Clinical pancreatic islet transplantation can be considered one of the safest and least invasive transplant procedures. Remarkable progress has occurred in both the technical aspects of islet cell ...processing and the outcomes of clinical islet transplantation. With >1,500 patients treated since 2000, this therapeutic strategy has moved from a curiosity to a realistic treatment option for selected patients with type 1 diabetes mellitus (that is, those with hypoglycaemia unawareness, severe hypoglycaemic episodes and glycaemic lability). This Review outlines the techniques required for human islet isolation, in vitro culture before the transplant and clinical islet transplantation, and discusses indications, optimization of recipient immunosuppression and management of adjunctive immunomodulatory and anti-inflammatory strategies. The potential risks, long-term outcomes and advances in treatment after the transplant are also discussed to further move this treatment towards becoming a more widely available option for patients with type 1 diabetes mellitus and eventually a potential cure.
Context. The variable Sun is the most likely candidate for the natural forcing of past climate changes on time scales of 50 to 1000 years. Evidence for this understanding is that the terrestrial ...climate correlates positively with the solar activity. During the past 10 000 years, the Sun has experienced the substantial variations in activity and there have been numerous attempts to reconstruct solar irradiance. While there is general agreement on how solar forcing varied during the last several hundred years – all reconstructions are proportional to the solar activity – there is scientific controversy on the magnitude of solar forcing. Aims. We present a reconstruction of the total and spectral solar irradiance covering 130 nm–10 μm from 1610 to the present with an annual resolution and for the Holocene with a 22-year resolution. Methods. We assume that the minimum state of the quiet Sun in time corresponds to the observed quietest area on the present Sun. Then we use available long-term proxies of the solar activity, which are 10Be isotope concentrations in ice cores and 22-year smoothed neutron monitor data, to interpolate between the present quiet Sun and the minimum state of the quiet Sun. This determines the long-term trend in the solar variability, which is then superposed with the 11-year activity cycle calculated from the sunspot number. The time-dependent solar spectral irradiance from about 7000 BC to the present is then derived using a state-of-the-art radiation code. Results. We derive a total and spectral solar irradiance that was substantially lower during the Maunder minimum than the one observed today. The difference is remarkably larger than other estimations published in the recent literature. The magnitude of the solar UV variability, which indirectly affects the climate, is also found to exceed previous estimates.We discuss in detail the assumptions that lead us to this conclusion.
Transplantation of donor-derived islets into the liver is a successful cellular replacement therapy for individuals with diabetes. However, the hepatic vasculature is not an optimal transplant site ...for several reasons, including graft attrition and the inability to retrieve or image the islets. Here we describe islet transplantation into a prevascularized, subcutaneous site created by temporary placement of a medically approved vascular access catheter. In mice with streptozotocin (STZ)-induced diabetes, transplantation of ∼500 syngeneic islets into the resulting 'device-less' space reversed diabetes in 91% of mice and maintained normoglycemia for >100 days. The approach was also effective in mice with pre-existing diabetes, in another mouse strain that mounts a more vigorous inflammatory response, and across an allogeneic barrier. These results demonstrate that transient priming of a subcutaneous site supports diabetes-reversing islet transplantation in mouse models without the need for a permanent cell-encapsulation device.
Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue ...origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.
We report the long-term follow-up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton ...Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C-peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin-independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A1c was 6.3% (45 mmol/mol). All subjects experienced progressive decline in the C-peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation.
Since the advent of social networking site (SNS) technologies, adolescents’ use of these technologies has expanded and is now a primary way of communicating with and acquiring information about ...others in their social network. Overall, adolescents and young adults’ stated motivations for using SNSs are quite similar to more traditional forms of communication—to stay in touch with friends, make plans, get to know people better, and present oneself to others. We begin with a summary of theories that describe the role of SNSs in adolescents’ interpersonal relationships, as well as common methodologies used in this field of research thus far. Then, with the social changes that occur throughout adolescence as a backdrop, we address the ways in which SNSs intersect with key tasks of adolescent psychosocial development, specifically peer affiliation and friendship quality, as well as identity development. Evidence suggests that SNSs differentially relate to adolescents’ social connectivity and identity development, with sociability, self-esteem, and nature of SNS feedback as important potential moderators. We synthesize current findings, highlight unanswered questions, and recommend both methodological and theoretical directions for future research.
Poor maternal diet in pregnancy can influence fetal growth and development. We tested the hypothesis that poor maternal diet quality during pregnancy would increase neonatal adiposity (percent fat ...mass (%FM)) at birth by increasing the fat mass (FM) component of neonatal body composition.
Our analysis was conducted using a prebirth observational cohort of 1079 mother-offspring pairs. Pregnancy diet was assessed via repeated Automated Self-Administered 24-h dietary recalls, from which Healthy Eating Index-2010 (HEI-2010) scores were calculated for each mother. HEI-2010 was dichotomized into scores of ⩽57 and >57, with low scores representing poorer diet quality. Neonatal %FM was assessed within 72 h after birth with air displacement plethysmography. Using univariate and multivariate linear models, we analyzed the relationship between maternal diet quality and neonatal %FM, FM, and fat-free mass (FFM) while adjusting for prepregnancy body mass index (BMI), physical activity, maternal age, smoking, energy intake, preeclampsia, hypertension, infant sex and gestational age.
Total HEI-2010 score ranged between 18.2 and 89.5 (mean: 54.2, s.d.: 13.6). An HEI-2010 score of ⩽57 was significantly associated with higher neonatal %FM (β=0.58, 95% confidence interval (CI) 0.07-1.1, P<0.05) and FM (β=20.74; 95% CI 1.49-40.0; P<0.05) but no difference in FFM.
Poor diet quality during pregnancy increases neonatal adiposity independent of maternal prepregnancy BMI and total caloric intake. This further implicates maternal diet as a potentially important exposure for fetal adiposity.
The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial ...function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules, including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation after treatment with thapsigargin and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect against ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell-derived β-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo.
Numerous studies have reported that ambient air pollution, which has both
local and long-range sources, causes adverse impacts on the environment and
human health. Previous studies have investigated ...the impacts of
transboundary air pollution (TAP) in East Asia, albeit primarily through
analyses of episodic events. In addition, it is useful to better understand
the spatiotemporal variations in TAP and the resultant impact on the
environment and human health. This study aimed at assessing and
quantifying the air quality impacts in Japan and South Korea due to local emissions and TAP from sources in East Asia - one of the most polluted
regions in the world. We applied state-of-the-science atmospheric
models to simulate air quality in East Asia and then analyzed the air
quality and acid deposition impacts of both local emissions and TAP sources
in Japan and South Korea. Our results show that ∼ 30 % of
the annual average ambient PM2.5 concentrations in Japan and South
Korea in 2010 were contributed to by local emissions within each country, while
the remaining ∼ 70 % were contributed to by TAP from other
countries in the region. More detailed analyses also revealed that the local
contribution was higher in the metropolises of Japan (∼ 40 %–79 %) and South Korea (∼ 31 %–55 %) and that minimal
seasonal variations in surface PM2.5 occurred in Japan, whereas there was a
relatively large variation in South Korea in the winter. Further, among all
five studied anthropogenic emission sectors of China, the industrial sector
represented the greatest contributor to annual surface PM2.5
concentrations in Japan and South Korea, followed by the residential and
power generation sectors. Results also show that TAP's impact on acid
deposition (SO42- and NO3-) was larger than TAP's impact
on PM2.5 concentrations (accounting for over 80 % of the total
deposition), and that seasonal variations in acid deposition were similar
for both Japan and South Korea (i.e., higher in both the winter and summer).
Finally, wet deposition had a greater impact on mixed forests in Japan and
savannas in South Korea. Given these significant impacts of TAP in the
region, it is paramount that cross-national efforts should be taken to mitigate air
pollution problems across East Asia.
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