Association of polygenic scores with chronic kidney disease phenotypes in a longitudinal study of older adults

Risk of chronic kidney disease (CKD) is influenced by environmental and genetic factors and increases sharply in individuals 70 years and older. Polygenic scores (PGS) for kidney disease-related traits have shown promise but require validation in well-characterized cohorts. Here, we assessed the performance of recently developed PGSs for CKD-related traits in a longitudinal cohort of healthy older individuals enrolled in the Australian ASPREE randomized controlled trial of daily low-dose aspirin with CKD risk at baseline and longitudinally. Among 11,813 genotyped participants aged 70 years or more with baseline eGFR measures, we tested associations between PGSs and measured eGFR at baseline, clinical phenotype of CKD, and longitudinal rate of eGFR decline spanning up to six years of follow-up per participant. A PGS for eGFR was associated with baseline eGFR, with a significant decrease of 3.9 mL/min/1.73m2 (95% confidence interval -4.17 to -3.68) per standard deviation (SD) increase of the PGS. This PGS, as well as a PGS for CKD stage 3 were both associated with higher risk of baseline CKD stage 3 in cross-sectional analysis (Odds Ratio 1.75 per SD, 95% confidence interval 1.66-1.85, and Odds Ratio 1.51 per SD, 95% confidence interval 1.43-1.59, respectively). Longitudinally, two separate PGSs for eGFR slope were associated with significant kidney function decline during follow-up. Thus, our study demonstrates that kidney function has a considerable genetic component in older adults, and that new PGSs for kidney disease-related phenotypes may have potential utility for CKD risk prediction in advanced age

Comparison of the Relationship between Lying and Standing Ultrasonography Measures of Muscle Morphology with Isometric and Dynamic Force Production Capabilities

The purpose of the current study was (1) to examine the differences between standing and lying measures of vastus lateralis (VL), muscle thickness (MT), pennation angle (PA), and cross-sectional area (CSA) using ultrasonography; and (2) to explore the relationships between lying and standing measures with isometric and dynamic assessments of force production—specifically peak force, rate of force development (RFD), impulse, and one-repetition maximum back squat. Fourteen resistance-trained subjects (age = 26.8 ± 4.0 years, height = 181.4 ± 6.0 cm, body mass = 89.8 ± 10.7 kg, back squat to body mass ratio = 1.84 ± 0.34) agreed to participate. Lying and standing ultrasonography images of the right VL were collected following 48 hours of rest. Isometric squat assessments followed ultrasonography, and were performed on force platforms with data used to determine isometric peak force (IPF), as well as RFD and impulse at various time points. Forty-eight hours later, one-repetition maximum back squats were performed by each subject. Paired-samples t-tests revealed statistically significant differences between standing and lying measurements of MT (p \u3c 0.001), PA (p \u3c 0.001), and CSA (p ≤ 0.05), with standing values larger in all cases. Further, standing measures were correlated more strongly and abundantly to isometric and dynamic performance. These results suggest that if practitioners intend to gain insight into strength-power potential based on ultrasonography measurements, performing the measurement collection with the athlete in a standing posture may be preferred

Repetition-to-Repetition Differences Using Cluster and Accentuated Eccentric Loading in the Back Squat

The current investigation was an examination of the repetition-to-repetition magnitudes and changes in kinetic and kinematic characteristics of the back squat using accentuated eccentric loading (AEL) and cluster sets. Trained male subjects (age = 26.1 ± 4.1 years, height = 183.5 ± 4.3 cm, body mass = 92.5 ± 10.5 kg, back squat to body mass ratio = 1.8 ± 0.3) completed four load condition sessions, each consisting of three sets of five repetitions of either traditionally loaded straight sets (TL), traditionally loaded cluster sets (TLC), AEL cluster sets (AEC), and AEL straight sets where only the initial repetition had eccentric overload (AEL1). Eccentric overload was applied using weight releasers, creating a total eccentric load equivalent to 105% of concentric one repetition maximum (1RM). Concentric load was 80% 1RM for all load conditions. Using straight sets (TL and AEL1) tended to decrease peak power (PP) (d = −1.90 to −0.76), concentric rate of force development (RFDCON) (d = −1.59 to −0.27), and average velocity (MV) (d = −3.91 to −1.29), with moderate decreases in MV using cluster sets (d = −0.81 to −0.62). Greater magnitude eccentric rate of force development (RFDECC) was observed using AEC at repetition three (R3) and five (R5) compared to all load conditions (d = 0.21⁻0.65). Large within-condition changes in RFDECC from repetition one to repetition three (∆REP1⁻3) were present using AEL1 (d = 1.51), demonstrating that RFDECC remained elevated for at least three repetitions despite overload only present on the initial repetition. Overall, cluster sets appear to permit higher magnitude and improved maintenance of concentric outputs throughout a set. Eccentric overload with the loading protocol used in the current study does not appear to potentiate concentric output regardless of set configuration but may cause greater RFDECC compared to traditional loading

Comparison of the Relationship between Lying and Standing Ultrasonography Measures of Muscle Morphology with Isometric and Dynamic Force Production Capabilities

The purpose of the current study was (1) to examine the differences between standing and lying measures of vastus lateralis (VL), muscle thickness (MT), pennation angle (PA), and cross-sectional area (CSA) using ultrasonography; and (2) to explore the relationships between lying and standing measures with isometric and dynamic assessments of force production—specifically peak force, rate of force development (RFD), impulse, and one-repetition maximum back squat. Fourteen resistance-trained subjects (age = 26.8 ± 4.0 years, height = 181.4 ± 6.0 cm, body mass = 89.8 ± 10.7 kg, back squat to body mass ratio = 1.84 ± 0.34) agreed to participate. Lying and standing ultrasonography images of the right VL were collected following 48 hours of rest. Isometric squat assessments followed ultrasonography, and were performed on force platforms with data used to determine isometric peak force (IPF), as well as RFD and impulse at various time points. Forty-eight hours later, one-repetition maximum back squats were performed by each subject. Paired-samples t-tests revealed statistically significant differences between standing and lying measurements of MT (p \u3c 0.001), PA (p \u3c 0.001), and CSA (p ≤ 0.05), with standing values larger in all cases. Further, standing measures were correlated more strongly and abundantly to isometric and dynamic performance. These results suggest that if practitioners intend to gain insight into strength-power potential based on ultrasonography measurements, performing the measurement collection with the athlete in a standing posture may be preferred

Repetition-to-Repetition Differences Using Cluster and Accentuated Eccentric Loading in the Back Squat

The current investigation was an examination of the repetition-to-repetition magnitudes and changes in kinetic and kinematic characteristics of the back squat using accentuated eccentric loading (AEL) and cluster sets. Trained male subjects (age = 26.1 ± 4.1 years, height = 183.5 ± 4.3 cm, body mass = 92.5 ± 10.5 kg, back squat to body mass ratio = 1.8 ± 0.3) completed four load condition sessions, each consisting of three sets of five repetitions of either traditionally loaded straight sets (TL), traditionally loaded cluster sets (TLC), AEL cluster sets (AEC), and AEL straight sets where only the initial repetition had eccentric overload (AEL1). Eccentric overload was applied using weight releasers, creating a total eccentric load equivalent to 105% of concentric one repetition maximum (1RM). Concentric load was 80% 1RM for all load conditions. Using straight sets (TL and AEL1) tended to decrease peak power (PP) (d = −1.90 to −0.76), concentric rate of force development (RFDCON) (d = −1.59 to −0.27), and average velocity (MV) (d = −3.91 to −1.29), with moderate decreases in MV using cluster sets (d= −0.81 to −0.62). Greater magnitude eccentric rate of force development (RFDECC) was observed using AEC at repetition three (R3) and five (R5) compared to all load conditions (d = 0.21–0.65). Large within-condition changes in RFDECC from repetition one to repetition three (∆REP1–3) were present using AEL1 (d = 1.51), demonstrating that RFDECC remained elevated for at least three repetitions despite overload only present on the initial repetition. Overall, cluster sets appear to permit higher magnitude and improved maintenance of concentric outputs throughout a set. Eccentric overload with the loading protocol used in the current study does not appear to potentiate concentric output regardless of set configuration but may cause greater RFDECCcompared to traditional loadin

Association of 25-hydroxyvitamin D deficiency with NT-pro BNP levels in patients with acute myocardial infarction: a cross-sectional analysis

<p>Abstract</p> <p>Background</p> <p>Nutritional vitamin D deficiency is an emerging risk factor for acute myocardial infarction (AMI) and heart failure. The association of 25-hydroxyvitamin D levels with N-terminal pro B-type natriuretic peptide (NT-proBNP), a robust prognostic marker for post-AMI mortality and heart failure, is unknown and could illuminate a potential pathway for adverse outcomes among post-AMI patients with 25-hydroxyvitamin D deficiency.</p> <p>Methods</p> <p>In a cross-sectional analysis, we studied 238 AMI patients from 21 U.S. centers to test the association of nutritional vitamin D (25-hydroxyvitamin D [25(OH)D]) deficiency with NT-proBNP levels. Levels of 25(OH)D levels were categorized as normal (≥30 ng/mL), insufficient (>20 - <30 ng/mL), deficient (>10 - ≤20 ng/mL), or severely deficient (≤10 ng/mL).</p> <p>Results</p> <p>Low 25(OH)D levels were found in 95.7% of AMI patients. No significant trends for higher mean baseline log NT-proBNP levels in severely deficient (6.9 ± 1.3 pg/mL), deficient (6.9 ± 1.2 pg/mL), and insufficient (6.9 ± 0.9 pg/ml) groups were observed as compared with patients having normal (6.1 ± 1.7 pg/mL) levels, <it>P </it>= 0.17. Findings were similar in the subset of patients who had follow-up NT-proBNP levels drawn at one month. In multivariate regression modeling, after adjusting for multiple covariates, 25(OH)D was not associated with NT-proBNP.</p> <p>Conclusions</p> <p>Potential associations between nutritional vitamin D deficiency and prognosis in the setting of AMI are unlikely to be mediated through NT-proBNP pathways. Future studies should examine other mechanisms, such as inflammation and vascular calcification, by which 25(OH)D deficiency could mediate adverse outcomes post-AMI.</p

Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D

Medulloblastoma is the most common malignant brain tumor of childhood. Despite numerous advances, clinical challenges range from recurrent and progressive disease to long-term toxicities in survivors. The lack of more effective, less toxic therapies results from our limited understanding of medulloblastoma growth. Although TP53 is the most commonly altered gene in cancers, it is rarely mutated in medulloblastoma. Accumulating evidence, however, indicates that TP53 pathways are disrupted in medulloblastoma. Wild-typep53-induced phosphatase 1 (WIP1 or PPM1D) encodes a negative regulator of p53. WIP1 amplification (17q22-q23) and its overexpression have been reported in diverse cancer types. We examined primary medulloblastoma specimens and cell lines, and detected WIP1 copy gain and amplification prevalent among but not exclusively in the tumors with 17q gain and isochromosome 17q (i17q), which are among the most common cytogenetic lesions in medulloblastoma. WIP1 RNA levels were significantly higher in the tumors with 17q gain or i17q. Immunoblots confirmed significant WIP1 protein in primary tumors, generally higher in those with 17q gain or i17q. Under basal growth conditions and in response to the chemotherapeutic agent, etoposide, WIP1 antagonized p53-mediated apoptosis in medulloblastoma cell lines. These results indicate that medulloblastoma express significant levels of WIP1 that modulate genotoxic responsiveness by negatively regulating p53

Overexpressed TP73 induces apoptosis in medulloblastoma

Abstract Background Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated ΔNp73 to assess their effects on growth. Methods We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of TP73 RNA including the full-length transcript and the 5'-terminal variants that encode the ΔNp73 isoform, as well as TP53 RNA using quantitative real time-RTPCR. Protein expression of TAp73 and ΔNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on TP73 RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and ΔNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods. Results Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant TP73 RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated ΔNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or ΔNp73 induced apoptosis under basal growth conditions in vitro and sensitized them to cell death in response to chemotherapeutic agents. Conclusion These results indicate that primary medulloblastomas express significant levels of TP73 isoforms, and suggest that they can modulate the survival and genotoxic responsiveness of medulloblastomas cells

Blood Parasites in Owls with Conservation Implications for the Spotted Owl (Strix occidentalis)

The three subspecies of Spotted Owl (Northern, Strix occidentalis caurina; California, S. o. occidentalis; and Mexican, S. o. lucida) are all threatened by habitat loss and range expansion of the Barred Owl (S. varia). An unaddressed threat is whether Barred Owls could be a source of novel strains of disease such as avian malaria (Plasmodium spp.) or other blood parasites potentially harmful for Spotted Owls. Although Barred Owls commonly harbor Plasmodium infections, these parasites have not been documented in the Spotted Owl. We screened 111 Spotted Owls, 44 Barred Owls, and 387 owls of nine other species for haemosporidian parasites (Leucocytozoon, Plasmodium, and Haemoproteus spp.). California Spotted Owls had the greatest number of simultaneous multi-species infections (44%). Additionally, sequencing results revealed that the Northern and California Spotted Owl subspecies together had the highest number of Leucocytozoon parasite lineages (n = 17) and unique lineages (n = 12). This high level of sequence diversity is significant because only one Leucocytozoon species (L. danilewskyi) has been accepted as valid among all owls, suggesting that L. danilewskyi is a cryptic species. Furthermore, a Plasmodium parasite was documented in a Northern Spotted Owl for the first time. West Coast Barred Owls had a lower prevalence of infection (15%) when compared to sympatric Spotted Owls (S. o. caurina 52%, S. o. occidentalis 79%) and Barred Owls from the historic range (61%). Consequently, Barred Owls on the West Coast may have a competitive advantage over the potentially immune compromised Spotted Owls