of infectious agents that causes great economic loss in the productivity of cattle herds. Several studies have sought natural compounds with acaricidal activity to control ticks, without allowing the development of resistance, without causing environmental damage, and without presenting toxicity to the hosts. The activity of ozone on the natural biomolecules of living beings has been studied as an alternative to control arthropods and acaricidal effects were shown on ticks. The aim of the present study was to assess the acaricidal effect on larvae and engorged females of R. microplus according to ozone dose. Larvae (n = 377) were distributed in 10 groups and engorged females (n = 284) were distributed in 14 groups. One group was used as control (not exposed to ozone) and the other groups were exposed to ozone gas for 5-105 min. Ozone had a dose-dependent acaricidal effect on both larvae and engorged females. Dosages between 355 and 2130 mg/L min had a delayed acaricidal effect (12-180 h), leading to the death of all engorged females before laying eggs, whereas doses between 3195 and 7455 mg/L min showed immediate acaricidal effect (5 min to 4 h). Doses between 1775 and 6390 mg/L min had an immediate (up to 5 min) acaricidal effect on the larvae of this species. Further studies should consider longer follow-up times during the assessment of the acaricidal activity against ticks.

The effect of capromorelin on glycemic control in healthy dogs.

Capromorelin is a ghrelin-receptor agonist widely used as an appetite stimulant in dogs. Capromorelin disrupts glucose homeostasis in cats but information regarding its effects on canine glucose homeostasis is lacking. The study objective was to evaluate the effect of capromorelin on glucose homeostatic mechanisms in healthy dogs. Eight clinically healthy client-owned adult dogs were enrolled in this prospective, cross-over, placebo-controlled study. Dogs were randomized to receive capromorelin (Entyce, 3 mg/kg) or placebo, q24h for 3 d. A wk later, treatments were crossed over. Interstitial glucose (IG) concentrations were measured using a flash glucose monitoring system throughout. On d 1 of each treatment, blood glucose (BG), insulin, glucagon, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were measured before drug administration, then before and 30-120 min after feeding a glucose-rich diet (Ensure Plus, 21 kcal/kg). Data were analyzed as a 2-period crossover design using generalized least squares estimation. Capromorelin administration increased mean 48 h IG by10% and mean BG by 20% at 90 and 120 min post-prandially (P < 0.0001). Post-prandially, there was a time-by-treatment effect for insulin (P = 0.03) and GIP (P = 0.0002) because capromorelin doubled geometric mean insulin concentrations at 120 min and increased geometric mean GIP concentrations more rapidly than after placebo. There were no differences in glucagon or GLP-1 concentrations between treatment groups. The increase in post-prandial blood glucose was not the result of overt suppression of incretin hormone secretion. There was also no suppressive effect of capromorelin on insulin.

The rs2165241 polymorphism of the Loxl1 gene in postmenopausal women with pelvic organ prolapse.

OBJECTIVE: This study aimed to verify the presence of polymorphism rs2165241 of the lysyl oxidase-like 1 (Loxl1) gene and its association with pelvic organ prolapse (POP) in Brazilian women and determine risk factors for POP development. METHODS: The study was previously approved by the local research and ethics board. Postmenopausal women were included and divided into POP (stages III and IV) and control (stages 0 and I) groups. Peripheral blood samples were collected, and the DNA sequence of interest was analyzed by real-time reverse-transcriptase polymerase chain reaction. We used logistic regression and considered a recessive model of inheritance for the analysis, with p < 0.05 for significance. RESULTS: A total of 836 women were assessed: 426 POP cases and 410 controls. The frequencies of CC, CT and TT genotypes were similar in both groups. Age (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.07; 1.14), number of vaginal births (OR = 17.06, 95% CI = 5.94; 48.97), family history (OR = 2.87, 95% CI = 1.57; 5.22) and weight of largest newborn (OR = 1.001, 95% CI = 1.0003; 1.001) were independent risk factors for POP, while multiple cesarean sections (two or more) was protective (OR = 0.17, 95% CI = 0.07; 0.42). CONCLUSION: No association was detected between rs2165241 of the Loxl1 gene and POP.

Female urinary incontinence: effective treatment strategies.

Urinary incontinence is a dysfunction that tremendously affects women's quality of life, involving social, emotional and economic aspects. Although various treatments for urinary incontinence have been described, it is important to know which of them are truly effective. This review seeks to determine the current available therapies for women with stress urinary incontinence and overactive bladder syndrome, based on the best scientific evidence.

Nanostructuring of the conjugated polyelectrolyte poly[9,9-bis(4-sulfonylbutoxyphenyl)fluorene-2,7-diyl-2,2'-bithiophene] in liquid crystalline C12E4 in bulk water and aligned thin films.

We report on the conjugated polyelectrolyte 12 mM poly[9,9-bis(4-sulfonylbutoxyphenyl) fluorene-2,7-diyl-2,2'-bithiophene] (PBS-PF2T) mixed in concentrated aqueous 680 mM tetraethylene glycol monododecyl ether (C12E4) in bulk and thin films. A blue-shift in the fluorescence spectrum demonstrates breakup of PBS-PF2T aggregates in bulk aqueous C12E4. Small-angle X-ray scattering data indicate that this mixture follows a very similar phase behaviour to binary mixtures of a pure surfactant with water, including a micellar phase below about 20 °C, a lamellar phase in between about 20 and 70 °C and a proposed coexistence of water and the liquid surfactant solution above 70 °C. Molecular dynamics simulations reproduce these transitions and suggest that PBS-PF2T is incorporated into the surfactant headgroup region, and is, on average, perpendicular to the alkyl chains. In wet thin films, grazing-incidence small-angle X-ray scattering shows that the phase window for the lamellar phase becomes much narrower, located at about 30-34 °C. Weakly ordered phases exist both below and above these temperatures. These phases are isotropic, but lamellae become aligned in a stacked manner on the surface whether approached from low or high temperatures. Dry films are disordered but can be reversibly ordered and disordered and aligned and misaligned by maintaining the temperature at 30-34 °C and switching relative outside humidity between 32% and 100%.

The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.

Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.-66T → C, rs2252281) and MATE2 (g.-130G → A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.

A common 5'-UTR variant in MATE2-K is associated with poor response to metformin.

Multidrug and toxin extrusion 2 (MATE2-K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2-K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2-K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants-c.485C>T and c.1177G>A-were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2-K basal promoter haplotypes containing the most common variant, g.-130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF-1). Patients with diabetes who were homozygous for g.-130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (-0.027 (-0.076, 0.033)), as compared with carriers of the reference allele, g.-130G (-0.15 (-0.17, -0.13)) (P=0.002). Our study showed that MATE2-K plays a role in the antidiabetes response to metformin.

Functional characterization of liver enhancers that regulate drug-associated transporters.

Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five--located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1--exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response.

Skin eruption and thrombocytopaenia in a woman with glaucoma: a case report.

Antibiotic and non-antibiotic sulphonamides are often prescribed. Although chemical differences make cross-reactivity rare, reactions may be severe in patients allergic to sulphur. Adverse reactions are common with sulphonamides but low platelets and skin changes are rarely associated with eye-drops for glaucoma. A woman treated with dorzolamide and timolol presented with disseminated eruption. On admission, her physical examination was unremarkable except for the skin changes and severe thrombocytopaenia was detected. Skin biopsy showed hyperkeratosis, acanthosis, perivascular and periadnexal infiltrates with no vasculitis. After discontinuation of eye-drops, the eruption improved but low platelets persisted. Skin changes reappeared with use of dapsone which suggested sulphonamide cross-reactivity.

Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics.

The goal of this study was to determine the effects of genetic variation in the organic cation transporter 1, OCT1, on the pharmacokinetics of the antidiabetic drug, metformin. Twenty healthy volunteers with known OCT1 genotype agreed to participate in the study. Each subject received two oral doses of metformin followed by collection of blood and urine samples. OCT1 genotypes had a significant (P<0.05) effect on metformin pharmacokinetics, with a higher area under the plasma concentration-time curve (AUC), higher maximal plasma concentration (Cmax), and lower oral volume of distribution (V/F) in the individuals carrying a reduced function OCT1 allele (R61C, G401S, 420del, or G465R). The effect of OCT1 on metformin pharmacokinetics in mice was less than in humans possibly reflecting species differences in hepatic expression level of the transporter. Our studies suggest that OCT1 genotype is a determinant of metformin pharmacokinetics.

Effects of genetic variation in the novel organic cation transporter, OCTN1, on the renal clearance of gabapentin.

Gabapentin is an anticonvulsant that is widely prescribed for epilepsy and other neuropathic disorders. The pharmacokinetics, particularly the absorption and renal elimination, of gabapentin appear to involve membrane transporters. In this study, we tested the hypothesis that organic cation transporter 1 (OCTN1), a multispecific transporter expressed at the apical membrane in intestine and kidney, plays a role in gabapentin pharmacokinetics and that the common variant of OCTN1, OCTN1-L503F, contributes to variation in the pharmacokinetics of the drug. We observed that OCTN1 facilitates the Na+-independent transport of gabapentin, and that the OCTN1-L503F variant is deficient in gabapentin transport activity in stably transfected HEK-293 cells (fourfold enhanced uptake of gabapentin by OCTN1-503L vs twofold enhanced uptake by OCTN1-L503F, compared to mock-transfected cells). In clinical studies, we found that in subjects homozygous for the L503F variant, gabapentin renal clearance (CL(R)) approximates the glomerular filtration rate (mean+/-SE: 110+/-12 ml/min, n=9), whereas in subjects homozygous for the reference allele, gabapentin undergoes net secretion in the kidney (141+/-7.8 ml/min, n=11, P<0.05). Creatinine clearance and OCTN1 genotype accounted for 56% of the variation in CL(R) and were the only significant predictors of CL(R) (P<0.05). Importantly, OCTN1 genotype was the only significant predictor of net secretion of gabapentin (P<0.008). Oral bioavailability of gabapentin was not affected by OCTN1 genotype. We conclude that OCTN1 contributes to active tubular secretion of gabapentin, and that this effect may be diminished or absent in individuals carrying the OCTN1-L503F polymorphism. These results provide clinical evidence of the role of genetic variation in renal drug transporters in active drug secretion in vivo.

Clinical and urodynamic evaluation in women with stress urinary incontinence treated by periurethral collagen injection.

OBJECTIVE: To evaluate the success of treatment with periurethral collagen injections in patients suffering from stress urinary incontinence (SUI) with bladder neck hypermobility and intrinsic sphincter deficiency. MATERIALS AND METHODS: Forty women suffering from (SUI) were selected and divided into GI (consisting of 13 women with SUI and bladder neck hypermobility) and GII (consisting of 27 women with SUI and intrinsic sphincter deficiency). Periurethral collagen was injected followed by a subjective evaluation (the need for urinary protectors) and an objective evaluation through urodynamic study before and after the treatment. RESULTS: It was noticed that after 9 months there was a decrease in the need of urinary protectors in the two groups. It was observed through the urodynamic study that either cure or improvement was achieved in 46% in GI and 40.7% in GII. There was a significant increase in the leak pressure in GII. Moreover, there was a decrease in the volume of urine leak in the two groups, being the results in GII statistically significant. CONCLUSIONS: It was concluded that the periurethral collagen injection is useful for the treatment of the SUI. The results in hypermobility are similar to those in intrinsic sphincter deficiency. In fact, it is a very simple out patient's procedure, with little side effects.

Clinical and urodynamic evaluation in women with stress urinary incontinence treated by periurethral collagen injection

OBJECTIVE: To evaluate the success of treatment with periurethral collagen injections in patients suffering from stress urinary incontinence (SUI) with bladder neck hypermobility and intrinsic sphincter deficiency MATERIALS AND METHODS: Forty women suffering from (SUI) were selected and divided into GI (consisting of 13 women with SUI and bladder neck hypermobility) and GII (consisting of 27 women with SUI and intrinsic sphincter deficiency). Periurethral collagen was injected followed by a subjective evaluation (the need for urinary protectors) and an objective evaluation through urodynamic study before and after the treatment RESULTS: It was noticed that after 9 months there was a decrease in the need of urinary protectors in the two groups. It was observed through the urodynamic study that either cure or improvement was achieved in 46 percent in GI and 40.7 percent in GII. There was a significant increase in the leak pressure in GII. Moreover, there was a decrease in the volume of urine leak in the two groups, being the results in GII statistically significant CONCLUSIONS: It was concluded that the periurethral collagen injection is useful for the treatment of the SUI. The results in hypermobility are similar to those in intrinsic sphincter deficiency. In fact, it is a very simple out patient's procedure, with little side effects.

Parallel avenues in the evolution of hearts and pumping organs.

Research in animal models established that tinman, a key gene in Drosophila dorsal vessel development, is an orthologue of Nkx2-5, a key gene in vertebrate cardiac development. Similarities between the arthropod dorsal vessel and vertebrate hearts are interpreted in light of concepts such as homology or convergence. We discuss this controversy in the context of the evolution of animal circulatory pumps and propose the distinction between peristaltic and chambered pumps as a fundamental parameter for evolutionary comparisons between bilaterian pumps. Neither homology nor convergence is satisfactory to explain the origins of hearts and pumping organs. Instead, we propose that animal pumps derive from parallel improvements of an ancestral, peristaltic design represented by a layer of myocytes at the external walls of primitive vessels. This paradigm unifies disparate views, impacts our understanding of bilaterian evolution and may be helpful to interpret similarities between pumping organs of phylogenetically relevant species and emerging models.

Infrared spectroscopy of racemic and enantiomeric forms of atenolol.

The molecular structure of conformational isomorphs given by X-ray diffraction for racemic and enantiomeric atenolol were optimized at the HF/6-31G* level of theory and the infrared spectra of the structure were calculated. These spectra are used to characterize the differences between the various atenolol conformers. The spectra of the (R,S)- and S-atenolol solid forms were recorded and the bands corresponding to the functional groups identified with the aid of the calculated spectra, fitting analysis, temperature effect and H/D isotopic exchange. Particular attention was paid to the stretch vibration modes of the functional groups present in the atenolol.

Infrared study of the acidic and basic forms of betaxolol.

Betaxolol and its respective hydrochloride salt were studied in solution by computational calculations and infrared spectroscopy. The solution molecular conformations were taken to be the same as those exhibited by the compounds in the solid state given by X-ray diffraction and calculated after full geometry optimization by ab initio Hartree-Fock methods using the 6-31G(d) basis set. Infrared spectra of carbon tetrachloride solutions provide valuable information on the structure of the compounds in non-polar solvents at different concentrations.

Effect of tibolone on cytochrome c oxidase I, beta-2-microglobulin and vascular endothelial growth factor gene expression in the lower urinary tract of castrated rats.

INTRODUCTION: The objective of this study was to evaluate the effect of tibolone on cytochrome oxidase I (COX I), beta-2-microglobulin (B2M) and vascular endothelial growth factor (VEGF) gene expression in the lower urinary tract of castrated rats. These genes are related to cell energy, cellular immunity and vascularization processes. METHODS: Fifty adult castrated rats remained at rest for 28 days. Thereafter they were randomly divided into two groups of 25 animals each. The lower urinary tract (bladder and urethra) was extracted in animals of one group and the other group received tibolone at a dose of 0.25 microg/animal/day for another 28 days followed by removal of the lower urinary tract. Total RNA was extracted from animals of both groups, forming two pools. After RT-PCR (reverse transcriptase polymerase chain reaction), expression of COX I, B2M and VEGF genes was evaluated by agarose gel electrophoresis, visualized by UV illumination. RESULTS: Expression of the three genes (COX I, B2M and VEGF) was greater in the group treated with tibolone. CONCLUSION: The use of tibolone increases the expression of COX, B2M and VEGF genes in the lower urinary tract as compared with that in castrated rats.

Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3).

The human concentrative nucleoside transporter, CNT3 (SLC28A3), plays an important role in mediating the cellular entry of a broad array of physiological nucleosides and synthetic anticancer nucleoside analog drugs. As a first step toward understanding the genetic basis for interindividual differences in the disposition and response to antileukemic nucleoside analogs, we examined the genetic and functional diversity of CNT3. In all, 56 variable sites in the exons and flanking intronic region of SLC28A3 were identified in a collection of 270 DNA samples from US populations (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). Of the 16 coding region variants, 12 had not been previously reported. Also, 10 resulted in amino-acid changes and three of these had total allele frequencies of >/=1%. Nucleotide diversity (pi) at nonsynonymous and synonymous sites was estimated to be 1.81 x 10(4) and 18.13 x 10(4), respectively, suggesting that SLC28A3 is under negative selection. All nonsynonymous variants, constructed by site-directed mutagenesis and expressed in Xenopus laevis oocytes, transported purine and pyrimidine model substrates, except for c. 1099G>A (p. Gly367Arg). This rare variant alters an evolutionarily conserved site in the putative substrate recognition domain of CNT3. The presence of three additional evolutionarily conserved glycine residues in the vicinity of p. Gly367Arg that are also conserved in human paralogs suggest that these glycine residues are critical in the function of the concentrative nucleoside transporter family. The genetic analysis and functional characterization of CNT3 variants suggest that this transporter does not tolerate nonsynonymous changes and is important for human fitness.

Urodynamic alterations after pelvic floor exercises for treatment of stress urinary incontinence in women.

The following study improves the effectiveness of pelvic floor exercise in women with stress urinary incontinence. A group of 27 women with stress urinary incontinence performed specific pelvic floor exercises twice a week for 45 minutes under a therapist's supervision for a period of 12 weeks. This group had urodynamic and urethral pressure profile studies and filled in a daily diary. The patients self-evaluated their symptoms. After the therapy, the urodynamic and urethreal pressure profile studies were repeated and the results were: 66.7% patients were self-evaluated as cured; 14.8% improved and 18.5% unchanged. The urodynamic results showed that 48.2 % of the patients did not have urinary loss, however, 51,8% of the patients that had a loss showed an increase in vesicle volume, and only 7.3% remained unchanged. The results show that pelvic floor exercises are an effective and low cost treatment for stress urinary incontinence rehabilitation.