IL-21 receptor expression in human tendinopathy

The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward and early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly up regulated by proinflammatory cytokines (TNFα/IL-1β) in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy

Is elevated creatinine level a contraindication to endovascular aneurysm repair?

AbstractPurposeIt is widely believed that chronic renal insufficiency (CRI) greatly increases the risk associated with endovascular abdominal aortic aneurysm repair (EVAR) and is a relative contraindication to the procedure and to the use of intra-arterial contrast agents (IACA). We reviewed a 5-year EVAR experience to determine whether the procedure and use of IACA have an important deleterious effect on renal function in patients with and without pre-existing CRI.MethodsEndovascular aneurysm repair (EVAR) was performed in 200 patients with a variety of endografts, with intra-arterial contrast agents. The patients were retrospectively assigned to three groups on the basis of preoperative serum creatinine concentration (Cr): group 1 (n = 108), Cr less than 1.5 mg/dL (normal range); group 2 (n = 65), Cr 1.5 to 2.0 mg/dL; group 3 (n = 27), Cr 2.1 to 3.5 mg/dL. No patients had undergone hemodialysis. In groups 2 and 3, patients received hydration perioperatively, and received mannitol intraoperatively; no nephrotoxic drugs were administered during the procedure, other than nonionic contrast agent (Omnipaque 350).ResultsThe incidence of postoperative complications between the three study groups was not statistically different. In group 1 a transient increase in serum Cr (>30% over baseline and >1.4 mg/dL) was noted in three patients (2.7%), two of whom (1.9%) required temporary hemodialysis and one (0.9%) who died of renal failure. In group 2 a transient increase in serum Cr was noted in two patients (3.1%); both patients (3.1%) required temporary hemodialysis, and one patient (1.5%) died of renal failure. In group 3 a transient increase in serum Cr was noted in two patients (7.4%); one patient (3.7%) required temporary hemodialysis, and one patient (3.7%) died of renal failure. Perioperative hypotension significantly increased the risk for elevated serum Cr and death (P < .05), and larger contrast volume was associated with an increase in serum Cr (P < .05) during the postoperative period.ConclusionsEVAR with intra-arterial contrast agents can be accomplished in patients with chronic renal insufficiency who do not require dialysis, with limited and acceptable morbidity and mortality, similar to that observed with open aneurysm repair. Contrary to other reports in which perioperative precautions were not used, our study shows that with EVAR the risk for worsening renal failure, dialysis, and death is only slightly, and not significantly, greater in patients with preoperative chronic renal insufficiency compared with patients with normal renal function. Perioperative hypotension and increased contrast volume are significant risk factors for postoperative increase in serum Cr and death. With appropriate precautions such as averting perioperative hypotension and limiting the volume of nonionic contrast agents, elevated Cr need not be a contraindication to EVAR with intra-arterial contrast agents

Holocene sediment distribution on the inner continental shelf of northeastern South Carolina : implications for the regional sediment budget and long-term shoreline response

This paper is not subject to U.S. copyright. The definitive version was published in Continental Shelf Research 56 (2013): 56-70, doi:10.1016/j.csr.2013.02.004.High-resolution geophysical and sediment sampling surveys were conducted offshore of the Grand Strand, South Carolina to define the shallow geologic framework of the inner shelf. Results are used to identify and map Holocene sediment deposits, infer sediment transport pathways, and discuss implications for the regional coastal sediment budget. The thickest deposits of Holocene sediment observed on the inner shelf form shoal complexes composed of moderately sorted fine sand, which are primarily located offshore of modern tidal inlets. These shoal deposits contain ∼67 M m3 of sediment, approximately 96% of Holocene sediment stored on the inner shelf. Due to the lack of any significant modern fluvial input of sand to the region, the Holocene deposits are likely derived from reworking of relict Pleistocene and older inner-shelf deposits during the Holocene marine transgression. The Holocene sediments are concentrated in the southern part of the study area, due to a combination of ancestral drainage patterns, a regional shift in sediment supply from the northeast to the southwest in the late Pleistocene, and proximity to modern inlet systems. Where sediment is limited, only small, low relief ridges have formed and Pleistocene and older deposits are exposed on the seafloor. The low-relief ridges are likely the result of a thin, mobile veneer of sediment being transported across an irregular, erosional surface formed during the last transgression. Sediment textural trends and seafloor morphology indicate a long-term net transport of sediment to the southwest. This is supported by oceanographic studies that suggest the long-term sediment transport direction is controlled by the frequency and intensity of storms that pass through the region, where low pressure systems yield net along-shore flow to the southwest and a weak onshore component. Current sediment budget estimates for the Grand Strand yield a deficit for the region. Volume calculations of Holocene deposits on the inner shelf suggest that there is sufficient sediment to balance the sediment budget and provide a source of sediment to the shoreline. Although the processes controlling cross-shelf sediment transport are not fully understood, in sediment-limited environments such as the Grand Strand, erosion of the inner shelf likely contributes significant sediment to the beach system

S100A8 & S100A9: alarmin mediated inflammation in tendinopathy

Alarmins S100A8 and S100A9 are endogenous molecules released in response to environmental triggers and cellular damage. They are constitutively expressed in immune cells such as monocytes and neutrophils and their expression is upregulated under inflammatory conditions. The molecular mechanisms that regulate inflammatory pathways in tendinopathy are largely unknown therefore identifying early immune effectors is essential to understanding the pathology. Based on our previous investigations highlighting tendinopathy as an alarmin mediated pathology we sought evidence of S100A8 &amp; A9 expression in a human model of tendinopathy and thereafter, to explore mechanisms whereby S100 proteins may regulate release of inflammatory mediators and matrix synthesis in human tenocytes. Immunohistochemistry and quantitative RT-PCR showed S100A8 &amp; A9 expression was significantly upregulated in tendinopathic tissue compared with control. Furthermore, treating primary human tenocytes with exogenous S100A8 &amp; A9 significantly increased protein release of IL-6, IL-8, CCL2, CCL20 and CXCL10; however, no alterations in genes associated with matrix remodelling were observed at a transcript level. We propose S100A8 &amp; A9 participate in early pathology by modulating the stromal microenvironment and influencing the inflammatory profile observed in tendinopathy. S100A8 and S100A9 may participate in a positive feedback mechanism involving enhanced leukocyte recruitment and release of pro-inflammatory cytokines from tenocytes that perpetuates the inflammatory response within the tendon in the early stages of disease

Calibrative approaches to protein solubility modeling of a mutant series using physicochemical descriptors

A set of physicochemical properties describing a protein of known structure is employed for a calibrative approach to protein solubility. Common hydrodynamic and electrophoretic properties routinely measured in the bio-analytical laboratory such as zeta potential, dipole moment, the second osmotic virial coefficient are first estimated in silico as a function a pH and solution ionic strength starting with the protein crystal structure. The utility of these descriptors in understanding the solubility of a series of ribonuclease Sa mutants is investigated. A simple two parameter model was trained using solubility data of the wild type protein measured at a restricted number of solution pHs. Solubility estimates of the mutants demonstrate that zeta potential and dipole moment may be used to rationalize solubility trends over a wide pH range. Additionally a calibrative model based on the protein’s second osmotic virial coefficient, B22 was developed. A modified DVLO type potential along with a simplified representation of the protein allowed for efficient computation of the second viral coefficient. The standard error of prediction for both models was on the order of 0.3 log S units. These results are very encouraging and demonstrate that these models may be trained with a small number of samples and employed extrapolatively for estimating mutant solubilities

Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer:a nested case-control study

Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer

Malaria in HIV-Infected Children Receiving HIV Protease-Inhibitor- Compared with Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy, IMPAACT P1068s, Substudy to P1060

HIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort.

BACKGROUND: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. METHODS: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. RESULTS: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade. CONCLUSIONS: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.This work was supported by the World Cancer Research Fund (2011/419) and Cancer Research UK (C18281/A19169). The Integrative Epidemiology Unit (IEU) is supported by the MRC and the University of Bristol (G0600705, MC_UU_12013/19), and the Integrative Cancer Epidemiology Programme is supported by Cancer Research UK programme grant C18281/A19169. The National Institute for Health Research (NIHR) Bristol Nutrition Biomedical Research Unit is funded by the NIHR and is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The ProtecT study is supported by the UK NIHR Health Technology Assessment (HTA) Programme (HTA 96/20/99; ISRCTN20141297). Funding for PRACTICAL and the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/ A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 – the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. We acknowledge support from the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s12916-016-0602-