Abstract
Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, ...supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.
Graphical Abstract
Graphical Abstract
Objectives
To develop a local consensus to guide medical practitioners and psychiatrists on the use of bupropion in different psychiatric conditions in Hong Kong.
Methods
By utilizing the modified ...Delphi technique, a group of 10 local physicians with extensive experience in the management of major depressive disorder (MDD) developed and voted (using an anonymous, electronic voting system) on the practicality of recommendation of a set of consensus statements on the clinical use and understanding of bupropion in Hong Kong.
Results
There was a very high degree of agreement among the panelists on the 11 finalized consensus statements.
Conclusions
The present consensus statements are developed as general recommendations for medical practitioners and psychiatrists to be practically referred to in clinical settings.
In
, vacuolar sorting receptor isoform 1 (VSR1) sorts 12S globulins to the protein storage vacuoles during seed development. Vacuolar sorting is mediated by specific protein-protein interactions ...between VSR1 and the vacuolar sorting determinant located at the C terminus (ctVSD) on the cargo proteins. Here, we determined the crystal structure of the protease-associated domain of VSR1 (VSR1-PA) in complex with the C-terminal pentapeptide (
RVAAA
) of cruciferin 1, an isoform of 12S globulins. The
RVA
motif forms a parallel β-sheet with the switch III residues (
TMD
) of VSR1-PA, and the
AA
motif docks to a cradle formed by the cargo-binding loop (
RGDCYF
), making a hydrophobic interaction with Tyr99. The C-terminal carboxyl group of the ctVSD is recognized by forming salt bridges with Arg95. The C-terminal sequences of cruciferin 1 and vicilin-like storage protein 22 were sufficient to redirect the secretory red fluorescent protein (spRFP) to the vacuoles in
protoplasts. Adding a proline residue to the C terminus of the ctVSD and R95M substitution of VSR1 disrupted receptor-cargo interactions in vitro and led to increased secretion of spRFP in
protoplasts. How VSR1-PA recognizes ctVSDs of other storage proteins was modeled. The last three residues of ctVSD prefer hydrophobic residues because they form a hydrophobic cluster with Tyr99 of VSR1-PA. Due to charge-charge interactions, conserved acidic residues, Asp129 and Glu132, around the cargo-binding site should prefer basic residues over acidic ones in the ctVSD. The structural insights gained may be useful in targeting recombinant proteins to the protein storage vacuoles in seeds.
Most of the literature of single-vendor single-buyer integrated production-inventory models for deteriorating items assumed a fixed production rate. Little attention has been paid to finding the ...optimal production rate for minimizing the total system cost. This paper investigates how production rate affects the total system cost, and develops a solution procedure for finding the optimal production rate for the traditional models. Based on the findings, this paper proposes an integrated single-vendor single-buyer model of an exponentially deteriorating item, in which non-stop production is considered and production rate is included as one of the decision variables. It has been shown, with numerical examples, that the proposed model can provide a lower cost solution than the traditional models which assume a fixed production rate. The proposed model also considers deterioration during deliveries, which is usually neglected in the literature of inventory models of deteriorating items. Furthermore, the proposed model is extended to relax the constant cost parameter assumption, which is prevalent even in non-constant production rate models, and optimize the cost for a system in which some of the cost parameters are production rate dependent.
Fabry Disease (FD) is a systemic disorder that can result in cardiovascular, renal, and neurovascular disease leading to reduced life expectancy. FD should be considered in the differential of all ...patients with unexplained left ventricular hypertrophy (LVH). We therefore performed a prospective screening study in Edmonton and Hong Kong using Dried Blood Spot (DBS) testing on patients with undiagnosed LVH. Participants found to have unexplained LVH on echocardiography were invited to participate and subsequently subjected to DBS testing. DBS testing was used to measure α-galactosidase (α-GAL) enzyme activity and for mutation analysis of the α-galactosidase (GLA) gene, both of which are required to make a diagnosis of FD. DBS testing was performed as a screening tool on patients (n = 266) in Edmonton and Hong Kong, allowing for detection of five patients with FD (2% prevalence of FD) and one patient with hydroxychloroquine-induced phenocopy. Left ventricular mass index (LVMI) by GLA genotype showed a higher LVMI in patients with IVS4 + 919G > A mutations compared to those without the mutation. Two patients were initiated on ERT and hydroxychloroquine was discontinued in the patient with a phenocopy of FD. Overall, we detected FD in 2% of our screening cohort using DBS testing as an effective and easy to administer screening tool in patients with unexplained LVH. Utilizing DBS testing to screen for FD in patients with otherwise undiagnosed LVH is clinically important due to the availability of effective therapies and the value of cascade screening in extended families.
This study examineed how parental investment and parental psychological well-being mediate the effects of family income on the intellectual development of children from low-income families in Hong ...Kong. The study followed a sample of 139 children from their final year of kindergarten (K3) through to their second year of primary education (P2) between 2015 and 2017. Path analysis was conducted to examine how family income was associated with children’s cognitive and English language ability (Raven’s Standard Progressive Matrices and Peabody Picture Vocabulary Test-IV) through the parental investment and parental stress pathways. The results supported the hypothesis that parental investment and parental stress mediate the income effects on children’s learning outcome in the Asian context. The negative effects of low family income on children’s cognitive and English language abilities were mediated by the level of parental stress and the extent to which parents were authoritative in their parenting. Parental stress was also found to increase the likelihood of their children having behavioral problems, and that in turn undermined the cognitive development of the children. The level of money that parents invest in their children also mediated the negative effects of low family income on the children’s English language ability. The results suggested that interventions that target the variables that mediate the effects of income on child development are an effective alternative to a direct cash transfer for children in low-income families in Hong Kong.
•This is the first published case series of Allan-Herndon-Dudley Syndrome in Hong Kong Chinese over the last 20 years.•Two novel variants were identified in SLC16A2 for Allan-Herndon-Dudley ...Syndrome.•Full thyroid function profile should be considered early for all pediatric patients with unexplained developmental delay.•The potential of expanding newborn thyroid function screening may prove promising for early diagnosis of MCT8 deficiency.
Allan-Herndon-Dudley syndrome (MCT 8 deficiency) is an X-linked recessive condition caused by hemizygous pathogenic variants in SLC16A2 encoding the monocarboxylate transporter 8 (MCT8). Patients present with global developmental delay and neurological impairment, and abnormal serum thyroid function tests. The drug, 3,3′,5 triiodothyroacetic acid (TRIAC), was recently demonstrated to improve the endocrinological profile. Improvement in diagnostic approach is key to earlier start of treatment.
We described four Chinese patients with MCT8 deficiency undergoing different diagnostic odysseys. Their initial presentation included global developmental delay and dystonia. Patient 2 also had epilepsy. Patients 1 and 2 presented with two novel variants: (1)hemizygous NM_006517.4(SLC16A2):c.1170 + 2 T > A; p.(?), and (2)hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17) respectively. Patients 3 and 4 were biological brothers harboring hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17), which was first reported in 2004. We obtained the measurement of triiodothyronine (T3) and reverse T3 (rT3) from dried blood spot samples collected on Day 1 of life from Patient 1 and studied the biomarkers (rT3 and T3/rT3 ratio) proposed by Iwayama et al. for the detection of MCT8 deficiency at birth. Our data verified the significantly reduced rT3 level in Patient 1, compared with healthy newborns, although low T3 level and comparable T3/rT3 ratio with controls were detected.
Patients with MCT8 deficiency often undergo diagnostic odysseys. An early diagnosis could be missed by a normal newborn thyroid function screening result based on biochemical measurement of TSH and/or T4/fT4. Early detection of rT3 is key to improving current diagnostic approach.
We recommend that full thyroid function profile (TSH, T4/fT4, T3/fT3, rT3) be considered early for all pediatric patients presenting with unexplained developmental delay and/or dystonia. The potential inclusion of rT3 measurement in newborn screening may prove promising.
Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce the rates of major cardiovascular events, including myocardial infarction in people with type 2 diabetes, and decrease infarct size while ...preserving ventricular function in preclinical studies. Nevertheless, the precise cellular sites of GLP-1R expression that mediate the cardioprotective actions of GLP-1 in the setting of ischemic cardiac injury are uncertain.
Publicly available single cell RNA sequencing (scRNA-seq) datasets on mouse and human heart cells were analyzed for Glp1r/GLP1R expression. Fluorescent activated cell sorting was used to localize Glp1r expression in cell populations from the mouse heart. The importance of endothelial and hematopoietic cells for the cardioprotective response to liraglutide in the setting of acute myocardial infarction (MI) was determined by inactivating the Glp1r in Tie2+ cell populations. Cardiac gene expression profiles regulated by liraglutide were examined using RNA-Seq to interrogate mouse atria and both infarcted and non-infarcted ventricular tissue after acute coronary artery ligation.
In mice, cardiac Glp1r mRNA transcripts were exclusively detected in endocardial cells by scRNA-seq. In contrast, analysis of human heart by scRNA-seq localized GLP1R mRNA transcripts to populations of atrial and ventricular cardiomyocytes. Moreover, very low levels of GIPR, GCGR and GLP2R mRNA transcripts were detected in the human heart. Cell sorting and RNA analyses detected cardiac Glp1r expression in endothelial cells (ECs) within the atria and ventricle in the ischemic and non-ischemic mouse heart. Transcriptional responses to liraglutide administration were not evident in wild type mouse ventricles following acute MI, however liraglutide differentially regulated genes important for inflammation, cardiac repair, cell proliferation, and angiogenesis in the left atrium, while reducing circulating levels of IL-6 and KC/GRO within hours of acute MI. Inactivation of the Glp1r within the Tie2+ cell expression domain encompassing ECs revealed normal cardiac structure and function, glucose homeostasis and body weight in Glp1rTie2-/- mice. Nevertheless, the cardioprotective actions of liraglutide to reduce infarct size, augment ejection fraction, and improve survival after experimental myocardial infarction (MI), were attenuated in Glp1rTie2-/- mice.
These findings identify the importance of the murine Tie2+ endothelial cell GLP-1R as a target for the cardioprotective actions of GLP-1R agonists and support the importance of the atrial and ventricular endocardial GLP-1R as key sites of GLP-1 action in the ischemic mouse heart. Hitherto unexplored species-specific differences in cardiac GLP-1R expression challenge the exclusive use of mouse models for understanding the mechanisms of GLP-1 action in the normal and ischemic human heart.
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•The cardiac GLP-1R is predominantly expressed in Tie2+ endothelial cells.•The endocardium is a major site of GLP-1R expression.•The cardioprotective actions of liragutide require the GLP-1R within Tie2+ cells.•Liraglutide preferentially regulates atrial vs. ventricular cardiac gene expression.
Numerous studies have reported the prevention of falls through exercise among cognitively healthy older people. This study aimed to determine whether the current evidence supports that physical ...exercise is also efficacious in preventing falls in older adults with cognitive impairment.
Two independent reviewers searched MEDLINE; EMBASE; PsycINFO; the Cumulative Index to Nursing & Allied Health Literature; the Cochrane Central Register of Controlled Trials; the Cochrane Bone, Joint, and Muscle Trauma Group Specialized Register; ClinicalTrials.gov; and the UK Clinical Research Network Study Portfolio up to July 2013 without language restriction. We included randomized controlled trials that examined the efficacy of physical exercise in older adults with cognitive impairment. The methodological qualities of the included trials were appraised according to the criteria developed for the Cochrane review of fall prevention trials. The primary outcome measure was the rate ratio of falls. A meta-analysis was performed to estimate the pooled rate ratio and summarize the results of the trials on fall prevention through physical exercise.
Seven randomized controlled trials involving 781 participants were included, 4 of which examined solely older people with cognitive impairment. Subgroup data on persons with cognitive impairment were obtained from the other 3 trials that targeted older populations in general. The meta-analysis showed that physical exercise had a significant effect in preventing falls in older adults with cognitive impairment, with a pooled estimate of rate ratio of 0.68 (95% confidence interval 0.51-0.91).
The present analysis suggests that physical exercise has a positive effect on preventing falls in older adults with cognitive impairment. Further studies will be required to determine the modality and frequency of exercise that are optimal for the prevention of falls in this population.
Currently, the challenges deriving from the complex and dynamic socio-political context in Hong Kong influence principals’ and teachers’ relationships and interactions. Academic autonomy in Hong Kong ...secondary schools is not simply granted by the principals, it is influenced by the society, school conditions and key stakeholders. This study employed qualitative methods to examine how principals negotiate the political context surrounding citizenship education and how these practices influence the civic learning in schools. The results revealed that in school citizenship education, when principals lacked a clear vision of citizenship education, most teachers were compliant and avoided discussing controversial political topics with their students. Such teachers had less autonomy and consequently less self-efficacy. When principals mediated the diverse needs of students and balanced the different expectations of school stakeholders, there were both compliant and critical teachers. Teacher autonomy and self-efficacy were also affected by the current socio-political context in Hong Kong. When principals had a clear school civic mission, the results differed across schools. These findings suggest that principals have to reflect on their own understanding of the purposes and perspectives of citizenship education significantly to meet the multiple demands of a complicated and turbulent socio-political environment.
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