Evo-devo of human adolescence: beyond disease models of early puberty

Despite substantial heritability in pubertal development, much variation remains to be explained, leaving room for the influence of environmental factors to adjust its phenotypic trajectory in the service of fitness goals. Utilizing evolutionary development biology (evo-devo), we examine adolescence as an evolutionary life-history stage in its developmental context. We show that the transition from the preceding stage of juvenility entails adaptive plasticity in response to energy resources, other environmental cues, social needs of adolescence and maturation toward youth and adulthood. Using the evolutionary theory of socialization, we show that familial psychosocial stress fosters a fast life history and reproductive strategy rather than early maturation being just a risk factor for aggression and delinquency. Here we explore implications of an evolutionary-developmental-endocrinological-anthropological framework for theory building, while illuminating new directions for research

Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.

BACKGROUND: Physiotherapy, and speech and language therapy are emerging non-pharmacological treatments for refractory chronic cough. We aimed to investigate the efficacy of a physiotherapy, and speech and language therapy intervention (PSALTI) to improve health-related quality of life (HRQoL) and to reduce cough frequency in patients with refractory chronic cough. METHODS: In this multicentre randomised controlled trial, patients with refractory chronic cough were randomised to four weekly 1:1 sessions of either PSALTI consisting of education, laryngeal hygiene and hydration, cough suppression techniques, breathing exercises and psychoeducational counselling or control intervention consisting of healthy lifestyle advice. We assessed the change in HRQoL at week 4 with the Leicester Cough Questionnaire (LCQ). Secondary efficacy outcomes included 24-hour objective cough frequency (Leicester Cough Monitor) and cough reflex sensitivity. The primary analysis used an analysis of covariance adjusted for baseline measurements with the intention-to-treat population. This study was registered at UK Clinical Research Network (UKCRN ID 10678). FINDINGS: Between December 2011 and April 2014, we randomly assigned 75 participants who underwent baseline assessment (34 PSALTI and 41 controls). In the observed case analysis, HRQoL (LCQ) improved on average by 1.53 (95% CI 0.21 to 2.85) points more in PSALTI group than with control (p=0.024). Cough frequency decreased by 41% (95% CI 36% to 95%) in PSALTI group relative to control (p=0.030). The improvements within the PSALTI group were sustained up to 3 months. There was no significant difference between groups in the concentration of capsaicin causing five or more coughs. INTERPRETATION: Greater improvements in HRQoL and cough frequency were observed with PSALTI intervention. Our findings support the use of PSALTI for patients with refractory chronic cough. TRIAL REGISTRATION NUMBER: UKCRN ID 10678 and ISRCTN 73039760; Results

[89Zr]Oxinate4 for long-term in vivo cell tracking by positron emission tomography

Purpose 111In (typically as [111In]oxinate3) is a gold standard radiolabel for cell tracking in humans by scintigraphy. A long half-life positron-emitting radiolabel to serve the same purpose using positron emission tomography (PET) has long been sought. We aimed to develop an 89Zr PET tracer for cell labelling and compare it with [111In]oxinate3 single photon emission computed tomography (SPECT). Methods [89Zr]Oxinate4 was synthesised and its uptake and efflux were measured in vitro in three cell lines and in human leukocytes. The in vivo biodistribution of eGFP-5T33 murine myeloma cells labelled using [89Zr]oxinate4 or [111In]oxinate3 was monitored for up to 14 days. 89Zr retention by living radiolabelled eGFP-positive cells in vivo was monitored by FACS sorting of liver, spleen and bone marrow cells followed by gamma counting. Results Zr labelling was effective in all cell types with yields comparable with 111In labelling. Retention of 89Zr in cells in vitro after 24 h was significantly better (range 71 to >90 %) than 111In (43–52 %). eGFP-5T33 cells in vivo showed the same early biodistribution whether labelled with 111In or 89Zr (initial pulmonary accumulation followed by migration to liver, spleen and bone marrow), but later translocation of radioactivity to kidneys was much greater for 111In. In liver, spleen and bone marrow at least 92 % of 89Zr remained associated with eGFP-positive cells after 7 days in vivo. Conclusion [89Zr]Oxinate4 offers a potential solution to the emerging need for a long half-life PET tracer for cell tracking in vivo and deserves further evaluation of its effects on survival and behaviour of different cell types

αA-Crystallin Peptide 66SDRDKFVIFLDVKHF80 Accumulating in Aging Lens Impairs the Function of α-Crystallin and Induces Lens Protein Aggregation

The eye lens is composed of fiber cells that are filled with α-, β- and γ-crystallins. The primary function of crystallins is to maintain the clarity of the lens through ordered interactions as well as through the chaperone-like function of α-crystallin. With aging, the chaperone function of α-crystallin decreases, with the concomitant accumulation of water-insoluble, light-scattering oligomers and crystallin-derived peptides. The role of crystallin-derived peptides in age-related lens protein aggregation and insolubilization is not understood.We found that αA-crystallin-derived peptide, (66)SDRDKFVIFLDVKHF(80), which accumulates in the aging lens, can inhibit the chaperone activity of α-crystallin and cause aggregation and precipitation of lens crystallins. Age-related change in the concentration of αA-(66-80) peptide was estimated by mass spectrometry. The interaction of the peptide with native crystallin was studied by multi-angle light scattering and fluorescence methods. High molar ratios of peptide-to-crystallin were favourable for aggregation and precipitation. Time-lapse recordings showed that, in the presence of αA-(66-80) peptide, α-crystallin aggregates and functions as a nucleus for protein aggregation, attracting aggregation of additional α-, β- and γ-crystallins. Additionally, the αA-(66-80) peptide shares the principal properties of amyloid peptides, such as β-sheet structure and fibril formation.These results suggest that crystallin-derived peptides such as αA-(66-80), generated in vivo, can induce age-related lens changes by disrupting the structure and organization of crystallins, leading to their insolubilization. The accumulation of such peptides in aging lenses may explain a novel mechanism for age-related crystallin aggregation and cataractogenesis

Spontaneous and deliberate future thinking: A dual process account

© 2019 Springer Nature.This is the final published version of an article published in Psychological Research, licensed under a Creative Commons Attri-bution 4.0 International License. Available online at: https://doi.org/10.1007/s00426-019-01262-7.In this article, we address an apparent paradox in the literature on mental time travel and mind-wandering: How is it possible that future thinking is both constructive, yet often experienced as occurring spontaneously? We identify and describe two ‘routes’ whereby episodic future thoughts are brought to consciousness, with each of the ‘routes’ being associated with separable cognitive processes and functions. Voluntary future thinking relies on controlled, deliberate and slow cognitive processing. The other, termed involuntary or spontaneous future thinking, relies on automatic processes that allows ‘fully-fledged’ episodic future thoughts to freely come to mind, often triggered by internal or external cues. To unravel the paradox, we propose that the majority of spontaneous future thoughts are ‘pre-made’ (i.e., each spontaneous future thought is a re-iteration of a previously constructed future event), and therefore based on simple, well-understood, memory processes. We also propose that the pre-made hypothesis explains why spontaneous future thoughts occur rapidly, are similar to involuntary memories, and predominantly about upcoming tasks and goals. We also raise the possibility that spontaneous future thinking is the default mode of imagining the future. This dual process approach complements and extends standard theoretical approaches that emphasise constructive simulation, and outlines novel opportunities for researchers examining voluntary and spontaneous forms of future thinking.Peer reviewe

Development of an evidence-based checklist for the detection of drug related problems in type 2 diabetes

Objective To develop an evidence-based checklist to identify potential drug related problems (PDRP) in patients with type 2 diabetes. Setting The evidence based checklist was applied to records of ambulatory type 2 diabetes patients in New South Wales, Australia. Method After comprehensive review of the literature, relevant medication groups and potential drug related problems in type 2 diabetes were identified. All the relevant information was then structured in the form of a checklist. To test the utility of the evidence-based checklist a cross-sectional retrospective study was conducted. The PDRP checklist was applied to the data of 148 patients with established type 2 diabetes and poor glycaemic control. The range and extent of DRPs in this population were identified, which were categorized using the PCNE classification. In addition, the relationship between the total as well as each category of DRPs and several of the patients’ clinical parameters was investigated. Main outcome measure: Number and category of DRPs per patient. Results The PDRP checklist was successfully developed and consisted of six main sections. 682 potential DRPs were identified using the checklist, an average of 4.6 (SD = 1.7) per patient. Metabolic and blood pressure control in the study subjects was generally poor: with a mean HbA1c of 8.7% (SD = 1.5) and mean blood pressure of 139.8 mmHg (SD = 18.1)/81.7 mmHg (SD = 11.1). The majority of DRPs was recorded in the categories ‘therapy failure’ (n = 264) and ‘drug choice problem’ (n = 206). Potentially non-adherent patients had a significantly higher HbA1c than patients who adhered to therapy (HbA1c of 9.4% vs. 8.5%; P = 0.01). Conclusion This is the first tool developed specifically to detect potential DRPs in patients with type 2 diabetes. It was used to identify DRPs in a sample of type 2 diabetes patients and demonstrated the high prevalence of DRPs per patient. The checklist may assist pharmacists and other health care professionals to systematically identify issues in therapy and management of their type 2 diabetes patients and enable earlier intervention to improve metabolic control

Whole-genome array-CGH for detection of submicroscopic chromosomal imbalances in children with mental retardation

Chromosomal imbalances are the major cause of mental retardation (MR). Many of these imbalances are caused by submicroscopic deletions or duplications not detected by conventional cytogenetic methods. Microarray-based comparative genomic hybridization (array-CGH) is considered to be superior for the investigation of chromosomal aberrations in children with MR, and has been demonstrated to improve the diagnostic detection rate of these small chromosomal abnormalities. In this study we used 1 Mb genome-wide array-CGH to screen 48 children with MR and congenital malformations for submicroscopic chromosomal imbalances, where the underlying cause was unknown. All children were clinically investigated and subtelomere FISH analysis had been performed in all cases. Suspected microdeletion syndromes such as deletion 22q11.2, Williams-Beuren and Angelman syndromes were excluded before array-CGH analysis was performed. We identified de novo interstitial chromosomal imbalances in two patients (4%), and an interstitial deletion inherited from an affected mother in one patient (2%). In another two of the children (4%), suspected imbalances were detected but were also found in one of the non-affected parents. The yield of identified de novo alterations detected in this study is somewhat less than previously described, and might reflect the importance of which selection criterion of patients to be used before array-CGH analysis is performed. However, array-CGH proved to be a high-quality and reliable tool for genome-wide screening of MR patients of unknown etiology

A longitudinal study of nest occupancy, trail networks and foraging in a polydomous wood ant population

Most ant colonies live in a single nest (monodomy) or a group of nests (polydomy). However, the length of time for which nests are inhabited varies significantly between different species. Although colonies of some species frequently move nest sites, in others, colonies inhabit the same nest or group of nests for many years. Similarly, in some species foraging and resource-sharing trails are highly dynamic, while in other species trails are used for years. Wood ants are a group of keystone species that inhabit many northern hemisphere woodlands, where they are important predators of invertebrates and indirectly act as herbivores through the farming of aphids. Wood ant colonies exhibit both monodomy and polydomy, and can inhabit nests for many years. Trails in wood ant colonies are also thought to be relatively stable. However, information about colony dynamics is mostly anecdotal as, until now, no longitudinal datasets have been collected. In this study, we collected data from ten polydomous wood ant colonies annually for 8 years and a subset of four colonies 16 times over 2 years. We found that most polydomous wood ant nests are abandoned in the first 2 years after being constructed and are more likely to be abandoned in the latter part of the active season. However, the rate of nest abandonment decreases after 2 years and is lower in larger nests. We also found that wood ant trails are relatively static within an active season and become more static later in the season as trails become established

Management of an extrasphincteric fistula in an HIV-positive patient by using fibrin glue: a case report with tips and tricks

<p>Abstract</p> <p>Background</p> <p>Individuals with impaired immunity are at higher risk of perianal diseases. Concerning complex anal fistulas impaired healing and complication rates are also higher. Definitive treatment of a fistula aims controlling the purulent discharge and prevents its recurrence. It depends mainly on the trajectory of the fistula and the underlying disease.</p> <p>We present a case of a HIV-positive patient with a complex extrasphincteric anal fistula who was treated successfully with fibrin glue application. We further, discuss tips and tricks when applying fibrin glue as plugging material in complex anal fistulas.</p> <p>Case presentation</p> <p>A sixty-one-year-old HIV-positive male referred to us for warts and extrasphincteric fistula. Because of the patients' immunological status, we opted against surgery and recommended fibrin glue plugging. The patient was discharged the same day. A follow-up examination was performed 5 days after the initial fibrin glue application showing that the fistula canal was obstructed. Three months and a year post-intervention the fistula tract remains closed.</p> <p>Conclusion</p> <p>The best treatment for a disease gives at least the same result with the other treatments with minimised risk for the life of the patient and minimal application effort. Conservative closure of fistula with fibrin plugging is simple, safe and with less morbidity than surgery. Our patient was successfully treated without endangering his life despite his precarious medical state. Not everybody believes in the effectiveness of fibrin glue application, however we consider this solution in cases of complex fistulas at least as primary procedure in special populations such as the immunosupressed.</p

MHC Class I Bound to an Immunodominant Theileria parva Epitope Demonstrates Unconventional Presentation to T Cell Receptors

T cell receptor (TCR) recognition of peptide-MHC class I (pMHC) complexes is a crucial event in the adaptive immune response to pathogens. Peptide epitopes often display a strong dominance hierarchy, resulting in focusing of the response on a limited number of the most dominant epitopes. Such T cell responses may be additionally restricted by particular MHC alleles in preference to others. We have studied this poorly understood phenomenon using Theileria parva, a protozoan parasite that causes an often fatal lymphoproliferative disease in cattle. Despite its antigenic complexity, CD8+ T cell responses induced by infection with the parasite show profound immunodominance, as exemplified by the Tp1214–224 epitope presented by the common and functionally important MHC class I allele N*01301. We present a high-resolution crystal structure of this pMHC complex, demonstrating that the peptide is presented in a distinctive raised conformation. Functional studies using CD8+ T cell clones show that this impacts significantly on TCR recognition. The unconventional structure is generated by a hydrophobic ridge within the MHC peptide binding groove, found in a set of cattle MHC alleles. Extremely rare in all other species, this feature is seen in a small group of mouse MHC class I molecules. The data generated in this analysis contribute to our understanding of the structural basis for T cell-dependent immune responses, providing insight into what determines a highly immunogenic p-MHC complex, and hence can be of value in prediction of antigenic epitopes and vaccine design