McArdle disease: a unique study model in sports medicine

McArdle disease is arguably the paradigm of exercise intolerance in humans. This disorder is caused by inherited deficiency of myophosphorylase, the enzyme isoform that initiates glycogen breakdown in skeletal muscles. Because patients are unable to obtain energy from their muscle glycogen stores, this disease provides an interesting model of study for exercise physiologists, allowing insight to be gained into the understanding of glycogen-dependent muscle functions. Of special interest in the field of muscle physiology and sports medicine are also some specific (if not unique) characteristics of this disorder, such as the so-called 'second wind' phenomenon, the frequent exercise-induced rhabdomyolysis and myoglobinuria episodes suffered by patients (with muscle damage also occurring under basal conditions), or the early appearance of fatigue and contractures, among others. In this article we review the main pathophysiological features of this disorder leading to exercise intolerance as well as the currently available therapeutic possibilities.

‘Complementary & alternative medicine’ (CAM): ethical and policy issues

Editorial for Bioethics 2016. 30:(2)

The reproductive biology of the exploited razor clam, Ensis siliqua, in the Irish Sea

Knowledge of the reproductive cycle of a species is a prerequisite for sustainable management of a fishery. The infaunal marine bivalve, Ensis siliqua, is a commercially important species in Europe, and is exploited in many countries, including Ireland, where it is sold by wet weight. Seasonal variations in the reproductive cycle of subtidal razor clams from the Skerries region of the Irish Sea, an important fisheries area, were examined between June 2010 and September 2011 while monitoring weight. Histological examination revealed that the E. siliqua sex-ratio was not different from parity, and no hermaphrodites were observed in the samples collected. In the summer months of 2010 all female clams were either spent or in early development, with just a small percentage of males still spawning. The gonads of both sexes developed over the autumn and winter months of 2010, with the first spawning individuals recorded in January 2011. Spawning peaked in March 2011, but unlike in 2010, spawning continued through June and July with all animals spent in August 2011. The earlier and longer spawning period found in this species in 2011 compared to 2010 may have been due to the colder than normal temperature observed during the winter of 2010 plus the relatively warmer temperatures of Spring 2011, which could have affected the gametogenic development of E. siliqua in the Irish Sea. It was noted that wet weight dropped in the summer months of both years, immediately after the spawning period which may impact on the practicality of fishing for this species during this period. Timing of development and spawning is compared with other sites in the Irish Sea and elsewhere in Europe, including the Iberian Peninsula.

The reproductive biology of the soft shell clam Mya arenaria in Ireland and the possible impacts of climate variability

Little is known about the biology of the softshell clam in Europe, despite it being identified as a potential species to culture for food in the future. Monthly samples of the softshell clam, Mya arenaria, were collected intertidally from Co. Wexford, Ireland, over a period of sixteen months. The mean weight of sampled individuals was 7 4 ± 4 . 9  g and mean length was 8 . 2 ± 0 . 2  cm. Histological examination revealed a female-to-male ratio of 1 : 1.15. In 2010, M. arenaria at this site matured over the summer months, with both sexes either ripe or spawning by August. A single spawning event was recorded in 2010, completed by November. Two unusually cold winters, followed by a warmer-than-average spring, appear to have affected M. arenaria gametogenesis in this area, potentially affecting the time of spawning, fertilisation success, and recruitment of this species. No hermaphrodites were observed in the samples collected, nor were any pathogens observed. Timing of development and spawning is compared with the coasts of eastern North America and with other European coasts.

Career choice in medicine

Background: Career Choice in Medicine is an important and problematic topic. Medical education has been framed as professional identity development, yet career choice has not been viewed as a matter of identity. My primary aim was to offer new insights by exploring career choice using Figured Worlds theory, a socio-cultural theory of identity. Graduate retention is a challenge for many countries, including Ireland. My secondary aim was to address a gap in the data on postgraduate trainees in Ireland and to use the Irish case to illustrate points transferable to other contexts. Methodology & Methods: This was a predominantly qualitative Mixed Methods programme of research. My qualitative studies were oriented towards social constructionism. I collated existing data from the Royal College of Physicians of Ireland (RCPI) and HSE-MET to describe trainees and their career paths. I surveyed Basic Specialist Training trainees (n=333) about their career plans. I surveyed new trainees (n=527) about their expectations of training and all RCPI trainees about their experiences of training (n=1246). I conducted semi-structured interviews with 18 medical students and doctors. A subgroup (n=6) provided longitudinal data. Figured Worlds theory and Gee’s discourse tools were used for analysis. Results: I have used the case of medical training and career choice in Ireland to explain how social, political and cultural context, and day to day experiences in the cultural world of medicine, shaped doctors’ career choices. My qualitative findings described a unifying model of career choice, consisting of priming, exposure, positioning and open-endedness, which can guide the design of interventions to shape and support career choice. Conclusion: My original contribution has been to demonstrate the fruitfulness of framing career choice in terms of identity development. This represents a turn in the conversation about career choice, which brings new starting points and moves the dialogue forward.

Significant reproductive skew in the facultatively polygynous ant Pheidole pallidula

Reproductive skew - the extent to which reproduction is unevenly shared between individuals in a social group - varies greatly between and within animal species. In this study, we investigated how queens share parentage in polygynous (multiple queen) colonies of the Mediterranean ant Pheidole pallidula. We used highly polymorphic microsatellites markers to determine parentage of gynes (new queens), males and workers in P. pallidula field colonies. The comparison of the genotypes of young and adult workers revealed a very low queen turnover (less than 2%). The first main finding of the study of reproductive skew in these colonies was that there was a significant departure from equal contribution of queens to gyne, male and worker production. Reproductive skew was greater for male production than for queen and worker production. There was no relationship between the magnitude of the reproductive skew and the number of reproductive queens per colony, their relatedness and the overall colony productivity, some of the factors predicted to influence the extent of reproductive skew. Finally, our study revealed for the first time a trade-off in the relative contribution of nestmate queens to gyne and worker production. The queens contributing more to gyne production contributed significantly less to worker production.

A strategy to advance the evidence base in palliative medicine: formation of a palliative care research cooperative group.

BACKGROUND: Palliative medicine has made rapid progress in establishing its scientific and clinical legitimacy, yet the evidence base to support clinical practice remains deficient in both the quantity and quality of published studies. Historically, the conduct of research in palliative care populations has been impeded by multiple barriers including health care system fragmentation, small number and size of potential sites for recruitment, vulnerability of the population, perceptions of inappropriateness, ethical concerns, and gate-keeping. METHODS: A group of experienced investigators with backgrounds in palliative care research convened to consider developing a research cooperative group as a mechanism for generating high-quality evidence on prioritized, clinically relevant topics in palliative care. RESULTS: The resulting Palliative Care Research Cooperative (PCRC) agreed on a set of core principles: active, interdisciplinary membership; commitment to shared research purposes; heterogeneity of participating sites; development of research capacity in participating sites; standardization of methodologies, such as consenting and data collection/management; agile response to research requests from government, industry, and investigators; focus on translation; education and training of future palliative care researchers; actionable results that can inform clinical practice and policy. Consensus was achieved on a first collaborative study, a randomized clinical trial of statin discontinuation versus continuation in patients with a prognosis of less than 6 months who are taking statins for primary or secondary prevention. This article describes the formation of the PCRC, highlighting processes and decisions taken to optimize the cooperative group's success.

Effects of Aging and Moderate Calorie Restriction on the Reproductive Axis of the Male Rhesus Macaque (Macaca mulatta)

Calorie restriction (CR) has been established as the only non-genetic method of altering longevity and attenuating biological changes associated with aging. This nutritional paradigm has been effective in nematodes, flies, rodents, dogs and possibly non-human primates. Its long history notwithstanding, little is known regarding the exact mechanism(s) of CR action or its potential impact on the hypothalamic-pituitary-gonadal (HPG) axis. The objectives of this project were to: 1) analyze neuroendocrine changes to the HPG axis that occur with aging and 2) evaluate the effects of moderate CR on reproductive function in male rhesus macaques. Pituitary gene expression profiling, semi-quantitative RT-PCR (sqRT-PCR) and immunohistochemistry showed circadian clock mechanism components present in three age categories of macaques, demonstrated age differences in expression for Per2, indicated differential expression of Per2 and Bmal1 at opposing time points and revealed daily rhythmic expression of REV-ERBα protein. These data indicate the ability of the macaque pituitary to express core-clock genes, their protein products, and to do so in a 24-hour rhythm. Young Adult CON and CR pituitary gene expression profiles detected potential differential expression in <150 probesets. A decline in>TSHR and CGA was detected in CR macaques as measured by sqRT-PCR. Other genes investigated showed no diet-induced changes. Young Adult CON and CR testicular gene expression profiles detected potential differential expression in <300 probesets although mRNA expression was not altered based on sqRT-PCR and real-time RT-PCR. Age-related>and/or diet-induced changes in HSD17β3, INSL3, CSNK1E and CGA were observed in a separate experiment with CGA in Old Adult CR subjects returning to youthful levels. Semen samples were collected from Young Adult CON and CR macaques. Normal spermiogram measures, ZP-binding, AR assay and SCSA^® were conducted and indicated no differences between CON and CR-treated animals. Both groups exhibited similar daily testosterone profiles with no differences in mean or maximum levels; however, daily minimum testosterone levels were lower in CON animals. It appears that moderate CR had limited impact on neuroendocrine or reproductive function in male rhesus macaques based on our selected endpoints. Thus, advantageous CR health benefits can be achieved without obvious negative consequences to the HPG axis.

A widespread chromosomal inversion polymorphism contributes to a major life-history transition, local adaptation, and reproductive isolation.

The role of chromosomal inversions in adaptation and speciation is controversial. Historically, inversions were thought to contribute to these processes either by directly causing hybrid sterility or by facilitating the maintenance of co-adapted gene complexes. Because inversions suppress recombination when heterozygous, a recently proposed local adaptation mechanism predicts that they will spread if they capture alleles at multiple loci involved in divergent adaptation to contrasting environments. Many empirical studies have found inversion polymorphisms linked to putatively adaptive phenotypes or distributed along environmental clines. However, direct involvement of an inversion in local adaptation and consequent ecological reproductive isolation has not to our knowledge been demonstrated in nature. In this study, we discovered that a chromosomal inversion polymorphism is geographically widespread, and we test the extent to which it contributes to adaptation and reproductive isolation under natural field conditions. Replicated crosses between the prezygotically reproductively isolated annual and perennial ecotypes of the yellow monkeyflower, Mimulus guttatus, revealed that alternative chromosomal inversion arrangements are associated with life-history divergence over thousands of kilometers across North America. The inversion polymorphism affected adaptive flowering time divergence and other morphological traits in all replicated crosses between four pairs of annual and perennial populations. To determine if the inversion contributes to adaptation and reproductive isolation in natural populations, we conducted a novel reciprocal transplant experiment involving outbred lines, where alternative arrangements of the inversion were reciprocally introgressed into the genetic backgrounds of each ecotype. Our results demonstrate for the first time in nature the contribution of an inversion to adaptation, an annual/perennial life-history shift, and multiple reproductive isolating barriers. These results are consistent with the local adaptation mechanism being responsible for the distribution of the two inversion arrangements across the geographic range of M. guttatus and that locally adaptive inversion effects contribute directly to reproductive isolation. Such a mechanism may be partially responsible for the observation that closely related species often differ by multiple chromosomal rearrangements.

Love is in the air: Sociality and pair bondedness influence sifaka reproductive signalling

© 2013 The Association for the Study of Animal Behaviour.Social complexity, often estimated by group size, is seen as driving the complexity of vocal signals, but its relation to olfactory signals, which arguably arose to function in nonsocial realms, remains underappreciated. That olfactory signals also may mediate within-group interaction, vary with social complexity and promote social cohesion underscores a potentially crucial link with sociality. To examine that link, we integrated chemical and behavioural analyses to ask whether olfactory signals facilitate reproductive coordination in a strepsirrhine primate, the Coquerel's sifaka, Propithecus coquereli. Belonging to a clade comprising primarily solitary, nocturnal species, the diurnal, group-living sifaka represents an interesting test case. Convergent with diurnal, group-living lemurids, sifakas expressed chemically rich scent signals, consistent with the social complexity hypothesis for communication. These signals minimally encoded the sex of the signaller and varied with female reproductive state. Likewise, sex and female fertility were reflected in within-group scent investigation, scent marking and overmarking. We further asked whether, within breeding pairs, the stability or quality of the pair's bond influences the composition of glandular signals and patterns of investigatory or scent-marking behaviour. Indeed, reproductively successful pairs tended to show greater similarity in their scent signals than did reproductively unsuccessful pairs, potentially through chemical convergence. Moreover, scent marking was temporally coordinated within breeding pairs and was influenced by past reproductive success. That olfactory signalling reflects social bondedness or reproductive history lends support to recent suggestions that the quality of relationships may be a more valuable proxy than group size for estimating social complexity. We suggest that olfactory signalling in sifakas is more complex than previously recognized and, as in other socially integrated species, can be a crucial mechanism for promoting group cohesion and maintaining social bonds. Thus, the evolution of sociality may well be reflected in the complexity of olfactory signalling.

Explanatory Model for the Use of Traditional Medicines in Kilimanjaro, Tanzania

Introduction: Traditional medicines are one of the most important means of achieving total health care coverage globally, and their importance in Tanzania extends beyond the impoverished rural areas. Their use remains high even in urban settings among the educated middle and upper classes. They are a critical component healthcare in Tanzania, but they also can have harmful side effects. Therefore we sought to understand the decision-making and reasoning processes by building an explanatory model for the use of traditional medicines in Tanzania.

Methods: We conducted a mixed-methods study between December 2013 and June 2014 in the Kilimanjaro Region of Tanzania. Using purposive sampling methods, we conducted focus group discussions (FGDs) and in-depth interviews of key informants, and the qualitative data were analyzed using an inductive Framework Method. A structured survey was created, piloted, and then administered it to a random sample of adults. We reported upon the reliability and validity of the structured survey, and we used triangulation from multiple sources to synthesize the qualitative and quantitative data.

Results: A total of five FGDs composed of 59 participants and 27 in-depth interviews were conducted in total. 16 of the in-depth interviews were with self-described traditional practitioners or herbal vendors. We identified five major thematic categories that relate to the decision to use traditional medicines in Kilimanjaro: healthcare delivery, disease understanding, credibility of the traditional practices, health status, and strong cultural beliefs.

A total of 473 participants (24.1% male) completed the structured survey. The most common reasons for taking traditional medicines were that they are more affordable (14%, 12.0-16.0), failure of hospital medicines (13%, 11.1-15.0), they work better (12%, 10.7-14.4), they are easier

to obtain (11%, 9.48-13.1), they are found naturally or free (8%, 6.56-9.68), hospital medicines have too many chemical (8%, 6.33-9.40), and they have fewer side effects (8%, 6.25-9.30). The most common uses of traditional medicines were for symptomatic conditions (42%), chronic diseases (14%), reproductive problems (11%), and malaria and febrile illnesses (10%). Participants currently taking hospital medicines for chronic conditions were nearly twice as likely to report traditional medicines usage in the past year (RR 1.97, p=0.05).

Conclusions: We built broad explanatory model for the use of traditional medicines in Kilimanjaro. The use of traditional medicines is not limited to rural or low socioeconomic populations and concurrent use of traditional medicines and biomedicine is high with frequent ethnomedical doctor shopping. Our model provides a working framework for understanding the complex interactions between biomedicine and traditional medicine. Future disease management and treatment programs will benefit from this understanding, and it can lead to synergistic policies with more effective implementation.

Mechanosensitive neurons on the internal reproductive tract contribute to egg-laying-induced acetic acid attraction in Drosophila.

Selecting a suitable site to deposit their eggs is an important reproductive need of Drosophila females. Although their choosiness toward egg-laying sites is well documented, the specific neural mechanism that activates females' search for attractive egg-laying sites is not known. Here, we show that distention and contraction of females' internal reproductive tract triggered by egg delivery through the tract plays a critical role in activating such search. We found that females start to exhibit acetic acid (AA) attraction prior to depositing each egg but no attraction when they are not laying eggs. Artificially distending the reproductive tract triggers AA attraction in non-egg-laying females, whereas silencing the mechanosensitive neurons we identified that can sense the contractile status of the tract eliminates such attraction. Our work uncovers the circuit basis of an important reproductive need of Drosophila females and provides a simple model for dissecting the neural mechanism that underlies a reproductive need-induced behavioral modification.

The IGNITE network: a model for genomic medicine implementation and research.

BACKGROUND: Patients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility. METHODS: To address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.ignite-genomics.org ) Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches. RESULTS: This paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years. CONCLUSIONS: The IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.