The efficacy and tolerability of tarafenacin, a new muscarinic acetylcholine receptor M3 antagonist in patients with overactive bladder; randomised, double-blind, placebo-controlled phase 2 study.

OBJECTIVES: To evaluate the dose-response relationship of tarafenacin, an antimuscarinic agent in development phase, for efficacy and safety, at daily doses of 0.2 and 0.4 mg for the treatment of overactive bladder (OAB) PATIENTS AND METHODS: This multicentre, placebo-controlled, randomised, double-blind, phase 2b study was conducted. Patients were randomised to tarafenacin 0.2 mg, tarafenacin 0.4 mg or placebo daily for 12 weeks. Adult patients with OAB for at least 6 months, with an average of ≥ 8 micturitions per day and ≥ 3 incontinence episodes or a total of ≥ 6 urgency episodes per 3 days were enrolled. The primary objective was to compare the mean changes in the number of micturitions per 24 h of the two doses of tarafenacin compared with placebo from baseline to 12 weeks after treatment. RESULTS: A total of 334 patients were screened, of whom 235 patients were randomised. The mean decrease in the number of micturitions per 24 h from baseline to 12 weeks was statistically higher in the tarafenacin 0.4 mg group (-2.43 ± 2.21 times per day, p = 0.033) and non-statistically significant in the tarafenacin 0.2 mg group (-1.92 ± 2.45 times per day, p = 0.393) when compared with the placebo group (-1.77 ± 2.95 times per day). There were no statistically significant differences in the mean change of urgency episodes per 24 h among three groups. The most common adverse event was dry mouth. There were no significant differences in blurred vision and constipation compared with placebo. CONCLUSIONS: Tarafenacin 0.4 mg decreased the number of micturitions in patients with OAB after 12 weeks compared with placebo, and the dose-response relationship of tarafenacin 0.2 and 0.4 mg was confirmed. Both dose levels of tarafenacin were well tolerated.

Effect of cotton padding on the setting properties of plaster slabs.

INTRODUCTION: Plaster of Paris (PoP) impregnated bandages have been used to maintain the position of bones and joints for over a century. Classically, wool dressing is applied to the limb before the PoP, which can then be moulded to the desired shape. A modification of this practice is to wrap the PoP bandages circumferentially in cotton before wetting and applying to the patient in an attempt to reduce inhalation of plaster dust and reduce mess. However, this may affect the water content of the cast and therefore also its setting properties and strength. This study compared the setting properties of PoP casts when used with and without cotton wrapping. METHODS: Sixty specimens, compliant with the American Society for Testing and Materials standards for three-point bending tests, were prepared, with thirty wrapped in cotton. All were weighed before and after water immersion, and wrapped around a plastic cylinder to mimic limb application. Bending stiffness and yield strength was measured on a servohydraulic materials testing machine at 2, 6, 12, 24, 48 and 72 hours. RESULTS: The water content of cotton-wrapped plaster was significantly higher (50%) than that of standard plaster. It had significantly lower strength up to 24 hours and significantly lower stiffness up to 72 hours. CONCLUSIONS: The initial decrease in strength and stiffness of the cast wrapped in cotton may comprise the ability of the backslab to hold the joint or bone in an optimal position. Any modification of the standard plaster slab application technique should allow for the potential adverse effects on the plaster setting properties.

The effect of the creation of a ring-fenced orthopaedic ward on length of stay for elective arthroplasty patients.

INTRODUCTION: More than 150,000 hip and knee joint replacements are carried out in the United Kingdom yearly, and variations in length of stay [LOS] affects the overall costs of the procedures. This audit assesses the effect of the introduction of specialist ward on LOS following arthroplasty. METHOD: A combination of prospective and retrospective data on length of stay, demographics, and surgical site infections [SSI] were collected for the six months before and six months after the specialist ward was opened. Primary lower limb arthroplasty data was evaluated. American Society of Anaesthesiologists Physical Status Scores [ASA] for all admissions for lower limb arthroplasty were compared. RESULTS: Mean LOS for 222 patients managed in general orthopaedic wards was 7.61 days compared to 5.67 days for 191 patients managed in a dedicated arthroplasty ward. Three surgical site infections [SSIs] were noted in the general ward compared to zero in the specialist ward. CONCLUSIONS: This audit demonstrates a two-day reduction in LOS for patients managed in a ring-fenced ward. The cause of the reduction is multifactorial and not solely due to a trend for reduced SSI but influenced by many other changes cascading from the original organisational revision. Overall reduced stay however can only increase efficiency if downstream resources are available. Other units may wish to explore the benefits from similar dedicated wards in response to a growing demand for arthroplasty within a system of fixed resources.

Direct visualization of optical frequency invisibility cloak based on silicon nanorod array.

A new invisibility cloak was recently proposed for hiding objects in front of a highly reflecting mirror. This cloak requires only modest values of optical constants with minimal anisotropy and thus can be implemented by using non-resonant dielectric materials, making it an ideal system for optical frequency operation. We implemented the cloak using an array of silicon nanorods fabricated by electron-beam lithography. We then directly visualized the cloaking effect by monitoring the light propagation inside the device using the near-field optical microscopy.

Sub-trochanteric fracture of the femur following electric shock.

We report a case of a unilateral sub-trochanteric femoral fracture resulting from an accidental electric shock: an unusual injury. It is well documented that fractures occurring from electrical injuries commonly involve the upper extremities; those affecting the lower limb have rarely been documented. Such injuries need to be identified and treated without delay.

Antioxidative activity of naringin and lovastatin in high cholesterol-fed rabbits.

The consumption of a cholesterol-enriched diet increases the degree of lipid peroxidation, which is one of the early processes of atherosclerosis. The aim of this trial was to determine the antioxidative effects of the citrus bioflavonoid, naringin, a potent cholesterol-lowering agent, compared to the cholesterol-lowering drug, lovastatin, in rabbits fed a high cholesterol diet. Male rabbits were served a high-cholesterol (0.5%, w/w) diet or high-cholesterol diet supplemented with either naringin (0.5% cholesterol, 0.05% naringin, w/w) or lovastatin (0.5% cholesterol, 0.03% lovastatin, w/w) for 8 weeks to determine the plasma and hepatic lipid peroxide, plasma vitamin A and E levels, and hepatic hydrogen peroxide levels, along with the hepatic antioxidant enzyme activities and gene expressions. Only the lovastatin group showed significantly lower plasma and hepatic lipid peroxide levels compared to the control group. The naringin supplementation significantly increased the activities of both hepatic SOD and catalase by 33% and 20%, respectively, whereas the lovastatin supplementation only increased the catalase activity by 23% compared to control group. There was no difference in the GSH-Px activities between the various groups. Content of H2O2 in hepatic mitochondria was significantly lower in groups supplemented with lovastatin and naringin than in control group. However, there was no difference in cytosolic H2O2 content in liver between groups. The concentration of plasma vitamin E was significantly increased by the naringin supplementation. When comparing the antioxidant enzyme gene expression, the mRNA expression of SOD, catalase and GSH-Px was significantly up-regulated in the naringin-supplemented group. Accordingly, these results would appear to indicate that naringin, a citrus bioflavonoid, plays an important role in regulating antioxidative capacities by increasing the SOD and catalase activities, up-regulating the gene expressions of SOD, catalase, and GSH-Px, and protecting the plasma vitamin E. In contrast, lovastatin exhibited an inhibitory effect on the plasma and hepatic lipid peroxidation and increased the hepatic catalase activity in high-cholesterol fed rabbits.

The ontogeny of scarless healing II: EGF and PDGF-B gene expression in fetal rat skin and fibroblasts as a function of gestational age.

Twenty years ago, surgeons noted the ability of early-gestation fetal skin to heal in a scarless manner. Since that time, numerous investigators have attempted to elucidate the mechanisms behind this phenomenon. As a result of this effort, it is now well established that many animals undergo a transition late in development from scarless cutaneous healing to a scar-forming, adultlike phenotype. The authors have been interested in the role played by cytokines known to be involved in the adult wound-healing process and how they relate to scarless repair. They therefore asked the following question: Are genes for epidermal growth factor (EGF) and platelet-derived growth factor-B (PDGF-B) expressed differentially as a function of gestational age in fetal rat skin and dermal fibroblasts? To answer this question, skin from fetal Sprague-Dawley rats (N = 56) at time points that represented both the scarless and scar-forming periods of rat gestation was harvested. In addition, fibroblasts derived from fetal rat skin were cultured in vitro at similar times. These cells were expanded in culture and, when confluent, total ribonucleic acid from both fibroblasts and whole skin was extracted and subjected to Northern blot analysis with probes for EGF and PDGF-B. Results demonstrated that neither EGF nor PDGF-B gene expression changed markedly as a function of gestational age in fetal fibroblasts alone. In whole skin, however, both EGF and PDGF-B demonstrated a marked decrease in gene expression with increasing gestational age. Furthermore, the most striking decrease in gene expression for both cytokines came between 16 and 18 days of gestation-the transition point between scarless and scar-forming repair in the fetal rat. These data suggest that EGF and PDGF may play a role in the mechanism of scarless cutaneous repair. Moreover, it appears that fetal fibroblasts are not the cell type responsible for this differential gene expression. These results raise questions about the unique cytokine milieu likely to be present during the time of scarless healing and the cells that ultimately guide the mechanisms leading to skin regeneration.

Vitamin E improves microsomal phospholipase A2 activity and the arachidonic acid cascade in kidney of diabetic rats.

The purpose of the present study was to investigate the effects of vitamin E on microsomal phospholipase A2 activity and the arachidonic acid cascade in the kidneys of streptozotocin (STZ)-induced diabetic rats. Sprague-Dawley male rats weighing 100 +/- 10 g were randomly assigned to one normal and three STZ-induced diabetic groups. The diabetic groups were fed a vitamin E-free diet (the DM-0E group), 40 mg vitamin E/kg diet (the DM-40E group) or a 400 mg vitamin E/kg diet (the DM-400E group). The kidney vitamin E concentrations were 59 and 49% lower in the DM-0E and DM-40E groups, respectively, than in the normal group. The kidney thiobarbituric acid reactive substance concentrations in the DM-0E, DM-40E and DM-400E groups were 119, 84 and 33% greater, respectively, than that in the normal group. The concentration in the DM-400E group was 39% lower than that in the DM-0E group. The phospholipase A2 (PLA2) activity in the kidney microsomes of the DM-0E-40E and DM-400E groups were 88, 58 and 35% greater, respectively, than that in the normal group. The activity in the DM-400E group was 28% lower than that in the DM-0E group and 16% lower than that in the DM-40E group. The differences in the phospholipids in the kidney microsomes included reductions in the phosphatidylcholine and phosphatidylethanolamine compositions. Phosphatidylethanolamine hydrolysis in the kidney microsomes of the DM-0E and DM-40E groups were 84 and 64%, which did not differ from the DM-400E group. The formation of thromboxane A2 (TXA2) in the kidney microsomes was 137 and 70% greater in the DM-0E and DM-40E groups, respectively, than in the normal group. TXA2 formation did not differ between the DM-400E and normal groups. The formation of prostacyclin in the kidney microsomes was 60 and 44% lower in the DM-0E and DM-40E groups, respectively, than in the normal group, whereas the DM-400E group did not differ from that in the normal group. The ratio of prostacyclin to TXA2 was 82 and 65% lower than normal in the DM-0E and DM-40E groups, respectively. Kidney function appears to be improved by vitamin E supplementation due to its antithrombus action, which in turn controls the arachidonic acid cascade system.

Effects of green tea catechin on phospholipase A2 activity and antithrombus in streptozotocin diabetic rats.

The purpose of this study was to investigate the effects of dietary green tea catechin on phospholipase A2 (PLA2) activity and the antithrombotic reaction of platelets in streptozotocin (STZ)-diabetic rats. Sprague-Dawley male rats weighing 100 +/- 10 g were randomly divided into one normal and three STZ-diabetic groups, which were subdivided into catechin-free group (DM-0C), 0.5% catechin group (DM-0.5C) and 1% catechin group (DM-1C). The activity level of platelet phospholipase A2 was higher in the diabetic groups than in the normal group, while it was lower in DM-0.5C and DM-1C than in DM-0C. The activity of platelet cyclooxygenase in DM-0C was 1.1-fold as high as in the normal group, but was significantly reduced by catechin supplementation. The platelet thromboxane A2 (TXA2) formation became higher in DM-0C as compared to the normal group, but not in DM-0.5C and DM-1C. The synthesis of aortic prostacyclin (PGI2) was lower in DM-0C and DM-0.5C than in the normal group. The PGI2/TXA2 ratio was decreased to 55% in DM-0C, but was restored by catechin supplementation. These results indicate that STZ-diabetic rats are sensitive to platelet aggregation and thrombosis, and that the abnormality can be improved by dietary catechin.

The prognostic significance of proliferation-associated nucleolar protein p120 expression in prostate adenocarcinoma: a comparison with cyclins A and B1, Ki-67, proliferating cell nuclear antigen, and p34cdc2.

BACKGROUND: In this study, the authors evaluated the prognostic significance of the expression of nucleolar antigen p120, along with other cell proliferation-associated proteins, in prostate adenocarcinomas (PACs) and compared the results with previously reported data on p34cdc2 cyclin-dependent kinase (p34 cdk). METHODS: Archival sections from 132 PACs were immunostained with monoclonal antibodies against p120, cyclin A, cyclin B1, Ki-67, and proliferating cell nuclear antigen (PCNA). The DNA content of each tumor was determined by the Feulgen method using image analysis. The immunohistochemistry (IHC) results were correlated with tumor grade, stage, margin positivity, metastasis, ploidy, and postsurgical disease recurrence. RESULTS: The overall positivity for the various proteins follows: p120, 36%; cyclin A, 35%; cyclin B1, 43%; Ki-67, 46%; and PCNA, 32%. p120 correlated with grade (P = 0.004), stage (P = 0.01), ploidy (P = 0.02), margin positivity (P = 0.03), and metastasis (P = 0.004). Cyclin B1 correlated with ploidy (P = 0.04) and grade (P = 0.05), Ki-67 with grade (P = 0.02) and margins (P = 0.03), and PCNA with grade (P = 0.01). Significant coexpression among these proteins was noted, as was a significant association between the expression of these markers and that previously reported for p34 cdk. In univariate analysis, p120 (P = 0.01), cyclin A (P = 0.01) and p34 cdk (P = 0.002) correlated with disease recurrence. In multivariate analysis of all these proteins, only p34 cdk independently predicted postsurgical recurrence (P = 0.05). CONCLUSIONS: Nucleolar antigen p120 expression appears to be an additional marker of aggressiveness in PACs. The significant coexpression of the various cell cycle regulatory proteins support their collective role in tumor cell proliferation, with p34 cdk positivity being an independent predictor of postsurgical recurrence.

Effects of green tea catechin on hepatic microsomal phospholipase A2 activities and changes of hepatic phospholipid species in streptozotocin-induced diabetic rats.

In this study, male Sprague-Dawley rats weighing 70 +/- 5 g were divided into a control (normal) group and three different diabetes mellitus (DM) groups that were supplemented with catechin-free (DM-0C), 0.5% catechin dietary (DM-0.5C), and 1% catechin (DM-1.0C). The animals were maintained on an experimental diet for four weeks. At this point, they were injected with streptozotocin (STZ) to induce diabetes, and they were sacrificed on the 6th day to determine the activities of phospholipase A2 (PLA2) and the changes of phospholipid species by catechin supplementation. In liver tissues, no significant differences were found between the PC hydrolysis of a normal group and a diabetic group; however, PE hydrolysis of the DM-0C, DM-0.5C, and DM-1.0C groups increased by 68.9%, 34.01%, and 26.9%, respectively, compared with the normal group. Although the PLA2 activity of the DM-0C group in the liver tissues increased 91% compared with the normal group, the PLA2 activity of DM-0.5C and DM-1.0C, which were fed catechin, increased 50% and 56%, respectively, compared with the normal group. In the liver tissues, peroxide values of the DM-0C, the DM-0.5C, and the DM-1.0C groups were increased 109%, 32.8%, and 46.7%, respectively, compared with the normal group. Based on these results for STZ-induced diabetic rats, lipid peroxidation seems to be accelerated specifically with the increased PLA2 activities. Thus if antioxidants like catechin were supplementation, the activity of PLA2 and PE hydrolysis can be altered and the accumulation of lipid peroxide would be decreased. Therefore we concluded that the antioxidant catechin for diabetic animals can significantly reduce PLA2 activities and lipid peroxide formation.

Differential effect of adrenalectomy on rat liver metallothionein mRNA levels in basal and stress conditions.

Liver metallothionein (MT) mRNA and serum MT levels of adrenalectomized (ADX) and sham-ADX rats in basal and stress (1, 3 or 6 h of restraint) conditions have been measured. Serum MT levels were overall lower in ADX than in sham-ADX rats. Basal liver MT mRNA levels were increased in ADX rats, suggesting that glucocorticoids have an inhibitory role on the regulation of liver MT synthesis. In contrast, liver MT mRNA levels were increased by stress in sham-ADX but not in ADX rats, suggesting a stimulatory role for glucocorticoids. These results suggest that glucocorticoids have a different role in liver MT regulation depending on the physiological situation.

Metallothionein accumulation in CHO Cdr cells in response to lead treatment.

For CHO Cdr cells the presence of lead acetate in the media in concentrations above 1 mM leads to gradual cell death, as measured by the reduction of [3H]thymidine incorporation into DNA. These cells accumulate an increased amount of newly synthesized metallothionein. Typical 9S metallothionein mRNA could be detected by hybridization using metallothionein cDNA probes, with maximal accumulation occurring after 4-h exposure of cells to 2 mM lead acetate. The intracellular levels of metallothionein protein increase continually with time; metallothionein was identified by its richness in cysteine, chromatographic and electrophoretic behavior and reactiveness to carboxyamidomethylation. When separated by an anion-exchanger, both isospecies MT I and MT II could be observed, as they were identical in every respect tested to those induced by zinc chloride. The induction of metallothionein by lead was not due to an increase in intracellular zinc levels, as zinc uptake was unaffected by the presence of lead acetate in the media.