Why are there no proven therapies for genetic mitochondrial diseases?

Although mitochondrial disease research in general is robust, adequate treatment of these life-threatening conditions has lagged, partly because of a persistence of clinical anecdotes as substitutes for scientifically and ethically rigorous clinical trials. Here I summarize the key lessons learned from some of the “first generation” of randomized controlled trials for genetic mitochondrial diseases and suggest how future trials may benefit from both past experience and exciting new resources available for patient-oriented research and training in this field.     

Why is revitalizing clinical research so important, yet so difficult?

We believe that support for academic clinical research has greatly declined in recent decades. Here we discuss our views on why this has happened. We define clinical or patient-oriented research as limited to the study of human beings or populations of individuals, and argue that its eclipse in favor of basic and "translational" research is the result of inappropriate conceptual paradigms or "models" for medical advances. We believe that medical history shows that the "bench-to-bedside" model is inadequate to explain most recent progress and that clinical advances themselves often lead to new basic research. Discussion of alternate conceptual frameworks for biomedical research should help lead to changes in funding and organizational structures that might finally revitalize clinical research.     

The Rockefeller University Hospital (1910-2010): creating the science of medicine

The year 2010 marked the centennial of the Rockefeller University Hospital, one of the great philanthropic achievements of 20th-century science. For 100 years, the Hospital played a central role in the development and growth of medical science by enabling physician-scientists to make intensive study of human biology and disease. With ingenuity and devotion, they greatly enriched clinical medicine as well as basic biological science. This account emphasizes the founding and first half-century of the Hospital as it became a germinal center for clinical investigation. The second half of the century saw rapid change in medicine and health care with vexing problems, many yet unsolved. This history should serve as a call to arms for maintaining the linkage of science and medicine, supporting patient-oriented research as a basic discipline of medicine.     

The high level of nutritional niche overlap between red fox (<Emphasis Type="Italic">Vulpes vulpes</Emphasis>) and sympatric golden jackal (<Emphasis Type="Italic">Canis aureus</Emphasis>) affects the body weight of juvenile foxes

In the period of August 2013 to September 2015, we collected and measured the body weight of 246 red fox (Vulpes vulpes) carcasses collected during hunts. A portion of these red foxes (n = 153) was originally from habitats they shared with the golden jackal (Canis aureus), while the other portion (n = 93) had almost no contact with this species. We analyzed the body weight of red foxes from both areas according to age (adult-cub) as well as gender. We have found that the younger animals that live sympatrically with the golden jackal weigh less than those from the golden jackal-free territory regardless of gender. In the case of adult red foxes, the habitat-related differences between body weight were found to be insignificant. These results suggest that the high level of nutritional niche overlap between sympatric red fox and golden jackal could affect the body weight of juvenile red foxes.     

"Galton's Asset" and "Flower's Problem Cultural Networks and Cultural Units in Cross-Cultural Research Ml (Or, Male Genital Mutilations and Polygyny in Cross-Cultural Perspective)

Edward Tylor had envisioned anthropology to be comprised of ethnology and ethnography in equal parts, but today ethnography dominates the field. In this paper, we examine two reasons for the refugee status of ethnology. First, we look at the notorious "Galton effect." Second, we examine the problem of defining and using cultural units, particularly when positivistic and static theories and methods of culture have been largely discredited by anthropology. We argue against any formulaic solutions to these problems and show that for each research question one needs to reconsider the criteria for how to construct cultural units and how to ensure that the cultures under study are not merely replicas of one another. We show that previous solutions to these issues are limited because they fail to appreciate the contingent and multidimensional nature of culture. We also argue that, instead of a "Galton problem," there is actually a "Galton asset," which can be used to study historical and emergent communicative networks. [Keywords: cross–cultural research, Galton problem, cultural units, methods and theory]     

Inconsistencies in Quality of Life Data Collection in Clinical Trials: A Potential Source of Bias? Interviews with Research Nurses and Trialists

Background

Patient-reported outcomes (PROs), such as health-related quality of life (HRQL) are increasingly used to evaluate treatment effectiveness in clinical trials, are valued by patients, and may inform important decisions in the clinical setting. It is of concern, therefore, that preliminary evidence, gained from group discussions at UK-wide Medical Research Council (MRC) quality of life training days, suggests there are inconsistent standards of HRQL data collection in trials and appropriate training and education is often lacking. Our objective was to investigate these reports, to determine if they represented isolated experiences, or were indicative of a potentially wider problem.

Methods And Findings

We undertook a qualitative study, conducting 26 semi-structured interviews with research nurses, data managers, trial coordinators and research facilitators involved in the collection and entry of HRQL data in clinical trials, across one primary care NHS trust, two secondary care NHS trusts and two clinical trials units in the UK. We used conventional content analysis to analyze and interpret our data. Our study participants reported (1) inconsistent standards in HRQL measurement, both between, and within, trials, which appeared to risk the introduction of bias; (2), difficulties in dealing with HRQL data that raised concern for the well-being of the trial participant, which in some instances led to the delivery of non-protocol driven co-interventions, (3), a frequent lack of HRQL protocol content and appropriate training and education of trial staff, and (4) that HRQL data collection could be associated with emotional and/or ethical burden.

Conclusions

Our findings suggest there are inconsistencies in the standards of HRQL data collection in some trials resulting from a general lack of HRQL-specific protocol content, training and education. These inconsistencies could lead to biased HRQL trial results. Future research should aim to develop HRQL guidelines and training programmes aimed at supporting researchers to carry out high quality data collection.     

Dynamics of the history of photosynthesis research

A personal view of the history of progress in photosynthesis research beginning in the seventeenth century and ending in 1992 is presented in a chart form. The 350-year time span is divided arbitrarily into seven periods by the development junctures, which are likened to bamboo joints. The tempo of progress is reflected in the duration of the periods, starting from over 200 years for Period I, which progressively shortens in subsequent periods. This brief introduction highlights some of the events to show the dynamic nature of the progress in photosynthesis research.Professor emeritus of Okayama University, Okayama, Japan; correspondence address: Yokoi-kami, 507-66, Okayama City, Okayama, 701-11, Japan     

中国神经科学十年进程

为了迎接21世纪的挑战,推动我国神经科学基础研究的快速发展,中国科学院于1999年底在上海成立了中国科学院神经科学研究所(下简称上海神经所).经过十余年的发展,上海神经所取得了突出的成就,跻身国际水平研究所行列,为我国神经科学发展做出了重要贡献。     

Testosterone and endurance exercise: development of the "exercise-hypogonadal male condition"

During the last 30 years a large number of research studies have been conducted examining reproductive endocrine dysfunction in exercising women. The number of similar studies examining men is still relatively small. Nevertheless, an increasing amount of research studies in men indicate endurance exercise training has significant effects upon the major male reproductive hormone, testosterone, and the hypothalamic-pituitary-testicular axis that regulates reproductive hormones. This review article addresses one reproductive endocrine dysfunction found in exercising men, what has been deemed the "exercise-hypogonadal male condition". Specifically, men with this condition exhibit basal (resting-state) free and total testosterone levels that are significantly and persistently reduced. The exact physiological mechanism inducing the reduction of testosterone is currently unclear, but is postulated to be a dysfunction (or perhaps a readjustment) within the hypothalamic-pituitary-testicular regulatory axis. The time course for the development of the "exercise-hypogonadal condition" or the threshold of exercise training necessary to induce the condition remains unresolved. The potential exists for these reduced testosterone levels within the exercise-hypogonadal male to disrupt and be detrimental to some anabolic or androgenic testosterone-dependent physiological processes. Unfortunately, extremely few research studies have addressed whether such processes are affected, and thus findings are inconclusive. Conversely, the alterations in testosterone levels brought about by endurance exercise training have the potential for cardiovascular protective effects and thus could be beneficial to the health of these men. Current evidence suggests this condition is limited to men who have been persistently involved in chronic endurance exercise training for extended periods of time (i.e., years). Many questions, however, regarding the male reproductive endocrine adaptive process to exercise and exercise training remain unanswered, necessitating the need for further research on this topic.     

Statistical Use in Clinical Studies: Is There Evidence of a Methodological Shift?

Background

Several studies indicate that the statistical education model and level in medical training fails to meet the demands of clinicians, especially when they want to understand published clinical research. We investigated how study designs and statistical methods in clinical studies have changed in the last twenty years, and we identified the current trends in study designs and statistical methods in clinical studies.

Methods

We reviewed 838 eligible clinical study articles that were published in 1990, 2000, and 2010 in four journals New England Journal of Medicine, Lancet, Journal of the American Medical Association and Nature Medicine. The study types, study designs, sample designs, data quality controls, statistical methods and statistical software were examined.

Results

Substantial changes occurred in the past twenty years. The majority of the studies focused on drug trials (61.6%, n = 516). In 1990, 2000, and 2010, there was an incremental increase in RCT studies (74.4%, 82.8%, and 84.0%, respectively, p = 0.013). Over time, there was increased attention on the details of selecting a sample and controlling bias, and there was a higher frequency of utilizing complex statistical methods. In 2010, the most common statistical methods were confidence interval for superiority and non-inferiority comparison (41.6%), survival analysis (28.5%), correction analysis for covariates (18.8%) and Logistic regression (15.3%).

Conclusions

These findings indicate that statistical measures in clinical studies are continuously developing and that the credibility of clinical study results is increasing. These findings provide information for future changes in statistical training in medical education.     

Coming changes in accepted wisdom about "osteoporosis"

Here a voice from the past suggests 28 changes that will affect how people study, manage, classify and think about "osteoporoses" today. Those changes depend mainly on two things: (i) "Connecting the dots" between diverse evidence and ideas from many fields and sources in order to find larger "messages" hidden in mountains of often poorly-organized lesser details, (ii) and features of the still-evolving Utah paradigm of skeletal physiology. That paradigm sums contributions from many people who worked in many fields for over 100 years. In one view it is the most important development in skeletal physiology since Rudolf Virchow and others realized approximately 150 years ago that cells provide the basis for human physiology and diseases. This article emphasizes the above messages instead of the details. The messages affect ideas about the nature, pathogenesis, diagnosis, classification, study and management of osteopenias and osteoporoses, as well as some roles of muscle, drugs, hormones, other agents and fatigue damage, in those disorders. Those larger messages also concern how to classify "osteoporosis fractures", how to define bone health, the choice of absorptiometric methods for noninvasive evaluations of bones, osteopenias and muscle strength, and new criteria for selecting patient cohorts for "risk-of-fracture" analyses and in searches for genetic roles in "osteoporoses". Finally, those larger messages identify many new targets for research that should prove unusually useful in clinical and pharmaceutical domains and work.     

Identification of reliable predictors of golden sun moth <Emphasis Type="Italic">Synemon plana</Emphasis> habitat over multiple survey years can benefit conservation,restoration and surveys for new populations

Native grasslands, and the fauna that inhabit them, are globally some of the most threatened ecosystems and organisms. Knowledge of the relative importance of climate, landscape context and site-based resources for local insect populations is critical for the restoration and conservation of these communities. We investigated the site and landscape-scale best predictors of occurrence and abundance over three consecutive years of sampling, for the critically endangered golden sun moth Synemon plana in south-eastern Australia. We found eight vegetation factors to be significantly associated with golden sun moth occurrence using data from combined survey data and data for each year alone; we identified just three common factors from year to year. Modelling indicated that Austrostipa and Rytidosperma species richness was the most consistent parameter, but for each year alone, there was a combination of aspect, landscape position and Austrostipa and Rytidosperma species richness. Our study shows that environmental characteristics where golden sun moth occur are relatively predictable over multiple years. This information can be used to protect sites where monitoring of extant populations is yet to occur, predict the location of new populations in the region, and restore adjacent habitat that is suitable but degraded.     

Molecular estimation of eulipotyphlan divergence times and the evolution of "Insectivora"

"Insectivores" are one of the key groups in understanding mammalian origins. For years, systematics of "Lipotyphla" taxa remained extremely unstable and challenged. Today, with the application of molecular techniques, "Lipotyphla" appears to be a paraphyletic assemblage that encompasses hedgehogs, shrews, and moles (i.e., Eulipotyphla-a member of Laurasiatheria), and golden moles and tenrecs (i.e., Afrosoricida-a member of Afrotheria). Based on nuclear genes and on this well-established phylogenetic framework, we estimated Bayesian relaxed molecular clock divergence times among major lineages of "Lipotyphla." Crown placental mammals are shown to diversify 102+/-6 million years ago (Mya; mean+/-one standard-deviation), followed by Boreoeutheria (94+/-6 Mya), Laurasiatheria (85+/-5 Mya), and Eulipotyphla (73+/-5), with moles separating from hedgehogs+shrews just at the K/T boundary (65+/-5 Mya). During the Early and Middle Eocene, all extant eulipotyphlan subfamilies originated: Uropsilinae (52+/-5 Mya), and Desmaninae, Talpinae, Erinaceinae, Hylomyinae, Soricinae, and Crocidurinae (38-42+/-5 Mya). Afrosoricida separated from Macroscelidae 69+/-5 Mya, golden moles from tenrecs 63+/-5 Mya, and the diversification within tenrecs occurred 43+/-5 Mya. Divergence times are shown to be in reasonably good agreement with the fossil record of eulipotyphlans, but not with the one of afrosoricid "insectivores." Eulipotyphlans diversification might have been sculpted by variations in paleoclimates of the cenozoic era.     

Noël Bernard (1874–1911): orchids to symbiosis in a dozen years,one century ago

Noël Bernard, the famous discoverer of the symbiotic germination of orchid seeds, died a one hundred years ago in 1911, at the age of 37. Here we remember his life, personality, training and contributions to science. He studied at the Ecole Normale Supérieure and took courses on microbiology at the Pasteur institute. He was also an admirer of Darwin. We briefly summarize some of his inspiring research in botany, plant physiology and symbiosis, especially that on orchid seed germination and tuber formation, published over a period of only 12 years. We briefly consider his legacy and the research that has recently been published in Symbiosis, which extends the various fields of research that Noël Bernard pioneered.     

Ten-year stability of EEG biofeedback results for a hyperactive boy who failed fourth grade perceptually impaired class

Ten years ago, the first successful application of a clinical,private-practice based, EEG 14-Hz biofeedback training regimen for the treatment of learning disorders was performed by the author. After the 10-year-old boy, with presenting symptomology including a developmental reading disorder, hyperactivity, and an educational classification of perceptually impaired, continued symptom free for a period oftwo years, his case was submitted for publication. Ten years after his termination from successful treatment, his ongoingly normal social and academic functioning is noted and his EEG brainwave signature examined and compared with a population of 24 used-to-be learning disabled, one-half of which had a pretreatment state including the educational classification of perceptually impaired. This 10-year follow-up confirms the long-term stability of the results of this EEG 14-Hz biofeedback regimen. Current findings on recent medical research identifying a major cerebral locus of dysfunction for hyperkinesis and how it supports the electrode placements of this clinical office setting regimen is also discussed.     

A systematic review of the effects of physical training on load carriage performance

Soldiers are often required to carry heavy loads during military operations. This article reports on a systematic literature review examining the influence of physical training on load carriage performance. Several literature databases, reference lists, and other sources were explored to find studies that quantitatively examined the effects of physical training on the time taken for individuals to complete a set distance carrying an external load, with the majority of the load contained in a backpack. Effect sizes (Cohen's d statistic) were used in meta-analyses to examine the changes in load carriage performance after various modes of physical training. Effect sizes quantified training-related changes in terms of SD units. Ten original research studies met the review criteria. Meta-analysis indicated that large training effects (≥0.8SD units) were apparent when progressive resistance training was combined with aerobic training and when that training was conducted at least 3 times per week, over at least 4 weeks. When progressive load-carriage exercise was part of the training program, much larger training effects were evident (summary effect size [SES] = 1.7SD units). Field-based training that combined a wide variety of training modes and included progressive load-carriage exercise was also very effective in improving load carriage performance (SES = 1.1SD units). Aerobic training alone or resistance training alone had smaller and more variable effects, depending on the study. This review indicates that combinations of specific modes of physical training can substantially improve load carriage performance.     

神经内科硕士研究生临床和科研能力的培养

临床医学硕士研究生阶段是培养临床和科研思维能力的重要阶段,从某种意义上说是人生和医疗生涯的关键时期。神经内科硕士研究生不仅应该具有一定的临床工作能力,还应具有一定的科研能力。临床工作能力培养包括临床基本功的培训,基本理论的加强和基本技能的培养,临床思维能力的培养及医患沟通能力的培养等多个方面。科研能力包括文献阅读能力、科研思维能力和论文写作能力等。这样,硕士研究生毕业后不仅能够诊治神经内科常见病和多发病,会思考临床工作中的问题,更重要的是能想办法探索和解决这些问题。这也是硕士研究生和本科生的本质区别。因此,研究生阶段是医学生涯一个重要的里程碑,临床和科研能力的培养对个人未来的发展具有十分重要的意义。     

The NVVC: here, there and everywhere

When I started my cardiology training, back in 1976, cardiology in the Netherlands was highly dependent on internal medicine. Coronary care and intensive care units were led by internal medicine physicians in most hospitals in the Netherlands whereas in the US (where I had worked for a while) cardiology was a discipline in its own right, at least in university centres. In our country, this changed rapidly in the ensuing years and the Netherlands Society of Cardiology (NVVC) played a key role in this process.     

秦岭地区金丝猴(Rhinopithecus roxellanae)的群体行为与生态习性的观察

金丝猴(Rhinopithecus roxellanae M.-E)这一我国的珍贵动物,自1870年法国人Milne-Edwards订名以来,直到解放前均只有分类上的描述。解放后,对其生活习性及地理分布(刘诗峰,1959;宋志明、罗志腾,1959;郑永烈,1959;赵肯堂,1959;郑荣梁,1960)以及种群结构(胡锦矗,1980)等方面均作过不少很有价值的观察报道。本文是在前人工作的基础上,对金丝猴几个行为生态在观察研究的同时,并对其形成这些行为的原因作一初步分析。