A systematic review of the safety of lisdexamfetamine dimesylate

BACKGROUND: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). RESULTS: In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. CONCLUSIONS: The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants

Incidentalomas during imaging for primary hyperparathyroidism—incidence and clinical outcomes

Background: Imaging for pre-operative localisation of parathyroid glands in primary hyperparathyroidism is now routine. This has led to the detection of incidental lesions (incidentalomas) in other organs, the nature of which is not well characterised. The aim of this study was to determine the incidence, characteristics and outcomes in patients who had incidental findings on parathyroid imaging. Methods: Records of patients who underwent imaging for primary hyperparathyroidism over 2 years were reviewed to identify incidental lesions detected on parathyroid imaging. Patients with persistent or renal hyperparathyroidism were excluded. Details on the management of detected incidentalomas were obtained from patient records. Results: Incidentalomas were identified in 17 of 170 patients (10 %) undergoing parathyroid imaging. Incidentalomas included thyroid (n = 11), breast (n = 3), lateral compartment of the neck (n = 1), lung (n = 1) and clavicle (n = 1). However, no disease of clinical significance needing treatment was detected on further investigation. Conclusions: Although a significant proportion of patients undergoing parathyroid imaging had incidental lesions detected, these seem to be of little clinical significance. The morbidity and cost of further interventions on these incidentalomas need to be weighed against the benefits of routine imaging in improving outcomes of first-time surgery in patients with primary hyperparathyroidism. Keywords: Parathyroid gland, Primary hyperparathyroidism, Imaging, Incidentaloma

NETIMIS: Dynamic Simulation of Health Economics Outcomes Using Big Data

Many healthcare organizations are now making good use of electronic health record (EHR) systems to record clinical information about their patients and the details of their healthcare. Electronic data in EHRs is generated by people engaged in complex processes within complex environments, and their human input, albeit shaped by computer systems, is compromised by many human factors. These data are potentially valuable to health economists and outcomes researchers but are sufficiently large and complex enough to be considered part of the new frontier of ‘big data’. This paper describes emerging methods that draw together data mining, process modelling, activity-based costing and dynamic simulation models. Our research infrastructure includes safe links to Leeds hospital’s EHRs with 3 million secondary and tertiary care patients. We created a multidisciplinary team of health economists, clinical specialists, and data and computer scientists, and developed a dynamic simulation tool called NETIMIS (Network Tools for Intervention Modelling with Intelligent Simulation; http://www.netimis.com) suitable for visualization of both human-designed and data-mined processes which can then be used for ‘what-if’ analysis by stakeholders interested in costing, designing and evaluating healthcare interventions. We present two examples of model development to illustrate how dynamic simulation can be informed by big data from an EHR. We found the tool provided a focal point for multidisciplinary team work to help them iteratively and collaboratively ‘deep dive’ into big data

Brain activation of the defensive and appetitive survival systems in obsessive compulsive disorder

Several studies have shown that basic emotions are responsible for a significant enhancement of early visual processes and increased activation in visual processing brain regions. It may be possible that the cognitive uncertainty and repeated behavioral checking evident in Obsessive Compulsive Disorder (OCD) is due to the existence of abnormalities in basic survival circuits, particularly those associated with the visual processing of the physical characteristics of emotional-laden stimuli. The objective of the present study was to test if patients with OCD show evidence of altered basic survival circuits, particularly those associated with the visual processing of the physical characteristics of emotional stimuli. Fifteen patients with OCD and 12 healthy controls underwent functional magnetic resonance imaging acquisition while being exposed to emotional pictures, with different levels of arousal, intended to trigger the defensive and appetitive basic survival circuits. Overall, the present results seem to indicate dissociation in the activity of the defense and appetitive survival systems in OCD. Results suggest that the clinical group reacts to basic threat with a strong activation of the defensive system mobilizing widespread brain networks (i.e., frontal, temporal, occipital-parietal, and subcortical nucleus) and blocking the activation of the appetitive system when facing positive emotional triggers from the initial stages of visual processing (i.e., superior occipital gyrus)

Detection of changes in gene regulatory patterns, elicited by perturbations of the Hsp90 molecular chaperone complex, by visualizing multiple experiments with an animation

<p>Abstract</p> <p>Background</p> <p>To make sense out of gene expression profiles, such analyses must be pushed beyond the mere listing of affected genes. For example, if a group of genes persistently display similar changes in expression levels under particular experimental conditions, and the proteins encoded by these genes interact and function in the same cellular compartments, this could be taken as very strong indicators for co-regulated protein complexes. One of the key requirements is having appropriate tools to detect such regulatory patterns.</p> <p>Results</p> <p>We have analyzed the global adaptations in gene expression patterns in the budding yeast when the Hsp90 molecular chaperone complex is perturbed either pharmacologically or genetically. We integrated these results with publicly accessible expression, protein-protein interaction and intracellular localization data. But most importantly, all experimental conditions were simultaneously and dynamically visualized with an animation. This critically facilitated the detection of patterns of gene expression changes that suggested underlying regulatory networks that a standard analysis by pairwise comparison and clustering could not have revealed.</p> <p>Conclusions</p> <p>The results of the animation-assisted detection of changes in gene regulatory patterns make predictions about the potential roles of Hsp90 and its co-chaperone p23 in regulating whole sets of genes. The simultaneous dynamic visualization of microarray experiments, represented in networks built by integrating one's own experimental with publicly accessible data, represents a powerful discovery tool that allows the generation of new interpretations and hypotheses.</p

A novel role for RecA under non-stress: promotion of swarming motility in Escherichia coli K-12

BACKGROUND: Bacterial motility is a crucial factor in the colonization of natural environments. Escherichia coli has two flagella-driven motility types: swimming and swarming. Swimming motility consists of individual cell movement in liquid medium or soft semisolid agar, whereas swarming is a coordinated cellular behaviour leading to a collective movement on semisolid surfaces. It is known that swimming motility can be influenced by several types of environmental stress. In nature, environmentally induced DNA damage (e.g. UV irradiation) is one of the most common types of stress. One of the key proteins involved in the response to DNA damage is RecA, a multifunctional protein required for maintaining genome integrity and the generation of genetic variation. RESULTS: The ability of E. coli cells to develop swarming migration on semisolid surfaces was suppressed in the absence of RecA. However, swimming motility was not affected. The swarming defect of a ΔrecA strain was fully complemented by a plasmid-borne recA gene. Although the ΔrecA cells grown on semisolidsurfaces exhibited flagellar production, they also presented impaired individual movement as well as a fully inactive collective swarming migration. Both the comparative analysis of gene expression profiles in wild-type and ΔrecA cells grown on a semisolid surface and the motility of lexA1 [Ind-] mutant cells demonstrated that the RecA effect on swarming does not require induction of the SOS response. By using a RecA-GFP fusion protein we were able to segregate the effect of RecA on swarming from its other functions. This protein fusion failed to regulate the induction of the SOS response, the recombinational DNA repair of UV-treated cells and the genetic recombination, however, it was efficient in rescuing the swarming motility defect of the ΔrecA mutant. The RecA-GFP protein retains a residual ssDNA-dependent ATPase activity but does not perform DNA strand exchange. CONCLUSION: The experimental evidence presented in this work supports a novel role for RecA: the promotion of swarming motility. The defective swarming migration of ΔrecA cells does not appear to be associated with defective flagellar production; rather, it seems to be associated with an abnormal flagellar propulsion function. Our results strongly suggest that the RecA effect on swarming motility does not require an extensive canonical RecA nucleofilament formation. RecA is the first reported cellular factor specifically affecting swarming but not swimming motility in E. coli. The integration of two apparently disconnected biologically important processes, such as the maintenance of genome integrity and motility in a unique protein, may have important evolutive consequences

Delayed and Accelerated Aging Share Common Longevity Assurance Mechanisms

Mutant dwarf and calorie-restricted mice benefit from healthy aging and unusually long lifespan. In contrast, mouse models for DNA repair-deficient progeroid syndromes age and die prematurely. To identify mechanisms that regulate mammalian longevity, we quantified the parallels between the genome-wide liver expression profiles of mice with those two extremes of lifespan. Contrary to expectation, we find significant, genome-wide expression associations between the progeroid and long-lived mice. Subsequent analysis of significantly over-represented biological processes revealed suppression of the endocrine and energy pathways with increased stress responses in both delayed and premature aging. To test the relevance of these processes in natural aging, we compared the transcriptomes of liver, lung, kidney, and spleen over the entire murine adult lifespan and subsequently confirmed these findings on an independent aging cohort. The majority of genes showed similar expression changes in all four organs, indicating a systemic transcriptional response with aging. This systemic response included the same biological processes that are triggered in progeroid and long-lived mice. However, on a genome-wide scale, transcriptomes of naturally aged mice showed a strong association to progeroid but not to long-lived mice. Thus, endocrine and metabolic changes are indicative of “survival” responses to genotoxic stress or starvation, whereas genome-wide associations in gene expression with natural aging are indicative of biological age, which may thus delineate pro- and anti-aging effects of treatments aimed at health-span extension

Curcumin activates the p38MPAK-HSP25 pathway in vitro but fails to attenuate diabetic nephropathy in DBA2J mice despite urinary clearance documented by HPLC

<p>Abstract</p> <p>Background</p> <p>Curcumin has anti-inflammatory, anti-oxidant, and anti-proliferative properties, and depending upon the experimental circumstances, may be pro- or anti-apoptotic. Many of these biological actions could ameliorate diabetic nephropathy.</p> <p>Methods/Design</p> <p>Mouse podocytes, cultured in basal or high glucose conditions, underwent acute exposure to curcumin. Western blots for p38-MAPK, COX-2 and cleaved caspase-3; isoelectric focusing for HSP25 phosphorylation; and DNase I assays for F- to G- actin cleavage were performed for <it>in vitro </it>analyses. <it>In vivo </it>studies examined the effects of dietary curcumin on the development of diabetic nephropathy in streptozotocin (Stz)-induced diabetes in DBA2J mice. Urinary albumin to creatinine ratios were obtained, high performance liquid chromatography was performed for urinary curcuminoid measurements, and Western blots for p38-MAPK and total HSP25 were performed.</p> <p>Results</p> <p>Curcumin enhanced the phosphorylation of both p38MAPK and downstream HSP25; inhibited COX-2; induced a trend towards attenuation of F- to G-actin cleavage; and dramatically inhibited the activation of caspase-3 in <it>vitro</it>. In curcumin-treated DBA2J mice with Stz-diabetes, HPLC measurements confirmed the presence of urinary curcuminoid. Nevertheless, dietary provision of curcumin either before or after the induction of diabetes failed to attenuate albuminuria.</p> <p>Conclusions</p> <p>Apart from species, strain, early differences in glycemic control, and/or dosing effects, the failure to modulate albuminuria may have been due to a decrement in renal HSP25 or stimulation of the 12/15 lipoxygenase pathway in DBA2J mice fed curcumin. In addition, these studies suggest that timed urine collections may be useful for monitoring curcumin dosing and renal pharmacodynamic effects.</p

Phenotypic characterisation of regulatory T cells in dogs reveals signature transcripts conserved in humans and mice

Regulatory T cells (Tregs) are a double-edged regulator of the immune system. Aberrations of Tregs correlate with pathogenesis of inflammatory, autoimmune and neoplastic disorders. Phenotypically and functionally distinct subsets of Tregs have been identified in humans and mice on the basis of their extensive portfolios of monoclonal antibodies (mAb) against Treg surface antigens. As an important veterinary species, dogs are increasingly recognised as an excellent model for many human diseases. However, insightful study of canine Tregs has been restrained by the limited availability of mAb. We therefore set out to characterise CD4+CD25high T cells isolated ex vivo from healthy dogs and showed that they possess a regulatory phenotype, function, and transcriptomic signature that resembles those of human and murine Tregs. By launching a cross-species comparison, we unveiled a conserved transcriptomic signature of Tregs and identified that transcript hip1 may have implications in Treg function