Cancer biomarker discovery is critically dependent on the integrity of biofluid and tissue samples acquired from study participants. Multi-omic profiling of candidate protein, lipid, and metabolite ...biomarkers is confounded by timing and fasting status of sample collection, participant demographics and treatment exposures of the study population. Contamination by hemoglobin, whether caused by hemolysis during sample preparation or underlying red cell fragility, contributes 0-10 g/L of extraneous protein to plasma, serum, and Buffy coat samples and may interfere with biomarker detection and validation. We analyzed 617 plasma, 701 serum, and 657 buffy coat samples from a 7-year longitudinal multi-omic biomarker discovery program evaluating 400+ participants with or at risk for pancreatic cancer, known as Project Survival. Hemolysis was undetectable in 93.1% of plasma and 95.0% of serum samples, whereas only 37.1% of buffy coat samples were free of contamination by hemoglobin. Regression analysis of multi-omic data demonstrated a statistically significant correlation between hemoglobin concentration and the resulting pattern of analyte detection and concentration. Although hemolysis had the greatest impact on identification and quantitation of the proteome, distinct differentials in metabolomics and lipidomics were also observed and correlated with severity. We conclude that quality control is vital to accurate detection of informative molecular differentials using OMIC technologies and that caution must be exercised to minimize the impact of hemolysis as a factor driving false discovery in large cancer biomarker studies.
This study assessed the impact of fruit temperature on the phenolic metabolism of grape berries (
Vitis vinifera L. cv. Merlot) grown under field conditions with controlled exposure to sunlight. ...Individual cluster temperatures were manipulated in situ. Diurnal temperature fluctuation was damped by daytime cooling and nighttime heating of clusters. Daytime-only and nighttime-only temperature controls were applied for comparison. Berry temperatures were recorded continuously to compare the chemical data. Samples collected at véraison indicated that damping the diurnal temperature fluctuation advanced the onset of ripening. Those berries were larger (double-damped: 0.753
±
0.015
g
berry
−1 vs control: 0.512
±
0.034
g
berry
−1) and more colored than all others. Development of phenolic metabolites was followed by two reversed-phase high performance liquid chromatography methods and gel permeation chromatography. These methods provided information on anthocyanins, proanthocyanidins, flavonols, flavan-3-ol monomers, and polymeric material. Damping the diurnal temperature fluctuation reduced proanthocyanidin mean degree of polymerization (double-damped: 21.8
±
1.0 vs control: 28.0
±
1.7). Proanthocyanidin accumulation at véraison was linearly related to heat summation over the developmental period with nighttime heating yielding the highest concentration and daytime cooling yielding the lowest (night-heat: 1.46
±
0.13
mg
berry
−1 vs day-cool: 0.97
±
0.09
mg
berry
−1). Damping the diurnal temperature fluctuation had a marked effect on the rate of fruit development whereas total heat summation had more of an effect on phenolic metabolism alone. The results provide insight on the direct effect of temperature on phenolic metabolism.
Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among ...older children due to lower acquired immunity, and this has implications for ongoing control strategies.
We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked it to data on residence and insecticide-treated net (ITN) use. This included data from 69,104 children aged from 3 mo to 13 y admitted to Kilifi County Hospital between 1 January 1990 and 31 December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the following predictors: location of the residence, calendar time, the child's age, ITN use, and the enhanced vegetation index (a proxy for soil moisture). The proportion of malaria slide-positive admissions declined from 0.56 (95% confidence interval CI 0.54-0.58) in 1998 to 0.07 (95% CI 0.06-0.08) in 2009 but then increased again through to 0.24 (95% CI 0.22-0.25) in 2014. Older children accounted for most of the increase after 2009 (0.035 95% CI 0.030-0.040 among young children compared to 0.22 95% CI 0.21-0.23 in older children). There was a nonlinear relationship between malaria risk and prevalence of ITN use within a 2 km radius of an admitted child's residence such that the predicted malaria positive fraction varied from ~0.4 to <0.1 as the prevalence of ITN use varied from 20% to 80%. In this observational analysis, we were unable to determine the cause of the decline in malaria between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use.
Following a period of reduced transmission, a cohort of older children emerged who have increased susceptibility to malaria. Further reductions in malaria transmission are needed to mitigate the increasing burden among older children, and universal ITN coverage is a promising strategy to achieve this goal.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Unicompartmental knee replacement (UKR) has substantial benefits over total knee replacement (TKR) but has higher revision rates. The cementless Oxford UKR was introduced to address this but ...there are concerns about fixation and tibial plateau fractures. The first long-term study of the device with clinical and radiographic outcomes is reported.
Methods
The first 1000 medial cementless Oxford UKR were prospectively identified and followed up by independent physiotherapists. Survival was calculated using the endpoints reoperation, revision, revision to TKR, major revision requiring revision TKR components and patient mortality. The Oxford Knee Score (OKS), Tegner Activity Score and American Knee Society Score (AKSS) were recorded and radiographs analysed.
Results
The ten year survival was 96.6% (CI 94.8–97.8), 97.5% (CI 95.7–98.5), 98.9% (CI 97.7–99.4) and 99.6% (CI 98.8–99.9) using reoperation, revision, revision to TKR and major revision as the endpoint, respectively. Commonest causes for revision were bearing dislocation (
n
= 7, 0.7%), disease progression (
n
= 4, 0.4%) and pain (
n
= 2, 0.2%). There was one lateral tibial plateau fracture and one femoral component loosening. At 10 years, the mean OKS was 41.2 (SD 9.8), Tegner 2.8 (SD 1.3), AKSS-O 89.1 (SD 13.0) and AKSS-F 80.4 (SD 14.6). There were no pathological radiolucencies or complete radiolucent lines. There were no implant-related deaths.
Conclusions
The cementless Oxford UKR is a safe procedure with excellent long-term clinical results. Our results suggest that reliable fixation was achieved with only one (0.1%) revision for loosening (femoral), no radiographic evidence of loosening in the remaining cases and no fractures related to implantation.
Level of evidence
III.
The reconstitution of anti-viral cellular immunity following hematopoietic stem cell transplantation (HSCT) is crucial in preventing cytomegalovirus (CMV)-associated complications. Thus immunological ...monitoring has emerged as an important tool to better target pre-emptive anti-viral therapies. However, traditional laboratory-based assays are too cumbersome and complicated to implement in a clinical setting. Here we conducted a prospective study of a new whole blood assay (referred to as QuantiFERON-CMV®) to determine the clinical utility of measuring CMV-specific CD8+ T-cell responses as a prognostic tool. Forty-one evaluable allogeneic HSCT recipients underwent weekly immunological monitoring from day 21 post-transplant and of these 21 (51.2%) showed CMV reactivation and 29 (70.7%) developed acute graft-versus-host disease (GvHD). Patients with acute GvHD (grade ≥ 2) within 6 weeks of transplant showed delayed reconstitution of CMV-specific T-cell immunity (p = 0.013) and a higher risk of CMV viremia (p = 0.026). The median time to stable CMV-specific immune reconstitution was 59 days and the incidence of CMV reactivation was lower in patients who developed this than those who did not (27% versus 65%; p = 0.031). Furthermore, a failure to reconstitute CMV-specific immunity soon after the onset of CMV viraemia was associated with higher peak viral loads (5685 copies/ml versus 875 copies/ml; p = 0.002). Hence, QuantiFERON-CMV® testing in the week following CMV viremia can be useful in identifying HSCT recipients at risk of complicated reactivation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The correlation between tannin structure and corresponding activity was investigated by measuring the thermodynamics of interaction between tannins isolated from commercial red wine fermentations and ...a polystyrene divinylbenzene HPLC column. Must and/or wine samples were collected throughout fermentation/maceration from five Napa Valley wineries. By varying winery, fruit source, maceration time, and cap management practice, it was considered that a reasonably large variation in commercially relevant tannin structure would result. Tannins were isolated from samples collected using low pressure chromatography and were then characterized by gel permeation chromatography and acid-catalyzed cleavage in the presence of excess phloroglucinol (phloroglucinolysis). Corresponding tannin activity was determined using HPLC by measuring the thermodynamics of interaction between isolated tannin and a polystyrene divinylbenzene HPLC column. This measurement approach was designed to determine the ability of tannins to hydrophobically interact with a hydrophobic surface. The results of this study indicate that tannin activity is primarily driven by molecular size. Compositionally, tannin activity was positively associated with seed tannins and negatively associated with skin and pigmented tannins. Although measured indirectly, the extent of tannin oxidation as determined by phloroglucinolysis conversion yield suggests that tannin oxidation at this stage of production reduces tannin activity. Based upon maceration time, this study indicates that observed increases in perceived astringency quality, if related to tannin chemistry, are driven by tannin molecular mass as opposed to pigmented tannin formation or oxidation. Overall, the results of this study give new insight into tannin structure–activity relationships which dominate during extraction.
Purpose
The aim of this study was to report and compare the long-term revision rate, revision indications and patient reported outcome measures of cemented and cementless unicompartmental knee ...replacements (UKR).
Methods
Databases Medline, Embase and Cochrane Central of Controlled Trials were searched to identify all UKR studies reporting the ≥ 10 year clinical outcomes. Revision rates per 100 component years % per annum (% pa) were calculated by fixation type and then, subgroup analyses for fixed and mobile bearing UKRs were performed. Mechanisms of failure and patient reported outcome measures are reported.
Results
25 studies were eligible for inclusion with a total of 10,736 UKRs, in which there were 8790 cemented and 1946 cementless knee replacements. The revision rate was 0.73% pa (CI 0.66–0.80) and 0.45% pa (CI 0.34–0.58) per 100 component years, respectively, with the cementless having a significantly (
p
< 0.001) lower overall revision rate. Therefore, based on these studies, the expected 10-year survival of cementless UKR would be 95.5% and cemented 92.7%. Subgroup analysis revealed this difference remained significant for the Oxford UKR (0.37% pa vs 0.77% pa,
p
< 0.001), but for non-Oxford UKRs there were no significant differences in revision rates of cemented and cementless UKRs (0.57% pa vs 0.69% pa,
p
= 0.41). Mobile bearing UKRs had significantly lower revision rates than fixed bearing UKRs in cementless (
p
= 0.001), but not cemented groups (
p
= 0.13). Overall the revision rates for aseptic loosening and disease progression were significantly lower (
p
= 0.02 and
p
= 0.009 respectively) in the cementless group compared to the cemented group (0.06 vs 0.13% pa and 0.10 vs 0.21% pa respectively).
Conclusions
Cementless fixation had reduced long-term revision rates compared to cemented for the Oxford UKR. For the non-Oxford UKRs, the revision rates of cementless and cemented fixation types were equivalent. Therefore, cementless UKRs offer at least equivalent if not lower revision rates compared to cemented UKRs.
Level of evidence
III.
National joint registries report increasing revision rates with decreasing patient age for all types of joint arthroplasty. This study aimed to explore the effect of age on function and revision risk ...in patients undergoing medial meniscal-bearing UKA.
A prospectively followed cohort of 1000 consecutive medial meniscal-bearing UKAs at a designer center was analyzed. All knees were implanted for recommended indications and had mean 10-year follow-up. Patients were grouped by age at surgery (<55, 55 to <65, 65 to <75, 75+). Oxford Knee Scores (OKS) were assessed at 5 and 10 years. Component-time revision incidence rates and Kaplan-Meier implant survival were calculated.
Mean patient age at surgery was 66.6 years (range, 33-88). All age-groups had significant (P < .001) improvement in OKS over time, and at 5 years achieved a median OKS of 44. At 10 years, median OKS, from youngest group to eldest, were 44, 45, 42, and 39, with the eldest group having a significantly lower OKS (P < .01). Ten-year implant survival rates were 97%, 94%, 94%, and 93%, respectively, and was not significantly associated with age at UKA.
Medial meniscal-bearing UKA provides good functional outcomes in all age-groups; however, in older patients (75+), the functional outcome deteriorated at 10 years presumably due to deteriorating health. Contrary to registry observations, the revision rate was not higher in younger patients. These results suggest that, with correct indications, patient age should not be considered a contraindication to medial meniscal-bearing UKA.
Grape seed procyanidins (PC) are flavan-3-ol oligomers and polymers known for their biological activity in the gut. Grape seed extract (GSE) have been reported to reduce intestinal injury in a rat ...model of mucositis. We sought to investigate effects of purified PC fractions differing in mean degree of polymerization (mDP) combined with 5-Fluorouracil (5-FU) chemotherapy on the viability of colon cancer cells (Caco-2).
SixPC fractions (F1-F6) were isolated from Cabernet Sauvignon seeds at two ripeness stages: pre-veraison unripe (immature) and ripe (mature), utilizing step gradient, low-pressure chromatography on a Sephadex LH-20 resin. Fractions were tested on Caco-2 cells, alone and in combination with 5-FU. Eluted fractions were characterized by phloroglucinolysis and gel permeation chromatography. Cell viability was determined by the 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) (MTT) assay.
All isolated fractions significantly reduced Caco-2 cell viability compared to the control (P<0.05), but F2 and F3 (mDP 2-6) were the most active fractions (immature F2 = 32% mDP 2.4, F3 = 35% mDP 5.8 and mature F2 = 13% mDP 3.6 and F3 = 17% mDP 5.9; percentage of viable cells remaining) on Caco-2 cells. When combined with 5-FU, immature fractions F1-F3 enhanced the cell toxicity effects of 5-FU by 27-73% (P<0.05). Mature seed PC fractions (F1-F4) significantly enhanced the toxicity of 5-FU by 60-83% against Caco-2 cells (P<0.05). Moreover, some fractions alone were more potent at decreasing viability in Caco-2 cells (P<0.05; immature fractions = 65-68% and mature fractions = 83-87%) compared to 5-FU alone (37%).
PCs of mDP 2-6 (immature F1-F3 and mature F1 and F4)not only enhanced the impact of 5-FU in killing Caco-2 cells, but also surpassed standard 5-FU chemotherapy as an anti-cancer agent.The bioactivity of PC is therefore attributed primarily to lower molecular weight PCs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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