Alterations in sweet taste function in adults with diabetes mellitus: a systematic review and potential implications.

Diet therapy for diabetes involves controlling carbohydrate intake in order to manage blood glucose concentrations. Simple carbohydrates, like sucrose, quickly and potently raise blood glucose when ingested, and are typically perceived as sweet. Sweetness is innately pleasurable and contributes to the positive hedonic evaluation of foods and beverages. There is some evidence to suggest that individuals with diabetes mellitus may be less able to detect sweetness, which could result in increased intake and, thus, more difficulty managing blood glucose. A systematic review that included PubMed, PsycInfo, and Embase databases was conducted. Inclusion criteria included observational studies that investigated the sweet taste function of adults with and without diabetes mellitus (Prospero CRD42021225058). The quality of the final included studies was assessed using the Academy of Nutrition and Dietetics' Evidence Analysis Library Quality Criteria Checklist: Primary Research tool. Eighteen studies that compared sweet taste thresholds, intensity ratings, or hedonic responses in adults both with and without diabetes were included. Differences in sweet taste thresholds, both detection and recognition, indicated that individuals with diabetes were less sensitive than healthy controls. The same findings were observed for intensity ratings. Only two studies examined hedonic responses; results were inconclusive.

Combining dynamic Monte Carlo with machine learning to study nanoparticle translocation.

Resistive pulse sensing (RPS) measurements of nanoparticle translocation have the ability to provide information on single-particle level characteristics, such as diameter or mobility, as well as ensemble averages. However, interpreting these measurements is complex and requires an understanding of nanoparticle dynamics in confined spaces as well as the ways in which nanoparticles disrupt ion transport while inside a nanopore. Here, we combine Dynamic Monte Carlo (DMC) simulations with Machine Learning (ML) and Poisson-Nernst-Planck calculations to simultaneously simulate nanoparticle dynamics and ion transport during hundreds of independent particle translocations as a function of nanoparticle size, electrophoretic mobility, and nanopore length. The use of DMC simulations allowed us to explicitly investigate the effects of Brownian motion and nanoparticle/nanopore characteristics on the amplitude and duration of translocation signals. Simulation results were verified with experimental RPS measurements and found to be in quantitative agreement.

Accounting for Surgical Confounding Factors Affecting Dual-Energy X-ray Absorptiometry in a Large Clinical Trial.

Joint replacements are among the most common orthopedic procedures performed in the U.S. and will continue to increase with the aging population. It is therefore necessary to account for these and other confounding factors, such as breast implants, when performing dual-energy X-ray absorptiometry (DXA) measurements. Whole-body DXA scans were performed in 771 participants (men ≥50 yr and women ≥55 yr) to assess bone mineral density (BMD) and body composition (fat and lean mass). In the DXA scan analyses of participants with internal metal, these affected regions of interest were replaced with measures from the unaffected, contralateral side, consistent with recommendations of the International Society for Clinical Densitometry. T-scores and Z-scores were recalculated using default sex and ethnicity-matched databases. We also explored effects of breast implants on bone density and body composition analyses. Approximately 13.1% of participants had internal metal artifacts at baseline. Replacing metal artifacts with the unaffected, contralateral side decreased the whole-body BMD by an average of 8.1% (SEM 0.84%; n = 67). In participants with unilateral hip (n = 17) and knee replacements (n = 20), BMD was decreased by an average of 14.1% (SEM 1.7%) and 11.2% (SEM 1.1%), respectively. Fat and lean mass were not significantly affected by metal artifacts, as differences between values with and without metal were within 1%. Two participants had bilateral breast implants, and in a separate trial, one participant had a unilateral breast implant. Bone mineral content (BMC) in the region with the breast implant was 5.8 times higher than the contralateral side, and whole-body BMC was increased by 4.7%. Metal artifacts and breast implants can confound DXA whole-body bone but not fat and lean results. It is therefore important in clinical studies to account for these factors to detect physiologically relevant differences in bone measures.

A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma.

Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure.

Composite estimation to combine spatially overlapping environmental monitoring surveys.

Long-term environmental monitoring surveys are designed to achieve a desired precision (measured by variance) of resource conditions based on natural variability information. Over time, increases in resource variability and in data use to address issues focused on small areas with limited sample sizes require bolstering of attainable precision. It is often prohibitive to do this by increasing sampling effort. In cases with spatially overlapping monitoring surveys, composite estimation offers a statistical way to obtain a precision-weighted combination of survey estimates to provide improved population estimates (more accurate) with improved precisions (lower variances). We present a composite estimator for overlapping surveys, a summary of compositing procedures, and a case study to illustrate the procedures and benefits of composite estimation. The study uses the two terrestrial monitoring surveys administered by the Bureau of Land Management (BLM) that entirely overlap. Using 2015-18 data and 13 land-health indicators, we obtained and compared survey and composite indicator estimates of percent area meeting land-health standards for sagebrush communities in Wyoming's Greater Sage-Grouse (Centrocercus urophasianus) Core and NonCore conservation areas on BLM-managed lands. We statistically assessed differences in indicator estimates between the conservation areas using composite estimates and estimates of the two surveys individually. We found composite variance to be about six to 24 units lower than 37% of the survey variances and composite estimates to differ by about six to 10 percentage points from six survey estimates. The composite improvements resulted in finding 11 indicators to statistically differ (p <0.05) between the conservation areas compared to only six and seven indicators for the individual surveys. Overall, we found composite estimation to be an efficient and useful option for improving environmental monitoring information where two surveys entirely overlap and suggest how this estimation method could be beneficial where environmental surveys partially overlap and in small area applications.

PROTOCOL: Effects of social prescribing for older adults: An evidence and gap map.

Objectives This is the protocol for an evidence and gap map. The objectives are as follows: The aim of this evidence and gap map is to map the available evidence on the effectiveness of social prescribing interventions addressing a non-medical, health-related social need for older adults in any setting. Specific objectives are as follows: 1.To identify existing evidence from primary studies and systematic reviews on the effects of community-based interventions that address non-medical, health-related social needs of older adults to improve their health and wellbeing.2.To identify research evidence gaps for new high-quality primary studies and systematic reviews.3.To highlight evidence of health equity considerations from included primary studies and systematic reviews.

Early Changes in Tumor-Naive Cell-Free Methylomes and Fragmentomes Predict Outcomes in Pembrolizumab-Treated Solid Tumors.

Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment-length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify cancer-specific methylation (CSM) and fragment-length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïve mutation-agnostic ctDNA approach integrating methylomics and fragmentomics could predict outcomes in patients treated with pembrolizumab. SIGNIFICANCE: Analysis of methylation and fragment length in plasma using cfMeDIP-seq provides a tumor-naive approach to measure ctDNA with results comparable with a tumor-informed bespoke ctDNA. Early kinetics within the first weeks of treatment in methylation and fragment quantity can predict outcomes with pembrolizumab in patients with various advanced solid tumors. This article is featured in Selected Articles from This Issue, p. 897.

Effect of (poly)phenol-rich 'Daux Belan' apple supplementation on diet-induced obesity and glucose intolerance in C57BL/6NCrl mice.

Obesity is a state of metabolic dysfunction that can lead to dyslipidemia and impaired glucose homeostasis. Apple polyphenols have been shown to ameliorate dyslipidemia/metabolic dysfunction in humans. The influence of apple (poly)phenols on energy metabolism in high-fat (HF) diet-induced obese mice remains controversial. This study examined the effect of dietary supplementation of (poly)phenol-rich 'Daux Belan' apple (DB; 6.2 mg gallic acid equivalence (GAE)/mouse/day; 0.15% (poly)phenol) in the form of freeze-dried powder on glucose and lipid metabolism in male HF-fed C57BL/6NCrl mice, in comparison to low-(poly)phenol-containing 'Zestar' apple (Z; 0.4 mg GAE/mouse/day). Obesity, glucose intolerance, hypertriglyceridemia, and hepatic lipid vacuolation were induced by HF feeding while circulating cholesterol levels remained unchanged. DB apple supplementation did not protect against HF-induced body weight gain, hyperglycemia, hepatic triglyceride level elevation, and hepatic lipid vacuolation at the tested dosage. Future studies should be conducted with increased DB dosage and employ apple (poly)phenols supplemented in the form of extracts or sugar-free powder.

Double Trouble: Whole-Genome Doubling Distinguishes Early from Late Ovarian Cancer.

Dramatic differences in outcome between early- and late-stage high-grade serous ovarian cancer (HGSC) suggest perhaps distinct genetic origins due to differences in exposures to mutational processes. Evidence to support this hypothesis was recently reported by comparative analysis of copy-number signatures between early- and late-stage HGSCs. See related article by Cheng et al., p. 2911.

Interleukin-10 repletion suppresses pro-inflammatory cytokines and decreases liver pathology without altering viral replication in murine cytomegalovirus (MCMV)-infected IL-10 knockout mice.

OBJECTIVE AND DESIGN: To determine the role of interleukin-10 (IL-10) in protecting against the deleterious pro-inflammatory cytokine response to murine cytomegalovirus (MCMV), we studied the impact of IL-10 repletion in MCMV-infected IL-10 knockout (KO) mice. MATERIALS AND METHODS: IL-10 KO mice were infected with a sub-lethal dose of MCMV and treated daily with 5 µg of mouse recombinant IL-10 (mrIL-10). Cytokine transcription, viral load, cytokine expression and liver histopathology were assessed in IL-10 treated and untreated mice. RESULTS: mrIL-10 repletion suppressed the exaggerated pro-inflammatory cytokine response observed in IL-10 KO mice (vs. control) both systemically and at the organ level, without affecting viral load. Levels of IFN-γ and TNF-α mRNA in livers of treated mice were ~50-70-fold lower than in untreated mice at day 5 post-infection (p ≤ 0.05). In spleens and sera, levels of IFN-γ and IL-6 were significantly lower in treated mice than in untreated mice at day 5-7 post-infection (p ≤ 0.05). IL-10 blunting of cytokine responses was accompanied by attenuation of inflammation in livers of treated mice. CONCLUSIONS: Repletion of IL-10 modulates the exaggerated pro-inflammatory cytokine responses that characterize IL-10 KO mice and protects against liver damage without altering viral load. IL-10 may be useful to control dysregulated pro-inflammatory cytokines responses during CMV infection.

Cannabidiol-based natural health products for companion animals: Recent advances in the management of anxiety, pain, and inflammation.

Recent advances in cannabidiol (CBD) use in canines and felines for anxiety management, pain management, and anti-inflammatory effects were reviewed using a literature search conducted with the following keywords: CBD, anxiety, inflammation, pain, dogs, cats, and companion animals. For decades, research on CBD has been hindered due to the status of cannabis (C. sativa L.) as an illicit drug. Limited safety data show that CBD is well-tolerated in dogs, with insufficient information on the safety profile of CBD in cats. Upon oral supplementation of CBD, elevation in liver enzymes was observed for both dogs and cats, and pharmacokinetics of CBD are different in the two species. There is a significant gap in the literature on the therapeutic use of CBD in cats, with no feline data on anxiety, pain, and inflammation management. There is evidence that chronic osteoarthritic pain in dogs can be reduced by supplementation with CBD. Furthermore, experiments are required to better understand whether CBD has an influence on noise-induced fear and anxiolytic response. Preliminary evidence exists to support the analgesic properties of CBD in treating chronic canine osteoarthritis; however, there are inter- and intra-species differences in pharmacokinetics, tolerance, dosage, and safety of CBD. Therefore, to validate the anxiety management, pain management, and anti-inflammatory efficacy of CBD, it is essential to conduct systematic, randomized, and controlled trials. Further, the safety and efficacious dose of CBD in companion animals warrants investigation.

Cost-effectiveness of olaparib versus routine surveillance in the maintenance setting for patients with BRCA-mutated advanced ovarian cancer after response to first-line platinum-based chemotherapy in Singapore.

OBJECTIVE: To evaluate the cost-effectiveness of olaparib as a maintenance treatment versus routine surveillance (RS) in patients with BRCA mutated (BRCAm) advanced ovarian cancer (OC) following response to first-line platinum-based chemotherapy in Singapore. METHODS: A 4-health state partitioned survival model was developed to simulate the lifetime (50 years) incremental cost-effectiveness ratio (ICER) of olaparib versus RS from a healthcare payer perspective. Progression-free survival, time to second disease progression, and overall survival were estimated using SOLO-1 data and extrapolated beyond the trial period using parametric survival models. Any patient who remained progression-free at year 7 was assumed to be no longer at risk of progression. Mortality rates were based on all-cause mortality, adjusted based on BRCA1/2 mutation. Health state utilities and adverse event frequencies were from SOLO-1. Drug costs were from local public healthcare institutions. Healthcare resource usage and costs were from local clinician input and publications. A 3% discount rate was applied to costs and outcomes. Deterministic and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of results. RESULTS: The base-case analysis of olaparib maintenance therapy versus RS resulted in an ICER of Singapore dollar (SGD) 19,822 per quality-adjusted life-year (QALY) gained. The ICER was most sensitive to variations in the discount rate. PSA demonstrated that olaparib had an 87% probability of being cost-effective versus RS at a willingness-to-pay of SGD 60,000 per QALY gained. CONCLUSION: Olaparib has a high potential of being a cost-effective maintenance treatment versus RS for patients with BRCA1/2m advanced OC after response to first-line chemotherapy in Singapore.

From Emergency Department Visit to Readmission After Esophagectomy: Analysis of Burden and Risk Factors.

BACKGROUND: Frequent emergency department (ED) visits occur after esophagectomy. We aimed to identify the incidence of and risk factors for conversion from ED visit to inpatient admission. METHODS: A retrospective cohort study was performed of consecutive esophagectomies at a tertiary Canadian center (1999 to 2014). Multivariable regression analyses identified factors associated with conversion from ED visit to admission. RESULTS: There were 520 esophagectomies with 6% inhospital mortality (n = 31). Of those discharged, 29.7% (n = 145) had one or more emergency visit and 43.4% (n = 63) of these patients were readmitted to the hospital. First-time ED visits resulted in inpatient conversion 23.4% of the time (n = 34); successive ED visits resulted in increasing conversion. On multivariable analysis, anastomotic leak (adjusted odds ratio 2.45; 95% confidence interval, 1 to 6.01; P = .05) was independently associated with higher odds of conversion to admission. Sensitivity analysis using Poisson regression to model conversion as a rate identified that living in regions further away was associated with lower conversion rate to admission (risk ratio 0.35; 95% confidence interval, 0.13 to 0.94; P = .04). CONCLUSIONS: Although postesophagectomy ED utilization is high, the majority of visits do not convert to admission. With each increasing ED visit, likelihood of converting to admission increases. Anastomotic leakage was associated with higher odds of conversion to admission, possibly related to development of strictures. Access to urgent outpatient endoscopy may help reduce the incidence of ED visits and admission. Although living in regions further away is associated with lower conversion rates to admission at the index hospital, that may be due to patients utilizing closer local hospitals.

Effects of Vitamin D3 Supplementation on Body Composition in the VITamin D and OmegA-3 TriaL (VITAL).

CONTEXT: Although observational studies show inverse associations between vitamin D status and body weight/adiposity, there are few large randomized controlled trials (RCTs) investigating this relationship. OBJECTIVE: To determine whether vitamin D3 supplementation lowers weight or improves body composition. DESIGN: The VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled RCT including 25 871 US adults. This ancillary study was completed in a sub-cohort that underwent body composition assessments at baseline and 2-year follow-up (89% retention). SETTING: Harvard Clinical and Translational Science Center in Boston. PARTICIPANTS: 771 participants (men ≥ 50 and women ≥ 55 years). INTERVENTIONS: 2 × 2 factorial design of supplemental vitamin D3 (2000 IU/day) and/or omega-3 fatty acids (1 g/day). MAIN OUTCOME MEASURES: Endpoints were 2-year changes in weight, body mass index (BMI), waist circumference, and total and/or regional fat and lean tissue measures determined by dual-energy X-ray absorptiometry. Effect modification by clinical variables and total and free 25-hydroxyvitamin D (25[OH]D) levels was explored. RESULTS: There were no effects of supplemental vitamin D3vs placebo on weight, BMI, or measures of adiposity and lean tissue. Effects did not vary by sex, race/ethnicity, fat mass index, or baseline total or free 25(OH)D levels. Vitamin D3 supplementation did slightly improve body fat percentage in participants with normal BMI at baseline, but not in the overweight or obese (P for interaction = 0.04). CONCLUSIONS: Daily vitamin D3 supplementation vs placebo in the general older population did not improve weight or body composition. Whether supplemental vitamin D3 may benefit individuals with normal BMI warrants further study.

Connexin40 imparts conduction heterogeneity to atrial tissue.

Impulse propagation in cardiac tissue is a complex process in which intercellular coupling through gap junction channels is a critical component. Connexin40 (Cx40) is an abundant gap junction protein that is expressed in atrial myocytes. Alterations in the expression of Cx40 have been implicated in atrial arrhythmogenesis. The purpose of the current study was to assess the role of Cx40 in atrial impulse propagation. High-resolution optical mapping was used to study conduction in the right and left atrial appendages of isolated Langendorff-perfused murine hearts. Wild-type (Cx40(+/+)), heterozygous (Cx40(+/-)), and knockout (Cx40(-/-)) mice, both adult and embryonic, were studied to assess the effects of reduced Cx40 expression on sinus node function and conduction velocity at different pacing cycle lengths (100 and 60 ms). In both adult and late-stage embryonic Cx40(+/+) mice, heterogeneity in CV was found between the right and left atrial appendages. Either partial (Cx40(+/-)) or complete (Cx40(-/-)) deletion of Cx40 was associated with the loss of conduction heterogeneity in both adult and embryonic mice. Additionally, sinus node impulse initiation was found to be ectopic in Cx40(-/-) mice at 15.5 days postcoitus, whereas Cx40(+/+) mice showed normal activation occurring near the crista terminalis. Our findings suggest that Cx40 plays an essential role in establishing interatrial conduction velocity heterogeneity in the murine model. Additionally, we describe for the first time a developmental requirement for Cx40 in normal sinus node impulse initiation at 15.5 days postcoitus.

Targeted Inhibition of the E3 Ligase SCFSkp2/Cks1 Has Antitumor Activity in RB1-Deficient Human and Mouse Small-Cell Lung Cancer.

The RB1 tumor suppressor gene is mutated in highly aggressive tumors including small-cell lung cancer (SCLC), where its loss, along with TP53, is required and sufficient for tumorigenesis. While RB1-mutant cells fail to arrest at G1-S in response to cell-cycle restriction point signals, this information has not led to effective strategies to treat RB1-deficient tumors, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/Trp53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, which was confirmed as the mechanism of protection by using knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind/inhibit Skp2 have in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using genetic and pharmacologic approaches, antitumor activity was seen with Skp2 loss or inhibition in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. Our data highlight a downstream actionable target in RB1-deficient cancers, for which there are currently no targeted therapies available. SIGNIFICANCE: There are no effective therapies for SCLC. The identification of an actionable target downstream of RB1, inactivated in SCLC and other advanced tumors, could have a broad impact on its treatment.

Postoperative but not intraoperative transfusions are associated with respiratory failure after pneumonectomy.

OBJECTIVES: Transfusion of blood products has been associated with increased risk of post-pneumonectomy respiratory failure. It is unclear whether intraoperative or postoperative transfusions confer a higher risk of respiratory failure. Our objective was to assess the role of transfusions in developing post-pneumonectomy respiratory failure. METHODS: We performed a retrospective cohort study using prospectively collected data on consecutive pneumonectomies between 2005 and 2015. Patient records were reviewed for intraoperative/postoperative exposures. Univariable and multivariable analyses were performed. RESULTS: Of the 251 pneumonectomies performed during the study period, 24 (9.6%) patients suffered respiratory failure. Ninety-day mortality was 5.6% (n = 14) and was more likely in patients with respiratory failure (7/24 vs 7/227, P < 0.001). Intraoperative and postoperative transfusions occurred in 42.2% (n = 106) and 44.6% (n = 112) of patients, respectively and were predominantly red blood cells. On univariable analysis, both intraoperative (P = 0.03) and postoperative transfusion (P = 0.004) were associated with a higher risk of respiratory failure. The multivariable model significantly predicted respiratory failure with an area under curve (AUC) = 0.88 (P = 0.001). On multivariable analysis, the only independent predictors of respiratory failure were postoperative transfusions [adjusted odds ratio (aOR) 6.54, 95% confidence interval (CI) 1.74-24.59; P = 0.005] and lower preoperative forced expiratory volume (adjusted OR 0.96, 95% CI 0.93-0.99; P = 0.03). Estimated blood loss was not significantly different (P = 0.91) between those with (median 800 ml, interquartile range 300-2000 ml) and without respiratory failure (median 800 ml, interquartile range 300-2000 ml). CONCLUSIONS: Respiratory failure occurred in 9.6% of patients post-pneumonectomy and confers a higher risk of 90-day mortality. Postoperative (but not intraoperative) transfusion was the strongest independent predictor associated with respiratory failure. Intraoperative transfusion may be in reaction to active/unpredictable blood loss and may not be easily modifiable. However, postoperative transfusion may be modifiable and potentially avoidable. Transfusion thresholds should be assessed in light of potential cost-benefit trade-offs.

Abeta42 is essential for parenchymal and vascular amyloid deposition in mice.

Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.

Abnormal conduction and morphology in the atrioventricular node of mice with atrioventricular canal targeted deletion of Alk3/Bmpr1a receptor.

BACKGROUND: The atrioventricular (AV) node is essential for the sequential excitation and optimized contraction of the adult multichambered heart; however, relatively little is known about its formation from the embryonic AV canal. A recent study demonstrated that signaling by Alk3, the type 1a receptor for bone morphogenetic proteins, in the myocardium of the AV canal was required for the development of both the AV valves and annulus fibrosus. To test the hypothesis that bone morphogenetic protein signaling also plays a role in AV node formation, we investigated conduction system function and AV node morphology in adult mice with conditional deletion of Alk3 in the AV canal. METHODS AND RESULTS: High-resolution optical mapping with correlative histological analysis of 28 mutant hearts revealed 4 basic phenotypic classes based on electrical activation patterns and volume-conducted ECGs. The frequency of AV node conduction and morphological abnormalities increased from no detectable anomalies (class I) to severe defects (class IV), which included the presence of bypass tracts, abnormal ventricular activation patterns, fibrosis of the AV node, and twin AV nodes. CONCLUSIONS: The present findings demonstrate that bone morphogenetic protein signaling is required in the myocardium of the AV canal for proper AV junction development, including the AV node.