Safety and effectiveness of Colpexin Sphere in the treatment of pelvic organ prolapse

Our objective was to determine the safety and effectiveness of Colpexin Sphere in women with advanced genital prolapse. A total of 39 subjects were enrolled in our prospective multicenter clinical trial, and 27 completed the full 16-week assessment. At baseline, subjects were fitted with a sphere, instructed on insertion and removal, and educated on a regimen of pelvic floor muscle exercises performed with the device in place. Efficacy was evaluated by a baseline vs 16-week comparison of pelvic organ prolapse staging and pelvic floor muscle strength assessment. Safety evaluation included, but was not limited to, an assessment of vaginal mucosal integrity. Subjects also completed a patient satisfaction questionnaire at the end of the study. Improvement in the prolapse of at least one vaginal segment was seen in 81.5% of the subjects, while 63% exhibited improved muscle function on digital examination at 16 weeks. Twenty-five (92.6%) would recommend the device to treat prolapse, and most found it easy to insert (96.3%) and remove (100%). In short-term usage, problems with urination (29.6%) and defecation (72%) were reported, primarily due to device displacement. Two subjects developed superficial vaginal mucosal ulceration, which resolved spontaneously. No significant adverse events were reported.     

Effect of Carbon Nanofibers on Physical,Adhesion and Rheological Properties of Liquid Epoxidized Natural Rubber Modified Asphalt

This study aimed to evaluate the effects of carbon nanofibers (CNFs) on the performance of liquid epoxidized natural rubber (LENR)-modified asphalt. The physical, adhesion and rheological properties were determined by several tests such as penetration, elastic recovery, ring and ball softening point, Brookfield rotational viscometer, AFM and dynamic shear rheometer. LENR was used at concentrations of 3, 6, and 9%, while CNFs were used at contents of 0.3, 0.4, and 0.5% by weight of asphalt. Conventional test results showed that the increases in LENR and LENR/CNFs composite contents in binder leads to an increase in the hardness and consistency and a reduction in the temperature susceptibility of base asphalt. Adhesion results revealed that the addition of CNFs significantly increases the adhesion and bonding properties of base and rubberized binders. Rheological properties analysis exhibited that LENR improved the viscoelastic properties and permanent deformation resistance of asphalt at different temperatures and frequencies. On the other hand, it was found that the addition of CNFs significantly improves the stiffness, elasticity, and hardness of LENR-modified binders. The 6% LENR and 0.4% CNFs were found to be the optimum to enhance the physical, adhesion, and rheological properties of asphalt in this study. Thus, it can be stated that the addition of CNFs is promising to improve the performance of rubberized binders for high temperature applications.     

Mechanism of voltage sensing in Ca2+- and voltage-activated K+ (BK) channels

In neurosecretion, allosteric communication between voltage sensors and Ca²⁺ binding in BK channels is crucially involved in damping excitatory stimuli. Nevertheless, the voltage-sensing mechanism of BK channels is still under debate. Here, based on gating current measurements, we demonstrate that two arginines in the transmembrane segment S4 (R210 and R213) function as the BK gating charges. Significantly, the energy landscape of the gating particles is electrostatically tuned by a network of salt bridges contained in the voltage sensor domain (VSD). Molecular dynamics simulations and proton transport experiments in the hyperpolarization-activated R210H mutant suggest that the electric field drops off within a narrow septum whose boundaries are defined by the gating charges. Unlike Kv channels, the charge movement in BK appears to be limited to a small displacement of the guanidinium moieties of R210 and R213, without significant movement of the S4.

Excitable tissues accomplish their signaling functions thanks in part to the interplay of several voltage-sensitive ion channels (1–6). Hence, to understand these processes, it is crucial to establish how voltage-sensitive ion channels sense changes in the electric field across the membrane, an issue that has been a matter of extensive study and intense debate for decades. The most widely accepted mechanism proposes the existence of voltage-sensor domains (VSDs), modules that undergo two or more discrete conformational states in response to changes in the membrane voltage. The simplest model considers two states: active (A), which promotes pore opening, and resting (R), which promotes channel closing. To accomplish its function, VSDs contain voltage-sensitive particles, which move in response to changes in the electric field. This movement triggers the interconversion between the two discrete conformational states. These voltage-sensing particles are typically the guanidine groups of arginine residues within the S4 transmembrane segment, which undergo a combination of rotational, translational, and tilting movement in response to changes in membrane voltage (7–14).The large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channels have a wide distribution in mammalian tissues (15–18), where they participate in a diversity of physiological processes. Their malfunction is often related to diverse pathological conditions (19, 20). BK channel open probability is independently regulated by membrane depolarization and intracellular Ca²⁺ concentration (21, 22), each stimulus being detected by specialized modules. Like other voltage-sensitive K⁺ (Kv) channels, BK is an homotetramer in which each of its α subunits consists of a pore domain (PD; S5-S6 transmembrane segments), a voltage-sensing domain (VSD; S1–S4 transmembrane segments) containing a positively charged S4, and a cytosolic C-terminal regulatory domain, which contains the Ca²⁺-binding sites (23, 24). Also, like some members of other K⁺ channel families (25, 26), the VSD and PD of BK are non–domain swapped (23, 24). BK channels display some distinctive structural and functional features: Despite sharing the selectivity filter sequence with Kv channels, BK unitary conductance and selectivity are exquisitely high (27–30). The BK α subunit has an additional transmembrane segment S0 [therefore, its N terminus faces the extracellular medium (31)], and the voltage sensitivity in BK channels is significantly lower than that of Kv channels, presumably because of their lower number of gating charges (32).Although thoroughly studied, research into BK VSD and its voltage dependence has faced several technical obstacles. The relatively small gating charge per channel (32) and the large conductance of the BK pore makes isolating of the gating currents from the ionic currents a tough experimental challenge. In addition, because mutations of VSD residues can produce very large shifts in both the gating charge-voltage (Q(V)) and the conductance-voltage G(V)) relationships (33), it is necessary to use extreme voltages to accurately measure the voltage dependence of some mutants. Consequently, the identification of BK gating charges has been addressed by using indirect approaches (33, 34). The combination of electrophysiology measurements and kinetic modeling suggests a decentralized VSD in the BK channel, where four charged residues (D153 and R167 in S2, D186 in S3, and R213 in S4) act as voltage sensor particles (33). A recent report of the atomistic cryo-electron microscopy (cryo-EM) structures of the human BK channel and its homolog in Aplysia californica (AcSlo) revealed minor structural differences between the VSD in both the Ca²⁺-bound (open pore) and the Ca²⁺-unbound (closed pore) conformations (23, 24, 35). This result can be explained if the conformational changes of the BK VSD upon activation are small compared to those that occur during the activation of other channels, such as HCN channels (12–14).In this study, we identified voltage-sensing particles in the BK channel by using a direct functional approach, involving gating of current measurements and analysis of the Q(V) curves spanning 800 mV in the voltage axis. Systematic neutralization of the individual charged residues in the VSD (S1–S4) revealed that only the neutralization of two arginines in S4 (R210 and R213) changed the voltage dependence of the Q(V) curves. Neutralization of other VSD charges point to roles in tuning of the half-activation voltage of the VSD and its allosteric coupling with the PD. Molecular dynamics (MD) simulations based on the cryo-EM structures of the human BK channel (35) as templates suggested that R210 and R213 lie in a very narrow septum separating intra- and extracellular water-filled vestibules. This interpretation is consistent with the robust hyperpolarization-activated proton currents generated when R210 is mutated to the protonable amino acid histidine. Overall, our results point to a unique and distinctive mode of activation in BK: In contrast to Kv channels, where positive charges move one by one through a charge transfer center (absent in BK channels) that spans the entire electric field (36, 37), charge movement in BK channels is limited to the small displacement of R210 and R213, which itself constitutes a narrow septum where the electric field drops.     

Disability Adjusted Life Years (DALYs) and rehabilitation

Purpose: The Disability Adjusted Life Year (DALY) is a unit that was developed for use in cost-effectiveness analysis and epidemiology studies. It is a combined measure of both death and disability, and has been extensively utilized in several countries and across various conditions. The purpose of this paper is to examine the implications for rehabilitation of the widespread use of this measure. Method: The premises upon which the disability weight were developed are examined in the light of existing literature. Conclusion: It is concluded that, whereas the incorporation of the impact of disability on disease burden is to be lauded, the DALY is insensitive to changes in disability status. Consequently, resource allocation to rehabilitation activities based on cost-effectiveness analysis using DALYs may be diminished. There is also a dearth of epidemiological information relating to disability and it is incumbent on rehabilitation professionals to address this lack. The DALY protocol is under revision and those concerned with rehabilitation issues should contribute to the debates surrounding cost-effectiveness analysis and the units that are used to determine the effectiveness component.     

Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence

PURPOSE: We evaluated the efficacy and safety of an oxybutynin transdermal delivery system (TDS) in a general population of patients with overactive bladder and urge or mixed urinary incontinence. MATERIALS AND METHODS: Following symptom stabilization or treatment withdrawal 520 adult patients were randomized to 12 weeks of double-blind daily treatment with 1.3, 2.6 or 3.9 mg. oxybutynin TDS or placebo administered twice weekly, followed by a 12-week open-label, dose titration period to assess efficacy and safety further. Evaluations included patient urinary diaries, incontinence specific quality of life and safety. RESULTS: A dose of 3.9 mg. daily oxybutynin TDS significantly reduced the number of weekly incontinence episodes (median change -19.0 versus -14.5, p = 0.0165), reduced average daily urinary frequency (mean change -2.3 versus -1.7, p = 0.0457), increased average voided volume (median change 24 versus 6 ml., p = 0.0063) and significantly improved quality of life (Incontinence Impact Questionnaire total score, p = 0.0327) compared with placebo. Average voided volume increased in the daily 2.6 mg. group (19 ml., p = 0.0157) but there were no other significant differences between 1.3 and 2.6 mg. oxybutynin TDS and placebo. The most common adverse event was application site pruritus (oxybutynin TDS 10.8% to 16.8%, placebo 6.1%). Dry mouth incidence was similar in both groups (7.0% versus 8.3%, p not significant). In the open-label period a sustained reduction of nearly 3 incontinence episodes per day was reported for all groups. CONCLUSIONS: Doses of 2.6 and 3.9 mg. oxybutynin TDS daily improve overactive bladder symptoms and quality of life, and are well tolerated. Transdermal oxybutynin is an innovative new treatment for overactive bladder.     

Double‐lung versus heart‐lung transplantation for precapillary pulmonary arterial hypertension: a 24‐year single‐center retrospective study

Transplant type for end‐stage pulmonary vascular disease remains debatable. We compared recipient outcome after heart‐lung (HLT) versus double‐lung (DLT) transplantation. Single‐center analysis (38 HLT–30 DLT; 1991–2014) for different causes of precapillary pulmonary hypertension (PH): idiopathic (22); heritable (two); drug‐induced (nine); hepato‐portal (one); connective tissue disease (four); congenital heart disease (CHD) (24); chronic thromboembolic PH (six). HLT decreased from 91.7% [1991–1995] to 21.4% [2010–2014]. Re‐intervention for bleeding was higher after HLT; (P = 0.06) while primary graft dysfunction grades 2 and 3 occurred more after DLT; (P < 0.0001). Graft survival at 90 days, 1, 5, 10, and 15 years was 93%, 83%, 70%, 47%, and 35% for DLT vs. 82%, 74%, 61%, 48%, and 30% for HLT, respectively (log‐rank P = 0.89). Graft survival improved over time: 100%, 93%, 87%, 72%, and 72% in [2010–2014] vs. 75%, 58%, 42%, 33%, and 33% in [1991–1995], respectively; P = 0.03. No difference in chronic lung allograft dysfunction (CLAD)‐free survival was observed: 80% & 28% for DLT vs. 75% & 28% for HLT after 5 and 10 years, respectively; P = 0.49. Primary graft dysfunction in PH patients was lower after HLT compared to DLT. Nonetheless, overall graft and CLAD‐free survival were comparable and improved over time with growing experience. DLT remains our preferred procedure for all forms of precapillary PH, except in patients with complex CHD.     

Differential Effect of Diarrhea on FK506 Versus Cyclosporine A Trough Levels and Resultant Prevention of Allograft Rejection in Renal Transplant Recipients

Diarrhea is the most frequently reported adverse event in patients treated with mycophenolate mofetil. Twenty-six renal transplant patients on a mycophenolate mofetil-based immunosuppressive regime with persistent afebrile diarrhea were examined. Diarrhea caused a significant rise in FK-506 trough levels despite intake of stable doses, necessitating FK-506 dose reductions of 30% to obtain pre-diarrhea trough levels. In contrast, trough levels of cyclosporine A remained stable without dose adjustments. This suggests that absorption and/or metabolism is differentially altered for FK506 compared with cyclosporine A in patients with diarrhea. In nine patients mycophenolate mofetil was reduced or stopped because of persistent diarrhea without identifiable cause. This resulted in end-stage renal disease because of chronic rejection in two patients, and in acute rejection in two patients, all taking FK506 and steroids. Therefore, dose adjustments of FK506 in patients with diarrhea must be carefully monitored, especially when doses of mycophenolate mofetil are also reduced.     

The free TRAM procedure in breast reconstruction: choice of vascular receptor site

In this study, 70 consecutive cases of breast reconstruction with the use of a free Transverse Rectus Abdominal Myocutaneous (TRAM) flap were reviewed with respect to the type of recipient vessels. We describe our evolution of choice of the receptor vessels. The deep inferior epigastric artery was anastomosed to the thoracodorsal artery in 15 cases. In 55 cases the internal mammary artery (IMA) was used as a recipient vessel. The deep inferior epigastric vein was anastomosed to the thoracodorsal vein in 15 cases, to the cephalic vein in eight cases, the external jugular vein in 16 cases and to the internal mammary vein (IMV) in 31 cases. Total flap necrosis occurred in four cases. In an additional four cases there was partial necrosis requiring minor operative correction. In six cases venous outflow problems were the cause of flap necrosis. The external jugular vein (n = 3) and cephalic vein (n = 2) were relatively frequently involved in cases of venous outflow problems. One flap was rescued 5 days after surgery following venous thrombosis by inserting a vein graft. The IMA and vein proved to be reliable and easy to access as recipient vessels for anastomosing the vessels of the free TRAM.