Polyanalgesic Consensus Conference-2012: Recommendations to Reduce Morbidity and Mortality in Intrathecal Drug Delivery in the Treatment of Chronic Pain.

Introduction:  Targeted intrathecal drug infusion to treat moderate to severe chronic pain has become a standard part of treatment algorithms when more conservative options fail. This therapy is well established in the literature, has shown efficacy, and is an important tool for the treatment of both cancer and noncancer pain; however, it has become clear in recent years that intrathecal drug delivery is associated with risks for serious morbidity and mortality. Methods:  The Polyanalgesic Consensus Conference is a meeting of experienced implanting physicians who strive to improve care in those receiving implantable devices. Employing data generated through an extensive literature search combined with clinical experience, this work group formulated recommendations regarding awareness, education, and mitigation of the morbidity and mortality associated with intrathecal therapy to establish best practices for targeted intrathecal drug delivery systems. Results:  Best practices for improved patient care and outcomes with targeted intrathecal infusion are recommended to minimize the risk of morbidity and mortality. Areas of focus include respiratory depression, infection, granuloma, device-related complications, endocrinopathies, and human error. Specific guidance is given with each of these issues and the general use of the therapy. Conclusions:  Targeted intrathecal drug delivery systems are associated with risks for morbidity and mortality that can be devastating. The panel has given guidance to treating physicians and healthcare providers to reduce the incidence of these problems and to improve outcomes when problems occur.

Wind Monitoring of the Saylorville and Red Rock Reservoir Bridges with Remote, Cellular-Based Notifications, May 2012

Following a high wind event on January 24, 2006, at least five people claimed to have seen or felt the superstructure of the Saylorville Reservoir Bridge in central Iowa moving both vertically and laterally. Since that time, the Iowa Department of Transportation (DOT) contracted with the Bridge Engineering Center at Iowa State University to design and install a monitoring system capable of providing notification of the occurrence of subsequent high wind events. In subsequent years, a similar system was installed on the Red Rock Reservoir Bridge to provide the same wind monitoring capabilities and notifications to the Iowa DOT. The objectives of the system development and implementation are to notify personnel when the wind speed reaches a predetermined threshold such that the bridge can be closed for the safety of the public, correlate structural response with wind-induced response, and gather historical wind data at these structures for future assessments. This report describes the two monitoring systems, their components, upgrades, functionality, and limitations, and results from one year of wind data collection at both bridges.

Counter-ion effect on surfactant-DNA gel particles as controlled DNA delivery systems

The ability to entrap drugs within vehicles and subsequently release them has led to new treatments for a number of diseases. Based on an associative phase separation and interfacial diffusion approach, we developed a way to prepare DNA gel particles without adding any kind of cross-linker or organic solvent. Among the various agents studied, cationic surfactants offered particularly efficient control for encapsulation and DNA release from these DNA gel particles. The driving force for this strong association is the electrostatic interaction between the two components, as induced by the entropic increase due to the release of the respective counter-ions. However, little is known about the influence of the respective counter-ions on this surfactant-DNA interaction. Here we examined the effect of different counter-ions on the formation and properties of the DNA gel particles by mixing DNA (either single- (ssDNA) or double-stranded (dsDNA)) with the single chain surfactant dodecyltrimethylammonium (DTA). In particular, we used as counter-ions of this surfactant the hydrogen sulfate and trifluoromethane sulfonate anions and the two halides, chloride and bromide. Effects on the morphology of the particles obtained, the encapsulation of DNA and its release, as well as the haemocompatibility of these particles, are presented, using the counter-ion structure and the DNA conformation as controlling parameters. Analysis of the data indicates that the degree of counter-ion dissociation from the surfactant micelles and the polar/hydrophobic character of the counter-ion are important parameters in the final properties of the particles. The stronger interaction with amphiphiles for ssDNA than for dsDNA suggests the important role of hydrophobic interactions in DNA.

Therapeutic monitoring of antidepressants in the era of pharmacogenetics studies.

As for other drugs, there is a large interindividual variability of the plasma concentrations of antidepressants for a given dose. Within the last 2 decades, a very large number of pharmacogenetic studies have made it possible to understand the importance of genetic factors on the disposition of drugs in the organism, many of them at the levels of drug metabolism. Polymorphism of CYP2D6 and of other drug-metabolizing enzymes may thus lead to very large differences in drug exposure between patients and possibly also to toxicity or ineffective drug concentrations in some subjects. In consequence, dose recommendations of antidepressants based on genotypes, justified by the principle of administering bioequivalent individualized drug doses, are now proposed. However, blood (and thus possibly brain) concentrations also depend on other factors than the genetic makeup of the patients. Therapeutic drug monitoring of antidepressants allows us to take into account the influence of factors such as comedications, diet, smoking habit, impaired organ function, and compliance. Therapeutic drug monitoring and genotyping are thus complementary, and their combined use contributes to improve pharmacotherapy with antidepressants and other drugs.

Transscleral Coulomb-controlled iontophoresis of methylprednisolone into the rabbit eye: influence of duration of treatment, current intensity and drug concentration on ocular tissue and fluid levels.

The major problems associated with the use of corticosteroids for the treatment of ocular diseases are their poor intraocular penetration to the posterior segment when administered locally and their secondary side effects when given systemically. To circumvent these problems more efficient methods and techniques of local delivery are being developed. The purposes of this study were: (1) to investigate the pharmacokinetics of intraocular penetration of hemisuccinate methyl prednisolone (HMP) after its delivery using the transscleral Coulomb controlled iontophoresis (CCI) system applied to the eye or after intravenous (i.v.) injection in the rabbit, (2) to test the safety of the CCI system for the treated eyes and (3) to compare the pharmacokinetic profiles of HMP intraocular distribution after CCI delivery to i.v. injection. For each parameter evaluated, six rabbit eyes were used. For the CCI system, two concentrations of HMP (62.5 and 150mg ml(-1)), various intensities of current and duration of treatment were analyzed. In rabbits serving as controls the HMP was infused in the CCI device but without applied electric current. For the i.v. delivery, HMP at 10mg kg(-1)as a 62.5mg ml(-1)solution was used. The rabbits were observed clinically for evidence of ocular toxicity. At various time points after the administration of drug, rabbits were killed and intraocular fluids and tissues were sampled for methylprednisolone (MP) concentrations by high pressure liquid chromatography (HPLC). Histology examinations were performed on six eyes of each group. Among groups that received CCI, the concentrations of MP increased in all ocular tissues and fluids in relation to the intensities of current used (0.4, 1.0 and 2.0mA/0.5cm(2)) and its duration (4 and 10min). Sustained and highest levels of MP were achieved in the choroid and the retina of rabbit eyes treated with the highest current and 10min duration of CCI. No clinical toxicity or histological lesions were observed following CCI. Negligible amounts of MP were found in ocular tissues in the CCI control group without application of current. Compared to i.v. administration, CCI achieved higher and more sustained tissue concentrations with negligible systemic absorption. These data demonstrate that high levels of MP can be safely achieved in intraocular tissues and fluids of the rabbit eye, using CCI. With this system, intraocular tissues levels of MP are higher than those achieved after i.v. injection. Furthermore, if needed, the drug levels achieved with CCI can be modulated as a function of current intensity and duration of treatment. CCI could therefore be used as an alternative method for the delivery of high levels of MP to the intraocular tissues of both the anterior and posterior segments.

Field Monitoring of Curved Girder Bridges with Integral Abutments, TPF-5(169), 2014

Nationally, there are questions regarding the design, fabrication, and erection of horizontally curved steel girder bridges due to unpredicted girder displacements, fit-up, and locked-in stresses. One reason for the concerns is that up to one-quarter of steel girder bridges are being designed with horizontal curvature. There is also an urgent need to reduce bridge maintenance costs by eliminating or reducing deck joints, which can be achieved by expanding the use of integral abutments to include curved girder bridges. However, the behavior of horizontally curved bridges with integral abutments during thermal loading is not well known nor understood. The purpose of this study was to investigate the behavior of horizontal curved bridges with integral abutment (IAB) and semi-integral abutment bridges (SIAB) with a specific interest in the response to changing temperatures. The long-term objective of this effort is to establish guidelines for the use of integral abutments with curved girder bridges. The primary objective of this work was to monitor and evaluate the behavior of six in-service, horizontally curved, steel-girder bridges with integral and semi-integral abutments. In addition, the influence of bridge curvature, skew and pier bearing (expansion and fixed) were also part of the study. Two monitoring systems were designed and applied to a set of four horizontally curved bridges and two straight bridges at the northeast corner of Des Moines, Iowa—one system for measuring strains and movement under long term thermal changes and one system for measuring the behavior under short term, controlled live loading. A finite element model was developed and validated against the measured strains. The model was then used to investigate the sensitivity of design calculations to curvature, skew and pier joint conditions. The general conclusions were as follows: (1) There were no measurable differences in the behavior of the horizontally curved bridges and straight bridges studied in this work under thermal effects. For preliminary member sizing of curved bridges, thermal stresses and movements in a straight bridge of the same length are a reasonable first approximation. (2) Thermal strains in integral abutment and semi-integral abutment bridges were not noticeably different. The choice between IAB and SIAB should be based on life – cycle costs (e.g., construction and maintenance). (3) An expansion bearing pier reduces the thermal stresses in the girders of the straight bridge but does not appear to reduce the stresses in the girders of the curved bridge. (4) An analysis of the bridges predicted a substantial total stress (sum of the vertical bending stress, the lateral bending stress, and the axial stress) up to 3 ksi due to temperature effects. (5) For the one curved integral abutment bridge studied at length, the stresses in the girders significantly vary with changes in skew and curvature. With a 10⁰ skew and 0.06 radians arc span length to radius ratio, the curved and skew integral abutment bridges can be designed as a straight bridge if an error in estimation of the stresses of 10% is acceptable.

Monitoring one-year compliance to antihypertension medication in the Seychelles.

OBJECTIVE: To examine the compliance to medication among newly diagnosed hypertensive patients screened from the general population of the Seychelles, a rapidly developing country. METHODS: Among the 1067 participants to a population-based survey for cardiovascular risk factors, hypertension was discovered in 50 (previously unaware of having hypertension and having blood pressure > or = 160/95 mmHg over 3 visits). These 50 patients were placed on a daily one-pill regimen of medication (bendrofluazide, atenolol, or a combination of hydrochlorothiazide and atenolol) and compliance to the regimen was assessed over 12 months using electronic pill containers. Satisfactory compliance was defined as taking the medication on 6 or 7 days a week on average (which corresponds to a mean compliance level of > or = 86%). FINDINGS: In the first month, fewer than half (46%) of the new hypertension patients achieved satisfactory compliance, and only about one-quarter (26%) achieved this level by the twelfth month. Compliance was better among the 23 participants who regularly attended medical follow-up, with nearly three-quarters of these patients (74%) achieving satisfactory compliance during the first month and over one-half (55%) by the twelfth month. There was a direct association between mean 12-month compliance level and having a highly skilled occupation; having good health awareness; and regularly attending medical appointments. In contrast, there was an inverse relationship between mean compliance level and heavy drinking. CONCLUSION: The low proportion of people selected from the general population who were capable of sustaining satisfactory compliance to antihypertension medication may correspond to the maximum effectiveness of medication interventions based on a screening and treatment strategy in the general population. The results stress the need for both high-risk and population approaches to improve hypertension control.

Severe hypertension following accidental clonidine overdose during the refilling of an implanted intrathecal drug delivery system.

BACKGROUND:   Complications associated with intrathecal pumps may be linked to the surgical procedure, the implanted device, or the medication itself.¦CASE REPORTS:   Three patients treated chronically with intrathecal clonidine presented with clonidine overdose due to inadvertent extravasation during the refilling procedure. All patients experienced loss of consciousness and severe systemic hypertension that required aggressive parenteral treatment.¦DISCUSSION:   Clonidine is an alpha-2 agonist with a nearly 100% bioavailability after oral or rectal administration. With high plasma concentration secondary to massive systemic overdose, the specificity for the alpha-2 receptor is lost and an alpha-1 agonist activity predominates and causes marked hypertension. Management of clonidine overdose consists of supportive therapy guided by signs and symptoms.¦CONCLUSION:   Inadvertent injection into the subcutaneous pocket rather than the reservoir is rare but very dangerous as the drug cannot be retrieved and massive doses are involved. Signs and symptoms of systemic overdose with drugs commonly used in implanted drugs delivery system should be well known to ensure early diagnosis and treatment.

Vectorisation intra-oculaire [Drug delivery to target the posterior segment of the eye].

Retinal diseases are nowadays the most common causes of vision threatening in developed countries. Therapeutic advances in this field are hindered by the difficulty to deliver drugs to the posterior segment of the eye. Due to anatomical barriers, the ocular biodisponibility of systemically administered drugs remains poor, and topical instillation is not adequate to achieve therapeutic concentrations of drugs in the back of the eye. Ocular drug delivery has thus become one of the main challenges of modern ophthalmology. A multidisciplinary research is being conducted worldwide including pharmacology, biomaterials, ophthalmology, pharmaceutics, and biology. New promising fields have been developed such as implantable or injectable slow release intravitreal devices and degradable polymers, dispersed polymeric systems for intraocular drug delivery, and transscleral delivery devices such as iontophoresis, osmotic pumps or intra-scleraly implantable materials. The first clinical applications emerging from this research are now taking place, opening new avenues for the treatment of retinal diseases.

French summaries of product characteristics: content in relation to therapeutic monitoring of psychotropic drugs.

The prescription information (summary of product characteristics, SPC) is compiled by the pharmaceutical industry as required by the national regulatory authorities. They vary in their content about the properties of drugs and about the usefulness of therapeutic drug monitoring (TDM) in the blood of patients. Based on a previous study carried out in Germany, the degree of agreement of French SPC for 59 psychotropic drugs with the existing medico-scientific evidence in the area of TDM was examined using a recently developed instrument. A summary score of SPC content (SPCC) related to TDM (SPCC(TDM)) has been calculated and compared with the level of recommendation of TDM of the AGNP-TDM expert group consensus guidelines for TDM in psychiatry [AGNP: Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association for neuropsychopharmacology and pharmacopsychiatry)]. Among the antidepressants, antipsychotics, tranquillizers/hypnotic agents and mood stabilizers, the highest SPCC(TDM) scores in the French SPC were reached for imipramine (16), haloperidol (6), clonazepam (8) and lithium (23), respectively. Results were similar to those obtained from the analysis of German SPC, and considerable disagreement was found between the information on TDM in SPC and existing medico-scientific evidence, albeit less in the case of mood stabilizers. Taking into account the recommendations of the AGNP-TDM expert group guidelines, there is a deficit in the French SPC concerning TDM-relevant information. An amelioration of this situation could help to improve the clinical practice of TDM of psychotropic drugs, as the SPC is a widely used tool.

Quorum-sensing systems in staphylococci as therapeutic targets.

The staphylococci are an ever-present threat in our world, capable of causing a wide range of infections, and are a persistent presence in the clinical environment. As the number of antimicrobial compounds effective against staphylococci decreases, because of the acquisition and spread of antibiotic resistance, there is a growing need for novel therapeutic molecules. Intra and inter-species communication (quorum sensing) is a biologically significant phenomenon that has been associated with virulence, intracellular survival, and biofilm formation. Quorum sensing molecules of staphylococci and other species (e.g. Pseudomonas aeruginosa) can inhibit virulence factor production and/or growth of staphylococci, leading to the possibility that interference with staphylococcal quorum-sensing systems could be a way of controlling the diverse infections caused by the staphylococci. In this article, we discuss the potential of quorum-sensing systems of staphylococci as therapeutic targets.

A new poly(ortho ester)-based drug delivery system as an adjunct treatment in filtering surgery.

PURPOSE: Pharmacologic modulation of wound healing after glaucoma filtering surgery remains a major clinical challenge in ophthalmology. Poly(ortho ester) (POE) is a bioerodible and biocompatible viscous polymer potentially useful as a sustained drug delivery system that allows the frequency of intraocular injections to be reduced. The purpose of this study was to determine the efficacy of POE containing a precise amount of 5-fluorouracil (5-FU) in an experimental model of filtering surgery in the rabbit. METHODS: Trabeculectomy was performed in pigmented rabbit eyes. An ointmentlike formulation of POE containing 1% wt/wt 5-FU was injected subconjunctivally at the site of surgery, during the procedure. Intraocular pressure (IOP), bleb persistence, and ocular inflammatory reaction were monitored until postoperative day 30. Quantitative analysis of 5-FU was performed in the anterior chamber. Histologic analysis was used to assess the appearance of the filtering fistula and the polymer's biocompatibility. RESULTS: The decrease in IOP from baseline and the persistence of the filtering bleb were significantly more marked in the 5-FU-treated eyes during postoperative days 9 through 28. Corneal toxicity triggered by 5-FU was significantly lower in the group that received 5-FU in POE compared with a 5-FU tamponade. Histopathologic evaluation showed that POE was well tolerated, and no fibrosis occurred in eyes treated with POE containing 5-FU. CONCLUSIONS: In this rabbit model of trabeculectomy, the formulation based on POE and containing a precise amount of 5-FU reduced IOP and prolonged bleb persistence in a way similar to the conventional method of a 5-FU tamponade, while significantly reducing 5-FU toxicity.

Intraocular implants for extended drug delivery: therapeutic applications.

An overview of ocular implants with therapeutic application potentials is provided. Various types of implants can be used as slow release devices delivering locally the needed drug for an extended period of time. Thus, multiple periocular or intraocular injections of the drug can be circumvented and secondary complications minimized. The various compositions of polymers fulfilling specific delivery goals are described. Several of these implants are undergoing clinical trials while a few are already commercialized. Despite the paramount progress in design, safety and efficacy, the place of these implants in our clinical therapeutic arsenal remains limited. Miniaturization of the implants allowing for their direct injection without the need for a complicated surgery is a necessary development avenue. Particulate systems which can be engineered to target specifically certain cells or tissues are another promising alternative. For ocular diseases affecting the choroid and outer retina, transscleral or intrasscleral implants are gaining momentum.

On the Condition Monitoring of Induction machines

The research of condition monitoring of electric motors has been wide for several decades. The research and development at universities and in industry has provided means for the predictive condition monitoring. Many different devices and systems are developed and are widely used in industry, transportation and in civil engineering. In addition, many methods are developed and reported in scientific arenas in order to improve existing methods for the automatic analysis of faults. The methods, however, are not widely used as a part of condition monitoring systems. The main reasons are, firstly, that many methods are presented in scientific papers but their performance in different conditions is not evaluated, secondly, the methods include parameters that are so case specific that the implementation of a systemusing such methods would be far from straightforward. In this thesis, some of these methods are evaluated theoretically and tested with simulations and with a drive in a laboratory. A new automatic analysis method for the bearing fault detection is introduced. In the first part of this work the generation of the bearing fault originating signal is explained and its influence into the stator current is concerned with qualitative and quantitative estimation. The verification of the feasibility of the stator current measurement as a bearing fault indicatoris experimentally tested with the running 15 kW induction motor. The second part of this work concentrates on the bearing fault analysis using the vibration measurement signal. The performance of the micromachined silicon accelerometer chip in conjunction with the envelope spectrum analysis of the cyclic bearing faultis experimentally tested. Furthermore, different methods for the creation of feature extractors for the bearing fault classification are researched and an automatic fault classifier using multivariate statistical discrimination and fuzzy logic is introduced. It is often important that the on-line condition monitoring system is integrated with the industrial communications infrastructure. Two types of a sensor solutions are tested in the thesis: the first one is a sensor withcalculation capacity for example for the production of the envelope spectra; the other one can collect the measurement data in memory and another device can read the data via field bus. The data communications requirements highly depend onthe type of the sensor solution selected. If the data is already analysed in the sensor the data communications are needed only for the results but in the other case, all measurement data need to be transferred. The complexity of the classification method can be great if the data is analysed at the management level computer, but if the analysis is made in sensor itself, the analyses must be simple due to the restricted calculation and memory capacity.