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Activation of the cGMP/PKG pathway inhibits electrical activity in rabbit urethral interstitial cells of Cajal by reducing the spatial spread of Ca 2+ waves
Get PDFIn the present study we used a combination of patch clamping and fast confocal Ca 2+ imaging to examine the effects of activators of the nitric oxide (NO)/cGMP pathway
on pacemaker activity in freshly dispersed ICC from the rabbit urethra, using the
amphotericin B perforated patch configuration of the patch-clamp technique. The nitric oxide donor, DEA-NO, the soluble guanylyl cyclase activator YC-1 and the membrane-permeant analogue of cGMP, 8-Br-cGMP inhibited spontaneous transient depolarizations (STDs) and spontaneous transient inward currents (STICs) recorded under current-clamp and voltageclamp conditions, respectively. Caffeine-evoked Cl – currents were unaltered in the presence of SP-8-Br-PET-cGMPs, suggesting that activation of the cGMP/PKG pathway does not block Cl – channels directly or interfere with Ca 2+ release via ryanodine receptors (RyR). However, noradrenaline-evoked Cl – currents were attenuated by SP-8-Br-PET-cGMPs, suggesting that activation of cGMP-dependent protein kinase (PKG) may modulate release of Ca 2+ via IP 3 receptors (IP 3 R).When urethral interstitial cells (ICC) were loaded with Fluo4-AM (2 μM), and viewed with a confocal microscope, they fired regular propagating Ca 2+ waves, which originated in one or more regions of the cell. Application of DEA-NO or other activators of the cGMP/PKG pathway did not significantly affect the oscillation frequency of these cells, but did significantly reduce their spatial spread. These effects were mimicked by the IP 3 R blocker, 2-APB (100 μM).
These data suggest that NO donors and activators of the cGMP pathway inhibit electrical activity of urethral ICC by reducing the spatial spread of Ca 2+
waves, rather than decreasing wave frequency
A Risk Management Capability Model for use in Medical Device Companies
No full textMedical device software is a risky business. Failure of the software can have potentially catastrophic effects, leading to injury of patients or even death. It is therefore no surprise that regulators throughout the world are penalising medical device manufacturers that do not demonstrate that sufficient attention is devoted to the areas of hazard analysis and risk management (RM) throughout the software lifecycle. If a medical device company fails to comply with the regulations of a given country, in effect they surrender their legal right to market their device in that country. With so much at stake, it is in everybody’s best interest that the medical device manufacturer gets it right.
However, with so many different standards, regulatory guidance papers and industry guides on RM, the task of collating this information into a usable model is itself daunting. This paper seeks to extract the important concepts from a number of industry accepted standards and guides, and present them as a generic usable model for the medical device software industry
Ca 2+ signalling in urethral interstitial cells of Cajal
No full textInterstitial cells of Cajal (ICC) in the urethra have been proposed as specialized pacemakers that are involved in the generation of urethral tone and therefore the maintenance of urinary continence. Recent studies on freshly dispersed ICC from the urethra of rabbits have demonstrated that pacemaker activity in urethra ICC is characterized by spontaneous transient depolarizations (STDs) under current clamp and spontaneous transient inward currents (STICs) under voltage clamp. When these events were simultaneously recorded with changes in intracellular Ca 2+ (using a Nipkow spinning disk confocal microscope) they were found to be associated with global Ca 2+ oscillations. In this short review we will consider some of these recent findings regarding the contribution of intracellular Ca 2+ stores and Ca 2+ influx to the generation of pacemaker activity in urethral ICC with particular emphasis on the contribution of reverse Na + /Ca 2+ exchange (NCX)
The position of the Gulf Stream and lake nitrate concentrations in southwest Ireland
Get PDFA positive relationship was observed between winter nitrate concentrations in two lakes in SW Ireland and the latitudinal position of the Gulf Stream position in the previous spring. Weaker but statistically significant relationships were apparent between the Gulf Stream position and weather variables, as well as soil moisture levels, in the same year. Wind speed, cloud cover and precipitation in May and June were negatively related to the Gulf Stream position in April. In contrast, air temperature and sunshine hours in May and June and the magnitude of the soil moisture deficit in June were positively related. There was also a positive correlation between the magnitude of the early summer soil moisture deficit and lake nitrate concentrations in the following winter. This three way linkage implies that the concentration of winter nitrate in these lakes is influenced by a sequence of related factors that are initiated by the latitudinal position of the Gulf Stream. In this sequence the position of the Gulf Stream appears to influence early summer weather in SW Ireland which in turn dictates the extent of moisture deficit in catchment soils and, consequently, the degree of nitrate loss to surface waters in the autumn. This connection, between events in the Atlantic Ocean, weather systems in the North West Atlantic and processes in catchment soils in SW Ireland has implications for both the quality and quantity of biota in lakes and catchments in the region
Contribution of reverse Na + –Ca 2+ exchange to spontaneous activity in interstitial cells of Cajal in the rabbit urethra
Get PDFInterstitial cells of Cajal (ICC) isolated from the rabbit urethra exhibit regular Ca
2+ oscillations that are associated with spontaneous transient inward currents (STICs) recorded under voltage clamp. Their frequency is known to be very sensitive to external Ca 2+ concentration but the mechanism of this has yet to be elucidated. In the present study experiments were performed to assess the role of Na + –Ca 2+ exchange (NCX) in this process. Membrane currents were recorded using the patch clamp technique and measurements of intracellular Ca 2+ were made using fast confocal microscopy. When reverse mode NCX was enhanced by decreasing the external Na + concentration [Na + ] o from 130 to 13 mM, the frequency of global Ca 2+ oscillations and STICs increased. Conversely, inhibition of reverse mode NCX by KB-R7943 and SEA0400 decreased the frequency of Ca 2+ oscillations and STICs. Application of caffeine (10 mM) and noradrenaline (10 μM) induced transient Ca 2+ -activated chloride currents (I ClCa ) at −60 mV due to release of Ca 2+ from ryanodine- and inositol trisphosphate (IP 3 )-sensitive Ca 2+ stores, respectively, but these responses were not blocked by KB-R7943 or SEA0400 suggesting that neither drug blocked Ca 2+ -activated chloride channels or Ca 2+ release from stores. Intact strips of rabbit urethra smooth muscle develop spontaneous myogenic tone. This tone was relaxed by application of SEA0400 in a concentration-dependent fashion. Finally, single cell RT-PCR experiments revealed that isolated ICC from the rabbit urethra only express the type 3 isoform of the Na + –Ca 2+ exchanger (NCX3). These results suggest that frequency of spontaneous activity in urethral ICC can be modulated by Ca 2+ entry via reverse NCX
Developing a configuration management model for use in the medical device industry
No full textThis paper outlines the development of a Configuration Management model for the MEDical device software industry (CMMED). The paper details how medical device regulations associated with Configuration Management (CM) may be satisfied by adopting less than half of the practices from the CM process area of the Capability Maturity Model Integration (CMMI). It also investigates how the CMMI CM process area may be extended with additional practices that are outside the remit of the CMMI, but are required in order to satisfy medical device regulatory guidelines
Electrochemical Characterisation of an Os (II) Conjugated Polymer in Aqueous Electrolytes
No full textThe electrochemical behaviour of an Os (II) complex of the structurally well-defined conjugated polymer alternating regioregularly alkylated thiophene and 2,2’-bipyridine units
(P4Os) has been elucidated in aqueous solution. In typical aqueous electrolyte systems the cyclic voltammogram of the resulting P4Os film exhibits a one electron reversible process corresponding to the Os3+/2+ redox system. However the observance of this reversible couple did depend upon the concentration of the supporting electrolyte. It was found that the Os3+ form did form ion-pairs with an anion from the electrolyte solution. Preliminary investigations
into the homogeneous charge transport dynamics associated with this redox couple have been undertaken. The technique of cyclic voltammetry, and hence the Randles-Sevick expression, in conjunction with platinum microelectrodes have been employed to determine the DCT c value
Electrochemical Properties of an Osmium (II) copolymer film and its electrocatalytic ability towards the oxidation of ascorbic acid in acidic and neutral pH
No full textCopolymerisation of an Osmium (II) functionalised pyrrole moiety, Osmium -bis-N,N’-(2,2’-bipyridyl)-N-(pyridine-4-ylmethyl-(8-pyrrole-1yl-octyl)-amine)chloride (1) with 3-
methylthiophene was carried out. The resulting conducting polymer film exhibited a clear redox couple associated with the Os3+/2+ response and the familiar conducting polymer
backbone signature. The effect of film thickness upon the redox properties of the copolymer was investigated in organic electrolyte solutions. Scanning electron micrographs (SEM) along with energy dispersive X-ray (EDX) spectra of the copolymerised films were undertaken, both
after formation and redox cycling in neutral buffer solution. These clearly show that electrolyte is incorporated into the polymer film upon redox cycling through the Os3+/2+ redox system. The Os3+/2+ response associated with the copolymer was seen to be significantly
altered in the presence of ascorbic acid both in acidic and neutral pH buffer solutions. This pointed to an electrocatalytic reaction between the ascorbic acid and the Os3+ form of the copolymer. Under acidic conditions the copolymer film exhibited a sensitivity of 1.76 (± 0.05)
uA / mM with a limit of detection (LOD) of 1.45 μM for ascorbic acid. Under neutral pH conditions the copolymer exhibited a sensitivity of 19.26 (±1.05) uA / mM with a limit of detection (LOD) of 1.28 μM for ascorbic acid
Organization and function of ICC in the urinary tract.
No full textICC are found in both the upper and lower urinary tract. They are not found in the ureter itself but are confined to the lamina propria of the renal pelvis and pelvi-calyceal junction. They do not appear to have a primary pacemaker role (this is ascribed to atypical smooth muscle cells in the same location) but rather conduct and amplify the pacemaker signals generated by the atypical smooth muscle cells. In the bladder, ICC are widely distributed in the sub-urothelial region, in the lamina propria and at the margins of the detrusor smooth muscle bundles. Again they appear not to have a pacemaking role and such evidence as there is would suggest that they have a role in the modulation of signal transduction. The strongest evidence that ICC in the urinary tract act as pacemakers comes from studies of those in the urethra. Isolated ICC show regular spontaneous depolarizations in current clamp which resemble very closely the slow waves recorded from intact tissue. In voltage clamp they show abundant calcium-activated chloride current and spontaneous transient inward currents which can be blocked by chloride channel blockers. However, their role in the modulation of urethral tone has yet to be fully elucidated
Configuration Management Process Improvement for the Medical Device Industry
No full textThis paper outlines how the goals, practices and capability levels for the configuration management (CM) process area within a software process improvement (SPI) framework have been developed. This framework addresses an opportunity to integrate the regulatory issues and SPI mechanisms so as to achieve improvements that are critical to the development of software for medical devices [1].
Software is becoming an increasingly important aspect of medical devices and medical device regulation. Medical devices can only be marketed if compliance and approval from the appropriate regulatory bodies of the Food and Drug Administration (FDA) [2] (US requirement), and the European Commission under its Medical Device Directives (MDD) [3] (CE marking requirement) is achieved. Integrated into the design process of medical devices, is the requirement of the production and maintenance of a device technical file, incorporating a design history file. Design history illustrates the well documented, defined and controlled processes and outputs, undertaken in the development of medical devices and for our particular consideration with this framework - the software components