Expression of Secretin and its Receptor Along the Intestinal Tract in Type 2 Diabetes Patients and Healthy Controls.

CONTEXT: The hormone secretin (SCT) is released from intestinal S cells and acts via the SCT receptor (SCTR). Circulating SCT levels increase after Roux-en-Y gastric bypass surgery and have been associated with massive weight loss and high remission rates of type 2 diabetes (T2D) linked to these operations. Exogenous SCT was recently shown to reduce ad libitum food intake in healthy volunteers. OBJECTIVE: To understand SCT biology and its potential role in T2D pathophysiology, we examined the intestinal mucosal expression profile of SCT and SCTR and evaluated the density of S cells along the intestinal tract of individuals with T2D and healthy controls. METHODS: Using immunohistochemistry and messenger RNA (mRNA) sequencing, we analyzed intestinal mucosa biopsies sampled along the small intestine at 30-cm intervals and from 7 well-defined anatomical sites along the large intestine (during 2 sessions of double-balloon enteroscopy) in 12 individuals with T2D and 12 healthy controls. RESULTS: Both groups exhibited a progressive and similar decrease in SCT and SCTR mRNA expression and S-cell density along the small intestine, with reductions of 14, 100, and 50 times, respectively, in the ileum compared to the duodenum (used as reference). Negligible amounts of SCTR and SCT mRNA, as well as low S-cell density, were found in the large intestine. No significant differences were observed between the groups. CONCLUSION: SCT and SCTR mRNA expression and S-cell density were abundant in the duodenum and decreased along the small intestine. Very low SCT and SCTR mRNA levels and S-cell numbers were observed in the large intestine, without aberrations in individuals with T2D compared to healthy controls.

Expression of Neurotensin and Its Receptors Along the Intestinal Tract in Type 2 Diabetes Patients and Healthy Controls.

CONTEXT: Enteroendocrine N cells secrete neurotensin (NTS). NTS reduces food intake in rodents and may increase insulin release. In humans, postprandial NTS responses increase following Roux-en-Y gastric bypass, associating the hormone with the glucose- and body weight-lowering effects of these procedures. OBJECTIVE: We looked at N cell density and mucosal messenger RNA (mRNA) expression profiles of NTS and NTS receptors in type 2 diabetes (T2D) patients and healthy controls. METHODS: Using double-balloon enteroscopy, 12 patients with T2D and 12 sex-, age-, and body mass index-matched healthy controls had mucosa biopsies taken from the entire length of the small intestine (at 30-cm intervals) and from 7 anatomically well-defined locations in the large intestine. Biopsies were analyzed using immunohistochemistry and mRNA sequencing. RESULTS: N cell density and NTS mRNA expression gradually increased from the duodenum to the ileum, while negligible NTS-positive cells and NTS mRNA expression were observed in the large intestine. NTS receptor 1 and 2 mRNA expression were not detected, but sortilin, a single-pass transmembrane neuropeptide receptor of which NTS also is a ligand, was uniformly expressed in the intestines. Patients with T2D exhibited lower levels of NTS-positive cells and mRNA expression than healthy controls, but this was not statistically significant after adjusting for multiple testing. CONCLUSION: This unique intestinal mapping of N cell density and NTS expression shows increasing levels from the small intestine's proximal to distal end (without differences between patients with T2D and healthy controls), while negligible N-cells and NTS mRNA expression were observed in the large intestine. Sortilin was expressed throughout the intestines in both groups; no NTS receptor 1 or 2 mRNA expression were detected.

Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on intestinal morphology and perfusion in patients with short bowel syndrome: Findings from a randomized phase 2 trial.

BACKGROUND: The proadaptive effects of glucagon-like peptide-2 (GLP-2) include stimulation of intestinal mucosal growth as well as intestinal blood flow and angiogenesis. We have recently reported that daily subcutaneous injections of glepaglutide, a long-acting GLP-2 analog, improved intestinal absorptive function in patients with short bowel syndrome (SBS). As secondary and exploratory end points, the effects of glepaglutide on intestinal morphology and perfusion are reported. METHODS: The following assessments were done in 18 patients with SBS in a randomized, crossover, dose-finding, phase 2 trial before and after three weeks of treatment with glepaglutide: plasma citrulline and mucosa biopsies to assess changes in (1) intestinal morphology by immunohistochemistry and (2) gene expressions associated with absorption, proliferation, and markers of tight-junction integrity by quantitative polymerase chain reaction. Intestinal perfusion was assessed in stoma nipples by laser speckle contrast imaging and quantitative fluorescence angiography with indocyanine green. RESULTS: In the 1- and 10-mg dose groups, glepaglutide significantly increased plasma citrulline by 15.3 µmol/L (P = 0.001) and 15.6 µmol/L (P = 0.001), respectively. Trends toward an increase in villus height, crypt depth, and epithelium height were seen in the same groups. No significant changes were seen in gene expressions or intestinal perfusion. CONCLUSION: The increase in plasma citrulline and the morphological improvements may partly account for improvement in the intestinal absorptive function. However, the finding of a stability in perfusion after three weeks of treatment with glepaglutide may have been preceded by a more profound acute-phase increase in intestinal perfusion at treatment initiation.

Mapping prohormone processing by proteases in human enteroendocrine cells using genetically engineered organoid models.

Enteroendocrine cells (EECs) secrete hormones in response to ingested nutrients to control physiological processes such as appetite and insulin release. EEC hormones are synthesized as large proproteins that undergo proteolytic processing to generate bioactive peptides. Mutations in EEC-enriched proteases are associated with endocrinopathies. Due to the relative rarity of EECs and a paucity of in vitro models, intestinal prohormone processing remains challenging to assess. Here, human gut organoids in which EECs can efficiently be induced are subjected to CRISPR-Cas9-mediated modification of EEC-expressed endopeptidase and exopeptidase genes. We employ mass spectrometry-based analyses to monitor peptide processing and identify glucagon production in intestinal EECs, stimulated upon bone morphogenic protein (BMP) signaling. We map the substrates and products of major EECs endo- and exopeptidases. Our studies provide a comprehensive description of peptide hormones produced by human EECs and define the roles of specific proteases in their generation.

Painful lower limb nodules as first symptom of resectable pancreatic acinar cell cancer: a case report.

BACKGROUND: Pancreatic panniculitis is characterized by subcutaneous fat necrosis and is a rare presentation of an underlying pancreatic disease, appearing in approximately 2-3% of all patients with a pancreatic disease. The nodules usually involve the lower extremities. Pancreatic panniculitis is commonly associated with acute or chronic pancreatitis, and occasionally with pancreatic cancer, especially acinar cell carcinoma. CASE PRESENTATION: A 77-year-old Caucasian woman with no significant medical history was referred to our center with multiple painful, itchy, and warm red/blue cutaneous nodules on the left lower leg. These skin lesions were consistent with the clinical diagnosis of panniculitis. The skin biopsy obtained showed a predominantly lobular panniculitis with fat necrosis of which the aspect was highly suspicious for pancreatic panniculitis. Further analysis revealed high lipase serum of > 3000 U/L (normal range < 60 U/L), and on computed tomography scan a mass located between the stomach and the left pancreas was seen. Endoscopic ultrasonography-guided fine-needle biopsy confirmed the diagnosis of acinar cell carcinoma. After discussing the patient in the pancreatobiliary multidisciplinary team meeting, laparoscopic distal pancreatectomy including splenectomy and en bloc wedge resection of the stomach due to tumor in-growth was performed. The cutaneous nodules on both legs disappeared 1-2 days after surgery. No long-term complications were reported during follow-up. One year after surgery, the patient presented with similar symptoms as preoperatively. Computed tomography scan showed local recurrence and distal metastases, which were subsequently confirmed by biopsy. She started with palliative folinic acid-fluorouracil-irinotecan-oxaliplatin chemotherapy but stopped after two cycles because of disease progression. The patient died 2 months later, 13 months after surgical resection. CONCLUSION: This case illustrates the importance of clinically recognizing cutaneous nodules and pathological recognizing the specific microscopic changes as sign of a (malignant) pancreatic disease.

Long-term exposure to transportation noise and risk for atrial fibrillation: A Danish nationwide cohort study.

BACKGROUND: Epidemiological studies have linked transportation noise and cardiovascular diseases, however, atrial fibrillation (AF) has received limited attention. We aimed to investigate the association between transportation noise and AF risk. METHODS: Over the period 1990-2017 we estimated road and railway noise (Lden) at the most and least exposed façades for all residential addresses across Denmark. We estimated time-weighted mean noise exposure for 3.6 million individuals age ≥35 years. Of these, 269,756 incident cases of AF were identified with a mean follow-up of 13.0 years. Analyses were conducted using Cox proportional hazards models with adjustment for individual and area-level sociodemographic covariates and long-term residential air pollution. RESULTS: A 10 dB higher 10-year mean road traffic noise at the most and least exposed façades were associated with incidence rate ratios (IRR) and 95% confidence intervals (CI) for AF of 1.006 (1.001-1.011) and 1.013 (1.007-1.019), respectively. After further adjustment for PM2.5, the IRRs (CIs) were 1.000 (0.995-1.005) and 1.007 (1.000-1.013), respectively. For railway noise, the IRRs per 10 dB increase in 10-year mean exposure were 1.017 (1.007-1.026) and 1.035 (1.021-1.050) for the most and least exposed façades, respectively, and were slightly attenuated when adjusted for PM2.5. Aircraft noise between 55 and 60 dB and ≥60 dB were associated with IRRs of 1.055 (0.996-1.116) and 1.036 (0.931-1.154), respectively, when compared to <45 dB. CONCLUSION: Transportation noise seems to be associated with a small increase in AF risk, especially for exposure at the least exposed façade.

Hepatocyte-specific perturbation of NAD+ biosynthetic pathways in mice induces reversible nonalcoholic steatohepatitis-like phenotypes.

Nicotinamide phosphoribosyltransferase (NAMPT) converts nicotinamide to NAD+. As low hepatic NAD+ levels have been linked to the development of nonalcoholic fatty liver disease, we hypothesized that ablation of hepatic Nampt would affect susceptibility to liver injury in response to diet-induced metabolic stress. Following 3 weeks on a low-methionine and choline-free 60% high-fat diet, hepatocyte-specific Nampt knockout (HNKO) mice accumulated less triglyceride than WT littermates but had increased histological scores for liver inflammation, necrosis, and fibrosis. Surprisingly, liver injury was also observed in HNKO mice on the purified control diet. This HNKO phenotype was associated with decreased abundance of mitochondrial proteins, especially proteins involved in oxidoreductase activity. High-resolution respirometry revealed lower respiratory capacity in purified control diet-fed HNKO liver. In addition, fibrotic area in HNKO liver sections correlated negatively with hepatic NAD+, and liver injury was prevented by supplementation with NAD+ precursors nicotinamide riboside and nicotinic acid. MS-based proteomic analysis revealed that nicotinamide riboside supplementation rescued hepatic levels of oxidoreductase and OXPHOS proteins. Finally, single-nucleus RNA-Seq showed that transcriptional changes in the HNKO liver mainly occurred in hepatocytes, and changes in the hepatocyte transcriptome were associated with liver necrosis. In conclusion, HNKO livers have reduced respiratory capacity, decreased abundance of mitochondrial proteins, and are susceptible to fibrosis because of low NAD+ levels. Our data suggest a critical threshold level of hepatic NAD+ that determines the predisposition to liver injury and supports that NAD+ precursor supplementation can prevent liver injury and nonalcoholic fatty liver disease progression.

Histological Analyses of Capsular Contracture and Associated Risk Factors: A Systematic Review.

BACKGROUND: Capsular contracture is a severe complication to breast surgery with implants. Previous studies suggest multiple risk factors are associated with capsular contracture, but the etiology is still unknown. We performed a literature review to investigate existing studies on histological analyses of breast implant capsules and how clinical risk factors impact the capsule morphology. METHODS: The literature search was conducted in PubMed. Studies that performed histological analyses of breast implant capsules were included. Animal studies or studies with a study population of less than five patients were excluded. RESULTS: Fifty-two studies were included. The histological analyses showed that the breast implant capsules were organized in multiple layers with an inner layer of synovial-like metaplasia which was reported to diminish in capsules with capsular contracture. The remaining layers of the capsule mostly consisted of collagen. The alignment of the collagen fibers differed between contracted and non-contracted capsules, and capsules with higher Baker grade were generally thickest and contained more tissue inflammation. Studies investigating capsules affected by radiotherapy found a more pronounced inflammatory response and the capsules were generally thicker and fibrotic compared with nonirradiated capsules. CONCLUSIONS: The included studies offer valuable insights into the histological changes caused by capsular contracture and their relation to clinical risk factors. Further studies with larger sample sizes and more strict inclusion criteria are needed to further investigate implant capsules and the role of the synovial-like metaplasia for the development of capsular contracture. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/00266 .

Expression of Cholecystokinin and its Receptors in the Intestinal Tract of Type 2 Diabetes Patients and Healthy Controls.

BACKGROUND: Cholecystokinin (CCK) is a gut hormone originally known for its effects on gallbladder contraction and release of digestive enzymes. CCK, however, also mediates satiety and stimulate insulin secretion. Knowledge of the distribution of CCK-producing enteroendocrine cells (I cells) in humans is sparse. The general notion, based on animal data, is that I cells are present mainly in the proximal small intestine. We examined the occurrence of I cells (immunohistochemically) and the expression of CCK messenger RNA (mRNA) as well as CCK1 and CCK2 receptor mRNA along the intestines in healthy individuals and patients with type 2 diabetes. METHODS: Mucosal biopsies collected with 30-cm intervals in the small intestine and from seven anatomical locations in the large intestine (using double-balloon enteroscopy) from 12 patients with type 2 diabetes and 12 gender-, age-, and body mass index-matched healthy individuals were analyzed using mRNA sequencing and immunohistochemical staining. RESULTS: We observed a gradual decrease in CCK mRNA expression and density of CCK-immunoreactive cells from duodenum to ileum. Very few CCK-immunoreactive cells and nearly undetectable CCK mRNA expression were found in the large intestine. No significant differences were seen between the groups. Expression of CCK receptors was observed in the duodenum of both groups. CONCLUSIONS: Both density of CCK cells and expression of CCK mRNA decreased through the small intestine in both groups with low levels in the large intestine. Patients with type 2 diabetes did not have altered density of CCK cells or expression of CCK mRNA in intestinal mucosa.

The development of a glucose prediction model in critically ill patients.

PURPOSE: The aim of the current study is to develop a prediction model for glucose levels applicable for all patients admitted to the ICU with an expected ICU stay of at least 24 h. This model will be incorporated in a closed-loop glucose system to continuously and automatically control glucose values. METHODS: Data from a previous single-center randomized controlled study was used. All patients received a FreeStyle Navigator II subcutaneous CGM system from Abbott during their ICU stay. The total dataset was randomly divided into a training set and a validation set. A glucose prediction model was developed based on historical glucose data. Accuracy of the prediction model was determined using the Mean Squared Difference (MSD), the Mean Absolute Difference (MAD) and a Clarke Error Grid (CEG). RESULTS: The dataset included 94 ICU patients with a total of 134,673 glucose measurements points that were used for modelling. MSD was 0.410 ± 0.495 for the model, the MAD was 5.19 ± 2.63 and in the CEG 99.8% of the data points were in the clinically acceptable regions. CONCLUSION: In this study a glucose prediction model for ICU patients is developed. This study shows that it is possible to accurately predict a patient's glucose 30 min ahead based on historical glucose data. This is the first step in the development of a closed-loop glucose system.

Long-term air pollution and road traffic noise exposure and COPD: the Danish Nurse Cohort.

BACKGROUND: While air pollution has been linked to the development of chronic obstructive pulmonary disease (COPD), evidence on the role of environmental noise is just emerging. We examined the associations of long-term exposure to air pollution and road traffic noise with COPD incidence. METHODS: We defined COPD incidence for 24 538 female nurses from the Danish Nurse Cohort (age >44 years) as the first hospital contact between baseline (1993 or 1999) and 2015. We estimated residential annual mean concentrations of particulate matter with an aerodynamic diameter <2.5 µm (PM2.5) since 1990 and nitrogen dioxide (NO2) since 1970 using the Danish Eulerian Hemispheric Model/Urban Background Model/Air Geographic Information System modelling system, and road traffic noise (Lden) since 1970 using the Nord2000 model. Time-varying Cox regression models were applied to assess the associations of air pollution and road traffic noise with COPD incidence. RESULTS: 977 nurses developed COPD during a mean of 18.6 years' follow-up. We observed associations with COPD for all three exposures with HRs and 95% CIs of 1.19 (1.01-1.41) per 6.26 µg·m-3 for PM2.5, 1.13 (1.05-1.20) per 8.19 µg·m-3 for NO2 and 1.15 (1.06-1.25) per 10 dB for Lden. Associations with NO2 and Lden attenuated slightly after mutual adjustment, but were robust to adjustment for PM2.5. Associations with PM2.5 were attenuated to null after adjustment for either NO2 or Lden. No potential interaction effect was observed between air pollutants and noise. CONCLUSION: Long-term exposure to air pollution, especially traffic-related NO2, and to road traffic noise were independently associated with COPD.

Long-term exposure to ambient air pollution and road traffic noise and asthma incidence in adults: The Danish Nurse cohort.

BACKGROUND: Ambient air pollution is likely a risk factor for asthma, and recent evidence suggests the possible relevance of road traffic noise. OBJECTIVES: We examined the associations of long-term exposure to air pollution and road traffic noise with adult-asthma incidence. METHODS: We followed 28,731 female nurses (age > 44 years) from the Danish Nurse Cohort, recruited in 1993 and 1999, for first hospital contact for asthma from 1977 until 2015. We estimated residential annual mean concentrations of particulate matter with diameter < 2.5 µm (PM2.5) since 1990 and nitrogen dioxide (NO2) since 1970 with the Danish DEHM/UBM/AirGIS modeling system, and road traffic noise (Lden) since 1970 with the Nord2000 model. Time-varying Cox regression models were used to associate air pollution and road traffic noise exposure with asthma incidence. RESULTS: During 18.6 years' mean follow-up, 528 out of 23,093 participants had hospital contact for asthma. The hazard ratios (HR) and 95% confidence intervals for asthma incidence associated with 3-year moving average exposures were 1.29 (1.03, 1.61) per 6.3 µg/m3 for PM2.5, 1.16 (1.07, 1.27) per 8.2 µg/m3 for NO2, and 1.12 (1.00, 1.25) per 10 dB for Lden. The HR for NO2 remained unchanged after adjustment for either PM2.5 or Lden, while the HRs for PM2.5 and Lden attenuated to unity after adjustment for NO2. CONCLUSIONS: Long-term exposure to air pollution was associated with adult-asthma incidence independently of road traffic noise, with NO2 most relevant. Road traffic noise was not independently associated with adult-asthma incidence.

Improved diabetic wound healing by LFcinB is associated with relevant changes in the skin immune response and microbiota.

Bovine lactoferricin (LFcinB) has antimicrobial and immunomodulatory properties; however, the effects on diabetic wound healing remain poorly understood. The wound healing potential of LFcinB was investigated with in vitro, ex vivo, and in vivo models. Cell migration and proliferation were tested on keratinocytes and on porcine ears. A type 1 diabetic mouse model was also used to evaluate wound healing kinetics, bacterial diversity patterns, and the effect of LFcinB on oxidative stress, macrophage phenotype, angiogenesis, and collagen deposition. LFcinB increased keratinocyte migration in vitro (p < 0.05) and ex vivo (p < 0.001) and improved wound healing in diabetic mice (p < 0.05), though not in normoglycemic control mice. In diabetic mouse wounds, LFcinB treatment led to the eradication of Bacillus pumilus, a decrease in Staphylococcus aureus, and an increase in the Staphylococcus xylosus prevalence. LFcinB increased angiogenesis in diabetic mice (p < 0.01), but this was decreased in control mice (p < 0.05). LFcinB improved collagen deposition in both diabetic and control mice (p < 0.05). Both oxidative stress and the M1-to-M2 macrophage ratios were decreased in LFcinB-treated wounds of diabetic animals (p < 0.001 and p < 0.05, respectively) compared with saline, suggesting a downregulation of inflammation in diabetic wounds. In conclusion, LFcinB treatment demonstrated noticeable positive effects on diabetic wound healing.

Transportation noise and gestational diabetes mellitus: A nationwide cohort study from Denmark.

BACKGROUND: Few studies have investigated whether road traffic noise is associated with gestational diabetes mellitus (GDM), and have yielded inconsistent findings. We aimed to investigate whether maternal exposure to residential transportation noise, before and during pregnancy, was associated with GDM in a nationwide cohort. METHODS: From the Danish population (2004-2017) we identified 629,254 pregnancies using the Danish Medical Birth Register. By linkage with the National Patient Registry, we identified 15,973 pregnancies complicated by GDM. Road traffic and railway noise (Lden) at the most and least exposed façades for all residential addresses from five years before pregnancy until birth were estimated for all. Analyses were conducted using generalized estimating equation models with adjustment for various individual and area-level sociodemographic covariates gathered from Danish registries, as well as green space and air pollution (PM2.5) estimated for all addresses. RESULTS: We found no positive associations between road traffic noise at either façade and GDM. For railway noise, a 10 dB increase in railway noise at the most and least exposed façades during the first trimester was associated with GDM, with an odds ratio (OR) of 1.06 (95% confidence interval (CI): 1.03-1.10) and 1.07 (95% CI: 1.02-1.13), respectively. We found indications of higher odds of GDM among women exposed to both high road traffic and railway noise at the least exposed facade during the first trimester (OR: 1.24; 95% CI: 1.07-1.44). CONCLUSION: In conclusion, this nationwide study suggests that railway noise but not road traffic noise might be associated with GDM.

Decreased number of colonic tuft cells in quiescent ulcerative colitis patients.

BACKGROUND: Colonic tuft cells are epithelial chemosensory cells involved in barrier integrity, modulation of inflammatory responses and gut homeostasis. Recent evidence indicates an involvement of tuft cells in ulcerative colitis pathogenesis, though mechanisms remain largely unknown.Here, we quantified the colonic tuft cell population in patients with quiescent ulcerative colitis as compared to patients without identified colonic disease (controls). METHODS: In this retrospective study, we obtained endoscopic colonic sigmoid biopsies from 14 patients with quiescent ulcerative colitis and from 17 controls. In a blinded central-reading design, we identified tuft cells by immunohistochemistry using a cyclooxygenase-1 antibody as a marker and performed a simple counting by visual inspection. Poisson regression was employed for statistics and results were adjusted for gender, age and smoking status. RESULTS: Ulcerative colitis patients demonstrated a 55% reduced tuft cell count in colonic mucosa compared with the control group (95% confidence limit: range 31-71%, P = 0.0002). Ulcerative colitis patients had a mean tuft cells count of 46 tuft cells/mm2 (95% CI, 36-59), while controls demonstrated a mean of 104 tuft cells/mm2 (95% CI, 79-136). No interactions of other covariates, such as age, smoking status, total duration of ulcerative colitis disease and duration of clinical remission prior to study inclusion were detected between ulcerative colitis patients and controls. CONCLUSION: Quiescent ulcerative colitis patients have a relatively low number of colonic tuft cells. Further studies are warranted to explore the potential involvement of tuft cells in ulcerative colitis pathogenesis.

Long-Term Exposure to Air Pollution and Incidence of Myocardial Infarction: A Danish Nurse Cohort Study.

BACKGROUND: Air pollution exposure has been linked to coronary heart disease, although evidence on PM2.5 and myocardial infarction (MI) incidence is mixed. OBJECTIVES: This prospective cohort study aimed to investigate associations between long-term exposure to air pollution and MI incidence, adjusting for road traffic noise. METHODS: We used data from the nationwide Danish Nurse Cohort on 22,882 female nurses (>44 years of age) who, at recruitment in 1993 or 1999, reported information on cardiovascular disease risk factors. Data on MI incidence was collected from the Danish National Patient Register until the end of 2014. Annual mean concentrations of particulate matter (PM) with a diameter <2.5 µg/m3 (PM2.5), PM10, nitrogen dioxide (NO2), and nitrogen oxides (NOx) at the nurses' residences since 1990 (PM10 and PM2.5) or 1970 (NO2 and NOx) were estimated using the Danish Eulerian Hemispheric Model/Urban Background Model/AirGIS (DEHM/UBM/AirGIS) dispersion model. We used time-varying Cox regression models to examine the association between 1- and 3-y running means of these pollutants, as well as 23-y running means of NO2 and NOx, with both overall and fatal incident MI. Associations were explored in three progressively adjusted models: Model 1, adjusted for age and baseline year; Model 2, with further adjustment for potential confounding by lifestyle and cardiovascular disease risk factors; and Model 3, with further adjustment for road traffic noise, modeled as the annual mean of a weighted 24-h average (Lden). RESULTS: Of the 22,882 women, 641 developed MI during a mean follow-up of 18.6 y, 121 (18.9%) of which were fatal. Reported hazard ratios (HRs) were based on interquartile range increases of 5.3, 5.5, 8.1, and 11.5 µg/m3 for PM2.5, PM10, NO2, and NOx, respectively. In Model 1, we observed a positive association between a 3-y running mean of PM2.5 and an overall incident MI with an HR= 1.20 (95% CI: 1.07, 1.35), which attenuated to HR= 1.06 (95% CI: 0.92, 1.23) in Model 2. In Model 1 for incident fatal MI, we observed a strong association with a 3-y running mean of PM2.5, with an HR= 1.69 (95% CI: 1.33, 2.13), which attenuated to HR= 1.35 (95% CI: 1.01, 1.81) in Model 2. Similar associations were seen for PM10, with 3-y, Model 2 estimates for overall and fatal incident MI of HR= 1.06 (95% CI: 0.91, 1.23) and HR= 1.35 (95% CI: 1.01, 1.81), respectively. No evidence of an association was observed for NO2 or NOx. For all pollutants, associations in Model 2 were robust to further adjustment for road traffic noise in Model 3 and were similar for a 1-y running mean exposure. CONCLUSIONS: We found no association between long-term exposure to PM2.5, PM10, NO2, or NOx and overall MI incidence, but we observed positive associations for PM2.5 and PM10 with fatal MI. We present novel findings that the association between PM and MI incidence is robust to adjustment for road traffic noise. https://doi.org/10.1289/EHP5818.

Long-term residential road traffic noise and mortality in a Danish cohort.

Transportation noise is a growing public health concern worldwide and epidemiological evidence has linked road traffic noise with mortality. However, incongruent effect estimates have been reported between incidence and mortality studies. Therefore, the present study aimed to investigate whether long-term exposure to residential road traffic noise at the most and least exposed façades was associated with all-cause, cardiovascular disease (CVD), ischemic heart disease (IHD), stroke, respiratory, or cancer mortality in a Danish cohort study. In a cohort of 52,758 individuals from Copenhagen and Aarhus, we estimated road traffic noise at the most and least exposed façades, as well as ambient air pollution, at all present and historical residential addresses from 1987 to 2016. Using the Danish cause of death register we identified cause-specific mortality. Analyses were conducted using Cox proportional hazards models. Ten-year time-weighted mean road traffic noise exposure at the most exposed façade was associated with an 8% higher risk for all-cause mortality per interquartile range (IQR; 10.4 dB) higher exposure level (95% CI: 1.05-1.11). Higher risks were also observed for CVD (HR = 1.13, 95% CI: 1.06-1.19) and stroke (HR = 1.11, 95% CI: 0.99-1.25) mortality. Road traffic noise at the least exposed façade (per IQR; 8.4 dB) was associated with CVD (HR = 1.09, 95% CI: 1.03-1.15), IHD (HR = 1.10, 95% CI: 1.01-1.21) and stroke (HR = 1.06, 95% CI: 0.95-1.19) mortality. Results were robust to adjustment for PM2.5 and NO2. In conclusion, this study adds to the body of evidence linking exposure to road traffic noise with higher risk of mortality.

High-resolution assessment of road traffic noise exposure in Denmark.

Recent studies show associations between transportation noise and various diseases. However, selection bias remains an inherent limitation in many cohort studies. In this study, we aimed to model road traffic noise exposure across the entire Danish population and investigate its distribution in relation to area-level socioeconomic indicators and green space. Based on the Nordic prediction method, we estimated road traffic noise for all Danish residential addresses, in total 2,761,739 addresses, for the years 1995, 2000, 2005, 2010, and 2015 at the most and least exposed façades. Area-level sociodemographic variables encompassing education, income, and unemployment were collected and residential green within a 150 m radius buffer at the address level was estimated using high-resolution national land use classification data. Median levels of noise at both the most and least exposed facades across Denmark increased slightly from 1995 to 2015. Correlations between most and least exposed façades varied based on population density and building type, with the highest correlations between the most and least exposed façades found for semidetached homes and lowest for multistory buildings. Increasing median noise levels were observed across increasing levels of higher education, lower income, and higher unemployment. A decreasing trend in median noise levels with increasing levels of green space was observed. In conclusion, we showed that it is feasible to estimate nationwide, address-specific exposure over a long time-period. Furthermore, the low correlations found between most and least exposed façade for multistory buildings, which characterize metropolitan centers, suggests that the most exposed façade estimation used in most previous studies and predicts exposure at the silent façade relatively poorly.

Paracrine crosstalk between intestinal L- and D-cells controls secretion of glucagon-like peptide-1 in mice.

DPP-4 inhibitors, used for treatment of type 2 diabetes, act by increasing the concentrations of intact glucagon-like peptide-1 (GLP-1), but at the same time, they inhibit secretion of GLP-1, perhaps by a negative feedback mechanism. We hypothesized that GLP-1 secretion is feedback regulated by somatostatin (SS) from neighboring D-cells, and blocking this feedback circuit results in increased GLP-1 secretion. We used a wide range of experimental techniques, including gene expression analysis, immunohistochemical approaches, and the perfused mouse intestine to characterize the paracrine circuit controlling GLP-1 and SS. We show that 1) antagonizing the SS receptor (SSTr) 2 and SSTr5 led to increased GLP-1 and SS secretion in the mouse, 2) SS exhibits strong tonic inhibition of GLP-1 secretion preferentially through SSTr5, and 3) the secretion of S was GLP-1 receptor dependent. We conclude that SS is a tonic inhibitor of GLP-1 secretion, and interventions in the somatostain-GLP-1 paracrine loop lead to increased GLP-1 secretion.

Immunomodulatory potential of Nisin A with application in wound healing.

Antimicrobial peptides can have a dual role with both antimicrobial activity against a broad range of bacteria and immunomodulatory effect, making them attractive as therapeutic treatment of difficult wounds. Nisin A is widely known for its antimicrobial activity, and a preliminary study demonstrated that it increased wound closure, but the mechanism behind its effect is unknown. The aim of this study is to elucidate the wound healing potential of Nisin A and the mechanism behind. First, an epithelial and endothelial cell line, human keratinocyte (HaCaT) and human umbilical vein endothelial cell, were used to demonstrate migration and proliferation effects in vitro. From HaCaT cells and peripheral blood mononuclear cell, changes in cytokine levels were shown by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Second, the ex vivo porcine wound healing model was used to investigate the re-epithelization potential of Nisin A. Finally, the model Galleria mellonella was used to confirm antimicrobial activity and to investigate potential immunomodulatory effects in vivo. Here, we demonstrated that Nisin A affected migration significantly of both human umbilical vein endothelial cell and HaCaT cells (p < 0.05) but not proliferation, potentially by decreasing the levels of proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-8 (p < 0.001). Furthermore, Nisin A treatment diminished lipopolysaccharide-induced tumor necrosis factor-α levels from peripheral blood mononuclear cells and monocyte chemoattractant protein-1 from HaCaT cells (p < 0.001). Furthermore, Nisin A did not affect proliferation ex vivo either but increased re-epithelization of the porcine skin. Nisin A improved survival of G. mellonella significantly from Staphylococcus epidermidis (p < 0.001) but not from Escherichia coli, indicating that Nisin A did not help the larvae to survive the infection in a different than direct antimicrobial way. All together this makes Nisin A a potential treatment to use in wound healing, as it increases the mobility of skin cells, dampens the effect of lipopolysaccharide and proinflammatory cytokines, and decreases bacterial growth.