Cellular metabolism of substance P produces neurokinin-1 receptor peptide agonists with diminished cyclic AMP signaling.

Substance P (SP) is released from sensory nerves in the arteries and heart. It activates neurokinin-1 receptors (NK1Rs) causing vasodilation, immune modulation, and adverse cardiac remodeling. The hypothesis was tested: SP and SP metabolites activate different second messenger signaling pathways. Macrophages, endothelial cells, and fibroblasts metabolized SP to N- and C-terminal metabolites to varying extents. SP 5-11 was the most abundant metabolite followed by SP 1-4, SP 7-11, SP 6-11, SP 3-11, and SP 8-11. In NK1R-expressing human embryonic kidney 293 (HEK293) cells, SP and some C-terminal SP metabolites stimulate the NK1R, promoting the dissociation of several Gα proteins, including Gαs and Gαq from their ßγ subunits. SP increases intracellular calcium concentrations ([Ca]i) and cyclic 3',5'-adenosine monophosphate (cAMP) accumulation with similar -log EC50 values of 8.5 ± 0.3 and 7.8 ± 0.1 M, respectively. N-terminal metabolism of SP by up to five amino acids and C-terminal deamidation of SP produce peptides that retain activity to increase [Ca]i but not to increase cAMP. C-terminal metabolism results in the loss of both activities. Thus, [Ca]i and cAMP signaling are differentially affected by SP metabolism. To assess the role of N-terminal metabolism, SP and SP 6-11 were compared with cAMP-mediated activities in NK1R-expressing 3T3 fibroblasts. SP inhibits nuclear factor κB (NF-κB) activity, cell proliferation, and wound healing and stimulates collagen production. SP 6-11 had little or no activity. Cyclooxygenase-2 (COX-2) expression is increased by SP but not by SP 6-11. Thus, metabolism may select the cellular response to SP by inhibiting or redirecting the second messenger signaling pathway activated by the NK1R.NEW & NOTEWORTHY Endothelial cells, macrophages, and fibroblasts metabolize substance P (SP) to N- and C-terminal metabolites with SP 5-11 as the most abundant metabolite. SP activates neurokinin-1 receptors to increase intracellular calcium and cyclic AMP. In contrast, SP metabolites of N-terminal metabolism and C-terminal deamidation retain the ability to increase calcium but lose the ability to increase cyclic AMP. These new insights indicate that the metabolism of SP directs cellular functions by regulating specific signaling pathways.

Hospital use and cancer treatment by age and socioeconomic status in the last year of life: A Norwegian population-based study of patients dying of cancer.

INTRODUCTION: Cancer is the leading cause of death in Norway. In this nationwide study we describe the number and causes of hospital admissions and treatment in the final year of life for patients who died of cancer, as well as the associations to age and socioeconomic status (SES). MATERIALS AND METHODS: From nationwide registries covering 2010-2014, we identified all patients who were diagnosed with cancer 12-60 months before death and had cancer as their reported cause of death. We examined the number of overnight hospital stays, causes of admission, and treatment (chemotherapy, radiotherapy, surgical procedures) offered during the last year of life by individual (age, sex, comorbidity), cancer (type, stage, months since diagnosis), and socioeconomic variables (co-residential status, income, education). RESULTS: The analytical sample included 17,669 patients; 8,247 (47%) were female, mean age was 71.7 years (standard deviation 13.7). At diagnosis, 31% had metastatic disease, while 29% had an intermediate or high comorbidity burden. Altogether, 94% were hospitalized during their final year, 82% at least twice, and 33% six times or more. Patients spent a median of 23 days in hospital (interquartile range 11-41), and altogether 38% died there. Younger age, bladder and ovarian cancer, not living alone, and higher income were associated with having ≥6 hospitalizations. Cancer-related diagnoses were the main causes of hospitalizations (65%), followed by infections (11%). Around 51% had ≥1 chemotherapy episode, with large variations according to patient age and SES; patients who were younger, did not live alone, had high education, and high income received more chemotherapy. Radiotherapy was received by 15% and declined with age, and the variation according to SES characteristics was minor. Of the 12,940 patients with a cancer type where surgery is a main treatment modality, only 835 (6%) underwent surgical procedures for their primary tumor in the last year of life. DISCUSSION: Most patients who die of cancer are hospitalized multiple times during the last year of life. Hospitalizations and treatment decline with advancing age. Living alone and having low income is associated with fewer hospitalizations and less chemotherapy treatment. Whether this indicates over- or undertreatment across various groups warrants further exploration.

Scavenger receptor class B type I is required for efficient glucose uptake and metabolic homeostasis in adipocytes.

Obesity is a worldwide epidemic and places individuals at a higher risk for developing comorbidities that include cardiovascular disease and type 2 diabetes. Adipose tissue contains adipocytes that are responsible for lipid metabolism and reducing misdirected lipid storage. Adipocytes facilitate this process through insulin-mediated uptake of glucose and its subsequent metabolism into triglycerides for storage. During obesity, adipocytes become insulin resistant and have a reduced ability to mediate glucose import, thus resulting in whole-body metabolic dysfunction. Scavenger receptor class B type I (SR-BI) has been implicated in glucose uptake in skeletal muscle and adipocytes via its native ligands, apolipoprotein A-1 and high-density lipoproteins. Further, SR-BI translocation to the cell surface in adipocytes is sensitive to insulin stimulation. Using adipocytes differentiated from ear mesenchymal stem cells isolated from wild-type and SR-BI knockout (SR-BI -/- ) mice as our model system, we tested the hypothesis that SR-BI is required for insulin-mediated glucose uptake and regulation of energy balance in adipocytes. We demonstrated that loss of SR-BI in adipocytes resulted in inefficient glucose uptake regardless of cell surface expression levels of glucose transporter 4 compared to WT adipocytes. We also observed reduced glycolytic capacity, increased lipid biosynthesis, and dysregulated expression of lipid metabolism genes in SR-BI -/- adipocytes compared to WT adipocytes. These results partially support our hypothesis and suggest a novel role for SR-BI in glucose uptake and metabolic homeostasis in adipocytes.

Mission Disimpaction: Endoscopic Management of Stercoral Colitis in an Adolescent.

Stercoral colitis is a rare entity of inflammatory colitis with high morbidity and mortality attributable to colonic fecaloma impaction, often a result of chronic constipation. Despite demographic imbalance favoring elders, children hold comparative risk factors for chronic constipation. Suspicion for stercoral colitis is warranted in nearly every stage of life. Computerized tomography (CT) is diagnostic for stercoral colitis, where radiological findings correlate to high sensitivity and specificity. Difficulty exists discerning from other acute and chronic intestinal etiologies with overlapping nonspecific symptoms and laboratory markers. Management involves prompt risk assessment for perforation and immediate disimpaction to avoid ischemic injury, with endoscopic directed disimpaction standard of care for nonoperative measures. Our case describes stercoral colitis in an adolescent with contributive risk factors for fecaloma impaction and is one of the first adolescent case reports involving successful endoscopic management.

Immigration, mortality, and national life expectancy in the Nordic region, 1990-2019.

•Immigrants have higher life expectancy at age 1 than the native-born in Denmark, Finland and Norway do from 1990 to 2019.•Immigrants in Denmark, Finland and Norway increasingly enhance national life expectancy at age 1 over time.•Immigrants in Sweden have lower life expectancy at age 1 than native-born in Sweden do in 1990, but similar levels by 2019.•The effect of immigrants on national life expectancy at age 1 in Sweden transforms from negative to positive over time.•The unique mortality of immigrants affects rankings of life expectancy at age 1 in the Nordic region in recent years.

The effect of age on specialized palliative care use in the last year of life for patients who die of cancer: A nationwide study from Norway.

INTRODUCTION: Specialized palliative care (SPC) is beneficial towards end of life because of its holistic approach to improve quality of life and comfort of patients and their families. Few studies have described how patient age, sex, comorbidities, and socioeconomic status (SES) are associated with SPC use in nonselective populations who die of cancer. This study aimed to evaluate the use of SPC in the year preceding death by all Norwegian individuals with a recent cancer diagnosis who died of cancer. MATERIALS AND METHODS: From nationwide registries, we identified patients with a recent (<5 years) cancer diagnosis who died during 2010-2014. Using binary logistic regression models, we estimated the probability of receiving hospital-based SPC during the last year of life according to individual (age, sex, comorbidity), cancer (stage, type, and months since diagnosis), and SES (e.g., living alone, household income, and education) characteristics. RESULTS: The analytical sample contained 45,521 patients with a median age at death of 75 years; 46% were women. The probability of receiving hospital-based SPC in the total cohort was 0.43 (95% confidence interval [CI] 0.42-0.43). Use of SPC was higher if patients were younger, female, had limited comorbidity, metastatic disease, had one the following cancer types: colorectal, pancreatic, bladder, kidney, or gastric, were diagnosed more than six months before death, and had higher SES. Adjusted model results suggested that the probability of using SPC in the last year of life for patients aged 80-89 years was 0.31 (95% CI 0.30-0.32), compared to a probability of 0.63 (95% CI 0.61-0.65) for patients aged 50-59 years. For patients ≥90 years, the probability was 0.16 (95% CI 0.15-0.18). DISCUSSION: Less hospital-based SPC use among older patients, males, and those with lower SES indicates possible under-treatment in these groups. Future studies should be designed to determine the underlying reasons for these observed differences.

A Pilot Clinical Study to Investigate the Hypomethylating Properties of Freeze-dried Black Raspberries in Patients with Myelodysplastic Syndrome or Myeloproliferative Neoplasm.

Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are bone marrow disorders characterized by cytopenias and progression to acute myeloid leukemia. Hypomethylating agents (HMAs) are Food and Drug Administration-approved therapies for MDS and MDS/MPN patients. HMAs have improved patients' survival and quality of life when compared with other therapies. Although HMAs are effective in MDS and MDS/MPN patients, they are associated with significant toxicities that place a large burden on patients. Our goal is to develop a safer and more effective HMA from natural products. We previously reported that black raspberries (BRBs) have hypomethylating effects in the colon, blood, spleen, and bone marrow of mice. In addition, BRBs exert hypomethylating effects in patients with colorectal cancer and familial adenomatous polyposis. In the current study, we conducted a pilot clinical trial to evaluate the hypomethylating effects of BRBs in patients with low-risk MDS or MDS/MPN. Peripheral blood mononuclear cells (PBMCs) were isolated before and after three months of BRB intervention. CD45+ cells were isolated from PBMCs for methylation analysis using a reduced-representation bisulfite sequencing assay. Each patient served as their own matched control, with their measurements assessed before intervention providing a baseline for post-intervention results. Clinically, our data showed that BRBs were well-tolerated with no side effects. When methylation data was combined, BRBs significantly affected methylation levels of 477 promoter regions. Pathway analysis suggests that BRB-induced intragenic hypomethylation drives leukocyte differentiation. A randomized, placebo-controlled clinical trial of BRB use in low-risk MDS or MDS/MPN patients is warranted.

Swimming behavior of emigrating Chinook Salmon smolts.

Swimming behavior of Chinook Salmon (Oncorhynchus tshawytscha) smolts affects transit time, route selection and survival in complex aquatic ecosystems. Behavior quantified at the river reach and junction scale is of particular importance for route selection and predator avoidance, though few studies have developed field-based approaches for quantifying swimming behavior of juvenile migratory fishes at this fine spatial scale. Two-dimensional acoustic fish telemetry at a river junction was combined with a three-dimensional hydrodynamic model to estimate in situ emigration swimming behavior of federally-threatened juvenile Chinook salmon smolts. Fish velocity over ground was estimated from telemetry, while the hydrodynamic model supplied simultaneous, colocated water velocities, with swimming velocity defined by the vector difference of the two velocities. Resulting swimming speeds were centered around 2 body lengths/second, and included distinct behaviors of positive rheotaxis, negative rheotaxis, lateral swimming, and passive transport. Lateral movement increased during the day, and positive rheotaxis increased in response to local hydrodynamic velocities. Swim velocity estimates were sensitive to the combination of vertical shear in water velocities and vertical distribution of fish.

Ubiquitin is a carbon dioxide-binding protein.

The identification of CO2-binding proteins is crucial to understanding CO2-regulated molecular processes. CO2 can form a reversible posttranslational modification through carbamylation of neutral N-terminal α-amino or lysine ε-amino groups. We have previously developed triethyloxonium (TEO) ion as a chemical proteomics tool for covalent trapping of carbamates, and here, we deploy TEO to identify ubiquitin as a mammalian CO2-binding protein. We use 13C-NMR spectroscopy to demonstrate that CO2 forms carbamates on the ubiquitin N terminus and ε-amino groups of lysines 6, 33, 48, and 63. We demonstrate that biologically relevant pCO2 levels reduce ubiquitin conjugation at lysine-48 and down-regulate ubiquitin-dependent NF-κB pathway activation. Our results show that ubiquitin is a CO2-binding protein and demonstrates carbamylation as a viable mechanism by which mammalian cells can respond to fluctuating pCO2.

Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI-Mediated High-Density Lipoprotein Uptake.

Objective: To investigate the role of adipocyte Pcpe2 (procollagen C-endopeptidase enhancer 2) in SR-BI (scavenger receptor class BI)-mediated HDL-C (high-density lipoprotein cholesterol) uptake and contributions to adipose lipid storage. Approach and Results: Pcpe2, a glycoprotein devoid of intrinsic proteolytic activity, is believed to participate in extracellular protein-protein interactions, supporting SR-BI- mediated HDL-C uptake. In published studies, Pcpe2 deficiency increased the development of atherosclerosis by reducing SR-BI-mediated HDL-C catabolism, but the biological impact of this deficiency on adipocyte SR-BI-mediated HDL-C uptake is unknown. Differentiated cells from Ldlr-/-/Pcpe2-/- (Pcpe2-/-) mouse adipose tissue showed elevated SR-BI protein levels, but significantly reduced HDL-C uptake compared to Ldlr-/- (control) adipose tissue. SR-BI-mediated HDL-C uptake was restored by preincubation of cells with exogenous Pcpe2. In diet-fed mice lacking Pcpe2, significant reductions in visceral, subcutaneous, and brown adipose tissue mass were observed, despite elevations in plasma triglyceride and cholesterol concentrations. Significant positive correlations exist between adipose mass and Pcpe2 expression in both mice and humans. Conclusions: Overall, these findings reveal a novel and unexpected function for Pcpe2 in modulating SR-BI expression and function as it relates to adipose tissue expansion and cholesterol balance in both mice and humans.

Interrelationships Among Fertility, Internal Migration,and Proximity to Nonresident Family:A Multilevel Multiprocess Analysis.

Past research has found that relations to nonresident family can influence individual fertility and migration behaviors separately. However, fertility and migration outcomes may also be interrelated, suggesting potential links across all three demographic processes. With this in mind, we track a cohort of women in Norway from age 18 to 31, recording the emergence of birth and migration events as well as their proximity to nonresident family networks (siblings and parents). Using a multilevel multiprocess statistical framework, with observations nested within women and equations for births, migrations, and proximity to nonresident family estimated simultaneously, our results support the notion that linked lives matter. Even in early adulthood, proximity to nonresident family has a positive effect on transitions to motherhood, whereas the presence of children (itself an outcome of past fertility) is associated with lower propensities to migrate. Mothers also have higher propensities to be living near family than women without children. The presence of local nonresident family reduces propensities for second and third migrations. However, after accounting for unobserved heterogeneity and selection, we observe a small positive effect of proximity to family on first migrations undertaken after age 18. Significant cross-process residual correlations exist across all three outcomes, suggesting that separately estimated model estimates may be vulnerable to bias emerging from unobserved sources of heterogeneity and selection. Our analysis therefore suggests that decisions about fertility, migration, and proximity to family are jointly determined and endogenous, and they should be analyzed simultaneously when possible.

Chronic Pectoralis Major Rupture Reconstruction With Interpositional Acellular Dermal Allograft.

Background: Pectoralis major tendon (PMT) rupture commonly occurs in males 20 to 39 years of age. PMT rupture is most often associated with gym-based exercise, with attempted bench press being the most common causative event, but it is also associated with contact or impact sports. Delayed presentation, misdiagnoses, and chronic PMT rupture can result in a therapeutic dilemma. Case Series: We present 2 cases of chronic PMT rupture that were operatively managed using acellular dermal allograft as an interposition graft. Patients' final follow-ups were at 20 and 30 months, respectively. Strength in their pectoralis major muscle was well preserved on the contralateral side: 88% for patient 1 and 110% for patient 2. Conclusion: Our reported technique using an interpositional acellular dermal allograft is a good option to treat chronic PMT rupture.

Migration after union dissolution in the United States: The role of non-resident family.

Separation from a spouse or cohabiting partner is associated with a high likelihood of moving, even over long distances. In this paper, we use longitudinal data from the Panel Study of Income Dynamics for the United States to analyze the role of non-resident family in the migration of separated people immediately after and in the years following union dissolution. We explore both migration in general and return migration among separated people, drawing comparisons to married and never-married people. We find that having parents, children, or siblings living close by substantially deters migration, especially among separated people. We also find marked positive effects of having family members in the county where the respondent grew up on the likelihood of returning there. Separated people are especially likely to return, compared to others, if they have parents in their county of origin. Furthermore, a lack of an effect of years of education on migration, and a negative effect of this variable on return migration, suggest that migration after separation is less related to human-capital considerations than other types of migration.

Separation and Elevated Residential Mobility: A Cross-Country Comparison.

This study investigates the magnitude and persistence of elevated post-separation residential mobility (i.e. residential instability) in five countries (Australia, Belgium, Germany, the Netherlands, and the UK) with similar levels of economic development, but different welfare provisions and housing markets. While many studies examine residential changes related to separation in selected individual countries, only very few have compared patterns across countries. Using longitudinal data and applying Poisson regression models, we study the risk of a move of separated men and women compared with cohabiting and married individuals. We use time since separation to distinguish between moves due to separation and moves of separated individuals. Our analysis shows that separated men and women are significantly more likely to move than cohabiting and married individuals. The risk of a residential change is the highest shortly after separation, and it decreases with duration since separation. However, the magnitude of this decline varies by country. In Belgium, mobility rates remain elevated for a long period after separation, whereas in the Netherlands, post-separation residential instability appears brief, with mobility rates declining rapidly. The results suggest that housing markets are likely to shape the residential mobility of separated individuals. In countries, where mortgages are easy to access and affordable rental properties are widespread, separated individuals can rapidly adjust their housing to new family circumstances; in contrast, in countries with limited access to homeownership and small social rental markets, separated individuals experience a prolonged period of residential instability.

Effect of HIV pre-exposure prophylaxis (PrEP) on detection of early infection and its impact on the appropriate post-PrEP deferral period.

INTRODUCTION: HIV antivirals for pre-exposure prophylaxis (PrEP) are known to affect detection of early HIV infection through suppression of viral load and delayed seroconversion. To cover potential delay in HIV detection associated with PrEP use by blood donors in the context of international reductions in sexual activity-based deferral periods, we analysed the available data to determine the appropriate minimum post-PrEP deferral period for blood donation. MATERIALS AND METHODS: Published cases of incident HIV infection when PrEP use was objectively demonstrable were identified, consisting principally of seroconverters from the Partners PrEP study (a clinical trial of PrEP efficacy). Data were reviewed to determine the impact of PrEP on the detection of HIV RNA, p24 Ag and seroconversion delay. RESULTS: Nucleic acid testing (NAT) detected early HIV infection in the presence of PrEP prior to or in concordance with serological testing in approximately 90% of cases. Undetectable HIV RNA would rebound to detectable levels within two months of PrEP cessation. PrEP delayed p24 antigen detection and antibody seroconversion by about 7 days. CONCLUSION: Even when daily PrEP is continued, it is likely that the majority of early HIV infections are detectable by individual donation (ID)-NAT, with p24 Ag or antibody seroconversion occurring conservatively within four weeks of exposure. HIV RNA levels also rebound rapidly in the absence of PrEP. In Australia, a three-month deferral period for blood donation after the last dose of PrEP provides an appropriate safety margin to mitigate the residual risk of transfusion-transmitted HIV.

Migration for family and labour market outcomes in Sweden.

Using information on stated motives for migrating among working-age individuals in the 2007 Swedish Motives for Migration survey (N = 1,852), we use multinomial logistic regression to examine whether and how moves for family reasons are linked to labour market outcomes in ways that differ from migration initiated for other motives, including more overtly labour-related factors. The results indicate that family-based migration is associated with worse labour market outcomes than migration for employment or other reasons. Additionally, family-motivated migrants with co-resident children are more likely to experience labour market deterioration than those without children. Among those who were unemployed before moving, those who reported family as a motive for moving were significantly more likely to be employed after the move. These results help us better assess how families and social networks impact economic outcomes-negatively in some circumstances and positively in others.

The ins and outs of lipid rafts: functions in intracellular cholesterol homeostasis, microparticles, and cell membranes: Thematic Review Series: Biology of Lipid Rafts.

Cellular membranes are not homogenous mixtures of proteins; rather, they are segregated into microdomains on the basis of preferential association between specific lipids and proteins. These microdomains, called lipid rafts, are well known for their role in receptor signaling on the plasma membrane (PM) and are essential to such cellular functions as signal transduction and spatial organization of the PM. A number of disease states, including atherosclerosis and other cardiovascular disorders, may be caused by dysfunctional maintenance of lipid rafts. Lipid rafts do not occur only in the PM but also have been found in intracellular membranes and extracellular vesicles (EVs). Here, we focus on discussing newly discovered functions of lipid rafts and microdomains in intracellular membranes, including lipid and protein trafficking from the ER, Golgi bodies, and endosomes to the PM, and we examine lipid raft involvement in the production and composition of EVs. Because lipid rafts are small and transient, visualization remains challenging. Future work with advanced techniques will continue to expand our knowledge about the roles of lipid rafts in cellular functioning.

Edible Mushrooms Reduce Atherosclerosis in Ldlr-/- Mice Fed a High-Fat Diet.

BACKGROUND: Commonly consumed mushrooms, portobello (PBM) and shiitake (SHM), are abundant in nutrients, soluble dietary fibers, and bioactive compounds that have been implicated as beneficial in reducing inflammation, improving lipid profiles, and ameliorating heart disease and atherosclerosis, an inflammatory disease of the arteries. OBJECTIVE: The aim of this study was to determine effects of PBM and SHM in preventing atherosclerosis and associated inflammation in an animal model. METHODS: Four-week-old Ldlr-/- male mice were divided into 5 dietary groups for 16 wk: a low-fat control (LF-C, 11 kcal% fat), high-fat control (HF-C, 18.9 kcal% fat), HF + 10% (wt:wt) PBM (HF-PBM, 19.5 kcal% fat) or SHM (HF-SHM, 19.7 kcal% fat) powder, and HF + mushroom control mix (MIX-C, 19.6 kcal% fat), a diet best matched to the average macronutrient content of both mushrooms. Body composition was measured using MRI. Aortic tricuspid valves and aortas were collected and stained to quantify plaque formation. Adhesion molecule expression was quantified by immunohistochemistry. Plasma lipid and cytokine concentrations were measured. RESULTS: We found that mice fed a HF-SHM diet had ∼86% smaller aortic lesion area than mice in both HF-C (P < 0.01) and MIX-C (P < 0.01) groups and also expressed 31-48% lower vascular cell adhesion molecule-1 levels (P < 0.05) than all other groups. Similarly, HF-PBM-fed mice displayed a 70% reduction in aortic lesion area in the tricuspid valve only (P < 0.05). Both mushroom-fed groups had lower weight gain and fat mass (P < 0.05) than the control groups. CONCLUSION: These results suggest that consumption of PBMs and particularly SHMs is effective in preventing development of high-fat diet-induced atherosclerosis in Ldlr-/- mice. Future studies will determine active components in mushrooms responsible for this beneficial effect.