Environmental drivers of increased ecosystem respiration in a warming tundra.

Arctic and alpine tundra ecosystems are large reservoirs of organic carbon1,2. Climate warming may stimulate ecosystem respiration and release carbon into the atmosphere3,4. The magnitude and persistency of this stimulation and the environmental mechanisms that drive its variation remain uncertain5-7. This hampers the accuracy of global land carbon-climate feedback projections7,8. Here we synthesize 136 datasets from 56 open-top chamber in situ warming experiments located at 28 arctic and alpine tundra sites which have been running for less than 1 year up to 25 years. We show that a mean rise of 1.4 °C [confidence interval (CI) 0.9-2.0 °C] in air and 0.4 °C [CI 0.2-0.7 °C] in soil temperature results in an increase in growing season ecosystem respiration by 30% [CI 22-38%] (n = 136). Our findings indicate that the stimulation of ecosystem respiration was due to increases in both plant-related and microbial respiration (n = 9) and continued for at least 25 years (n = 136). The magnitude of the warming effects on respiration was driven by variation in warming-induced changes in local soil conditions, that is, changes in total nitrogen concentration and pH and by context-dependent spatial variation in these conditions, in particular total nitrogen concentration and the carbon:nitrogen ratio. Tundra sites with stronger nitrogen limitations and sites in which warming had stimulated plant and microbial nutrient turnover seemed particularly sensitive in their respiration response to warming. The results highlight the importance of local soil conditions and warming-induced changes therein for future climatic impacts on respiration.

Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis.

OBJECTIVE: Type 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with ß-cell selective loss of the glucagon receptor (Gcgrfl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor (GCGR) signalling on pan-islet [Ca2+]I activity and insulin secretion. METHODS: Metabolic profiling was conducted on Gcgrß-cell-/- and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for ß-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in ß-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. RESULTS: Gcgrß-cell-/- mice exhibited higher glucose levels following intraperitoneal glucose challenge (control 12.7 mmol/L ± 0.6 vs. Gcgrß-cell-/- 15.4 mmol/L ± 0.0 at 15 min, p = 0.002); fasting glycaemia was not different to controls. In vitro, Gcgrß-cell-/- islets showed profound loss of pan-islet [Ca2+]I waves in response to glucose which was only partially rescued in vivo. Diet induced obesity and hyperglycaemia also resulted in a loss of co-ordinated [Ca2+]I waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n = 8). CONCLUSION: These data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised [Ca2+]I waves and support a possible therapeutic role for glucagonergic agents to restore the insulin secretory capacity lost in T2D.

Real-world hepatitis C prevalence and treatment uptake at opioid agonist therapy clinics in Ontario, Canada.

Widespread screening for hepatitis C virus (HCV) is necessary for Canada to meet its HCV elimination goals by 2030. People who currently or previously injected drugs are at high risk for HCV. Opioid agonist therapy (OAT, such as methadone and buprenorphine) has been shown to help stabilize the lives of people who are opioid-dependent. The distribution of OAT in North America typically requires daily, weekly, or monthly clinic visits and presents an opportunity for engagement, screening and treatment for those at high-risk of HCV. In this study, HCV screening was conducted by staff at OAT clinics in Ontario from 2016 to 2020 and those with chronic infections were treated on-site with direct-acting antivirals. Point-of-care or dried blood spot (DBS) testing was used for antibodies, DBS or serum for HCV RNA and serum for HCV RNA at SVR12 (sustained virological response). Clinics screened 1954 people (mean age 40 years ±12, 63% male). Forty-five percent were antibody positive, of whom 64% were HCV RNA+. Eighty percent of those RNA+ set an appointment in which 99% attended. Ninety-six percent started treatment with 87% completing treatment. Sixty-eight percent of people who completed treatment submitted a sample for SVR12 testing of which 97% achieved a virological cure. Results suggest that HCV screening and treatment at OAT clinics is feasible, effective and warrants expansion. Data suggest strong treatment adherence due to high rates of SVR12 comparable with other OAT-based HCV treatment programs. The lack of SVR12 sampling could be addressed by either on-site phlebotomy or incentivizing SVR12 sampling.

Associations of changes in physical activity and sedentary time with weight recurrence after bariatric surgery: a 5-year prospective study.

BACKGROUND: Increasing physical activity and limiting sedentary time may minimize weight recurrence after bariatric surgery. However, few studies have evaluated potential associations of objectively-measured physical activity and sedentary time with post-surgical weight recurrence over time. AIMS: To evaluate associations of change in physical activity and sedentary time with weight recurrence after bariatric surgery. METHODS: Participants from the Oslo Bariatric Surgery Study, a prospective cohort study, wore an ActiGraph monitor for seven days at 1- and 5 years after surgery to assess daily physical activity and sedentary time. Participants' weight was measured at in-person clinic visits. Chi-square Test and Paired-samples T-test evaluated group differences and change over time, while Pearson's Correlation, multiple logistic and linear regression investigated associations between variables. RESULTS: Five years after surgery 79 participants (70.5% response rate, 81% female) (mean (sd) age: 54.0 (±9.3), BMI: 32.1 (±4.7)) had valid monitor data. Participants increased their sedentary time (71.4 minutes/day (95% CI: 54.2-88.6, p = <0.001)) and reduced daily steps (-1411.1 (95% CI: 737.8-208.4), p = <0.001), light physical activity (-54.1 min/day (95% CI: 40.9-67.2, p = <0.001)), and total physical activity (-48.2 (95% CI: 34.6-63.3), p = <0.001) from 1- to 5 years after surgery. No change was found for moderate-to-vigorous intensity physical activity. No associations were found between changes in steps, physical activity or sedentary time and weight recurrence. CONCLUSION: Participants increased sedentary time and decreased light- and total physical activity between 1- and 5 years post-surgery. Overall, changes in physical activity and sedentary time were not associated with weight recurrence. Interventions to help patients increase physical activity and limit sedentary time after bariatric surgery are needed.

Drinking water magnesium and cardiovascular mortality: A cohort study in Denmark, 2005-2016.

INTRODUCTION: Cardiovascular diseases are globally a major cause of death. Magnesium deficiency is associated with several diseases including cardiovascular diseases. OBJECTIVE: To examine if a low concentration of magnesium in drinking water is associated with increased cardiovascular mortality and mortality due to acute myocardial infarction and stroke. METHODS: A nationwide population-based cohort study using national health registries was used. A total of 4,274,132 individuals aged 30 years or more were included. Magnesium concentration in drinking water was estimated by linkage of residential addresses in the period 2005-2016 with the national drinking water quality monitoring database. The association between magnesium concentration in drinking water and cardiovascular mortality and mortality due to acute myocardial infarction and stroke was examined using a Poisson regression of number of deaths and logarithmic transformation of follow-up time as offset. The incidence rate ratio (IRR) was adjusted for differences in age, sex, calendar year, cohabitation, country of origin, and socioeconomic status. RESULTS: Median magnesium concentration in drinking water at inclusion was 12.4 mg/L (range: 1.37-54.2 mg/L). The adjusted IRR for cardiovascular mortality was 0.96 (95% CI: 0.94; 0.97) for the lowest magnesium quintile (<6.5 mg/L) as compared to the highest magnesium quintile (>21.9 mg/L). The adjusted IRR for mortality due to acute myocardial infarction and stroke was 1.22 (1.17; 1.27) and 0.96 (0.93; 0.99), respectively, for the lowest magnesium quintile as compared to the highest quintile A decreasing mortality due to acute myocardial infarction was seen with an increasing magnesium concentration in a dose-response manner. CONCLUSION: Low concentrations of magnesium in drinking water were associated with an increased mortality due to acute myocardial infarction. Low concentrations of magnesium in drinking water were associated with decreased cardiovascular mortality, and mortality due to stroke.

Assessment of chloride natural background levels by applying statistical approaches. Analyses of European coastal aquifers in different environments.

Estimated natural background levels (NBLs) are needed to assess groundwater chemical status according to the EU Groundwater Directive. They are commonly derived for different substances by applying statistical methodologies. Due to the complexity of the sea water intrusion process, some of those methods do not always provide appropriate assessment of chloride NBLs. This paper analyzes the applicability of different NBL estimation methods in five EU coastal aquifers with significant differences in available datasets and hydrogeological settings. A sensitivity analysis of results to different constraints was performed to remove samples with anthropogenic impacts. A novel statistical approach combining different methods to identify the range of chloride NBLs is proposed. In all pilots the estimated NBLs were below 85 mg/L and fitted well with previous studies and expert judgment, except Campina del Faro aquifer (the maximum being 167.5 mg/L). Although this approach is more time consuming, it provides a more robust solution.

Association of Medication Regimen Complexity With Clinical Endpoints in Pediatric Patients With Cystic Fibrosis.

OBJECTIVE: Cystic fibrosis (CF) patients and caregivers are impacted by the number of pharmacological agents and unique administration needs; however, no data currently assesses how medication regimen complexity impacts clinical outcomes in this population. The objective of this study is to evaluate if an association exists between increased medication regimen complexity and clinical endpoints in pediatric patients with CF. METHODS: This retrospective analysis included all pediatric patients with CF (ages 5-20 years) with at least 2 pharmacist encounters and acceptable pulmonary function tests at our pediatric pulmonary clinic during 2017. Each patient's medication regimen was scored using the validated Medication Regimen Complexity Index (MRCI) tool. The primary outcome was the correlation between MRCI score and lung function. Secondary endpoints included growth, number of infections requiring antibiotics, and hospitalizations. RESULTS: MRCI scores of the 113 included patients ranged from 2 to 101 points. A negative correlation was found between initial and final MRCI score and initial and final forced expiratory volume in 1 second (FEV1; r = -0.323, p = 0.0005 and r = -0.287, p = 0.0021, respectively). MRCI scores were negatively correlated with BMI percentile for both encounters (r = -0.162 and r = -0.125) but were not significant. Higher MRCI scores were associated with increased use of oral and intravenous antibiotics and hospital admissions. CONCLUSIONS: Higher MRCI scores are correlated with a significant decrease in FEV1, increased need for antibiotic therapy, and more hospital admissions in pediatric patients with CF. Larger studies are needed to determine if a correlation exists between MRCI score and growth.

Microplastics do not increase bioaccumulation of petroleum hydrocarbons in Arctic zooplankton but trigger feeding suppression under co-exposure conditions.

Arctic sea ice has alarmingly high concentrations of microplastics (MPs). Additionally, sea ice reduction in the Arctic is opening new opportunities for the oil and maritime industries, which could increase oil pollution in the region. Yet knowledge of the effects of co-exposure to MPs and crude oil on Arctic zooplankton is lacking. We tested the influence of MPs (polyethylene, 20.7 µm) on polycyclic aromatic hydrocarbon (PAH) bioaccumulation and oil toxicity in the key arctic copepod Calanus hyperboreus after exposure to oil with and without dispersant. Up to 30% of the copepods stopped feeding and fecal pellet production rates were reduced after co-exposure to oil (1 µL L-1) and MPs (20 MPs mL-1). The PAH body burden was ~3 times higher in feeding than in non-feeding copepods. Copepods ingested both MPs and crude oil droplets. MPs did not influence bioaccumulation of PAHs in copepods or their fecal pellets, but chemical dispersant increased bioaccumulation, especially of ≥4 ring-PAHs. Our results suggest that MPs do not act as vectors of PAHs in Arctic marine food webs after oil spills, but, at high concentrations (20 MPs mL-1), MPs can trigger behavioral stress responses (e.g., feeding suppression) to oil pollution in zooplankton.

Menoci: lightweight extensible web portal enhancing data management for biomedical research projects.

BACKGROUND: Biomedical research projects deal with data management requirements from multiple sources like funding agencies' guidelines, publisher policies, discipline best practices, and their own users' needs. We describe functional and quality requirements based on many years of experience implementing data management for the CRC 1002 and CRC 1190. A fully equipped data management software should improve documentation of experiments and materials, enable data storage and sharing according to the FAIR Guiding Principles while maximizing usability, information security, as well as software sustainability and reusability. RESULTS: We introduce the modular web portal software menoci for data collection, experiment documentation, data publication, sharing, and preservation in biomedical research projects. Menoci modules are based on the Drupal content management system which enables lightweight deployment and setup, and creates the possibility to combine research data management with a customisable project home page or collaboration platform. CONCLUSIONS: Management of research data and digital research artefacts is transforming from individual researcher or groups best practices towards project- or organisation-wide service infrastructures. To enable and support this structural transformation process, a vital ecosystem of open source software tools is needed. Menoci is a contribution to this ecosystem of research data management tools that is specifically designed to support biomedical research projects.

Combined effects of exposure to engineered silver nanoparticles and the water-soluble fraction of crude oil in the marine copepod Calanus finmarchicus.

While it is likely that ENPs may occur together with other contaminants in nature, the combined effects of exposure to both ENPs and environmental contaminants are not studied sufficiently. In this study, we investigated the acute and sublethal toxicity of PVP coated silver nanoparticles (AgNP) and ionic silver (Ag+; administered as AgNO3) to the marine copepod Calanus finmarchicus. We further studied effects of single exposures to AgNPs (nominal concentrations: low 15 µg L-1 NPL, high 150 µg L-1 NPH) or Ag+ (60 µg L-1), and effects of co-exposure to AgNPs, Ag+ and the water-soluble fraction (WSF; 100 µg L-1) of a crude oil (AgNP + WSF; Ag++WSF). The gene expression and the activity of antioxidant defense enzymes SOD, CAT and GST, as well as the gene expression of HSP90 and CYP330A1 were determined as sublethal endpoints. Results show that Ag+ was more acutely toxic compared to AgNPs, with 96 h LC50 concentrations of 403 µg L-1 for AgNPs, and 147 µg L-1 for Ag+. Organismal uptake of Ag following exposure was similar for AgNP and Ag+, and was not significantly different when co-exposed to WSF. Exposure to AgNPs alone caused increases in gene expressions of GST and SOD, whereas WSF exposure caused an induction in SOD. Responses in enzyme activities were generally low, with significant effects observed only on SOD activity in NPL and WSF exposures and on GST activity in NPL and NPH exposures. Combined AgNP and WSF exposures caused slightly altered responses in expression of SOD, GST and CYP330A1 genes compared to the single exposures of either AgNPs or WSF. However, there was no clear pattern of cumulative effects caused by co-exposures of AgNPs and WSF. The present study indicates that the exposure to AgNPs, Ag+, and to a lesser degree WSF cause an oxidative stress response in C. finmarchicus, which was slightly, but mostly not significantly altered in combined exposures. This indicated that the combined effects between Ag and WSF are relatively limited, at least with regard to oxidative stress.

Combined analysis of group recorded feed intake and individually recorded body weight and litter size in mink.

In the mink industry, feed costs are the largest variable expense and breeding for feed efficient animals is warranted. Implementation of selection for feed efficiency must consider the relationships between feed efficiency and the current selection traits BW and litter size. Often, feed intake (FI) is recorded on a cage with a male and a female and there is sexual dimorphism that needs to be accounted for. Study aims were to (1) model group recorded FI accounting for sexual dimorphism, (2) derive genetic residual feed intake (RFI) as a measure of feed efficiency, (3) examine the relationship between feed efficiency and BW in males (BWM) and females (BWF) and litter size at day 21 after whelping (LS21) in Danish brown mink and (4) investigate direct and correlated response to selection on each trait of interest. Feed intake records from 9574 cages, BW records on 16 782 males and 16 875 females and LS21 records on 6446 yearling females were used for analysis. Genetic parameters for FI, BWM, BWF and LS21 were obtained using a multivariate animal model, yielding sex-specific additive genetic variances for FI and BW to account for sexual dimorphism. The analysis was performed in a Bayesian setting using Gibbs sampling, and genetic RFI was obtained from the conditional distribution of FI given BW using genetic regression coefficients. Responses to single trait selection were defined as the posterior distribution of genetic superiority of the top 10% of animals after conditioning on the genetic trends. The heritabilities ranged from 0.13 for RFI in females and LS21 to 0.59 for BWF. Genetic correlations between BW in both sexes and LS21 and FI in both sexes were unfavorable, and single trait selection on BW in either sex showed increased FI in both sexes and reduced litter size. Due to the definition of RFI and high genetic correlation between BWM and BWF, selection on RFI did not significantly alter BW. In addition, selection on RFI in either sex did not affect LS21. Genetic correlation between sexes for FI and BW was high but significantly lower than unity. The high correlations across sex allowed for selection on standardized averages of animals' breeding values (BVs) for RFI, FI and BW, which yielded selection responses approximately equal to the responses obtained using the sex-specific BVs. The results illustrate the possibility of selecting against RFI in mink with no negative effects on BW and litter size.

Effect of Calcipotriene/Betamethasone Dipropionate 0.005%/0.064% Foam on Target Lesions in Plaque Psoriasis: A Post-Hoc Analysis

Objective: Investigate the effect of fixed-combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam on target lesion severity in plaque psoriasis. Design: Post-hoc analysis was conducted on data from a Phase 3, randomized, double-blind, multicenter clinical study of Cal/BD foam in the treatment of psoriasis vulgaris for 4 weeks (PSO-FAST; NCT01866163). Participants: In PSO-FAST, 426 patients (≥18 years) with psoriasis vulgaris (≥mild severity) were randomized 3:1 to Cal/BD foam (n=323) or vehicle foam (n=103), applied once daily. Measurements: Assessments included (1) target lesion severity (redness, scaliness, and thickness) at baseline and weeks 1, 2, and 4; and (2) the proportion of patients with ≥50% reduction in total sign score (TSS-50) from baseline at weeks 1, 2, and 4. Results: A greater proportion of patients achieved considerable improvement (a score of 0 or 1) in the severity of target lesions after 4 weeks of treatment with Cal/BD foam vs vehicle foam at week 4 (redness: 76.2% vs 21.4%; P<.001; scaliness: 91.3% vs 61.2%; P<.001; and thickness: 83.3% vs 35.0%; P<.001, respectively). Rapid onset of efficacy was observed as early as week 1. Significantly more patients also achieved TSS-50 at week 4 with Cal/BD foam vs vehicle foam for their target lesions regardless of treatment area, including the elbows and knees (P<.05 for all). Conclusions: Significant improvements in target lesion severity were achieved with up to 4 weeks of treatment with once-daily Cal/BD foam for adults with plaque psoriasis versus vehicle foam, with rapid onset of efficacy observed at week 1. J Drugs Dermatol. 2020;19(2)121-126. doi:10.36849/JDD.2020.4750

The cause of death in bacterial meningitis.

BACKGROUND: Death from bacterial meningitis is rarely attributed to the actual event causing death. The present study therefore categorized and characterized the cause and time of death due to bacterial meningitis. METHODS: In a cohort of patients > 15 years of age with community acquired bacterial meningitis the medical records were reviewed, and a clinical cause of death categorized into six main categories: 1) CNS complications, 2) Systemic complications, 3) Combination of systemic and CNS complications, 4) Sudden death, 5) Withdrawal of care, or 6) Unknown. RESULTS: We identified 358 patients of which 84 (23%) died in-hospital. Causes of death were ascribed to CNS complications in 43%, Systemic complications in 39%, Combined CNS and systemic complications in 4%, Sudden death in 7% and withdrawal of care in 5%. Brain herniation, circulatory failure, intractable seizures and other brain injury were the most common specific causes of death within 14 days from admission (55%). CONCLUSION: Fatal complications due to the primary infection - meningitis - is most common within 14 days of admission. The diversity of complications causing death in meningitis suggest that determining the clinical cause of death is essential to the evaluation of novel treatment strategies.

Oral semaglutide versus injectable glucagon-like peptide-1 receptor agonists: a cost of control analysis.

Aims: The efficacy and safety of oral semaglutide, the first glucagon-like peptide-1 (GLP-1) receptor agonist developed for oral administration for the treatment of type 2 diabetes, was evaluated in the PIONEER clinical trial program, and a recently published network meta-analysis allowed comparison with further injectable GLP-1 receptor agonists. The present study aimed to assess the short-term cost- effectiveness of oral semaglutide 14 mg versus subcutaneous once-weekly dulaglutide 1.5 mg, once-weekly exenatide 2 mg, twice-daily exenatide 10 µg, once-daily liraglutide 1.8 mg, once-daily lixisenatide 20 µg, and once-weekly semaglutide 1 mg, in terms of the cost per patient achieving glycated hemoglobin (HbA1c) targets (cost of control).Materials and methods: Cost of control was calculated by dividing the annual treatment costs associated with an intervention by the proportion of patients achieving the treatment target with an intervention, with outcomes calculated for targets of HbA1c ≤6.5% and HbA1c <7.0% for all included GLP-1 receptor agonists. Annual treatment costs were accounted in 2019 United States dollars (USD), based on 2019 wholesale acquisition cost.Results: For the treatment target of HbA1c ≤6.5%, once-weekly semaglutide 1 mg and oral semaglutide 14 mg were associated with the lowest costs of control, at USD 15,430 and USD 17,383 per patient achieving target, respectively. Similarly, the cost of control was lowest with once-weekly semaglutide 1 mg at USD 12,627 per patient achieving target, followed by oral semaglutide 14 mg at USD 13,493 per patient achieving target for the target of HbA1c <7.0%. All other interventions were associated with higher cost of control values for both targets.Conclusions: Oral semaglutide 14 mg is likely to be cost-effective versus dulaglutide, exenatide (once weekly and twice daily), liraglutide, and lixisenatide in terms of bringing people with type 2 diabetes to glycemic control targets of HbA1c ≤6.5% and HbA1c <7.0% in the US.

Role of Nuclear Medicine in Imaging.

Nuclear medicine (NM) plays a unique role in the detection of infection and inflammation. This review looks at different methods that are used for detection of infections and explains how they differ from cross-sectional imaging such as computed tomography and magnetic resonance imaging. Images are provided to aid understanding and interpretation of NM scans. There is also a brief discussion of future techniques that can alter the use of NM for infection work up.

The Impact of Self-Monitoring Blood Glucose Adherence On Glycemic Goal Attainment in an Indigent Population, With Pharmacy Assistance.

Self-monitoring of bood glucose alone is not a good predictor of HbA1c goal attainment. Health plans might benefit from formulary restrictions to provide more cost-effective care, without negatively impacting glycemic control. And by using targeted inteventions, healthcare providers could help maximize SMBG's clinical benefit for patients who receive test strips. Self-monitoring of blood glucose (SMBG) can be an important tool in diabetes treatment, both for patient self-management and for guiding clinicians regarding medication adjustments. Evidence supports the association of SMBG with clinical outcomes in patients with type-1 diabetes mellitus (T1DM) although it is mixed for patients with type-2 diabetes mellitus (T2DM). The cost of SMBG comprises a substantial portion of the total cost for patients with diabetes, and test strips are one of the main expenditures of the University of North Carolina Medical Center Pharmacy Assistance Program (PAP), which provides medication coverage, including test strips, to indigent patients who have no pharmacy insurance. The objective of this study is to evaluate the utility of SMBG based on the impact of test-strip adherence on glycemic goal attainment in an indigent population that is provided with low-copay test strips. This retrospective cohort study included patients with T1DM or T2DM who were enrolled in PAP in 2016 and who received a prescription for test strips during the 90 days prior to hemoglobin A1c (HbA1c) measurement. Adherence was defined as the proportion of days covered (PDC) > 0.8. Of the 498 patients encountered, 20% of the adherent group (n = 245) and 25% of the nonadherent group (n = 253) had a goal of HbA1c < 7% (P = 0.24). There were no differences in mean HbA1c between the groups, except in the multiple daily injections (MDI) of the insulin subgroup (8.9% vs. 9.6%, P = 0.009). The adherent group was 80% less likely to have a diabetes-related hospitalization (odds ratio [OR], 0.2; 95% CI, 0.04-0.92). The total test-strip cost to PAP was more than $200,000. In conclusion, in an indigent population, adherence to SMBG does not correlate with glycemic goal attainment and imposes a substantial cost burden on the healthcare system.

Canine and human sinoatrial node: differences and similarities in the structure, function, molecular profiles, and arrhythmia.

The sinoatrial node (SAN) is the primary pacemaker in canine and human hearts. The SAN in both species has a unique three-dimensional heterogeneous structure characterized by small pacemaker myocytes enmeshed within fibrotic strands, which partially insulate the cells from aberrant atrial activation. The SAN pacemaker tissue expresses a unique signature of proteins and receptors that mediate SAN automaticity, ion channel currents, and cell-to-cell communication, which are predominantly similar in both species. Recent intramural optical mapping, integrated with structural and molecular studies, has revealed the existence of up to five specialized SAN conduction pathways that preferentially conduct electrical activation to atrial tissues. The intrinsic heart rate, intranodal leading pacemaker shifts, and changes in conduction in response to physiological and pathophysiological stimuli are similar. Structural and/or functional impairments due to cardiac diseases including heart failure cause SAN dysfunctions (SNDs) in both species. These dysfunctions are usually manifested as severe bradycardia, tachy-brady arrhythmias, and conduction abnormalities including exit block and SAN reentry, which could lead to atrial tachycardia and fibrillation, cardiac arrest, and heart failure. Pharmaceutical drugs and implantable pacemakers are only partially successful in managing SNDs, emphasizing a critical need to develop targeted mechanism-based therapies to treat SNDs. Because several structural and functional characteristics are similar between the canine and human SAN, research in these species may be mutually beneficial for developing novel treatment approaches. This review describes structural, functional, and molecular similarities and differences between the canine and human SAN, with special emphasis on arrhythmias and unique causal mechanisms of SND in diseased hearts.