Dietary 23-hydroxy ursolic acid protects against diet-induced weight gain and hyperglycemia by protecting monocytes and macrophages against nutrient stress-triggered reprogramming and dysfunction and preventing adipose tissue inflammation.

The aim of this study was to determine whether the atheroprotective phytochemical 23-hydroxy ursolic acid protects against diet-induced obesity and hyperglycemia by preventing nutrient stress-induced monocyte reprogramming. After a two week run-in period on a defined, phytochemical-free low-fat maintenance diet, 12-week old female C57BL/6J mice were either kept on the maintenance diet for additional 13 weeks or switched to either a high-calorie diet, a high-calorie diet supplemented with either 0.05% 23-hydroxy ursolic acid or a high-calorie diet supplemented with 0.2% 23-hydroxy ursolic acid. Dietary supplementation with 23-hydroxy ursolic acid reduced weight gain and adipose tissue mass, prevented hyperglycemia, hyperleptinemia and adipose tissue inflammation, and preserved glucose tolerance. 23-Hydroxy ursolic acid also preserved blood monocyte mitogen-activated protein kinase phosphatase-1 activity, a biomarker of monocyte health, and reduced macrophage content in the adipose tissue. Targeted gene profiling by qRT-PCR using custom-designed TaqMan® Array Cards revealed that dietary 23-hydroxy ursolic acid converts macrophages into a transcriptionally hyperactive phenotype with enhanced antioxidant defenses and anti-inflammatory potential. In conclusion, our findings show that dietary 23-hydroxy ursolic acid exerts both anti-obesogenic effects through multiple mechanisms. These include improving glucose tolerance, preventing hyperleptinemia, maintaining blood monocyte function, reducing recruitment of monocyte-derived macrophages into adipose tissues during nutrient stress, and converting these macrophages into an anti-inflammatory, potentially inflammation-resolving phenotype, all contributing to reduced adipose tissue inflammation. Our data suggest that 23-hydroxy ursolic acid may serve as an oral therapeutic and dietary supplement suited for patients at risk for obesity, impaired glucose tolerance and cardiovascular disease.

End of life care for long-term care residents with dementia, chronic illness and cancer: prospective staff survey.

BACKGROUND: Little is known about the quality of end of life care in long-term care (LTC) for residents with different diagnostic trajectories. The aim of this study was to compare symptoms before death in LTC for those with cancer, dementia or chronic illness. METHODS: After-death prospective staff survey of resident deaths with random cluster sampling in 61 representative LTC facilities across New Zealand (3709 beds). Deaths (n = 286) were studied over 3 months in each facility. Standardised questionnaires - Symptom Management (SM-EOLD) and Comfort Assessment in End of life with Dementia (CAD-EOLD) - were administered to staff after the resident's death. RESULTS: Primary diagnoses at the time of death were dementia (49%), chronic illness (30%), cancer (17%), and dementia and cancer (4%). Residents with cancer had more community hospice involvement (30%) than those with chronic illness (12%) or dementia (5%). There was no difference in mean SM-EOLD in the last month of life by diagnosis (cancer 26.9 (8.6), dementia 26.5(8.2), chronic illness 26.9(8.6). Planned contrast analyses of individual items found people with dementia had more pain and those with cancer had less anxiety. There was no difference in mean CAD-EOLD scores in the week before death by diagnosis (total sample 33.7(SD 5.2), dementia 34.4(SD 5.2), chronic illness 33.0(SD 5.1), cancer 33.3(5.1)). Planned contrast analyses showed significantly more physical symptoms for those with dementia and chronic illness in the last month of life than those with cancer. CONCLUSIONS: Overall, symptoms in the last week and month of life did not vary by diagnosis. However, sub-group planned contrast analyses found those with dementia and chronic illness experienced more physical distress during the last weeks and months of life than those with cancer. These results highlight the complex nature of LTC end of life care that requires an integrated gerontology/palliative care approach.

Replicated evolutionary inhibition of a complex ancestral behaviour in an adaptive radiation.

Adaptive radiations often exhibit high levels of phenotypic replication, a phenomenon that can be explained by selection on standing variation in repeatedly divergent environments or by the influence of ancestral plasticity on selection in divergent environments. Here, we offer the first evidence that plastic loss of expression of a complex display in a novel environment, followed by selection against expression, could lead to replicated evolutionary inhibition of the phenotype. In both ancestral (oceanic) and benthic (freshwater) populations of the threespine stickleback fish, cannibalism is common and males defending nests respond to approaching groups with a complex diversionary display. This display is not exhibited by males in allopatric, limnetic (freshwater) populations from which cannibalistic groups are absent. Laboratory-reared males from three limnetic populations exhibit a reduced tendency to respond to cannibalistic foraging groups relative to laboratory-reared ancestral and benthic males, but still are capable of producing a similar array of forms of the display despite many generations of disuse. Thus, replication in adaptive radiations can reflect reduced expression of an ancestral trait followed by evolutionary inhibition while the population retains the capacity to express the trait under extreme ancestral conditions.

Family experiences of the transition to palliative care in aged residential care (ARC): a qualitative study.

PURPOSE: To address a gap in the literature by exploring bereaved families' perceptions of the transition to palliative care for their relative in long-term care. METHODS: In-depth interviews were conducted with a convenience sample of twenty-six family members who were most involved in the care of residents who had died within the last 12 months. Interviews explored care, perceptions of staff palliative care knowledge, communication with staff, care planning and decision-making. The range of responses fit the Donabedian (1966) health care model of structure/process/outcome. In the case of long-term care, structure includes staff training; process is the manner of care and outcome would be a 'good' (or bad) death. RESULTS: There was little evidence that a well-managed transition to a palliative approach to care was being initiated. Key themes included: 1) unrecognised need for transition; 2) information gaps and 3) feeling 'out of the loop'. Ten subthemes were also identified. IMPLICATIONS: Engaging family and relevant internal and external health providers in care planning not only promotes care in line with resident wishes but also assists family bereavement. Results indicate the need for the development of a new collaborative, multidisciplinary model to enhance the delivery of palliative care in long-term care.

Practical urinalysis in the cat: 2: Urine microscopic examination 'tips and traps'.

SERIES OUTLINE: This is the second article in a two-part series on urinalysis in the cat. The specific focus is urine microscopic examination. Part 1, which appeared in the March 2016 issue, discussed urine macroscopic examination. PRACTICAL RELEVANCE: Urinalysis is an essential procedure in feline medicine but often little attention is paid to optimising the data yielded or minimising factors that can affect the results. CLINICAL CHALLENGES: For the best results, appropriately collected urine should be prepared promptly by specialist laboratory personnel for the relevant tests and assessed by a clinical pathologist. This is invariably impractical in clinical settings but careful attention can minimise artefacts and allow maximum useful information to be obtained from this seemingly simple process. AUDIENCE: Clinical pathologists would be familiar with the information provided in this article, but it is rarely available to general or specialist practitioners, and both groups can potentially benefit. EQUIPMENT: Most of the required equipment is routinely available to veterinarians. However, instructions have been provided to give practical alternatives for specialist procedures in some instances. EVIDENCE BASE: The evidence base for feline microscopic urinalysis is quite poor and information has largely been extrapolated from the human literature. Information from feline studies has been included where available. In addition, practical clinicopathological and clinical observations are provided.

Practical urinalysis in the cat: 1: Urine macroscopic examination 'tips and traps'.

SERIES OUTLINE: This is the first article in a two-part series on urinalysis in the cat. The focus of Part 1 is urine macroscopic examination. Part 2, to appear in the May 2016 issue, discusses urine microscopic examination. PRACTICAL RELEVANCE: Urinalysis is an essential procedure in feline medicine but often little attention is paid to optimising the data yielded or minimising factors that can affect the results. CLINICAL CHALLENGES: For the best results, appropriately collected urine should be prepared promptly by specialist laboratory personnel for the relevant tests and assessed by a clinical pathologist. This is invariably impractical in clinical settings but careful attention can minimise artefacts and allow maximum useful information to be obtained from this seemingly simple process. AUDIENCE: Clinical pathologists would be familiar with the information provided in this article, but it is rarely available to general or specialist practitioners, and both can potentially benefit. EQUIPMENT: Most of the required equipment is routinely available to veterinarians. However, instructions have been provided to give practical alternatives for specialist procedures in some instances. EVIDENCE BASE: Evidence for much of the data on urinalysis in cats is lacking. Validation of the human equipment used routinely, such as dipsticks, is also lacking. As such, the evidence base for feline urinalysis is quite poor and information has largely been extrapolated from the human literature. Information from feline studies has been included where available. In addition, practical clinicopathological and clinical observations are provided.

Underage drinking: prevalence and correlates of risky drinking measures among youth aged 12-20.

BACKGROUND: Underage drinking and its effects have been researched extensively. However, no study to date has examined how the levels of drinking that have been defined as risky for adults might relate to youth who have a heightened physiological vulnerability to alcohol. OBJECTIVES: To examine a range of drinking measures that go beyond common measures of youth alcohol use to gain a more detailed understanding of the nature of underage drinking and its associated correlates and outcomes. METHODS: Analyzing data from a 2013 nationally representative US survey, we examined a variety of measures of alcohol use among 24,445 youth (weighted N = 381,155,562), the demographic groups most likely to have reported drinking in these ways, and associations between these measures of drinking and a number of adverse outcomes. RESULTS: On all measures of potentially risky drinking, including meeting diagnostic criteria for an alcohol use disorder, underage drinkers exceeded the rates found for adults. Independent of sex, race, and age, youth who reported drinking in ways that exceeded guidelines set for adults had increased odds of meeting diagnostic criteria for an alcohol, tobacco, or other drug use disorder, and of reporting a number of health problems. CONCLUSIONS: The high rates at which youth report engaging in a range of risky drinking behaviors suggest a need for a more nuanced approach to substance use and mental health screening and interventions in clinical practice. The findings also underscore the need to address apparent misconceptions about what constitutes unhealthy or unsafe alcohol use among youth.

Cutaneous asthenia (Ehlers-Danlos-like syndrome) of Burmese cats.

OF CASES: A 6-month-old Burmese kitten developed focal skin lesions following a routine ovariohysterectomy. These were eventually attributed to the patient struggling during catheter placement and induction of anaesthesia. The lesions were caused by fluid extravasation in the subcutis and ischaemic necrosis of the overlying dermis, giving rise to an eschar-like appearance. Such lesions have been seen previously in Burmese cats with cutaneous asthenia and it is thought that they arise due to poor collagenous support for dermal blood vessels. An increased skin extensibility index (>23%) supported a diagnosis of cutaneous asthenia (Ehlers-Danlos-like syndrome), which has been reported as an inherited condition of Burmese cats in Australia, New Zealand and Europe. An additional Burmese cat with cutaneous asthenia is presented in detail, with lifetime follow-up and further salient observations by the owner, a veterinarian. Photographs of three other affected Burmese cats are provided to illustrate the range of presentations encountered with this condition. All five affected cats were presented with eschars, atrophic alopecia and increased skin extensibility, while one cat also had skin ulcers. Routine histopathological examination, including use of special stains such as trichrome, was unhelpful in establishing the diagnosis. CLINICAL REVIEW: The clinical features of this genetic disease of Burmese cats are reviewed, especially in relation to the postulated 'vasculopathy' that gives rise to characteristic skin lesions. Long term management of this condition is discussed briefly.

Evolutionary Influences of Plastic Behavioral Responses Upon Environmental Challenges in an Adaptive Radiation.

At the end of the 19th century, the suggestion was made by several scientists, including J. M. Baldwin, that behavioral responses to environmental change could both rescue populations from extinction (Baldwin Effect) and influence the course of subsequent evolution. Here we provide the historical and theoretical background for this argument and offer evidence of the importance of these ideas for understanding how animals (and other organisms that exhibit behavior) will respond to the rapid environmental changes caused by human activity. We offer examples from long-term research on the evolution of behavioral and other phenotypes in the adaptive radiation of the threespine stickleback fish (Gasterosteus aculeatus), a radiation in which it is possible to infer ancestral patterns of behavioral plasticity relative to the post-glacial freshwater radiation in northwestern North America, and to use patterns of parallelism and contemporary evolution to understand adaptive causes of responses to environmental modification. Our work offers insights into the complexity of cognitive responses to environmental change, and into the importance of examining multiple aspects of the phenotype simultaneously, if we are to understand how behavioral shifts contribute to the persistence of populations and to subsequent evolution. We conclude by discussing the origins of apparent novelties induced by environmental shifts, and the importance of accounting for geographic variation within species if we are to accurately anticipate the effects of anthropogenic environmental modification on the persistence and evolution of animals.

The exclusion of nicotine: closing the gap in addiction policy and practice.

Addiction is a complex brain disease with frequently overlapping expressions involving nicotine, alcohol, and other drugs. Yet current health care practices, public policies, and national treatment data too often exclude nicotine or address its use as completely separate from other forms of substance use and addiction, compromising patients' health and incurring unnecessary health care costs. Effective prevention and treatment requires the inclusion of nicotine in a comprehensive approach addressing all manifestations of addiction within health care policy and practice.

Addressing the critical health problem of adolescent substance use through health care, research, and public policy.

The use of addictive substances-tobacco, alcohol, and other drugs-during adolescence interferes with brain development and increases the risk of serious health and mental health conditions, including addiction. Yet, adolescents live in a culture in which family, social, community, and media influences regularly bombard them with pro-substance use messages, creating an environment in which substance use is considered an expected behavior, rather than a considerable health risk. To prevent the significant harm that falls to teens and young adults because of substance use, The National Center on Addiction and Substance Abuse at Columbia University (CASA Columbia) undertook a study to explore how adolescent brain development relates to the risk of substance use and addiction; the cultural influences that create an environment in which substance use is considered normative behavior; individual factors that make some teens more disposed to substance use and addiction; and evidence-based prevention and treatment strategies for addressing this problem. The recently published report Adolescent Substance Use: America's #1 Public Health Problem concludes that risky substance use is a major public health problem that can be ameliorated through evidence-based public health measures, including education about the disease and its risk factors, screenings, and clinical interventions, and that addiction can be treated and managed effectively within routine health care practice and specialty care.

Lower respiratory tract infections in cats: reaching beyond empirical therapy.

PRACTICAL RELEVANCE: Lower respiratory tract infections (LRTIs) in cats can be due to bacteria, parasites, fungi and viruses. This review details the practical investigation of these infections and highlights specific therapy where possible. The aim is to avoid the all-too-frequent temptation in practice to treat cats with lower respiratory tract signs empirically for feline bronchial disease (FBD)/asthma. This is potentially hazardous as immunosuppressive therapy for FBD/asthma could exacerbate disease due to a LRTI. Empirical treatment of suspected LRTI is also difficult to recommend given the wide range of potential pathogens. CLINICAL CHALLENGES: Making a clinical ante-mortem diagnosis of LRTI in a cat can be challenging. Consistent historical, clinical, haematological and radiographic abnormalities are often lacking and findings may be non-specific. Astute clinical acumen, thorough investigation and high quality laboratory analysis are usually required for a diagnosis. Bronchoalveolar lavage, if feasible, and tests for lungworm should be routine in cats with lower respiratory tract signs. Lung fine needle aspiration may be useful in cases of diffuse or nodular pulmonary disease. Histopathology is rarely employed in ante-mortem investigations. EVIDENCE BASE: The authors have reviewed a substantial body of literature to provide information on many of the reported bacterial, parasitic, fungal and viral pathogens, including some that occur in Asia. Attention has been given to specific therapy for each pathogen, with evidence-based comments when there is a deviation from routine recommendations.

Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial.

BACKGROUND: Identification of new ways to increase access to antiretroviral therapy in Africa is an urgent priority. We assessed whether home-based HIV care was as effective as was facility-based care. METHODS: We undertook a cluster-randomised equivalence trial in Jinja, Uganda. 44 geographical areas in nine strata, defined according to ratio of urban and rural participants and distance from the clinic, were randomised to home-based or facility-based care by drawing sealed cards from a box. The trial was integrated into normal service delivery. All patients with WHO stage IV or late stage III disease or CD4-cell counts fewer than 200 cells per microL who started antiretroviral therapy between Feb 15, 2005, and Dec 19, 2006, were eligible, apart from those living on islands. Follow-up continued until Jan 31, 2009. The primary endpoint was virological failure, defined as RNA more than 500 copies per mL after 6 months of treatment. The margin of equivalence was 9% (equivalence limits 0.69-1.45). Analyses were by intention to treat and adjusted for baseline CD4-cell count and study stratum. This trial is registered at http://isrctn.org, number ISRCTN 17184129. FINDINGS: 859 patients (22 clusters) were randomly assigned to home and 594 (22 clusters) to facility care. During the first year, 93 (11%) receiving home care and 66 (11%) receiving facility care died, 29 (3%) receiving home and 36 (6%) receiving facility care withdrew, and 8 (1%) receiving home and 9 (2%) receiving facility care were lost to follow-up. 117 of 729 (16%) in home care had virological failure versus 80 of 483 (17%) in facility care: rates per 100 person-years were 8.19 (95% CI 6.84-9.82) for home and 8.67 (6.96-10.79) for facility care (rate ratio [RR] 1.04, 0.78-1.40; equivalence shown). Two patients from each group were immediately lost to follow-up. Mortality rates were similar between groups (0.95 [0.71-1.28]). 97 of 857 (11%) patients in home and 75 of 592 (13%) in facility care were admitted at least once (0.91, 0.64-1.28). INTERPRETATION: This home-based HIV-care strategy is as effective as is a clinic-based strategy, and therefore could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care.

Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship.

BACKGROUND: Organisms resistant to antimicrobials continue to emerge and spread. This study was performed to measure the medical and societal cost attributable to antimicrobial-resistant infection (ARI). METHODS: A sample of high-risk hospitalized adult patients was selected. Measurements included ARI, total cost, duration of stay, comorbidities, acute pathophysiology, Acute Physiology and Chronic Health Evaluation III score, intensive care unit stay, surgery, health care-acquired infection, and mortality. Hospital services used and outcomes were abstracted from electronic and written medical records. Medical costs were measured from the hospital perspective. A sensitivity analysis including 3 study designs was conducted. Regression was used to adjust for potential confounding in the random sample and in the sample expanded with additional patients with ARI. Propensity scores were used to select matched control subjects for each patient with ARI for a comparison of mean cost for patients with and without ARI. RESULTS: In a sample of 1391 patients, 188 (13.5%) had ARI. The medical costs attributable to ARI ranged from $18,588 to $29,069 per patient in the sensitivity analysis. Excess duration of hospital stay was 6.4-12.7 days, and attributable mortality was 6.5%. The societal costs were $10.7-$15.0 million. Using the lowest estimates from the sensitivity analysis resulted in a total cost of $13.35 million in 2008 dollars in this patient cohort. CONCLUSIONS: The attributable medical and societal costs of ARI are considerable. Data from this analysis could form the basis for a more comprehensive evaluation of the cost of resistance and the potential economic benefits of prevention programs.

A test of the "flexible stem" model of evolution: ancestral plasticity, genetic accommodation, and morphological divergence in the threespine stickleback radiation.

If an ancestral stem group repeatedly colonizes similar environments, developmental plasticity specific to that group should consistently give rise to similar phenotypes. Parallel selection on those similar phenotypes could lead to the repeated evolution of characteristic ecotypes, a property common to many adaptive radiations. A key prediction of this "flexible stem" model of adaptive radiation is that patterns of phenotypic divergence in derived groups should mirror patterns of developmental plasticity in their common ancestor. The threespine stickleback radiation provides an excellent opportunity to test this prediction because the marine form is representative of the ancestral stem group, which has repeatedly given rise to several characteristic ecotypes. We examined plasticity of several aspects of shape and trophic morphology in response to diets characteristic of either the derived benthic ecotype or the limnetic ecotype. When marine fish were reared on alternative diets, plasticity of head and mouth shape paralleled phenotypic divergence between the derived ecotypes, supporting the flexible stem model. Benthic and limnetic fish exhibited patterns of plasticity similar to those of the marine population; however, some differences in population means were present, as well as subtle differences in shape plasticity in the benthic population, indicating a role for genetic accommodation in this system.

Heat shock protein 90 modulates endothelial nitric oxide synthase activity and vascular reactivity in the newborn piglet pulmonary circulation.

Heat shock protein 90 (Hsp90) binding to endothelial nitric oxide synthase (eNOS) is an important step in eNOS activation. The conformational state of bound Hsp90 determines whether eNOS produces nitric oxide (NO) or superoxide (O(2)(*-)). We determined the effects of the Hsp90 antagonists geldanamycin (GA) and radicicol (RA) on basal and ACh-stimulated changes in vessel diameter, cGMP production, and Hsp90:eNOS coimmunoprecipitation in piglet resistance level pulmonary arteries (PRA). In perfused piglet lungs, we evaluated the effects of GA and RA on ACh-stimulated changes in pulmonary arterial pressure (Ppa) and perfusate accumulation of stable NO metabolites (NOx(-)). The effects of GA and RA on ACh-stimulated O(2)(*-) generation was investigated in cultured pulmonary microvascular endothelial cells (PMVEC) by dihydroethidine (DHE) oxidation and confocal microscopy. Hsp90 inhibition with GA or RA reduced ACh-mediated dilation, abolished the ACh-stimulated increase in cGMP, and reduced eNOS:Hsp90 coprecipitation. GA and RA also inhibited the ACh-mediated changes in Ppa and NOx(-) accumulation rates in perfused lungs. ACh increased the rate of DHE oxidation in PMVEC pretreated with GA and RA but not in untreated cells. The cell-permeable superoxide dismutase mimetic M40401 reversed GA-mediated inhibition of ACh-induced dilation in PRA. We conclude that Hsp90 is a modulator of eNOS activity and vascular reactivity in the newborn piglet pulmonary circulation. Uncoupling of eNOS with GA or RA inhibits ACh-mediated dilation by a mechanism that involves O(2)(*-) generation.

Lymphangiosarcoma in two cats.

Lymphangiosarcoma is a malignant neoplasm of the lymphatic endothelium that is rare in cats. This report describes two cases of feline lymphangiosarcoma that originated in the distal limb, causing intractable lymphoedema and serosanguineous discharge with ecchymoses in local and distant sites. In association with the neoplasia, one cat had cortical bone lysis of multiple metacarpal bones of the affected limb and the other had severe immune-mediated haemolytic anaemia (IMHA). The disease in both cases affected young cats and progressed rapidly. Persistent distal limb lymphoedema with serosanguineous discharge is suggestive of lymphangiosarcoma especially when local or distal ecchymoses are evident.

beta-Agonist enhances type 2 T-cell survival and accumulation.

BACKGROUND: Neurohumoral modulation of immune system function is poorly understood. beta-Adrenergic receptor ligands (beta-agonists) subserve numerous physiologic processes but also function as pathogenic or therapeutic agents in numerous diseases with inflammatory components. OBJECTIVES: We sought to establish the effects of beta-agonists and prostaglandin E(2) (PGE(2)) on antigen-dependent and antigen-independent accumulation of IL-13(+) (type 2) and IFN-gamma(+) (type 1) T cells. We also sought to clarify the mechanisms mediating the effects of these G protein-coupled receptor agonists. METHODS: Effects of beta-agonists or PGE(2) on T-cell subtype accumulation were assessed in peripheral blood lymphocytes cultured with alphaCD3/CD28 or IL-2 by using flow cytometry. The role of cyclic AMP-dependent protein kinase (PKA) in mediating agonist effects was assessed by means of characterization of (1) phosphorylation of an intracellular PKA substrate and (2) T cells from patients with lupus possessing a natural defect in PKA activation. RESULTS: beta-Agonists, in contrast to PGE(2), increased IL-2-induced accumulation of human type 2 T cells, an effect attributable to differential activation of PKA affecting regulation of cell proliferation and apoptosis. In T cells from patients with lupus exhibiting defective PKA activation, both beta-agonists and PGE(2) promoted an increase in type 2 T-cell accumulation. CONCLUSION: G(s)-coupled receptors have the capacity to elicit prosurvival signaling in type 2 T cells, which, in most instances, is obscured by concomitant and antimitogenic PKA activation. CLINICAL IMPLICATIONS: beta-Agonists and other G(s)-coupled receptor agonists have the potential to regulate T-cell development to affect disease pathogenesis or the efficacy of therapies, and variability of effect relates to the ability to stimulate PKA activity.