Diet and Meal Pattern Determinants of Glucose Levels and Variability in Adults with and without Prediabetes or Early-Onset Type 2 Diabetes: A Pilot Study.

This observational pilot study examined the association between diet, meal pattern and glucose over a 2-week period under free-living conditions in 26 adults with dysglycemia (D-GLYC) and 14 with normoglycemia (N-GLYC). We hypothesized that a prolonged eating window and late eating occasions (EOs), along with a higher dietary carbohydrate intake, would result in higher glucose levels and glucose variability (GV). General linear models were run with meal timing with time-stamped photographs in real time, and diet composition by dietary recalls, and their variability (SD), as predictors and glucose variables (mean glucose, mean amplitude of glucose excursions [MAGE], largest amplitude of glucose excursions [LAGE] and GV) as dependent variables. After adjusting for calories and nutrients, a later eating midpoint predicted a lower GV (ß = -2.3, SE = 1.0, p = 0.03) in D-GLYC, while a later last EO predicted a higher GV (ß = 1.5, SE = 0.6, p = 0.04) in N-GLYC. A higher carbohydrate intake predicted a higher MAGE (ß = 0.9, SE = 0.4, p = 0.02) and GV (ß = 0.4, SE = 0.2, p = 0.04) in N-GLYC, but not D-GLYC. In summary, our data suggest that meal patterns interact with dietary composition and should be evaluated as potential modifiable determinants of glucose in adults with and without dysglycemia. Future research should evaluate causality with controlled diets.

Circulating Branched Chain Amino Acids and Cardiometabolic Disease.

Branched chain amino acids (BCAAs) are essential for protein homeostasis, energy balance, and signaling pathways. Changes in BCAA homeostasis have emerged as pivotal contributors in the pathophysiology of several cardiometabolic diseases, including type 2 diabetes, obesity, hypertension, atherosclerotic cardiovascular disease, and heart failure. In this review, we provide a detailed overview of BCAA metabolism, focus on molecular mechanisms linking disrupted BCAA homeostasis with cardiometabolic disease, summarize the evidence from observational and interventional studies investigating associations between circulating BCAAs and cardiometabolic disease, and offer valuable insights into the potential for BCAA manipulation as a novel therapeutic strategy for cardiometabolic disease.

The effectiveness of inhaled Cannabis flower for the treatment of agitation/irritability, anxiety, and common stress.

BACKGROUND: An observational research design was used to evaluate which types of commonly labeled Cannabis flower product characteristics are associated with changes in momentary feelings of distress-related symptoms. METHODS: We used data from 2306 patient-directed cannabis administration sessions among 670 people who used the real-time Cannabis effects recording software, Releaf App, between June 6, 2016, and February 23, 2019, for tracking the effects of Cannabis flower consumption. Fixed effects multivariable panel regression techniques were used to establish overall relief by symptom type and to determine which labeled product characteristics (e.g., subspecies/subtype, inhalation method, and major cannabinoid contents) showed the strongest correlation with changes in momentary feelings of agitation/irritability, anxiety, and stress, along with experienced side effects. RESULTS: In total, a decrease in symptom intensity levels was reported in 95.51% of Cannabis usage sessions, an increase in 2.32% of sessions, and no change in 2.16% of sessions. Fixed effects models showed, on average, respondents recorded a maximum symptom intensity reduction of 4.33 points for agitation/irritability (SE = 0.20, p < 0.01), 3.47 points for anxiety (SE = 0.13, p < 0.01), and 3.98 for stress (SE = 0.12, p < 0.01) on an 11-point visual analog scale. Fixed effects regressions showed that, controlling for time-invariant user characteristics, mid and high tetrahydrocannabinol (THC) levels were the primary independent predictor of increased symptom relief, and that when broken out by symptom type, this effect was only statistically significant for our largest sample of users, those reporting anxiety rather than agitation/irritability or stress. Cannabidiol (CBD) levels were generally not associated with changes in symptom intensity levels. In a minority of cannabis use sessions (< 13%), cannabis users reported anxiogenic-related negative side effects (e.g., feeling anxious, irritable, paranoid, rapid pulse, or restless), whereas in a majority of sessions (about 66%), users reported positive anxiolytic side effects (e.g., feeling chill, comfy, happy, optimistic, peaceful, or relaxed). CONCLUSIONS: The findings suggest the majority of patients in our sample experienced relief from distress-related symptoms following consumption of Cannabis flower, and that among product characteristics, higher THC levels were the strongest predictors of relief.

Evidence of Vertical Transmission of the Snake Fungal Pathogen Ophidiomyces ophiodiicola.

Snake fungal disease (ophidiomycosis) is an emerging infection of snakes caused by Ophidiomyces ophiodiicola. Little is known about mechanisms of this pathogen's transmission and its implications for conservation of wild snake populations. We report four cases with evidence of vertical transmission of O. ophiodiicola from dam to offspring.

Mu Opioid Receptor Agonist DAMGO Produces Place Conditioning, Abstinence-induced Withdrawal, and Naltrexone-Dependent Locomotor Activation in Planarians.

Unlike the behavioral effects planarians display when exposed to cocaine, amphetamines, cathinones, ethanol and sucrose, effects of opioid receptor agonists, especially mu opioid receptor agonists, are poorly defined in these flatworms. Here, we tested the hypothesis that planarians exposed to a selective mu opioid receptor agonist, DAMGO (0.1, 1, 10 µM), would display a triad of opioid-like effects (place conditioning, abstinence-induced withdrawal, and motility changes). DAMGO was selected versus morphine because of its greater mu opioid receptor selectivity. In place conditioning and abstinence experiments, the planarian light/dark test (PLDT) was utilized (i.e., planarians are placed into a petri dish containing water that is split into light and dark compartments and time spent in the compartments is determined). Planarians conditioned with DAMGO (1 µM) spent more time on the drug-paired side compared to water controls. In abstinence experiments, planarians exposed to DAMGO for 30 min were removed and then placed into water, where light avoidance (e.g. defensive responding) and depressant-like effects (i.e., decreased motility) were quantified. Compared to water controls, DAMGO-withdrawn planarians spent less time in the light (10 µM) and displayed decreased motility (1, 10 µM). Acute DAMGO exposure (1 µM) produced hypermotility that was antagonized by naltrexone (1, 10, 100 µM). In contrast, acute exposure to the kappa opioid receptor agonist U50,488H (0.1, 1, 10 µM) resulted in decreased motility. Our results show that a mu opioid agonist produces mammalian-like behavioral responses in planarians that may be related to addiction and suggest opioid-like behavioral effects are conserved in invertebrates.

The goal of making friends for youth with disabilities: creating a goal menu.

BACKGROUND: Clinicians working with youth with disabilities have acknowledged making friends as a commonly identified client goal. Clinicians find this goal difficult to address, as there are no measures that provide a breakdown of making friends into functional steps. In addition, research on friendship has traditionally focused on characteristics and quality of friendships rather than the friend-making process as a whole. A goal menu, comprised of a variety of steps that address the goal of making friends, would provide guidance to clinicians challenged with this goal in practice. PURPOSE: To develop an understanding of the friend-making process as a first step towards the development of a goal menu for the goal of making friends. METHODS: A literature review, youth focus group and expert clinician semi-structured interviews and consultation were used to generate a comprehensive data set. Established qualitative methods were used to sort and group the data into categories. A thematic analysis of the categories was performed. RESULTS: Analysis revealed four themes integral to the friend-making process: person factors influencing friend-making, making friend-making a priority, opportunity for friend-making and motivation to make friends. An additional theme identified as occasionally involved in the process was a little bit of luck in making friends. CONCLUSIONS: The themes generated by this research indicate that actionable target areas exist for the somewhat abstract notion of friend-making and the authors recommend that clinicians explore beyond person factors when addressing the goal of making friends. As a next step, the identified themes will provide the foundation for a goal menu, ultimately enabling clinicians to address the goal of making friends in a more efficient and effective manner.

Physicians declining patient enrollment in a critical care trial: a case study in thromboprophylaxis.

PURPOSE: To analyze the frequency, rationale and determinants of attending physicians requesting that their eligible patients not be approached for participation in a thromboprophylaxis trial. METHODS: Research personnel in 67 centers prospectively documented eligible non-randomized patients due to physicians declining to allow their patients to be approached. RESULTS: In 67 centers, 3,764 patients were enrolled, but 1,460 eligible patients had no consent encounter. For 218 (14.9 %) of these, attending physicians requested that their patients not be approached. The most common reasons included a high risk of bleeding (31.2 %) related to fear of heparin bioaccumulation in renal failure, the presence of an epidural catheter, peri-operative status or other factors; specific preferences for thromboprophylaxis (12.4 %); morbid obesity (9.6 %); uncertain prognosis (6.4 %); general discomfort with research (3.7 %) and unclear reasons (17.0 %). Physicians were more likely to decline when approached by less experienced research personnel; considering those with[10 years of experience as the reference category, the odds ratios (OR) for physician refusals to personnel without trial experience was 10.47 [95 % confidence interval (CI) 2.19-50.02] and those with less than 10 years experience was 1.72 (95 % CI 0.61-4.84). Physicians in open rather than closed units were more likely to decline (OR 4.26; 95 % CI 1.27-14.34). Refusals decreased each year of enrollment compared to the pilot phase. CONCLUSIONS: Tracking, analyzing, interpreting and reporting the rates and reasons for physicians declining to allow their patients to be approached for enrollment provides insights into clinicians' concerns and attitudes to trials. This information can encourage physician communication and education, and potentially enhance efficient recruitment.

Ensembl Genomes: extending Ensembl across the taxonomic space.

Ensembl Genomes (http://www.ensemblgenomes.org) is a new portal offering integrated access to genome-scale data from non-vertebrate species of scientific interest, developed using the Ensembl genome annotation and visualisation platform. Ensembl Genomes consists of five sub-portals (for bacteria, protists, fungi, plants and invertebrate metazoa) designed to complement the availability of vertebrate genomes in Ensembl. Many of the databases supporting the portal have been built in close collaboration with the scientific community, which we consider as essential for maintaining the accuracy and usefulness of the resource. A common set of user interfaces (which include a graphical genome browser, FTP, BLAST search, a query optimised data warehouse, programmatic access, and a Perl API) is provided for all domains. Data types incorporated include annotation of (protein and non-protein coding) genes, cross references to external resources, and high throughput experimental data (e.g. data from large scale studies of gene expression and polymorphism visualised in their genomic context). Additionally, extensive comparative analysis has been performed, both within defined clades and across the wider taxonomy, and sequence alignments and gene trees resulting from this can be accessed through the site.

Ensembl 2009.

The Ensembl project (http://www.ensembl.org) is a comprehensive genome information system featuring an integrated set of genome annotation, databases, and other information for chordate, selected model organism and disease vector genomes. As of release 51 (November 2008), Ensembl fully supports 45 species, and three additional species have preliminary support. New species in the past year include orangutan and six additional low coverage mammalian genomes. Major additions and improvements to Ensembl since our previous report include a major redesign of our website; generation of multiple genome alignments and ancestral sequences using the new Enredo-Pecan-Ortheus pipeline and development of our software infrastructure, particularly to support the Ensembl Genomes project (http://www.ensemblgenomes.org/).

Measuring knife stab penetration into skin simulant using a novel biaxial tension device.

This paper describes the development and use of a biaxial measurement device to analyse the mechanics of knife stabbings. In medicolegal situations it is typical to describe the consequences of a stabbing incident in relative terms that are qualitative and descriptive without being numerically quantitative. Here, the mechanical variables involved in the possible range of knife-tissue penetration events are considered so as to determine the necessary parameters that would need to be controlled in a measurement device. These include knife geometry, in-plane mechanical stress state of skin, angle and speed of knife penetration, and underlying fascia such as muscle or cartilage. Four commonly available household knives with different geometries were used: the blade tips in all cases were single-edged, double-sided and without serrations. Appropriate synthetic materials were used to simulate the response of skin, fat and cartilage, namely polyurethane, compliant foam and ballistic soap, respectively. The force and energy applied by the blade of the knife and the out of plane displacement of the skin were all used successfully to identify the occurrence of skin penetration. The skin tension is shown to have a direct effect on both the force and energy for knife penetration and the depth of out of plane displacement of the skin simulant prior to penetration: larger levels of in-plane tension in the skin are associated with lower penetration forces, energies and displacements. Less force and energy are also required to puncture the skin when the plane of the blade is parallel to a direction of greater skin tension than when perpendicular. This is consistent with the observed behaviour when cutting biological skin: less force is required to cut parallel to the Langer lines than perpendicularly and less force is required to cut when the skin is under a greater level of tension. Finally, and perhaps somewhat surprisingly, evidence is shown to suggest that the quality control processes used to manufacture knives fail to produce consistently uniform blade points in knives that are nominally identical. The consequences of this are that the penetration forces associated with nominally identical knives can vary by as much as 100%.

Effects of methylphenidate on cognition and apathy in normal pressure hydrocephalus: a case study and review.

The psychostimulant methylphenidate has been previously shown to improve cognitive performance in both normal control volunteers and patient populations. In the present case study, the effects of methylphenidate on cognitive and behavioural function were examined in a single patient with idiopathic normal pressure hydrocephalus (NPH) who had undergone ventriculoperitoneal shunting. A double-blind placebo-controlled ABBA drug design was employed, with the administration of two different doses of methylphenidate followed by neuropsychological assessment on a number of psychometric tests and cognitive tasks drawn from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Methylphenidate produced a dose-dependent positive improvement in behavioural measures in the patient associated with a reduction in apathy. It also had a dose-independent enhancing effect on performance of a Spatial Recognition task. These findings require replication in a large sample of patients to determine whether methylphenidate may prove to be generally useful in enhancing cognition and reducing apathy in normal pressure hydrocephalus.

The basal ganglia and rule-governed language use: evidence from vascular and degenerative conditions.

The Declarative/Procedural Model of Pinker, Ullman and colleagues claims that the basal ganglia are part of a fronto-striatal procedural memory system which applies grammatical rules to combine morphemes (the smallest meaningful units in language) into complex words (e.g. talk-ed, talk-ing). We tested this claim by investigating whether striatal damage or loss of its dopaminergic innervation is reliably associated with selective regular past tense deficits in patients with subcortical cerebrovascular damage, Parkinson's disease or Huntington's disease. We focused on past tense morphology since this allows us to contrast the regular past tense (jump-jumped), which is rule-based, with the irregular past tense (sleep-slept), which is not. We used elicitation and priming tasks to test patients' ability to comprehend and produce inflected forms. We found no evidence of a consistent association between striatal dysfunction and selective impairment of regular past tense morphology, suggesting that the basal ganglia are not essential for processing the regular past tense as a sequence of morphemes, either in comprehension or production, in contrast to the claims of the Declarative/Procedural Model. All patient groups showed normal activation of semantic and morphological representations in comprehension, despite difficulties suppressing semantically appropriate alternatives when trying to inflect novel verbs. This is consistent with previous reports that striatal dysfunction spares automatic activation of linguistic information, but disrupts later language processes that require inhibition of competing alternatives.

Ensembl 2005.

The Ensembl (http://www.ensembl.org/) project provides a comprehensive and integrated source of annotation of large genome sequences. Over the last year the number of genomes available from the Ensembl site has increased by 7 to 16, with the addition of the six vertebrate genomes of chimpanzee, dog, cow, chicken, tetraodon and frog and the insect genome of honeybee. The majority have been annotated automatically using the Ensembl gene build system, showing its flexibility to reliably annotate a wide variety of genomes. With the increased number of vertebrate genomes, the comparative analysis provided to users has been greatly improved, with new website interfaces allowing annotation of different genomes to be directly compared. The Ensembl software system is being increasingly widely reused in different projects showing the benefits of a completely open approach to software development and distribution.

The Vertebrate Genome Annotation (Vega) database.

The Vertebrate Genome Annotation (Vega) database (http://vega.sanger.ac.uk) has been designed to be a community resource for browsing manual annotation of finished sequences from a variety of vertebrate genomes. Its core database is based on an Ensembl-style schema, extended to incorporate curation-specific metadata. In collaboration with the genome sequencing centres, Vega attempts to present consistent high-quality annotation of the published human chromosome sequences. In addition, it is also possible to view various finished regions from other vertebrates, including mouse and zebrafish. Vega displays only manually annotated gene structures built using transcriptional evidence, which can be examined in the browser. Attempts have been made to standardize the annotation procedure across each vertebrate genome, which should aid comparative analysis of orthologues across the different finished regions.

The DNA sequence and analysis of human chromosome 13.

Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.

Ensembl 2004.

The Ensembl (http://www.ensembl.org/) database project provides a bioinformatics framework to organize biology around the sequences of large genomes. It is a comprehensive and integrated source of annotation of large genome sequences, available via interactive website, web services or flat files. As well as being one of the leading sources of genome annotation, Ensembl is an open source software engineering project to develop a portable system able to handle very large genomes and associated requirements. The facilities of the system range from sequence analysis to data storage and visualization and installations exist around the world both in companies and at academic sites. With a total of nine genome sequences available from Ensembl and more genomes to follow, recent developments have focused mainly on closer integration between genomes and external data.

Clinical practice guidelines for suctioning the airway of the intubated and nonintubated patient.

OBJECTIVE: To provide physicians, physiotherapists, nurses and respiratory therapists with guidelines for the application of airway suctioning. DESIGN: This clinical practice guideline was developed using the model by Browman and colleagues. A working group of representatives from four professional colleges (nurses, physicians and surgeons, physiotherapists and respiratory therapists) and research experts was formed to conduct a systematic review, develop evidence-based recommendations and generate clinical practice guidelines. MEDLINE (1966 to 1998), CINAHL (1982 to 1997) and EMBASE (1974 to 1996) as well as the reference lists of identified articles were searched. Inclusion of articles was determined by at least two group members, and studies were classified according to type. Randomized, controlled; randomized; and nonrandomized crossover and comparative cohort trials were grouped by type of intervention and population for use in the development of recommendations. Other observational and animal studies dealing with adverse effects of suctioning were included in the review but were not used in the development of recommendations. Input on the evidence-based recommendations was sought and incorporated from members of all four professions and from experts on content and methodology. SETTING: Any setting (hospital or home) where suctioning is performed. POPULATION: Intubated and nonintubated adults, infants and children. RESULTS AND CONCLUSIONS: An attempt was made to develop recommendations in each of the subcategories of suctioning techniques addressed by at least one study. In some subcategories, definite recommendations were made (13 in adults, and three in children and infants); in other subcategories, insufficient evidence precluded recommendations. The recommendations addressed the following aspects of suctioning: preoxygenation, hyperinflation, insufflation, hyperoxygenation, hyperventilation, saline instillation, adaptor use, medication use, open and closed systems, and various types of catheters.

Molecular scaffold protein and cellular responses.

Mitogen-activated kinases (MAPK) regulate many diverse cellular processes, including growth, differentiation and responses to stress. The organization of MAPKs through the use of scaffolding proteins is crucial for the selective activation of these kinases by different stimuli. Recent studies identify beta-arrestins as members of the family of MAPK scaffold proteins. beta-Arrestins not only shut off signaling by uncoupling G-protein-coupled receptors (GPCRs) from their heterotrimeric G proteins, but also contribute to the specificity of GPCRs signaling by recruiting and activating selective MAPKs.

Cyclin-dependent kinase 2 nucleocytoplasmic translocation is regulated by extracellular regulated kinase.

Activation of cyclin-dependent kinase 2 (CDK2)-cyclin E in the late G(1) phase of the cell cycle is important for transit into S phase. In Chinese hamster embryonic fibroblasts (IIC9) phosphatidylinositol 3-kinase and ERK regulate alpha-thrombin-induced G(1) transit by their effects on cyclin D1 protein accumulation (Phillips-Mason, P. J., Raben, D. M., and Baldassare, J. J. (2000) J. Biol. Chem. 275, 18046-18053). Here, we show that ERK also affects CDK2-cyclin E activation by regulating the subcellular localization of CDK2. Ectopic expression of cyclin E rescues the inhibition of alpha-thrombin-induced activation of CDK2-cyclin E and transit into S phase brought about by treatment of IIC9 cells with LY29004, a selective inhibitor of mitogen stimulation of phosphatidylinositol 3-kinase activity. However, cyclin E expression is ineffectual in rescuing these effects when ERK activation is blocked by treatment with PD98059, a selective inhibitor of MEK activation of ERK. Investigation into the mechanistic reasons for this difference found the following. 1) Although treatment with LY29004 inhibits alpha-thrombin-stimulated nuclear localization, ectopic expression of cyclin E rescues CDK2 translocation. 2) In contrast to treatment with LY29004, ectopic expression of cyclin E fails to restore alpha-thrombin-stimulated nuclear CDK2 translocation in IIC9 cells treated with PD98059. 3) CDK2-cyclin E complexes are not affected by treatment with either inhibitor. These data indicate that, in addition to its effects on cyclin D1 expression, ERK activity is an important controller of the translocation of CDK2 into the nucleus where it is activated.