Progressive White Matter Injury in Preclinical Dutch Cerebral Amyloid Angiopathy.

Autosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D-CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D-CAA carriers and non-carriers, we observed divergence of white matter injury measures between D-CAA carriers and non-carriers prior to the appearance of cerebral microbleeds and >14 years before the average age of first symptomatic hemorrhage. These results indicate that white matter disruption measures may be valuable cross-sectional and longitudinal biomarkers of D-CAA progression. ANN NEUROL 2022;92:358-363.

Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults.

INTRODUCTION: Immune dysregulation is implicated in neurodegeneration and altered cytokine levels are seen in people with dementia. However, whether cytokine levels are predictive of cognitive decline in cognitively unimpaired (CU) elderly, especially in the setting of elevated amyloid beta (Aß), remains unclear. METHODS: We measured nine cytokines in the baseline plasma of 298 longitudinally followed CU elderly and assessed whether these measures were associated with cognitive decline, alone or synergistically with Aß. We next examined associations between cytokine levels and neuroimaging biomarkers of Aß/tau/neurodegeneration. RESULTS: Higher IL-12p70 was associated with slower cognitive decline in the setting of higher Aß (false discovery rate [FDR] = 0.0023), whereas higher IFN-γ was associated with slower cognitive decline independent of Aß (FDR = 0.013). Higher IL-12p70 was associated with less tau and neurodegeneration in participants with higher Aß. DISCUSSION: Immune dysregulation is implicated in early-stage cognitive decline, and greater IL-12/IFN-γ axis activation may be protective against cognitive decline and early-stage AD progression.

Race and socioeconomic differences associated with endovascular peripheral vascular interventions for newly diagnosed claudication.

BACKGROUND: Despite guidelines cautioning against the use of endovascular peripheral vascular interventions (PVI) for claudication, more than 1.3 million PVI procedures are performed annually in the United States. We aimed to describe national rates of PVI for claudication, and identify patient and county-level risk factors associated with a high rate of PVI. METHODS: We used the Medicare claims database to identify all Medicare beneficiaries with a new diagnosis of claudication between January 2015 and June 2017. A hierarchical logistic regression model accounting for patient age, sex, comorbidities; county region and setting; and a patient race-county median income interaction was used to assess the associations of race and income with a high PVI rate. RESULTS: We identified 1,201,234 patients with a new diagnosis of claudication for analysis. Of these, 15,227 (1.27%) underwent a PVI. Based on hierarchical logistic regression accounting for patient and county-level factors, black patients residing in low-income counties had a significantly higher odds of undergoing PVI than their white counterparts (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.20-1.40), whereas the odds of PVI for black versus white patients was similar in high-income counties (OR, 1.06; 95% CI, 0.99-1.14). PVI rates were higher for low versus high-income counties in both the black (OR, 1.46; 95% CI, 1.31-1.64) and white (OR, 1.19; 95% CI, 1.12-1.27) groups. There were no significant associations of Hispanic, Asian, North American native, or other races with PVI in either low- or high-income counties after risk adjustment (all P ≥ .09). CONCLUSIONS: In the Medicare population, the mean rate of PVI of 12.7 per 1000 claudication patients varies significantly based on race and income. Our data suggest there are racial and socioeconomic differences in the treatment of claudication across the United States.

Drug-eluting stents are associated with improved outcomes for the treatment of infrainguinal bypass graft stenoses.

BACKGROUND: Existing endovascular therapies for failing infrainguinal bypass grafts are associated with modest patency rates. The use of everolimus drug-eluting stents (eDESs) for endovascular bypass graft revision has not yet been reported. The objective of this study was to describe and to compare clinical outcomes of eDESs vs percutaneous cutting balloons (PCBs) vs percutaneous transluminal angioplasty (PTA) for the treatment of infrainguinal bypass graft stenoses. METHODS: A multicenter, single-institution retrospective analysis of patients with infrainguinal bypass graft stenoses treated by endovascular intervention (August 2010-December 2017) was conducted. The primary study outcome was primary patency of the treated lesion. The secondary outcome was limb salvage. Outcomes are described overall and stratified by endovascular treatment modality using Kaplan-Meier curves and log-rank tests. RESULTS: During the 7-year study period, 43 patients with 78 infrainguinal bypass stenoses were treated by endovascular intervention (eDES, 15; PCB, 23; PTA, 40). Mean age was 63.3 ± 1.7 years, 53.5% were male, and 55.8% were black. The majority of patients were diabetic (60.5%) with a history of smoking (74.4%), and nearly all (83.7%) had two or more comorbidities. Half (48.7%) of bypasses treated were femoral-popliteal bypasses, followed by popliteal-distal (25.6%) and femoral-tibial (25.6%) configurations. The location of revision was the proximal anastomosis in 37.2%, midbypass in 25.6%, and distal anastomosis in 37.2%. There were no significant differences in baseline characteristics, bypass configuration, or revision location between treatment groups (P ≥ .19). Technical success for endovascular bypass intervention was 100%. At 2 years after intervention, primary patency was significantly better for patients treated with eDES (81.8%) compared with PCB (54.7%) or PTA (33.2%; log-rank, P = .03). Limb salvage was achieved in 93.6% of patients, including 86.7%, 91.3%, and 97.5% for eDES, PCB, and PTA, respectively (P = .30). CONCLUSIONS: This is the first study reporting the results of eDESs for the treatment of infrainguinal bypass graft stenoses. Use of eDESs for endovascular bypass graft revision not only is feasible but may have better primary patency than other endovascular therapies. These data suggest that eDESs may be considered a safe and efficacious endovascular technique in the armamentarium for treatment of infrainguinal bypass graft stenoses.

Long-term Outcomes of an Endovascular-First Approach for Diabetic Patients With Predominantly Tibial Disease Treated in a Multidisciplinary Setting.

BACKGROUND: Randomized studies suggest that open lower extremity revascularization procedures are associated with improved outcomes compared with endovascular peripheral vascular interventions (PVIs). However, advances in endovascular technologies and treatment by multidisciplinary limb preservation teams have shown improved outcomes. The aim of our study was to compare perioperative and long-term outcomes after open versus PVI procedures in diabetic patients with chronic limb-threatening ischemia (CLTI) treated in a multidisciplinary setting. METHODS: All patients presenting to our multidisciplinary diabetic limb-preservation service from 6/2012 to 07/2018 were enrolled in a prospective database. Patients who underwent either an open lower extremity bypass (LEB) or a PVI for CLTI were included in the analysis. Perioperative (30-day) complications and 4-year patency and limb salvage rates were compared between PVI and LEB using chi-squared tests, Kaplan-Meier curve analyses, and stepwise multivariable Cox proportional hazards models. RESULTS: A total of 195 lower extremity revascularization procedures were performed in 120 patients (mean age: 65.0 ± 1.0 years, 61.7% male, 63.3% black), including 53 (27.2%) open procedures and 142 (72.8%) PVIs. Nearly two-thirds of procedures (65.6%) treated multilevel diseases, while 27.2% treated isolated tibial disease and 7.2% treated isolated femoropopliteal disease. More than half of the procedures (53.3%) were performed for Wound, Ischemia, and foot Infection (WIfI) classification stage 4 limbs, 25.1% for stage 3, and 21.6% for stage 1/2. In the LEB group, 67.9% of targets were infrapopliteal. In the PVI group, 63.4% of procedures were isolated tibial interventions or were multilevel interventions including the tibial segment. Perioperative complications occurred in 52.8% of LEB versus 12.0% of PVI (P < 0.001). At 4 years postoperatively, there was no significant difference in crude (unadjusted) primary patency for PVI versus LEB (34.5 ± 6.6% vs. 49.6 ± 8.1, P = 0.89). Secondary patency was better for the LEB group (50.3 ± 7.4% vs. 55.4 ± 7.5%; P = 0.04), but amputation-free survival was similar (65.1 ± 6.7% vs. 60.9 ± 9.7%; P = 0.79). After adjusting for baseline differences between groups, primary patency (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.34 to 1.10) and amputation-free survival (HR: 1.51; 95% CI: 0.71 to 2.34) remained similar for PVI versus LEB, but secondary patency was persistently lower for PVI (HR: 0.35; 95% CI: 0.14 to 0.90). CONCLUSIONS: In this cohort of diabetic patients with CLTI undergoing predominantly tibial interventions, open revascularization was associated with a higher risk of perioperative complications than PVIs. While secondary patency rates were better after LEBs, our data suggest that an endovascular-first approach results in equivalent long-term amputation-free survival for diabetic patients treated in a multidisciplinary setting.

Duplex Ultrasound Assessment and Outcomes of Renal Malperfusion Syndromes after Acute Aortic Dissection.

BACKGROUND: We investigated the feasibility of renal duplex ultrasound in the identification of renal malperfusion in acute aortic dissection and evaluated whether intervention for renal malperfusion improved outcomes over best medical management alone. METHODS: All patients with acute aortic dissections involving the renovisceral aorta who underwent a duplex ultrasound were included (2004-2016). We assessed duplex findings among patients who developed acute kidney injury (AKI; 50% increase in serum creatinine) and compared AKI, 30-day mortality, and overall survival among patients who underwent a procedure to treat malperfusion versus those who did not. RESULTS: Of 37 patients with acute dissection involving the renovisceral aorta (73% were male, 59% had type B dissection, mean follow-up 4.6 ± 0.6 years), 70% developed AKI, 11% required dialysis, and 5% developed permanent dialysis dependence. AKI was correlated with higher peak creatinine levels (4.2 vs. 2.2 mg/dL, P < 0.001), although 30-day mortality and overall survival were similar (both, P ≥ 0.24). Progression to AKI was associated with significantly lower end-diastolic velocity (EDV) measurements on renal duplex (17 vs. 27 cm/sec, P = 0.03); an EDV threshold of 23 cm/sec had a positive predictive value of 85% for AKI. Operative intervention (n = 10) was associated with lower follow-up creatinine (0.9 vs. 2.1 mg/dL, P = 0.002), although there was no difference in progression to dialysis dependence, 30-day mortality, or overall survival (all, P ≥ 0.34). CONCLUSIONS: Patients who developed AKI demonstrated characteristic renal duplex ultrasound findings with lower EDV measurements in the distal renal arteries bilaterally. Performing a renal malperfusion procedure was associated with normalization of postoperative creatinine without affecting 30-day mortality or overall survival.

Obesity-induced changes in lipid mediators persist after weight loss.

BACKGROUND: Obesity induces significant changes in lipid mediators, however, the extent to which these changes persist after weight loss has not been investigated. SUBJECTS/METHODS: We fed C57BL6 mice a high-fat diet to generate obesity and then switched the diet to a lower-fat diet to induce weight loss. We performed a comprehensive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues (including adipose, liver, muscle and hypothalamus) and plasma. RESULTS: We found that changes induced by obesity were largely reversible in most metabolic tissues but the adipose tissue retained a persistent obese metabolic signature. Prostaglandin signaling was perturbed in the obese state and lasting increases in PGD2, and downstream metabolites 15-deoxy PGJ2 and delta-12-PGJ2 were observed after weight loss. Furthermore expression of the enzyme responsible for PGD2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. We found that inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. Increased HPGDS expression was also observed in human adipose tissues obtained from obese compared with lean individuals. We then measured circulating levels of PGD2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss. CONCLUSIONS: These results suggest that lasting changes in lipid mediators induced by obesity, still present after weight loss, may play a role in the biological drive to regain weight.

Peak season plant activity shift towards spring is reflected by increasing carbon uptake by extratropical ecosystems.

Climate change is lengthening the growing season of the Northern Hemisphere extratropical terrestrial ecosystems, but little is known regarding the timing and dynamics of the peak season of plant activity. Here, we use 34-year satellite normalized difference vegetation index (NDVI) observations and atmospheric CO2 concentration and δ13 C isotope measurements at Point Barrow (Alaska, USA, 71°N) to study the dynamics of the peak of season (POS) of plant activity. Averaged across extratropical (>23°N) non-evergreen-dominated pixels, NDVI data show that the POS has advanced by 1.2 ± 0.6 days per decade in response to the spring-ward shifts of the start (1.0 ± 0.8 days per decade) and end (1.5 ± 1.0 days per decade) of peak activity, and the earlier onset of the start of growing season (1.4 ± 0.8 days per decade), while POS maximum NDVI value increased by 7.8 ± 1.8% for 1982-2015. Similarly, the peak day of carbon uptake, based on calculations from atmospheric CO2 concentration and δ13 C data, is advancing by 2.5 ± 2.6 and 4.3 ± 2.9 days per decade, respectively. POS maximum NDVI value shows strong negative relationships (p < .01) with the earlier onset of the start of growing season and POS days. Given that the maximum solar irradiance and day length occur before the average POS day, the earlier occurrence of peak plant activity results in increased plant productivity. Both the advancing POS day and increasing POS vegetation greenness are consistent with the shifting peak productivity towards spring and the increasing annual maximum values of gross and net ecosystem productivity simulated by coupled Earth system models. Our results further indicate that the decline in autumn NDVI is contributing the most to the overall browning of the northern high latitudes (>50°N) since 2011. The spring-ward shift of peak season plant activity is expected to disrupt the synchrony of biotic interaction and exert strong biophysical feedbacks on climate by modifying the surface albedo and energy budget.

Resection of retroperitoneal sarcoma en-bloc with inferior vena cava: 20 year outcomes of a single institution.

BACKGROUND: Margin negative resection offers the best chance of long-term survival in retroperitoneal sarcoma (RPS). En-bloc resection of adjacent structures, including the inferior vena cava (IVC), is often required to achieve negative margins. We review our 20-year experience of en-bloc IVC and RPS resection. METHODS: Retrospective review of patients with RPS resection involving the IVC were matched 1:3 by age and histology to RPS without IVC resection. Prognostic factors for overall survival (OS) and disease free survival (DFS) were assessed. RESULTS: Thirty-two patients underwent RPS resection en-bloc with IVC. They were matched with 96 cases of RPS without IVC resection. Median OS of 59 months and DFS 18 months in IVC resection group was comparable to RPS resection without vascular involvement: median OS 65 months, DFS 18 months (P = 0.519, P = 0.604). On multivariate analyses, R2 margin (OS: HR = 6.52 [95%CI: 1.18-36.09], P = 0.032) was associated with inferior OS. R2 margin and increased number of organs resected (DFS: HR = 5.07, [1.15-22.27], P = 0.031, HR = 1.28 [1.01-1.62], P = 0.014) were associated with inferior DFS. Reconstructions included graft (n = 19, 59%), patch (n = 4, 13%), primary repair (n = 6, 19%), and ligation (n = 4, 13%). CONCLUSIONS: RPS resection en-bloc with IVC can achieve equivalent rates of DFS and OS to patients without vascular involvement.

The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system predicts wound healing but not major amputation in patients with diabetic foot ulcers treated in a multidisciplinary setting.

OBJECTIVE: The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) threatened limb classification has been shown to correlate well with risk of major amputation and time to wound healing in heterogeneous diabetic and nondiabetic populations. Major amputation continues to plague the most severe stage 4 WIfI patients, with 1-year amputation rates of 20% to 64%. Our aim was to determine the association between WIfI stage and wound healing and major amputation among patients with diabetic foot ulcers (DFUs) treated in a multidisciplinary setting. METHODS: All patients presenting to our multidisciplinary DFU clinic from July 2012 to December 2015 were enrolled in a prospective database. Wound healing and major amputation were compared for patients stratified by WIfI classification. RESULTS: There were 217 DFU patients with 439 wounds (mean age, 58.3 ± 0.8 years; 58% male, 63% black) enrolled, including 28% WIfI stage 1, 11% stage 2, 33% stage 3, and 28% stage 4. Peripheral arterial disease and dialysis were more common in patients with advanced (stage 3 or 4) wounds (P ≤ .05). Demographics of the patients, socioeconomic status, and comorbidities were otherwise similar between groups. There was a significant increase in the number of active wounds per limb at presentation with increasing WIfI stage (stage 1, 1.1 ± 0.1; stage 4, 1.4 ± 0.1; P = .03). Mean wound area (stage 1, 2.6 ± 0.6 cm2; stage 4, 15.3 ± 2.8 cm2) and depth (stage 1, 0.2 ± 0.0 cm; stage 4, 0.8 ± 0.1 cm) also increased progressively with increasing wound stage (P < .001). Minor amputations (stage 1, 18%; stage 4, 56%) and revascularizations (stage 1, 6%; stage 4, 55%) were more common with increasing WIfI stage (P < .001). On Kaplan-Meier analysis, WIfI classification was predictive of wound healing (P < .001) but not of major amputation (P = .99). For stage 4 wounds, the mean wound healing time was 190 ± 17 days, and risk of major amputation at 1 year was 5.7% ± 3.2%. CONCLUSIONS: Among patients with DFU, the WIfI classification system correlated well with wound healing but was not associated with risk of major amputation at 1 year. Although further prospective research is warranted, our results suggest that use of a multidisciplinary approach for DFUs may augment healing time and reduce amputation risk compared with previously published historical controls of standard wound care among patients with advanced stage 4 disease.

Multinucleated Giant Cancer Cells Produced in Response to Ionizing Radiation Retain Viability and Replicate Their Genome.

Loss of wild-type p53 function is widely accepted to be permissive for the development of multinucleated giant cells. However, whether therapy-induced multinucleation is associated with cancer cell death or survival remains controversial. Herein, we demonstrate that exposure of p53-deficient or p21WAF1 (p21)-deficient solid tumor-derived cell lines to ionizing radiation (between 2 and 8 Gy) results in the development of multinucleated giant cells that remain adherent to the culture dish for long times post-irradiation. Somewhat surprisingly, single-cell observations revealed that virtually all multinucleated giant cells that remain adherent for the duration of the experiments (up to three weeks post-irradiation) retain viability and metabolize 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), and the majority (>60%) exhibit DNA synthesis. We further report that treatment of multinucleated giant cells with pharmacological activators of apoptosis (e.g., sodium salicylate) triggers their demise. Our observations reinforce the notion that radiation-induced multinucleation may reflect a survival mechanism for p53/p21-deficient cancer cells. With respect to evaluating radiosensitivity, our observations underscore the importance of single-cell experimental approaches (e.g., single-cell MTT) as the creation of viable multinucleated giant cells complicates the interpretation of the experimental data obtained by commonly-used multi-well plate colorimetric assays.

Effect of Bacillus subtilis Natto on Meat Quality and Skatole Content in TOPIGS Pigs.

This study investigated the effect of Bacillus subtilis (B. subtilis) natto on meat quality and skatole in TOPIGS pigs. Sixty TOPIGS pigs were randomly assigned to 3 groups (including 5 pens per group, with 4 pigs in each pen) and fed with basic diet (control group), basic diet plus 0.1% B. subtilis natto (B group), and basic diet plus 0.1% B. subtilis natto plus 0.1% B. coagulans (BB group), respectively. All pigs were sacrificed at 100 kg. Growth performance, meat quality, serum parameters and oxidation status in the three groups were assessed and compared. Most parameters regarding growth performance and meat quality were not significantly different among the three groups. However, compared with the control group, meat pH24, fat and feces skatole and the content of Escherichia coli (E. Coli), Clostridium, NH3-N were significantly reduced in the B and BB groups, while serum total cholesterol, high density lipoprotein, the levels of liver P450, CYP2A6, and CYP2E1, total antioxidant capability (T-AOC) and glutathione peroxidase and Lactobacilli in feces were significantly increased in the B and BB groups. Further, the combined supplementation of B. subtilis natto and B. coagulans showed more significant effects on the parameters above compared with B. subtilis, and Clostridium, and NH3-N. Our results indicate that the supplementation of pig feed with B. subtilis natto significantly improves meat quality and flavor, while its combination with B. coagulans enhanced these effects.

Expression and prognostic significance of microRNA-451 in human epithelial ovarian cancer.

OBJECTIVE: MicroRNA-451 has been proved to be downregulated in many human malignancies and correlated with tumor progression. However, its expression and clinical significance in epithelial ovarian cancer (EOC) is still unclear. The aim of this study was to explore the effects of miR-451 in EOC tumorigenesis and development. MATERIALS AND METHODS: The expression levels of miR-451 were quantified by qRT-PCR in 115 EOC and 34 normal ovarian tissues, and correlated with clinicopathological factors and prognosis. MTT, flow cytometric assay, and transwell invasion assay were used to test the proliferation, apoptosis, and invasion of SKOV-3 EOC cells transfected with miR-451 mimics or negative control (NC) RNA-oligonucleotides. RESULTS: MiR-451 expression was significantly downregulated in EOC compared with normal ovarian tissues. Low level of miR-451 was associated with advanced FIGO stage (p = 0.005), higher serum CA125 expression level (p = 0.005), and lymph node metastasis (p = 0.002). Multivariate Cox regression analysis identified decreased miR-451 expression as an independent factor predicting poor prognosis for EOC patients. In addition, transfection of miR-451 mimics in SKOV-3 was able to reduce cell proliferation, promote cell apoptosis, and inhibit cell invasion. CONCLUSIONS: miR-451 may act not only as a novel diagnostic and prognostic marker, but also as a potential target for molecular therapy of EOC.

Spontaneous γH2AX Foci in Human Solid Tumor-Derived Cell Lines in Relation to p21WAF1 and WIP1 Expression.

Phosphorylation of H2AX on Ser139 (γH2AX) after exposure to ionizing radiation produces nuclear foci that are detectable by immunofluorescence microscopy. These so-called γH2AX foci have been adopted as quantitative markers for DNA double-strand breaks. High numbers of spontaneous γH2AX foci have also been reported for some human solid tumor-derived cell lines, but the molecular mechanism(s) for this response remains elusive. Here we show that cancer cells (e.g., HCT116; MCF7) that constitutively express detectable levels of p21WAF1 (p21) exhibit low numbers of γH2AX foci (<3/nucleus), whereas p21 knockout cells (HCT116p21-/-) and constitutively low p21-expressing cells (e.g., MDA-MB-231) exhibit high numbers of foci (e.g., >50/nucleus), and that these foci are not associated with apoptosis. The majority (>95%) of cells within HCT116p21-/- and MDA-MB-231 cultures contain high levels of phosphorylated p53, which is localized in the nucleus. We further show an inverse relationship between γH2AX foci and nuclear accumulation of WIP1, an oncogenic phosphatase. Our studies suggest that: (i) p21 deficiency might provide a selective pressure for the emergence of apoptosis-resistant progeny exhibiting genomic instability, manifested as spontaneous γH2AX foci coupled with phosphorylation and nuclear accumulation of p53; and (ii) p21 might contribute to positive regulation of WIP1, resulting in dephosphorylation of γH2AX.

N-capping motifs promote interaction of amphipathic helical peptides with hydrophobic surfaces and drastically alter hydrophobicity values of individual amino acids.

Capping rules, which govern interactions of helical peptides with hydrophobic surfaces, were never established before due to lack of methods for the direct measurement of polypeptide structure on the interphase boundary. We employed proteomic techniques and peptide retention modeling in reversed-phase chromatography to generate a data set sufficient for amino acid population analysis at helix ends. We found that interactions of amphipathic helical peptides with a hydrophobic C18 phase are induced by a unique motif featuring hydrophobic residues in the N1 and N2 positions adjacent to the N-cap (Asn, Asp, Ser, Thr, Gly), followed by Glu, Gln, or Asp in position N3 to complete a capping box. A favorable N-capping arrangement prior to amphipathic helix may result in the highest hydrophobicity (retention on C18 columns) of Asp/Asn (or Glu/Gln) peptide analogues among all naturally occurring amino acids when placed in N-cap or N3 position, respectively. These results contradict all previously reported hydrophobicity scales and provide new insights into our understanding of the phenomenon of hydrophobic interactions.

Characterization and complete separation of major cyclolinopeptides in flaxseed oil by reversed-phase chromatography.

Organoleptic properties of flaxseed oil deteriorate during storage due to methionine oxidation in its major cyclolinopeptides. Cyclolinopeptide E was previously identified as being responsible for the manifestation of bitter taste with flaxseed oil ageing. We developed a chromatographic procedure to monitor the oxidation of major cyclic peptides in flaxseed oil. We also used liquid chromatography with mass spectrometry and high-efficiency core-shell reversed-phase sorbents to study the separation of cyclolinopeptides in detail. The Kinetex(TM) family of stationary phases (C8, C18, phenyl-hexyl) was tested, along with the standard porous Luna(TM) C18(2) media. We found that only the phenyl-hexyl stationary phase allows for complete resolution of major cyclolinopeptides, thus permitting direct UV monitoring of degree of conversion for cyclolinopeptide B into C and L into E. We also report, for the first time, a significant effect of peak splitting for some methionine S-oxide (Mso) containing cyclolinopeptides, which most likely appear due to diastereomerization. This results in poor separation efficiency for cyclolinopeptides F, G, and E, and gives baseline resolution of diastereomeric pairs for cyclolinopeptides I and P. Thus, a single oxidation of cyclolinopeptide N yields three distinct chromatographic peaks corresponding to cyclolinopeptide T (cyclo-MsoLMPFFWV, reported for the first time) and pair of cyclolinopeptide I (cyclo-MLMsoPFFWV) diastereomers.

Author Correction: High expression of MMP14 is associated with progression and poor short-term prognosis in muscle-invasive bladder cancer.

Correction to: Eur Rev Med Pharmacol Sci 2020; 24 (12): 6605-6615-DOI: 10.26355/eurrev_202006_21646-published online on June 25, 2020. After publication, the authors have applied some corrections to the galley proof: -       In Table II, data display in MMP14 expression between Low and high group was inverted. This correction does not involve any statistical data modification and does not affect the conclusion of the article. The correct table display should be as follows: -       In Figure 4F, the cell invasion image of siRNA-2 group in T24 was misplaced. The authors have adjusted the brightness and contrast appropriately as well. The correct Figure 4F display should be as follows: There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/21646.

Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard Aging Brain Study.

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau.

Clinical and genetic features of 5 Chinese patients with X-linked lymphoproliferative syndrome.

In this study, we report the clinical and genetic features of Chinese patients with X-linked lymphoproliferative syndrome (XLP). Male patients with fulminant infectious mononucleosis (FIM), Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) or persistent EBV viremia were enrolled in this study. Direct sequencing was used to detect SH2D1A/XIAP gene mutations. The patients' clinical features were assessed by retrieval of data from medical records. Twenty-one male patients with FIM, EBV-associated HLH or persistent EBV viremia were evaluated. Four patients had SH2D1A mutations, and one patient had an XIAP mutation. All five of these patients had symptoms of HLH and EBV infection. Among the five patients, the youngest one was only 1 month old at onset. One patient exhibited hypogammaglobulinemia. Of four patients evaluated for immunological function, all exhibited reduced CD4/CD8 ratios. Three patients had rapid disease progression and died. One patient received haematopoietic stem cell transplantation and is well. The overall clinical phenotypes of Chinese patients with XLP matched previous reports. For patients with severe EBV-associated HLH, our results indicate the need to examine the possibility of XLP.

Impact of chemiluminescent enzyme immunoassay screening for human parvovirus B19 antigen in Japanese blood donors.

BACKGROUND: To reduce the risk of human parvovirus B19 (B19V) transmission through contaminated blood for transfusion and plasma-derived products, the Japanese Red Cross (JRC) Blood Centers introduced B19V antigen screening by chemiluminescent enzyme immunoassay (CLEIA-B19V) in 2008. STUDY DESIGN AND METHODS: Donor samples that were positive by CLEIA-B19V screening were tested for B19V DNA. The sensitivity of CLEIA-B19V was tested using samples of all three genotypes and B19V DNA-positive donations. B19V DNA-positive donations and pooled plasma were quantitatively assayed for B19V DNA. B19V DNA-positive donations were phylogenetically analyzed by polymerase chain reaction direct sequencing. RESULTS: The sensitivity of CLEIA-B19V was inferred to be approximately 6.3 log IU/mL with the genotype samples and 6.4 log IU/mL with B19V DNA-positive donor samples. Of 417 CLEIA-B19V-positive samples from 1,035,560 donations in Hokkaido, Japan, 101 were positive for B19V DNA. The 198 strains of B19V DNA-positive donations in Hokkaido over the past 15 years clustered exclusively with Genotype 1. After introduction of CLEIA-B19V, the viral load for B19V DNA in all 772 pooled plasma for fractionation from donors in nationwide Japan did not exceed 4 log IU/mL. CONCLUSION: CLEIA-B19V can detect all three genotypes of B19V (viral load >6.3 log IU/mL) and limit the viral load (<4 log IU/mL) in pooled plasma, and thus such screening has further reduced the risk of transfusion-transmitted B19V infection. These results show that CLEIA-B19V screening at the JRC Blood Centers can be an alternative approach to comply with recommendations regarding B19V in the United States and Europe.