Getting muscles moving again after botulinum toxin: novel therapeutic challenges

The use of botulinum neurotoxins for the treatment of muscle hyperactivity and spasticity disorders has been remarkably successful, owing to the abilities of the toxins to elicit prolonged localized paralysis and the rarity of serious adverse effects. However, botulinum toxins are the most deadly protein toxins known, and existing antidotes possess limited effectiveness. Paradoxically, in situ, the intoxicated motoneuron does not die. It reacts by emanating a sprouting network known to implement new functional synapses, leading to resumption of neurotransmission. Recent studies have highlighted ways of accelerating this natural recovery process to overcome paralysis successfully. Developing new therapeutic strategies and treatments for botulism will require more research into the molecular understanding of this 'naturally occurring' recovery process.

Use of oesophagogastroscopy to assess the response of oesophageal carcinoma to neoadjuvant therapy

Background: Approximately 25 per cent of patients with oesophageal cancer who undergo neoadjuvant chemoradiotherapy have no evidence of tumour in the resected specimen (complete pathological response). Those who do not respond have a poor 5-year survival compared with complete responders, regardless of whether or not they undergo surgery. Selecting for surgery only those who have a response to neoadjuvant therapy has the potential to improve overall survival as well as to rationalize the management of non-responders. This study assessed the accuracy of oesophagogastroscopy in this setting. Methods: A prospective database of 804 patients undergoing oesophageal resection for carcinoma was reviewed. Endoscopic assessment of the response to neoadjuvant therapy in 100 consecutive patients was compared with the pathological assessment of response. The survival for each level of response was compared. Results: At endoscopy 30 patients were considered to have had a complete response. This was confirmed pathologically in 15 patients. Survival was improved in those with a pathologically confirmed complete response (3-year survival rate 62.4 (s.e. 12.9) per cent) compared with non-responders (16.3 (s.e. 6.6) per cent). Those with microscopic residual disease also had an improved 3-year survival rate (46.3 (s.e. 12.2) per cent); however, oesophagogastroscopy failed to identify this subset. Conclusion: Oesophagogastroscopy may be useful in the assessment of tumour response to neoadjuvant therapy. However, owing to its poor accuracy patients should not be excluded from further therapeutic intervention on the basis of this assessment alone.

What is the best size descriptor to use for pharmacokinetic studies in the obese?

The prevalence of obesity in the western world is dramatically rising, with many of these individuals requiring therapeutic intervention for a variety of disease states. Despite the growing prevalence of obesity there is a paucity of information describing how doses should be adjusted, or indeed whether they need to be adjusted, in the clinical setting. This review is aimed at identifying which descriptors of body size provide the most information about the relationship between dose and concentration in the obese. The size descriptors, weight, lean body weight, ideal body weight, body surface area, body mass index, fat-free mass, percent ideal body weight, adjusted body weight and predicted normal body weight were considered as potential size descriptors. We conducted an extensive review of the literature to identify studies that have assessed the quantitative relationship between the parameters clearance (CL) and volume of distribution (V) and these descriptors of body size. Surprisingly few studies have addressed the relationship between obesity and CL or V in a quantitative manner. Despite the lack of studies there were consistent findings: (i) most studies found total body weight to be the best descriptor of V. A further analysis of the studies that have addressed V found that total body weight or another descriptor that incorporated fat mass was the preferred descriptor for drugs that have high lipophilicity; (ii) in contrast, CL was best described by lean body mass and no apparent relationship between lipophilicity or clearance mechanism and preference for body size descriptor was found. In conclusion, no single descriptor described the influence of body size on both CL and V equally well. For drugs that are dosed chronically, and therefore CL is of primary concern, dosing for obese patients should not be based on their total weight. If a weight-based dose individualization is required then we would suggest that chronic drug dosing in the obese subject should be based on lean body weight, at least until a more robust size descriptor becomes available.

Yield response of rice (Oryza sativa L.) genotypes to drought under rainfed lowlands 4. Vegetative stage screening in the dry season

Screening for drought resistance of rainfed lowland rice using drought score (leaf death) as a selection index has a long history of use in breeding programs. Genotypic variation for drought score during the vegetative stage in two dry season screens was examined among 128 recombinant inbred lines from four biparental crosses. The genotypic variation detected for drought score in the dry season was used to examine the reliability of the dry season screening method to estimate relative grain yield of genotypes under different types of drought stress in the wet season. Large genotypic variation for drought score existed in two experiments (A and B). However, there was no relationship between the drought scores of genotypes determined in these two experiments. Different patterns of development and severity of drought stress in these two experiments, i.e. slow development and mild plant water deficit in experiment A and fast development and severe plant water deficit in experiment B, were identified as the major factors contributing to the genotypes responding differently. Larger drought score in the dry season experiments was associated with lower grain yield under specific drought stress conditions in the wet season, but the association was weak to moderate and significant only in particular drought conditions. In most cases, a significant phenotypic and moderate genetic correlation between drought score in the dry season and grain yield in the wet season existed only when both drought score and grain yield of genotypes were affected by similar patterns and severity of drought stress in their respective experimental environments. The dry season environments used to measure genotypic variation for drought score should be managed to correspond to relevant types of drought environment that are frequent in the wet season. The efficiency of using the drought score as an indirect selection criterion for improving grain yield for drought conditions was lower than the direct selection for grain yield, and hence wet season screening with grain yield as a selection criterion would be more efficient. However, using drought score as a selection index, a larger number of genotypes can be evaluated than for wet season grain yield. Therefore, it is possible to apply higher selection intensities using the drought score system, and the selected lines can be further tested for grain yield in the wet season. (C) 2004 Elsevier B.V. All rights reserved.

Coronary flow responses to exercise training: further evidence of the benefit of an underutilized therapeutic modality

Inactivity is associated with endothelial dysfunction and the development of cardiovascular disease. Exercise training has a favourable effect in the management of hypertension, heart failure and ischaemic heart disease. These beneficial effects are probably mediated through improvements of vascular function and, in this issue of Clinical Science, Hagg and co-authors propose a coronary artery effect. The use of a Doppler technique for non-invasive assessment of coronary flow reserve in a small animal model is an exciting aspect of this study. If feasible in the hands of other investigators, the availability of sequential coronary flow measurements in animal models may help improve our understanding of the mechanisms of disorders of the coronary circulation.

Psychoanalytic perspectives on substance use and antisocial personality disorder

Psychoanalysis and related psychodynamic psychotherapies have historically had a limited engagement with substance use and antisocial personality disorders. This in part reflects an early preoccupation with 'transference neuroses' and in part reflects later de-emphasis of diagnosis and focus on therapeutic process. Nonetheless, psychoanalytic perspectives can usefully inform thinking about approaches to treatment of such disorders and there are psychoanalytic constructs that have specific relevance to their treatment. This paper reviews some prominent strands of psychoanalytic thinking as they pertain to the treatment of substance abuse and antisocial personality disorders. It is argued that, while Freudian formulations lead to a primarily pessimistic view of the prospect of treatment of such disorders, both the British object relations and the North American self psychology traditions suggest potentially productive approaches. Finally the limited empirical evidence from brief psycho dynamically informed treatments of substance use disorders is reviewed. It is concluded that such treatments are not demonstrably effective but that, since no form of psychotherapy has established high efficacy with substance use disorders, brief psychdynamic therapies are not necessarily of lesser value than other treatments and may have specific value for particular individuals and in particular treatment contexts.

The use of e-mail in the therapy process

The therapeutic letter has a long history, with roots in psychoanalytic work and continuing application in family therapy. The advent of e-mail has allowed another form for therapeutic written communication which, while incorporating the benefits of therapeutic letters, adds to these. It has also opened up some potential risks. This article incorporates a brief review of the literature covering therapeutic written communication and offers a case example where e-mail was used as an adjunct in face-to-face therapy with a client who experienced attachment difficulties. This therapy was informed by systemic and psychoanalytic traditions. The authors explore a variety of technical matters including the timing and Crafting of e-mail responses, the integration of written communication with face-to-face therapy, impact on the therapeutic relationship and management of crisis. Ethical issues such as confidentiality and duty of care are also considered.

Use of pulse transit time to distinguish respiratory events from tidal breathing in sleeping children

Study objectives: Currently, esophageal pressure monitoring is the "gold standard" measure for inspiratory efforts, hut its invasive nature necessitates a better tolerated and noninvasive method to be used on children. Pulse transit time (PTT) has demonstrated its potential as a noninvasive surrogate marker for inspiratory efforts. The principle velocity determinant of PTT is the change in stiffness of the arterial wall and is inversely correlated to BP. Moreover, PTT has been shown to identify changes in inspiratory effort via the BP fluctuations induced by negative pleural pressure swings. In this study, the capability of PTT to classify respiratory, events during sleep as either central or obstructive in nature was investigated. Setting and participants: PTT measure was used in adjunct to routine overnight polysomnographic studies performed on 33 children (26 boys and 7 girls; mean +/- SD age, 6.7 +/- 3.9 years). The accuracy of PTT measurements was then evaluated against scored corresponding respiratory events in the polysomnography recordings. Results: Three hundred thirty-four valid respiratory events occurred and were analyzed. One hundred twelve obstructive events (OEs) showed a decrease in mean PTT over a 10-sample window that had a probability of being correctly ranked below the baseline PTT during tidal breathing of 0.92 (p < 0.005); 222 central events (CEs) showed a decrease in the variance of PTT over a 10-sample window that had a probability of being ranked below the baseline PTT of 0.94 (p < 0.005). This indicates that, at a sensitivity of 0.90, OEs can be detected with a specificity of 0.82 and CEs can be detected with a specificity of 0.80. Conclusions: PTT is able to categorize CEs and OEs accordingly in the absence of motion artifacts, including hypopneas. Hence, PTT shows promise to differentiate respiratory, events accordingly and can be an important diagnostic tool in pediatric respiratory sleep studies.< 0.005); 222 central events (CEs) showed a decrease in the variance of PTT over a 10-sample window that had a probability of being ranked below the baseline PTT of 0.94 (p < 0.005). This indicates that, at a sensitivity of 0.90, OEs can be detected with a specificity of 0.82 and CEs can be detected with a specificity of 0.80. Conclusions: PTT is able to categorize CEs and OEs accordingly in the absence of motion artifacts, including hypopneas. Hence, PTT shows promise to differentiate respiratory, events accordingly and can be an important diagnostic tool in pediatric respiratory sleep studies.');"

Rice morphogenesis and plant architecture: Measurement, specification and the reconstruction of structural development by 3D architectural modelling

Background and Aims The morphogenesis and architecture of a rice plant, Oryza sativa, are critical factors in the yield equation, but they are not well studied because of the lack of appropriate tools for 3D measurement. The architecture of rice plants is characterized by a large number of tillers and leaves. The aims of this study were to specify rice plant architecture and to find appropriate functions to represent the 3D growth across all growth stages. Methods A japonica type rice, 'Namaga', was grown in pots under outdoor conditions. A 3D digitizer was used to measure the rice plant structure at intervals from the young seedling stage to maturity. The L-system formalism was applied to create '3D virtual rice' plants, incorporating models of phenological development and leaf emergence period as a function of temperature and photoperiod, which were used to determine the timing of tiller emergence. Key Results The relationships between the nodal positions and leaf lengths, leaf angles and tiller angles were analysed and used to determine growth functions for the models. The '3D virtual rice' reproduces the structural development of isolated plants and provides a good estimation of the fillering process, and of the accumulation of leaves. Conclusions The results indicated that the '3D virtual rice' has a possibility to demonstrate the differences in the structure and development between cultivars and under different environmental conditions. Future work, necessary to reflect both cultivar and environmental effects on the model performance, and to link with physiological models, is proposed in the discussion.

Quantifying the use of the statin antilipemic drugs: Comparisons and contrasts between Nova Scotia, Canada, and Queensland, Australia

Background: jurisdictions are developing public drug insurance systems to improve access to pharmaceuticals, cost-effective prescribing, and patient health and well-being. We compared 2 Jurisdictions with different pharmaceutical policies to determine prescribing patterns for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (le, statins). Objective: The aim of this work was to investigate the feasibility of using available prescription admimstrative databases to compare the use of statins in Queensland, Australia, and in Nova Scotia, Canada. Methods: Data from the Nova Scotia Pharmacare Program and the Health Insurance Commission in Australia were used to obtain dispensing data. Utilization was compared for the 5-year period from 1997 through 2001, using the World Health Organization anatomic therapeutic chemical/defined daily dose (DDD) system. Results: In the year 2001, there were 177,000 beneficiaries in the public drug plan in Nova Scotia (62% aged &GE; 65 years old) and 960,000 concession beneficiaries (pensioners and social security recipients, 61% aged &GE; 65 years) in Queensland. These 2 groups were comparable. The overall utilization of statin medications increased steadily in both areas over the study period, from 50 to 205 DDD/1000 beneficiaries per day. Comparison of the 2 growth lines showed no statistically significant differences in overall statin use despite differences in brand availabilities and policies about prescribing. In the year 2001, atorvastatin was the most commonly prescribed statin in both areas, comprising 46% of statin use in Nova Scotia and 51% in Queensland. Mean doses of each statin prescribed were slightly above the DDDs. Expenditure on statins per 1000 beneficiaries and per DDD were similar in each jurisdiction, being slightly higher in Nova Scotia. Conclusions: Despite differences in pharmaceutical reimbursement systems, use of the statins was similar in Nova Scotia and Queensland. The feasibility of the methodology was demonstrated. Future studies, including comparisons of drug utilization for other classes of drugs for which drug policies may be divergent (eg, different pricing structures or prior authorization requirements), or for which less evidence for appropriate use is available, may be useful. © 2005 Excerpta Medica, Inc.

Disease prevalence among dogs and cats in the United States and Australia and proportions of dogs and cats that receive therapeutic diets or dietary supplements

Objective-To estimate disease prevalence among dogs and cats in the United States and Australia and proportions of dogs and cats that receive therapeutic diets or dietary supplements. Design-Telephone survey. Sample Population-Dog and cat owners located in 5 geographic areas. Procedures-A telephone survey was administered to dog and cat owners. Results-Of 18,194 telephone calls that were made, 1,104 (6%) were to individuals who owned at least I dog or cat and agreed to participate. Information was collected for 635 dogs and 469 cats. Only 14 (1%) respondents indicated that their pet was unhealthy, but 176 (16%) indicated that their pets had 1 or more diseases. The most common diseases were musculoskeletal, dental, and gastrointestinal tract or hepatic disease. Many owners (n = 356) reported their pets were overweight or obese, but only 3 reported obesity as a health problem in their pets. Owners of 28 (2.5%) animals reported that they were feeding a therapeutic diet, with the most common being diets for animals with renal disease (n = 5), reduced-calorie diets (5), and reduced-fat diets (4). Owners of 107 of 1,076 (9.9%) animals reported administering dietary supplements to their pets. Multivitamins (n = 53 animals), chondroprotective agents (22), and fatty acids (13) were the most common dietary supplements used. Conclusions and Clinical Relevance-Results suggest that most dogs and cats reported by their owners to have a health problem were not being fed a therapeutic diet. In addition, the rate of dietary supplement use was lower than that reported for people.

Minimising cold damage during reproductive development among temperate rice genotypes. II. Genotypic variation and flowering traits related to cold tolerance screening

Low temperature during microspore development increases spikelet sterility and reduces grain yield in rice (Oryza sativa L.). The objectives of this study were to determine genotypic variation in spikelet sterility in the field in response to low-temperature and then to examine the use of physio-morphological traits at flowering to screen for cold tolerance. Multiple-sown field experiments were conducted over 4 consecutive years in the rice-growing region of Australia to increase the likelihood of encountering low-temperature during microspore development. More than 50 cultivars of various origins were evaluated, with 7 cultivars common to all 4 years. The average minimum temperature for 9 days during microspore development was used as a covariate in the analysis to compare cultivars at a similar temperature. The low-temperature conditions in Year 4 identified cold-tolerant cultivars such as Hayayuki and HSC55 and susceptible cultivars such as Sasanishiki and Doongara. After low temperature conditions, spikelet sterility was negatively correlated with the number of engorged pollen grains, anther length, anther area, anther width, and stigma area. The number of engorged pollen grains and anther length were found to be facultative traits as their relationships with spikelet sterility were identified only after cold water exposure and did not exist under non-stressed conditions.