A soluble activin Type IIA receptor induces bone formation and improves skeletal integrity

Diseases that affect the regulation of bone turnover can lead to skeletal fragility and increased fracture risk. Members of the TGF-superfamily have been shown to be involved in the regulation of bone mass. Activin A, a TGF-� signaling ligand, is present at high levels in bone and may play a role in the regulation of bone metabolism. Here we demonstrate that pharmacological blockade of ligand signaling through the high affinity receptor for activin, type II activin receptor (ActRIIA), by administration of the soluble extracellular domain of ActRIIA fused to a murine IgG2a-Fc, increases bone formation, bone mass, and bone strength in normal mice and in ovariectomized mice with established bone loss. These observations support the development of this pharmacological strategy for the treatment of diseases with skeletal fragility.

The alcohol culture of mature-aged women : similarities and differences across borders

Introduction: Relatively few attempts have been made to describe and understand women’s alcohol consumption beyond adolescence and young adulthood. In particular, there has been a lack of studies focusing on the alcohol culture that surrounds and guides mature-aged women’s drinking. As part of a larger cross-national comparison, the present study sought to address this gap by identifying the shared beliefs and values that impact on drinking outcomes among mature-aged women in Sweden and Australia. Method: The study was guided by an ethnographic methodology. To generate data, a series of semi-structured interview were conducted with 17 Australian (age = 45-57 years; M = 52.1, SD = 3.9) and 19 Swedish (age = 45-58 years; M = 52.2, SD = 4.8) women. All interviews were transcribed verbatim and thematically analysed. Results: With age, the focus of alcohol as a single purpose vehicle for intoxication had given way to a focus on the enjoyment and ritual of drinking itself; taste had become increasingly important and alcohol was strongly associated with pleasurable environments and experiences. The view of alcohol as a taste experience was particularly pronounced among the Swedish women, with alcohol (most commonly wine) often seen as inseparable from food. Among the Swedish women, this view of alcohol was also associated with a strong de-emphasis of the pharmacological effects of alcohol. In contrast, several Australian women understood and used alcohol as relief for anxiety and stress. Moderate drinking was linked to the social construction of both age and gender in the two samples, while heavy or abusive alcohol consumption was associated with strong proscriptive norms and stigma. Conclusions: Australian and Swedish women share a number of beliefs and values around alcohol, however, these findings also show unique country-level differences. Implications for drinking outcomes are discussed.

Modeling of protein signaling networks in clinical proteomics

Molecular interactions that underlie pathophysiological states are being elucidated using techniques that profile proteomicend points in cellular systems. Within the field of cancer research, protein interaction networks play pivotal roles in the establishment and maintenance of the hallmarks of malignancy, including cell division, invasion, and migration. Multiple complementary tools enable a multifaceted view of how signal protein pathway alterations contribute to pathophysiological states.One pivotal technique is signal pathway profiling of patient tissue specimens. This microanalysis technology provides a proteomic snapshot at one point in time of cells directly procured from the native context of a tumor micro environment. To study the adaptive patterns of signal pathway events over time, before and after experimental therapy, it is necessary to obtain biopsies from patients before, during, and after therapy. A complementary approach is the profiling of cultured cell lines with and without treatment. Cultured cell models provide the opportunity to study short-term signal changes occurring over minutes to hours. Through this type of system, the effects of particular pharmacological agents may be used to test the effects of signal pathway inhibition or activation on multiple endpoints within a pathway. The complexity of the data generated has necessitated the development of mathematical models for optimal interpretation of interrelated signaling pathways. In combination,clinical proteomic biopsy profiling, tissue culture proteomic profiling, and mathematical modeling synergistically enable a deeper understanding of how protein associations lead to disease states and present new insights into the design of therapeutic regimens.

A comparative study of Sr-incorporated mesoporous bioactive glass scaffolds for regeneration of osteopenic bone defects

SUMMARY: Recently, the use of the pharmacological agent strontium ranelate has come to prominence for the treatment of osteoporosis. While much investigation is focused on preventing disease progression, here we fabricate strontium-containing scaffolds and show that they enhance bone defect healing in the femurs of rats induced by ovariectomy. INTRODUCTION: Recently, the use of the pharmacological agent strontium ranelate has come to prominence for the treatment of osteoporosis due to its ability to prevent bone loss in osteoporotic patients. Although much emphasis has been placed on using pharmacological agents for the prevention of disease, much less attention has been placed on the construction of biomaterials following osteoporotic-related fracture. The aim of the present study was to incorporate bioactive strontium (Sr) trace element into mesoporous bioactive glass (MBG) scaffolds and to investigate their in vivo efficacy for bone defect healing in the femurs of rats induced by ovariectomy. METHODS: In total, 30 animals were divided into five groups as follows: (1) empty defect (control), (2) empty defects with estrogen replacement therapy, (3) defects filled with MBG scaffolds alone, (4) defects filled with MBG + estrogen replacement therapy, and (5) defects filled with strontium-incorporated mesopore-bioglass (Sr-MBG) scaffolds. RESULTS: The two groups demonstrating the highest levels of new bone formation were the defects treated with MBG + estrogen replacement therapy and the defects receiving Sr-MBG scaffolds as assessed by μ-CT and histological analysis. Furthermore, Sr scaffolds had a reduced number of tartrate-resistant acid phosphatase-positive cells when compared to other modalities. CONCLUSION: The results from the present study demonstrate that the local release of Sr from bone scaffolds may improve fracture repair. Future large animal models are necessary to investigate the future relationship of Sr incorporation into biomaterials.

Psychotropics and challenging behaviour in people with an intellectual disability

Hilmer and Gnjidic drew attention to the pharmacological management of behavioural problems in nursing home residents, and called for a reduction in inappropriate prescribing and the development of alternative management strategies.1 We extend these concerns to another vulnerable population — people with intellectual disability. Historically, this population is one of the most medicated groups in modern society.

5-HT(2B) receptors are required for serotonin-selective antidepressant actions

The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking the serotonin transporter and rely on long-term adaptations of pre- and post-synaptic receptors. We show here that long-term behavioral and neurogenic SSRI effects are abolished after either genetic or pharmacological inactivation of 5-HT(2B) receptors. Conversely, direct agonist stimulation of 5-HT(2B) receptors induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (i) this receptor is expressed by raphe serotonergic neurons, (ii) the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT(2B) receptors and (iii) a selective 5-HT(2B) agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT(2B) receptors. The 5-HT(2B) receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT(2B) receptor should be considered as a new tractable target in the combat against depression.

Do nursing students have the recall of bioscience necessary to study pharmacology?

Background: For medical and allied health students, bioscience knowledge underpins the successful scaffolding of learning in their developmental and advanced level units. Many of these students complete theory-based Bioscience units, followed by a unit in Pharmacology, which specifically requires knowledge of anatomy, physiology and microbiology. In general, studies of recall report relatively large losses over short retention intervals (months), which accumulate, but level off, for longer retention intervals (years) (Custers, 2010). However, there are no studies that specifically test the recall of bioscience knowledge by allied health students. Methods: We are tracking the recall of bioscience in nursing students prior to, and during, their Pharmacology unit. In each semester, students complete short, basic, knowledge-based MCQ quizzes on concepts from (i) the gastrointestinal system and (ii) fundamental microbiology. Students were given 5 days warning about the microbiology quizzes but were given no warning prior to the gastrointestinal system quiz. Performance in these quizzes was compared to individual student’s results in the final examination on these topics in the first semester of their degree. Results: At the start of the study, the nursing students performed better in the exam MCQs on the gastrointestinal system than on microbiology. In the exam, the students’ mean marks for the gastrointestinal system ranged from 69–83%, and this was successively reduced to 63%, 53% and 49% after 4, 9 and 16 months, respectively. The mean exam marks for microbiology was 48–58%, and this did not change significantly after 4 (63%), 9 (59%) or 16 months (47%). This suggests that warning the nursing students that they were to be quizzed on microbiology may have helped their recall. However, after 16 months regardless of the subject, the nursing students undertaking the Pharmacology unit recalled less than half of the bioscience quiz answers. Conclusions: Nursing students may not have the recall of bioscience necessary to study pharmacology, and this may limit their success in pharmacology. Reference: Custers, E. J. F. M. (2010). Long-term retention of basic science knowledge: a review study. Advances in Health Science Education, 15, 109–128.

A pseudo-marginal sequential Monte Carlo algorithm for random effects models in Bayesian sequential design

A computationally efficient sequential Monte Carlo algorithm is proposed for the sequential design of experiments for the collection of block data described by mixed effects models. The difficulty in applying a sequential Monte Carlo algorithm in such settings is the need to evaluate the observed data likelihood, which is typically intractable for all but linear Gaussian models. To overcome this difficulty, we propose to unbiasedly estimate the likelihood, and perform inference and make decisions based on an exact-approximate algorithm. Two estimates are proposed: using Quasi Monte Carlo methods and using the Laplace approximation with importance sampling. Both of these approaches can be computationally expensive, so we propose exploiting parallel computational architectures to ensure designs can be derived in a timely manner. We also extend our approach to allow for model uncertainty. This research is motivated by important pharmacological studies related to the treatment of critically ill patients.

The effects of exercise and adipose tissue lipolysis on plasma adiponectin concentration and adiponectin receptor expression in human skeletal muscle

Objective It has been suggested that adiponectin regulates plasma free fatty acid (FFA) clearance by stimulating FFA uptake and/or oxidation in muscle. We aimed to determine changes in plasma adiponectin concentration and adiponectin receptor 1 and 2 mRNA expression in skeletal muscle during and after prolonged exercise under normal, fasting conditions (high FFA trial; HFA) and following pharmacological inhibition of adipose tissue lipolysis (low FFA trial; LFA). Furthermore, we aimed to detect and locate adiponectin in skeletal muscle tissue. Methods Ten subjects performed two exercise trials (120 min at 50% VO2max). Indirect calorimetry was used to determine total fat oxidation rate. Plasma samples were collected at rest, during exercise and during post-exercise recovery to determine adiponectin, FFA and glycerol concentrations. Muscle biopsies were taken to determine adiponectin protein and adiponectin receptor 1 and 2 mRNA expression and to localise intramyocellular adiponectin. Results Basal plasma adiponectin concentrations averaged 6.57±0.7 and 6.63±0.8 mg/l in the HFA and LFA trials respectively, and did not change significantly during or after exercise. In the LFA trial, plasma FFA concentrations and total fat oxidation rates were substantially reduced. However, plasma adiponectin and muscle adiponectin receptor 1 and 2 mRNA expression did not differ between trials. Immunohistochemical staining of muscle cross-sections showed the presence of adiponectin in the sarcolemma of individual muscle fibres and within the interfibrillar arterioles. Conclusion Plasma adiponectin concentrations and adiponectin receptor 1 and 2 mRNA expression in muscle are not acutely regulated by changes in adipose tissue lipolysis and/or plasma FFA concentrations. Adiponectin is abundantly expressed in muscle, and, for the first time, it has been shown to be present in/on the sarcolemma of individual muscle fibres.

The effect of topical adrenergic and anticholinergic agents on the choroidal thickness of young healthy adults

The human choroid is capable of rapidly changing its thickness in response to a variety of stimuli. However little is known about the role of the autonomic nervous system in the regulation of the thickness of the choroid. Therefore, we investigated the effect of topical parasympatholytic and sympathomimetic agents upon the choroidal thickness and ocular biometrics of young healthy adult subjects. Fourteen subjects (mean age 27.9 ± 4 years) participated in this randomized, single-masked, placebo-controlled study. Each subject had measurements of choroidal thickness (ChT) and ocular biometrics of their right eye taken before, and then 30 and 60 min following the administration of topical pharmacological agents. Three different drugs: 2% homatropine hydrobromide, 2.5% phenylephrine hydrochloride and a placebo (0.3% hydroxypropyl methylcellulose) were tested in all subjects; each on different days (at the same time of the day) in randomized order. Participants were masked to the pharmacological agent being used at each testing session. The instillation of 2% homatropine resulted in a small but significant increase in subfoveal ChT at 30 and 60 min after drug instillation (mean change 7 ± 3 μm and 14 ± 2 μm respectively; both p < 0.0001). The parafoveal choroid also exhibited a similar magnitude, significant increase in thickness with time after 2% homatropine (p < 0.001), with a mean change of 7 ± 0.3 μm and 13 ± 1 μm (in the region located 0.5 mm from the fovea center), 6 ± 1 μm and 12.5 ± 1 μm (1 mm from the fovea center) and 6 ± 2 μm and 12 ± 2 μm (1.5 mm from the fovea center) after 30 and 60 min respectively. Axial length decreased significantly 60 min after homatropine (p < 0.01). There were also significant changes in lens thickness (LT) and anterior chamber depth (ACD) (p < 0.05) associated with homatropine instillation. No significant changes in choroidal thickness, or ocular biometrics were found after 2.5% phenylephrine or placebo at any examination points (p > 0.05). In human subjects, significant increases in subfoveal and parafoveal choroidal thickness occurred after administration of 2% homatropine and this implies an involvement of the parasympathetic system in the control of choroidal thickness in humans.

The fatty acid synthase inhibitor triclosan : repurposing an anti-microbial agent for targeting prostate cancer

Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non-malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer.

Understanding Pathophysiology - ANZ adaptation [1st edition.]

Pathophysiology is a complex, though essential, component of all undergraduate nursing courses and there is an identified need for a text tailored specifically for the Australian and New Zealand student. The entrenched bio-medical terminology can often be difficult to relate to nursing practice. To overcome this, the authors have presented pathophysiology in an accessible manner appropriate to undergraduate students, providing a balance between science, clinical case material and pharmacology. This adaptation prioritises the diseases relevant to nursing students and presents them according to their prevalence and rate of incidence in Australia and New Zealand. This focused approach prepares students for the presentations they will experience in a clinical setting. Each body system is explored first by structure and function, then by alteration.This establishes the physiology prior to addressing the diseases relative to the system and allows the student to analyse and compare the normal versus altered state. A lifespan approach is incorporated in the Alterations chapters, as each chapter addresses childhood diseases through to the aged with respect to each body system. A new section on Contemporary Health Issues examines the effects of an aging population and lifestyle choices on the overall health of our society. These are explored through specific chapters on Stress; Genes and the Environment; Obesity and Diabetes; Cancer; Mental Illness and Indigenous health issues. Concept maps are used to assist students to understand the basic concepts of each chapter and are used as a foundation for more complex discussions. Clinical case studies are also included in each chapter to bring pathophysiology into practice. Each patient case study will highlight relevant symptoms of a given disease within a clinical setting. This is analysed with respect to the relevancy of each given symptom, their respective affect on body systems and the best course of pharmacological treatment. This forthcoming textbook is an adaptation of Understanding Pathophysiology 4e by Huether & McCance. It builds on the strengths of the US edition while tailoring it to the specific needs of Australia and New Zealand undergraduate nursing students. As such it is an invaluable text which will compliment your suite of Elsevier nursing titles.

Primary and secondary neural networks of auditory prepulse inhibition: a functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle response

Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMGrecorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating.

Mice behaviorally selected for high Pavlovian fear memory exhibit fear generalization, HPA-axis alterations and increased basal activity in cortico-limbic circuits

Biological factors underlying individual variability in fearfulness and anxiety have important implications for stress-related psychiatric illness including PTSD and major depression. Using an advanced intercross line (AIL) derived from C57BL/6 and DBA/2J mouse strains and behavioral selection over 3 generations, we established two lines exhibiting High or Low fear behavior after fear conditioning. Across the selection generations, the two lines showed clear differences in training and tests for contextual and conditioned fear. Before fear conditioning training, there were no differences between lines in baseline freezing to a novel context. However, after fear conditioning High line mice demonstrated pronounced freezing in a new context suggestive of poor context discrimination. Fear generalization was not restricted to contextual fear. High fear mice froze to a novel acoustic stimulus while freezing in the Low line did not increase over baseline. Enhanced fear learning and generalization are consistent with transgenic and pharmacological disruption of the hypothalamic-pituitary-adrenal axis (HPA-axis) (Brinks, 2009, Thompson, 2004, Kaouane, 2012). To determine whether there were differences in HPA-axis regulation between the lines, morning urine samples were collected to measure basal corticosterone. Levels of secreted corticosterone in the circadian trough were analyzed by corticosterone ELISA. High fear mice were found to have higher basal corticosterone levels than low line animals. Examination of hormonal stress response components by qPCR revealed increased expression of CRH mRNA and decreased mRNA for MR and CRHR1 in hypothalamus of high fear mice. These alterations may contribute to both the behavioral phenotype and higher basal corticosterone in High fear mice. To determine basal brain activity in vivo in High and Low fear mice we used manganese-enhanced magnetic resonance imaging (MEMRI). Analysis revealed a pattern of basal brain activity made up of amygdala, cortical and hippocampal circuits that was elevated in the High line. Ongoing studies also seek to determine the relative balance of excitatory and inhibitory tone in the amygdala and hippocampus and the neuronal structure of its neurons. While these heterogeneous lines are selected on fear memory expression, HPA-axis alterations and differences in hippocampal activity segregate with the behavioral phenotypes. These differences are detectable in a basal state strongly suggesting these are biological traits underlying the behavioral phenotype (Johnson et al, 2011).