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Introduction: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns., Methods: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented., Results: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected., Discussion: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FB is supported by the NIHR biomedical research center at UCLH. MD received honoraria for lectures from Bayer Vital and Sanofi Genzyme, Consultant for Hovid Berhad and Roche Pharma. RWP received honoraria from GE Healthcare and is co-lead of Neurofilament light consortium. CHS is supported by an Alzheimer's Society Fellowship. The remaining authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Impaired endogenous nitric oxide (NO) production may contribute to graft failure and premature mortality in kidney transplant recipients (KTR). We investigated potential associations of 24-h urinary NOx (NO 3 -  + NO 2 - ) excretion (uNOx) with long-term outcomes. uNOx was determined by HPLC and GC-MS in 698 KTR and in 132 kidney donors before and after donation. Additionally, we measured urinary nitroso species (RXNO) by gas-phase chemiluminescence. Median uNOx was lower in KTR compared to kidney donors (688 [393-1076] vs. 1301 [868-1863] before donation and 1312 [982-1853] μmol/24 h after donation, P < 0.001). During median follow-up of 5.4 [4.8-6.1] years, 150 KTR died (61 due to cardiovascular disease) and 83 experienced graft failure. uNOx was inversely associated with all-cause mortality (HR per doubling of uNOx: 0.84 [95% CI 0.75-0.93], P < 0.001) and cardiovascular mortality (HR 0.78 [95% CI 0.67-0.92], P = 0.002). The association of uNOx with graft failure was lost when adjusted for renal function (HR per doubling of uNOx: 0.89 [95% CI 0.76-1.05], P = 0.17). There were no significant associations of urinary RXNO with outcomes. Our study suggests that KTR have lower NO production than healthy subjects and that lower uNOx is associated with a higher risk of all-cause and cardiovascular mortality., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It is unknown whether meat intake is beneficial for long-term patient and graft survival in kidney transplant recipients (KTR)., Objectives: We first investigated the association of the previously described meat intake biomarkers 1-methylhistidine and 3-methylhistidine with intake of white and red meat as estimated from a validated food frequency questionnaire (FFQ). Second, we investigated the association of the meat intake biomarkers with long-term outcomes in KTR., Methods: We measured 24-h urinary excretion of 1-methylhistidine and 3-methylhistidine by validated assays in a cohort of 678 clinically stable KTR. Cross-sectional associations were assessed by linear regression. We used Cox regression analyses to prospectively study associations of log2-transformed biomarkers with mortality and graft failure., Results: Urinary 1-methylhistidine and 3-methylhistidine excretion values were median: 282; interquartile range (IQR): 132-598 µmol/24 h and median: 231; IQR: 175-306 µmol/24 h, respectively. Urinary 1-methylhistidine was associated with white meat intake [standardized β (st β): 0.20; 95% CI: 0.12, 0.28; P < 0.001], whereas urinary 3-methylhistidine was associated with red meat intake (st β: 0.30; 95% CI: 0.23, 0.38; P < 0.001). During median follow-up for 5.4 (IQR: 4.9-6.1) y, 145 (21%) died and 83 (12%) developed graft failure. Urinary 3-methylhistidine was inversely associated with mortality independently of potential confounders (HR per doubling: 0.55; 95% CI: 0.42, 0.72; P < 0.001). Both urinary 1-methylhistidine and urinary 3-methylhistidine were inversely associated with graft failure independent of potential confounders (HR per doubling: 0.84; 95% CI: 0.73, 0.96; P = 0.01; and 0.59; 95% CI: 0.41, 0.85; P = 0.004, respectively)., Conclusions: High urinary 3-methylhistidine, reflecting higher red meat intake, is independently associated with lower risk of mortality. High urinary concentrations of both 1- and 3-methylhistidine, of which the former reflects higher white meat intake, are independently associated with lower risk of graft failure in KTR. Future intervention studies are warranted to study the effect of high meat intake on mortality and graft failure in KTR, using these biomarkers., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Introduction: Patients with complete occlusion of the internal carotid artery (CAO) are vulnerable to cerebral hypoperfusion. Since cerebral hypoperfusion is associated with accelerated cognitive decline, patients with CAO may have an increased risk of cognitive impairment. We aimed to assess the prevalence and profile of cognitive impairment in patients with CAO and to explore the relation between hemodynamic impairment and cognitive functioning., Methods: We systematically searched Medline and EMBASE for studies including patients with symptomatic or asymptomatic CAO subjected to cognitive testing that were published between 1980 and 2017. We did not include patients with carotid stenosis. We obtained data on type of study, patient characteristics, cerebral imaging and neuropsychological testing. In addition, we extracted data on potential causes of systemic hemodynamic impairment and the presence and stage of cerebral hemodynamic impairment. We assessed methodological quality of included studies with the Newcastle-Ottawa Scale., Results: We found eight studies comprising 244 patients (mean age 61 years, 76% male, 93% symptomatic CAO). The proportion of patients with cognitive impairment ranged from 54 to 71% in four studies; in the other four studies patients with CAO performed worse on cognitive testing than controls, but results were not quantified. Impairment was reported in all cognitive domains. We found no data on the association between systemic hemodynamic impairment and cognitive functioning. Studies that assessed whether cerebral hemodynamic impairment was associated with cognitive functioning showed conflicting results., Conclusion: In patients with CAO, cognitive impairment is present in about half to two-thirds of patients and is not restricted to specific cognitive domains. The effect of systemic and cerebral hemodynamic impairment on cognitive functioning in patients with CAO deserves further study., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Renal transplant recipients (RTR) are at risk of decline of graft function and premature mortality, with high blood pressure as an important risk factor for both. To study the association of the Dietary Approach to Stop Hypertension (DASH) diet with these adverse events, we conducted a prospective cohort study of adult RTR. Dietary data were collected using a validated 177-item food frequency questionnaire and an overall DASH-score was obtained. We included 632 stable RTR (mean ± standard deviation age 53.0 ± 12.7 years, 57% men). Mean DASH score was 23.8 ± 4.7. During median follow-up of 5.3 (interquartile range, 4.1-6.0) years, 119 (18.8%) RTR had renal function decline, defined as a combined endpoint of doubling of serum creatinine and death-censored graft failure, and 128 (20.3%) died. In Cox-regression analyses, RTR in the highest tertile of the DASH score had lower risk of both renal function decline (hazard ratio [HR] = 0.57; 95% confidence interval [CI], 0.33-0.96, P = .03) and all-cause mortality (HR = 0.52; 95%CI, 0.32-0.83, P = .006) compared to the lowest tertile, independent of potential confounders. Adherence to a DASH-style diet is associated with lower risk of both renal function decline and all-cause mortality. These results suggest that a healthful diet might benefit long-term outcome in RTR., (© 2018 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur after treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the development of tMNs following ASCT at the molecular level by whole-exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMNs as compared with de novo myelodysplastic syndrome (MDS) (median 27 vs 12 mutations; P = .001). The mutations found in tMNs did not carry a clear aging-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMNs and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. By use of TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the patients with tMNs. Reconstruction of clonal patterns based on VAFs revealed that premalignant clones can be present more than 7 years preceding a tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development after ASCT originates in HSCs bearing (pre-)tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of premalignant clones and monitoring of their evolutionary trajectory may help to predict the development of tMNs and guide early intervention in the future., (© 2018 by The American Society of Hematology.)

Background: Low plasma concentrations of pyridoxal 5'-phosphate (PLP) are common in renal transplant recipients (RTRs) and confer increased risk of long-term mortality. To our knowledge, it is not known whether low plasma PLP concentrations have functional (i.e., intracellular) consequences and, if so, whether such consequences are associated with increased risk of mortality. Objectives: We assessed the association of plasma PLP with functional vitamin B-6 status and explored the potential association of functional vitamin B-6 status with long-term mortality in RTRs. Design: In a longitudinal cohort of 678 stable RTRs with a median follow-up of 5.3 y (IQR: 4.8-6.1 y) and 297 healthy controls, PLP, plasma 3-hydroxykynurenine (3-HK), and xanthurenic acid (XA) were analyzed via validated assays. PLP was used as direct biomarker for vitamin B-6 status, and the 3-HK:XA ratio was used as functional biomarker of vitamin B-6 status with a higher ratio reflecting worse functional vitamin B-6 status. Results: Median PLP, 3-HK, and XA concentrations were 41 nmol/L (IQR: 29-60 nmol/L), 40.1 nmol/L (IQR: 33.0-48.0 nmol/L), and 19.1 nmol/L (IQR: 14.5-24.9 nmol/L), respectively, in healthy controls compared with 29 nmol/L (IQR: 17-50 nmol/L), 61.5 nmol/L (IQR: 45.6-86.5 nmol/L), and 25.5 nmol/L (IQR: 17.2-40.0 nmol/L), respectively, in RTRs (all P < 0.001). RTRs had a higher median 3-HK:XA ratio (2.38; IQR: 1.68-3.49) than did healthy controls (2.13; IQR: 1.63-2.71) ( P < 0.05). In RTRs, the 3-HK:XA ratio was inversely associated with plasma PLP (β = -0.21, P < 0.001). Moreover, a higher 3-HK:XA ratio was independently associated with increased risk of all-cause mortality (HR per SD increment: 1.30; 95% CI: 1.13, 1.49), cancer mortality (HR per SD increment: 1.47; 95% CI: 1.12, 1.95), and infectious disease mortality (HR per SD increment: 1.50; 95% CI: 1.21, 1.86) in RTRs. Conclusions: Vitamin B-6-deficient RTRs have a worse functional vitamin B-6 status than do healthy controls and vitamin B-6-sufficient RTRs. Worse functional vitamin B-6 status in RTRs is independently associated with an increased risk of mortality particularly because of cancer and infectious disease. This trial was registered at clinicaltrials.gov as NCT02811835., (© 2017 American Society for Nutrition.)

Background: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes., Objective: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL., Methods: A NGS gene panel was analysed in 24 patients with EL., Results: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767&#95;786del was most frequently detected., Conclusion: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Previous studies have reported low circulating concentrations of pyridoxal-5-phospate (PLP) in renal transplant recipients (RTRs). It is unknown whether this is because of low intake or altered handling, and it is also unknown whether variation in circulating concentrations of PLP influences long-term outcome. Objective: We compared vitamin B-6 intake and circulating PLP concentrations of RTRs with those of healthy controls and investigated long-term clinical implications of vitamin B-6 deficiency in stable outpatient RTRs. Design: In a longitudinal cohort of 687 stable RTRs (57% male; mean ± SD age: 53 ± 13 y) with a median (IQR) follow-up of 5.3 y (4.8-6.1 y) and 357 healthy controls (47% male; age 54 ± 11 y), baseline vitamin B-6 was measured as plasma PLP by high-performance liquid chromatography (HPLC). Vitamin B-6 deficiency was defined as PLP <20 nmol/L, and insufficiency as PLP 20-30 nmol/L. Dietary intake was assessed by validated food-frequency questionnaires. Results: At inclusion [5.3 y (1.8-12.1 y) after transplantation], the mean vitamin B-6 intakes in RTRs and healthy controls were 1.77 ± 0.49 and 1.85 ± 0.56 mg/d, respectively ( P = 0.23). In these groups, the median plasma PLP concentrations were 29 nmol/L (17-50 nmol/L) and 41 nmol/L (29-60 nmol/L), respectively ( P < 0.001). Accordingly, deficiency was present in 30% of RTRs compared with 11% of healthy controls. PLP concentrations were inversely associated with glucose homeostasis variables and inflammation variables (all P < 0.01). During follow-up, 149 (21%) RTRs died and 82 (12%) developed graft failure. In RTRs, vitamin B-6 deficiency was associated with considerably higher mortality risk (HR 2.14; 95% CI: 1.48, 3.08) than a sufficient vitamin B-6 status, independent of potential confounders. No associations were observed for graft failure ( P = 0.18). Conclusions: Vitamin B-6 deficiency is common in RTRs and does not seem to be a consequence of inadequate intake. In addition, this deficient state is clinically relevant and independently associated with an increased risk of mortality in RTRs. The cohort on which the study was based [TransplantLines Food and Nutrition Biobank and Cohort Study (TxL-FN)] was registered at clinicaltrials.gov as NCT02811835., (© 2017 American Society for Nutrition.)

Background: Renal transplant recipients (RTRs) have commonly been urged to limit their potassium intake during renal insufficiency and may adhere to this principle after transplantation. Importantly, in experimental animal models, low dietary potassium intake induces kidney injury through stimulation of ammoniagenesis. In humans, low potassium intake is an established risk factor for high blood pressure., Objective: We hypothesized that low 24-h urinary potassium excretion [UKV; urinary potassium concentration × volume], the gold standard for assessment of dietary potassium intake, represents a risk factor for graft failure and mortality in RTRs. In secondary analyses, we aimed to investigate whether these associations could be explained by ammoniagenesis, plasma potassium, or blood pressure., Design: In a prospective cohort of 705 RTRs, we assessed dietary potassium intake by a single 24-h UKV and food-frequency questionnaires. Cox regression analyses were used to investigate prospective associations with outcome., Results: We included 705 stable RTRs (mean ± SD age: 53 ± 13 y; 57% men) at 5.4 y (IQR: 1.9-12.0 y) after transplantation and 253 kidney donors. Mean ± SD UKV was 73 ± 24 mmol/24 h in RTRs compared with 85 ± 25 mmol/24 h in kidney donors. During follow-up for 3.1 y (IQR: 2.7-3.9 y), 45 RTRs developed graft failure and 83 died. RTRs in the lowest sex-specific tertile of UKV (women, <55 mmol/24 h; men, <65 mmol/24 h) had an increased risk of graft failure (HR: 3.70; 95% CI: 1.64, 8.34) and risk of mortality (HR; 2.66; 95% CI: 1.53, 4.61), independent of potential confounders. In causal path analyses, 24-h urinary ammonia excretion, plasma potassium, and blood pressure did not affect these associations., Conclusions: Our results indicate that low UKV is associated with a higher risk of graft failure and mortality in RTRs. Specific attention for adequate potassium intake after transplantation seems warranted. This trial was registered at clinicaltrials.gov as NCT02811835., (© 2016 American Society for Nutrition.)

Background and Aims: A high circulating fibroblast growth factor 23 (FGF23) level is an independent risk factor for cardiovascular mortality in renal transplant recipients and the general population. N-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) may contribute to cardiovascular risk reduction. We investigated whether fish and EPA-DHA intake are related to FGF23 levels in renal transplant recipients., Methods and Results: We performed a cross-sectional analysis in 619 stable renal transplant recipients (mean age 53 years, 57% male, estimated glomerular filtration rate [eGFR] 53 ± 20 mL/min/1.73 m(2)). Dietary intake was assessed by a 177-item food frequency questionnaire. Serum intact FGF23 was measured by ELISA. We examined differences in FGF23 levels across categories of fish and EPA-DHA intake using analysis of variance models adjusted for age, sex, dietary and lifestyle factors and key determinants of FGF23. Patients consumed on average 15 g of fish and 139 mg EPA-DHA/day. Median FGF23 was 62 pg/mL (IQR 43-98 pg/mL). Higher dietary EPA-DHA and fish intake were associated with lower serum FGF23 levels. Subgroup analyses revealed that particularly in patients with reduced renal function (eGFR <60 mL/min/1.73 m(2)), adjusted FGF23 levels (114, 79, 75 pg/mL, P = 0.0001) were inversely associated with tertiles of EPA-DHA intake. Similarly, we observed an inverse association between fish consumption and serum FGF23 levels in adjusted analyses., Conclusion: A higher intake of fish and dietary n-3 fatty acids (EPA-DHA) is related to lower circulating FGF23 levels in renal transplant recipients. Further research is needed to assess the causality of this association and the clinical implications., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic interventions, the number of patients with end stage renal disease steadily increases. Hydrogen sulfide (H(2)S) is an endogenously produced gasotransmitter with vasodilatory, anti-inflammatory and antioxidant properties. These beneficial characteristics make H(2)S an attractive candidate for pharmacological use in hypertensive renal disease. We investigated the protective properties of H(2)S in angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with the H(2)S donor NaHS and major H(2)S metabolite sodium thiosulfate (STS) during three weeks of Ang II infusion reduced hypertension, proteinuria, oxidative stress and renal functional and structural deterioration. In an ex vivo isolated perfused kidney setup, NaHS, but not STS, reduced intrarenal pressure. The effect of NaHS could partially be explained by its activation of the ATP-sensitive potassium channels. In conclusion, treatment with H(2)S attenuates Ang II-associated functional and structural renal deterioration, suggesting that intervention in H(2)S production pathways has potential therapeutic benefit and might be a valuable addition to the already existing antihypertensive and renoprotective therapies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Once patients with kidney disease progress to end-stage renal failure, transplantation is the preferred option of treatment resulting in improved quality of life and reduced mortality compared to dialysis. Although 1-year survival has improved considerably, graft and patient survival in the long term have not been concurrent, and therefore new tools to improve long-term graft and patient survival are warranted. Over the past decades, the gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) have emerged as potent cytoprotective mediators in various diseases. All three gasotransmitters are endogenously produced messenger molecules that possess vasodilatory, anti-apoptotic, anti-inflammatory and anti-oxidant properties by influencing an array of intracellular signaling processes. Although many regulatory functions of gasotransmitters have overlapping actions, differences have also been reported. In addition, crosstalk between NO, CO and H2S results in synergistic regulatory effects. Endogenous and exogenous manipulation of gasotransmitter levels modulates several processes involved in renal transplantation. This review focuses on mechanisms of gas-mediated cytoprotection and complex interactions between gasotransmitters in renal transplantation., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Cerebral white matter lesions (WML) are associated with cognitive impairment, and carotid revascularization with cognitive worsening or improvement. We assessed the relation between WML severity and changes in cognition after carotid endarterectomy or stenting., Methods: Patients with symptomatic carotid artery stenosis, enrolled in the International Carotid Stenting Study (ISRCTN25337470), underwent detailed neuropsychological examinations (NPEs) before and after 6 months. Cognitive results were standardized into z-scores, from which a sum score was calculated. The primary outcome was the mean difference (MD) in sum score between baseline and follow-up. Changes in sum score were related to WML severity with the 'age-related white matter changes' score, assessed on baseline MRI-FLAIR. Three groups were formed based on this score., Results: Eighty-nine patients had both baseline MRI and NPE, of these 77 had a calculable cognitive difference score. The cognitive sum score at six months was worse than at baseline: MD, -0.21; 95% CI, -0.32 to -0.09. The change in sum score did not depend on WML load: MD for no-to-mild WML, -0.15; 95% CI, -0.39 to 0.09, for moderate WML, -0.27; 95% CI, -0.48 to -0.06; and for severe WML, -0.21; 95% CI, -0.40 to -0.04. This did not change essentially after adjustment for baseline factors., Conclusion: Cognitive functioning deteriorated after carotid revascularization, regardless of baseline WML burden., (© 2013 Elsevier B.V. All rights reserved.)

Aim: To examine the relation of performance on the self-administered Test Your Memory test (TYM) and the Mini-Mental State Examination (MMSE) with a comprehensive neuropsychological assessment in a population sample including people with modest cognitive decrements., Methods: Eighty-six participants (aged 56-77 years), without known cognitive dysfunction, performed a neuropsychological assessment including MMSE, and were asked to fill out the TYM. The relation between both the TYM and the MMSE and a neuropsychological assessment was examined by means of correlation analyses, area under the ROC curves for discriminating between a "normal" and "modest decrements"(≥1SD below the sample mean) group, and Bland-Altman plots., Results: Correlation with the full neuropsychological assessment was significantly stronger for the TYM than the MMSE (r=0.78 versus r=0.55; Steiger's Z=2.66, p<0.01). The TYM showed an area under the ROC-curve of 0.88 (95% CI 0.80 to 0.97) for differentiating between "normal" and "modest decrements" compared with 0.71 (0.53 to 0.90) for the MMSE. Bland-Altman plots showed limits of agreement for the TYM of -1.10 to 1.10 and for the MMSE of -1.39 to 1.38., Conclusions: The TYM showed good correlation with a neuropsychological assessment, performed better in discriminating between variations of cognition and showed more agreement with a neuropsychological assessment than the MMSE., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The metabolic syndrome (MetS) is associated with cognitive deficits and atherosclerotic vascular disease. We examined whether the relation between the MetS and cognitive dysfunction is mediated by measures of atherosclerosis or the presence of clinically manifest cardiovascular disease., Methods: In 380 individuals (153 with MetS; 60-87 years) from the population based Hoorn Study, measures of atherosclerosis including carotid intima-media thickness (c-IMT), flow mediated dilation (FMD), ankle-brachial index and the presence of clinically manifest cardiovascular disease were assessed at baseline and 7 later years at follow-up. Cognitive functioning (information processing speed, memory, and attention and executive functioning) was assessed at follow-up. The relation between the MetS, atherosclerosis and cognitive functioning was assessed with linear regression analysis., Results: Individuals with MetS showed worse performance on information processing speed (adjusted mean difference z-score ± SE: -0.22 ± 0.6; p = 0.01) and attention and executive functioning (-0.32 ± 0.07; p < 0.001), but not on the domain memory. The affected cognitive domains were also associated with measures of atherosclerosis (standardised B (95%CI) c-IMT: -0.14 (-0.24; -0.05); p < 0.01; FMD: 0.13 (0.02; 0.24), p < 0.05) and a history of clinically manifest cardiovascular disease: (-0.29 (-0.47; -0.11); p < 0.01). However, the relation between the MetS and cognitive functioning did not change after adjustment for c-IMT, FMD or a history of clinically manifest cardiovascular disease (p > 0.05)., Conclusion: In this population based cohort, the relation between the MetS and cognitive dysfunction was not mediated by atherosclerosis or a history of cardiovascular disease. These findings should stimulate future studies to elucidate alternative mechanisms underlying cognitive deficits in individuals with MetS., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Chromosomal translocations involving t(14;18)(q32;q21) and the chromosome 3q27 region are common in B-cell non-Hodgkin lymphoma of germinal center cell origin. Grade 3B follicular lymphoma (FL), consisting almost exclusively of centroblasts, is a distinct subgroup of follicular lymphomas that has more in common clinically with the aggressive diffuse large B-cell lymphomas than with their indolent FL grade 1 and 2 counterparts. We studied the cytogenetic and molecular genetic aberrations by classic cytogenetics, polymerase chain reaction, Southern blot hybridization, and fluorescence in situ hybridization, with special emphasis on t(14;18), affecting bcl-2, and 3q27 rearrangement, affecting bcl-6, in 32 cases of FL grade 3B. Three distinctive subgroups were identified based upon the existence of breakpoint 3q27, a translocation t(14;18), or the absence of both. Group I involved a t(14;18) and no 3q27 aberrations (n = 13); group II was without a t(14;18) and without 3q27 aberrations (n = 9), but had other cytogenetic aberrations; and group III was without a t(14;18) but with aberrations involving 3q27 (n = 10). None of the FL grade 3B cases harbored both a t(14;18) and 3q27 aberration. These results, in particular the finding of a mutual exclusiveness of bcl-2 and bcl-6 rearrangement, indicate at least 3 different pathways of oncogenesis in FL grade 3B. FL grade 3B with bcl-2 rearrangement probably is part of the same entity as the other follicular lymphomas (1, 2, 3A), whereas the cases with 3q27 abnormalities or other unrelated translocations are more closely related to the majority of diffuse large-cell lymphomas of germinal center cell origin.

Deletion of the multidrug resistance gene MRP1 has been demonstrated in acute myeloid leukemia (AML) patients with inversion of chromosome 16 (inv[16]). These AML patients are known to have a relatively favorable prognosis, which suggests that MRP1 might play an important role in determining clinical outcome. This study analyzed MRP1 deletion by fluorescent in situ hybridization (FISH), with a focus on inv(16) AML patients. Functional activity of multidrug resistance protein (MRP) was studied in a flow cytometric assay with the use of the MRP substrate carboxyfluorescein (CF) and the inhibitor MK-571. MRP1, MRP2, and MRP6 messenger RNA (mRNA) expression was determined with reverse transcriptase-polymerase chain reaction (RT-PCR). The results were compared with normal bone marrow cells. MRP1 deletion was detected in 7 AML patients; 2 cases showed no MRP1 FISH signals, and 5 cases had 1 MRP1 signal, whereas in 4 AML patients with inv(16) no MRP1 deletions were observed. A variability in MRP activity, expressed as CF efflux-blocking by MK-571, was observed (efflux-blocking factors varied between 1.2 and 3.6); this correlated with the number of MRP1 genes (r = 0.91, P <. 01). MRP activity in the AML cases was not different from normal hematopoietic cells. MRP1 mRNA was detected in patients with 1 or 2 MRP1 FISH signals, but not in patients with no MRP1 signals. MRP2 and MRP6 mRNA were expressed predominantly in AML samples with 1 MRP1 signal, whereas in normal bone marrow cells no MRP2 and MRP6 mRNA was observed. In conclusion, this study shows that MRP activity varies among inv(16) AML cases and does not differ from that in normal hematopoietic cells; this might be in part due to the up-regulation of other MRP genes.

Cytogenetic analysis was performed on peripheral blood lymphocytes of members of a family with inherited renal cell cancer. Four family members in three generations developed multiple/bilateral renal cell carcinomas of the clear cell type. In one additional case a bladder carcinoma was diagnosed. In two of the renal cell carcinoma patients a constitutional t(2;3)(q35;q21) was encountered, whereas in the two other (deceased) patients the presence of this translocation could be deduced. Also, the bladder cancer patient was found to be positive for t(2;3)(q35;q21). This is the third familial renal cell carcinoma-associated chromosomal translocation ever described. The previously reported cases also involved chromosome 3, thereby supporting the notion that this chromosome may play a crucial role in the development of renal cell carcinomas. Interestingly, the translocation breakpoints in these three families map at different locations, suggesting that multiple genes on chromosome 3 may be involved.

Endothelial cells play an important role in the regulation of fibrinolysis by the production of several key regulatory proteins. The cytokines tumor necrosis factor (TNF), lymphotoxin, and interleukin-1 (IL-1), but not interleukin-6, increase the production of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells, whereas they have no stimulatory effect on the production of tissue-type plasminogen activator (t-PA). Primary cultures of human endothelial cells release very little urokinase-type plasminogen activator (u-PA). We report here that TNF and lymphotoxin induce, in a concentration-dependent way, the production of both cellular and secreted u-PA antigen in primary and subcultured human endothelial cells. The TNF-induced increase was accompanied by a more than 10-fold increase in u-PA mRNA. Upon stimulation of early passage umbilical vein endothelial cells by TNF, u-PA was predominantly secreted at the basolateral side, whereas PAI activity and t-PA were found in more equal amounts at the apical and basolateral sides of the cell monolayers. TNF-stimulated u-PA secretion by subcultured human aorta endothelial cells showed only a marginal polarity. The u-PA antigen was present in a plasmin-activatable form (single chain u-PA) and in a nonactivatable form (probably u-PA: PAI-1 complex). During the induction of u-PA by TNF, the ratio between plasmin-activatable u-PA and total u-PA decreased markedly. This may indicate that TNF also increases the degree of u-PA activation. The parallel induction of the synthesis and secretion of both u-PA and PAI-1 by endothelial cells adds a new aspect to the alterations of the fibrinolytic system caused by inflammatory mediators. This aspect may be significant for the regulation of cell-associated and interstitial plasminogen activator activity.

Serotonin is released by activated platelets and may promote platelet aggregation and epicardial coronary artery constriction in animal models. Serotonin may have similar effects in humans and, thus may be a mediator of certain ischemic syndromes. However, the role of serotonin in human ischemic heart disease has not been studied. Since evaluation of transcardiac serotonin metabolism requires that blood samples be obtained through long catheters, it is possible that artifactual changes in serotonin concentration could occur because of platelet activation in the catheters themselves. Accordingly, to determine if serotonin could be measured through long catheters without artifactual changes, the authors obtained paired blood samples by gentle aspiration through a large bore steel needle and a 100-cm polyurethane catheter placed in the femoral vein of 13 patients. All samples were processed to obtain platelet-poor plasma and then analyzed by a sensitive radioenzymatic assay. Blood sampling through long catheters did not cause a systematic alteration in plasma serotonin concentration. Mean serotonin concentration from the femoral vein through a needle was 22.3 +/- 26.55 ng/ml (mean +/- standard deviation), and that obtained through a long catheter was 20.0 +/- 26.29 ng/ml (p = 0.34). The authors conclude that carefully obtaining blood samples through long catheters does not significantly alter the plasma serotonin concentration and thus the accurate measurement of transcardiac serotonin concentrations is possible using these methods.

Cisplatin is a platinum-containing antitumor agent whose usefulness is limited by nephrotoxicity. We examined the effects of cisplatin on a representative, transporting epithelium--the frog skin. Cisplatin (10(-3)M) from the mucosal surface increased the active transport of sodium by 35 to 40%, as monitored by short-circuit current. The cisplatin-induced increase in short-circuit current was inhibited by amiloride and was additive to the effects of vasopressin (20 mU/ml of serosal solution). Cisplatin from the mucosal surface also decreased transeptithelial electrical resistance by about 35% and increased the permeability to sodium, chloride, and urea. None of these effects of cisplatin occurred with platinum sulfate, platinum chloride, or the trans-isomer of cisplatin. Accordingly, we conclude that cisplatin increases the permeability of the mucosal surface of the frog skin to sodium, chloride, and urea and that these changes are related to the cis-configuration of the drug rather than simply its heavy metal moiety.

The vascular endothelium plays an important role in fibrinolysis by producing tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). The monokine tumor necrosis factor (human recombinant TNF) increased the production of PAI by cultured human endothelial cells from umbilical vein (twofold) and from foreskin microvessles (four to eight fold). This was demonstrated by titration of endothelial cell-conditioned medium with t-PA, by reverse fibrin autography, and by immunoprecipitation of [35S]PAI-1 by anti-PAI-1 IgG. TNF also induced a marked increase of PAI-1 messenger RNA (mRNA) in the cells. The stimulation of PAI activity by TNF was seen at 4 U/mL and reached a maximum at 500 U/mL. Human recombinant lymphotoxin and interleukin-1 (alpha and beta) also stimulated the production of PAI activity, while interleukin-6 was ineffective. Separate additions of TNF or interleukin-1 (IL-1) at optimal concentrations (500 U/mL and 5 U/mL, respectively) resulted in a comparable stimulation of PAI production by endothelial cells. The simultaneous addition of both mediators resulted in an additive effect. The effect of TNF could not be prevented by the addition of polymyxin B or by anti-IL-1 antibodies. Therefore, it is unlikely that TNF acts through the induction of IL-1 secretion by endothelial cells. Two hours after a bolus injection of 250,000 U/kg TNF into rats, a fivefold increase in circulating PAI levels was found. In the next ten hours, the levels returned to normal. Blood platelets do not significantly contribute to the increase in circulating PAI, because the number of platelets did not change after TNF injection and the amount of PAI in blood platelets is not sufficient for several hours during an increase in PAI activity. The acute phase reactants, fibrinogen and alpha 2-antiplasmin in rat plasma, were altered little if any two to 24 hours after injection of 250,000 U/kg TNF. In vitro, TNF did not change PAI production by human and rat hepatocytes in primary monolayer culture. Therefore, it is most likely that vascular endothelial cells contribute to the increased amount of circulating PAI induced by TNF in vivo. This increase in PAI activity might decrease fibrinolysis.