CFTR modulator therapies - Effect on life expectancy in people with cystic fibrosis.

CFTR modulators have dramatically changed the clinical course of CF in those fortunate enough to receive them. Inevitably, randomised controlled trials during the development of these drugs are too short to use mortality as an outcome. Evidence for their effect on life expectancy are best gained from real world registry studies specifically looking at mortality, but these are only available for ivacaftor to date. Therefore, indirect evidence must be obtained by looking at outcomes known to affect mortality and seeing the effect of these drugs on those outcomes.

Estrogen receptor-alpha knockouts and maternal memory in nulliparous rats.

The current study investigated the role of estrogen receptor alpha (Esr1) in maternal memory in rats, comparing the induction and retention responses of Esr1 knockout (KO) and wild type (WT) nulliparous rats towards foster pups. Thirty days after completion of induction testing, subjects were tested for the retention of maternal care in their home cage and then for maternal behaviors in a novel cage. Both WT and Esr1 KO females displayed similar latencies to respond to foster young during the initial induction testing. Likewise, reinduction latencies to display full maternal responsiveness were similar in the Esr1 KO and WT groups during maternal memory testing in the home cage. However, in the novel cage testing WT subjects displayed modest modifications in maternal care. WT females had shorter latencies to first retrieve and mouth a test pup. These findings suggest that while Esr1 does not appear to affect the establishment of maternal care or the display of maternal memory, it may modulate aspects of pup-directed behaviors associated with the reinduction of maternal care in female rats.

Experiences of coeliac disease in a changing gluten-free landscape.

BACKGROUND: Coeliac disease is an autoimmune disorder triggered by the ingestion of gluten. In recent years, there has been considerable increase in the availability of gluten-free products in North America. The present study investigated how the recent proliferation of the gluten-free industry has affected individuals living with coeliac disease, with a primary focus on their social lives and relationships. METHODS: Interpretive phenomenology was utilised for study design and analysis. Semi-structured interviews were conducted with 17 adults diagnosed with coeliac disease in Calgary, Alberta. Interviews were audio recorded and then transcribed for analysis. RESULTS: People living with coeliac disease experience the growth of the gluten-free industry as a 'double-edged sword'. Although they are grateful for more palatable gluten-free options, they are increasingly faced with misunderstandings about the severity of coeliac disease as a result of many noncoeliac disease individuals subscribing to the gluten-free diet. This 'double-edged sword' made certain types of social situations more easily manageable (e.g. more gluten-free options available at restaurants), whereas others produced distress (e.g. increased risk of inadvertently consuming gluten). Participants also felt they may be perceived or even perceived themselves differently (e.g. felt high maintenance). To help mitigate these social ramifications of following the gluten-free diet, participants utilised various strategies. CONCLUSIONS: The sole medical recommendation of a gluten-free diet fails to acknowledge the ongoing difficulties those with coeliac disease can endure in the current gluten-free landscape. Recommendations beyond the gluten-free diet are advisable to alleviate many of the indirect burdens revealed in the present study.

Mercury-induced aggregation of human lens γ-crystallins reveals a potential role in cataract disease.

Cataract disease results from non-amyloid aggregation of eye lens proteins and is the leading cause of blindness in the world. A variety of studies have implicated both essential and xenobiotic metals as potential etiological agents in cataract disease. Essential metal ions, such as copper and zinc, are known to induce the aggregation in vitro of human γD crystallin, one of the more abundant γ-crystallins in the core of the lens. In this study, we expand the investigation of metal-crystallin interactions to heavy metal ions, such as divalent lead, cadmium and mercury. The impact of these metal ions in the non-amyloid aggregation, protein folding and thermal stability of three homologous human lens γ-crystallins has been evaluated using turbidity assays, electron microscopy, electronic absorption and circular dichroism spectroscopies. Our results show that Hg(II) ions can induce the non-amyloid aggregation of human γC and γS crystallins, but not γD crystallin. The mechanism of Hg-induced aggregation involves direct metal-protein interactions, loss of thermal stability, partial unfolding of the N-terminal domain of these proteins, and formation of disulfide-bridged dimers. Putative Hg(II) binding sites in γ-crystallins involved in metal-induced aggregation are discussed. This study reveals that mercury ions can induce the aggregation of human lens proteins, uncovering a potential role of this heavy metal ion in the bioinorganic chemistry of cataract disease.

Subliminal and supraliminal processing of reward-related stimuli in anorexia nervosa.

BACKGROUND: Previous studies have highlighted the role of the brain reward and cognitive control systems in the etiology of anorexia nervosa (AN). In an attempt to disentangle the relative contribution of these systems to the disorder, we used functional magnetic resonance imaging (fMRI) to investigate hemodynamic responses to reward-related stimuli presented both subliminally and supraliminally in acutely underweight AN patients and age-matched healthy controls (HC). METHODS: fMRI data were collected from a total of 35 AN patients and 35 HC, while they passively viewed subliminally and supraliminally presented streams of food, positive social, and neutral stimuli. Activation patterns of the group × stimulation condition × stimulus type interaction were interrogated to investigate potential group differences in processing different stimulus types under the two stimulation conditions. Moreover, changes in functional connectivity were investigated using generalized psychophysiological interaction analysis. RESULTS: AN patients showed a generally increased response to supraliminally presented stimuli in the inferior frontal junction (IFJ), but no alterations within the reward system. Increased activation during supraliminal stimulation with food stimuli was observed in the AN group in visual regions including superior occipital gyrus and the fusiform gyrus/parahippocampal gyrus. No group difference was found with respect to the subliminal stimulation condition and functional connectivity. CONCLUSION: Increased IFJ activation in AN during supraliminal stimulation may indicate hyperactive cognitive control, which resonates with clinical presentation of excessive self-control in AN patients. Increased activation to food stimuli in visual regions may be interpreted in light of an attentional food bias in AN.

Acute effects of exercise on appetite, ad libitum energy intake and appetite-regulatory hormones in lean and overweight/obese men and women.

BACKGROUND: Acute exercise does not elicit compensatory changes in appetite parameters in lean individuals; however, less is known about responses in overweight individuals. This study compared the acute effects of moderate-intensity exercise on appetite, energy intake and appetite-regulatory hormones in lean and overweight/obese individuals. METHODS: Forty-seven healthy lean (n=22, 11 females; mean (s.d.) 37.5 (15.2) years; 22.4 (1.5) kg m-2) and overweight/obese (n=25, 11 females; 45.0 (12.4) years, 29.2 (2.9) kg m-2) individuals completed two, 8 h trials (exercise and control). In the exercise trial, participants completed 60 min treadmill exercise (59 (4)% peak oxygen uptake) at 0-1 h and rested thereafter while participants rested throughout the control trial. Appetite ratings and concentrations of acylated ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) were measured at predetermined intervals. Standardised meals were consumed at 1.5 and 4 h and an ad libitum buffet meal was provided at 7 h. RESULTS: Exercise suppressed appetite (95% confidence interval (CI) -3.1 to -0.5 mm, P=0.01), and elevated delta PYY (95% CI 10 to 17 pg ml-1, P<0.001) and GLP-1 (95% CI 7 to 10 pmol l-1, P<0.001) concentrations. Delta acylated ghrelin concentrations (95% CI -5 to 3 pg ml-1, P=0.76) and ad libitum energy intake (95% CI -391 to 346 kJ, P=0.90) were similar between trials. Subjective and hormonal appetite parameters and ad libitum energy intake were similar between lean and overweight/obese individuals (P⩾0.27). The exercise-induced elevation in delta GLP-1 was greater in overweight/obese individuals (trial-by-group interaction P=0.01), whereas lean individuals exhibited a greater exercise-induced increase in delta PYY (trial-by-group interaction P<0.001). CONCLUSIONS: Acute moderate-intensity exercise transiently suppressed appetite and increased PYY and GLP-1 in the hours after exercise without stimulating compensatory changes in appetite in lean or overweight/obese individuals. These findings underscore the ability of exercise to induce a short-term energy deficit without any compensatory effects on appetite regardless of weight status.

Temporal delay discounting in acutely ill and weight-recovered patients with anorexia nervosa.

BACKGROUND: Patients with anorexia nervosa (AN) are characterized by a very low body weight but readily give up immediate rewards (food) for long-term goals (slim figure), which might indicate an unusual level of self-control. This everyday clinical observation may be quantifiable in the framework of the anticipation-discounting dilemma. METHOD: Using a cross-sectional design, this study compared the capacity to delay reward in 34 patients suffering from acute AN (acAN), 33 weight-recovered AN patients (recAN) and 54 healthy controls. We also used a longitudinal study to reassess 21 acAN patients after short-term weight restoration. A validated intertemporal choice task and a hyperbolic model were used to estimate temporal discounting rates. RESULTS: Confirming the validity of the task used, decreased delay discounting was associated with age and low self-reported impulsivity. However, no group differences in key measures of temporal discounting of monetary rewards were found. CONCLUSIONS: Increased cognitive control, which has been suggested as a key characteristic of AN, does not seem to extend the capacity to wait for delayed monetary rewards. Differences between our study and the only previous study reporting decreased delay discounting in adult AN patients may be explained by the different age range and chronicity of acute patients, but the fact that weight recovery was not associated with changes in discount rates suggests that discounting behavior is not a trait marker in AN. Future studies using paradigms with disorder-specific stimuli may help to clarify the role of delay discounting in AN.

Interleukin-6 in combination with the interleukin-6 receptor stimulates glucose uptake in resting human skeletal muscle independently of insulin action.

AIM: To examine if the physiological concentrations of both interleukin-6 (IL-6), in combination with IL-6 receptor (IL-6R), are able to stimulate glucose uptake in human skeletal muscle and to identify the associated signalling pathways. METHODS: Skeletal muscle tissue (~60 mg) obtained from healthy female volunteers via muscle biopsy was subjected to incubation in the absence or presence of insulin (60 µU/ml), recombinant human IL-6 (rhIL-6) (4 ng/ml) or a combination of rhIL-6 (4 ng/ml) and rhIL-6R (100 ng/ml) for 30 min, with glucose transport measured for each incubation. Western blot analysis was conducted on key signalling proteins, protein kinase B (PKB/Akt), adenosine monophosphate kinase (AMPK) and mammalian target of rapamycin (mTOR) to gain an early insight into any differing transport mechanisms. RESULTS: Human skeletal muscle exhibited increased glucose uptake with insulin (1.85-fold; p < 0.05) and stimulated phosphorylation of PKB/Akt and AMPK (0.98 ± 0.23 and 1.49 ± 0.13, respectively, phosphorylated: total; p < 0.05). IL-6/IL-6R increased phosphorylation of mTOR (fourfold, p < 0.05) compared to insulin, IL-6 alone and basal control. IL-6 did not stimulate glucose uptake but combined with IL-6R, induced 1.5-fold increase in glucose uptake (p < 0.05) and phosphorylation of AMPK (0.95 ± 0.19; phosphorylated: total, p < 0.05). CONCLUSIONS: IL-6 in combination with IL-6R and not IL-6 alone increased glucose uptake in human skeletal muscle. IL-6/IL-6R-mediated glucose uptake occurred independently of PKB/Akt phosphorylation, showing that IL-6/IL-6R-induced glucose uptake is dependent on a divergent pathway.

The effect of physical activity on mediators of inflammation.

Being physically active and undertaking exercise on a regular basis are critical lifestyle behaviours which protect against the development of numerous chronic metabolic conditions. One of the key mechanisms by which physical activity exerts favourable health effects appears to be due to its capacity to reduce chronic low-grade inflammation. Single bouts of exercise have a potent anti-inflammatory influence with recent advances describing important effects of acute exercise on inflammatory mediators produced within skeletal muscle (myokines), adipose tissue (adipokines) and leucocytes. The accumulated effects of physical activity or exercise training on systemic inflammation have been studied widely within epidemiological research; however, information from intervention trials is still emerging. Current data suggest that the most marked improvements in the inflammatory profile are conferred with exercise performed at higher intensities, with combined aerobic and resistance exercise training potentially providing the greatest benefit. The purpose of this review is to describe recent advances in our understanding surrounding the acute and chronic effects of physical activity on key mediators of inflammation. Within this, particular attention is given to the interleukin-6 system owing to its apparent centrality in mediating the anti-inflammatory effects of exercise.

Indications of a spatial variation of the fine structure constant.

We previously reported Keck telescope observations suggesting a smaller value of the fine structure constant α at high redshift. New Very Large Telescope (VLT) data, probing a different direction in the Universe, shows an inverse evolution; α increases at high redshift. Although the pattern could be due to as yet undetected systematic effects, with the systematics as presently understood the combined data set fits a spatial dipole, significant at the 4.2 σ level, in the direction right ascension 17.5 ± 0.9 h, declination -58 ± 9 deg. The independent VLT and Keck samples give consistent dipole directions and amplitudes, as do high and low redshift samples. A search for systematics, using observations duplicated at both telescopes, reveals none so far which emulate this result.

Diet- but not exercise-induced iso-energetic deficit induces compensatory appetitive responses.

Although physical exercise and dietary restriction can be both used to induce energy deficits, they have been suggested to favor different compensatory appetitive responses. While dietary restriction might favor increased subsequent energy intake and appetite sensations, such compensatory responses have not been observed after a similar deficit by exercise. The present work provides a first overview of the actual evidences discussing the effects of iso-energetic deficits induced by exercise versus dietary restriction on subsequent energy intake, appetite sensations, and on the potentially involved hedonic and physiological mechanisms.

Requirement of the chemokine receptor CXCR3 for acute allograft rejection.

Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein-coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-gamma-inducible protein of 10 kD (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T cell alpha chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3(-/)-) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3(-/)- allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR(+/+) mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.

LHRH-Conjugated Drugs as Targeted Therapeutic Agents for the Specific Targeting and Localized Treatment of Triple Negative Breast Cancer.

Bulk chemotherapy and drug release strategies for cancer treatment have been associated with lack of specificity and high drug concentrations that often result in toxic side effects. This work presents the results of an experimental study of cancer drugs (prodigiosin or paclitaxel) conjugated to Luteinizing Hormone-Releasing Hormone (LHRH) for the specific targeting and treatment of triple negative breast cancer (TNBC). Injections of LHRH-conjugated drugs (LHRH-prodigiosin or LHRH-paclitaxel) into groups of 4-week-old athymic female nude mice (induced with subcutaneous triple negative xenograft breast tumors) were found to specifically target, eliminate or shrink tumors at early, mid and late stages without any apparent cytotoxicity, as revealed by in vivo toxicity and ex vivo histopathological tests. Our results show that overexpressed LHRH receptors serve as binding sites on the breast cancer cells/tumor and the LHRH-conjugated drugs inhibited the growth of breast cells/tumor in in vitro and in vivo experiments. The inhibitions are attributed to the respective adhesive interactions between LHRH molecular recognition units on the prodigiosin (PGS) and paclitaxel (PTX) drugs and overexpressed LHRH receptors on the breast cancer cells and tumors. The implications of the results are discussed for the development of ligand-conjugated drugs for the specific targeting and treatment of TNBC.

Heterogeneity of vertebrate luteinizing hormone-releasing hormone.

Radioimmunoassay and chromatography analyses of hypothalamic luteinizing hormone-releasing hormone (LHRH) have demonstrated the presence of LHRH-like immunoreactive peptides in a wide range of vertebrates. Contrary to previous reports, the molecule differs in various vertebrates. Avian, reptilian, and teleostean LHRH's are chemically distinct from the mammalian peptide but are in themselves indistinguishable. However, amphibian LHRH appears to be identical to the mammalian peptide. These findings have interesting evolutionary implications.

The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor.

Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) are multifunctional cytokines with many similar activities. LIF is structurally and functionally related to another cytokine, Oncostatin M (OSM), that binds to the high-affinity LIF receptor but not to the low-affinity LIF receptor. A complementary DNA was isolated that encodes the high-affinity converting subunit of the LIF receptor. The converter conferred high-affinity binding of both LIF and OSM when expressed with the low-affinity LIF receptor and is identical to the signal transducing subunit of the IL-6 receptor, gp130. The gp130 subunit alone confers low-affinity binding of OSM when expressed in COS-7 cells. This receptor system resembles the high-affinity receptors for granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5, which share a common subunit.

Role of medical intervention in slowing the growth of small abdominal aortic aneurysms.

Abdominal aortic aneurysm is a common-but preventable-cause of death in elderly men; 4% of men at the age of 65 years have an aorta >3 cm in diameter. Continued expansion runs the risk of aneurysm rupture, a condition that is fatal in all but 15% of individuals. A national screening programme has commenced that aims to reduce the number of deaths from aneurysm rupture by 50%. The programme will detect a large number of men with a small aneurysm who are not in imminent danger of rupture, but who will join a regular ultrasound programme of surveillance. If the aneurysm expansion rate could be reduced, fewer men would be at risk of aneurysm rupture, and fewer would need elective aneurysm repair. A considerable amount is known about the pathophysiology of aneurysm growth. Exploring pharmacological means to delay or reduce aneurysm growth could make a considerable contribution to any screening programme. A number of case control studies have suggested that some antihypertensive drugs, non-steroidal anti-inflammatory drugs, antibiotics, and statins may reduce aneurysm growth rates. Data from controlled studies have provided less secure conclusions. Use of these medications, together with lifestyle modification such as stopping smoking, could become standard advice to men with a small aortic aneurysm. Further studies of novel agents and larger controlled trials of existing drugs are warranted.

Sex Differences in Cognitive Flexibility and Resting Brain Networks in Middle-Aged Marmosets.

Sex differences in human cognitive performance are well characterized. However, the neural correlates of these differences remain elusive. This issue may be clarified using nonhuman primates, for which sociocultural influences are minimized. We used the marmoset (Callithrix jacchus) to investigate sex differences in two aspects of executive function: reversal learning and intradimensional/extradimensional (ID/ED) set shifting. Stress reactivity and motor function were also assessed. In agreement with human literature, females needed more trials than males to acquire the reversals. No sex differences in ED set shifting or motivational measures were observed. The findings suggest enhanced habit formation in females, perhaps due to striatal estrogenic effects. Both sexes showed increased urinary cortisol during social separation stressor, but females showed an earlier increase in cortisol and a greater increase in agitated locomotion, possibly indicating enhanced stress reactivity. Independent of sex, basal cortisol predicted cognitive performance. No sex differences were found in motor performance. Associations between brain networks and reversal learning performance were investigated using resting state fMRI. Resting state functional connectivity (rsFC) analyses revealed sex differences in cognitive networks, with differences in overall neural network metrics and specific regions, including the prefrontal cortex, caudate, putamen, and nucleus accumbens. Correlations between cognitive flexibility and neural connectivity indicate that sex differences in cognitive flexibility are related to sex-dependent patterns of resting brain networks. Overall, our findings reveal sex differences in reversal learning, brain networks, and their relationship in the marmoset, positioning this species as an excellent model to investigate the biological basis of cognitive sex differences.

Comparing the Mechanical Response of Di-, Tri-, and Tetra-functional Resin Epoxies with Reactive Molecular Dynamics.

The influence of monomer functionality on the mechanical properties of epoxies is studied using Molecular Dynamics (MD) with the Reax Force Field (ReaxFF). From deformation simulations, the Young's modulus, yield point, and Poisson's ratio are calculated and analyzed. The results demonstrate an increase in stiffness and yield strength with increasing resin functionality. Comparison between the network structures of distinct epoxies is further advanced by the Monomeric Degree Index (MDI). Experimental validation demonstrates the MD results correctly predict the relationship in Young's moduli. Therefore, ReaxFF is confirmed to be a useful tool for studying the mechanical behavior of epoxies.

The effect of exercise training on intrahepatic triglyceride and hepatic insulin sensitivity: a systematic review and meta-analysis.

This systematic review and meta-analysis determined the impact of structured exercise training, and the influence of associated weight loss, on intrahepatic triglyceride (IHTG) in individuals with non-alcoholic fatty liver disease (NAFLD). It also examined its effect on hepatic insulin sensitivity in individuals with or at increased risk of NAFLD. Analyses were restricted to studies using magnetic resonance spectroscopy or liver biopsy for the measurement of IHTG and isotope-labelled glucose tracer for assessment of hepatic insulin sensitivity. Pooling data from 17 studies (373 exercising participants), exercise training for one to 24 weeks (mode: 12 weeks) elicits an absolute reduction in IHTG of 3.31% (95% CI: -4.41 to -2.22%). Exercise reduces IHTG independent of significant weight change (-2.16 [-2.87 to -1.44]%), but benefits are substantially greater when weight loss occurs (-4.87 [-6.64 to -3.11]%). Furthermore, meta-regression identified a positive association between percentage weight loss and absolute reduction in IHTG (ß = 0.99 [0.62 to 1.36], P < 0.001). Pooling of six studies (94 participants) suggests that exercise training also improves basal hepatic insulin sensitivity (mean change in hepatic insulin sensitivity index: 0.13 [0.05 to 0.21] mg m-2  min-1 per µU mL-1 ), but available evidence is limited, and the impact of exercise on insulin-stimulated hepatic insulin sensitivity remains unclear.