Development of a decision support tool to compare diagnostic strategies for establishing the herd status for infectious diseases: An example with Salmonella Dublin infection in dairies.

The diagnosis of infectious diseases at herd level can be challenging as different stakeholders can have conflicting priorities. The current study proposes a "proof of concept" of an approach that considers a reasonable number of criteria to rank plausible diagnostic strategies using multi-criteria decision analysis (MCDA) methods. The example of Salmonella Dublin diagnostic in Québec dairy herds is presented according to two epidemiological contexts: (i) in herds with no history of S. Dublin infection and absence of clinical signs, (ii) in herds with a previous history of infection, but absence of clinical signs at the moment of testing. Multiple multiparty exchanges were conducted to determine: 1) stakeholders' groups; 2) the decision problem; 3) solutions to the problem (options) or diagnostic strategies to be ordered; 4) criteria and indicators; 5) criteria weights; 6) the construction of a performance matrix for each option; 7) the multi-criteria analyses using the visual preference ranking organization method for enrichment of evaluations approach; 8) the sensitivity analyses, and 9) the final decision. A total of nine people from four Québec's organizations (the dairy producers provincial association along with the DHI company, the ministry of agriculture, the association of veterinary practitioners, and experts in epidemiology) composed the MCDA team. The decision problem was "What is the optimal diagnostic strategy for establishing the status of a dairy herd for S. Dublin infection when there are no clinical signs of infection?". Fourteen diagnostic strategies composed of the three following parameters were considered: 1) biological samples (bulk tank milk or blood from 10 heifers aged over three months); 2) sampling frequencies (one to three samples collection visits); 3) case definitions to conclude to a positive status using imperfect milk- or blood-ELISA tests. The top-ranking diagnostic strategy was the same in the two contexts: testing the bulk tank milk and the blood samples, all samples collected during one visit and the herd being assigned a S. Dublin positive status if one sample is ELISA-positive. The final decision favored the top-ranking option for both contexts. This MCDA approach and its application to S. Dublin infection in dairy herds allowed a consensual, rational, and transparent ranking of feasible diagnostic strategies while taking into account the diagnostic tests accuracy, socio-economic, logistic, and perception considerations of the key actors in the dairy industry. This promising tool can be applied to other infectious diseases that lack a well-established diagnostic procedure to define a herd status.

Vaccination protocols in Québec dairy herds.

Information is needed on vaccination protocols used by veterinarians and dairy producers to prevent and control infections in dairy herds. This observational study described farm's vaccination standard operating procedures (SOP) developed by veterinarians in collaboration with dairy producers in Québec. Data pertaining to vaccination protocols and dairy producer practices were collected as part of the biosecurity component of the National Mandatory Quality Assurance Certification Program (proAction). Generalized statistical mixed-effects models were used to assess associations between dairy herd characteristics and the vaccination SOP, encompassing various vaccination types. These included any vaccination, core vaccines only (bovine respiratory syncytial virus, infectious bovine rhinotracheitis herpesvirus, parainfluenza virus type 3, bovine viral diarrhea virus type 1 and type 2) and vaccination against diarrhea, mastitis, or clostridial diseases. These models accounted for random variations related to clustering by veterinarians and veterinary clinics. Furthermore, the variance of the outcome was partitioned into producer, veterinarian, and veterinary clinic levels to explore the proportion of the total variance attributable to each group. A total of 3,759 standardized vaccination procedures completed between 2018 and 2021 were analyzed. At least one vaccination target was included in the vaccination SOP in 89% of the dairy herds. The most frequently included vaccine in the SOP was core vaccines, comprising 88%, followed by mastitis (22%), neonatal diarrhea (18%), and clostridial diseases (15%). The vaccination SOPs, particularly core, mastitis, and diarrhea vaccinations, mainly varied due to the veterinarian's characteristics, followed by the clinic's characteristics. In contrast, the decision to included clostridial vaccination primarily varied with the veterinary clinic (76%). Organic producers generally included fewer vaccinations in their SOPs, including core vaccines, than conventional producers. In addition, producers who were providing access to pasture had fewer vaccination SOP for vaccination against mastitis and neonatal diarrhea but more vaccination SOP for clostridial vaccination.

Barriers and facilitators to implementing a new regulation restricting antimicrobial use in dairy production in Québec, Canada: A qualitative study.

With the emergence of antimicrobial resistance (AMR), many countries are implementing restrictive regulations to reduce antimicrobial use (AMU) in animal production. Although these measures are effective at the national level, their implementation may generate challenges for producers and veterinarians. The objective of this study was to explore the barriers and facilitators of implementing a new regulation restricting the use of antimicrobials of very high importance for human health in the dairy production sector in the province of Québec, Canada. Individual interviews were conducted with fifteen veterinarians and twenty-seven dairy producers. Thematic analysis was performed based on the COM-B model of behavior change (capability-opportunity-motivation-behavior). Our results indicated that the lack of availability of alternative treatments, the long delays related to diagnostic tests and the fear of economic consequences were major barriers to the implementation of the regulation. A small number of producers also perceived that the regulation negatively impacted the health and wellbeing of their animals. Additionally, participants acknowledged the importance of early education and training to better understand the purpose of the regulation and increase its acceptability. Lastly, most participants reported that they had not only reduced their use of antimicrobials of very high importance for human health following the regulation, but they had also increased preventive practices on their farm. This study reveals that the implementation of restrictive regulations to reduce AMU in animal production can lead to multiple challenges in practice. Our results highlight the need for better communication and training of producers and veterinarians before and during the implementation of similar regulations in the future and underline the importance of measuring the direct and indirect impacts of those regulations on productivity and on animal health and wellbeing.

Clonal and plasmidic dissemination of critical antimicrobial resistance genes through clinically relevant ExPEC and APEC-like lineages (ST) in the dairy cattle population of Québec, Canada.

Antimicrobial resistance can be effectively limited by improving the judicious use of antimicrobials in food production. However, its effect on the spread of AMR genes in animal populations is not well described. In the province of Québec, Canada, a new legislation implemented in 2019 has led to an unprecedented reduction in the use of critical antimicrobials in dairy production. We aimed to investigate the potential link between ESBL/AmpC E. coli isolated before and after legislation and to determine the presence of plasmids carrying genes responsible for critical AMR. We collected fecal samples from calves, cows, and manure pit from 87 Québec dairy farms approximately 2 years before and 2 years after the legislation came into effect. The whole genomes of 183 presumptive ESBL/AmpC E. coli isolated after cefotaxime enrichment were sequenced. Their phylogenetic characteristics (MLST, serogroup, cgMLST) and the presence of virulence and resistance genes and replicons were examined. A maximum likelihood phylogenetic tree was constructed based on single nucleotide polymorphism (SNPs). We identified 10 clonal lineages (same cgMLST) and 7 clones (SNPs ≤ 52). Isolates belonging to these clones could be found on different farms before and after the legislation, strongly suggesting a clonal spread of AMR genes in the population during this 4-year period. All isolates were multidrug resistant (MDR), with clone 2 being notable for the presence of macrolide, fluoroquinolone, and third-generation cephalosporin resistance genes. We also identified clinically relevant ExPEC (ST10) and APEC-like lineages (ST117, ST58, ST88) associated with the presence of ExPEC and APEC virulence genes, respectively. Our data also suggests the presence of one epidemic plasmid belonging to the IncY incompatibility group and carrying qnrs1 and blaCTX-M-15. We demonstrated that AMR genes spread through farms and can persist over a 4-year period in the dairy cattle population through both plasmids and E. coli clones, despite the restriction of critical antimicrobial use. MDR ExPEC and APEC-like STs are present in the normal microbiota of cattle (more frequently in calves). These data increase our knowledge on gene dissemination dynamics and highlight the fact that biosecurity measures should be enhanced in this industry to limit such dissemination.

Impact of a Regulation Restricting Critical Antimicrobial Usage on Prevalence of Antimicrobial Resistance in Escherichia coli Isolates From Fecal and Manure Pit Samples on Dairy Farms in Québec, Canada.

To tackle antimicrobial resistance (AMR), one of the major health threats of this century, the World Health Organization (WHO) endorsed a global action plan in 2015. This plan calls countries to develop national actions to address AMR. The province of Québec, Canada, adopted a new regulation on the 25th of February 2019, to limit the use in food animals of antimicrobials of very high importance in human medicine. We aimed to establish the impact of this regulation by comparing the AMR situation in dairy cattle in Québec ~2 years before and 2 years after its introduction. We sampled calves, cows, and the manure pit in 87 farms. Generic and putative ESBL/AmpC E. coli were tested for susceptibility to 20 antimicrobials. Logistic regression was used to investigate whether the probability of antimicrobial resistance differed between isolates obtained from the pre and post regulation periods by sample type (calves, cows, manure pit) and in general. To identify AMR genes dissemination mechanisms, we sequenced the whole genome of 15 generic isolates. In the generic collection, at the herd level, the proportion of multidrug resistant (MDR) isolates, decreased significantly from 83 to 71% (p = 0.05). Folate inhibitor and aminoglycoside resistances demonstrated a significant decrease. However, when analyzed by sample type (calves, cows, manure pit), we did not observe a significant AMR decrease in any of these categories. In the ESBL/AmpC collection, we did not detect any significant difference between the two periods. Also, the general resistance gene profile was similar pre and post regulation. We identified both clonal and plasmidic dissemination of resistance genes. In conclusion, as early as 2 years post regulation implementation, we observed a significant decrease in MDR in the dairy industry in Quebec in the generic E. coli collection with folate inhibitor and aminoglycoside resistances showing the most significant decrease. No other significant decreases were yet observed.

Evidence of a decrease in sales of antimicrobials of very high importance for humans in dairy herds after a new regulation restricting their use in Quebec, Canada.

In the province of Quebec, Canada, a new regulation restricting usage of antimicrobials of very high importance for human health (Health Canada: category 1 antimicrobials) in production animals is effective since February 2019. The objective of this study was to estimate changes in AM sales in dairy herds after the implementation of the regulation. Therefore, invoice data were extracted from veterinary software, Vet-Expert, used by most dairy veterinarians in the province of Quebec, and antimicrobial quantities were transformed in Canadian defined course doses for cattle (DCDbovCA). The sum of antimicrobials sales monthly in each herd was estimated in DCDbovCA from June 2016 to May 2020. To evaluate the herd-level change in AM sales and the impact of different factors, the number of DCDbovCA by herd from June 2017 to May 2018 (pre-regulation period) were compared with those of June 2019 to May 2020 (post-regulation period). Total category 1 AM sales of 3,569 Quebec's herds went from a range of 14,258 to 21,528 DCDbovCA/month to a range of 1,494 to 4,707 DCDbovCA/month after the implementation of the new regulation. Moreover, using data from 3,337 herds, we estimated a mean (95% confidence interval) reduction in 19 DCDbovCA/herd-year (14.8, 24.2), while the pre-regulation herd-level category 1 AM sales was 26 DCDbovCA/herd-year. This reduction was achieved without evidence of an increase in other antimicrobials. Finally, the veterinary facility associated with the herd was an important determinant of the herd-level reduction in category 1 antimicrobials. This study was the first to quantify a significant reduction in category 1 AM sales following the implementation of a restrictive regulation in dairy production in Canada. These results demonstrate that such an approach is effective to reduce the sales of a specific category of antimicrobial in animal production.

Comparison of Quantification Methods to Estimate Farm-Level Usage of Antimicrobials in Medicated Feed in Dairy Farms from Québec, Canada.

Monitoring antimicrobial usage (AMU) in dairy cattle is becoming common in a growing number of countries, with the ultimate goal to improve practices, reduce the development of antimicrobial resistance, and protect human health. However, antimicrobials delivered as feed additives can be missed by some of the quantification methods usually implemented. Our objective was to compare three methods of quantification of in-feed AMU in Québec dairy herds. We recruited 101 dairy producers for one year in the Québec province. Quantities of antimicrobials were calculated by farm from: (1) feed mills invoices (reference method); (2) veterinary prescriptions; and (3) information collected during an in-person interview of each producer. We standardized AMU rates in kilograms per 100 cow-years and compared the reference method to both alternative methods using concordance correlation coefficients and Bland-Altman plots. Antimicrobial usage was well estimated by veterinary prescriptions (concordance correlation coefficient (CCC) = 0.66) or by the approximation using producer's data (CCC = 0.73) when compared with actual deliveries by feed mills. Users of medically important antimicrobials for human medicine (less than 10% of the farms) were easily identified using veterinary prescriptions. Given that veterinary prescriptions were mostly electronic (90%), this method could be integrated as part of a monitoring system in Québec.

Comparison of Quantification Methods to Estimate Farm-Level Usage of Antimicrobials Other than in Medicated Feed in Dairy Farms from Québec, Canada.

The objective of the study was to compare three quantification methods to a "garbage can audit" (reference method, REF) for monitoring antimicrobial usage (AMU) from products other than medicated feed over one year in 101 Québec dairy farms. Data were collected from veterinary invoices (VET method), from the "Amélioration de la Santé Animale au Québec" provincial program (GOV method), and from farm treatment records (FARM method). The AMU rate was reported in a number of Canadian Defined Course Doses for cattle (DCDbovCA) per 100 cow-years. Electronic veterinary sales data were obtained for all farms for VET and GOV methods. For the FARM method, a herd management software was used by 68% of producers whereas farm treatment records were handwritten for the others; records could not be retrieved in 4% of farms. Overall, agreement was almost perfect between REF and VET methods (concordance correlation coefficient (CCC) = 0.83), but moderate between REF and GOV (CCC = 0.44), and between REF and FARM (CCC = 0.51). Only a fair or slight agreement was obtained between any alternative method of quantification and REF for oral and intrauterine routes. The billing software used by most of Québec's dairy veterinary practitioners seems promising in terms of surveillance and benchmarking of AMU in the province.

Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study.

Polyphenols are promising nutritional bioactives exhibiting beneficial effect on age-related cognitive decline. This study evaluated the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on memory of healthy elderly subjects (60-70 years-old). A bicentric, randomized, double-blind, placebo-controlled trial was conducted with 215 volunteers receiving 600 mg/day of PEGB (containing 258 mg flavonoids) or a placebo for 6 months. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. Secondary outcomes included verbal episodic and recognition memory (VRM) and working memory (SSP). There was no significant effect of PEGB on the PAL on the whole cohort. Yet, PEGB supplementation improved VRM-free recall. Stratifying the cohort in quartiles based on PAL at baseline revealed a subgroup with advanced cognitive decline (decliners) who responded positively to the PEGB. In this group, PEGB consumption was also associated with a better VRM-delayed recognition. In addition to a lower polyphenol consumption, the urine metabolomic profile of decliners revealed that they excreted more metabolites. Urinary concentrations of specific flavan-3-ols metabolites were associated, at the end of the intervention, with the memory improvements. Our study demonstrates that PEGB improves age-related episodic memory decline in individuals with the highest cognitive impairments.

Supplementation with Resveratrol and Curcumin Does Not Affect the Inflammatory Response to a High-Fat Meal in Older Adults with Abdominal Obesity: A Randomized, Placebo-Controlled Crossover Trial.

Background: High-fat meals induce postprandial inflammation. Resveratrol is a polyphenol known to prevent comorbidities associated with cardiovascular disease and exerts an anti-inflammatory action. There is also an increasing body of evidence supporting the role of curcumin, a polyphenol from the curcuminoid family, as a modulator of proinflammatory processes. Objective: The objectives of this study were to investigate the following: 1) the bioavailability of resveratrol consumed in combination with curcumin after consumption of a high-fat meal; and 2) the acute combined effects of this combination on the postprandial inflammatory response of subjects with abdominal obesity. Methods: In a double blind, crossover, randomized, placebo-controlled study, 11 men and 11 postmenopausal women [mean ± SD age: 62 ± 5 y; mean ± SD body mass index (in kg/m2): 29 ± 3] underwent a 6-h oral fat tolerance test on 2 occasions separated by 1-2 wk: once after consumption of a dietary supplement (200 mg resveratrol and 100 mg curcumin, Res/Cur) and once after consumption of a placebo (cellulose). Plasma concentrations of total resveratrol and its major metabolites as well as inflammatory markers, adhesion molecules, and whole blood NFκB1 and PPARA gene expression were measured during both fat tolerance tests. Results: Kinetics of resveratrol and identified metabolites revealed rapid absorption patterns but also relatively limited bioavailability based on free resveratrol concentrations. Supplementation with Res/Cur did not modify postprandial variations in circulating inflammatory markers (C-reactive protein, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesion molecules [soluble E-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1] compared to placebo (PTreatment×Time > 0.05). However, Res/Cur significantly decreased the cumulative postprandial response of sVCAM-1, compared to placebo (incremental area under the curve -4643%, P = 0.01). Postprandial variations of whole-blood PPARA and NFKB1 gene expression were not different between Res/Cur and placebo treatments. Conclusions: Acute supplementation with Res/Cur has no impact on the postprandial inflammation response to a high-fat meal in abdominally obese older adults. Further studies are warranted to examine how resveratrol and curcumin may alter the vascular response to a high-fat meal. This trial was registered at clinicaltrials.gov as NCT01964846.

Correlates of reactive hyperemic index in men and postmenopausal women.

The aim of the present study was to investigate the differences in digital reactive hyperemic index (RHI) in men and postmenopausal women. We investigated the differences in and correlates of RHI, measured by peripheral artery tonometry (PAT), in a group of 82 men (mean age ± SD: 55.6 ± 8.2 years; body mass index: 29.0 ± 4.2 kg/m(2)) and 125 postmenopausal women (58.9 ± 5.2 years; 27.7 ± 4.1 kg/m(2)). We also examined fRHI values (natural log of the PAT ratio of the 90-120 seconds post-occlusion interval) and augmentation index (AIx) as a measure of arterial stiffness. We found that RHI, fRHI and AIx were significantly lower in men compared to postmenopausal women (p<0.0001). We also found that fRHI values were significantly lower in individuals with (MetS+) versus without (MetS-) the metabolic syndrome (MetS). Endothelial inflammation was present in MetS+ subjects as indicated by increased plasma soluble intercellular adhesion molecule-1 (sICAM-1) (p<0.001) and E-selectin (p=0.0519) concentrations compared to MetS- individuals. No significant difference was found in RHI or AIx between MetS+ versus MetS- individuals. In summary, our study reveals that men have an impairment of endothelial function, assessed by digital PAT, compared to postmenopausal women. Furthermore, we show that the presence of the MetS is characterized by endothelial dysfunction, as suggested by lower fRHI, as well as by endothelial inflammation, which likely contributes to the increased cardiovascular disease risk associated with the MetS. ClinicalTrials.gov Identifier: NCT01085019.

A randomised crossover placebo-controlled trial investigating the effect of brown seaweed (Ascophyllum nodosum and Fucus vesiculosus) on postchallenge plasma glucose and insulin levels in men and women.

This study examined the impact of brown seaweed on post-load plasma glucose and insulin concentrations in men and women. Twenty-three participants (11 men, 12 women) aged 19-59 years were recruited in this double-blind, randomized, placebo-controlled crossover study. The test product consisted of a commercially available blend of brown seaweed (Ascophyllum nodosum and Fucus vesiculosus) with known inhibitory action on α-amylase and α-glucosidase activities (InSea²). Two 250 mg seaweed capsules and 2 placebo capsules were consumed on each occasion 30 min prior to the consumption of 50 g of carbohydrates from bread. Plasma glucose and insulin concentrations were measured over a period of 3 h postcarbohydrate ingestion at predetermined time points. Both treatments were separated by a 1-week washout period. Data were analysed using mixed models for repeated measures. Compared with placebo, consumption of seaweed was associated with a 12.1% reduction in the insulin incremental area under the curve (p = 0.04, adjusted for baseline) and a 7.9% increase in the Cederholm index of insulin sensitivity (p < 0.05). The single ingestion of 500 mg of brown seaweed had no significant effect on the glucose response (p = 0.24, adjusted for baseline). Glucose and insulin responses were similar between men and women. Consumption of the seaweed capsules was not associated with any adverse event. These data suggest that brown seaweed may alter the insulin homeostasis in response to carbohydrate ingestion.

Impact of Bifidobacterium animalis subsp. lactis BB-12 and, Lactobacillus acidophilus LA-5-containing yoghurt, on fecal bacterial counts of healthy adults.

This randomized, placebo-controlled, double blind, parallel dose-response study investigated the impact of 4-week commercial yoghurt consumption supplemented with Bifidobacterium animalis subsp. lactis (BB-12) and Lactobacillus acidophilus (LA-5) on fecal bacterial counts of healthy adults. Fifty-eight volunteers were randomly assigned to three different groups: 1. placebo (no probiotic, no starter and no green tea extract); 2. Yoptimal (10(9)cfu/100g of BB-12 and LA-5 and 40mg of green tea extract) and 3. Yoptimal-10 (10(10)cfu/100g of BB-12, 10(9)cfu/100g of LA-5 and 40mg of green tea extract). These yoghurt products also contained Lactobacillus delbrueckii subsp. bulgaricus (10(7)cfu/100g) and Streptococcus thermophilus (10(10)cfu/100g). The quantitative PCR (qPCR) results showed that there were significant increases (P=0.02) in bifidobacteria counts with the Yoptimal treatment as compared to baseline. The fecal numbers of B. animalis subsp. lactis and LA-5 significantly increased in the two probiotic treatments compared to the placebo treatment. Viable counts of fecal lactobacilli were significantly higher (P=0.05) and those of enterococci were significantly lower (P=0.04) after the intervention when compared to placebo. No significant difference was observed between treatments in volunteers' weight, waist girth, blood pressure, fasting plasma triglyceride and HDL-C concentrations, as well as cholesterol/HDL-cholesterol ratio. However, a significant increase in plasma cholesterol levels was observed in the placebo group (P=0.0018) but the levels remained stable in the two probiotic yoghurt groups. These results show that probiotic strains supplemented in the form of yoghurt remain active during gut transit and are associated with an increase in beneficial bacteria and a reduction in potentially pathogenic bacteria. This trial was registered at clinicaltrials.gov as NCT00730626.

Verbal and visual memory impairments among young offspring and healthy adult relatives of patients with schizophrenia and bipolar disorder: selective generational patterns indicate different developmental trajectories.

OBJECTIVE: Memory deficits have been shown in patients affected by schizophrenia (SZ) and bipolar (BP)/mood disorder. We recently reported that young high-risk offspring of an affected parent were impaired in both verbal episodic memory (VEM) and visual episodic memory (VisEM). Understanding better the trajectory of memory impairments from childhood to adult clinical status in risk populations is crucial for early detection and prevention. In multigenerational families densely affected by SZ or BP, our aim was to compare the memory impairments observed in young nonaffected offspring with memory functioning in nonaffected adult relatives and patients. METHODS: For 20 years, we followed up numerous kindreds in the Eastern Québec population. After having characterized the Diagnostic and Statistical Manual of Mental Disorders phenotypes, we assessed cognition (N = 381) in 3 subsamples in these kindreds and in controls: 60 young offspring of a parent affected by SZ or BP, and in the adult generations, 92 nonaffected adult relatives and 40 patients affected by SZ or BP. VEM was assessed with the California Verbal Learning Test and VisEM with the Rey figures. RESULTS: The VEM deficits observed in the offspring were also found in adult relatives and patients. In contrast, the VisEM impairments observed in the young offspring were present only in patients, not in the adult relatives. CONCLUSION: Implications for prevention and genetic mechanisms can be drawn from the observation that VEM and VisEM would show distinct generational trajectories and that the trajectory associated with VisEM may offer a better potential than VEM to predict future risk of developing the disease.

Retinal response to light in young nonaffected offspring at high genetic risk of neuropsychiatric brain disorders.

BACKGROUND: In neuropsychiatric brain disorders, such as schizophrenia (SZ) and bipolar disorder (BD), the biased effect of chronic drug therapy and the toxic effect of illness once installed constitute obstacles to the identification of valid biomarkers. Such biomarkers could lie at the level of retinal function where anomalies have already been reported in adults suffering from neuropsychiatric disorders. Here, we report a specific electroretinographic (ERG) anomaly in young nonaffected and nonmedicated offspring at high genetic risk (HR) of these disorders. METHODS: Electroretinography was performed in 29 HR offspring having one parent affected by DSM-IV SZ or BD (mean age: 20.8 years, SD 4.4) and 29 healthy control subjects (mean age: 20.6 years, SD 4.2). The HRs' parents descended from multigenerational families affected by SZ or BD. RESULTS: Rod ERG (b-wave amplitude at V(max)) in HRs was significantly lower than control subjects (p < .0001; effect size of -1.47), whereas the cone ERG V(max) showed no difference (p = .27). No effects of gender, age, and seasons of testing were observed. The anomaly in retinal response (rod V(max) b-wave amplitude) was observed independently of parents' diagnosis (SZ; p = .007, effect size of -1.09; BD: p < .0001, effect size of -1.88) and was present in both the younger and older HRs (effect size of -1.6 and -1.8, respectively). CONCLUSIONS: A rod retinal response anomaly before the age of the disease incidence may represent an early and specific biomarker of risk with meaning for further genetic and prevention research.

Shared neurocognitive dysfunctions in young offspring at extreme risk for schizophrenia or bipolar disorder in eastern quebec multigenerational families.

BACKGROUND: Adult patients having schizophrenia (SZ) or bipolar disorder (BP) may have in common neurocognitive deficits. Former evidence suggests impairments in several neuropsychological functions in young offspring at genetic risk for SZ or BP. Moreover, a dose-response relation may exist between the degree of familial loading and cognitive impairments. This study examines the cognitive functioning of high-risk (HR) offspring of parents having schizophrenia (HRSZ) and high-risk offspring of parents having bipolar disorder (HRBP) descending from densely affected kindreds. METHODS: The sample consisted of 45 young offspring (mean age of 17.3 years) born to a parent having SZ or BP descending from large multigenerational families of Eastern Québec that are densely affected by SZ or BP and followed up since 1989. The offspring were administered a lifetime best-estimate diagnostic procedure (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) and an extensive standard neuropsychological battery. Raw scores were compared with age- and gender-matched controls. RESULTS: The offspring displayed differences in memory and executive functions when compared with controls. Moderate to large effect sizes (Cohen d) ranging from 0.65 to 1.25 (for IQ and memory) were observed. Several of the cognitive dysfunctions were present in both HRSZ and HRBP, even when considering DSM-IV clinical status. CONCLUSIONS: HRSZ and HRBP shared several aspects of their cognitive impairment. Our data suggest that the extremely high genetic and familial loading of these HRs may have contributed to a quantitatively increased magnitude of the cognitive impairments in both HR subgroups, especially in memory. These offspring at heightened risk present difficulties in processing information that warrant preventive research.

Intravascular kinetics of C-reactive protein and their relationships with features of the metabolic syndrome.

OBJECTIVE: The objective of the study was to describe, for the first time, the intravascular kinetics of C-reactive protein (CRP), using stable isotopes, and its relationship with features of the metabolic syndrome. METHODS: Sixteen men and 16 women [aged 49 +/- 9 years, body mass index (BMI) 28.7 +/- 4.5 kg/m(2)] underwent a 12-h primed-constant infusion of 5,5,5-(2)H(3)-l-leucine. CRP was purified from the plasma fraction rho greater than 1.25 g/ml by affinity chromatography, and isotopic enrichment over time was determined by gas chromatography/mass spectrometry. RESULTS: The CRP fractional catabolic rate was 60% higher in men than women (0.49 +/- 1.83 vs. 0.30 +/- 1.80 pool/d, P = 0.03), but this difference was no longer significant in a multivariate model that included several features associated with the metabolic syndrome. The CRP production rate (PR) and pool size were not statistically different between sexes. Plasma CRP concentrations were more strongly correlated with the PR (r = 0.80, P < 0.0001) than with the fractional catabolic rate of CRP (r = 0.39, P < 0.05). The PR of CRP was positively correlated with waist girth (r = 0.53, P < 0.01), plasma low-density lipoprotein apolipoprotein B-100 (r = 0.42, P = 0.07), triglyceride (r = 0.41, P = 0.06), and IL-6 concentrations (r = 0.61, P = 0.0008) and inversely correlated with high-density lipoprotein-cholesterol (r = -0.47, P = 0.03) and adiponectin (r = -0.63, P < 0.0005) after adjustment for sex. Blood pressure and low-density lipoprotein-cholesterol showed no association with CRP kinetics. CONCLUSION: The PR of CRP appeared as the main determinant of CRP concentrations and showed significant associations with features of the metabolic syndrome as well as with adipose tissue-derived cytokines such as IL-6 and adiponectin.

Endothelial lipase and the metabolic syndrome.

PURPOSE OF REVIEW: Several in-vitro and in-vivo animal studies indicate that endothelial lipase plays a key role in the intravascular remodeling of lipoproteins, particularly HDL. This review integrates this body of knowledge with more recent data in humans linking endothelial lipase to HDL metabolism and other features of the metabolic syndrome. RECENT FINDINGS: Human studies generally support the involvement of endothelial lipase in modulating plasma HDL. The association between endothelial lipase and metabolism of apolipoprotein B-containing lipoproteins in humans, however, has not been entirely consistent with previous findings in vitro and in animals. Finally, elevated plasma endothelial lipase has been associated with abdominal obesity and hypertension, and there is now compelling evidence that inflammation and in-vivo regulation of endothelial lipase may be intrinsically related. SUMMARY: Accumulating evidence indicates that endothelial lipase plays a role in the etiology of the atherogenic plasma lipoprotein profile characteristic of the metabolic syndrome. Increased endothelial lipase activity is linked to the underlying proinflammatory state in this condition. Further studies are required, however, to define the extent to which endothelial lipase contributes to the dyslipidemia of the metabolic syndrome relative to other important regulating factors, such as lipoprotein lipase, hepatic lipase, and cholesterol ester transfer protein.

Endothelial lipase is associated with inflammation in humans.

The aim of this study was to investigate the extent to which inflammation is linked with plasma endothelial lipase (EL) concentrations among healthy sedentary men. Plasma C-reactive protein (CRP) concentrations were measured with a highly sensitive commercial immunoassay, plasma interleukin-6 (IL-6) concentrations were measured using a commercial ELISA, and plasma secretory phospholipase A(2) type IIA (sPLA(2)-IIA) concentrations were measured using a commercial assay in a sample of 74 moderately obese men (mean body mass index, 29.8 +/- 5.2 kg/m(2)). Plasma EL concentrations were positively correlated with various indices of obesity, fasting plasma insulin, and plasma CRP, IL-6, and sPLA(2)-IIA concentrations. Multiple regression analyses revealed that plasma CRP concentrations explained 14.5% (P = 0.0008) of the variance in EL concentrations. When entered into the model, LPL activity accounted for 16.1% (P < 0.0001) and plasma CRP concentrations accounted for 20.9% (P < 0.0001) of the variance in EL concentrations. The combined impact of visceral adipose tissue (VAT) and of an inflammation score on EL concentrations was investigated. Among subjects with high or low VAT, those having a high inflammation score based on plasma CRP, IL-6, and sPLA(2)-IIA concentrations had increased plasma EL concentrations (P = 0.0005). In conclusion, our data reveal a strong association between proinflammatory cytokines and plasma EL concentrations among healthy people with low or high VAT levels.