On the role of specific drug binding in modelling arterial eluting stents

In this paper we consider drug binding in the arterial wall following delivery by a drug-eluting stent. Whilst it is now generally accepted that a non-linear saturable reversible binding model is required to properly describe the binding process, the precise form of the binding model varies between authors. Our particular interest in this manuscript is in assessing to what extent modelling specific and non-specific binding in the arterial wall as separate phases is important. We study this issue by extending a recently developed coupled model of drug release and arterial tissue distribution, and comparing simulated profiles of drug concentration and drug mass in each phase within the arterial tissue

Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.

Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the β cell in adult mice reportedly has more modest effects. To inactivate Tcf7l2 highly selectively in β cells from the earliest expression of the Ins1 gene (∼E11.5) we have therefore used a Cre recombinase introduced at the Ins1 locus. Tcfl2(fl/fl)::Ins1Cre mice display impaired oral and intraperitoneal glucose tolerance by 8 and 16 weeks, respectively, and defective responses to the GLP-1 analogue liraglutide at 8 weeks. Tcfl2(fl/fl)::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced. Glucose- and GLP-1-induced intracellular free Ca(2+) increases, and connectivity between individual β cells, were both lowered by Tcf7l2 deletion in islets from mice maintained on a high (60%) fat diet. Finally, analysis by optical projection tomography revealed ∼30% decrease in β cell mass in pancreata from Tcfl2(fl/fl)::Ins1Cre mice. These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination. The possible relevance of these findings for the action of TCF7L2 polymorphisms associated with Type 2 diabetes in man is discussed

Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass

Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the β cell in adult mice reportedly has more modest effects. To inactivate Tcf7l2 highly selectively in β cells from the earliest expression of the Ins1 gene (∼E11.5) we have therefore used a Cre recombinase introduced at the Ins1 locus. Tcfl2fl/fl::Ins1Cre mice display impaired oral and intraperitoneal glucose tolerance by 8 and 16 weeks, respectively, and defective responses to the GLP-1 analogue liraglutide at 8 weeks. Tcfl2fl/fl::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced. Glucose- and GLP-1-induced intracellular free Ca2+ increases, and connectivity between individual β cells, were both lowered by Tcf7l2 deletion in islets from mice maintained on a high (60%) fat diet. Finally, analysis by optical projection tomography revealed ∼30% decrease in β cell mass in pancreata from Tcfl2fl/fl::Ins1Cre mice. These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination. The possible relevance of these findings for the action of TCF7L2 polymorphisms associated with Type 2 diabetes in man is discusse

Animal models of GWAS-identified type 2 diabetes genes

More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics

The pore-forming subunit MCU of the mitochondrial Ca2+ uniporter is required for normal glucose-stimulated insulin secretion in vitro and in vivo in mice

Aims/hypothesis Mitochondrial oxidative metabolism is central to glucose-stimulated insulin secretion (GSIS). Whether Ca2+ uptake into pancreatic beta cell mitochondria potentiates or antagonises this process is still a matter of debate. Although the mitochondrial Ca2+ importer (MCU) complex is thought to represent the main route for Ca2+ transport across the inner mitochondrial membrane, its role in beta cells has not previously been examined in vivo. Methods Here, we inactivated the pore-forming subunit of the MCU, encoded by Mcu, selectively in mouse beta cells using Ins1Cre-mediated recombination. Whole or dissociated pancreatic islets were isolated and used for live beta cell fluorescence imaging of cytosolic or mitochondrial Ca2+ concentration and ATP production in response to increasing glucose concentrations. Electrophysiological recordings were also performed on whole islets. Serum and blood samples were collected to examine oral and i.p. glucose tolerance. Results Glucose-stimulated mitochondrial Ca2+ accumulation (p< 0.05), ATP production (p< 0.05) and insulin secretion (p< 0.01) were strongly inhibited in beta cell-specific Mcu-null (βMcu-KO) animals, in vitro, as compared with wild-type (WT) mice. Interestingly, cytosolic Ca2+ concentrations increased (p< 0.001), whereas mitochondrial membrane depolarisation improved in βMcu-KO animals. βMcu-KO mice displayed impaired in vivo insulin secretion at 5 min (p< 0.001) but not 15 min post-i.p. injection of glucose, whilst the opposite phenomenon was observed following an oral gavage at 5 min. Unexpectedly, glucose tolerance was improved (p< 0.05) in young βMcu-KO (<12 weeks), but not in older animals vs WT mice. Conclusions/interpretation MCU is crucial for mitochondrial Ca2+ uptake in pancreatic beta cells and is required for normal GSIS. The apparent compensatory mechanisms that maintain glucose tolerance in βMcu-KO mice remain to be established

Hippocampus Shape Analysis and Late-Life Depression

Major depression in the elderly is associated with brain structural changes and vascular lesions. Changes in the subcortical regions of the limbic system have also been noted. Studies examining hippocampus volumetric differences in depression have shown variable results, possibly due to any volume differences being secondary to local shape changes rather than differences in the overall volume. Shape analysis offers the potential to detect such changes. The present study applied spherical harmonic (SPHARM) shape analysis to the left and right hippocampi of 61 elderly subjects with major depression and 43 non-depressed elderly subjects. Statistical models controlling for age, sex, and total cerebral volume showed a significant reduction in depressed compared with control subjects in the left hippocampus (F1,103 = 5.26; p = 0.0240) but not right hippocampus volume (F1,103 = 0.41; p = 0.5213). Shape analysis showed significant differences in the mid-body of the left (but not the right) hippocampus between depressed and controls. When the depressed group was dichotomized into those whose depression was remitted at time of imaging and those who were unremitted, the shape comparison showed remitted subjects to be indistinguishable from controls (both sides) while the unremitted subjects differed in the midbody and the lateral side near the head. Hippocampal volume showed no difference between controls and remitted subjects but nonremitted subjects had significantly smaller left hippocampal volumes with no significant group differences in the right hippocampus. These findings may provide support to other reports of neurogenic effects of antidepressants and their relation to successful treatment for depressive symptoms

Anatomical and Functional Deficits in Patients with Amnestic Mild Cognitive Impairment

Background: Anatomical and functional deficits have been studied in patients with amnestic mild cognitive impairment (MCI). However, it is unclear whether and how the anatomical deficits are related to the functional alterations. Present study aims to characterize the association between anatomical and functional deficits in MCI patients. Methods: Seventeen amnestic MCI patients and 18 healthy aging controls were scanned using a T1 Weighted MPRAGE sequence and a gradient-echo echo-planar imaging sequence. Clinical severity of MCI patients was evaluated by usin

Summary of the proceedings of the International Forum 2021: "A more visible radiologist can never be replaced by AI"

The ESR International Forum at the ECR 2021 discussed effects of artificial intelligence on the future of radiology and the need for increased visibility of radiologists. The participating societies were invited to submit written reports detailing the current situation in their country or region. The European Society of Radiology (ESR) established the ESR International Forum in order to discuss hot topics in the profession of radiology with non-European radiological partner societies. At the ESR International Forum 2021, different strategies, initiatives and ideas were presented with regard to radiology community’s response to the changes caused by the emerging AI technology

The Neuronal Transition Probability (NTP) Model for the Dynamic Progression of Non-REM Sleep EEG: The Role of the Suprachiasmatic Nucleus

Little attention has gone into linking to its neuronal substrates the dynamic structure of non-rapid-eye-movement (NREM) sleep, defined as the pattern of time-course power in all frequency bands across an entire episode. Using the spectral power time-courses in the sleep electroencephalogram (EEG), we showed in the typical first episode, several moves towards-and-away from deep sleep, each having an identical pattern linking the major frequency bands beta, sigma and delta. The neuronal transition probability model (NTP) – in fitting the data well – successfully explained the pattern as resulting from stochastic transitions of the firing-rates of the thalamically-projecting brainstem-activating neurons, alternating between two steady dynamic-states (towards-and-away from deep sleep) each initiated by a so-far unidentified flip-flop. The aims here are to identify this flip-flop and to demonstrate that the model fits well all NREM episodes, not just the first. Using published data on suprachiasmatic nucleus (SCN) activity we show that the SCN has the information required to provide a threshold-triggered flip-flop for timing the towards-and-away alternations, information provided by sleep-relevant feedback to the SCN. NTP then determines the pattern of spectral power within each dynamic-state. NTP was fitted to individual NREM episodes 1–4, using data from 30 healthy subjects aged 20–30 years, and the quality of fit for each NREM measured. We show that the model fits well all NREM episodes and the best-fit probability-set is found to be effectively the same in fitting all subject data. The significant model-data agreement, the constant probability parameter and the proposed role of the SCN add considerable strength to the model. With it we link for the first time findings at cellular level and detailed time-course data at EEG level, to give a coherent picture of NREM dynamics over the entire night and over hierarchic brain levels all the way from the SCN to the EEG