Eicosapentaenoic acid and oxypurinol in the treatment of muscle wasting in a mouse model of cancer cachexia

Cancer cachexia is a wasting condition, driven by systemic inflammation and oxidative stress. This study investigated eicosapentaenoic acid (EPA) in combination with oxypurinol as a treatment in a mouse model of cancer cachexia. Mice with cancer cachexia were randomized into 4 treatment groups (EPA (0.4 g/kg/day), oxypurinol (1 mmol/L ad-lib), combination, or control), and euthanized after 29 days. Analysis of oxidative damage to DNA, mRNA analysis of pro-oxidant, antioxidant and proteolytic pathway components, along with enzyme activity of pro- and antioxidants were completed on gastrocnemius muscle. The control group displayed earlier onset of tumor compared to EPA and oxypurinol groups (P&lt;0.001). The EPA group maintained body weight for an extended duration (20 days) compared to the oxypurinol (5 days) and combination (8 days) groups (P&lt;0.05). EPA (18.2&plusmn;3.2 pg/ml) and combination (18.4&plusmn;3.7 pg/ml) groups had significantly higher 8-OH-dG levels than the control group (12.9&plusmn;1.4 pg/ml, P&le;0.05) indicating increased oxidative damage to DNA. mRNA levels of GPx1, MURF1 and MAFbx were higher following EPA treatment compared to control (P&le;0.05). Whereas oxypurinol was associated with higher GPx1, MnSOD, CAT, XDH, MURF1, MAFbx and UbB mRNA compared to control (P&le;0.05). Activity of total SOD was higher in the oxypurinol group (32.2&plusmn;1.5 U/ml) compared to control (27.0&plusmn;1.3 U/ml, P&lt;0.01), GPx activity was lower in the EPA group (8.76&plusmn;2.0 U/ml) compared to control (14.0&plusmn;1.9 U/ml, P&lt;0.05), and catalase activity was lower in the combination group (14.4&plusmn;2.8 U/ml) compared to control (20.9&plusmn;2.0 U/ml, P&lt;0.01). There was no change in XO activity. The increased rate of weight decline in mice treated with oxypurinol indicates that XO may play a protective role during the progression of cancer cachexia, and its inhibition is detrimental to outcomes. In combination with EPA, there was little significant improvement from control, indicating oxypurinol is unlikely to be a viable treatment compound in cancer cachexia.<br /

Conflict Or Congruence? Maternal and Infant-Centric Factors Associated With Shorter Exclusive Breastfeeding Durations Among the Tsimane

Six months of exclusive breastfeeding (EBF) is considered optimal for infant health, though globally most infants begin complementary feeding (CF) earlier—including among populations that practice prolonged breastfeeding. Two frameworks for understanding patterns of early CF emerge in the literature. In the first, maternal and infant needs trade-off, as “maternal-centric” factors—related to time and energy demands, reproductive investment, cultural influences, and structural barriers— favor supplanting breastfeeding with earlier and increased CF. A second framework considers that “infant-centric” factors—related to infant energetic needs—favor CF before six months to supplement breastfeeding. We apply these two frameworks in examining early CF among the Tsimane—a high-fertility, high-mortality, forager-horticulturalist population residing in the Bolivian Amazon. Data were collected from a mixed-longitudinal sample of 161 Tsimane mother-infant pairs from August 2012 – April 2013. Tsimane mothers generally reported introducing CF because of perceived infant needs. However, CF is introduced with continued intensive breastfeeding, and generally coupled with premastication. Risks of earlier CF relative to the minimum hazard (estimated at 5 births) were elevated for lower and higher parity mothers, but were significantly greater only after 9 births. Seventeen percent of mothers reported introducing CF because of low milk supply. Introducing CF because of low milk was most common from 0-3 months of age and among higher parity mothers, which may reflect physiological constraints. Maternal reproductive trade-offs and perceived infant needs may help explain the low prevalence of EBF to six months among other populations in which breastfeeding is not structurally or culturally constrained

Intraspecific competition in the speckled wood butterfly Pararge aegeria: Effect of rearing density and gender on larval life history

In insects, the outcome of intraspecific competition for food during development depends primarily upon larval density and larval sex, but effects will also depend on the particular trait under consideration and the species under study. Experimental manipulations of larval densities of a Madeiran population of the speckled wood butterfly Pararge aegeria confirmed that intraspecific competition affected growth. As densities increased P. aegeria adults were smaller and larval development periods were longer. Sexes responded differently to rearing density. Females were more adversely affected by high density than males, resulting in females having smaller masses at pupation. Survivorship was significantly higher for larvae reared at low densities. No density effect on adult sex ratios was observed. Intraspecific competition during the larval stage would appear to carry a higher cost for females than males. This may confer double disadvantage since females are dependent on their larval derived resources for reproduction as they have little opportunity to accumulate additional resources as adults. This suggests that shortages of larval food could affect fecundity directly. Males, however, may be able to compensate for a small size by feeding as adults and/or by altering their mate location tactics

Methacholine challenge – Comparison of an ATS protocol to a new rapid single concentration technique

SummaryBronchial methacholine challenge is well established in asthma diagnostics and research. ATS guidelines propose a five step standard dosimeter (SDM) protocol with incremental concentrations of methacholine to calculate the concentration causing a 20% drop in FEV1 in an individual (PC20FEV1). In contrast, the aerosol provocation system (APS) by Viasys® automatically determines the administered dose of methacholine by measuring the effective nebulisation time and referring it to drug concentration and nebuliser power. Therefore, it offers a feasible and less time-consuming provocation procedure by applying incremental doses (PD20) of methacholine using a single concentration (16mg/mL methacholine, APS-SC). In this study we compared these two methods in 52 young adults (25±5.8 years). Following a screening visit, subjects were randomly assigned to undergo either SDM or APS-SC followed by the other method within 1 week. A close correlation between concentration and dosage causing a 20% fall of FEV1 was found (r=0.69, p<0.001).Using the ATS categorisation of bronchial responsiveness we interpreted the results of the APS-SC method as follows: PD20 methacholine<0.3mg as “moderate to severe BHR”, 0.3 – 0.6mg as “mild BHR”, 0.6 – 1.0mg as “borderline BHR”, and>1.0mg as “normal bronchial response”.We conclude that the five-step APS-SC is a suitable method, providing reliable results. In clinical practice the APS-SC is a timesaving procedure and less prone to errors since only one dilution of methacholine is necessary compared to the SDM

A holistic neuropsychological approach to cognitive remediation for a community-based mixed psychiatric sample

Background: Improved real world functioning is the ultimate goal of cognitive rehabilitation (which was developed for an acquired brain injury population), however, cognitive remediation for psychiatric populations focuses primarily on cognitive interventions (e.g., computerized cognitive training) and utilizes cognitive test results as outcomes. A broader range of neuropsychological interventions and outcome measures, incorporating real-world measures of functioning, is recommended for cognitive remediation program evaluation. Objective: To determine the feasibility and explore the effectiveness of a holistic cognitive remediation program administered by clinical neuropsychologists for a community-based mixed psychiatric treatment-seeking sample. Method: Twenty-five adults of mixed psychiatric aetiology were referred for a 10-week intervention (including four hours of weekly individual and group-based sessions). A broad array of outcomes was assessed post-intervention. Functional status, self-reported cognitive symptoms and quality of life was assessed at 11.3 months follow-up. Results: Eighteen of the referred participants (72%) completed the intervention. Completers showed: a high rate of functional cognitive goal attainment; increased employment rates; improved symptoms of psychological distress and quality of life; reduced self-report of cognitive difficulties; and improved auditory attention span and verbal memory. Self-report of reduced cognitive difficulties and improved quality of life was maintained approximately one year later. The majority of participants reported very high levels of satisfaction with the program. Conclusions: This intervention was acceptable to participants and associated with high satisfaction rates and gains in cognitive, psychological and functional outcomes. Findings suggest there are multiple benefits to adopting an intervention program that is holistic, individualized to the goals of the patient and facilitated by trained neuropsychologists

ATR promotes cilia signalling: links to developmental impacts

Mutations in ATR (ataxia telangiectasia and RAD3-related) cause Seckel syndrome (ATR-SS), a microcephalic primordial dwarfism disorder. Hitherto, the clinical manifestation of ATR deficiency has been attributed to its canonical role in DNA damage response signalling following replication fork stalling/collapse. Here, we show that ATR regulates cilia-dependent signalling in a manner that can be uncoupled from its function during replication. ATR-depleted or patient-derived ATR-SS cells form cilia of slightly reduced length but are dramatically impaired in cilia-dependent signalling functions, including growth factor and Sonic hedgehog signalling. To better understand the developmental impact of ATR loss of function, we also used zebrafish as a model. Zebrafish embryos depleted of Atr resembled ATR-SS morphology, showed a modest but statistically significant reduction in cilia length and other morphological features indicative of cilia dysfunction. Additionally, they displayed defects in left-right asymmetry including ambiguous expression of southpaw, incorrectly looped hearts and randomized localization of internal organs including the pancreas, features typically conferred by cilia dysfunction. Our findings reveal a novel role for ATR in cilia signalling distinct from its canonical function during replication and strengthen emerging links between cilia function and development

Fatty Acid Composition in the Mature Milk of Bolivian Forager-Horticulturalists: Controlled Comparisons With a US Sample

Breast milk fatty acid (FA) composition varies greatly among individual women, including in percentages of the long-chain polyunsaturated FAs (LCPUFA) 20:4n-6 (arachidonic acid, AA) and 22:6n-3 (docosahexaenoic acid, DHA), which are important for infant neurological development. It has been suggested that owing to wide variation in milk LCPUFA and low DHA in Western diets, standards of milk FA composition should be derived from populations consuming traditional diets. We collected breast milk samples from Tsimane women at varying lactational stages (6–82 weeks). The Tsimane are an indigenous, natural fertility, subsistence-level population living in Amazonia Bolivia. Tsimane samples were matched by lactational stage to samples from a US milk bank, and analysed concurrently for FA composition by gas-liquid chromatography. We compared milk FA composition between Tsimane (n = 35) and US (n = 35) mothers, focusing on differences in LCPUFA percentages that may be due to population-typical dietary patterns. Per total FAs, the percentages of AA, DHA, total n-3 and total n-6 LCPUFA were significantly higher among Tsimane mothers. Mean percentages of 18:2n-6 (linoleic acid) and trans FAs were significantly higher among US mothers. Tsimane mothers’ higher milk n-3 and n-6 LCPUFA percentages may be due to their regular consumption of wild game and freshwater fish, as well as comparatively lower intakes of processed foods and oils that may interfere with LCPUFA synthesis