Manganese peroxidases (MnPs) are key players in the ligninolytic system of white rot fungi. In Pleurotus ostreatus (the oyster mushroom) these enzymes are encoded by a gene family comprising nine members, mnp1 to -9 (mnp genes). Mn2+ amendment to P. ostreatus cultures results in enhanced degradation of recalcitrant compounds (such as the azo dye orange II) and lignin. In Mn2+-amended glucose-peptone medium, mnp3, mnp4, and mnp9 were the most highly expressed mnp genes. After 7 days of incubation, the time point at which the greatest capacity for orange II decolorization was observed, mnp3 expression and the presence of MnP3 in the extracellular culture fluids were predominant. To determine the significance of MnP3 for ligninolytic functionality in Mn2+-sufficient cultures, mnp3 was inactivated via the Δku80 strain-based P. ostreatus gene-targeting system. In Mn2+-sufficient medium, inactivation of mnp3 did not significantly affect expression of nontargeted MnPs or their genes, nor did it considerably diminish the fungal Mn2+-mediated orange II decolorization capacity, despite the significant reduction in total MnP activity. Similarly, inactivation of either mnp4 or mnp9 did not affect orange II decolorization ability. These results indicate functional redundancy within the P. ostreatus MnP gene family, enabling compensation upon deficiency of one of its members.
Seed dispersal is one of the most important mechanisms shaping biodiversity, and animals are one of the key dispersal vectors. Animal seed dispersal can directly or indirectly be altered by invasive organisms through the establishment of new or the disruption of existing seed dispersal interactions. So far it is known for a few gastropod species that they ingest and defecate viable plant seeds and consequently act as seed dispersers, referred to as gastropodochory. In a multi-species experiment, consisting of five different plant species and four different gastropod species, we tested with a fully crossed design whether gastropodochory is a general mechanism across native gastropod species, and whether it is altered by the invasive alien slug species Arion lusitanicus. Specifically, we hypothesized that a) native gastropod species consume the seeds from all tested plant species in equal numbers (have no preference), b) the voracious invasive alien slug A. lusitanicus – similarly to its herbivore behaviour – consumes a higher amount of seeds than native gastropods, and that c) seed viability is equal among different gastropod species after gut passage. As expected all tested gastropod species consumed all tested plant species. Against our expectation there was a difference in the amount of consumed seeds, with the largest and native mollusk Helix pomatia consuming most seeds, followed by the invasive slug and the other gastropods. Seed damage and germination rates did not differ after gut passage through different native species, but seed damage was significantly higher after gut passage through the invasive slug A. lusitanicus, and their germination rates were significantly reduced.
Obese patients with type 2 diabetes undergoing bariatric surgery experience significant and lasting weight loss and improved glycaemic control. However, bariatric surgical procedures such as Roux-en-Y gastric bypass are irreversible and associated with considerable short-term and long-term risks. The EndoBarrier Gastrointestinal Liner or duodenal-jejunal bypass sleeve (DJBS) is a fully reversible procedure that has been developed to treat obesity and type 2 diabetes. We aim to perform a systematic review and meta-analysis of safety and efficacy of DJBS.
Methods and analyses
A systematic review with meta-analysis (as per the preferred reporting items for systematic reviews and meta-analyses) of randomised controlled trials of the device (vs no intervention, sham and/or low-calorie diet) will be performed. Primary endpoints include change in body weight and glycated haemoglobin and safety. Secondary endpoints constitute changes in other glycaemic parameters and blood lipids and the proportion of patients discontinuing antidiabetic medication. MEDLINE, EMBASE, The Cochrane Library and Science Citation Index will be sought electronically along with manual searches. The primary meta-analysis will use random effects models due to an expected intertrial heterogeneity. Fixed effect meta-analysis will be executed to assess the impact of small trials. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs.
Ethics and dissemination
The study will describe the impact of DJBS on obesity and type 2 diabetes and possibly contribute to clinical decision-making. The results of this study will be disseminated by peer-reviewed publication and scientific presentations.
DIABETES & ENDOCRINOLOGY
The incretin effect on insulin secretion was investigated in 8 subjects with type 2 diabetes (T2D) and 8 with normal glucose tolerance (NGT), using 25, 75, and 125 g oral glucose tolerance tests (OGTT) and isoglycemic intravenous glucose infusions (IIGI). The ß-cell response was evaluated using a model embedding a dose-response (slope = glucose sensitivity), an early response (rate sensitivity), and potentiation (time-related secretion increase). The incretin effect, as OGTT/IIGI ratio, was calculated for each parameter. In NGT, the incretin effect on total secretion increased with dose (1.3±0.1, 1.7±0.2, 2.2±0.2 fold of IIGI, P<0.0001), mediated by a dose-dependent increase of the incretin effect on glucose sensitivity (1.9±0.4, 2.4±0.4, 3.1±0.4, P = 0.005), and a dose-independent enhancement of the incretin effect on rate sensitivity (894 , 454 , 783  pmol m−2 L mmol−1 above IIGI; median [interquartile range], P<0.0001). The incretin effect on potentiation also increased (0.97±0.06, 1.45±0.20, 1.24±0.16, P<0.0001). In T2D, the incretin effect on total secretion (1.0±0.1, 1.1±0.1, 1.3±0.1, P = 0.004) and glucose sensitivity (1.2±0.2, 1.3±0.2, 2.0±0.2, P = 0.005) were impaired vs NGT; however, the incretin effect on rate sensitivity increased already at 25 g (269 , 284 , 193  pmol m−2 L mmol−1 above IIGI; negligible IIGI rate sensitivity in T2D prevented the calculation of the fold increment). OGTT did not stimulate potentiation above IIGI (0.94±0.04, 0.89±0.06, 1.06±0.09; P<0.01 vs NGT). In the whole group, the incretin effect was inversely associated with total secretion during IIGI, although systematically lower in T2D. In conclusion, 1) In NGT, glucose sensitivity and potentiation mediate the dose-dependent incretin effect increase; 2) In T2D, the incretin effect is blunted vs NGT, but rate sensitivity is enhanced at all loads; 3) Relatively lower incretin effect in NGT is associated with higher secretion during IIGI, suggesting that the reduced incretin effect does not result from ß-cell dysfunction.
Glucagon-like peptide 1 (GLP1) is rapidly inactivated by dipeptidyl peptidase 4 (DPP4), but may interact with vagal neurons at its site of secretion. We investigated the role of vagal innervation for handling of oral and i.v. glucose.
Design and methods
Truncally vagotomised subjects (n=16) and matched controls (n=10) underwent 50 g-oral glucose tolerance test (OGTT)±vildagliptin, a DPP4 inhibitor (DPP4i) and isoglycaemic i.v. glucose infusion (IIGI), copying the OGTT without DPP4i.
Isoglycaemia was obtained with 25±2 g glucose in vagotomised subjects and 18±2 g in controls (P<0.03); thus, gastrointestinal-mediated glucose disposal (GIGD) – a measure of glucose handling (100%×(glucoseOGTT−glucoseIIGI/glucoseOGTT)) – was reduced in the vagotomised compared with the control group. Peak intact GLP1 concentrations were higher in the vagotomised group. Gastric emptying was faster in vagotomised subjects after OGTT and was unaffected by DPP4i. The early glucose-dependent insulinotropic polypeptide response was higher in vagotomised subjects. Despite this, the incretin effect was equal in both groups. DPP4i enhanced insulin secretion in controls, but had no effect in the vagotomised subjects. Controls suppressed glucagon concentrations similarly, irrespective of the route of glucose administration, whereas vagotomised subjects showed suppression only during IIGI and exhibited hyperglucagonaemia following OGTT. DPP4i further suppressed glucagon secretion in controls and tended to normalise glucagon responses in vagotomised subjects.
GIGD is diminished, but the incretin effect is unaffected in vagotomised subjects despite higher GLP1 levels. This, together with the small effect of DPP4i, is compatible with the notion that part of the physiological effects of GLP1 involves vagal transmission.
We carried out a systematic review of clinical studies investigating glucagon-like peptide-1 (GLP-1) secretion in patients with type 2 diabetes and non-diabetic controls and performed meta-analyses of plasma total GLP-1 concentrations during an OGTT and/or meal test.
Random effects models for the primary meta-analysis and random effects meta-regression, subgroup and regression analyses were applied.
Random effects meta-analysis of GLP-1 responses in 22 trials during 29 different stimulation tests showed that patients with type 2 diabetes (n=275) and controls without type 2 diabetes (n=279) exhibited similar responses of total GLP-1 (p=NS) as evaluated from peak plasma concentrations (weighted mean difference [95% CI] 1.09 pmol/l [−2.50, 4.67]), total AUC (tAUC) (159 pmol/l×min [−270, 589]), time-corrected tAUC (tAUC min−1) (0.99 pmol/l [−1.28, 3.27]), incremental AUC (iAUC) (−122 pmol/l×min [−410, 165]) and time-corrected iAUC (iAUC min−1) (−0.49 pmol/l [−2.16, 1.17]). Fixed effects meta-analysis revealed higher peak plasma GLP-1 concentrations in patients with type 2 diabetes. Subgroup analysis showed increased responses after a liquid mixed meal test (peak, tAUC and tAUC min−1) and after a 50 g OGTT (AUC and tAUC min−1), and reduced responses after a solid mixed meal test (tAUC min−1) among patients with type 2 diabetes. Meta-regression analyses showed that HbA1c and fasting plasma glucose predicted the outcomes iAUC and iAUC min−1, respectively.
The present analysis suggests that patients with type 2 diabetes, in general, do not exhibit reduced GLP-1 secretion in response to an OGTT or meal test, and that deteriorating glycaemic control may be associated with reduced GLP-1 secretion.
Glucagon-like peptide-1 (GLP-1); Gut hormones; Incretin secretion; Meta-analysis; Systematic review; Type 2 diabetes mellitus
Vitamin D deficiency is common among otherwise healthy pregnant women and may have consequences for them as well as the early development and long-term health of their children. However, the importance of maternal vitamin D status on offspring health later in life has not been widely studied. The present study includes an in-depth examination of the influence of exposure to vitamin D early in life for development of fractures of the wrist, arm and clavicle; obesity, and type 1 diabetes (T1D) during child- and adulthood.
The study is based on the fact that in 1961 fortifying margarine with vitamin D became mandatory in Denmark and in 1972 low fat milk fortification was allowed. Apart from determining the influences of exposure prior to conception and during prenatal life, we will examine the importance of vitamin D exposure during specific seasons and trimesters, by comparing disease incidence among individuals born before and after fortification. The Danish National databases assure that there are a sufficient number of individuals to verify any vitamin D effects during different gestation phases. Additionally, a validated method will be used to determine neonatal vitamin D status using stored dried blood spots (DBS) from individuals who developed the aforementioned disease entities as adults and their time and gender-matched controls.
The results of the study will contribute to our current understanding of the significance of supplementation with vitamin D. More specifically, they will enable new research in related fields, including interventional research designed to assess supplementation needs for different subgroups of pregnant women. Also, other health outcomes can subsequently be studied to generate multiple health research opportunities involving vitamin D. Finally, the results of the study will justify the debate of Danish health authorities whether to resume vitamin D supplementation policies.
Vitamin D; Food fortification; Prenatal exposure; Prevention; Type 1 diabetes; Obesity; Fractures
Few population based studies have investigated associations between parental history of alcoholism and the risk of alcoholism in offspring. The aim was to investigate in a large cohort the risk of Alcohol Use Disorders (AUD) in the offspring of parents with or without AUD and with or without hospitalisation for other psychiatric disorder (OPD).
Longitudinal birth cohort study of 7177 men and women born in Copenhagen between October 1959 and December 1961. Cases of AUD were identified in three Danish health registers and cases of OPD in the Danish Psychiatric Central Register. Offspring registration with AUD was analyzed in relation to parental registration with AUD and OPD. Covariates were offspring gender and parental social status.
Both maternal and paternal registration with AUD significantly predicted offspring risk of AUD (odds ratios 1.96; 95% CI 1.42-2.71 and 1.99; 95% CI 1.54-2.68, respectively). The association between maternal, but not paternal, OPD and offspring AUD was also significant (odds ratios 1.46; 95% CI 1.15-1.86 and 1.26; 95% CI 0.95-1.66, respectively). Other predictors were male gender and parental social status. A significant interaction was observed between paternal AUD and offspring gender on offspring AUD, and stratified analyses showed particularly strong associations of both paternal and maternal AUD with offspring AUD in female cohort members.
Parental AUD was associated with an increased risk of offspring AUD independent of other significant predictors, such as gender, parental social status and parental psychiatric hospitalisation with other diagnoses. Furthermore, this association appeared to be stronger among female than male offspring. The results suggest that inherited factors related to alcoholism are at least as important in determining the risk of alcoholism among daughters as among sons.
Alcohol use disorder; alcohol abuse; family history; parental risk; cohort study
The formation of 4-deoxyaurones, which serve as UV nectar guides in Bidens ferulifolia (Jacq.) DC., was established by combination of UV photography, mass spectrometry, and biochemical assays and the key step in aurone formation was studied. The yellow flowering ornamental plant accumulates deoxy type anthochlor pigments (6′-deoxychalcones and the corresponding 4-deoxyaurones) in the basal part of the flower surface whilst the apex contains only yellow carotenoids. For UV sensitive pollinating insects, this appears as a bicoloured floral pattern which can be visualized in situ by specific ammonia staining of the anthochlor pigments. The petal back side, in contrast, shows a faintly UV absorbing centre and UV absorbing rays along the otherwise UV reflecting petal apex. Matrix-free UV laser desorption/ionisation mass spectrometric imaging (LDI-MSI) indicated the presence of 9 anthochlors in the UV absorbing areas. The prevalent pigments were derivatives of okanin and maritimetin. Enzyme preparations from flowers, leaves, stems and roots of B. ferulifolia and from plants, which do not accumulate aurones e.g. Arabidopsis thaliana, were able to convert chalcones to aurones. Thus, aurone formation could be catalyzed by a widespread enzyme and seems to depend mainly on a specific biochemical background, which favours the formation of aurones at the expense of flavonoids. In contrast to 4-hydroxyaurone formation, hydroxylation and oxidative cyclization to the 4-deoxyaurones does not occur in one single step but is catalyzed by two separate enzymes, chalcone 3-hydroxylase and aurone synthase (catechol oxidase reaction). Aurone formation shows an optimum at pH 7.5 or above, which is another striking contrast to 4-hydroxyaurone formation in Antirrhinum majus L. This is the first example of a plant catechol oxidase type enzyme being involved in the flavonoid pathway and in an anabolic reaction in general.
Activation of CB1 receptors on axon terminals by exogenous cannabinoids (eg, Δ9-tetrahydrocannabinol) and by endogenous cannabinoids (endocannabinoids) released by postsynaptic neurons leads to presynaptic inhibition of neurotransmission. The aim of this study was to characterize the effect of cannabinoids on GABAergic synaptic transmission in the human neocortex. Brain slices were prepared from neocortical tissues surgically removed to eliminate epileptogenic foci. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in putative pyramidal neurons using patch-clamp techniques. To enhance the activity of cannabinoid-sensitive presynaptic axons, muscarinic receptors were continuously stimulated by carbachol. The synthetic cannabinoid receptor agonist WIN55212-2 decreased the cumulative amplitude of sIPSCs. The CB1 antagonist rimonabant prevented this effect, verifying the involvement of CB1 receptors. WIN55212-2 decreased the frequency of miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin, but did not change their amplitude, indicating that the neurotransmission was inhibited presynaptically. Depolarization of postsynaptic pyramidal neurons induced a suppression of sIPSCs. As rimonabant prevented this suppression, it is very likely that it was due to endocannabinods acting on CB1 receptors. This is the first demonstration that an exogenous cannabinoid inhibits synaptic transmission in the human neocortex and that endocannabinoids released by postsynaptic neurons suppress synaptic transmission in the human brain. Interferences of cannabinoid agonists and antagonists with synaptic transmission in the cortex may explain the cognitive and memory deficits elicited by these drugs.
CB1 cannabinoid receptor; endocannabinoid; GABAergic synaptic transmission; human; neocortex; Δ9-tetrahydrocannabinol; cannabinoids; GABA; psychopharmacology; molecular & cellular neurobiology; CB1 cannabinoid receptor; endocannabinoid; GABAergic synaptic transmission; human; neocortex
The aim of this study was to explore the left ventricular (LV) deformation changes and the potential impact of deformation on outcome in patients with proven light-chain (AL) amyloidosis and LV hypertrophy.
Cardiac involvement in AL amyloidosis patients is associated with poor outcome. Detecting regional cardiac function by advanced non-invasive techniques might be favorable for predicting outcome.
LV longitudinal, circumferential and radial peak systolic strains (Ssys) were assessed by speckle tracking imaging (STI) in 44 biopsy-proven systemic AL amyloidosis patients with LV hypertrophy (CA) and in 30 normal controls. Patients were divided into compensated (n = 18) and decompensated (n = 26) group based on clinical assessment and followed-up for a median period of 345 days.
Ejection fraction (EF) was preserved while longitudinal Ssys (LSsys) was significantly reduced in both compensated and decompensated groups. Survival was significantly reduced in decompensated group (35% vs. compensated 78%, P = 0.001). LSsys were similar in apical segments and significantly reduced in basal segments between two patient groups. LSsys at mid-segments were significantly reduced in all LV walls of decompensated group. Patients were further divided into 4 subgroups according to the presence or absence of reduced LSsys in no (normal), only basal (mild), basal and mid (intermediate) and all segments of the septum (severe). This staging revealed continuously worse prognosis in proportion to increasing number of segments with reduced LSsys (mortality: normal 14%, mild 27%, intermediate 67%, and severe 64%). Mid-septum LSsys<11% suggested a 4.8-fold mortality risk than mid-septum LSsys≥11%. Multivariate regression analysis showed NYHA class and mid-septum LSsys were independent predictors for survival.
Reduced deformation at mid-septum is associated with worse prognosis in systemic amyloidosis patients with LV hypertrophy.
Pleurotus ostreatus (the oyster mushroom) and other white rot filamentous basidiomycetes are key players in the global carbon cycle. P. ostreatus is also a commercially important edible fungus with medicinal properties and is important for biotechnological and environmental applications. Efficient gene targeting via homologous recombination (HR) is a fundamental tool for facilitating comprehensive gene function studies. Since the natural HR frequency in Pleurotus transformations is low (2.3%), transformed DNA is predominantly integrated ectopically. To overcome this limitation, a general gene targeting system was developed by producing a P. ostreatus PC9 homokaryon Δku80 strain, using carboxin resistance complemented by the development of a protocol for hygromycin B resistance protoplast-based DNA transformation and homokaryon isolation. The Δku80 strain exhibited exclusive (100%) HR in the integration of transforming DNA, providing a high efficiency of gene targeting. Furthermore, the Δku80 strains produced showed a phenotype similar to that of the wild-type PC9 strain, with similar growth fitness, ligninolytic functionality, and capability of mating with the incompatible strain PC15 to produce a dikaryon which retained its resistance to the corresponding selection and was capable of producing typical fruiting bodies. The applicability of this system is demonstrated by inactivation of the versatile peroxidase (VP) encoded by mnp4. This enzyme is part of the ligninolytic system of P. ostreatus, being one of the nine members of the manganese-peroxidase (MnP) gene family, and is the predominantly expressed VP in Mn2+-deficient media. mnp4 inactivation provided a direct proof that mnp4 encodes a key VP responsible for the Mn2+-dependent and Mn2+-independent peroxidase activity under Mn2+-deficient culture conditions.
Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.
multiple myeloma; somatic mutations; whole-exome sequencing; adhesion; receptor tyrosine kinases
copper/zinc alloys; methanol steam reforming; surface chemistry; water activation; X-ray photoelectron spectroscopy
The versatile-peroxidase (VP) encoded by mnp4 is one of the nine members of the manganese-peroxidase (MnP) gene family that constitutes part of the ligninolytic system of the white-rot basidiomycete Pleurotus ostreatus (oyster mushroom). VP enzymes exhibit dual activity on a wide range of substrates. As Mn2+ supplement to P. ostreatus cultures results in enhanced degradation of recalcitrant compounds and lignin, we examined the effect of Mn2+ on the expression profile of the MnP gene family. In P. ostreatus (monokaryon PC9), mnp4 was found to be the predominantly expressed mnp in Mn2+-deficient media, whereas strongly repressed (to approximately 1%) in Mn2+-supplemented media. Accordingly, in-vitro Mn2+-independent activity was found to be negligible. We tested whether release of mnp4 from Mn2+ repression alters the activity of the ligninolytic system. A transformant over-expressing mnp4 (designated OEmnp4) under the control of the β-tubulin promoter was produced. Now, despite the presence of Mn2+ in the medium, OEmnp4 produced mnp4 transcript as well as VP activity as early as 4 days after inoculation. The level of expression was constant throughout 10 days of incubation (about 0.4-fold relative to β-tubulin) and the activity was comparable to the typical activity of PC9 in Mn2+-deficient media. In-vivo decolorization of the azo dyes Orange II, Reactive Black 5, and Amaranth by OEmnp4 preceded that of PC9. OEmnp4 and PC9 were grown for 2 weeks under solid-state fermentation conditions on cotton stalks as a lignocellulosic substrate. [14C]-lignin mineralization, in-vitro dry matter digestibility, and neutral detergent fiber digestibility were found to be significantly higher (about 25%) in OEmnp4-fermented substrate, relative to PC9. We conclude that releasing Mn2+ suppression of VP4 by over-expression of the mnp4 gene in P. ostreatus improved its ligninolytic functionality.
To evaluate the glucose dependency of glucose-dependent insulinotropic polypeptide (GIP) effects on insulin and glucagon release in 10 healthy male subjects ([means ± SEM] aged 23 ± 1 years, BMI 23 ± 1 kg/m2, and HbA1c 5.5 ± 0.1%).
RESEARCH DESIGN AND METHODS
Saline or physiological doses of GIP were administered intravenously (randomized and double blinded) during 90 min of insulin-induced hypoglycemia, euglycemia, or hyperglycemia.
During hypoglycemia, GIP infusion caused greater glucagon responses during the first 30 min compared with saline (76 ± 17 vs. 28 ± 16 pmol/L per 30 min, P < 0.008), with similar peak levels of glucagon reached after 60 min. During euglycemia, GIP infusion elicited larger glucagon responses (62 ± 18 vs. −11 ± 8 pmol/L per 90 min, P < 0.005). During hyperglycemia, comparable suppression of plasma glucagon (−461 ± 81 vs. −371 ± 50 pmol/L per 90 min, P = 0.26) was observed with GIP and saline infusions. In addition, during hyperglycemia, GIP more than doubled the insulin secretion rate (P < 0.0001).
In healthy subjects, GIP has no effect on glucagon responses during hyperglycemia while strongly potentiating insulin secretion. In contrast, GIP increases glucagon levels during fasting and hypoglycemic conditions, where it has little or no effect on insulin secretion. Thus, GIP seems to be a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects on the two main pancreatic glucoregulatory hormones.
In addition to the lipid-lowering effect of bile acid sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate their potential as glucose-lowering agents in patients with T2DM.
Methods and analysis
In accordance with the preferred reporting items for systematic reviews and meta-analyses statement, a systematic review with meta-analysis of randomised clinical trials of BASs (vs placebo, oral antidiabetes drugs or insulin), reporting measures of glycaemic control in adult patients with T2DM, will be performed. Change in glycated haemoglobin constitutes the primary endpoint, and secondary endpoints include changes in fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, body weight and body mass index and adverse events. Electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE, along with manual searches in the reference lists of relevant papers. The analyses will be performed based on individual patient data and summarised data. The primary meta-analysis will be performed using random effects models owing to expected intertrial heterogeneity. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs.
Ethics and dissemination
The study will evaluate the potential of BASs as glucose-lowering agents and possibly contribute to the clinical management of patients with T2DM.
The study will be disseminated by peer-review publication and conference presentation.
PdIn intermetallic phases can be switched in methanol steam reforming between a CO2-selective multilayer and an In-diluted phase by annealing at 453 K or 623 K.
► A multilayer Pd1In1 phase in MSR is highly CO2-selective between 493 and 623 K. ► An In-diluted PdIn intermetallic phase yields CO formation via full methanol dehydrogenation. ► Higher reaction temperatures are needed for comparable CO2-TOF values as on supported PdIn/In2O3. ► A bimetal-oxide synergism for efficient CO2 formation is operative.
In situ X-ray photoelectron spectroscopy (in situ XPS) was used to study the structural and catalytic properties of Pd–In near-surface intermetallic phases in correlation with previously studied PdZn and PdGa.
Room temperature deposition of ∼4 monolayer equivalents (MLEs) of In metal on Pd foil and subsequent annealing to 453 K in vacuum yields a ∼1:1 Pd/In near-surface multilayer intermetallic phase. This Pd1In1 phase exhibits a similar “Cu-like” electronic structure and indium depth distribution as its methanol steam reforming (MSR)-selective multilayer Pd1Zn1 counterpart.
Catalytic characterization of the multilayer Pd1In1 phase in MSR yielded a CO2-selectivity of almost 100% between 493 and 550 K. In contrast to previously studied In2O3-supported PdIn nanoparticles and pure In2O3, intermediate formaldehyde is only partially converted to CO2 using this Pd1In1 phase. Strongly correlated with PdZn, on an In-diluted PdIn intermetallic phase with “Pd-like” electronic structure, prepared by thermal annealing at 623 K, methanol steam reforming is suppressed and enhanced CO formation via full methanol dehydrogenation is observed.
To achieve CO2-TOF values on the isolated Pd1In1 intermetallic phase as high as on supported PdIn/In2O3, at least 593 K reaction temperature is required. A bimetal-oxide synergism, with both bimetallic and oxide synergistically contributing to the observed catalytic activity and selectivity, manifests itself by accelerated formaldehyde-to-CO2 conversion at markedly lowered temperatures as compared to separate oxide and bimetal. Combination of suppression of full methanol dehydrogenation to CO on Pd1In1 inhibited inverse water–gas-shift reaction on In2O3 and fast water activation/conversion of formaldehyde is the key to the low-temperature activity and high CO2-selectivity of the supported catalyst.
PdIn near-surface alloy; Pd foil; Methanol dehydrogenation; Methanol steam reforming; Water activation; In situ X-ray photoelectron spectroscopy (AP-XPS)
Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α1-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×1011, 1.9×1012, and 6.0×1012 vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8+ subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.
Flotte and colleagues report on a phase 2 trial in which the same α1-antitrypsin (AAT) AAV vector as in phase 1 is administered intramuscularly to nine AAT-deficient individuals at one of three doses. Vector-derived expression of normal (M-type) AAT in serum is shown to be dose dependent, peaks on day 30, and persists for at least 90 days, although AAT levels were sub-therapeutic.
Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia.
Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients.
Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed.
We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted.
Schizophrenia; antipsychotic medication; overweight; diabetes; GLP-1; exenatide; liraglutide; neuroprotection; cognition
► A Pd1Ga1 surface without Ga2O3 contact is inactive for CO2 formation in methanol steam reforming. ► In situ XPS spectroscopy showed that water activation is blocked on Pd1Ga1. ► The valence band electronic structure of Pd1Ga1 favors selective dehydrogenation to H2CO. ► In oxidative steam reforming, the Pd1Ga1 surface behaves like extended Pd. ► Thus, total methanol oxidation by O2 at low temperatures is predominant.
In situ X-ray photoelectron spectroscopy and low-energy ion scattering were used to study the preparation, (thermo)chemical and catalytic properties of 1:1 PdGa intermetallic near-surface phases. Deposition of several multilayers of Ga metal and subsequent annealing to 503–523 K led to the formation of a multi-layered 1:1 PdGa near-surface state without desorption of excess Ga to the gas phase. In general, the composition of the PdGa model system is much more variable than that of its PdZn counterpart, which results in gradual changes of the near-surface composition with increasing annealing or reaction temperature.
In contrast to near-surface PdZn, in methanol steam reforming, no temperature region with pronounced CO2 selectivity was observed, which is due to the inability of purely intermetallic PdGa to efficiently activate water. This allows to pinpoint the water-activating role of the intermetallic/support interface and/or of the oxide support in the related supported PdxGa/Ga2O3 systems, which exhibit high CO2 selectivity in a broad temperature range. In contrast, corresponding experiments starting on the purely bimetallic model surface in oxidative methanol reforming yielded high CO2 selectivity already at low temperatures (∼460 K), which is due to efficient O2 activation on PdGa. In situ detected partial and reversible oxidative Ga segregation on intermetallic PdGa is associated with total oxidation of intermediate C1 oxygenates to CO2.
PdGa near-surface intermetallic phase; Methanol dehydrogenation; Methanol steam reforming; Oxidative steam reforming; Water activation; Ambient-pressure XPS; In situ spectroscopy