Citations

Abstract Background. We recently published and validated the new serum creatinine (Scr)-based full-age-spectrum equation (FAScrea) for estimating the glomerular filtration rate (GFR) for healthy and kidney–diseased subjects of all ages. The equation was based on the concept of normalized Scr and shows equivalent to superior prediction performance to the currently recommended equations for children, adolescents, adults and older adults. Methods. Based on an evaluation of the serum cystatin C (ScysC) distribution, we defined normalization constants for ScysC (QcysC = 0.82 mg/L for ages <70 years and QcysC = 0.95 mg/L for ages ≥70 years). By replacing Scr/Qcrea in the FAScrea equation with ScysC/QcysC, or with the average of both normalized biomarkers, we obtained new ScysC-based (FAScysC) and combined Scr-/ScysC-based FAS equations (FAScombi). To validate the new FAScysC and FAScombi we collected data on measured GFR, Scr, ScysC, age, gender, height and weight from 11 different cohorts including n = 6132 unique white subjects (368 children, aged ≤18 years, 4295 adults and 1469 older adults, aged ≥70 years). Results. In children and adolescents, the new FAScysC equation showed significantly better performance [percentage of patients within 30% of mGFR (P30) = 86.1%] than the Caucasian Asian Paediatric Adult Cohort equation (P30 = 76.6%; P < 0.0001), or the ScysC-based Schwartz equation (P30 = 68.8%; P < 0.0001) and the FAScombi equation outperformed all equations with P30 = 92.1% (P < 0.0001). In adults, the FAScysC equation (P30 = 82.6%) performed equally as well as the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPIcysC) (P30 = 80.4%) and the FAScombi equation (P30 = 89.9%) was also equal to the combined CKD-EPI equation (P30 = 88.2%). In older adults, FAScysC was superior (P30 = 88.2%) to CKD-EPIcysC (P30 = 84.4%; P < 0.0001) and the FAScombi equation (P30 = 91.2%) showed significantly higher performance than the combined CKD-EPI equation (P30 = 85.6%) (P < 0.0001). Conclusion. The FAS equation is not only applicable to all ages, but also for all recommended renal biomarkers and their combinations.

AbstractBACKGROUNDB-type natriuretic peptides (BNPs) are used clinically to diagnose and monitor heart failure and are present in the circulation as multiple proBNP-derived fragments. We investigated the specificity of BNP immunoassays with glycosylated and nonglycosylated BNP, N-terminal proBNP (NT-proBNP), and proBNP peptides to probe the cross-reactivity of each assay.METHODSNine B-type natriuretic peptides were studied,including synthetic and recombinant BNP (Shionogi, Scios, Mayo), human and synthetic glycosylated and nonglycosylated NT-proBNP (HyTest, Roche Diagnostics), and human glycosylated and nonglycosylated proBNP (HyTest, Scios). Five BNP [Abbott, Abbott POC, Alere, Beckman Coulter, Siemens (Centaur)], 9 NT-proBNP [Ortho-Clinical Diagnostics, Roche, Response, bioMerieux, Siemens (Dimension, Immulite, Stratus CS), Mitsubishi] and 3 research-use-only proBNP immunoassays [Biosite (Alere), Bio-Rad, Goetze] were evaluated. Specificity was assessed by calculating the recovery between baseline and peptide-spiked human plasma pools at target concentrations of 100 ng/L BNP, 300 ng/L proBNP, or 450 ng/L NT-proBNP. All assays were performed in duplicate.RESULTSBNP and NT-proBNP assays demonstrated substantial cross-reactivity with proBNP peptides. NT-proBNP assays do not detect glycosylated forms of either NT-proBNP or proBNP. proBNP assays preferentially detect the BNP 1–32 peptide and have minimal cross-reactivity with BNP peptides and glycosylated proBNP.CONCLUSIONSBNP or NT-proBNP results are not transferable among the current existing immunoassays owing to their differences in cross-reactivity and ability to detect various glycosylated forms of proBNP-derived fragments. Opportunities remain to standardize and harmonize BNP and NT-proBNP assays, as well as to develop specific proBNP assays, to widen their clinical scope of use.

AbstractHeart failure (HF) patients appear to exhibit impaired thermoregulatory capacity during passive heating, as evidenced by diminished vascular conductance. Although some preliminary studies have described the thermoregulatory response to passive heating inHF, responses during exercise in the heat remain to be described. Therefore, the aim of this study was to compare thermoregulatory responses inHFand controls (CON) during exercise in the heat. TenHF(NYHAclasses I–II) and eightCONwere included. Core temperature (Tc), skin temperature (Tsk), and cutaneous vascular conductance (CVC) were assessed at rest and during 1 h of exercise at 60% of maximal oxygen uptake. Metabolic heat production (Hprod) and the evaporative requirements for heat balance (Ereq) were also calculated. Whole‐body sweat rate was determined from pre–post nude body mass corrected for fluid intake. WhileHprod(HF: 3.9 ± 0.9;CON: 6.4 ± 1.5 W/kg) andEreq(HF: 3.3 ± 0.9;CON: 5.6 ± 1.4 W/kg) were lower (P < 0.01) forHFcompared toCON, both groups demonstrated a similar rise inTc(HF: 0.9 ± 0.4;CON: 1.0 ± 0.3°C). Despite this similar rise inTc,Tsk(HF: 1.6 ± 0.7;CON: 2.7 ± 1.2°C), and the elevation inCVC(HF: 1.4 ± 1.0;CON: 3.0 ± 1.2 au/mmHg) was lower (P < 0.05) inHFcompared toCON. Additionally, whole‐body sweat rate (HF: 0.36 ± 0.15;CON: 0.81 ± 0.39 L/h) was lower (P = 0.02) inHFcompared toCON. Patients withHFappear to be limited in their ability to manage a thermal load and distribute heat content to the body surface (i.e., skin), secondary to impaired circulation to the periphery.

ABSTRACTBackgroundThe objectives of this study were to elucidate any potential association between α‐synuclein pathology and cognitive impairment and to determine the profile of cognitive impairment in multiple system atrophy (MSA) patients. To do this, we analyzed the clinical and pathologic features in autopsy‐confirmed MSA patients.MethodsWe retrospectively reviewed medical records, including neuropsychological test data, in 102 patients with autopsy‐confirmed MSA in the Mayo Clinic brain bank. The burden of glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were semiquantitatively scored in the limbic regions and middle frontal gyrus. We also assessed concurrent pathologies potentially causing dementia including Alzheimer's disease, hippocampal sclerosis, and cerebrovascular pathology.ResultsOf 102 patients, 33 (32%) were documented to have cognitive impairment. Those that received objective testing, deficits primarily in processing speed and attention/executive functions were identified, which suggests a frontal‐subcortical pattern of dysfunction. Of these 33 patients with cognitive impairment, 8 patients had concurrent pathologies of dementia. MSA patients with cognitive impairment had a greater burden of neuronal cytoplasmic inclusions in the dentate gyrus than patients without cognitive impairment, both including and excluding patients with concurrent pathologies of dementia.ConclusionsThe cognitive deficits observed in this study were more evident on neuropsychological assessment than with cognitive screens. Based on these findings, we recommend that clinicians consider more in‐depth neuropsychological assessments if patients with MSA present with cognitive complaints. Although we did not identify the correlation between cognitive deficits and responsible neuroanatomical regions, a greater burden of neuronal cytoplasmic inclusions in the limbic regions was associated with cognitive impairment in MSA. © 2016 International Parkinson and Movement Disorder Society

BACKGROUND Individuals from disadvantaged communities are among the millions of uninsured Americans gaining insurance under the Affordable Care Act. The extent to which health insurance can mitigate the effects of the social determinants of health on cancer care is unknown. METHODS This study linked the Surveillance, Epidemiology, and End Results registries to US Census data to study patients diagnosed with the 4 leading causes of cancer deaths between 2007 and 2011. A county‐level social determinant score was developed with 5 measures of wealth, education, and employment. Patients were stratified into quintiles, with the lowest quintile representing the most disadvantaged communities. Logistic regression and Cox proportional hazards models were used to estimate associations and cancer‐specific survival. RESULTS A total of 364,507 patients aged 18 to 64 years were identified (134,105 with breast cancer, 106,914 with prostate cancer, 62,606 with lung cancer, and 60,882 with colorectal cancer). Overall, patients from the most disadvantaged communities (median household income, $42,885; patients below the poverty level, 22%; patients completing college, 17%) were more likely to present with distant disease (odds ratio, 1.6; P < .001) and were less likely to receive cancer‐directed surgery (odds ratio, 0.8; P < .001) than the least disadvantaged communities (median income, $78,249; patients below the poverty level, 9%; patients completing college, 42%). The differences persisted across quintiles regardless of the insurance status. The effect of having insurance on cancer‐specific survival was more pronounced in disadvantaged communities (relative benefit at 3 years, 40% vs 31%). However, it did not fully mitigate the effect of social determinants on mortality (hazard ratio, 0.75 vs 0.68; P < .001). CONCLUSIONS Cancer patients from disadvantaged communities benefit most from health insurance, and there is a reduction in disparities in outcome. However, the gap produced by social determinants of health cannot be bridged by insurance alone. Cancer 2017;123:1219–1227. © 2016 American Cancer Society .

Objective Oncolytic viruses (OVs) represent promising, proinflammatory cancer treatments. Here, we explored whether OV-induced innate immune responses could simultaneously inhibit HCV while suppressing hepatocellular carcinoma (HCC). Furthermore, we extended this exemplar to other models of virus-associated cancer. Design and results Clinical grade oncolytic orthoreovirus (Reo) elicited innate immune activation within primary human liver tissue in the absence of cytotoxicity and independently of viral genome replication. As well as achieving therapy in preclinical models of HCC through the activation of innate degranulating immune cells, Reo-induced cytokine responses efficiently suppressed HCV replication both in vitro and in vivo. Furthermore, Reo-induced innate responses were also effective against models of HBV-associated HCC, as well as an alternative endogenous model of Epstein–Barr virus-associated lymphoma. Interestingly, Reo appeared superior to the majority of OVs in its ability to elicit innate inflammatory responses from primary liver tissue. Conclusions We propose that Reo and other select proinflammatory OV may be used in the treatment of multiple cancers associated with oncogenic virus infections, simultaneously reducing both virus-associated oncogenic drive and tumour burden. In the case of HCV-associated HCC (HCV-HCC), Reo should be considered as an alternative agent to supplement and support current HCV-HCC therapies, particularly in those countries where access to new HCV antiviral treatments may be limited.

Abstract BACKGROUND Neprilysin (NEP) is a membrane-bound neutral endopeptidase that degrades a variety of bioactive peptides. The substrates include natriuretic peptides (NPs), which are important regulating mediators for cardiovascular and renal biology. Inhibition of NEP activity and exogenous NP administration thus have emerged as potential therapeutic strategies for treating cardiorenal diseases. More recently, B-type natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP), 3′-5′ cyclic guanosine monophosphate (cGMP), and soluble NEP as biomarkers have also been investigated in heart failure (HF) trials and their predictive value are beginning to be recognized. CONTENT The biological functions of NEP and NPs are discussed. Enhancing NPs through NEP inhibition combined with renin–angiotensin–aldosterone system (RAAS) antagonism has proved to be successful in HF treatment, although future surveillance studies will be required. Direct NP enhancement through peptide delivery may have fewer potentially hazardous effects compared to NEP inhibition. Strategies of combined inhibition on NEP with other cardiorenal pathophysiological pathways are promising. Finally, monitoring BNP/NT-proBNP/cGMP concentrations during NEP inhibition treatment may provide supplemental benefits to conventional biomarkers, and the identification of soluble NEP as a novel biomarker for HF needs further investigation. SUMMARY In this review, the biology of NEP is summarized, with a focus on NP regulation. The degradation of NPs by NEP provides the rationale for NEP inhibition as a strategy for cardiorenal disease treatment. We also describe the current therapeutic strategies of NEP inhibition and NP therapeutics in cardiorenal diseases. Moreover, the discovery of its circulating form, soluble NEP, as a biomarker is also discussed.

Abstract Neurological disorders are one of the most important public health concerns in developed countries. Established brain imaging techniques such as magnetic resonance imaging (MRI) and x-ray computerised tomography (CT) have been essential in the identification and diagnosis of a wide range of disorders, although usually are insufficient in sensitivity for detecting subtle pathological alterations to the brain prior to the onset of clinical symptoms—at a time when prognosis for treatment is more favourable. The mechanical properties of biological tissue provide information related to the strength and integrity of the cellular microstructure. In recent years, mechanical properties of the brain have been visualised and measured non-invasively with magnetic resonance elastography (MRE), a particularly sensitive medical imaging technique that may increase the potential for early diagnosis. This review begins with an introduction to the various methods used for the acquisition and analysis of MRE data. A systematic literature search is then conducted to identify studies that have specifically utilised MRE to investigate the human brain. Through the conversion of MRE-derived measurements to shear stiffness (kPa) and, where possible, the loss tangent (rad), a summary of results for global brain tissue and grey and white matter across studies is provided for healthy participants, as potential baseline values to be used in future clinical investigations. In addition, the extent to which MRE has revealed significant alterations to the brain in patients with neurological disorders is assessed and discussed in terms of known pathophysiology. The review concludes by predicting the trends for future MRE research and applications in neuroscience.