Search

Mast cells (MCs) are derived from CD34+hematopoietic progenitors, consist of different subtypes, and are involved in several inflammatory conditions. However, our understanding of human MC developmental trajectories and subtypes has been limited by a scarcity of suitable cellular model systems. Herein, we developed an in vitromodel of human MC differentiation from induced pluripotent stem cells (iPSC) to study human MC differentiation trajectories. Flow cytometry characterization of hemopoietic cells derived from the myeloid cells-forming complex (MCFC) revealed an initial increase in Lin-CD34+hematopoietic progenitors within Weeks 1–3, followed by an increase in CD34-CD45RA-SSClowand SSChighhematopoietic cells. The Lin-CD34+hematopoietic progenitors consisted of SSClowCD45RA-CD123±c-Kit+FcεRI+populations that were β7-integrinhighCD203c+and β7-integrinhighCD203c-cells consistent with CMPFcεRI+cells. Flow cytometry and cytologic analyses of the CD34-Lin-(SSClow) population revealed hypogranular cell populations, predominantly characterized by CD45RA-CD123±c-Kit+FcεRI-β7-integrinlowand CD45RA-CD123±c-Kit-FcεRI+β7-integrinMidcells. Analyses of hypergranular SSChighcells identified Lin-CD34-CD45RA-c-Kit+FcεRI-and Lin-CD34-CD45RA-c-Kit+FcεRI+cells. scRNA-seq analysis of the cells harvested at week 4 of the MCFC culture revealed the presence of monocyte and granulocyte progenitors (n = 547 cells, 26.7 %), Erythrocyte / unknown (n = 85, 4.1 %), neutrophils / myelocytes (n = 211 cells, 10.2 %), mast cell progenitor 1 (n = 599, 29.1 %), mast cell progenitor 2 (n = 152, 7.4 %), committed mast cell precursor (n = 113, 5.5 %), and MCs (n = 353, 17.1 %). In silico analyses of the MC precursor and mature MC populations revealed transcriptionally distinct MC precursor subtype and mature MC states (CMA1+and CMA1-subtypes). Culturing MC precursor populations in MC maturation media (mast cell media II) led to homogenous mature MC populations as evidenced by high expression of high-affinity IgE receptor, metachromatic granules, presence of MC granule proteins (Tryptase and Chymase) and activation following substance P stimulation and FcεRI crosslinking. This human iPSC-based approach generates MC precursors and phenotypically mature and functional MC populations. This system will be a useful model to generate human MC populations and broaden our understanding of MC biology and transcriptional regulation of MC differentiation trajectories.

Calciphylaxis is a rare but highly disabling disease, occurring both in chronic kidney disease (CKD) with renal replacement therapy (RRT) and in normal renal function. Given the frequent coexistence of atrial fibrillation (AF) and CKD, anticoagulation is often required. Warfarin, as a promoter of vascular calcification, is frequently reported as a triggering factor of calciphylaxis. Here, we present the case of a 71-year old male patient with a history of AF and a previous ischaemic stroke, on RRT for three years and warfarin therapy. The patient presented with two painful necrotic skin ulcers over the right leg and a skin biopsy confirmed calciphylaxis. After discontinuation of warfarin, the lesions completely healed with sodium thiosulfate intravenous infusion and local wound treatment. A literature search was performed up to 1 September 2022 through PubMed. The following terms were searched in different combinations: ‘calciphylaxis’; ‘VKA’ [vitamin K antagonist]; ‘warfarin’; ‘haemodialysis’; ‘end-stage renal disease’; and ‘ulcer’. In our opinion, in patients requiring anticoagulant therapy, the introduction or continuation of vitamin K antagonists (VKAs) should be carefully balanced when calciphylaxis develops, and other options, such as enoxaparin or apixaban, should be considered. Clinical decisions for patients requiring haemodialysis and requiring anticoagulant therapy should take into account the possible risk of warfarin-induced calciphylaxis. Further studies are needed to clarify the safety, tolerability profile and outcomes of each currently available treatment in this patient population.

Awns illustrate an important photosynthetic organ of the cereal spike, especially under water stress. Barley (Hordeum vulgareL.) spikes are distinguished by long awns; nevertheless, the actual changes in barley awn dimensions under drought stress have not been adequately studied. In the present work, six barley genotypes with varying degrees of drought tolerance were investigated in a 2-year field experiment under well-watered (WW) and terminal drought stress (TDS) conditions based on randomized complete block design with three replications. The results showed that although TDS caused a notable reduction in awn dimensions compared to WW, the density of barbs on the awn surface significantly increased in all barley genotypes. In addition, the barb contact angle decreased significantly under TDS conditions compared to WW. Awn area had a significantly positive correlation with thousand grain weight and grain yield in both treatments and growing seasons. Also, highly significant correlations were observed between leaf stomatal conductance, awn area, and barb density under both conditions. In TDS, two genotypes demonstrated lower carbon isotope discrimination: Morocco, with higher awn dimensions, and PBYT 46, with a higher increase in barbs density on the awn surface and a lower canopy temperature. This research underlines barbs density on the awn surface by reflecting the light and a lower increase in the canopy temperature plays a more pivotal role than awn dimensions on water use efficiency in barley under terminal drought.

Panaligan, N.R.P. (2020). Health implications for recently detained unaccompanied immigrant children: The role of pediatric nurses. Pediatric Nursing, 46(5), 215-218, 244. Unaccompanied children continue to immigrate to the United States from Central America and Mexico seeking asylum and often reunification with family. As this influx continues, it is the responsibility of the medical community, including pediatric nurses, to address the health needs of these vulnerable children. This article reviews current health considerations of recently detained unaccompanied children, and the impact their experiences have on their physical and mental health. Key Words: Undocumented, detained, immigrant, health implications, mental health, access., Since 2014, the United States has experienced an influx of unaccompanied minors crossing the United States-Mexican border, many of whom are fleeing poverty, violence, and exploitation by gangs and drug [...]

Purpose: Women are exposed to vulnerabilities that can lead to drug use or hinder recovery. However, there is a dearth of studies on recovery programs for women. This study aims to add to the literature by examining the feasibility of a women-only aftercare program for recovering users in the Philippines. Design/methodology/approach: The study used a mixed-method design with pre and post-program surveys used to measure changes in participants’ recovery capital. Focused group discussions elicited participants’ context, their reactions, perceived outcomes and suggestions on the program. Findings: Women in the program shared narratives of pain, trauma and abuse before treatment. Participants reported significant improvements in personal, community and family recovery capital dimensions. The program enabled personal growth in the form of new knowledge, skills and self-confidence. The women-only program also provided a safe space for women, to receive support from other women, community members and family. However, the women continue to face continuing challenges related to stigma and discrimination and a lack of livelihood opportunities. Research limitations/implications: A limitation of the study was its small sample size and the lack of a control group. Another limitation was the variability in treatment received by the women, which could have affected overall outcomes. Future studies using a randomized control trial and longitudinal designs may provide more robust conclusions on the effectiveness of the program. Practical implications: Given punitive contexts, gender-sensitive and trauma-informed programs and services for women involved in drug use could potentially mitigate the abuse, stigma and vulnerabilities they experience. Originality/value: This study contributes to the sparse literature on women-only aftercare, particularly in countries that criminalize drug use.

Postoperative atrial fibrillation (POAF) is the most common arrhythmia following cardiac surgery (CS). It may occur between the 1st and the 4th postoperative day as acute POAF or between the 5th and the 30th as subacute (sPOAF). sPOAF is associated with higher thromboembolic risk, which consistently increase patients' morbidity. Neutrophil‐to‐lymphocyte ratio (NLR) is a low‐cost inflammatory index proposed as possible POAF predictor. Identification of patients' risk categories might lead to improved postoperative outcomes. The aim was to assess the incidence of sPOAF and to identify possible predictors in patients performing cardiovascular rehabilitation (CR) after CS. A single‐center cohort study was performed on 737 post‐surgical patients admitted to CR on sinus rhythm. Continuous monitoring with 12‐lead ECG telemetry was performed. We evaluated the predictive role of anamnestic, clinical, and laboratory data, including baseline NLR. Subacute POAF was documented in 170 cases (23.1%). At the multivariate analysis, age (OR 1.03; p= .001), mitral valve surgery (OR 1.77; p= .012), acute POAF (OR 2.97; p< .001), and NLR at baseline (OR 1.13; p= .042) were found to be independent predictive factors of sPOAF following heart surgery. sPOAF is common after CS. Age, mitral valve procedures, acute POAF, and preoperative NLR were proved to increase sPOAF occurrence in CR. NLR is an affordable and reliable parameter which might be used to qualify the risk of arrhythmias at CR admission. Identification of new predictors of postoperative atrial fibrillation may allow to improve patients' prognosis. Atrial fibrillation is a common complication following cardiac surgery. Age, mitral valve surgery, acute POAF, and baseline neutrophil‐to‐lymphocyte ratio resulted independent predictors of sPOAF. Identification of new arrhythmic predictors might be useful to categorize patients into risk categories in order to tailor treatment strategies and optimize postoperative prognosis.

Trees structure the Earth’s most biodiverse ecosystem, tropical forests. The vast number of tree species presents a formidable challenge to understanding these forests, including their response to environmental change, as very little is known about most tropical tree species. A focus on the common species may circumvent this challenge. Here we investigate abundance patterns of common tree species using inventory data on 1,003,805 trees with trunk diameters of at least 10 cm across 1,568 locations1–6in closed-canopy, structurally intact old-growth tropical forests in Africa, Amazonia and Southeast Asia. We estimate that 2.2%, 2.2% and 2.3% of species comprise 50% of the tropical trees in these regions, respectively. Extrapolating across all closed-canopy tropical forests, we estimate that just 1,053 species comprise half of Earth’s 800 billion tropical trees with trunk diameters of at least 10 cm. Despite differing biogeographic, climatic and anthropogenic histories7, we find notably consistent patterns of common species and species abundance distributions across the continents. This suggests that fundamental mechanisms of tree community assembly may apply to all tropical forests. Resampling analyses show that the most common species are likely to belong to a manageable list of known species, enabling targeted efforts to understand their ecology. Although they do not detract from the importance of rare species, our results open new opportunities to understand the world’s most diverse forests, including modelling their response to environmental change, by focusing on the common species that constitute the majority of their trees.

In the additive manufacturing powder bed fusion process with electron beam (PBF-EB) process, the thermal conductivity of the powder bed controls the interaction of the electron beam with the material, the heat transfer during the process, the cooling rate and, consequently, the final component microstructure. This property requires to be optimized, and the desired value is achieved at the present day only with a trial and error approach. This work proposes a numerical method that considers the powder bed’s geometrical characteristics, including the neck formation among the powder particles. Examples of model applications are reported, considering the Ti6Al4V alloy processed with the PBF-EB process.

The thermal conductivity of the powder bed during the electron beam powder bed fusion (PBF-EB) process strongly influences the process conduction and the quality of the components produced. The evaluation of this property is challenging. The models currently available in the literature cannot provide values of the thermal conductivity that consider the temperature evolution typical of the preheating step. This work presents a novel computational framework to evaluate the thermal conductivity of a powder bed for the PBF-EB process. The framework combines the thermal conditions of the PBF-EB process with information on the geometrical features of the powder bed and an analytic method to calculate the thermal conductivity and its variation with temperature and time. The proposed numerical framework is applied to the body centred structure (BCC), a typical arrangement that can emulate the PBF-EB conditions. The numerical framework is multiscale by nature, providing information about the whole powder bed starting from geometrical information about the neck among the powder particles.

Diaphragm dysfunction is a common complication following cardiac surgery. Its clinical impact is variable, ranging from the absence of symptoms to the acute respiratory failure. Post‐operative diaphragm dysfunction may negatively affect patients' prognosis delaying the weaning from the mechanical ventilation (MV), extending the time of hospitalization and increasing mortality. Ultrasonography is a valid tool to evaluate diaphragmatic impairment in different settings, like the Intensive Care Unit, to predict successful weaning from the MV, and the Cardiovascular Rehabilitation Unit, to stratify patients in terms of risk of functional recovery failure. The aim of this review is to describe the pathophysiology of post‐cardiac surgery diaphragm dysfunction, the techniques used for its diagnosis and the potential applications of diaphragm ultrasound.

As concrete producers in colder climates renovate their ready-mix plants, they are finding that direct-contact water heaters provide ample hot water on demand--at lower cost than traditional direct-fired hot water [...]

ABSTRACTSpain is the number one citrus-producing country in the European Union and the sixth worldwide, with more than six million tons of citrus produced annually. Seven biorational insecticides (paraffin oil, azadirachtin, kaolin, garlic extract, orange oil, potassium soap and diatomaceous earth) recommended for control of different pests in organic citrus orchards were evaluated against Trioza erytreae(Del Guercio) in semi-field and field trials. All products affected T. erytreaesurvival in both types of trials. In the semi-field trial, diatomaceous earth resulted in the highest percentage mortality of T. erytreaenymphs, followed by kaolin, apart from on the final day of assessment when the highest mortality was recorded for paraffin oil, though this effect was not significantly different to that of the other insecticides. In the 2018 field trial, orange oil treatment resulted in the highest mortality rate of T. erytreaenymphs, followed by azadirachtin and garlic extract. This work provides citrus growers with useful information on the effects of several biorational insecticides on T. erytreaeunder field and semi-field conditions. Overall, the optimal T. erytreaenymph mortality was achieved with diatomaceous earth and orange oil under semi-field and field conditions, respectively.

The role of left atrial appendage occlusion (LAAO) for atrial fibrillation patients that during oral anticoagulant therapy (OAC) suffer from ischemic events or present LAA sludge, and the best postinterventional anticoagulant regimen, need to be defined. We present our experience with a hybrid approach of LAAO+ lifelong OAC therapy in this cohort of patients. Out of 425 patients treated with LAAO, 102 underwent LAAO because, despite OAC, suffered from ischemic events or presented with LAA sludge. Patients without high bleeding risk were discharged with the aim of maintaining lifelong OAC. This cohort was then matched to a population who underwent LAAO in primary ischemic events prevention. The primary endpoint was the composite of all‐cause death and major adverse cardiovascular events consisting of ischemic stroke, systemic embolism (SE), and major bleeding. Procedural success was 98%, and 70% of patients were discharged with anticoagulant therapy. After a median follow‐up of 47.2 months, the primary endpoint occurred in 27 patients (26%). At multivariate analyses, coronary artery disease (OR 5.1, CI 1.89–14.27, p= .003) and OAC at discharge (OR 0.29, CI 0.11–0.80, p= .017) were associated with the primary endpoint. After propensity score matching, no significant difference was found in the survival free from the primary endpoint according to the indication for LAAO (p= .19). In this high‐ischemic risk cohort, LAAO + OAC seem a long‐term safe and effective therapeutical approach, with no difference in the survival free from the primary endpoint according to the indication for LAAO in a matched cohort. The role of left atrial appendage occlusion (LAAO) for atrial fibrillation patients that during oral anticoagulant therapy suffer from ischemic events is still a matter of debate. In the absence of a high bleeding risk, a hybrid approach of LAAO + lifelong anticoagulant therapy could be an effective novel strategy

We studied the magneto-optical Kerr effect (MOKE) of two-dimensional (2D) heterostructure CrI3/In2Se3/CrI3using density functional theory calculations and symmetry analysis. The spontaneous polarization in the In2Se3ferroelectric layer and the antiferromagnetic ordering in CrI3layers break the mirror and the time-reversal symmetry, thus activating MOKE. We show that the Kerr angle can be reversed by either the polarization or the antiferromagnetic order parameter. Our results suggest that ferroelectric and antiferromagnetic 2D heterostructures could be exploited for ultracompact information storage devices, where the information is encoded by the two ferroelectric or the two time-reversed antiferromagnetic states and the read-out is performed optically by MOKE.

EPA non-attainment areas are constantly under pressure to meet the Clean Air Standards of 1990. While a number of non-attainment areas exist throughout the country, California has been dealing with [...]

Surface-enhanced Raman optical activity (SEROA) has been extensively investigated due to its ability to directly probe stereochemistry and molecular structure. However, most works have focused on the Raman optical activity (ROA) effect arising from the chirality of the molecules on isotropic surfaces. Here, we propose a strategy for achieving a similar effect: i.e., a surface-enhanced Raman polarization rotation effect arising from the coupling of optically inactive molecules with the chiral plasmonic response of metasurfaces. This effect is due to the optically active response of metallic nanostructures and their interaction with molecules, which could extend the ROA potential to inactive molecules and be used to enhance the sensibility performances of surface-enhanced Raman spectroscopy. More importantly, this technique does not suffer from the heating issue present in traditional plasmonic-enhanced ROA techniques, as it does not rely on the chirality of the molecules.

Temporal metamaterials, based on time-varying constitutive properties, offer new exciting possibilities for advanced field manipulations. In this study, we explore the capabilities of anisotropic temporal slabs, which rely on abrupt changes in time from isotropic to anisotropic response (and vice versa). Our findings show that these platforms can effectively manipulate the wave-spin dimension, allowing for a range of intriguing spin-controlled photonic operations. We demonstrate these capabilities through examples of spin-dependent analog computing and spin–orbit interaction effects for vortex generation. These results provide new insights into the field of temporal metamaterials, and suggest potential applications in communications, optical processing and quantum technologies.

The simultaneous assessment of insulin action, secretion, and hepatic extraction is key to understanding postprandial glucose metabolism in nondiabetic and diabetic humans. We review the oral minimal method (i.e., models that allow the estimation of insulin sensitivity, β-cell responsivity, and hepatic insulin extraction from a mixed-meal or an oral glucose tolerance test). Both of these oral tests are more physiologic and simpler to administer than those based on an intravenous test (e.g., a glucose clamp or an intravenous glucose tolerance test). The focus of this review is on indices provided by physiological-based models and their validation against the glucose clamp technique. We discuss first the oral minimal model method rationale, data, and protocols. Then we present the three minimal models and the indices they provide. The disposition index paradigm, a widely used β-cell function metric, is revisited in the context of individual versus population modeling. Adding a glucose tracer to the oral dose significantly enhances the assessment of insulin action by segregating insulin sensitivity into its glucose disposal and hepatic components. The oral minimal model method, by quantitatively portraying the complex relationships between the major players of glucose metabolism, is able to provide novel insights regarding the regulation of postprandial metabolism. Diabetes 2014;63:1203-1213 | DOI: 10.2337/db13-1198, The simultaneous assessment of insulin action, insulin secretion, and hepatic extraction is key to understanding postprandial glucose metabolism in nondiabetic and diabetic humans and to putting therapeutic actions on solid [...]

The contribution of elevated glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y gastric bypass (RYGB) has been the subject of uncertainty. We used exendin-9,39, a competitive antagonist of GLP-1, to examine glucose metabolism, islet hormone secretion, and gastrointestinal transit in subjects after RYGB and in matched control subjects. Subjects were studied in the presence or absence of exendin-9,39 infused at 300 pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6 ± 0.5 vs. 2.0 ± 0.4 mol/6 h, P = 0.001). Exendin-9,39 decreased insulin concentrations 12.3 ± 2.2. vs. 18.1 ± 3.1 nmol/6 h, P = 0,002) and the β-cell response to glucose ([Φ.sub.Total], 13 ± 1 vs. 11 ± 1 x [10.sup.-9] [min.sup.-1], P = 0.01) but did not alter the disposition index (DI). In control subjects, exendin-9,39 also increased glucose (2.2 ± 0.4 vs. 1.7 ± 0.3 mol/6 h, P = 0.03) without accompanying changes in insulin concentrations, resulting in an impaired DI. Post-RYGB, acceleration of stomach emptying during the first 30 min by exendin-9,39 did not alter meal appearance, and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain whether this explains all of the changes after RYGB. Diabetes 2014;63:483-493 | DOI: 10.2337/db13-0954, Type 2 diabetes is a common metabolic disorder characterized by hyperglycemia arising from defects in insulin secretion and action. The increase in incidence and prevalence of type 2 diabetes is [...]

In this work, we consider Reconfigurable Intelligent Meta-surfaces (RIMs) to provide effective beam steering functionality, while enhancing the coverage of the fifth generation (5G) users in a urban city mobility context. In particular, we enable communications in the millimeter wave (mmWave) frequencies, that can occur simultaneously with other 5G communications. The main objective of this paper is to demonstrate the feasibility and advantages of an integrated Computed Vision (CV) approach for tuning the meta-atom states of a RIM structure working at mmWave frequency band, without estimating the interferes' radio channel. In particular, the CV system will feed a logic unit running a Machine Learning (ML) algorithm to compute in real-time the coding schemes, namely the sequence of binary states associated to each unit-cell of the RIM, in order to obtain the target reconfigurable radiation pattern. Specifically, a Genetic Algorithm (GA) is introduced to derive the most suitable radiation pattern for Beam Steering application, based on the input of a CV infrastructure. Results show the feasibility of such a kind of system, with an higher coverage achieved in dense scenarios, by improving the robustness against the potential blockages introduced by the mmWave technology. Moreover, we demonstrate the system is robust against the inaccuracy introduced by the CV and GA.

The thermal conductivity of the unmelted powder particles in an electron beam powder bed fusion (EB-PBF) process is mainly determined by its sintering degree. A proper thermal conductivity is required to dissipate the heat generated during the melting and improve the beam matter interaction. In this work, the thermal conductivity is evaluated by image-based methodologies and thermal diffusion simulations. The effective neck growth and dimension are numerically calculated using phase field sintering simulations. The proposed methodology is able to provide crucial insight for the process optimisation without performing any experiment.

Exendin-(9,39) is a competitive antagonist of glucagon-like peptide-1 (GLP-1) at its receptor. However, it is unclear if it has direct and unique effects of its own. We tested the hypothesis that exendin-(9,39) and GLP-1-(9,36)amide have direct effects on hormone secretion and p-cell function as well as glucose metabolism in healthy subjects. Glucose containing [3-³H]glucose was infused to mimic the systemic appearance of glucose after a meal. Saline, GLP-1-(9,36)amide, or exendin-(9,39) at 30 pmol/kg/min (Ex 30) or 300 pmol/kg/min (Ex 300) were infused in random order on separate days. Integrated glucose concentrations were slightly but significantly increased by exendin-(9,39) (365 ± 43 vs. 383 ± 35 vs. 492 ± 49 vs. 337 ± 50 mmol per 6 h, saline, Ex 30, Ex 300, and GLP-1-[9,36]amide, respectively; P = 0.05). Insulin secretion did not differ among groups. However, insulin action was lowered by exendin-(9,39) (25 ± 4 vs. 20 ± 4 vs. 18 ± 3 vs. 21 [+ or -] 4 [10.sup.-4] dL/kg[min per µU/mL]; P = 0.02), resulting in a lower disposition index (DI) during exendin-(9,39) infusion (1,118 ± 118 vs. 816 ± 83 vs. 725 ± 127 vs. 955 ± 166 [10.sup.-14] dL/kg/[min.sup.2] per pmol/L; P = 0.003). Endogenous glucose production and glucose disappearance did not differ significantly among groups. We conclude that exendin-(9,39), but not GLP-1-(9,36)amide, decreases insulin action and DI in healthy humans., The incretin hormone glucagon-like peptide-1 (GLP-1) arises by posttranslational processing of preproglucagon in the enteroendocrme L cells distributed throughout the intestine. GLP-1 secretion occurs within minutes of food ingestion, is [...]

We recently demonstrated a diurnal pattern to insulin action (i.e., insulin sensitivity [SI]) in healthy individuals with higher SI at breakfast than at dinner. To determine whether such a pattern exists in type 1 diabetes, we studied 19 subjects with C-peptide-negative diabetes (Hb[A.sub.1c] 7.1 ± 0.6%) on insulin pump therapy with normal gastric emptying. Identical mixed meals were ingested during breakfast, lunch, and dinner at 0700, 1300, and 1900 h in randomized Latin square of order on 3 consecutive days when measured daily physical activity was equal. The triple tracer technique enabled measurement of glucose fluxes. Insulin was administered according to the customary insulin:carbohydrate ratio for each participant. Although postprandial glucose excursions did not differ among meals, insulin concentration was higher (P < 0.01) and endogenous glucose production less suppressed (P < 0.049) at breakfast than at lunch. There were no differences in meal glucose appearance or in glucose disappearance between meals. Although there was no statistical difference (P = 0.34) in SI between meals in type 1 diabetic subjects, the diurnal pattern of SI taken across the three meals in its entirety differed (P = 0.016) from that of healthy subjects. Although the pattern in healthy subjects showed decreasing SI between breakfast and lunch, the reverse SI pattern was observed in type 1 diabetic subjects. The results suggest that in contrast to healthy subjects, SI diurnal pattern in type 1 diabetes is specific to the individual and cannot be extrapolated to the type 1 diabetic population as a whole, implying that artificial pancreas algorithms may need to be personalized., An optimal closed-loop control system will need to take into account alterations in physiological parameters that modulate glucose concentrations, including changes in insulin sensitivity (SI) related to meals and physical [...]

We designed an experiment to examine the effect of bile acid sequestration with Colesevelam on fasting and postprandial glucose metabolism in type 2 diabetes. To do so, we tested the hypothesis that Colesevelam increases the disposition index (DI), and this increase is associated with increased glucagon-like peptide-1 (GLP-1) concentrations. Thirty-eight subjects on metformin monotherapy were studied using a double-blind, placebo-controlled, parallel-group design. Subjects were studied before and after 12 weeks of Colesevelam or placebo using a labeled triple-tracer mixed meal to measure the rate of meal appearance (Meal Ra), endogenous glucose production (EGP), and glucose disappearance (Rd). Insulin sensitivity and β-cell responsivity indices were estimated using the oral minimal model and then used to calculate DI. Therapy with Colesevelam was associated with a decrease in fasting (7.0 ± 0.2 vs. 6.6 ± 0.2 mmol/L; P = 0.004) and postprandial glucose concentrations (3,145 ± 138 vs. 2,896 [+ or -] 127 retool/6 h; P = 0.01) in the absence of a change in insulin concentrations. Minimal model-derived indices of insulin secretion and action were unchanged. Postprandial GLP-1 concentrations were not altered by Colesevelam. Although EGP and Rd were unchanged, integrated Meal Ra was decreased by Colesevelam (5,191 ± 204 vs. 5,817 ± 204 µmol/kg/6 h; P = 0.04), suggesting increased splanchnic sequestration of meal-derived glucose., The bile acid sequestrants used therapeutically (for the treatment of hypercholesterolemia) such as cholestyramine, Colesevelam, and colestipol, increase the fecal excretion of bile acids by interrupting their enterohepatic circulation (1). [...]

OBJECTIVE--We sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age. RESEARCH DESIGN AND METHODS--We examined human autopsy pancreas from 167 [...]

Evaluation of the existence of a diurnal pattern of glucose tolerance after mixed meals is important to inform a closed-loop system of treatment for insulin requiring diabetes. We studied 20 [...]

OBJECTIVE--To test whether diabetic polyneuropathies (DPNs), retinopathy, or nephropathy is more prevalent in subjects with impaired glycemia (IG) (abnormality of impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or impaired [...]

OBJECTIVE--In humans, it is unclear if insulin resistance at the monocyte level is associated with atherosclerosis in vivo. Here we have studied first-degree relatives of patients with type 2 diabetes to investigate whether a reduction in components of the insulin signal transduction pathways, such as the insulin receptor (InsR) or InsR substrate 1 or 2 (IRS1 or IRS2), or a reduction in genetic modifiers of insulin action, such as the TIMP3/ADAM17 (tissue inhibitor of metalloproteinase 3/A disintegrin and metalloprotease domain 17) pathway, is associated with evidence of atherosclerosis. RESEARCH DESIGN AND METHODS---Insulin sensitivity was analyzed through euglycemic-hyperinsulinemic clamp, and subclinical atherosclerosis was analyzed through intimal medial thickness. Monocytes were isolated through magnetic cell sorting, and mRNA and proteins were extracted and analyzed by quantitative PCR and pathscan enzyme-linked immunosorbent assays, respectively. RESULTS--In monocyte cells from human subjects with increased risk for diabetes and atherosclerosis, we found that gene expression, protein levels, and tyrosine phosphorylation of IRS2, but not InsR or IRS1, were decreased. T1MP3 was also reduced, along with insulin resistance, resulting in increased ectodomain shedding activity of the metalloprotease ADAM17. CONCLUSIONS--Systemic insulin resistance and subclinical atherosclerosis are associated with decreased IRS2 and TIMP3 expression in circulating monocytes., Insulin resistance and compensatory hyperinsulinemia, both consequences of obesity and lipotoxicity, are well-known risk factors for the development of atherosclerosis (1). Recent findings from animal models outlined that a combination [...]

OBJECTIVE--Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals. RESEARCH DESIGN AND METHODS--A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tor Vergata Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.). RESULTS--Incidence of cardiovascular events per 100 person--years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80-2.70) in GHS, 2.31 (95% CI 1.22-4.34) in TVAS, and 1.36 (95% CI 0.88-2.10) in CREED, and 1.56 (95% CI 1.15-2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross-sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction). CONCLUSIONS--The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding. Diabetes 60:1000-1007, 2011, Morbidity and mortality due to cardiovascular disease (CVD) are highly prevalent (1), mostly because of the epidemics of obesity and type 2 diabetes (2-4). Environmental and genetic factors both contribute [...]

OBJECTIVE--The islet in type 2 diabetes is characterized by β-cell apoptosis, β-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in β-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum-associated degradation/ubiquitin/proteasome system. RESEARCH DESIGN AND METHODS--We used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832/13 cells and apoptosis was evaluated. RESULTS--We report accumulation of polyubiquinated proteins and UCH-L1 deficiency in β-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in β-cells induced endoplasmic reticulum stress leading to apoptosis. CONCLUSIONS--Our results indicate that defective protein degradation in β-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises β-cell Viability. Diabetes 60: 227-238, 2011, Type 2 diabetes is characterized by a progressive decline in β-cell function in the face of insulin resistance. Although the mechanisms underlying β-cell dysfunction are unknown, it is likely related [...]

The objective of this research is to gain a greater understanding of the cause of fasting and postprandial hyperglycemia in people with type 2 diabetes. Endogenous glucose production is excessive before eating and fails to appropriately suppress after eating in people with type 2 diabetes. This is due in part to impaired insulin-induced suppression of endogenous glucose production, which is observed early in the evolution of type 2 diabetes. Increased rates of gluconeogenesis and perhaps glycogenolysis contribute to hepatic insulin resistance. Insulin-induced stimulation of hepatic glucose uptake and hepatic glycogen synthesis are reduced in people with type 2 diabetes primarily due to decreased uptake of extracellular glucose presumably because of inadequate activation of hepatic glucokinase. Delayed insulin secretion results in higher peak glucose concentrations particularly when suppression of glucagon is impaired, whereas insulin resistance prolongs the duration of hyperglycemia, which can be marked when both hepatic and extra-hepatic insulin resistance are present. The premise of these studies, as well as those performed by many other investigators, is that an understanding of the pathogenesis of type 2 diabetes will enable the development of targeted therapies that are directed toward correcting specific metabolic defects in a given individual. I, as well as many other investigators, believe that such therapies are likely to be more effective and to have a lower risk than would occur if everyone were treated the same regardless of the underlying cause of their hyperglycemia. While we do not yet have sufficient knowledge to truly individualize therapy, in my opinion this approach will be the norm in the not too distant future. Diabetes 59:2697-2707, 2010, The discovery of insulin by Dr. Frederick Banting and Charles Best forever changed the lives of people with diabetes. When properly used, insulin prevents death from ketoacidosis in people with [...]

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1532-5415.2010.02773.x Byline: Stefano Rizza (1), Fabrizio Gigli (1), Angelica Galli (1), Barbara Micchelini (1), Davide Lauro (1), Renato Lauro (1), Massimo Federici (1) Keywords: adiponectin; elderly; coronary heart disease; inflammation Abstract: OBJECTIVES: To study the distribution of adiponectin isoforms in a group of very old patients. DESIGN: Cross-sectional. SETTING: Geriatric ambulatory clinic of the Department of Medicine at Policlinico 'Tor Vergata.' PARTICIPANTS: One hundred eight elderly adults (mean age 85.0[+ or -]3.2) with or without a history of a previous myocardial infarction as proof of established coronary artery disease (CAD) at least 3 months before entry into the study. Accordingly, subjects were divided into CAD positive (CAD+, n=50) and CAD negative (CAD-, n=58). MEASUREMENT: Assessment of adiponectin isoforms along with metabolic, lipid, and inflammatory profiles. RESULTS: CAD+ subjects had significantly higher levels of total adiponectin (Tot-Ad) and low-molecular-weight adiponectin (LMW-Ad) than CAD- subjects (P=.008 for both). LMW-Ad and high-sensitivity C-reactive protein were positively correlated, even after adjustment for waist circumference, sex, glomerular filtration rate, and presence of diabetes mellitus (correlation coefficient (r)=0.25, P=.05). This association was not confirmed when CAD+ subjects were analyzed alone. A positive association was found in CAD+ subjects between brain natriuretic peptide (BNP), high-molecular-weight adiponectin (HMW-Ad), and Tot-Ad (r=0.798 and r=0.795, P CONCLUSION: Distribution of adiponectin isoforms differed in populations of elderly subjects according to the presence of coronary atherosclerosis. The data support the hypothesis for a protective role of LMW-Ad during aging, although additional studies are needed to definitively clarify whether LMW-Ad plays a protective role in older people with a history of CAD. Author Affiliation: (1)From the Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. Article note: Address correspondence to Massimo Federici, Department of Internal Medicine, University of Rome-'Tor Vergata,' Via Montpellier 1, 00133 Rome, Italy. E-mail: federicm@uniroma2.it

Diabetes is characterized by accelerated atherosclerosis, although molecular mechanisms explaining this phenomenon are still undefined (1,2). We and others have shown that chronic hyperglycemia increases matrix metalloproteinase (MMP) and A [...], OBJECTIVE--Atherosclerosis is accelerated in subjects with type 2 diabetes by unknown mechanisms. We identified tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of A disintegrin and metalloprotease domain 17 (ADAM17) and other matrix metalloproteinases (MMPs), as a gene modifier for insulin resistance and vascular inflammation in mice. We tested its association with atherosclerosis in subjects with type 2 diabetes and identified Sirtuin 1 (SirT1) as a major regulator of TIMP3 expression. RESEARCH DESIGN AND METHODS--We investigated ADAM10, ADAM17, MMP9, TIMP1, TIMP2, TIMP3, and TIMP4 expression levels in human carotid atherosclerotic plaques (n = 60) from subjects with and without diabetes. Human vascular smooth muscle cells exposed to several metabolic stimuli were used to identify regulators of TIMP3 expression. SirT1 small interference RNA, cDNA, and TIMP3 promoter gene reporter were used to study SirT1-dependent regulation of TIMP3. RESULTS--Here, we show that in human carotid atherosclerotic plaques, TIMP3 was significantly reduced in subjects with type 2 diabetes, leading to ADAM17 and MMP9 overactivity. Reduced expression of TIMP3 was associated in vivo with SirT1 levels. In smooth muscle cells, inhibition of SirT1 activity and levels reduced TIMP3 expression, whereas SirT1 overexpression increased TIMP3 promoter activity. CONCLUSIONS--In atherosclerotic plaques from subjects with type 2 diabetes, the deregulation of ADAM17 and MMP9 activities is related to inadequate expression of TIMP3 via SifT1. Studies in vascular cells confirmed the role of SirT1 in tuning TIMP3 expression.

Tracer techniques have become an established part of metabolic research and indeed are a fundamental part of our understanding of carbohydrate metabolism in humans. This review is meant to provide [...]

OBJECTIVE--To determine whether deuterium enrichment on carbons 5 and 3 (C5/C3) in plasma glucose is influenced by processes other than gluconeogenesis and, if so, whether these processes are altered by type 2 diabetes. RESEARCH DESIGN AND METHODS--In this study, 10 obese diabetic and 10 obese nondiabetic subjects were infused intravenously with [3,5-²[H.sub.2]] galactose enriched at a C5-to-C3 ratio of 1.0 as well as the enrichment of deuterium on C5 and C3 of plasma glucose, measured with nuclear magnetic resonance using the acetaminophen glucuronide method. RESULTS--The ratio of deuterium enrichment on C5 and C3 of glucose was CONCLUSIONS--That the C5-to-C3 glucose ratio is, The deuterated water method is extensively used to measure gluconeogenesis in humans (1-7). One premise of this method is that there is negligible exchange of the lower three carbons of [...]

OBJECTIVE--In this study, we sought to determine whether postprandial insulin secretion, insulin action, glucose effectiveness, and glucose turnover were abnormal in type 2 diabetes. RESEARCH DESIGN AND METHODS--Fourteen subjects with [...]

OBJECTIVE--The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS--We measured insulin secretion and action as well [...]

OBJECTIVE--To determine the contribution of liver and viscera to splanchnic cortisol production in humans. RESEARCH DESIGN AND METHODS--D4 cortisol was infused intravenously; arterial, portal venous, and hepatic venous blood was sampled; and liver and visceral fat were biopsied in subjects undergoing hariatric surgery. RESULTS--Ratios of arterial and portal vein D4 cortisol/corti[sol.sub.total] (0.06 ± 0.01 vs. 0.06 ± 0.01) and D4 cortisol/D3 cortisol (1.80 ± 0.14 vs. 1.84 ± 0.14) did not differ, indicating that no visceral cortisol production or conversion of D4 cortisol to D3 cortisol via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) occurred. Conversely, ratios of both D4 cortisol to [cortisol.sub.total] (0.05 ± 0.01; P < 0.05) and D4 cortisol to D3 cortisol (1.33 ± 0.11; P < 0.001) were lower in the hepatic vein than in the portal vein, indicating production of both cortisol and D3 cortisol by the liver. The viscera did not produce either cortisol (-8.1 ± 2.6 µg/min) or D3 cortisol (-0.2 ± 0.1 µg/min). In contrast, the liver produced both cortisol (22.7 ± 3.90 µg/min) and D3 cortisol (1.9 ± 0.4 µg/min) and accounted for all splanchnic cortisol and D3 cortisol production. Additionally, 11β-HSD-1 mRNA was approximately ninefold higher (P < 0.01) in liver than in visceral fat. Although 11β-HSD-2 gene expression was very low in visceral fat, the viscera released cortisone (P < 0.001) and D3 cortisone (P < 0.01) into the portal vein. CONCLUSIONS--The liver accounts for all splanchnic cortisol production in obese nondiabetic humans. In contrast, the viscera releases cortisone into the portal vein, thereby providing substrate for intrahepatic cortisol production., Although it has been long known that glucocorticoids are potent regulators of glucose, fat, and protein metabolism, ghicocorticoids have not been thought to cause insulin resistance in either obese or [...]

The partial sinter between the powder particles during the electron beam – powder bed fusion (EB-PBF) process is fundamental to guarantee adequate thermal and electrical conductivities and conduct the process safely. The sintering degree is tuned by using the process parameters that, at the present day, are mainly optimised with an experimental trial and error approach. Simulation has proven the capability to reduce costs and time related to parameter optimisation. In the current work, a phase field model was developed to simulate sintering during the EB-PBF process. The novelty lies in simulating the sintering process under non isothermal conditions which emulate the heating of the powder due to the preheating and subsequent temperature decrease due to the layer additions. The results show a strong influence of the thermal history on the neck growth and dimension, which differ significantly with respect to the traditional approach to the sintering simulation which considers only constant temperature.

Prompted by the utilization of extended criteria donors, dual hypothermic oxygenated machine perfusion (D-HOPE) was introduced in liver transplantation to improve preservation. When donors after neurological determination of death (DBD) are used, D-HOPE effect on graft outcomes is unclear. To assess D-HOPE value in this setting and to identify ideal scenarios for its use, data on primary adult liver transplant recipients from January 2014 to April 2021 were analyzed using inverse probability of treatment weighting, comparing outcomes of D-HOPE-treated grafts (n= 121) with those preserved by static cold storage (n= 723). End-ischemic D-HOPE was systematically applied since November 2017 based on donor and recipient characteristics and transplant logistics. D-HOPE use was associated with a significant reduction of early allograft failure (OR: 0.24; 0.83; p= .024), grade ≥3 complications (OR: 0.57; p= .046), comprehensive complication index (−7.20 points; p= .003), and improved patient and graft survival. These results were confirmed in the subset of elderly donors (>75-year-old). Although D-HOPE did not reduce the incidence of biliary complications, its use was associated with a reduced severity of ischemic cholangiopathy. In conclusion, D-HOPE improves postoperative outcomes and reduces early allograft loss in extended criteria DBD grafts.