Thomas A. Buchanan
Sep 1, 2002; 51:2796-2803
Pathophysiology

Alexandra E. Butler
Jan 1, 2003; 52:102-110
Islet Studies

No sooner than the Government’s announced its intention to restart the economy, private sector groups are advocating for longer working hours to fast-track recovery during the COVID-19 pandemic. In a collaborative move, the Jamaica Manufacturers...

The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.

Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8–12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39–2.57) before to 1.09 (1.04–1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04–0.31] before to 0.49 (0.20–0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = –0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.

Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D₂ and D₃ receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (¹¹C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14–30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20–30 min; spleen as reference region) demonstrated a statistically significant reduction (–36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20–30 min) (R² = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20–30 min) (R² = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20–30 min) (R² = 0.57, P = 0.05), nor did mean baseline proinsulin (R² = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D₃ receptor and dopamine D₂ receptor in HCs. No colocalization of the dopamine D₃ receptor or dopamine D₂ receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D₃ receptor, dopamine D₂ receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D₃ receptor and dopamine D₂ receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for ¹¹C-(+)-PHNO, a dopamine D₃ receptor–preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, ⁶⁴Cu (half-life, 12.7 h) and ²²⁵Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of ⁶⁴Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of ⁶⁸Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, ²²⁵Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of ⁶⁴Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of ⁶⁴Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for ⁶⁴Cu-FAPI-04 than for ⁶⁸Ga-FAPI-04, except in the heart, and excretion in the urine was higher for ⁶⁸Ga-FAPI-04 than for ⁶⁴Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. ²²⁵Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that ⁶⁴Cu-FAPI-04 and ²²⁵Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

M2 macrophages play an important role in tissue repair and regeneration. They have also been found to modulate β-cell replication in mouse models of pancreatic injury and disease. We previously reported that β-cell replication is strongly increased in a subgroup of human organ donors characterized by prolonged duration of stay in an intensive care unit (ICU) and increased number of leukocytes in the pancreatic tissue. In the present study we investigated the relationship between duration of stay in the ICU, M2 macrophages, vascularization, and pancreatic cell replication. Pancreatic organs from 50 donors without diabetes with different durations of stay in the ICU were analyzed by immunostaining and digital image analysis. The number of CD68⁺CD206⁺ M2 macrophages increased three- to sixfold from ≥6 days’ duration of stay in the ICU onwards. This was accompanied by a threefold increased vascular density and a four- to ninefold increase in pancreatic cells positive for the replication marker Ki67. A strong correlation was observed between the number of M2 macrophages and β-cell replication. These results show that a prolonged duration of stay in the ICU is associated with an increased M2 macrophage number, increased vascular density, and an overall increase in replication of all pancreatic cell types. Our data show evidence of marked levels of tissue repair in the human donor pancreas.

China has been Africa’s largest trading partner since 2009, and as commerce and investment have increased, so have flows of people in both directions. With an estimated 1 million to 2 million Chinese migrants across Africa, some countries have relaxed their short-term visa requirements in hopes of facilitating cultural and business exchanges. High levels of Chinese investment do not, however, correlate with more liberal visa policies, as this article explores.

Governments on the receiving end of migrants and refugees reinforced their commitment to returns in 2017, sending or coercing migrants to move back to impoverished or violent homelands. The Dominican Republic pushed out some 70,000 Haitians and native born of Haitian descent, while more than 500,000 Afghans left Iran and Pakistan. Though many of these migrants chose to return, in practice the line between forced and voluntary returns is blurry.

OBJECTIVE

In patients with type 1 diabetes and end-stage renal disease, it is controversial whether a simultaneous pancreas-kidney (SPK) transplantation improves survival compared with kidney transplantation alone. We compared long-term survival in SPK and living- or deceased-donor kidney transplant recipients.

OBJECTIVE

Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients.

Jens J. Holst
May 1, 2011; 34:S251-S257
Diabetes Treatments

Boris P. Kovatchev
Jul 1, 2013; 36:1851-1858
Diabetes Care Symposium

Arcangelo Iannuzzi
Oct 1, 2004; 27:2506-2508
Brief Reports

K.M. Venkat Narayan
Sep 1, 2006; 29:2114-2116
BR Epidemiology/Health Services/Psychosocial Research

3M has signed a $126 million deal with the Pentagon to increase its production of N95 masks to 26 million per month beginning in October 2020.

OBJECTIVE

The long-term influences of sex hormone administration on insulin sensitivity and incretin hormones are controversial. We investigated these effects in 35 transgender men (TM) and 55 transgender women (TW) from the European Network for the Investigation of Gender Incongruence (ENIGI) study.

While much attention has been given to the move by U.S. Citizenship and Immigration Services to raise its application fees—including an 83 percent hike to apply for U.S. citizenship—the policy changes embedded in the proposed rule have been less scrutinized. The changes, including the elimination of most fee waivers for lower-income applicants, would likely reduce the number and shift the profile of those getting a green card or other immigration status.

As Congress works on a third legislation package in response to the coronavirus pandemic, the ADA is asking lawmakers to include provisions on how to assist dental practices and other small businesses facing economic burdens.

The ADA is urging Congress to continue supporting small businesses during the COVID-19 pandemic by increasing funding and streamlining the application process for Small Business Administration loans.

The U.S. Department of Homeland Security issued an alert April 8 warning that cybercriminals are increasingly exploiting the COVID-19 pandemic to target individuals, small and medium businesses and large organizations.

Certain high blood pressure medications may be linked with more serious illness from COVID-19, but they don't increase a person's risk for getting the disease, a new study published Tuesday by JAMA Cardiology reports.

A face-aging app could encourage young people to protect their skin from harmful UV rays and lessen their risk for skin cancer, a study published Wednesday by JAMA Dermatology has found.

OBJECTIVE

To examine differences in myocardial blood flow (MBF) at rest and during stress between patients with type 2 diabetes and controls, and to identify potential predictors of changes in MBF at rest and during stress.

OBJECTIVE

The aim of this study was to examine the association of circulating retinol-binding protein 4 (RBP4) levels with β-cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes.

Based on the newest forecasting models, AccuWeather forecasters have extended the upper range of hurricanes predicted for the Atlantic hurricane season.

As a practicing sex therapist, I often see two partners legitimately trying to bridge a satisfaction gap between each other, but they can’t seem to get the moves just right. If left unchecked, this can lead to resentment and conflict; however, couples who figure out how to speak to each other sexually (both verbally and nonverbally) have the highest success in terms of finding something that works for both of them. Making an environment conducive to this sort of positive growth requires a little bit of effort and the ability to listen. Drawing on my clinical experience, here are my top tips for increasing sexual satisfaction:

Sexually transmitted infections (STIs) are on the rise, and many people are curious about the reasons why. While the cause is obviously multifactorial, some have suggested that at least part of the rise in STIs may be due to increasing rates of pubic hair grooming in men and women alike. Given that it’s not uncommon for people to experience cuts and skin irritation from genital grooming practices, it at least sounds plausible in theory that pubic hair shaving could potentially increase infection risk. But what does the research actually say?

About 14,000 more students in the state are enrolled in special education, after the state lifted what it called a "benchmark" enrollment figure of 8.5 percent.

To give districts more flexibility in the face of teacher shortages, New York's education department is proposing to modify its regulations on teacher certifications.

Biden's campaign announced March 31 that the 2020 Democratic presidential candidate backs two local attempts to raise more tax revenue for schools.

Most New Jersey students get schooled in the arts, but time devoted to the subject has been dwindling.

London-Sydney Marathon -- History.

The state's supreme court said last year the state's legislature must come up with more money for its school system by the end of this month. Many predict $534 million won't be enough.

Edinburgh : printed by J. Stark, [1836?]

[Place of publication not identified] : [Publisher not identified], 1895.

[London] : Waterlow Bros. & Layton, Limited, [1893]

During Friday's "Pac-12 Perspective," Stanford head coach Tara VanDerveer spoke about Haley Jones' positionless game and how the Cardinal used the dynamic freshman in 2019-20. Download and listen wherever you get your podcasts.

Multi-Class Incremental Learning (MCIL) aims to learn new concepts by incrementally updating a model trained on previous concepts. However, there is an inherent trade-off to effectively learning new concepts without catastrophic forgetting of previous ones. To alleviate this issue, it has been proposed to keep around a few examples of the previous concepts but the effectiveness of this approach heavily depends on the representativeness of these examples. This paper proposes a novel and automatic framework we call mnemonics, where we parameterize exemplars and make them optimizable in an end-to-end manner. We train the framework through bilevel optimizations, i.e., model-level and exemplar-level. We conduct extensive experiments on three MCIL benchmarks, CIFAR-100, ImageNet-Subset and ImageNet, and show that using mnemonics exemplars can surpass the state-of-the-art by a large margin. Interestingly and quite intriguingly, the mnemonics exemplars tend to be on the boundaries between different classes.

The notion of incremental learning is to train an ANN algorithm in stages, as and when newer training data arrives. Incremental learning is becoming widespread in recent times with the advent of deep learning. Noise in the training data reduces the accuracy of the algorithm. In this paper, we make an empirical study of the effect of noise in the training phase. We numerically show that the accuracy of the algorithm is dependent more on the location of the error than the percentage of error. Using Perceptron, Feed Forward Neural Network and Radial Basis Function Neural Network, we show that for the same percentage of error, the accuracy of the algorithm significantly varies with the location of error. Furthermore, our results show that the dependence of the accuracy with the location of error is independent of the algorithm. However, the slope of the degradation curve decreases with more sophisticated algorithms

Carolyn M. Rutter, Jonathan Ozik, Maria DeYoreo, Nicholson Collier.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2189--2212.

Abstract:
Microsimulation models (MSMs) are used to inform policy by predicting population-level outcomes under different scenarios. MSMs simulate individual-level event histories that mark the disease process (such as the development of cancer) and the effect of policy actions (such as screening) on these events. MSMs often have many unknown parameters; calibration is the process of searching the parameter space to select parameters that result in accurate MSM prediction of a wide range of targets. We develop Incremental Mixture Approximate Bayesian Computation (IMABC) for MSM calibration which results in a simulated sample from the posterior distribution of model parameters given calibration targets. IMABC begins with a rejection-based ABC step, drawing a sample of points from the prior distribution of model parameters and accepting points that result in simulated targets that are near observed targets. Next, the sample is iteratively updated by drawing additional points from a mixture of multivariate normal distributions and accepting points that result in accurate predictions. Posterior estimates are obtained by weighting the final set of accepted points to account for the adaptive sampling scheme. We demonstrate IMABC by calibrating CRC-SPIN 2.0, an updated version of a MSM for colorectal cancer (CRC) that has been used to inform national CRC screening guidelines.

Kamran Kalbasi, Thomas Mountford.

Source: Bernoulli, Volume 26, Number 2, 1504--1534.

Abstract:
In this paper, we study the local times of vector-valued Gaussian fields that are ‘diagonally operator-self-similar’ and whose increments are stationary. Denoting the local time of such a Gaussian field around the spatial origin and over the temporal unit hypercube by $Z$, we show that there exists $lambdain(0,1)$ such that under some quite weak conditions, $lim_{n ightarrow+infty}frac{sqrt[n]{mathbb{E}(Z^{n})}}{n^{lambda}}$ and $lim_{x ightarrow+infty}frac{-logmathbb{P}(Z>x)}{x^{frac{1}{lambda}}}$ both exist and are strictly positive (possibly $+infty$). Moreover, we show that if the underlying Gaussian field is ‘strongly locally nondeterministic’, the above limits will be finite as well. These results are then applied to establish similar statements for the intersection local times of diagonally operator-self-similar Gaussian fields with stationary increments.

Wensheng Wang, Zhonggen Su, Yimin Xiao.

Source: Bernoulli, Volume 26, Number 2, 1410--1430.

Abstract:
We establish the exact moduli of non-differentiability of Gaussian random fields with stationary increments. As an application of the result, we prove that the uniform Hölder condition for the maximum local times of Gaussian random fields with stationary increments obtained in Xiao (1997) is optimal. These results are applicable to fractional Riesz–Bessel processes and stationary Gaussian random fields in the Matérn and Cauchy classes.

Benjamin Meyer
Jul 3, 2019; 39:5326-5335
Systems/Circuits

Peter Klivenyi
Jan 1, 2000; 20:1-7
Cellular

To view more press releases, please visit http://www.snl.com/irweblinkx/news.aspx?iid=1024452.