Effect of preoperative chemotherapy on the histopathological classification of gastric cancer.

BACKGROUND: In the era of individualized gastric cancer (GC) treatment, accurate determination of histological subtype becomes increasingly relevant. As yet, it is unclear whether preoperative chemotherapy may affect the histological subtype. The aim of this study was to assess concordance in histological subtype between pretreatment biopsies and surgical resection specimens before and after the introduction of perioperative treatment. METHODS: Histological subtype was centrally determined in paired GC biopsies and surgical resection specimens of patients treated with either surgery alone (SA) in the Dutch D1/D2 study or with preoperative chemotherapy (CT) in the CRITICS trial. The histological subtype as determined in the resection specimen was considered the gold standard. Concordance rates and sensitivity and specificity of intestinal, diffuse, mixed, and "other" subtypes of GC were analyzed. RESULTS: In total, 105 and 515 pairs of GC biopsies and resection specimens of patients treated in the SA and CT cohorts, respectively, were included. Overall concordance in the histological subtype was 72% in the SA and 74% in the CT cohort and substantially higher in the diffuse subtype (83% and 86%) compared to the intestinal (70% and 74%), mixed (21% and 33%) and "other" subtypes (54% and 54%). In the SA cohort, sensitivities and specificities were 0.88 and 0.71 in the intestinal, 0.67 and 0.93 in the diffuse, 0.20 and 0.98 in the mixed, and 0.50 and 0.93 in the "other" subtypes, respectively. CONCLUSION: Our results suggest that accurate determination of histological subtype on gastric cancer biopsies is suboptimal but that the impact of preoperative chemotherapy on histological subtype is negligible.

Changes in plasma levels of per- and polyfluoroalkyl substances (PFAS) are associated with changes in plasma lipids - A longitudinal study over 10 years.

BACKGROUND: Associations between per- and polyfluoroalkyl substances (PFAS), mainly PFOS and PFOA, and increased blood lipids have been reported primarily from cross-sectional studies. The aim of the present study was to investigate associations between multiple PFAS and blood lipids in a longitudinal fashion. METHODS: A total of 864 men and women aged 70 years and free from lipid medication were included from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study from Uppsala Sweden, 614 and 404 of those were reinvestigated at age 75 and 80. At all three occasions, eight PFAS were measured in plasma using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were also measured in plasma at all three occasions. Mixed-effects linear regression models were used to examine the relationship between the changes in PFAS levels and changes in lipid levels. RESULTS: Changes in plasma levels of six out of the eight investigated PFAS were positively associated with changes in plasma lipids after adjustment for sex, change in body mass index (BMI), smoking, physical activity, statin use (age was the same in all subjects), and correction for multiple testing. For example, changes in perfluorodecanoic acid (PFDA) were positively associated with the changes in total cholesterol (ß: 0.23, 95% confidence interval (CI): 0.14 to 0.32), triglycerides (ß: 0.08, 95% CI: 0.04-0.12) and HDL-cholesterol (ß: 0.08, 95% CI: 0.04-0.11). CONCLUSION: In this longitudinal study with three measurements over 10 years of both plasma PFAS and lipids, changes in six out of the eight investigated PFAS were positively associated with changes in plasma lipids, giving further support for a role of PFAS exposure in human lipid metabolism.

Serum levels of perfluoroalkyl substances (PFAS) and body composition - A cross-sectional study in a middle-aged population.

BACKGROUND: It has been suggested that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors with a potential to influence fat mass. OBJECTIVE: The primary hypothesis tested was that we would find positive relationships for PFAS vs measures of adiposity. METHODS: In 321 subjects all aged 50 years in the POEM study, five PFAS (perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA)) were measured in serum together with a Dual-energy X-ray absorptiometry (DXA) scan for determination of fat and lean mass. Whole-body magnetic resonance imaging scan was performed and the body was divided into >1 million voxels. Voxel-wise statistical analysis was carried out by a novel method denoted Imiomics. RESULTS: PFOS and PFHxS, did not show any consistent associations with body composition. However, PFOA, and especially PFNA and PFDA, levels were inversely related to most traditional measures reflecting the amount of fat in women, but not in men. In the Imiomics analysis of tissue volume, PFDA and PFNA levels were inversely related to the volume of subcutaneous fat, mainly in the arm, trunk and hip regions in women, while no such clear relationship was seen in men. Also, the visceral fat content of the liver, the pericardium, and the gluteus muscle were inversely related to PFDA and PFNA in women. DISCUSSION: Contrary to our hypothesis, some PFAS showed inverse relationships vs measurements of adiposity. CONCLUSION: PFOS and PFHxS levels in plasma did not show any consistent associations with body composition, but PFOA, and especially PFNA and PFDA were inversely related to multiple measures reflecting the amount of fat, but in women only.

Lipophilic Environmental Chemical Mixtures Released During Weight-Loss: The Need to Consider Dynamics.

Intentional weight loss can increase health risk in the long-term, despite short-term benefits, because human adipose tissue is widely contaminated with various lipophilic environmental contaminants, especially persistent organic pollutants (POPs). Recently, chronic exposure to low POPs has emerged as a new risk factor for common metabolic diseases and cardiovascular diseases. The amount of POPs released from adipocytes to the circulation increases during weight loss, thereby increasing POPs exposure of other critical organs. Possible harmful effects due to release of POPs during weight loss are opposite to those usually expected from losing weight. It is speculated that this tradeoff can explain recent puzzling findings on intensive weight loss. The presence of POPs in adipose tissue adds a challenge to weight management and an optimal strategy of weight management needs to consider both fat mass and dynamics of POPs.

Adjuvant chemotherapy is superior to chemoradiation after D2 surgery for gastric cancer in the per-protocol analysis of the randomized CRITICS trial.

BACKGROUND: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy (CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial. PATIENTS AND METHODS: The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib-Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival. RESULTS: Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios. CONCLUSION: After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).

The associations between p,p'-DDE levels and plasma levels of lipoproteins and their subclasses in an elderly population determined by analysis of lipoprotein content.

BACKGROUND: Lipoproteins at aberrant levels are known to play a role in cardiovascular disease. The metabolite of the insecticide dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), physically associates with lipids and accumulates in adipose tissue. Little is known about which lipoproteins associate with p,p'-DDE. An association between p,p'-DDE exposure and altered levels of circulating lipids was assessed in a large human cohort using a detailed analysis of lipoprotein content. METHODS: Plasma samples were collected from the subset of 75-year old Swedes in the Prospective Investigation of the Vasculature of Uppsala Seniors (PIVUS) cohort who were not prescribed lipid lowering medication (n = 571). p,p'-DDE concentrations in plasma were measured using high-throughput solid phase extraction and gas chromatography-high resolution mass spectrometry. Analysis of plasma lipoprotein content was performed with nuclear magnetic resonance spectroscopy. RESULTS: Detectable levels of p,p'-DDE were found in the plasma samples of all subjects. Elevated p,p'-DDE levels were associated with increased concentrations of lipoproteins of all diameters, with the exception of high density lipoprotein (HDL) of diameters between 14.3 nm-10.9 nm. Of the lipoprotein constituents, triglycerides were most uniformly associated with elevated p,p'-DDE across lipoproteins. p,p'-DDE was furthermore associated with apolipoprotein B, but not apolipoprotein A1. CONCLUSIONS: The positive associations observed between each lipoprotein class and elevated p,p'-DDE support previous data suggesting that p,p'-DDE interacts with lipoproteins within plasma. It is speculated that both physio-chemical and biological mechanisms may explain why p,p'-DDE does not uniformly associate with lipids across lipoproteins.

Developmental exposure to a very low dose of bisphenol A induces persistent islet insulin hypersecretion in Fischer 344 rat offspring.

BACKGROUND: In children with obesity, accentuated insulin secretion has been coupled with development of type 2 diabetes mellitus (T2DM). Bisphenol A (BPA) is a chemical with endocrine- and metabolism-disrupting properties which can be measured in a majority of the population. Exposure to BPA has been associated with the development of metabolic diseases including T2DM. OBJECTIVE: The aim of this study was to investigate if exposure early in life to an environmentally relevant low dose of BPA causes insulin hypersecretion in rat offspring. METHODS: Pregnant Fischer 344 rats were exposed to 0.5 (BPA0.5) or 50 (BPA50) µg BPA/kg BW/day via drinking water from gestational day 3.5 until postnatal day 22. Pancreata from dams and 5- and 52-week-old offspring were procured and islets were isolated by collagenase digestion. Glucose-stimulated insulin secretion and insulin content in the islets were determined by ELISA. RESULTS: Basal (5.5 mM glucose) islet insulin secretion was not affected by BPA exposure. However, stimulated (11 mM glucose) insulin secretion was enhanced by about 50% in islets isolated from BPA0.5-exposed 5- and 52-week-old female and male offspring and by 80% in islets from dams, compared with control. In contrast, the higher dose, BPA50, reduced stimulated insulin secretion by 40% in both 5- and 52-week-old female and male offspring and dams, compared with control. CONCLUSION: A BPA intake 8 times lower than the European Food Safety Authority's (EFSA's) current tolerable daily intake (TDI) of 4 µg/kg BW/day of BPA delivered via drinking water during gestation and early development causes islet insulin hypersecretion in rat offspring up to one year after exposure. The effects of BPA exposure on the endocrine pancreas may promote the development of metabolic disease including T2DM.

Developmental low-dose exposure to bisphenol A induces chronic inflammation, bone marrow fibrosis and reduces bone stiffness in female rat offspring only.

BACKGROUND: Developmental exposure to low doses of the endocrine disruptor bisphenol A (BPA) is known to alter bone tissue in young rodents, although how bone tissue is affected in aged animals is not well known. We have recently shown that low-dose developmental exposure to BPA increases procollagen type I N-terminal propeptide (P1NP) levels, a peptide formed during type 1 collagen synthesis, in plasma of 5-week-old female rat offspring while male offspring showed reduced bone size. OBJECTIVE: To analyze offspring bone phenotype at 52 weeks of age and clarify whether the BPA-induced increase in P1NP levels at 5 weeks is an early sign of bone marrow fibrosis development. METHODS: As in our 5-week study, pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5 µg/kg BW/day (BPA0.5), which is in the range of human daily exposure, or 50 µg/kg BW/day (BPA50) from gestational day 3.5 until postnatal day 22. Controls were given only vehicle. The offspring were sacrificed at 52 weeks of age. Bone effects were analyzed using peripheral quantitative and micro-computed tomography (microCT), 3-point bending test, plasma markers and histological examination. RESULTS: Compared to a smaller bone size at 5 weeks, at the age of 52 weeks, femur size in male offspring had been normalized in developmentally BPA-exposed rats. The 52-week-old female offspring showed, like the 5-week-old siblings, higher plasma P1NP levels compared to controls but no general increasing bone growth or strength. However, 2 out of 14 BPA-exposed female offspring bones developed extremely thick cortices later in life, discovered by systematic in vivo microCT scanning during the study. This was not observed in male offspring or in female controls. Biomechanical testing revealed that both doses of developmental BPA exposure reduced femur stiffness only in female offspring. In addition, histological analysis showed an increased number of fibrotic lesions only in the bone marrow of female rat offspring developmentally exposed to BPA. In line with this, plasma markers of inflammation, Tnf (in BPA0.5) and Timp1 (in BPA50) were increased exclusively in female offspring. CONCLUSIONS: Developmental BPA exposure at an environmentally relevant concentration resulted in female-specific effects on bone as well as on plasma biomarkers of collagen synthesis and inflammation. Even a dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4 µg/kg BW/day, appeared to induce bone stiffness reduction, bone marrow fibrosis and chronic inflammation in female rat offspring later in life.

Bridging between load-flow and Kuramoto-like power grid models: A flexible approach to integrating electrical storage units.

In future power systems, electrical storage will be the key technology for balancing feed-in fluctuations. With increasing share of renewables and reduction of system inertia, the focus of research expands toward short-term grid dynamics and collective phenomena. Against this backdrop, Kuramoto-like power grids have been established as a sound mathematical modeling framework bridging between the simplified models from nonlinear dynamics and the more detailed models used in electrical engineering. However, they have a blind spot concerning grid components, which cannot be modeled by oscillator equations, and hence do not allow one to investigate storage-related issues from scratch. Our aim here is twofold: First, we remove this shortcoming by adopting a standard practice in electrical engineering and bring together Kuramoto-like and algebraic load-flow equations. This is a substantial extension of the current Kuramoto-like framework with arbitrary grid components. Second, we use this concept and demonstrate the implementation of a storage unit in a wind power application with realistic feed-in conditions. We show how to implement basic control strategies from electrical engineering, give insights into their potential with respect to frequency quality improvement, and point out their limitations by maximum capacity and finite-time response. With that, we provide a solid starting point for the integration of flexible storage units into Kuramoto-like grid models enabling to address current problems like smart storage control, optimal siting, and rough cost estimations.

Endocrine-disrupting chemicals and risk of diabetes: an evidence-based review.

The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection of environmental endocrine-disrupting chemicals (EDCs) with diabetes and impaired glucose metabolism. The review summarises the literature on both cross-sectional and prospective studies in humans, as well as experimental in vivo and in vitro studies. The findings were subjected to evidence grading according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. We found >40 cross-sectional and seven prospective studies regarding EDCs and risk of diabetes. Taken together, there is moderate evidence for a relationship between exposure to dichlorodiphenyldichloroethylene (p,p'-DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane, and diabetes development. Regarding polychlorinated biphenyls (PCBs), it is likely that the rodent models used are not appropriate, and therefore the evidence is poorer than for p,p'-DDE. For other EDCs, such as bisphenol A, phthalates and perfluorinated chemicals, the evidence is scarce, since very few prospective studies exist. Brominated flame retardants do not seem to be associated with a disturbed glucose tolerance. Thus, evidence is accumulating that EDCs might be involved in diabetes development. Best evidence exists for p,p'-DDE. For other chemicals, both prospective studies and supporting animal data are still lacking.

Longitudinal changes in persistent organic pollutants (POPs) from 2001 to 2009 in a sample of elderly Swedish men and women.

BACKGROUND: Prospective cohort studies evaluating the temporal trends of background-level persistent organic pollutants (POPs) and their potential negative health effects in humans are needed. OBJECTIVE: The objectives of this study are to examine the five year longitudinal trend in chlorinated and brominated (Cl/Br) POP concentrations in a sample of elderly individuals and to investigate the relationship between gender, changes in body weight, plasma lipid levels and POP concentrations. METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, plasma samples were collected from the same individuals over a 5 year period. Originally 992 subjects (all aged 70) were sampled between 2001 and 2004 and 814 returning subjects (all aged 75) were sampled again from 2006 to 2009. Plasma concentrations of 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and one polybrominated diphenylether (BDE 47) were determined using high-throughput 96-well plate solid phase extraction and gas chromatography-high resolution mass spectrometry (GC-HRMS). RESULTS: During the 5-year follow-up, plasma concentrations of all POPs significantly decreased (p < 0.00001). Median reductions ranged from 4% (PCB105) to 45% (PCB 99), with most reductions being in the 30-40% range. For most POPs, a larger decline was seen in men than in women. The relationship between the weight change and change in POP concentrations was generally negative, but a positive relationship between lipid levels and POP concentrations when expressed as wet-weight was observed. In general, similar changes in POP concentrations and their relationships to body weight were observed regardless of using either wet-weight (pg/mL) or lipid-normalized (ng/g lipid) concentrations. CONCLUSION: In this longitudinal cohort study, gender and minor, but varying changes in body weight and lipid levels greatly influenced the individual-based changes in POP concentrations. In general, our findings suggest that men and women with larger decreases in body weight and greater increases in lipid levels have the slowest decline in body burden of POPs. Based on the results from this study, either wet-weight or lipid normalized concentrations can be used to determine the percent change in POP concentrations and their relationships to physiological changes and differences.

The association between p,p'-DDE levels and left ventricular mass is mainly mediated by obesity.

BACKGROUND AND OBJECTIVES: The pesticide metabolite p,p'-DDE has been associated with left ventricular (LV) mass and known risk factors for LV hypertrophy in humans and in experimental models. We hypothesized that the associations of p,p'-DDE with LV hypertrophy risk factors, namely elevated glucose, adiposity and hypertension, mediate the association of p,p'-DDE with LV mass. METHODS: p,p'-DDE was measured in plasma from 70-year-old subjects (n = 988) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). When these subjects were 70-, 75- and 80- years old, LV characteristics were measured by echocardiography, while fasting glucose, body mass index (BMI) and blood pressure were assessed with standard clinical techniques. RESULTS: We found that p,p'-DDE levels were associated with increased fasting glucose, BMI, hypertension and LV mass in separate models adjusted for sex. Structural equation modeling revealed that the association between p,p'-DDE and LV mass was almost entirely mediated by BMI (70%), and also by hypertension (19%). CONCLUSION: The obesogenic effect of p,p'-DDE is a major determinant responsible for the association of p,p'-DDE with LV mass.

Low-dose developmental bisphenol A exposure alters fatty acid metabolism in Fischer 344 rat offspring.

BACKGROUND: Bisphenol A (BPA) is an endocrine disruptor and also a suggested obesogen and metabolism-disrupting chemical. Accumulating data indicates that the fatty acid (FA) profile and their ratios in plasma and other metabolic tissues are associated with metabolic disorders. Stearoyl-CoA desaturase 1 (SCD-1) is a key regulator of lipid metabolism and its activity can be estimated by dividing the FA product by its precursor measured in blood or other tissues. OBJECTIVE: The primary aim of this study was to investigate the effect of low-dose developmental BPA exposure on tissue-specific FA composition including estimated SCD-1 activity, studied in 5- and 52-week (wk)-old Fischer 344 (F344) rat offspring. METHODS: Pregnant F344 rats were exposed to BPA via their drinking water corresponding to 0: [CTRL], 0.5: [BPA0.5], or 50 µg/kg BW/day: [BPA50], from gestational day 3.5 until postnatal day 22. RESULTS: BPA0.5 increased SCD-16 (estimated as the 16:1n-7/16:0 ratio) and SCD-18 (estimated as the 18:1n-9/18:0 ratio) indices in inguinal white adipose tissue triglycerides (iWAT-TG) and in plasma cholesterol esters (PL-CE), respectively, in 5-wk-old male offspring. In addition, BPA0.5 altered the FA composition in male offspring, e.g. by decreasing levels of the essential polyunsaturated FA linoleic acid (18:2n-6) in iWAT-and liver-TG. No differences were observed regarding the studied FAs in 52-wk-old offspring, although a slightly increased BW was observed in 52-wk-old female offspring. CONCLUSIONS: Low-dose developmental BPA exposure increased SCD-16 in iWAT-TG and SCD-18 in PL-CE of male offspring, which may reflect higher SCD-1 activity in these tissues. Altered desaturation activity and signs of altered FA composition are novel findings that may indicate insulin resistance in the rat offspring. These aforementioned results, together with the observed increased BW, adds to previously published data demonstrating that BPA can act as a metabolism disrupting chemical.

Changes in plasma levels of perfluoroalkyl substances (PFASs) are related to increase in carotid intima-media thickness over 10 years - a longitudinal study.

BACKGROUND: It has previously been reported that the environmental contaminants perfluoroalkyl substances (PFASs) are linked to atherosclerosis in cross-sectional studies. Since cross-sectional studies could be subject to reverse causation, the purpose of this study was to analyze if the longitudinal changes in PFASs during a 10-year follow-up were related to the change in carotid artery intima-media thickness (IMT, ultrasound) during the same period. METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 1016 individuals were investigated at age 70; 826 of them were reinvestigated at age 75 and 602 at age 80 years. Eight different PFASs were measured in plasma by ultra-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and IMT was measured at all three time points. Random-effects mixed regression models were used to examine the associations over time. RESULTS: IMT increased 0.058 mm during the 10-year period (p < 0.0001). Following adjustment for baseline values of PFASs (age 70) and sex, the changes in plasma levels of 6 of the 8 measured PFASs were significantly related to the change in IMT over the 10-year follow-up period in a positive fashion (p < 0.0062 using Bonferroni correction for 8 tests). Further adjustment for traditional cardiovascular (CV) risk factors (HDL and LDL cholesterol, smoking, systolic blood pressure, statin use, fasting glucose and serum triglycerides) affected these relationships only marginally. CONCLUSION: The change in plasma levels of several PFASs during 10 years was positively related to increase in IMT seen during the same period, giving prospective evidence that PFASs might interfere with the atherosclerotic process.

Genome-wide association study of toxic metals and trace elements reveals novel associations.

The accumulation of toxic metals in the human body is influenced by exposure and mechanisms involved in metabolism, some of which may be under genetic control. This is the first genome-wide association study to investigate variants associated with whole blood levels of a range of toxic metals. Eleven toxic metals and trace elements (aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead and zinc) were assayed in a cohort of 949 individuals using mass spectrometry. DNA samples were genotyped on the Infinium Omni Express bead microarray and imputed up to reference panels from the 1000 Genomes Project. Analyses revealed two regions associated with manganese level at genome-wide significance, mapping to 4q24 and 1q41. The lead single nucleotide polymorphism (SNP) in the 4q24 locus was rs13107325 (P-value = 5.1 × 10(-11), ß = -0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. The lead SNP in the 1q41 locus is rs1776029 (P-value = 2.2 × 10(-14), ß = -0.46). The SNP lies within the intronic region of SLC30A10, another transporter protein. Among other metals, the loci 6q14.1 and 3q26.32 were associated with cadmium and mercury levels (P = 1.4 × 10(-10), ß = -1.2 and P = 1.8 × 10(-9), ß = -1.8, respectively). Whole blood measurements of toxic metals are associated with genetic variants in metal transporter genes and others. This is relevant in inferring metabolic pathways of metals and identifying subsets of individuals who may be more susceptible to metal toxicity.

Circulating levels of perfluoroalkyl substances (PFASs) and carotid artery atherosclerosis.

BACKGROUND AND OBJECTIVE: During recent years, some persistent organic pollutants (POPs) have been linked to atherosclerosis. One group of POPs, the poly- and perfluoroalkyl substances (PFASs) have not been investigated with regard to atherosclerotic plaques. METHODS: Carotid artery atherosclerosis was assessed by ultrasound in 1016 subjects aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFASs were detected in >75% of participants' plasma by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). RESULTS: No significant linear associations were observed between the PFASs and intima-media thickness (IMT), or the echogenicity in the intima-media complex (IM-GSM, a marker of lipid infiltration in the artery) when men and women were analyzed together. Neither was occurrence of carotid plaques related to PFASs levels. However, highly significant interactions were observed between some PFASs and sex regarding both IM-GSM and plaque prevalence. Perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), were all related to IM-GSM in a positive fashion in women (p=0.002-0.003), while these relationships were negative in men. The levels of PFUnDA were significantly related to carotid plaque in women (OR 1.59, 95%CI 1.03-2.43, p=0.03), but not in men (OR 0.93, 95%CI 0.62-1.42, p=0.75). CONCLUSIONS: In this cross-sectional study, a pronounced gender difference was observed regarding associations between some PFASs, especially the long-chain PFUnDA, and markers of atherosclerosis, with more pronounced relationships found in women. These findings suggest a sex-specific role for PFASs in atherosclerosis.

Low-dose developmental exposure to bisphenol A induces sex-specific effects in bone of Fischer 344 rat offspring.

BACKGROUND: Bisphenol A (BPA) is a component of polycarbonate plastics to which humans are regularly exposed at low levels, and an endocrine disruptor with effects on several hormonal systems. Bone is a sensitive hormone target tissue, and we have recently shown that in utero and lactational exposure to 25µg BPA/kg BW/day alters femoral geometry in rat offspring. OBJECTIVE: To investigate bone effects in rat offspring after developmental exposure to a BPA dose in the range of human daily exposure (0.1-1.5µg/kg BW/day) as well as a dose to corroborate previous findings. METHODS: Pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5µg/kg BW/day: [0.5], (n=21) or 50µg/kg BW/day: [50], (n = 16) from gestational day 3.5 until postnatal day 22, while controls were given only vehicle (n = 25). The offspring was sacrificed at 5 weeks of age. Bone effects were analyzed using peripheral quantitative computed tomography (pQCT), the 3-point bending test, plasma markers of bone turnover, and gene expression in cortical bone and bone marrow. RESULTS: Compared to controls, male offspring developmentally exposed to BPA had shorter femurs. pQCT analysis revealed effects in the [0.5] group, but not in the [50] group; BPA reduced both trabecular area (-3.9%, p < 0.01) and total cross sectional area (-4.1%, p < 0.01) of femurs in the [0.5] group, whereas no effects were seen on bone density. Conversely, bone length and size were not affected in female offspring. However, the procollagen type I N-terminal propeptide (P1NP), a peptide formed during type 1 collagen synthesis, was increased in plasma (42%: p < 0.01) in female offspring exposed to [0.5] of BPA, although collagen gene expression was not increased in bone. The biomechanical properties of the bones were not altered in either sex. Bone marrow mRNA expression was only affected in male offspring. CONCLUSIONS: Developmental low-dose exposure to BPA resulted in sex-specific bone effects in rat offspring. A dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4µg/kg BW/day, reduced bone length and size in male rat offspring. Long-term studies are needed to clarify whether the increased plasma levels of P1NP in female offspring reflect development of fibrosis.

The effect of drinking water contaminated with perfluoroalkyl substances on a 10-year longitudinal trend of plasma levels in an elderly Uppsala cohort.

BACKGROUND: In 2012, drinking water contaminated with per- and polyfluoroalkyl substances (PFASs), foremost perfluorooctanesulfonic acid (PFOS) and perfluorohexanesulfonic acid (PFHxS) at levels over 20ng/L and 40ng/L, respectively, was confirmed in Uppsala, Sweden. OBJECTIVES: We assessed how a longitudinally sampled cohort's temporal trend in PFAS plasma concentration was influenced by their residential location and determined the plausible association or disparity between the PFASs detected in the drinking water and the trend in the study cohort. METHODS: The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort provided plasma samples three times from 2001 to 2014. Individuals maintaining the same zip code throughout the study (n = 399) were divided into a reference (no known PFAS exposure), low, intermediate and high exposure area depending on the proportion of contaminated drinking water received. Eight PFASs detected in the majority (75%) of the cohort's plasma samples were evaluated for significant changes in temporal PFAS concentrations using a random effects (mixed) model. RESULTS: PFHxS plasma concentrations continued to significantly increase in individuals living in areas receiving the largest percentage of contaminated drinking water (p < 0.0001), while PFOS showed an overall decrease. The temporal trend of other PFAS plasma concentrations did not show an association to the quality of drinking water received. CONCLUSIONS: The distribution of contaminated drinking water had a direct effect on the trend in PFHxS plasma levels among the different exposure groups, resulting in increased concentrations over time, especially in the intermediate and high exposure areas. PFOS and the remaining PFASs did not show the same relationship, suggesting other sources of exposure influenced these PFAS plasma trends.

A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction.

BACKGROUND: Neoadjuvant therapy improves long-term survival after oesophagectomy, treating oesophageal cancer, but the evidence to date is insufficient to determine which of the two main neoadjuvant therapy types, chemotherapy (nCT) or chemoradiotherapy (nCRT), is more beneficial. We aimed to compare the effects of nCT with those of nCRT. PATIENTS AND METHODS: This multicentre trial, which was conducted in Sweden and Norway, recruited 181 patients with carcinoma of the oesophagus or the gastro-oesophageal junction who were candidates for curative-intended treatment. The primary end point was histological complete response after neoadjuvant treatment, which has been shown to be correlated with increased long-term survival. Study participants were randomized to nCT or nCRT, followed by surgery with two-field lymphadenectomy. Three cycles of platin/5-fluorouracil were administered in both arms, whereas 40 Gy of concomitant radiotherapy was added in the nCRT arm. RESULTS: The trial met the primary end point, histological complete response being achieved in 28% after nCRT versus 9% after nCT (P = 0.002). Lymph-node metastases were observed in 62% in the nCT group versus 35% in the nCRT group (P = 0.001). The R0 resection rate was 87% after nCRT and 74% after nCT (P = 0.04). There was no difference in overall survival between the treatment arms. CONCLUSION: The addition of radiotherapy to neoadjuvant chemotherapy results in higher histological complete response rate, higher R0 resection rate, and a lower frequency of lymph-node metastases, without significantly affecting survival. CLINICALTRIALSGOV: NCT01362127 (https://clinicaltrials.gov; The full study protocol was registered in the Clinical Trials Database).

Circulating levels of perfluoroalkyl substances are associated with dietary patterns - A cross sectional study in elderly Swedish men and women.

BACKGROUND: In our daily life, we are exposed to perfluoroalkyl substances (PFAS) with possible health implications. The main exposure route for these substances is diet but comparative studies on how dietary habits influence exposure are lacking. OBJECTIVES: To examine the relations between blood levels of PFAS and adherence to three predefined dietary patterns (a WHO recommended diet, a Mediterranean-like diet, and a Low-Carbohydrate High-Protein (LCHP) diet) in an elderly Swedish population. METHODS: Dietary data from 7-day food records and serum concentrations of PFAS were obtained from a 70-year-old Swedish population (n=844), the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. The Healthy Diet Indicator score (based on WHO recommendations), the Mediterranean Diet Score and LCHP score were used to assess adherence. Multivariate linear regression was used to assess the associations between eight major PFAS and adherence to each dietary pattern. RESULTS: The WHO recommended diet was positively associated with perfluorohexane sulfonic acid (PFHxS). The LCHP diet was positively related to four out of eight PFAS; namely, perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFUnDA). The Mediterranean-like diet was positively associated with most PFAS; namely perfluorooctanoic acid (PFOA), perfluorooctane sulfonamide (PFOSA), PFHxS, PFNA, PFDA, and PFUnDA. CONCLUSIONS: All dietary patterns were positively associated with blood levels of PFAS. The highest body burden of PFAS was found in individuals with high adherence to a Mediterranean-like diet, whilst individuals who more closely followed the officially recommended diet displayed a lower body burden of these compounds.