CRYPTOCHROMES promote daily protein homeostasis.

The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock-controlled protein expression, driven by daily cycles of CRYPTOCHROME-dependent transcriptional feedback repression. To test this, we used quantitative mass spectrometry to compare wild-type and CRY-deficient fibroblasts under constant conditions. In CRY-deficient cells, we found that temporal variation in protein, phosphopeptide, and K+ abundance was at least as great as wild-type controls. Most strikingly, the extent of temporal variation within either genotype was much smaller than overall differences in proteome composition between WT and CRY-deficient cells. This proteome imbalance in CRY-deficient cells and tissues was associated with increased susceptibility to proteotoxic stress, which impairs circadian robustness, and may contribute to the wide-ranging phenotypes of CRY-deficient mice. Rather than generating large-scale daily variation in proteome composition, we suggest it is plausible that the various transcriptional and post-translational functions of CRY proteins ultimately act to maintain protein and osmotic homeostasis against daily perturbation.

Hybrid Blockchain for IoT-Energy Analysis and Reward Plan.

Blockchain technology has brought significant advantages for security and trustworthiness, in particular for Internet of Things (IoT) applications where there are multiple organisations that need to verify data and ensure security of shared smart contracts. Blockchain technology offers security features by means of consensus mechanisms; two key consensus mechanisms are, Proof of Work (PoW) and Practical Byzantine Fault Tolerance (PBFT). While the PoW based mechanism is computationally intensive, due to the puzzle solving, the PBFT consensus mechanism is communication intensive due to the all-to-all messages; thereby, both may result in high energy consumption and, hence, there is a trade-off between the computation and the communication energy costs. In this paper, we propose a hybrid-blockchain (H-chain) framework appropriate for scenarios where multiple organizations exist and where the framework enables private transaction verification and public transaction sharing and audit, according to application needs. In particular, we study the energy consumption of the hybrid consensus mechanisms in H-chain. Moreover, this paper proposes a reward plan to incentivize the blockchain agents so that they make contributions to the H-chain while also considering the energy consumption. While the work is generally applicable to IoT applications, the paper illustrates the framework in a scenario which secures an IoT application connected using a software defined network (SDN). The evaluation results first provide a method to balance the public and private parts of the H-chain deployment according to network conditions, computation capability, verification complexity, among other parameters. The simulation results demonstrate that the reward plan can incentivize the blockchain agents to contribute to the H-chain considering the energy consumption of the hybrid consensus mechanism, this enables the proposed H-chain to achieve optimal social welfare.

Insulin/IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding Time.

In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ∼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.

Caffeine is a risk factor for osteopenia of prematurity in preterm infants: a cohort study.

BACKGROUND: Caffeine, the most commonly used medication in Neonatal Intensive Care Units, has calciuric and osteoclastogenic effects. METHODS: To examine the association between the cumulative dose and duration of therapy of caffeine and osteopenia of prematurity, a retrospective cohort study was conducted including premature infants less than 31 weeks and birth weight less than 1500 g. Osteopenia of prematurity was evaluated using chest X-rays on a biweekly basis over 12 weeks of hospitalization. RESULTS: The cohort included 109 infants. 51% had osteopenia of prematurity and 8% had spontaneous rib fractures. Using the generalized linear mixed model, caffeine dose and duration of caffeine therapy showed a strong association with osteopenia of prematurity. Steroids and vitamin D were also significantly correlated with osteopenia of prematurity while diuretic use did not show a statistically significant effect. CONCLUSION: The cumulative dose and duration of therapy of caffeine, as well as steroid are associated with osteopenia of prematurity in this cohort. Future studies are needed to confirm these findings and determine the lowest dose of caffeine needed to treat effectively apnea of prematurity.

Common normal variants of pediatric vertebral development that mimic fractures: a pictorial review from a national longitudinal bone health study.

Children with glucocorticoid-treated illnesses are at risk for osteoporotic vertebral fractures, and growing awareness of this has led to increased monitoring for these fractures. However scant literature describes developmental changes in vertebral morphology that can mimic fractures. The goal of this paper is to aid in distinguishing between normal variants and fractures. We illustrate differences using lateral spine radiographs obtained annually from children recruited to the Canada-wide STeroid-Associated Osteoporosis in the Pediatric Population (STOPP) observational study, in which 400 children with glucocorticoid-treated leukemia, rheumatic disorders, and nephrotic syndrome were enrolled near glucocorticoid initiation and followed prospectively for 6 years. Normal variants mimicking fractures exist in all regions of the spine and fall into two groups. The first group comprises variants mimicking pathological vertebral height loss, including not-yet-ossified vertebral apophyses superiorly and inferiorly, which can lead to a vertebral shape easily over-interpreted as anterior wedge fracture, physiological beaking, or spondylolisthesis associated with shortened posterior vertebral height. The second group includes variants mimicking other radiologic signs of fractures: anterior vertebral artery groove resembling an anterior buckle fracture, Cupid's bow balloon disk morphology, Schmorl nodes mimicking concave endplate fractures, and parallax artifact resembling endplate interruption or biconcavity. If an unexpected vertebral body contour is detected, careful attention to its location, detailed morphology, and (if available) serial changes over time may clarify whether it is a fracture requiring change in management or simply a normal variant. Awareness of the variants described in this paper can improve accuracy in the diagnosis of pediatric vertebral fractures.

Clinical imaging guidelines part 1: a proposal for uniform methodology.

Inappropriate imaging can lead to unnecessary medical radiologic exposures and cost and may not answer the clinical question. Imaging referral guidelines inform the justification of radiologic procedures and facilitate the choice of the best test first, but their acceptance by referrers, use, and value may be limited by shortcomings in the methodology of development. Focusing on common, essential elements of methodology will help guideline developers. In 2012 and 2013, the International Atomic Energy Agency hosted Technical Meetings on Radiation Protection of Patients Through the Development of Appropriateness Criteria in Diagnostic Imaging. Participants identified and agreed on issues concerning development of imaging referral guidelines. Items based on the Appraisal of Guidelines for Research and Evaluation II instrument were amended with additional items including development and consensus group composition. Consensus was sought on 28 items, 18 of which were agreed should be uniform, and 10 should allow for regional differences. Further work is required to encourage, provide, and identify higher quality evidence and to agree on a grading system for recommendations. Many key areas are common to guideline developers globally, opening the way for international collaboration to help demystify, simplify, and justify.

Variability of physicians' thresholds for neuroimaging in children with recurrent headache.

BACKGROUND: We sought to determine the extent to which physicians agree about the appropriate decision threshold for recommending magnetic resonance imaging in a clinical practice guideline for children with recurrent headache. METHODS: We surveyed attending physicians in Canada practicing in community pediatrics, child neurology, pediatric radiology, and pediatric neurosurgery. For children in each of six risk categories, physicians were asked to determine whether they would recommend for or against routine magnetic resonance imaging of the brain in a clinical practice guideline for children with recurrent headache. RESULTS: Completed surveys were returned by 114 physicians. The proportion recommending routine neuroimaging for each risk group was 100% (50% risk), 99% (10% risk), 93% (4% risk), 54% (1% risk), 25% (0.4% risk), 4% (0.01% risk). Community pediatricians, physicians in practice >15 years, and physicians who believed they ordered neuroimaging less often than peers were less likely to recommend neuroimaging for the 1% risk group (all p < 0.05). CONCLUSIONS: There is no consensus among pediatric specialists regarding the appropriate decision threshold for neuroimaging in a clinical practice guideline for children with recurrent headache. Because of the impact that individual threshold preferences may have on guidelines, these findings support the need for careful composition of guideline committees and consideration of the role of patient and family preferences. Our findings also support the need for transparency in guidelines regarding how evidence was translated into recommendations and how conflicts were resolved.

Spine surgeons' requirements for imaging at the time of referral: a survey of Canadian spine surgeons.

BACKGROUND: Routine imaging of patients with spine-related complaints referred for surgical assessment may represent an inefficient use of technological resources. Our objective was to explore Canadian spine surgeons' requirements with respect to imaging studies accompanying spine-related referrals. METHODS: We administered an 8-item survey to all 100 actively practising surgeon members of the Canadian Spine Society that inquired about demographic variables and imaging requirements for patients referred with spine-related complaints. RESULTS: Fifty-five spine surgeons completed our survey, for a response rate of 55%. Most respondents (43; 78%) required imaging studies to accompany all spine-related referrals. The type of imaging required was highly variable, with respondents endorsing 7 different combinations. Half (47%) required magnetic resonance imaging and 38% required plain radiographs either alone or in combination with other forms of imaging. Half of the respondents refused to see 20% or more of all patients referred for spine-related complaints. CONCLUSION: Most Canadian spine surgeons require imaging studies to accompany spine-related referrals; however, the type and combination of studies is highly variable, and many patients who are referred are never seen (for a consultation). Standardization and optimization of imaging practices for patients with spine-related complaints referred for surgical assessment may be an important area for cost savings.

CONTEXTE: Le recours systématique aux épreuves d'imagerie chez les patients qui se plaignent de maux de dos et qui sont référés pour consultation en chirurgie pourrait constituer une utilisation inefficace des ressources technologiques. Notre objectif était d'analyser les épreuves d'imagerie demandées par les chirurgiens canadiens spécialistes de la colonne vertébrale, suite aux demandes de consultation qui leur sont adressées pour des patients qui ont des problèmes de colonne vertébrale. MÉTHODES: Nous avons administré un sondage en 8 questions aux 100 chirurgiens en pratique active qui forment la Canadian Spine Society; le questionnaire portait sur des variables démographiques et sur les demandes d'épreuves d'imagerie pour les patients qui leur sont référés pour des maux de dos. RÉSULTATS: Cinquante-cinq chirurgiens de la colonne ont répondu à notre sondage, pour un taux de réponse de 55 %. La plupart des répondants (43; 78 %) ont dit demander des épreuves d'imagerie pour toutes les références qui leur sont adressées pour des problèmes de colonne vertébrale. Les types d'épreuves d'imagerie demandés variaient considérablement et les répondants ont mentionné 7 combinaisons d'épreuves différentes. La moitié d'entre eux (47 %) demandaient une imagerie par résonnance magnétique et 38 % demandaient des radiographies ordinaires, seules ou combinées à d'autres modalités d'imagerie. La moitié des répondants ont dit refuser de voir 20 % ou plus de tous les patients qui leur étaient référés pour des maux de dos. CONCLUSION: La plupart des chirurgiens spécialistes de la colonne vertébrale au Canada demandent des épreuves d'imagerie pour tous les patients qui leur sont référés pour des problèmes de colonne vertébrale; toutefois, les types d'épreuves et leurs combinaisons sont très variables et de nombreux patients qui sont référés en consultation ne réussissent jamais à voir les spécialistes. La standardisation et l'optimisation des pratiques au chapitre de l'imagerie pour les patients qui souffrent de maux de dos et qui sont référés à un chirurgien représentent un poste budgétaire important où des économies pourraient être réalisées.

Radiographic characterization of the hands in Ritscher-Schinzel/3-C syndrome.

ABSTRACT: Ritscher-Schinzel Syndrome (RSS) is a clinically variable, autosomal recessive disorder, involving cardiac, cerebellar and craniofacial abnormalities. Numerous reports describe hand changes in RSS patients; however, a detailed characterization of the hands has not previously been performed. OBJECTIVE: The purpose of this study was to identify whether specific radiographic hand changes were characteristic of RSS and could serve as a diagnostic tool. MATERIALS AND METHODS: We performed a detailed radiographic hand characterization of 8 RSS patients. The patient population consisted of 5 males and 3 females from ages one month to 26 years, 7 months. The hands were characterized using metacarpophalangeal pattern (MCPP) profiles, carpal height and bone age analyses and assessment of bone morphology. RESULTS: There was generalized brachydactyly with the second ray being the most severely affected. There was significant shortening of the first metacarpal and the fifth distal phalanx. The MCPP profile generated showed a consistent wavy pattern with average Z-scores ranging from -0.15 (4(th) proximal phalanx) to -2.13 (1(st) metacarpal) and 0.53 (4(th) middle phalanx) to -1.73 (2(nd) proximal phalanx) for the left and right hands, respectively. Six of eight patients showed a decreased carpal height. Bone age was within normal limits for all patients. Our study population showed consistent radiographic changes including: overtubulation of the bones (especially metacarpals 2-4), prominent tufts of the distal phalanges and a hypoplastic fifth distal phalanx. CONCLUSION: The hand findings identified in this study can provide helpful diagnostic tools to clinicians when the diagnosis of RSS is being considered.