In recent years, a considerable amount of effort has been devoted, both in industry and academia, towards the behavioral modeling, evaluation and prediction of the hypothalamus pituitary thyroid ...system. Thyroid Systems Engineering targets an optimal treatment of people suffering from thyroid hormone disorders. The content is motivated by in-depth observations of such patients whose rich data supported the theoretical framework arising from formal mathematical reasoning, guided by the nature of thyroid physiology. Leveraging on the insights emerging from the unique combination of an electrical engineer working with a clinical thyroidologist, and both being scientists skilled in mathematics, the authors introduce this new discipline and field of scientific investigation aptly designated as Thyroid Systems Engineering. Readers will discover that mathematics can indeed model the behavior of the hypothalamus-pituitary-thyroid (HPT) axis. Focused on modeling, each of the eighteen chapters gives the reader a notion of the application of relevant mathematics to pertinent issues encountered in mainstream thyroidology. Many cellular processes resemble the flux of variables and states in a complex multi-parameter space through time analogous to current flow in electrical networks. It is then logical to apply the principles and physical laws of electrodynamics, electrical network theory, control systems theory and signal theory to many of the biological phenomena encountered in endocrinology. Such an approach is used liberally throughout the book and successfully yields elegant solutions to a number of models presented within. This book can serve as a reference to mathematical modeling in other aspects of endocrine physiology, and as the starting point for a fundamental course in medical modeling. It will appeal to postgraduates in electrical engineering, academic physicians and biomedical researchers. Further, readers equipped with advanced calculus, electrical network theory, co
Obesity induces profound transcriptome changes in adipocytes; recent evidence suggests that lncRNAs play key roles in this process. Here, we performed a comprehensive transcriptome study by RNA-Seq ...in adipocytes isolated from interscapular brown, inguinal and epididymal white adipose tissues in diet-induced obese mice. Our analysis reveals a set of obesity-dysregulated lncRNAs, many of which exhibit dynamic changes in fed
fasted state, potentially serving as novel molecular markers reflecting adipose energy status. Among the most prominent ones is
, an lncRNA transcribed from an enhancer region upstream of
Expression of
is sensitive to insulin and closely correlates to
expression across diverse pathophysiological conditions. Functionally, induction of
is essential for adipogenesis, and its presence is required for the maintenance of
expression
and
Direct interaction was detected between DNA loci of
and
in mature adipocytes, which diminished upon
knockdown. Our study establishes
as a new regulator of
.
The global burden of tuberculosis (TB) morbidity and mortality remains immense. A potential new approach to TB therapy is to augment protective host immune responses. We report that the antidiabetic ...drug metformin (MET) reduces the intracellular growth of Mycobacterium tuberculosis (Mtb) in an AMPK (adenosine monophosphate-activated protein kinase)-dependent manner. MET controls the growth of drug-resistant Mtb strains, increases production of mitochondrial reactive oxygen species, and facilitates phagosome-lysosome fusion. In Mtb-infected mice, use of MET ameliorated lung pathology, reduced chronic inflammation, and enhanced the specific immune response and the efficacy of conventional TB drugs. Moreover, in two separate human cohorts, MET treatment was associated with improved control of Mtb infection and decreased disease severity. Collectively, these data indicate that MET is a promising candidate host-adjunctive therapy for improving the effective treatment of TB.
Obesity is a serious epidemic health problem that can cause many other diseases including type 2 diabetes and cardiovascular diseases. Current approaches to combat obesity suffer from low ...effectiveness and adverse side effects. Here, a new self‐administrable and minimally invasive transdermal drug delivery strategy for home‐based long‐term treatment of obesity and other diseases is developed. Specifically, ultrathin, core‐shelled, and lance‐shaped polymeric drug reservoirs (micro‐lances MLs) are readily fabricated by a thermal pressing molding method and totally implanted into subcutaneous fat by lancing through the skin. Using a diet‐induced obese mouse model, it is shown that the development of obesity and associated metabolic disorders is effectively inhibited by applying therapeutic core‐shelled MLs once every 2 weeks. The outstanding therapeutic effects are attributable to highly localized and biphasic drug release, as well as combination therapy based on browning transformation of white fat and enhanced insulin sensitivity.
A self‐administrable and minimally invasive transdermal drug delivery strategy is developed using ultrathin, core‐shelled, polymeric micro‐lances (MLs). The therapeutic MLs can be readily fabricated by a thermal pressing molding method and totally implanted into subcutaneous fat by lancing through the skin. The potential of such an ML approach for long‐term home‐based treatment of obesity and associated metabolic diseases is demonstrated.
Objective
This study aimed to compare the associations of positron emission tomography (PET), magnetic resonance (MR), and infrared thermography (IRT) imaging modalities with energy expenditure (EE) ...after brown adipose tissue (BAT) activation using capsinoid ingestion and cold exposure.
Methods
Twenty participants underwent PET‐MR, IRT imaging, and whole‐body calorimetry after capsinoid ingestion and cold exposure. Standardized uptake values (SUV) and the fat fraction (FF) of the supraclavicular brown adipose tissue regions were estimated. The anterior supraclavicular temperature (Tscv) from IRT at baseline and postintervention was measured. Two‐hour post–capsinoid ingestion EE and post–cold exposure EE served as a reference to correlate fluorodeoxyglucose uptake, FF, and Tscv for BAT assessment. IRT images were geometrically transformed to overlay on PET‐MR for visualization of the hottest regions.
Results
The supraclavicular hot spot identified on IRT closely corresponded to the area of maximal fluorodeoxyglucose uptake on PET images. Controlling for body weight, post–cold exposure Tscv was a significant variable associated with EE (P = 0.025). The SUV was significantly inversely correlated with FF (P = 0.012) and significantly correlated with peak of Tscv during cold exposure in BAT‐positive participants (P = 0.022).
Conclusions
Tscv correlated positively with EE and was also significantly correlated with SUV after cold exposure. Both IRT and MR FF are promising methods to study BAT activity noninvasively.
Previous studies have shown that the sequential order of consuming different food components significantly impacts postprandial glucose and insulin excursions in prediabetes and type 2 diabetes, but ...the causative mechanisms in healthy humans remain ill-defined.
Using a typical Asian meal comprising vegetables, protein (chicken breast), and carbohydrate (white rice), the aim of this study was to examine the effect of food intake sequence on postprandial glucose, insulin and incretin secretions in healthy adults.
Sixteen healthy Chinese adults participated in a randomized, controlled, crossover meal trial. Subjects consumed in random order 5 experimental isocaloric meals that differed in the food intake sequence of vegetables, protein and carbohydrate. Glucose, insulin, incretins and satiety markers were measured over 3 h.
There were significant food intake sequence × time interaction effects on plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) concentrations (P < 0.001). In comparison with rice consumed first followed by vegetable and meat (R-VM), the overall postprandial glucose response was significantly attenuated after the food intake sequence of vegetable first, followed by meat and rice (V-MR) or meat first, followed by vegetable and rice (M-VR) or vegetable first followed by meat and rice (V-M-R) or vegetable, meat and rice consumed together (VMR). The insulin iAUC (0–60) was significant lower after V-M-R than M-VR, VMR and R-VM. V-M-R food intake sequence stimulated higher GLP-1 release than other meal sequences. However, GIP response was lower after V-MR and V-M-R than M-VR and R-MR food intake sequences.
Food macronutrient intake sequence can considerably influence its glycemic, insulinemic and incretin responses. V-M-R food intake sequence attenuates the glycemic response to a greater degree with accentuated GLP-1 stimulation without any increased demand for insulin. The sequence of food intake has great potential as a novel and simple behavioral strategy to modulate glycemic response in healthy adults.
The trial was registered at clinicaltrials.gov as NCT03533738.
Angiotensin II (AngII), a peptide hormone released by adipocytes, can be catabolized by adipose angiotensin-converting enzyme 2 (ACE2) to form Ang(1–7). Co-expression of AngII receptors (AT1 and AT2) ...and Ang(1–7) receptors (Mas) in adipocytes implies the autocrine regulation of the local angiotensin system upon adipocyte functions, through yet unknown interactive mechanisms. In the present study, we reveal the adipogenic effects of Ang(1–7) through activation of Mas receptor and its subtle interplays with the antiadipogenic AngII-AT1 signaling pathways. Specifically, in human and 3T3-L1 preadipocytes, Ang(1–7)-Mas signaling promotes adipogenesis via activation of PI3K/Akt and inhibition of MAPK kinase/ERK pathways, and Ang(1–7)-Mas antagonizes the antiadipogenic effect of AngII-AT1 by inhibiting the AngII-AT1-triggered MAPK kinase/ERK pathway. The autocrine regulation of the AngII/AT1-ACE2-Ang(1–7)/Mas axis upon adipogenesis has also been revealed. This study suggests the importance of the local regulation of the delicately balanced angiotensin system upon adipogenesis and its potential as a novel therapeutic target for obesity and related metabolic disorders.
Background: The autocrine regulation of Ang(1–7) upon adipogenesis is unknown.
Results: The autocrine counteractive interplays between Ang(1–7)-Mas and AngII-AT1 signaling upon adipogenesis are revealed.
Conclusion: The Ang(1–7)-Mas activation stimulates adipogenesis and antagonizes the antiadipogenic effect of AngII-AT1 activation.
Significance: The angiotensin system in adipose tissue may serve as a potential therapeutic target for obesity and related metabolic disorders.
Existing methods that use propensity scores for heterogeneous treatment effect estimation on non-experimental data do not readily extend to the case of more than two treatment options. In this work, ...we develop a new propensity score-based method for heterogeneous treatment effect estimation when there are three or more treatment options, and prove that it generates unbiased estimates. We demonstrate our method on a real patient registry of patients in Singapore with diabetic dyslipidemia. On this dataset, our method generates heterogeneous treatment recommendations for patients among three options: Statins, fibrates, and non-pharmacological treatment to control patients’ lipid ratios (total cholesterol divided by high-density lipoprotein level). In our numerical study, our proposed method generated more stable estimates compared to a benchmark method based on a multi-dimensional propensity score.
Medical apps are widely available, increasingly used by patients and clinicians, and are being actively promoted for use in routine care. However, there is little systematic evidence exploring ...possible risks associated with apps intended for patient use. Because self-medication errors are a recognized source of avoidable harm, apps that affect medication use, such as dose calculators, deserve particular scrutiny. We explored the accuracy and clinical suitability of apps for calculating medication doses, focusing on insulin calculators for patients with diabetes as a representative use for a prevalent long-term condition.
We performed a systematic assessment of all English-language rapid/short-acting insulin dose calculators available for iOS and Android.
Searches identified 46 calculators that performed simple mathematical operations using planned carbohydrate intake and measured blood glucose. While 59% (n = 27/46) of apps included a clinical disclaimer, only 30% (n = 14/46) documented the calculation formula. 91% (n = 42/46) lacked numeric input validation, 59% (n = 27/46) allowed calculation when one or more values were missing, 48% (n = 22/46) used ambiguous terminology, 9% (n = 4/46) did not use adequate numeric precision and 4% (n = 2/46) did not store parameters faithfully. 67% (n = 31/46) of apps carried a risk of inappropriate output dose recommendation that either violated basic clinical assumptions (48%, n = 22/46) or did not match a stated formula (14%, n = 3/21) or correctly update in response to changing user inputs (37%, n = 17/46). Only one app, for iOS, was issue-free according to our criteria. No significant differences were observed in issue prevalence by payment model or platform.
The majority of insulin dose calculator apps provide no protection against, and may actively contribute to, incorrect or inappropriate dose recommendations that put current users at risk of both catastrophic overdose and more subtle harms resulting from suboptimal glucose control. Healthcare professionals should exercise substantial caution in recommending unregulated dose calculators to patients and address app safety as part of self-management education. The prevalence of errors attributable to incorrect interpretation of medical principles underlines the importance of clinical input during app design. Systemic issues affecting the safety and suitability of higher-risk apps may require coordinated surveillance and action at national and international levels involving regulators, health agencies and app stores.
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