Enantiomers' potential in psychopharmacology--a critical analysis with special emphasis on the antidepressant escitalopram

Stereochemistry is now influencing most areas of pharmacotherapy, with a growing awareness in the field of psychiatry and, more specifically, depression. This is due to the fact that the enantiomers of many chiral drugs may have distinct pharmacological, pharmacokinetic and/or pharmacogenetic profiles. Consequently, in some instances there may be an advantage in using a single enantiomer over the racemic form-thus providing a basis for the development of new therapeutic agents, as well as the potential to improve current treatments. This review highlights some of the potential advantages and disadvantages that using single enantiomers might offer. The principles are exemplified through reference to the stereoselective properties of several established chiral psychotropic drugs, including thioridazine, methadone, trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. Emphasis is given to the treatment of depression and how the potential of one pure enantiomer-escitalopram, the S-enantiomer of the selective serotonin reuptake inhibitor citalopram-appears to be fulfilling its preclinical promise in the clinic.

Safer Construction and Maintenance Safer Construction and Maintenance Practices to Minimize Potential Liability by Counties from Accidents, September 1979

Tort claims resulting from alleged highway defects have introduced an additional element in the planning, design, construction, and maintenance of highways. A survey of county governments in Iowa was undertaken in order to quantify the magnitude and determine the nature of this problem. This survey included the use of mailed questionnaires and personal interviews with County Engineers. Highway-related claims filed against counties in Iowa amounted to about $52,000,000 during the period 1973 through 1978. Over $30,000,000 in claims was pending at the end of 1978. Settlements of judgments were made at a cost of 12.2% of the amount claimed for those claims that had been disposed of, not including costs for handling claims, attorney fees, or court costs. There was no clear time trend in the amount of claims for the six-year period surveyed, although the amount claimed in 1978 was about double the average for the preceding five years. Problems that resulted in claims for damages from counties have generally related to alleged omissions in the use of traffic control devices or defects, often temporary, resulting from alleged inadequacies in highway maintenance. The absence of stop signs or warning signs often has been the central issue in a highway-related tort claim. Maintenance problems most frequently alleged have included inadequate shoulders, surface roughness, ice o? snow conditions, and loose gravel. The variation in the occurrence of tort claims among 85 counties in Iowa could not be related to any of the explanatory variables that were tested. Claims appeared to have occurred randomly. However, using data from a sub sample of 11 counties, a significant relationship was shown probably to exist between the amount of tort claims and the extensiveness of use of warning signs on the respective county road systems. Although there was no indication in any county that their use of warning signs did not conform with provisions of the Manual on Uniform Traffic Control Devices (Federal Highway Administration, Government Printing Office, Washington, D.C., 1978), many more warning signs were used in some counties than would be required to satisfy this minimum requirement. Sign vandalism reportedly is a problem in all counties. The threat of vandalism and the added costs incurred thereby have tended to inhibit more extensive use of traffic control devices. It also should be noted that there is no indication from this research of a correlation between the intensiveness of sign usage and highway safety. All highway maintenance activities introduce some extraordinary hazard for motorists. Generally effective methodologies have evolved for use on county road systems for routine maintenance activities, procedures that tend to reduce the hazard to practical and reasonably acceptable levels. Blading of loose-surfaced roads is an example of such a routine maintenance activity. Alternative patterns for blading that were investigated as part of this research offered no improvements in safety when compared with the method in current use and introduced a significant additional cost that was unacceptable, given the existing limitations in resources available for county roads.

Durable, Cost-Effective Pavement Markings Phase I: Synthesis of Current Research, June 2001

Pavement marking technology is a continually evolving subject. There are numerous types of materials used in the field today, including (but not limited to) paint, epoxy, tape, and thermoplastic. Each material has its own set of unique characteristics related to durability, retro reflectivity, installation cost, and life-cycle cost. The Iowa Highway Research Board was interested in investigating the possibility of developing an ongoing program to evaluate the various products used in pavement marking. This potential program would maintain a database of performance and cost information to assist state and local agencies in determining which materials and placement methods are most appropriate for their use. The Center for Transportation Research and Education at Iowa State University has completed Phase I of this research: to identify the current practice and experiences from around the United States to recommend a further course of action for the State of Iowa. There has been a significant amount of research completed in the last several years. Research from Michigan, Pennsylvania, South Dakota, Ohio, and Alaska all had some common findings: white markings are more retro reflective than yellow markings; paint is by-and-large the least expensive material; paint tends to degrade faster than other materials; thermoplastic and tapes had higher retro reflective characteristics. Perhaps the most significant program going on in the area of pavement markings is the National Transportation Product Evaluation Program (NTPEP). This is an ongoing research program jointly conducted by the American Association of State Highway and Transportation Officials and its member states. Field and lab tests on numerous types of pavement marking materials are being conducted at sites representing four climatological areas. These results are published periodically for use by any jurisdiction interested in pavement marking materials performance.At this time, it is recommended that the State of Iowa not embark on a test deck evaluation program. Instead, close attention should be paid to the ongoing evaluations of the NTPEP program. Materials that fare well on the NTPEP test de cks should be considered for further field studies in Iowa.

Static and dynamic structure of liquid metals: Role of the different parts of the interaction potential

The influence of different parts of the interaction potential on the microscopic behavior of simple liquid metals is investigated by molecular dynamics simulation. The role of the soft-core repulsive, short-range attractive, and long-range oscillatory forces on the properties of liquid lithium close to the triple point is analyzed by comparing the results from simulations of identical systems but truncating the potential at different distances. Special attention is paid to dynamic collective properties such as the dynamic structure factors, transverse current correlation functions, and transport coefficients. It is observed that, in general, the effects of the short-range attractive forces are important. On the contrary, the influence of the oscillatory long-range interactions is considerably less, being the most pronounced for the dynamic structure factor at long wavelengths. The results of this work suggest that the influence of the attractive forces becomes less significant when temperature and density increase.

Safer Constrauction and Maintenance Practices to Minimize Potential Liabiliy by Counties from Accidents, Septemeber 1979

Tort claims resulting from alleged highway defects have introduced an additional element in the planning, design, construction, and maintenance of highways. A survey of county governments in Iowa was undertaken in order to quantify the magnitude and determine the nature of this problem. This survey included the use of mailed questionnaires and personal interviews with County Engineers. Highway-related claims filed against counties in Iowa amounted to about $52,000,000 during the period 1973 through 1978. Over $30,000,000 in claims was pending at the end of 1978. Settlements of judgments were made at a cost of 12.2% of the amount claimed for those claims that had been disposed of, not including costs for handling claims, attorney fees, or court costs. There was no clear time trend in the amount of claims for the six-year period surveyed, although the anount claimed in 1978 was about double the average for the preceding five years. Problems that resulted in claims for damages from counties have generally related to alleged omissions in the use of traffic control devices or defects, often temporary, resulting from alleged inadequacies in highway maintenance. The absence of stop signs or warning signs often has been the central issue in a highway-related tort claim. Maintenance problems most frequently alleged have included inadequate shoulders, surface roughness, ice o? snow conditions, and loose gravel. The variation in the occurrence of tort claims among 85 counties in Iowa could not be related to any of the explanatory variables that were tested. Claims hppeared to have occurred randomly. However, using data from a subsample of 11 counties, a significant relationship was shown probably to exist between the amount of tort claims and the extensiveness of use of wcirning signs on the respective county road systems. Although there was no indication in any county that their use of warning signs did not conform with provisions of the Manual on Uniform Traffic Control Devices (Federal Highway Administration, Government Printing Office, Washington, D.C., 1978), many more warning signs were used in some counties than would be required to satisfy this minimum requirement. Sign vandalism reportedly is a problem in all counties. The threat of vandalism and the added costs incurred thereby have tended to inhibit more extensive use of traffic control devices. It also should be noted that there is no indication from this research of a correlation between the intensiveness of sign usage and highway safety. All highway maintenance activities introduce some extraordinary hazard for motorists. Generally effective methodologies have evolved for use on county road systems for routine maintenance activities, procedures that tend to reduce the hazard to practical and reasonably acceptable levels. Blading of loose-surfaced roads is an examples such a routine maintenance activity. Alternative patterns for blading that were investigated as part of this research offered no improvements in safety when compared with the method in current use and introduced a significant additional cost that was unacceptable, given the existing limitations in resources available for county roads.

Durable, Cost-Effective Pavement Markings Phase I: Synthesis of Current Reseaech, June 2001

Pavement marking technology is a continually evolving subject. There are numerous types of materials used in the field today, including (but not limited to) paint, epoxy, tape, and thermoplastic. Each material has its own set of unique characteristics related to durability, retroreflectivity, installation cost, and life-cycle cost. The Iowa Highway Research Board was interested in investigating the possibility of developing an ongoing program to evaluate the various products used in pavement marking. This potential program would maintain a database of performance and cost information to assist state and local agencies in determining which materials and placement methods are most appropriate for their use. The Center for Transportation Research and Education at Iowa State University has completed Phase I of this research: to identify the current practice and experiences from around the United States to recommend a further course of action for the State of Iowa. There has been a significant amount of research completed in the last several years. Research from Michigan, Pennsylvania, South Dakota, Ohio, and Alaska all had some common findings: white markings are more retroreflective than yellow markings; paint is by-and-large the least expensive material; paint tends to degrade faster than other materials; thermoplastic and tapes had higher retroreflective characteristics. Perhaps the most significant program going on in the area of pavement markings is the National Transportation Product Evaluation Program (NTPEP). This is an ongoing research program jointly conducted by the American Association of State Highway and Transportation Officials and its member states. Field and lab tests on numerous types of pavement marking materials are being conducted at sites representing four climatological areas. These results are published periodically for use by any jurisdiction interested in pavement marking materials performance. At this time, it is recommended that the State of Iowa not embark on a test deck evaluation program. Instead, close attention should be paid to the ongoing evaluations of the NTPEP program. Materials that fare well on the NTPEP test de cks should be considered for further field studies in Iowa.

Neural differentiation and therapeutic potential of adipose tissue derived stem cells.

Neural tissue has historically been regarded as having poor regenerative capacity but recent advances in the growing fields of tissue engineering and regenerative medicine have opened new hopes for the treatment of nerve injuries and neurodegenerative disorders. Adipose tissue has been shown to contain a large quantity of adult stem cells (ASC). These cells can be easily harvested with low associated morbidity and because of their potential to differentiate into multiple cell types, their use has been suggested for a wide variety of therapeutic applications. In this review we examine the evidence indicating that ASC can stimulate nerve regeneration by both undergoing neural differentiation and through the release of a range of growth factors. We also discuss some of the issues that need to be addressed before ASC can be developed as an effective cellular therapy for the treatment of neural tissue disorders.

The Potential of Friction as a Tool for Winter Maintenance, TR-400, 1998

It is intuitively obvious that snow or ice on a road surface will make that surface more slippery and thus more hazardous. However, quantifying this slipperiness by measuring the friction between the road surface and a vehicle is rather difficult. If such friction readings could be easily made, they might provide a means to control winter maintenance activities more efficiently than at present. This study is a preliminary examination of the possibility of using friction as an operational tool in winter maintenance. In particular, the relationship of friction to traffic volume and speed, and accident rates is examined, and the current lack of knowledge in this area is outlined. The state of the art of friction measuring techniques is reviewed. A series of experiments whereby greater knowledge of how friction deteriorates during a storm and is restored by treatment is proposed. The relationship between plowing forces and the ice-pavement bond strength is discussed. The challenge of integrating all these potential sources of information into a useful final product is presented together with a potential approach. A preliminary cost-benefit analysis of friction measuring devices is performed and suggests that considerable savings might be realized if certain assumptions should hold true. The steps required to bring friction from its current state as a research tool to full deployment as an operational tool are presented and discussed. While much remains to be done in this regard, it is apparent that friction could be an extremely effective operational tool in winter maintenance activities of the future.

Potential and limitations of regulatory T-cell therapy in solid organ transplantation.

Over the past few years, the therapeutic potential of Treg has been highlighted in the field of autoimmune diseases and after allogeneic transplantation. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non-manipulated individuals, in particular when facing strong immune activation and expanding effector cells, such as in response to an allograft. Here we review current approaches being explored for Treg expansion in the perspective of clinical therapeutic protocols. We describe different Treg subsets that could be suitable for clinical application, as well as discuss factors such as the required dose of Treg, their antigen-specificity and in vivo stability, that have to be considered for optimal Treg-based immunotherapy in transplantation. Since Treg may not be sufficient as stand-alone therapy for solid organ transplantation in humans, we draw attention to possible hurdles and combination therapy with immunomodulatory drugs that could possibly improve the in vivo efficacy of Treg.

Transvaginal specimen extraction in colorectal surgery: current state of the art.

Aim  Background The expected benefit of transvaginal specimen extraction is reduced incision-related morbidity. Objectives A systematic review of transvaginal specimen extraction in colorectal surgery was carried out to assess this expectation. Method  Search strategy The following keywords, in various combinations, were searched: NOSE (natural orifices specimen extraction), colorectal, colon surgery, transvaginal, right hemicolectomy, left hemicolectomy, low anterior resection, sigmoidectomy, ileocaecal resection, proctocolectomy, colon cancer, sigmoid diverticulitis and inflammatory bowel diseases. Selection criteria Selection criteria included large bowel resection with transvaginal specimen extraction, laparoscopic approach, human studies and English language. Exclusion criteria were experimental studies and laparotomic approach or local excision. All articles published up to February 2011 were included. Results  Twenty-three articles (including a total of 130 patients) fulfilled the search criteria. The primary diagnosis was colorectal cancer in 51% (67) of patients, endometriosis in 46% (60) of patients and other conditions in the remaining patients. A concurrent gynaecological procedure was performed in 17% (22) of patients. One case of conversion to laparotomy was reported. In two patients, transvaginal extraction failed. In left- and right-sided resections, the rate of severe complications was 3.7% and 2%, respectively. Two significant complications, one of pelvic seroma and one of rectovaginal fistula, were likely to have been related to transvaginal extraction. The degree of follow up was specified in only one study. Harvested nodes and negative margins were adequate and reported in 70% of oncological cases. Conclusion  Vaginal extraction of a colorectal surgery specimen shows potential benefit, particularly when associated with a gynaecological procedure. Data from prospective randomized trials are needed to support the routine use of this technique.

Predicting current and future spatial community patterns of plant functional traits

Community-level patterns of functional traits relate to community assembly and ecosystem functioning. By modelling the changes of different indices describing such patterns - trait means, extremes and diversity in communities - as a function of abiotic gradients, we could understand their drivers and build projections of the impact of global change on the functional components of biodiversity. We used five plant functional traits (vegetative height, specific leaf area, leaf dry matter content, leaf nitrogen content and seed mass) and non-woody vegetation plots to model several indices depicting community-level patterns of functional traits from a set of abiotic environmental variables (topographic, climatic and edaphic) over contrasting environmental conditions in a mountainous landscape. We performed a variation partitioning analysis to assess the relative importance of these variables for predicting patterns of functional traits in communities, and projected the best models under several climate change scenarios to examine future potential changes in vegetation functional properties. Not all indices of trait patterns within communities could be modelled with the same level of accuracy: the models for mean and extreme values of functional traits provided substantially better predictive accuracy than the models calibrated for diversity indices. Topographic and climatic factors were more important predictors of functional trait patterns within communities than edaphic predictors. Overall, model projections forecast an increase in mean vegetation height and in mean specific leaf area following climate warming. This trend was important at mid elevation particularly between 1000 and 2000 m asl. With this study we showed that topographic, climatic and edaphic variables can successfully model descriptors of community-level patterns of plant functional traits such as mean and extreme trait values. However, which factors determine the diversity of functional traits in plant communities remains unclear and requires more investigations.

Circadian regulation of renal function and potential role in hypertension.

PURPOSE OF REVIEW: Previous studies have shown that a variety of specific renal functions exhibit circadian oscillations. This review aims to provide an update on the molecular mechanisms underlying circadian rhythms in the kidney, and to discuss how dysregulation of circadian rhythms can interfere with kidney function. RECENT FINDINGS: The molecular mechanism responsible for generating and maintaining circadian rhythms has been unraveled in great detail. This mechanism, known as the circadian clock, drives circadian oscillation in expression levels of a large number of renal mRNA transcripts. Several proteins critically involved in renal homeostatic functions have been shown to exhibit significant circadian oscillation in their expression levels or in their posttranslational modifications. In transgenic mouse models, disruption of circadian clock activity results in dramatic changes in the circadian pattern of urinary sodium and potassium excretion and causes significant changes in arterial blood pressure. A growing amount of evidence suggests that dysregulation of circadian rhythms is associated with the development of hypertension and accelerated progression of chronic kidney disease and cardiovascular disease in humans. Chronotherapy studies have shown that the efficacy of antihypertensive medication is greatly dependent on the circadian time of drug administration. SUMMARY: Recent research points to the major role of circadian rhythms in renal function and in control of blood pressure.

Transcranial direct current stimulation for the treatment of focal hand dystonia.

The treatment of writer's cramp, a task-specific focal hand dystonia, needs new approaches. A deficiency of inhibition in the motor cortex might cause writer's cramp. Transcranial direct current stimulation modulates cortical excitability and may provide a therapeutic alternative. In this randomized, double-blind, sham-controlled study, we investigated the efficacy of cathodal stimulation of the contralateral motor cortex in 3 sessions in 1 week. Assessment over a 2-week period included clinical scales, subjective ratings, kinematic handwriting analysis, and neurophysiological evaluation. Twelve patients with unilateral dystonic writer's cramp were investigated; 6 received transcranial direct current and 6 sham stimulation. Cathodal transcranial direct current stimulation had no favorable effects on clinical scales and failed to restore normal handwriting kinematics and cortical inhibition. Subjective worsening remained unexplained, leading to premature study termination. Repeated sessions of cathodal transcranial direct current stimulation of the motor cortex yielded no favorable results supporting a therapeutic potential in writer's cramp.

Modulatory effects of acid-sensing ion channels on action potential generation in hippocampal neurons.

Extracellular acidification has been shown to generate action potentials (APs) in several types of neurons. In this study, we investigated the role of acid-sensing ion channels (ASICs) in acid-induced AP generation in brain neurons. ASICs are neuronal Na(+) channels that belong to the epithelial Na(+) channel/degenerin family and are transiently activated by a rapid drop in extracellular pH. We compared the pharmacological and biophysical properties of acid-induced AP generation with those of ASIC currents in cultured hippocampal neurons. Our results show that acid-induced AP generation in these neurons is essentially due to ASIC activation. We demonstrate for the first time that the probability of inducing APs correlates with current entry through ASICs. We also show that ASIC activation in combination with other excitatory stimuli can either facilitate AP generation or inhibit AP bursts, depending on the conditions. ASIC-mediated generation and modulation of APs can be induced by extracellular pH changes from 7.4 to slightly <7. Such local extracellular pH values may be reached by pH fluctuations due to normal neuronal activity. Furthermore, in the plasma membrane, ASICs are localized in close proximity to voltage-gated Na(+) and K(+) channels, providing the conditions necessary for the transduction of local pH changes into electrical signals.

Distribution and agroclimatic characterization of potential cultivation regions of physic nut in Mexico

The purposes of this study were to determine the distribution and climatic patterns of current and future physic nut (Jatropha curcas) cultivation regions in Mexico, and to identify possible locations for in vivo germplasm banks establishment, using geographic information systems. Current climatic data were processed by Floramap software to obtain distribution maps and climatic patterns of regions where wild physic nuts could be found. DIVA-GIS software analyzed current climatic data (Worldclim model) and climatic data generated by CCM3 model to identify current and future physic nut cultivation regions, respectively. The distribution map showed that physic nut was present in most of the tropical and subtropical areas of Mexico, which corresponded to three agroclimatic regions. Climate types were Aw2, Aw1, and Bs1, for regions 1, 2 and 3, respectively. Nontoxic genotypes were associated with region 2, and toxic genotypes were associated with regions 1 and 3. According to the current and future cultivation regions identified, the best suitable ones to establish in vivo germplasm collections were the coast of Michoacán and the Isthmus of Tehuantepec, located among the states of Veracruz, Oaxaca and Chiapas.