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Aims: Type 1 diabetes (T1D) has a strong genetic predisposition and requires an environmental trigger to initiate the beta‐cell autoimmune destruction. The rate of childhood obesity has risen in parallel to the proportion of T1D, suggesting high‐fat diet (HFD)/obesity as potential environmental triggers for autoimmune diabetes. To explore this, non‐obese diabetic (NOD) mice were subjected to HFD and monitored for the development of diabetes, insulitis and beta‐cell stress. Materials and Methods: Four‐week‐old female NOD mice were placed on HFD (HFD‐NOD) or standard chow‐diet. Blood glucose was monitored weekly up to 40 weeks of age, and glucose‐ and insulin‐tolerance tests performed at 4, 10 and 15 weeks. Pancreata and islets were analysed for insulin secretion, beta‐cell mass, inflammation, insulitis and endoplasmic reticulum stress markers. Immune cell levels were measured in islets and spleens. Stool microbiome was analysed at age 4, 8 and 25 weeks. Results: At early ages, HFD‐NOD mice showed a significant increase in body weight, glucose intolerance and insulin resistance; but paradoxically, they were protected from developing diabetes. This was accompanied by increased insulin secretion and beta‐cell mass, decreased insulitis, increased splenic T‐regulatory cells and altered stool microbiome. Conclusions: This study shows that HFD protects NOD mice from autoimmune diabetes and preserves beta‐cell mass and function through alterations in gut microbiome, increased T‐regulatory cells and decreased insulitis. Further studies into the exact mechanism of HFD‐mediated prevention of diabetes in NOD mice could potentially lead to interventions to prevent or delay T1D development in humans. [ABSTRACT FROM AUTHOR]

A number of researchers have examined undocumented migration from Central America. This literature lacks information about adult beliefs regarding the motivations of minors who journey from Central America unaccompanied and undocumented. Using data from a recent survey conducted in Honduras, we examine adult Hondurans' beliefs about why unaccompanied minors leave the country unaccompanied. The dependent variable is a dummy variable that measures "why children leave the country." Predictor variables are attitudes toward smuggling, willingness to leave without documentation, deportation experience, age, income, and residence in the northern part of Honduras. Using multinomial logistic regression, we find support for four of the eight hypotheses. Findings indicate that adults from the northern region are most likely to believe minors would leave for reasons associated with undocumented immigration. Those who are younger, with lower incomes, and with less access to sanitation are more likely to believe minors would leave without documentation. [ABSTRACT FROM AUTHOR]

Type 1 diabetes results from the autoimmune destruction of pancreatic β cells, leading to insulin deficiency and hyperglycemia. Although multiple attempts have been made to slow the autoimmune process using immunosuppressive or immunomodulatory agents, there are still no effective treatments that can delay or reverse the progression of type 1 diabetes in humans. Recent studies support endoplasmic reticulum (ER) as a novel target for preventing the initiation of the autoimmune reaction, propagation of inflammation, and β cell death in type 1 diabetes. This review highlights recent findings on ER stress in β cells and development of type 1 diabetes and introduces potential new treatments targeting the ER to combat this disorder. [ABSTRACT FROM AUTHOR]

Background and objective The COPD Assessment Test ( CAT) is a recently introduced, simple-to-use health status instrument that takes less time to complete than better-established health status instruments. In chronic obstructive pulmonary disease ( COPD) patients, the CAT improves with pulmonary rehabilitation ( PR), and changes correlate with improvements in longer-established health status instruments such as the Chronic Respiratory Questionnaire ( CRQ). Increasing numbers of non- COPD patients are referred for PR, but it is not known whether the CAT is responsive to PR in these populations. Methods The CAT score was prospectively measured in 365 consecutive patients (255 COPD, 110 non- COPD) before and after an 8-week PR programme. Pre to post change in CAT was calculated for COPD and non- COPD patients, and correlated with change in the CRQ. Results For both non- COPD and COPD patients, there was a similar and significant improvement in the mean (95% confidence interval) CAT score following PR (non- COPD: −2.1 (−1.0, −3.2) vs COPD: −3.0 (−2.2, −3.8); P = 0.19). Change in CAT was significantly correlated with all domains of the CRQ in non- COPD patients (all P < 0.01). Conclusions As in COPD patients, the CAT is immediately responsive to PR in non- COPD patients. Even in unselected chronic respiratory disease patients undergoing PR, the CAT is a practical alternative to longer-established health status questionnaires. [ABSTRACT FROM AUTHOR]

Growth factors, hormones, and neurotransmitters have been implicated in the regulation of stem cell fate. Since various neural precursors express functional neurotransmitter receptors, which include G protein-coupled receptors, it is anticipated that they are involved in cell fate decisions. We detected μ-opioid receptor (MOR-1) and κ-opioid receptor (KOR-1) expression and immunoreactivity in embryonic stem (ES) cells and in retinoic acid-induced ES cell-derived, nestin-positive, neural progenitors. Moreover, these G protein-coupled receptors are functional, since [D-Ala²,MePhe4,Gly-ol5] enkephalin, a MOR-selective agonist, and U69,593, a KOR-selective agonist, induce a sustained activation of extracellular signal-regulated kinase (ERK) signaling throughout a 24-h treatment period in undifferentiated, self-renewing ES cells. Both opioids promote limited proliferation of undifferentiated ES cells via the ERK/MAP kinase signaling pathway. Importantly, biochemical and immunofluorescence data suggest that [D-Ala²,MePhe4,Gly-ol5]enkephalin and U69,593 divert ES cells from self-renewal and coax the cells to differentiate. In retinoic acid-differentiated ES cells, opioid-induced signaling features a biphasic ERK activation profile and an opioid-induced, ERK-independent inhibition of proliferation in these neural progenitors. Collectively, the data suggest that opioids may have opposite effects on ES cell self-renewal and ES cell differentiation and that ERK activation is only required by the latter. Finally, opioid modulation of ERK activity may play an important role in ES cell fate decisions by directing the cells to specific lineages. [ABSTRACT FROM AUTHOR]

Acute μ and κ opioids activate the ERK/MAPK phosphorylation cascade that represents an integral part of the signaling pathway of growth factors in astrocytes. By this cross-talk, opioids may impact neural development and plasticity among other basic neurobiological processes in vivo. The μ agonist, [D-ala²,mephe4,glyol5]enkephalin (DAMGO), induces a transient stimulation of ERK phosphorylation, whereas κ agonist, U69,593, engenders sustained ERK activation. Here we demonstrate that acute U69,593 and DAMGO stimulate ERK phosphorylation by utilization of different secondary messengers and protein kinase C (PKC) isoforms upstream of the growth factor pathway. Immortalized astrocytes transfected with either antisense calmodulin (CAM), a mutant μ opioid receptor that binds CaM poorly or a dominant negative mutant of PKCϵ were used as a model system to study μ signaling. Evidence was gained to implicate CAM and PKCϵ in DAMGO stimulation of ERK. DAMGO activation of PKCϵ and/or ERK was insensitive to selective inhibitors of Ca2+ mobilization, but it was blocked upon phospholipase C inhibition. These results suggest a novel mechanism wherein, upon DAMGO binding, CAM is released from the p receptor and activates phospholipase C. Subsequently, phospholipase C generates diacylglycerides that activate PKCϵ. In contrast, U69,593 appears to act via phosphoinositide 3-kinase, PKCζ, and Ca2+ mobilization. These signaling components were implicated based on studies with specific inhibitors and a dominant negative mutant of PKCζ. Collectively, our findings on acute opioid effects suggest that differences in their mechanism of signaling may contribute to the distinct outcomes on ERK modulation induced by chronic μ and κ opioids. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of pancreatic beta cells. Early events within the islet leading to T1D include increased beta cell ER and oxidative stress and increased inflammatory cytokines. Autophagy is a cellular pathway activated by cell stressors which leads to decreased cellular levels of ER stress and oxidative stress, and inactivates inflammatory pathways. While there is a good amount of data suggesting impaired autophagy in type 2 diabetes, relatively little is known about changes in autophagy during the development of T1D. In the following study we characterized changes in the autophagy pathway during development of T1D using NOD mice. We compared gene expression and autophagic flux in islets from female NOD mice prior to the onset of diabetes at 4, 8,10, and 12 weeks of age. At 10 weeks of age the inflammatory cytokines IL1-B and IL-6 and the ER stress marker CHOP were markedly elevated in NOD islets. In addition, at 10 weeks of age, TFEB expression was also significantly elevated in islets; indicating activation of the autophagy pathway. We then evaluated autophagic flux in NOD islets by measuring LC3-II accumulation in the presence or absence of chloroquine, an inhibitor of autophagosome to lysosomal fusion. LC3-II accumulation after CQ exposure was significantly lower in islets starting at 8 weeks of age, demonstrating an impairment in autophagic flux which precedes the development of islet ER stress and diabetes. This study demonstrates activation of the autophagy pathway when islets are expressing high ER and inflammatory stress markers during the development of T1D. However, despite activation, autophagic flux is reduced. Impairments in the autophagy pathway may worsen beta cell ER, oxidative and inflammatory stress, ultimately leading to cell death and hastening the progression to diabetes. These data suggest that therapies targeting restoration of autophagy should be evaluated as interventions to delay or prevent T1D. Disclosure: A. L. Clark: None. Z. Yan: None. M. S. Remedi: None. A. Diwan: None. Funding: Washington University Diabetes Research Center (P30DK020579 to A.L.C.); National Institutes of Health (R01DK123163, R56DK098584 to M.S.R.) [ABSTRACT FROM AUTHOR]

The authors comment on a study published in this issue of the journal which examined hypoglycemia-induced arrhythmia in patients with type 2 diabetes. Particular focus is given to the link between hypoglycemia and ischemic chest pain in patients with cardiac disease. The authors recommend further study on the mechanisms underlying cardiac arrhythmia during spontaneous hypoglycemia. Limitations of the study are also discussed.

For people with diabetes, recurrent episodes of hypoglycemia limit the brain's ability to sense dangerously low blood sugar levels. In this issue of the JCI, the mechanisms behind this clinical problem of hypoglycemia unawareness are addressed by Herzog et al. The authors provide compelling evidence that recurrent hypoglycemia enhances transport of lactate into the brain and, although not itself a major alternative fuel source, lactate may preserve neuronal function during hypoglycemia by maintaining neuronal glucose metabolism. These findings redefine our understanding of the brain's metabolic adaptations that result from recurrent hypoglycemia. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) has a strong genetic predisposition and requires an environmental trigger to initiate autoimmune destruction of beta cells. The rate of childhood obesity has risen in parallel to the rate of T1D, suggesting high fat diet (HFD) may be an environmental trigger in the development of autoimmune diabetes. Supporting this hypothesis, HFD can induce insulin resistance, beta cell stress, dysfunctional insulin production, and beta cell death. To explore the role of HFD in the development of T1D, 4 week-old non-obese diabetic (NOD) female mice were placed on HFD or chow diet (CD). At 10 weeks of age NOD mice fed with HFD demonstrated a significant increase in body weight and non-fasting blood glucose along with mild glucose intolerance compared with NOD CD fed mice. Histological analysis at 10 weeks of age revealed significantly less pancreatic immune cell infiltration and increased beta cell mass in HFD fed mice compared to CD fed mice. By 15 weeks of age, HFD fed NOD animals demonstrated impaired glucose tolerance similar to CD fed mice, increased glucose-stimulated insulin secretion and total insulin content, and insulin resistance. Surprisingly, at 25 weeks of age the HFD fed NOD mice were completely protected from the development of diabetes, while as expected 70% of NOD CD fed mice had developed diabetes. In summary, this study demonstrates that in the NOD model of T1D HFD reduced islet immune cell infiltration, increased beta cell mass, insulin content and insulin secretion protecting the mice from development of diabetes. The mechanism underlying this protection seems to be two-fold: expansion of beta cell mass and prevention of autoimmune-mediated beta cell death. Our data correlate with other recent studies indicating that early stimulation of beta cell replication can induce immune tolerance in NOD animals preventing T1D. Identification of the mechanisms by which HFD leads to prevention of diabetes in NOD animals may lead to the development of novel therapeutic interventions to prevent T1D in humans. Disclosure: A.L. Clark: None. Z. Yan: None. S.X. Chen: None. M. Fuess: None. G. McGinn: None. M.S. Remedi: None. Funding: National Institutes of Health (P30DK020579, K12HD076224-04) [ABSTRACT FROM AUTHOR]

• Manipulating plant defense hormones increases the impact of fungal pathogens. • Jasmonic acid application increased the impact of CT-Rust on Cirsium arvense. • This effect was seen for belowground but not aboveground biomass. Cirsium arvense, or Canada thistle, is one of the most detrimental weeds for agricultural production. Native to south-eastern Europe, the species is now found in Many parts of Asia, North America and Australasia. In North America and New Zealand the species is considered invasive, displacing native vegetation and reducing the quality of forage in rangelands and pastures. The autoecious fungus, Puccinia punctiformis , or CT-rust, shows potential as a control agent but rarely reaches epidemic proportions in natural populations. Manipulating plant defense hormones could alter host susceptibility and allow CT-rust to have more widespread impact. To determine if applying hormones increases the infection by the fungal pathogen, Canada thistle plants were inoculated and sprayed with jasmonic acid (JA) and salicylic acid (SA). Results show that jasmonic acid application interacted with inoculation, increasing infection rates, both incidence and severity, and impact of CT-rust. We found that JA increased infection rates by nearly 20%. Infection consistently reduced root biomass and this reduction was 45% greater with the addition of JA compared to untreated control. Addition of JA at the time of inoculation could make it a more effective control agent for Canada thistle. [ABSTRACT FROM AUTHOR]

β-Cell failure and loss of β-cell mass are key events in diabetes progression. Although insulin hypersecretion in early stages has been implicated in β-cell exhaustion/failure, loss of β-cell mass still occurs in KATP gain-of-function (GOF) mouse models of human neonatal diabetes in the absence of insulin secretion. Thus, we hypothesize that hyperglycemia-induced increased β-cell metabolism is responsible for β-cell failure and that reducing glucose metabolism will prevent loss of β-cell mass. To test this, KATP-GOF mice were crossed with mice carrying β-cell-specific glucokinase haploinsufficiency (GCK+/-), to genetically reduce glucose metabolism. As expected, both KATP-GOF and KATP-GOF/GCK+/- mice showed lack of glucose-stimulated insulin secretion. However, KATP-GOF/GCK+/- mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared with KATP-GOF mice. In addition, decreased plasma insulin and content, increased proinsulin, and augmented plasma glucagon observed in KATP-GOF mice were normalized to control levels in KATP-GOF/GCK+/- mice. Strikingly, KATP-GOF/GCK+/- mice demonstrated preserved β-cell mass and identity compared with the marked decrease in β-cell identity and increased dedifferentiation observed in KATP-GOF mice. Moreover KATP-GOF/GCK+/- mice demonstrated restoration of body weight and liver and brown/white adipose tissue mass and function and normalization of physical activity and metabolic efficiency compared with KATP-GOF mice. These results demonstrate that decreasing β-cell glucose signaling can prevent glucotoxicity-induced loss of insulin content and β-cell failure independently of compensatory insulin hypersecretion and β-cell exhaustion. [ABSTRACT FROM AUTHOR]

Background and objective The Clinical Chronic Obstructive Pulmonary Disease ( COPD) Questionnaire ( CCQ) is an easy to complete, health-related quality of life questionnaire which has been well-validated in COPD. The responsiveness of the CCQ in chronic respiratory disease patients other than COPD has not been previously described. The study aims were to determine if the CCQ in chronic respiratory disease correlates with other health related quality of life questionnaires, to assess the responsiveness of the CCQ to pulmonary rehabilitation and to determine the minimum important difference. Methods The CCQ, COPD Assessment Test ( CAT), the Chronic Respiratory Questionnaire ( CRQ) and St George's Respiratory Questionnaire ( SGRQ) were measured in 138 chronic respiratory disease patients completing pulmonary rehabilitation. Change in CCQ with pulmonary rehabilitation was correlated with change in the other questionnaires. The minimum important difference of the CCQ was calculated using distribution and anchor-based approaches. Results The CCQ, CAT, CRQ and SGRQ improved significantly with rehabilitation with effect sizes of −0.43, −0.26, 0.62, −0.37. Change in CCQ correlated significantly with CAT, CRQ and SGRQ (r = 0.53, −0.64, 0.30, all P < 0.0001). The minimum important difference was −0.42 at the population level and −0.4 at the individual level. Conclusions The CCQ is responsive to pulmonary rehabilitation in chronic respiratory disease patients, with an MID estimated at −0.4 at the individual level. [ABSTRACT FROM AUTHOR]

Background: The COPD Assessment Test (CAT) is a recently introduced instrument to assess health-related quality of life in COPD. We aimed to evaluate the longitudinal change in CAT following Pulmonary Rehabilitation (PR), and test the relationship between CAT and CRQ-Self Report (SR) over time. We hypothesised that the CAT would show similar responsiveness to PR as the CRQ-SR both in the short and medium-term. Methods: 118 COPD patients completed an eight-week outpatient multidisciplinary PR programme. CAT, CRQ-SR and the incremental shuttle walk (ISW) were measured prior to starting PR (T1), completion of PR (T2) and 6 months after completion of PR (T3). Results: There was a significant improvement in CAT, CRQ-SR and ISW immediately following PR (p < 0.001). Although there was decline between T2 and T3, CAT, CRQ-SR and ISW remained significantly better at T3 compared with T1 (ANOVA p < 0.001). Both between T1-T2 and between T2-T3, change in CAT correlated significantly with change in CRQ (both r = -0.44 and p < 0.001). The slope of the relationship between CAT change and CRQ-SR change at T1-T2 and T2-T3 was not significantly different (ANCOVA: intercept p = 0.79, interaction effect p = 0.95). Conclusions: In COPD, the CAT score is immediately responsive to PR and remains improved at 6 months. There is no significant difference in the short and medium term changes in the CAT and CRQ-SR following PR. We propose that for most clinical indications for assessing health-related quality of life in COPD, the CAT is a robust and practical alternative to longer-established instruments such as the CRQ-SR. [ABSTRACT FROM AUTHOR]

Abstract: In some regions of the developing rat brain such as the nucleus accumbens (Acb), mu opioid (MOP) receptor specific binding in the perinatal period exceeds that in the adult. To investigate the significance of these developmental changes, MOP and nociceptin/orphanin FQ (NOP) receptor binding and G protein coupling as determined by GTPγS binding experiments were examined in mesolimbic regions of postnatal day 2 (P2) pups and compared to those of their dams. Acb of the P2 pup exhibited 2-fold greater MOP receptor specific binding than that of the dam. In the ventral tegmental area (VTA), NOP specific binding was about 2-fold higher in the P2 pup. A correlation was found between MOP and NOP binding and their coupling to G protein on dam and P2 pup brain sections. However, the magnitude of increases in MOP and NOP receptor G protein coupling to G protein in P2 pups exceeded the 2-fold differences in binding between pups and dams. Furthermore, the amplitude of the MOP receptor G protein coupling in female P2 Acb was greater than increases in male P2 pup Acb. Differences in MOP and NOP binding and G protein coupling in other mesolimbic regions between P2 pups and dams were rarely observed. The data indicate that greater binding and G protein coupling of MOP and NOP receptors occur in discrete, mesolimbic regions of P2 pups when compared to their dams. It may be of significance that these brain regions, Acb and VTA, are undergoing maturation on P2. [Copyright &y& Elsevier]

Rationale Several randomised controlled trials support the provision of early pulmonary rehabilitation (PR) following hospitalisation for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, there is little real-world data regarding uptake, adherence and completion rates. Methods An audit was conducted to prospectively document referral, uptake, adherence and completion rates for early posthospitalisation outpatient PR in Northwest London over a 12-month period. Results Out of 448 hospital discharges for AECOPD, 90 referrals for post-hospitalisation PR were received. Only 43 patients received and completed PR (9.6% of all hospital discharges) despite a fully commissioned PR service. Conclusions Despite the strong evidence base, there are poor referral and uptake rates for early outpatient PR following hospitalisation for AECOPD, with only a small proportion of the intended target population receiving this intervention. [ABSTRACT FROM AUTHOR]

Background Age-related loss of muscle, sarcopenia, is recognised as a clinical syndrome with multiple contributing factors. International European Working Group on Sarcopenia in Older People (EWGSOP) criteria require generalised loss of muscle mass and reduced function to diagnose sarcopenia. Both are common in COPD but are usually studied in isolation and in the lower limbs. Objectives To determine the prevalence of sarcopenia in COPD, its impact on function and health status, its relationship with quadriceps strength and its response to pulmonary rehabilitation (PR). Methods EWGSOP criteria were applied to 622 outpatients with stable COPD. Body composition, exercise capacity, functional performance, physical activity and health status were assessed. Using a case-control design, response to PR was determined in 43 patients with sarcopenia and a propensity score-matched non-sarcopenic group. Results Prevalence of sarcopenia was 14.5% (95% CI 11.8% to 17.4%), which increased with age and Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) stage, but did not differ by gender or the presence of quadriceps weakness (14.9 vs 13.8%, p=0.40). Patients with sarcopenia had reduced exercise capacity, functional performance, physical activity and health status compared with patients without sarcopenia (p<0.001), but responded similarly following PR; 12/43 patients were no longer classified as sarcopenic following PR. Conclusions Sarcopenia affects 15% of patients with stable COPD and impairs function and health status. Sarcopenia does not impact on response to PR, which can lead to a reversal of the syndrome in select patients. [ABSTRACT FROM AUTHOR]

Background The Clinical COPD Questionnaire (CCQ) is a simple 10-item, health-related quality of life questionnaire (HRQoL) with good psychometric properties. However, little data exists regarding the responsiveness of the CCQ to pulmonary rehabilitation (PR) or the minimal clinically important difference (MCID). The study aims were to assess the responsiveness of the CCQ to PR, to compare the responsiveness of the CCQ to other HRQoL questionnaires and to provide estimates for the MCID. Methods The CCQ, St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Questionnaire (CRQ) and COPD Assessment Test (CAT) were measured in 261 patients with COPD before and after outpatient PR. Pre to post PR changes and Cohen's effect size were calculated. Changes in CCQ were compared with changes in other HRQoL questionnaires. Using an anchor-based approach and receiver operating characteristic (ROC) curves, the CCQ change cutoffs that identified patients achieving the known MCID for other health status questionnaires with PR were identified. Results The CCQ, SGRQ, CRQ and CAT all significantly improved with PR with an effect size of -0.39, -0.33, 0.62 and -0.25, respectively. CCQ change correlated significantly with change in SGRQ, CRQ and CAT (r=0.48, -0.56, 0.54, respectively; all p<0.001). ROC curves consistently identified a CCQ change cutoff of -0.4 as the best discriminating value to identify the MCID for the SGRQ, CRQ and CAT (area under curve: 0.71, 0.75 and 0.77, respectively; all p<0.001). Conclusions The CCQ is responsive to PR with an estimated clinically important improvement of -0.4 points. The CCQ is a practical alternative to more timeconsuming measures of HRQoL. [ABSTRACT FROM AUTHOR]

Background: The Short Physical Performance Battery (SPPB) is commonly used in gerontology, but its determinants have not been previously evaluated in COPD. In particular, it is unknown whether pulmonary aspects of COPD would limit the value of SPPB as an assessment tool of lower limb function.Methods: In 109 patients with COPD, we measured SPPB score, spirometry, 6-min walk distance, quadriceps strength, rectus femoris cross-sectional area, fat-free mass, physical activity, health status, and Medical Research Council dyspnea score. In a subset of 31 patients with COPD, a vastus lateralis biopsy was performed, and the biopsy specimen was examined to evaluate the structural muscle characteristics associated with SPPB score. The phenotypic characteristics of patients stratified according to SPPB were determined.Results: Quadriceps strength and 6-min walk distance were the only independent predictors of SPPB score in a multivariate regression model. Furthermore, while age, dyspnea, and health status were also univariate predictors of SPPB score, FEV 1 was not. Stratification by reduced SPPB score identified patients with locomotor muscle atrophy and increasing impairment in strength, exercise capacity, and daily physical activity. Patients with mild or major impairment defined as an SPPB score < 10 had a higher proportion of type 2 fibers (71% [14] vs 58% [15], P = .04).Conclusions: The SPPB is a valid and simple assessment tool that may detect a phenotype with functional impairment, loss of muscle mass, and structural muscle abnormality in stable patients with COPD. [ABSTRACT FROM AUTHOR]

Background Moving from sitting to standing is a common activity of daily living. The five-repetition sit-tostand test (5STS) is a test of lower limb function that measures the fastest time taken to stand five times from a chair with arms folded. The 5STS has been validated in healthy community-dwelling adults, but data in chronic obstructive pulmonary disease (COPD) populations are lacking. Aims To determine the reliability, validity and responsiveness of the 5STS in patients with COPD. Methods Test-retest and interobserver reliability of the 5STS was measured in 50 patients with COPD. To address construct validity we collected data on the 5STS, exercise capacity (incremental shuttle walk (ISW)), lower limb strength (quadriceps maximum voluntary contraction (QMVC)), health status (St George's Respiratory Questionnaire (SGRQ)) and composite mortality indices (Age Dyspnoea Obstruction index (ADO), BODE index (iBODE)). Responsiveness was determined by measuring 5STS before and after outpatient pulmonary rehabilitation (PR) in 239 patients. Minimum clinically important difference (MCID) was estimated using anchor-based methods. Results Test-retest and interobserver intraclass correlation coefficients were 0.97 and 0.99, respectively. 5STS time correlated significantly with ISW, QMVC, SGRQ, ADO and iBODE (r=-0.59, -0.38, 0.35, 0.42 and 0.46, respectively; all p<0.001). Median (25th, 75th centiles) 5STS time decreased with PR (Pre: 14.1 (11.5, 21.3) vs Post: 12.4 (10.2, 16.3) s; p<0.001). Using different anchors, a conservative estimate for the MCID was 1.7 s. Conclusions The 5STS is reliable, valid and responsive in patients with COPD with an estimated MCID of 1.7 s. It is a practical functional outcome measure suitable for use in most healthcare settings. [ABSTRACT FROM AUTHOR]

In addition to its use for heroin addiction pharmacotherapy in general, buprenorphine has advantages in treating maternal heroin abuse. To examine the gestational effects of buprenorphine on opioid receptor signaling, the [35S]-GTPγS in situ binding induced by the μ agonist [D-Ala2,MePhe4,Gly5-ol] enkephalin (DAMGO) or the nociceptin/orphanin FQ (N/OFQ) agonist was measured in mesolimbic structures of pup brains from pregnant rats administered with buprenorphine±naloxone, naloxone, or methadone by osmotic minipump. Drug- and gender-based changes in DAMGO- and N/OFQ-induced GTPγS binding were discovered in mesolimbic regions of dam, P2, and P7 brains. Buprenorphine and/or methadone gestational treatment attenuated DAMGO-induced GTPγS binding in some dam and male P2 mesolimbic regions. Methadone diminished DAMGO-induced GTPγS binding in almost all monitored brain regions of the dam but had few effects on their N/OFQ-induced GTPγS binding. Naloxone used in combination with buprenorphine blocked the inhibition by buprenorphine alone on DAMGO-induced GTPγS binding. In contrast to its inhibitory effects on DAMGO-induced GTPγS binding, buprenorphine stimulated N/OFQ-induced GTPγS binding in male P2 nucleus accumbens and lateral septum. Brain region-dependent gender differences in DAMGO-induced GTPγS binding were seen in P2 pups, and males showed greater sensitivity to buprenorphine and methadone than females. Our findings on μ opioid receptor (MOR) GTP-binding regulatory protein (G protein) coupling and its gender dependency are consistent with our earlier studies on μ receptor binding adaptation induced by buprenorphine in dams and neonatal rats after in utero treatment regimens, and they extend the gestational effects of this opiate to μ and N/OFQ receptor functionality. [Copyright &y& Elsevier]

A response from the author of the article "Sarcopenia in Chronic obstructive pulmonary disease (COPD)" in the 2015 issue is presented.