Hormonal responses to non-nutritive sweeteners in water and diet soda.

BACKGROUND: Non-nutritive sweeteners (NNS), especially in form of diet soda, have been linked to metabolic derangements (e.g. obesity and diabetes) in epidemiologic studies. We aimed to test acute metabolic effects of NNS in isolation (water or seltzer) and in diet sodas. METHODS: We conducted a four-period, cross-over study at the National Institutes of Health Clinical Center (Bethesda, Maryland). Thirty healthy adults consumed 355 mL water with 0 mg, 68 mg, 170 mg, and 250 mg sucralose, and 31 individuals consumed 355 mL caffeine-free Diet Rite Cola™, Diet Mountain Dew™ (18 mg sucralose, 18 mg acesulfame-potassium, 57 mg aspartame), and seltzer water with NNS (68 mg sucralose and 41 mg acesulfame-potassium, equivalent to Diet Rite Cola™) in randomized order, prior to oral glucose tolerance tests. Blood samples were collected serially for 130 min. Measures included GLP-1, GIP, glucose, insulin, C-peptide, glucose absorption, gastric emptying, and subjective hunger and satiety ratings. RESULTS: Diet sodas augmented active GLP-1 (Diet Rite Cola™ vs. seltzer water, AUC, p = 0.039; Diet Mountain Dew™ vs. seltzer water, AUC, p = 0.07), but gastric emptying and satiety were unaffected. Insulin concentrations were nominally higher following all NNS conditions without altering glycemia. Sucralose alone (at any concentration) did not affect metabolic outcomes. CONCLUSIONS: Diet sodas but not NNS in water augmented GLP-1 responses to oral glucose. Whether the trends toward higher insulin concentrations after NNS are of clinical importance remains to be determined. Our findings emphasize the need to test metabolic effects of NNS after chronic consumption. TRIAL REGISTRATION: The data for this manuscript were gathered from clinical trial #NCT01200940

Patients with MEN1 are at an increased risk for venous thromboembolism VTE risk in MEN1

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder predisposing to the development of multiple functional and non-functional neuroendocrine tumors (NETs). Only uncommon MEN1-associated functional NETs such as glucagonomas (<1%) and ACTH-producing tumors (<5%) are known to be associated with hypercoagulability. It is unknown if patients with MEN1 generally have increased risk of VTE. Methods: We queried a prospective natural history study of germline mutation positive MEN1 patients (n=286) between 1991-2019 for all lifetime events of VTE. Search terms were: DVT, thromb, embol, PE, pulmonary embolism, clot, hematology consult, anticoagulant, coumadin, lovenox, xarelto, warfarin, aspirin, rivaroxaban and apixaban. Incidence rates were calculated accounting for age and sex. Comparison was made to published incidence rates in healthy populations, different types of cancer, and Cushing's syndrome. Results: Thirty-six subjects (median age 45 years, range 16-75) experienced a VTE event, yielding a prevalence rate of 12.9%. The age-sex adjusted incidence rate of VTE is 9.11 per 1,000 patient-years, with a sex-adjusted lifetime incidence rate of 2.81 per 1,000 patient-years. MEN1-associated lifetime incidence rates are ~two-fold higher than the estimated annual incidence rate in the general population and are comparable to known risk in the setting of various types of cancer. Approximately 80% were diagnosed with pancreatic NETs, of which 24% were insulinomas. Fourteen patients (42%) experienced peri-operative VTE events. Conclusions: MEN1 patients have an increased risk of VTE. Further mechanistic investigation and validation from other MEN1 cohorts are needed to confirm the increased prevalence of VTE in MEN1

Regulatory mechanisms for 3′-end alternative splicing and polyadenylation of the Glial Fibrillary Acidic Protein, GFAP, transcript

The glial fibrillary acidic protein, GFAP, forms the intermediate cytoskeleton in cells of the glial lineage. Besides the common GFAPα transcript, the GFAPε and GFAPκ transcripts are generated by alternative mRNA 3′-end processing. Here we use a GFAP minigene to characterize molecular mechanisms participating in alternative GFAP expression. Usage of a polyadenylation signal within the alternatively spliced exon 7a is essential to generate the GFAPκ and GFAPκ transcripts. The GFAPκ mRNA is distinct from GFAPε mRNA given that it also includes intron 7a. Polyadenylation at the exon 7a site is stimulated by the upstream splice site. Moreover, exon 7a splice enhancer motifs supported both exon 7a splicing and polyadenylation. SR proteins increased the usage of the exon 7a polyadenylation signal but not the exon 7a splicing, whereas the polypyrimidine tract binding (PTB) protein enhanced both exon 7a polyadenylation and exon 7a splicing. Finally, increasing transcription by the VP16 trans-activator did not affect the frequency of use of the exon 7a polyadenylation signal whereas the exon 7a splicing frequency was decreased. Our data suggest a model with the selection of the exon 7a polyadenylation site being the essential and primary event for regulating GFAP alternative processing

Graft-versus-Host Disease Prophylaxis with Post- Transplantation Cyclophosphamide in Chronic Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation from an Unrelated or Mismatched Related Donor: A Comparative Study from the Chronic Malignancies Working Party of the EBMT (CMWP-EBMT).

peer reviewedOutcomes following allogeneic hematopoietic cell transplantation (allo-HCT) for chronic myeloid leukemia (CML) with post-transplantation cyclophosphamide (PTCy) using an unrelated donor (UD) or a mismatched related donor (MMRD) remain unknown. We report a retrospective comparison of PTCy-based allo-HCT from a UD, non-PTCy allo-HCT from a UD, and PTCy allo-HCT from an MMRD. Inclusion criteria were adult patients with CML undergoing first allo-HCT between 2012 and 2019 from a UD with either PTCy or non-PTCy graft-versus-host disease (GVHD) prophylaxis or from an MMRD using PTCy. The primary endpoint was GVHD-free/relapse-free survival (GRFS). A total of 1341 patients were included (82% in the non-PTCy UD cohort). With a median follow-up of 34.9 months, the 3-year GRFS was 43% in the non-PTCy cohort, 37% in the PTCy-UD cohort, and 39% PTCy-MMRD cohort (P = .15). Multivariable analyses revealed no significant differences among the 3 cohorts in terms of overall survival (OS), progression-free survival, RI, and nonrelapse mortality. Factors independently associated with worse OS in the overall cohort were Karnofsky Performance Status 2 (HR, 1.58; 95% CI, 1.15 to 2.17; P = .005). These results suggest that allo-HCT in patients with CML using either a UD or an MMRD with PTCy-based GVHD prophylaxis are feasible transplantation, platforms and that the disease stage at allo-HCT remains a major prognostic factor, highlighting the importance of closely monitoring CML patients and proposing transplantation when indicated when still in CP1

Basement membrane components are key players in specialized extracellular matrices

More than three decades ago, basement membranes (BMs) were described as membrane-like structures capable of isolating a cell from and connecting a cell to its environment. Since this time, it has been revealed that BMs are specialized extracellular matrices (sECMs) with unique components that support important functions including differentiation, proliferation, migration, and chemotaxis of cells during development. The composition of these sECM is as unique as the tissues to which they are localized, opening the possibility that such matrices can fulfill distinct functions. Changes in BM composition play significant roles in facilitating the development of various diseases. Furthermore, tissues have to provide sECM for their stem cells during development and for their adult life. Here, we briefly review the latest research on these unique sECM and their components with a special emphasis on embryonic and adult stem cells and their niches

Global respiratory syncytial virus–related infant community deaths

Background Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. Methods The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital. Results We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8−3.3) was lower than in-hospital (2.4 months; IQR: 1.5−4.0; P < .0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, P < 0.0001). Conclusions We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines

Short communication: Teat wall diameter and teat tissue thickness in dairy cows are affected by intramammary pressure and by the mechanical forces of machine milking.

The objective of this study was to validate and apply 2 different methods to record changes in teat tissue related to machine milking. Teat wall diameter was measured via B-mode ultrasound cross sectioning with a 7.5-MHz linear probe. Teat tissue thickness was measured using a cutimeter (spring-loaded caliper, spring constant 6.5 N/cm, 0.5 N at closed jaws). Both methods were applied at the teat barrel, 2 cm above the teat tip. In experiment 1, 24 teats from freshly slaughtered cows were used to perform ultrasound imaging (12 teats) or cutimeter measurements (12 teats) while the teat cisterns were filled with water to increase the intracisternal pressure from 0 to 30 kPa in steps of 1 kPa. Teat tissue thickness did not change at an intracisternal pressure from 0 to 10 kPa but increased with intracisternal pressure at levels >10 kPa. In contrast, teat wall diameter decreased with intracisternal pressure between 0 and 7 kPa but did not significantly change at a pressure ≥7 kPa up to 30 kPa. Significant Pearson correlation coefficients between intracisternal pressure and teat wall diameter were observed from 0 to 7 kPa (r = -0.38), and between intracisternal pressure and teat tissue thickness from 10 to 30 kPa (r = 0.45). In experiment 2, ultrasound and cutimeter measurements were performed in 12 lactating Holstein cows. Measurements before and during milking, immediately after cluster removal, with normal milking or with a 5-min overmilking, were performed and continued at 5-min intervals for 60 min and at 10-min intervals until 120 min. Additionally, with the 5-min overmilking treatment, measurements were continued at 60-min intervals up to 10 h after milking. Teat wall diameter decreased in response to milk ejection, followed by a continuous increase during the course of milking, with highest values after 5 min overmilking. Teat tissue thickness did not change during milking but was significantly increased after overmilking. Teat wall diameter and teat tissue thickness recovered to premilking levels within 35 min after normal milking and within 60 min after overmilking. Until 10 h after overmilking, the teat wall diameter decreased steadily, whereas teat tissue thickness was unfluctuating. In the physiologically relevant range of intramammary pressure, ultrasound measurements of the teat wall were affected by both intramammary pressure and mechanical forces, whereas cutimeter measurements were not affected by the intramammary pressure

Understanding the Metabolic and Health Effects of Low-calorie Sweeteners: Methodological Considerations and Implications for Future Research.

Consumption of foods, beverages, and packets containing low-calorie sweeteners (LCS) has increased markedly across gender, age, race/ethnicity, weight status, and socioeconomic subgroups. However, well-controlled intervention studies rigorously evaluating the health effects of LCS in humans are limited. One of the key questions is whether LCS are indeed a beneficial strategy for weight management and prevention of obesity. The current review discusses several methodological considerations in the design and interpretation of these studies. Specifically, we focus on the selection of study participants, inclusion of an appropriate control, importance of considering habitual LCS exposure, selection of specific LCS, dose and route of LCS administration, choice of study outcomes, and the context and generalizability of the study findings. These critical considerations will guide the design of future studies and thus assist in understanding the health effects of LCS

The distribution and evolution of supraglacial lakes on 79 degrees N Glacier (north-eastern Greenland) and interannual climatic controls

The Nioghalvfjerdsfjorden glacier (also known as the 79 degrees North Glacier) drains approximately 8% of the Greenland Ice Sheet. Supraglacial lakes (SGLs), or surface melt ponds, are a persistent summertime feature and are thought to drain rapidly to the base of the glacier and influence seasonal ice velocity. However, seasonal development and spatial distribution of SGLs in the north-east of Greenland are poorly understood, leaving a substantial error in the estimate of meltwater and its impacts on ice velocity. Using results from an automated detection of melt ponds, atmospheric and surface mass balance modelling, and reanalysis products, we investigate the role of specific climatic conditions in melt onset, extent, and duration from 2016 to 2019. The summers of 2016 and 2019 were characterised by above-average air temperatures, particularly in June, as well as a number of rainfall events, which led to extensive melt ponds to elevations up to 1600 m. Conversely, 2018 was particularly cold, with a large accumulated snowpack, which limited the development of lakes to altitudes less than 800 m. There is evidence of inland expansion and increases in the total area of lakes compared to the early 2000s, as projected by future global warming scenarios.11Nsciescopu