Adipocyte-Specific Deletion of Lamin A/C Largely Models Human Familial Partial Lipodystrophy Type 2.

Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate the function of lamin A/C in adipose tissue, we created mice with an adipocyte-specific loss of Lmna (Lmna ADKO). Although Lmna ADKO mice develop and maintain adipose tissues in early postnatal life, they show a striking and progressive loss of white and brown adipose tissues as they approach sexual maturity. Lmna ADKO mice exhibit surprisingly mild metabolic dysfunction on a chow diet, but on a high-fat diet they share many characteristics of FPLD2 including hyperglycemia, hepatic steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin and leptin. Whereas Lmna ADKO mice have reduced regulated and constitutive bone marrow adipose tissue with a concomitant increase in cortical bone, FPLD2 patients have reduced bone mass and bone mineral density compared with controls. In cell culture models of Lmna deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. Lmna ADKO mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues.

Effects of supplemental creatine and guanidinoacetic acid on spatial memory and the brain of weaned Yucatan miniature pigs.

The emergence of creatine as a potential cognitive enhancement supplement for humans prompted an investigation as to whether supplemental creatine could enhance spatial memory in young swine. We assessed memory performance and brain concentrations of creatine and its precursor guanidinoacetic acid (GAA) in 14-16-week-old male Yucatan miniature pigs supplemented for 2 weeks with either 200 mg/kg∙d creatine (+Cr; n = 7) or equimolar GAA (157 mg/kg∙d) (+GAA; n = 8) compared to controls (n = 14). Spatial memory tests had pigs explore distinct sets of objects for 5 min. Objects were spatially controlled, and we assessed exploration times of previously viewed objects relative to novel objects in familiar or novel locations. There was no effect of either supplementation on memory performance, but pigs successfully identified novel objects after 10 (p < 0.01) and 20 min (p < 0.01) retention intervals. Moreover, pigs recognized spatial transfers after 65 min (p < 0.05). Regression analyses identified associations between the ability to identify novel objects in memory tests and concentrations of creatine and GAA in cerebellum, and GAA in prefrontal cortex (p < 0.05). The concentration of creatine in brain regions was not influenced by creatine supplementation, but GAA supplementation increased GAA concentration in cerebellum (p < 0.05), and the prefrontal cortex of +GAA pigs had more creatine/g and less GAA/g compared to +Cr pigs (p < 0.05). Creatine kinase activity and maximal reaction velocity were also higher with GAA supplementation in prefrontal cortex (p < 0.05). In conclusion, there appears to be a relationship between memory performance and guanidino compounds in the cerebellum and prefrontal cortex, but the effects were unrelated to dietary supplementation. The cerebellum is identified as a target site for GAA accretion.

Dads: Progress in understanding the neuroendocrine basis of human fathering behavior.

We outline the progress on the hormonal basis of human paternal behavior during the past twenty years. Advances in understanding the roles of testosterone, prolactin, oxytocin and vasopressin in fathering behavior are described, along with recent research on hormonal interactions, such as those between testosterone and cortisol, and testosterone and the peptide hormones. In addition, we briefly describe the recent leaps forward in elucidating the neurobiological and neuroendocrine basis of fatherhood, made possible by fMRI technology. Emerging from this literature is a developing and complicated story about fatherhood, highlighting the need to further understand the interplay between behavior, physiology, social context, and individual genetic variation. Given the changing roles of parents in many societies, the continued growth of this research area will provide a strong empirical knowledge base about paternal behavior on which to create policies promoting fathers' involvement in their infants' lives.

Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis.

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch.

Physiological Indicators of Attachment in Domestic Dogs (Canis familiaris) and Their Owners in the Strange Situation Test.

Behaviorally, attachment is demonstrated when one individual maintains close proximity to another individual and shows distress upon separation. For 29 owner-dog dyads, we employed a modified Ainsworth's Strange Situation Test (SST) to investigate whether both members would show a physiological reaction to separation. Dogs experienced a series of separation from and reuniting events with their owners and were introduced to a stranger. Before and after the SST, saliva samples were taken from each dyad to measure stress-related analytes: cortisol (CORT) and chromogranin A (CgA). Dogs exhibited attachment behaviors toward owners as evidenced by more time spent in close proximity, more contact initiated and less time spent near the door, compared to episodes with the stranger. Dogs that initiated more contact with their owners in re-uniting episodes had lower CgA than dogs that initiated less contact, but their owners had higher CgA levels. Also during re-uniting episodes, dogs and owners spent more time near each other when owner CgA levels were low, owner CORT levels were high, and the dog had owner-reported separation anxiety. During the episodes alone with the stranger, dogs with higher CORT spent more time with the stranger. Finally, dogs' initial CgA levels were correlated with their owner's initial CORT levels, and dog final CORT levels were correlated with their owners' final CORT levels, suggesting some hormonal synchrony within the dyad. As all owner-dog dyads were assessed as securely attached, attachment style differences could not explain variation in hormonal or behavioral results. These results suggest that dogs may respond to owner hormonal state and/or behavior and demonstrate that individual differences in responses to a behavioral challenge reflect the stress physiology of both dogs and their owners.

Social behaviour of domestic dogs (Canis familiaris) in a public off-leash dog park.

This study examines the activity budgets and social behaviours initiated and received by 69 focal dogs in an off-leash dog park for 400 s after entry, a time of high activity about which little is known. Using motivationally-neutral labels for social behaviour categories, we describe the frequency of behaviours, and correlations among them. We then examine these relationships in the context of proposed functions for some behaviours in dogs, in terms of information gathering and communication, including visual and tactile signalling. Time spent with other dogs decreased rapidly over the visit, and much of this early interaction involved greeting the park newcomer. Snout-muzzle contact behaviours were ubiquitous, while other behaviours were rarely observed, including aggressive behaviours. Correlations among certain non-contact behaviours initiated and received by focal dogs are consistent with their function as visual signals that may influence the continuation and form of social interactions, and their possible role in social mimicry (i.e., play bow and pull-rear away). Age, sex, and number of dogs present in the park influenced specific aspects of dogs' activity budgets, and a few behaviours. This ethological study provides fundamental data on dog social behaviour in dog parks, about which surprisingly little has been published.

Balancing personal maintenance with parental investment in a chick-rearing seabird: physiological indicators change with foraging conditions.

Seabird parents use a conservative breeding strategy that favours long-term survival over intensive parental investment, particularly under harsh conditions. Here, we examine whether variation in several physiological indicators reflects the balance between parental investment and survival in common murres (Uria aalge) under a wide range of foraging conditions. Blood samples were taken from adults during mid-chick rearing from 2007 to 2014 and analysed for corticosterone (CORT, stress hormone), beta-hydroxybutyrate (BUTY, lipid metabolism reflecting ongoing mass loss), and haematocrit (reflecting blood oxygen capacity). These measures, plus body mass, were related to three levels of food availability (good, intermediate, and poor years) for capelin, the main forage fish for murres in this colony. Adult body mass and chick-feeding rates were higher in good years than in poor years and heavier murres were more likely to fledge a chick than lighter birds. Contrary to prediction, BUTY levels were higher in good years than in intermediate and poor years. Murres lose body mass just after their chicks hatch and these results for BUTY suggest that mass loss may be delayed in good years. CORT levels were higher in intermediate years than in good or poor years. Higher CORT levels in intermediate years may reflect the necessity of increasing foraging effort, whereas extra effort is not needed in good years and it is unlikely to increase foraging success in poor years. Haematocrit levels were higher in poor years than in good years, a difference that may reflect either their poorer condition or increased diving requirements when food is less available. Our long-term data set provided insight into how decisions about resource allocation under different foraging conditions are relating to physiological indicators, a relationship that is relevant to understanding how seabirds may respond to changes in marine ecosystems as ocean temperatures continue to rise.

Nurses' and midwives' revalidation preparation experiences at one NHS trust.

Since 1 April 2016, UK nurses and midwives have been required to undertake revalidation to maintain their registration with the Nursing and Midwifery Council. This article reports the results of a service evaluation to identify the revalidation preparation experiences of nurses and midwives at University College London Hospitals NHS Foundation Trust (UCLH). Findings suggest that the revalidation preparation process at UCLH supports staff to seek opportunities continually for practice feedback, reflect on their everyday experiences and link their learning to ongoing professional development.

Rescaling of temporal expectations during extinction.

Previous research suggests that extinction learning is temporally specific. Changing the conditioned stimulus (CS) duration between training and extinction can facilitate the loss of the conditioned response (CR) within the extinction session but impairs long-term retention of extinction. In 2 experiments using conditioned magazine approach with rats, we examined the relation between temporal specificity of extinction and CR timing. In Experiment 1, rats were trained on a 12-s, fixed CS-unconditional stimulus interval and then extinguished with CS presentations that were 6, 12, or 24 s in duration. The design of Experiment 2 was the same except rats were trained using partial rather than continuous reinforcement. In both experiments, extending the CS duration in extinction facilitated the diminution of CRs during the extinction session, but shortening the CS duration failed to slow extinction. In addition, extending (but not shortening) the CS duration caused temporal rescaling of the CR, in that the peak CR rate migrated later into the trial over the course of extinction training. This migration partially accounted for the faster loss of the CR when the CS duration was extended. Results are incompatible with the hypothesis that extinction is driven by cumulative CS exposure and suggest that temporally extended nonreinforced CS exposure reduces conditioned responding via temporal displacement rather than through extinction per se. (PsycINFO Database Record

Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor.

The ubiquitin ligase CUL3 is an essential regulator of neural crest specification whose aberrant activation has been linked to autism, schizophrenia, and hypertension. CUL3 exerts its roles by pairing with ∼90 distinct substrate adaptors, yet how the different CUL3-complexes are activated is poorly understood. Here, we show that CUL3 and its adaptor KLHL12 require two calcium-binding proteins, PEF1 and ALG2, for recognition of their substrate SEC31. PEF1 and ALG2 form a target-specific co-adaptor that translates a transient rise in cytosolic calcium levels into more persistent SEC31 ubiquitylation, which in turn triggers formation of large COPII coats and promotes collagen secretion. As calcium also instructs chondrocyte differentiation and collagen synthesis, calcium-dependent control of CUL3KLHL12 integrates collagen secretion into broader programs of craniofacial bone formation. Our work, therefore, identifies both calcium and CUL3 co-adaptors as important regulators of ubiquitylation events that control human development.

The stress response and exploratory behaviour in Yucatan minipigs (Sus scrofa): Relations to sex and social rank.

According to the coping styles hypothesis, an individual demonstrates an integrated behavioural and physiological response to environmental challenge that is consistent over time and across situations. Individual consistency in behavioural responses to challenge has been documented across the animal kingdom. Comparatively few studies, however, have examined inter-individual variation in the physiological response, namely glucocorticoid and catecholamine levels, the stress hormones secreted by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, respectively. Variation in coping styles between individuals may be explained in part by differences in social rank and sex. Using 20 Yucatan minipigs (Sus scrofa) we: (1) investigated the existence of consistent inter-individual variation in exploratory behaviour and the hormonal stress response, and tested for correlations as predicted by the coping styles hypothesis; and (2) evaluated whether inter-individual behavioural and hormonal variation is related to social rank and sex. Salivary stress biomarkers (cortisol, alpha-amylase, chromogranin A) were assessed in the presence and absence of a stressor consisting of social isolation in a crate for 10 min. Principal components analysis on a set of behavioural variables revealed two traits, which we labelled exploratory tendency and neophobia. Neither exploratory tendency nor neophobia predicted the physiological stress response. Subordinate pigs exhibited higher catecholamine levels compared to dominant conspecifics. We observed sex differences in the repeatability of salivary stress markers and reactivity of the stress systems. The results do not provide support for the existence of behavioural-physiological coping styles in pigs. Sex is an important determinant of the physiological stress response and warrants consideration in research addressing behavioural and hormonal variation.

Mammalian touch catches up.

An assortment of touch receptors innervate the skin and encode different tactile features of the environment. Compared with invertebrate touch and other sensory systems, our understanding of the molecular and cellular underpinnings of mammalian touch lags behind. Two recent breakthroughs have accelerated progress. First, an arsenal of cell-type-specific molecular markers allowed the functional and anatomical properties of sensory neurons to be matched, thereby unraveling a cellular code for touch. Such markers have also revealed key roles of non-neuronal cell types, such as Merkel cells and keratinocytes, in touch reception. Second, the discovery of Piezo genes as a new family of mechanically activated channels has fueled the discovery of molecular mechanisms that mediate and mechanotransduction in mammalian touch receptors.

Domestic/family violence death reviews: an international comparison.

Domestic/Family Violence Death Reviews (D/FVDRs) have been established in a number of high-income countries since 1990 as a mechanism to inform prevention-focused interventions to reduce domestic/family violence. D/FVDRs differ in their structure, governance, case identification processes and inclusion criteria, review measures, and outputs. Outside of the United States, the extent of heterogeneity across and within countries has not been explored. This study comprised an international comparison of D/FVDRs and their core elements to inform the establishment of D/FVDRs in other developed countries, and potentially low- and middle-income countries where violence is a leading cause of death. Such a review is also a necessary foundation for any future evaluation D/FVDRs. The review identified 71 jurisdictions where a D/FVDRs had been established in the past two decades, 25 of which met the inclusion criteria. All D/FVDRs examined stated a reduction in deaths as a goal of the review process; however, none reported an actual reduction. The focus of the D/FVDRs examined was on intimate partner homicides; however, more recently established D/FVDRs include other familial relationships. Almost one third of the D/FVDRs examined reported changes to the domestic/family system that occurred as a result of recommendations made from the review process. While similar in many ways, D/FVDRs differ along a number of important dimensions that make it difficult to identify best practices for jurisdictions considering the establishment of such an initiative. To share knowledge, existing networks should be expanded nationally and internationally to include jurisdictions that may be considering this initiative.

Evaluation of seabirds in Newfoundland and Labrador, Canada, as hosts of influenza A viruses.

Influenza A viruses infect a wide range of hosts, including many species of birds. Avian influenza A virus (AIV) infection appears to be most common in Anseriformes (ducks, geese, and swans) and some Charadriiformes (shorebirds and gulls), but many other birds also serve as hosts of AIV. Here, we evaluated the role of seabirds as hosts for AIV. We tested 3,160 swab samples from 13 seabird species between May 2008 and December 2011 in Newfoundland and Labrador, Canada. We also tested 156 serum samples for evidence of previous infection of AIV in Common Murres (Uria aalge) and Atlantic Puffins (Fratercula arctica). Avian influenza A virus was detected in breeding Common Murres and nonbreeding Thick-billed Murres (Uria lomvia), and Common Murres also had high antibody prevalence (44%). From these findings, combined with other studies showing AIV infection in murres, we conclude that murres are important for the ecology of AIV. For other species (Razorbill, Alca torda; Leach's Storm-Petrel, Oceanodroma leucorhoa; Black-legged Kittiwake, Rissa tridactyla; Atlantic Puffin) with good coverage (>100 samples) we did not detect AIV. However, serology indicates infection does occur in Atlantic Puffins, with 22% antibody prevalence found. The possibility of virus spread through dense breeding colonies and the long distance movements of these hosts make a more thorough evaluation of the role for seabirds as hosts of AIV important.

Basic concepts in the taxonomy of health-related behaviors, habits and lifestyle.

BACKGROUND: Health-related Habits (HrH) are a major priority in healthcare. However there is little agreement on whether exercise, diet, smoking or dental hygiene are better described as lifestyles, habits or behaviors, and on what is their hierarchical relationship. This research is aimed at representing the basic concepts which are assumed to constitute the conceptual framework enabling us to interpret and organize the field of HrH. METHODS: A group of 29 experts with different backgrounds agreed on the definition and hierarchy of HrH following an iterative process which involved framing analysis and nominal group techniques. RESULTS: Formal definitions of health-related behavior, habit, life-style and life-style profile were produced. In addition a series of basic descriptors were identified: health reserve, capital, risk and load. Six main categories of HrH were chosen based on relevance to longevity: diet/exercise, vitality/stress, sleep, cognition, substance use and other risk. Attributes of HrH are clinical meaningfulness, quantifiability, temporal stability, associated morbidity, and unitarity (non-redundancy). Two qualifiers (polarity and stages of change) have also been described. CONCLUSIONS: The concepts represented here lay the groundwork for the development of clinical and policy tools related to HrH and lifestyle. An adaptation of this system to define targets of health interventions and to develop the classification of person factors in ICF may be needed in the future.

Factors affecting subspecialty referrals by pediatric primary care providers for children with obesity-related comorbidities.

OBJECTIVE: To determine referral patterns from pediatric primary care to subspecialists for overweight/obesity and related comorbidities. METHODS: We used the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey to identify overweight/obesity and 5 related comorbidities in primary care visits between 2005 and 2009 by children 6 to 18 years. The primary outcome was whether the visit ended in referral. We used multivariable analysis to examine factors associated with referral. RESULTS: We identified 34,225 database visits. A total of 17.1% were with overweight (body mass index=85th to 94th percentile) or obese (body mass index≥95th percentile) patients. A total of 7.1% of primary care visits with overweight/obese children ended in referral. Referral was more likely when obesity was the reason for visit (odds ratio=2.83; 95% confidence interval=1.61-4.97) but was not associated with presence of a comorbidity (odds ratio=1.35; 95% confidence interval=0.75-2.44). CONCLUSIONS: Most overweight or obese children are not referred, regardless of comorbidity status. One reason may be low levels of appropriate diagnosis.

Sensitivity and specificity of obesity diagnosis in pediatric ambulatory care in the United States.

OBJECTIVE: We examined the sensitivity and specificity of an obesity diagnosis in a nationally representative sample of pediatric outpatient visits. METHODS: We used the 2005 to 2009 National Ambulatory Medical Care and National Hospital Ambulatory Medical Care surveys. We included visits with children 2 to 18 years, yielding a sample of 48 145 database visits. We determined 3 methods of identifying obesity: documented body mass index (BMI) ≥95th percentile; International Classification of Diseases, Ninth Revision (ICD-9) code; and positive answer to the question, "Does the patient now have obesity?" Using BMI as the gold standard, we calculated the sensitivity and specificity of a clinical obesity diagnosis. RESULTS: Among the 19.5% of children who were obese by BMI, 7.0% had an ICD-9 code and 15.2% had a positive response to questioning. The sensitivity of an obesity diagnosis was 15.4%, and the specificity was 99.2%. CONCLUSIONS: The sensitivity of the obesity diagnosis in pediatric ambulatory visits is low. Efforts are needed to increase identification of obese children.

Effects of diet composition on postprandial energy availability during weight loss maintenance.

BACKGROUND: The major circulating metabolic fuels regulate hunger, and each is affected by dietary composition. An integrated measure of postprandial energy availability from circulating metabolic fuels may help inform dietary recommendations for weight maintenance after weight loss. AIM: We examined the effect of low-fat (LF, 60% of energy from carbohydrate, 20% fat, 20% protein), low-glycemic index (LGI, 40%-40%-20%), and very low-carbohydrate (VLC, 10%-60%-30%) diets on total postprandial metabolic fuel energy availability (EA) during weight loss maintenance. METHODS: Eight obese young adults were fed a standard hypocaloric diet to produce 10-15% weight loss. They were then provided isocaloric LF, LGI, and VLC diets in a randomized crossover design, each for a 4-week period of weight loss maintenance. At the end of each dietary period, a test meal representing the respective diet was provided, and blood samples were obtained every 30 minutes for 5 hours. The primary outcome was EA, defined as the combined energy density (circulating level × relative energy content) of glucose, free fatty acids, and ß-hydroxybutyrate. Secondary outcomes were individual metabolic fuels, metabolic rate, insulin, glucagon, cortisol, epinephrine, and hunger ratings. Respiratory quotient was a process measure. Data were analyzed by repeated-measures analysis of variance, with outcomes compared in the early (30 to 150 min) and late (180 to 300 min) postprandial periods. RESULTS: EA did not differ between the test meals during the early postprandial period (p = 0.99). However, EA in the late postprandial period was significantly lower after the LF test meal than the LGI (p<0.0001) and VLC (p<0.0001) test meals. Metabolic rate also differed in the late postprandial period (p = 0.0074), with higher values on the VLC than LF (p = 0.0064) and LGI (p = 0.0066) diets. CONCLUSION: These findings suggest that an LF diet may adversely affect postprandial EA and risk for weight regain during weight loss maintenance.

Sustained Hox5 gene activity is required for respiratory motor neuron development.

Respiration in mammals relies on the rhythmic firing of neurons in the phrenic motor column (PMC), a motor neuron group that provides the sole source of diaphragm innervation. Despite their essential role in breathing, the specific determinants of PMC identity and patterns of connectivity are largely unknown. We show that two Hox genes, Hoxa5 and Hoxc5, control diverse aspects of PMC development including their clustering, intramuscular branching, and survival. In mice lacking Hox5 genes in motor neurons, axons extend to the diaphragm, but fail to arborize, leading to respiratory failure. Genetic rescue of cell death fails to restore columnar organization and branching patterns, indicating these defects are independent of neuronal loss. Unexpectedly, late Hox5 removal preserves columnar organization but depletes PMC number and branches, demonstrating a continuous requirement for Hox function in motor neurons. These findings indicate that Hox5 genes orchestrate PMC development through deployment of temporally distinct wiring programs.