Considering the Case for Biodiversity Cycles: Reexamining the Evidence for Periodicity in the Fossil Record

Medvedev and Melott (2007) have suggested that periodicity in fossil biodiversity may be induced by cosmic rays which vary as the Solar System oscillates normal to the galactic disk. We re-examine the evidence for a 62 million year (Myr) periodicity in biodiversity throughout the Phanerozoic history of animal life reported by Rohde & Mueller (2005), as well as related questions of periodicity in origination and extinction. We find that the signal is robust against variations in methods of analysis, and is based on fluctuations in the Paleozoic and a substantial part of the Mesozoic. Examination of origination and extinction is somewhat ambiguous, with results depending upon procedure. Origination and extinction intensity as defined by RM may be affected by an artifact at 27 Myr in the duration of stratigraphic intervals. Nevertheless, when a procedure free of this artifact is implemented, the 27 Myr periodicity appears in origination, suggesting that the artifact may ultimately be based on a signal in the data. A 62 Myr feature appears in extinction, when this same procedure is used. We conclude that evidence for a periodicity at 62 Myr is robust, and evidence for periodicity at approximately 27 Myr is also present, albeit more ambiguous.Comment: Minor modifications to reflect final published versio

Transvaginal ultrasound simulation and its effect on trainee confidence levels: A replacement for initial clinical training?

Introduction: The ScanTrainer transvaginal ultrasound simulator has been developed to facilitate initial training of transvaginal ultrasound skills without patient contact. Due to the intimate nature of the examination and in some cases, limited training opportunities, the need for simulation-based education in ultrasound has gained momentum. Currently, research into the effectiveness of the ScanTrainer is limited. Methods: A mixed method study was conducted in a single institution between October 2011 and January 2012. Participants were recruited using convenience sampling and allocated to the control (clinical training) or experimental (simulation training) group following a pre-test. After 10 hours of their allocated transvaginal ultrasound training method a post-test assessment was conducted and the results statistically analysed. Participants then experienced the alternative method of training and completed questionnaires. The results were used to inform semi-structured interviews for each group. Interview transcripts were interpreted using theme analysis. Results: A small number of doctors completed the study, nine (82%) out of the 11 recruited. The majority of participants (89%) felt that practice on the ScanTrainer can increase confidence prior to attempting a real transvaginal ultrasound scan. Average scores showed that the simulation training group outperformed the clinical training group on overall score and each of the five post-test components. No statistically significant differences were demonstrated for overall score (U = 13, P = 0.556) or the five components (P = 0.190–1). Conclusions: Transvaginal ultrasound training on the ScanTrainer has the potential to replace initial clinical training; however, further larger trials are required to evaluate. Clinically significant outcomes exist if the ScanTrainer training is proven to be more effective than initial clinical training. The ScanTrainer prepares a trainee and builds confidence to progress to clinical scanning, which has the potential to improve the patient experience

A 12-month phase 3 study of pasireotide in cushing's disease

BACKGROUND: Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. METHODS: In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 ??g (82 patients) or 900 ??g (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 ??g twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. RESULTS: Twelve of the 82 patients in the 600-??g group and 21 of the 80 patients in the 900-??g group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. CONCLUSIONS: The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.) Copyright © 2012 Massachusetts Medical Society

Diagnosis and Complications of Cushing's Syndrome: A Consensus Statement

In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized

A Minimal Threshold of c-di-GMP Is Essential for Fruiting Body Formation and Sporulation in Myxococcus xanthus

Generally, the second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) regulates the switch between motile and sessile lifestyles in bacteria. Here, we show that c-di-GMP is an essential regulator of multicellular development in the social bacterium Myxococcus xanthus. In response to starvation, M. xanthus initiates a developmental program that culminates in formation of spore-filled fruiting bodies. We show that c-di-GMP accumulates at elevated levels during development and that this increase is essential for completion of development whereas excess c-di-GMP does not interfere with development. MXAN3735 (renamed DmxB) is identified as a diguanylate cyclase that only functions during development and is responsible for this increased c-di-GMP accumulation. DmxB synthesis is induced in response to starvation, thereby restricting DmxB activity to development. DmxB is essential for development and functions downstream of the Dif chemosensory system to stimulate exopolysaccharide accumulation by inducing transcription of a subset of the genes encoding proteins involved in exopolysaccharide synthesis. The developmental defects in the dmxB mutant are non-cell autonomous and rescued by co-development with a strain proficient in exopolysaccharide synthesis, suggesting reduced exopolysaccharide accumulation as the causative defect in this mutant. The NtrC-like transcriptional regulator EpsI/Nla24, which is required for exopolysaccharide accumulation, is identified as a c-diGMP receptor, and thus a putative target for DmxB generated c-di-GMP. Because DmxB can be—at least partially—functionally replaced by a heterologous diguanylate cyclase, these results altogether suggest a model in which a minimum threshold level of c-di-GMP is essential for the successful completion of multicellular development in M. xanthus

Transition from Persistent to Anti-Persistent Correlations in Postural Sway Indicates Velocity-Based Control

The displacement of the center-of-pressure (COP) during quiet stance has often been accounted for by the control of COP position dynamics. In this paper, we discuss the conclusions drawn from previous analyses of COP dynamics using fractal-related methods. On the basis of some methodological clarification and the analysis of experimental data using stabilogram diffusion analysis, detrended fluctuation analysis, and an improved version of spectral analysis, we show that COP velocity is typically bounded between upper and lower limits. We argue that the hypothesis of an intermittent velocity-based control of posture is more relevant than position-based control. A simple model for COP velocity dynamics, based on a bounded correlated random walk, reproduces the main statistical signatures evidenced in the experimental series. The implications of these results are discussed

Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects.

BACKGROUND: Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis. METHODS: We investigated in vitro and in vivo effects of metformin in humans. RESULTS: Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in vitro cellular metabolism while inhibiting the mammalian target of rapamycin targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation and increased phagocytosis activity. Metformin administered to healthy human volunteers led to significant downregulation of genes involved in oxidative phosphorylation, mammalian target of rapamycin signaling, and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to nonclassical monocytes. At a functional level, metformin lowered ex vivo production of tumor necrosis factor α, interferon γ, and interleukin 1β but increased phagocytosis activity and reactive oxygen species production. CONCLUSION: Metformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis

Expressions of Multiple Neuronal Dynamics during Sensorimotor Learning in the Motor Cortex of Behaving Monkeys

Previous studies support the notion that sensorimotor learning involves multiple processes. We investigated the neuronal basis of these processes by recording single-unit activity in motor cortex of non-human primates (Macaca fascicularis), during adaptation to force-field perturbations. Perturbed trials (reaching to one direction) were practiced along with unperturbed trials (to other directions). The number of perturbed trials relative to the unperturbed ones was either low or high, in two separate practice schedules. Unsurprisingly, practice under high-rate resulted in faster learning with more pronounced generalization, as compared to the low-rate practice. However, generalization and retention of behavioral and neuronal effects following practice in high-rate were less stable; namely, the faster learning was forgotten faster. We examined two subgroups of cells and showed that, during learning, the changes in firing-rate in one subgroup depended on the number of practiced trials, but not on time. In contrast, changes in the second subgroup depended on time and practice; the changes in firing-rate, following the same number of perturbed trials, were larger under high-rate than low-rate learning. After learning, the neuronal changes gradually decayed. In the first subgroup, the decay pace did not depend on the practice rate, whereas in the second subgroup, the decay pace was greater following high-rate practice. This group shows neuronal representation that mirrors the behavioral performance, evolving faster but also decaying faster at learning under high-rate, as compared to low-rate. The results suggest that the stability of a new learned skill and its neuronal representation are affected by the acquisition schedule.United States-Israel Binational Science FoundationIsrael Science FoundationIda Baruch FundRosetrees Trus

An Exploration of the Relations between External Representations and Working Memory

It is commonly hypothesized that external representations serve as memory aids and improve task performance by means of expanding the limited capacity of working memory. However, very few studies have directly examined this memory aid hypothesis. By systematically manipulating how information is available externally versus internally in a sequential number comparison task, three experiments were designed to investigate the relation between external representations and working memory. The experimental results show that when the task requires information from both external representations and working memory, it is the interaction of information from the two sources that determines task performance. In particular, when information from the two sources does not match well, external representations hinder instead of enhance task performance. The study highlights the important role the coordination among different representations plays in distributed cognition. The general relations between external representations and working memory are discussed