Urinary FABP1 is a biomarker for impaired proximal tubular protein reabsorption and is synergistically enhanced by concurrent liver injury.

Urinary fatty acid binding protein 1 (FABP1, also known as liver-type FABP) has been implicated as a biomarker of acute kidney injury (AKI) in humans. However, the precise biological mechanisms underlying its elevation remain elusive. Here, we show that urinary FABP1 primarily reflects impaired protein reabsorption in proximal tubule epithelial cells (PTECs). Bilateral nephrectomy resulted in a marked increase in serum FABP1 levels, suggesting that the kidney is an essential organ for removing serum FABP1. Injected recombinant FABP1 was filtered through the glomeruli and robustly reabsorbed via the apical membrane of PTECs. Urinary FABP1 was significantly elevated in mice devoid of megalin, a giant endocytic receptor for protein reabsorption. Elevation of urinary FABP1 was also observed in patients with Dent disease, a rare genetic disease characterized by defective megalin function in PTECs. Urinary FABP1 levels were exponentially increased following acetaminophen overdose, with both nephrotoxicity and hepatotoxicity observed. FABP1-deficient mice with liver-specific overexpression of FABP1 showed a massive increase in urinary FABP1 levels upon acetaminophen injection, indicating that urinary FABP1 is liver-derived. Lastly, we employed transgenic mice expressing diphtheria toxin receptor (DT-R) either in a hepatocyte- or in a PTEC-specific manner, or both. Upon administration of diphtheria toxin (DT), massive excretion of urinary FABP1 was induced in mice with both kidney and liver injury, while mice with either injury type showed marginal excretion. Collectively, our data demonstrated that intact PTECs have a considerable capacity to reabsorb liver-derived FABP1 through a megalin-mediated mechanism. Thus, urinary FABP1, which is synergistically enhanced by concurrent liver injury, is a biomarker for impaired protein reabsorption in AKI. These findings address the use of urinary FABP1 as a biomarker of histologically injured PTECs that secrete FABP1 into primary urine, and suggest the use of this biomarker to simultaneously monitor impaired tubular reabsorption and liver function. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Vitamin D, Calcium, Parathyroid Hormone, and Sex Steroids in Bone Health and Effects of Aging.

Bone health of the elderly is a major global health concern, since about 1 in 3 women and 1 in 5 men suffer from bone loss and fractures, often called osteoporosis, in old age. Bone health is a complex issue affected by multiple hormones and minerals. Among all the hormones involved in bone health, calcitriol (also vitamin D), parathyroid, and sex hormones (especially estrogen) have been discussed in this review paper. We have discussed the metabolism of these hormones and their effects on bone health. Vitamin D can be obtained from diet or formed from 7-dehydrocholesterol found under the skin in the presence of sunlight. The active form, calcitriol, causes dimerization of vitamin D receptor and acts on the bones, intestine, and kidney to regulate the level of calcium in blood. Similarly, parathyroid hormone is secreted when the serum level of calcium is low. It helps regulate the level of blood calcium through calcitriol. Sex hormones regulate bone modeling at an early age and remodeling later in life. Loss of ovarian function and a decrement in the level of production of estrogen are marked by bone loss in elderly women. In the elderly, various changes in the calcium and vitamin D metabolism, such as decrease in the production of vitamin D, decrease in dietary vitamin D, decreased renal production, increased production of excretory products, decrease in the level of VDR, and decreased calcium absorption by the intestines, can lead to bone loss. When the elderly are diagnosed with osteoporosis, medications that directly target bone such as bisphosphonates, RANK ligand inhibitors, estrogen and estrogen analogues, estrogen receptor modulators, and parathyroid hormone receptor agonists are used. Additionally, calcium and vitamin D supplements are prescribed.

Prognostic significance of semi-quantitative FDG-PET parameters in stage I non-small cell lung cancer treated with carbon-ion radiotherapy.

PURPOSE: Prognostic significance of volumetric 18F-fluorodeoxyglucose (FDG) positron emission tomography/computer tomography (PET/CT) parameters in carbon-ion radiotherapy (C-ion RT) treated stage I non-small cell lung cancer, and need of histology-wise separate cut-off values for risk stratification were assessed. METHODS: Thirty-nine patients (29 men and 10 women, 71.9 ± 8.3 years) who underwent FDG PET/CT examinations before C-ion RT were retrospectively evaluated. FDG-PET parameters: standardized uptake values (SUVmax, SUVpeak, and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), and clinicopathological variables were assessed for prognosis using Cox proportional hazards regression analysis. Mann-Whitney test compared medians of significant parameters between adenocarcinoma (AC) and squamous cell carcinoma (SCC), and Kaplan-Meier curves were plotted for median-based low- and high-risk groups. RESULTS: Median follow-up period was 44.8 months. 1/2/3-year overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 94.9/84.3/70.8, 82.1/69.2/58.4 and 97.3/85.7/82.3%. Multivariate analysis revealed age (hazard ratio, HR: 1.09; 95% confidence interval, CI: 1.0-1.19, p < 0.05) and MTV (HR 4.83, 95% CI 1.21-19.27, p < 0.03) predicted OS, and only MTV predicted PFS (HR 5.3, CI 1.32-21.35, p < 0.02) independently. Compared with AC, SCC had higher MTV (median, 6.625cm3 vs 0.2 cm3, p < 0.01). Single MTV cut-off based on overall cohort was insignificant in SCC for PFS (p > 0.02); separate cut-offs of MTV, 0.2 cm3 for AC (p < 0.03) and 6.625 cm3 for SCC (p < 0.05) were relevant. CONCLUSION: Among all FDG PET/CT parameters, only MTV beared prognostic ability for stage I NSCLC treated with C-ion RT, and its histological variation may need consideration for risk-adapted therapeutic management.

Premenstrual Syndrome in Students of a Teaching Hospital.

BACKGROUND: Premenstrual syndrome is group of psychosomatic symptoms which occurs during second half of menstrual cycle. Significant number of reproductive aged females suffer from it with its impact on their daily activities. This study was conducted to assess the prevalence, severity and impacts of Premenstrual syndrome on female students of a teaching hospital of Kathmandu, Nepal. METHODS: This cross-sectional study was conducted among female students of a teaching hospital from Kathmandu over a period of three months. Premenstrual Symptom Screening Tool was used to quantify the symptoms severity and their effect in activities. In addition; patient profile, socioeconomic status were recorded. The obtained information was entered in Statistical Package for Social Sciences and analyzed. Findings were then interpreted using chi-square test. RESULTS: Out of the 285 respondents, 206 (72.3%) reported at least one premenstrual syndrome symptom of moderate to severe intensity among which 74 (25.9%) had at least one severe symptom. Six individuals (2.1%) fulfilled all criteria for Pre-Menstrual Dysphoric Disorder and 49 (17.2%) fulfilled the criteria for moderate to severe premenstrual syndrome and rest (80.7%) were having no or mild premenstrual syndrome with isolated symptoms. PMS was found to have significant association to menstrual bleeding (p?0.001) and severity of dysmenorrhea (p?0.001), family history of premenstrual syndrome (p=0.019) and physical activity (p=0.021). CONCLUSIONS: Premenstrual syndrome is common in female and has a considerable impact on day to day activities activities although its severe form Pre-Menstrual Dysphoric Disorder is less common.

Performance of a clinical/proteomic panel to predict obstructive peripheral artery disease in patients with and without diabetes mellitus.

Background: Patients with diabetes mellitus (DM) are at substantial risk of developing peripheral artery disease (PAD). We recently developed a clinical/proteomic panel to predict obstructive PAD. In this study, we compare the accuracy of this panel for the diagnosis of PAD in patients with and without DM. Methods and results: The HART PAD panel consists of one clinical variable (history of hypertension) and concentrations of six biomarkers (midkine, kidney injury molecule-1, interleukin-23, follicle-stimulating hormone, angiopoietin-1 and eotaxin-1). In a prospective cohort of 354 patients undergoing peripheral and/or coronary angiography, performance of this diagnostic panel to detect ≥50% stenosis in at least one peripheral vessel was assessed in patients with (n=94) and without DM (n=260). The model had an area under the receiver operating characteristic curve (AUC) of 0.85 for obstructive PAD. At optimal cut-off, the model had 84% sensitivity, 75% specificity, positive predictive value (PPV) of 84% and negative predictive value (NPV) of 75% for detection of PAD among patients with DM, similar as in those without DM. In those with DM, partitioning the model into five levels resulted in a PPV of 95% and NPV of 100% in the highest and lowest levels, respectively. Abnormal scores were associated with a shorter time to revascularisation during 4.3 years of follow-up. Conclusion: A clinical/biomarker model can predict with high accuracy the presence of PAD among patients with DM. Trial registration number: NCT00842868.

Effect of Neprilysin Inhibition on Various Natriuretic Peptide Assays.

BACKGROUND: With sacubitril/valsartan treatment, B-type natriuretic peptide (BNP) concentrations increase; it remains unclear whether change in BNP concentrations is similar across all assays for its measurement. Effects of sacubitril/valsartan on atrial natriuretic peptide (ANP) concentrations in patients are unknown. Lastly, the impact of neprilysin inhibition on mid-regional pro-ANP (MR-proANP), N-terminal pro-BNP (NT-proBNP), proBNP1-108, or C-type natriuretic peptide (CNP) is not well understood. OBJECTIVES: This study sought to examine the effects of sacubitril/valsartan on results from different natriuretic peptide assays. METHODS: Twenty-three consecutive stable patients with heart failure and reduced ejection fraction were initiated and titrated on sacubitril/valsartan. Change in ANP, MR-proANP, BNP (using 5 assays), NT-proBNP (3 assays), proBNP1-108, and CNP were measured over 3 visits. RESULTS: Average time to 3 follow-up visits was 22, 46, and 84 days. ANP rapidly and substantially increased with initiation and titration of sacubitril/valsartan, more than doubling by the first follow-up visit (+105.8%). Magnitude of ANP increase was greatest in those with concentrations above the median at baseline (+188%) compared with those with lower baseline concentrations (+44%); ANP increases were sustained. Treatment with sacubitril/valsartan led to inconsistent changes in BNP, which varied across methods assessed. Concentrations of MR-proANP, NT-proBNP, and proBNP1-108 variably declined after treatment; whereas CNP concentrations showed no consistent change. CONCLUSIONS: Initiation and titration of sacubitril/valsartan led to variable changes in concentrations of multiple natriuretic peptides. These results provide important insights into the effects of sacubitril/valsartan treatment on individual patient results, and further suggest the benefit of neprilysin inhibition may be partially mediated by increased ANP concentrations.

Blood kidney injury molecule-1 predicts short and longer term kidney outcomes in patients undergoing diagnostic coronary and/or peripheral angiography-Results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study.

BACKGROUND: Kidney injury is common in patients with cardiovascular disease. OBJECTIVES: We determined whether blood measurement of kidney injury molecule-1 (KIM-1), would predict kidney outcomes in patients undergoing angiographic procedures for various indications. METHODS: One thousand two hundred eight patients undergoing coronary and/or peripheral angiography were prospectively enrolled; blood was collected for KIM-1 measurement. Peri-procedural acute kidney injury (AKI) was defined as AKI within 48 hours of contrast exposure. Non-procedural AKI was defined as AKI beyond 48 hours. Development of chronic kidney disease (CKD) was defined as progression to an estimated glomerular filtration rate (eGFR) <60 milliliters/minute/1.73 m2 by study conclusion. Univariate and multivariable Cox proportional hazards models were used to identify predictors of non-procedural AKI, while univariate and multivariable logistic regression analysis was used to evaluate peri-procedural AKI and predictors of progression to CKD. RESULTS: During mean follow up of 4 years, peri-procedural AKI occurred in 5.0%, non-procedural AKI in 27.3%, and 12.4% developed new reduction in eGFR <60 mL/min/1.73 m2. Higher KIM-1 concentrations were associated with prevalent comorbidities associated with risk in cardiovascular disease and worse left ventricular function. In adjusted analyses, elevated pre- and post-procedural KIM-1 concentrations predicted not only peri-procedural AKI (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.09-2·18, P = .01 and OR 1.54, 95% CI 1.10-2.15, P = .01, respectively) and non-procedural AKI (hazard ratio [HR] 1·49, 95% CI 1·24-1·78, P < .001 and HR 1.46, 95% CI 1.23-1.74, P < .001, respectively), but also progression to CKD (OR 1.99, 95% CI 1.32-2.99, P = .001 and OR 2·02, 95% CI 1·35-3·03, P = .001, respectively). CONCLUSIONS: In a typical at-risk population undergoing coronary and/or peripheral angiography, blood concentrations of KIM-1 may predict incident peri-procedural and non-procedural AKI, as well as progression to CKD.

A clinical, proteomics, and artificial intelligence-driven model to predict acute kidney injury in patients undergoing coronary angiography.

BACKGROUND: Standard measures of kidney function are only modestly useful for accurate prediction of risk for acute kidney injury (AKI). HYPOTHESIS: Clinical and biomarker data can predict AKI more accurately. METHODS: Using Luminex xMAP technology, we measured 109 biomarkers in blood from 889 patients prior to undergoing coronary angiography. Procedural AKI was defined as an absolute increase in serum creatinine of ≥0.3 mg/dL, a percentage increase in serum creatinine of ≥50%, or a reduction in urine output (documented oliguria of <0.5 mL/kg per hour for >6 hours) within 7 days after contrast exposure. Clinical and biomarker predictors of AKI were identified using machine learning and a final prognostic model was developed with least absolute shrinkage and selection operator (LASSO). RESULTS: Forty-three (4.8%) patients developed procedural AKI. Six predictors were present in the final model: four (history of diabetes, blood urea nitrogen to creatinine ratio, C-reactive protein, and osteopontin) had a positive association with AKI risk, while two (CD5 antigen-like and Factor VII) had a negative association with AKI risk. The final model had a cross-validated area under the receiver operating characteristic curve (AUC) of 0.79 for predicting procedural AKI, and an in-sample AUC of 0.82 (P < 0.001). The optimal score cutoff had 77% sensitivity, 75% specificity, and a negative predictive value of 98% for procedural AKI. An elevated score was predictive of procedural AKI in all subjects (odds ratio = 9.87; P < 0.001). CONCLUSIONS: We describe a clinical and proteomics-supported biomarker model with high accuracy for predicting procedural AKI in patients undergoing coronary angiography.

Endothelin-1 Measurement in Patients Undergoing Diagnostic Coronary Angiography-Results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) Study.

BACKGROUND: Endothelin-1 (ET-1) is a vasoconstrictor produced by vascular endothelial cells and may play a role in risk for development of coronary artery disease (CAD) and heart failure (HF). In a cohort of 1084 patients referred for coronary angiography, we investigated cross-sectional associations between ET-1 concentrations and prevalent CAD, as well as value of ET-1 for prognostication of future cardiovascular events. METHODS: Associations between ET-1 and presence/severity of CAD were assessed. Patients were followed for a median of 4 years for outcomes including incident HF, myocardial infarction (MI), cardiovascular mortality, and all-cause mortality. RESULTS: The median concentration of ET-1 was 2.57 ng/L. Patients with ET-1 concentrations above the median were more likely to have higher risk clinical features. Among those without prevalent MI at presentation, ET-1 concentrations were not associated with presence or severity of CAD. In adjusted Cox proportional hazards analyses, log-transformed ET-1 concentrations predicted incident HF [hazard ratio (HR) = 1.51 per increase in log-SD; 95% CI, 1.06-2.15; P = 0.02] and all-cause mortality (HR = 1.61 per increase in log-SD; 95% CI, 1.03-2.53; P = 0.04). Concentrations of ET-1 above the median were associated with shorter time to incident HF, MI, cardiovascular mortality, all-cause mortality, and the composite of incident HF/MI/cardiovascular mortality (all log-rank P < 0.001). CONCLUSIONS: Despite epidemiologic links to CAD, we found no cross-sectional association between biologically active ET-1 and prevalent coronary atherosclerosis in an at-risk population referred for coronary angiography. Increased ET-1 concentrations independently predict incident HF and death and are associated with more near-term cardiovascular events.

Oral Antiplatelet and Anticoagulant Agents in the Prevention and Management of Ischemic Stroke.

Despite numerous advances over the last 50 years, stroke continues to be a leading cause of death and disability worldwide. The treatment and prevention of stroke has undergone extensive study, and significant advances in medical management have occurred within the past decade principally with the development of new classes of orally active anticoagulant drugs. Here we review these recent breakthroughs and the varying roles of anticoagulants and antiplatelet agents in the prevention and management of different ischemic stroke subtypes, as well as describe the benefits and ongoing challenges to incorporating the novel oral anticoagulants (NOACs) into clinical management guidelines. Current guidelines recommend (a) administration of the antiplatelet agent aspirin in the acute management of ischemic stroke, (b) antiplatelet therapy - aspirin, clopidogrel, dypiridamole - in the secondary prevention of noncardioembolic (large artery atherosclerosis) ischemic stroke, and (c) anticoagulants - warfarin and the NOACs - in the secondary prevention of cardioembolic (atrial fibrillation related) ischemic stroke. In phase III clinical trials of the NOACs, dabigatran 150mg BID and apixaban 5mg BID were superior to warfarin in the prevention of stroke/systemic embolism while rivaroxaban 20mg QD demonstrated noninferiority. Both dabigatran and rivaroxaban had similar rates of major bleeding as warfarin but apixaban showed significantly reduced incidence of this complication. As application of novel anticoagulant agents increases, with concomitant study in a variety of clinical settings; their promise in reducing the incidence of stroke, as well as that of therapeutic complications related to warfarin, should be further elaborated.

Trade-offs between biomass growth and inducible biosynthesis of polyhydroxybutyrate in transgenic poplar.

Polyhydroxybutyrate (PHB) is a bioplastic that can be produced in transgenic plants by the coexpression of three bacterial genes for its biosynthesis. PHB yields from plants have been constrained by the negative impacts on plant health that result from diversion of resources into PHB production; thus, we employed an ecdysone analogue-based system for induced gene expression. We characterized 49 insertion events in hybrid transgenic poplar (Populus tremula x alba) that were produced using Agrobacterium transformation and studied two high-producing events in detail. Regenerated plants contained up to 1-2% PHB (dry weight) in leaves after 6-8 weeks of induction. Strong induction was observed with 1-10 mm Intrepid and limited direct toxicity observed. Confocal fluorescence microscopy was used to visualize PHB granules in chloroplasts after chemical treatment to reduce autofluorescence. A greenhouse study indicated that there were no negative consequences of PHB production on growth unless the PHB content exceeded 1% of leaf weight; at PHB levels above 1%, growth (height, diameter and total mass) decreased by 10%-34%.

A differential drug screen for compounds that select against antibiotic resistance.

Antibiotics increase the frequency of resistant bacteria by providing them a competitive advantage over sensitive strains. Here, we develop a versatile assay for differential chemical inhibition of competing microbial strains, and use it to identify compounds that preferentially inhibit tetracycline-resistant relative to sensitive bacteria, thus "inverting" selection for resistance. Our assay distinguishes compounds selecting directly against specific resistance mechanisms and compounds whose selection against resistance is based on their physiological interaction with tetracycline and is more general with respect to resistance mechanism. A pilot screen indicates that both types of selection-inverting compounds are secreted by soil microbes, suggesting that nature has evolved a repertoire of chemicals that counteracts antibiotic resistance. Finally, we show that our assay can more generally permit simple, direct screening for drugs based on their differential activity against different strains or targets.