Social Vulnerability, Frailty and Self-Perceived Health: Findings from The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: Social vulnerability interacts with frailty and influences individuals' health status. Although frailty and social vulnerability are highly predictive of adverse outcomes, their relationship with self-perceived health(SPH) has been less investigated. METHODS: Data are from the Irish Longitudinal Study on Ageing(TILDA), a population-based longitudinal study of ageing. We included 4,222 participants aged ≥50 years (age 61.4±8.5 years;women 56%) from Wave 1 (2009-2011) followed over three longitudinal waves (2012,2014-2015,2016). Participants responded to single questions with five response options to rate their 1)physical health, 2)mental health, and 3)health compared to peers. 30-item Frailty (FI) and Social Vulnerability (SVI) indices were calculated using standardised methods. Multivariable regression analyses were performed to establish the association between FI and SVI cross-sectionally and longitudinally over 6 years. RESULTS: Cross-sectionally, SVI (mean:0.40±0.08; range:0.14-0.81) and FI (mean: 0.13±0.08; range:0.10-0.58) were modestly correlated (r=0.256), and independently associated with poor physical health (SVI: OR 1.43, 95%CI 1.15-1.78; FI: OR 3.16, 95%CI 2.54-3.93), poor mental health (SVI: OR 1.65, 95%CI 1.17-2.35; FI: OR 3.64, 95%CI 2.53-5.24), and poor health compared to peers (SVI: OR 1.41,95%CI 1.06-1.89; FI: OR 3.86, 95%CI 2.9-5.14). Longitudinally, FI and SVI were independently and positively associated with poor physical health (SVI: ß 1.08, 95%CI 0.76-1.39; FI: ß 1.97, 95%CI 1.58-2.36), poor mental health (SVI: ß 1.18, 95%CI 0.86-1.5; FI: ß 1.58, 95%CI 1.2-1.97), and poor overall health compared to peers (SVI: ß 0.78, 95%CI 0.89-1.33; FI: ß 1.74, 95%CI 0.47-1.1). CONCLUSIONS: In a large cohort of community-dwelling older adults, frailty and social vulnerability were associated with poor SPH and with risk of SPH decline over six years.

Nutritional composition of ultra-processed plant-based foods in the out-of-home environment: a multi-country survey with plant-based burgers.

Ultra-processed plant-based foods, such as plant-based burgers, have gained in popularity. Particularly in the out-of-home (OOH) environment, evidence regarding their nutritional profile and environmental sustainability is still evolving. Plant-based burgers available at selected OOH sites were randomly sampled in Amsterdam, Copenhagen, Lisbon and London. Plant-based burgers (patty, bread and condiment) (n 41) were lab analysed for their energy, macronutrients, amino acids and minerals content per 100 g and serving and were compared with reference values. For the plant-based burgers, the median values per 100 g were 234 kcal, 20·8 g carbohydrates, 3·5 g dietary fibre and 12·0 g fat, including 0·08 g TFS and 2·2 g SFA. Protein content was 8·9 g/100 g, with low protein quality according to amino acid composition. Median Na content was 389 mg/100 g, equivalent to 1 g salt. Compared with references, the median serving provided 31% of energy intake based on a 2000 kcal per day and contributed to carbohydrates (17-28%), dietary fibre (42%), protein (40%), total fat (48%), SFA (26%) and Na (54%). One serving provided 15-23% of the reference values for Ca, K and Mg, while higher contributions were found for Zn, Mn, P and Fe (30-67%). The ultra-processed plant-based burgers provide protein, dietary fibre and essential minerals and contain relatively high levels of energy, Na and total fats. The amino acid composition indicated low protein quality. The multifaceted nutritional profile of plant-based burgers highlights the need for manufacturers to implement improvements to better support healthy dietary habits, including reducing energy, Na and total fats.

Safety, regulatory and environmental issues related to breeding and international trade of edible insects in Africa.

Insect breeding or farming for food and feed is an emerging enterprise that can address the ever-growing demand for protein and curb high unemployment rates in Africa and beyond. However, for the sector to prosper, its value chain needs to be regulated to ensure sustainability and safety for consumers and the environment. Although a few African countries, such as Kenya, Uganda and Rwanda, have promulgated standards on the use of insects as food and feed, greater efforts are needed in other countries, and relevant policies governing the sector need to be formulated. All over the globe, attention to the regulation of the edible insect sector is increasing, and more investment in the industry is foreseen. Safety issues such as identifying which species should be reared, substrate quality and traceability imposed by importing countries will be critical for expansion of the sector. This paper analyses safety, regulatory and environmental issues related to breeding and international trade of edible insects in Africa and provides case studies and recommendations for sustainable use of insects for food and feed.

Les élevages et les fermes d'insectes destinés à l'alimentation humaine et animale sont de nouvelles entreprises qui pourraient répondre à la hausse continue de la demande en protéines tout en réduisant les taux élevés du chômage en Afrique et ailleurs. Néanmoins, pour que ce secteur puisse prospérer, sa chaîne de création de valeur doit être réglementée afin de garantir sa durabilité et son innocuité pour les consommateurs et l'environnement. Si un petit nombre de pays africains dont le Kenya, l'Ouganda et le Rwanda ont élaboré des normes applicables à l'utilisation des insectes pour l'alimentation humaine et animale, dans d'autres pays les efforts doivent se poursuivre et des politiques appropriées doivent être mises en place pour régir ce secteur. Partout dans le monde, la réglementation du secteur des insectes comestibles fait désormais l'objet d'une attention considérable et des investissements accrus dans la filière sont attendus. Les questions de sécurité telles que l'identification des insectes à élever, la qualité du substrat et la traçabilité exigée par les pays importateurs seront cruciales pour le développement du secteur. Les auteurs analysent les questions de sécurité et les enjeux réglementaires et environnementaux liés à l'élevage et au commerce international d'insectes comestibles en Afrique et présentent des études de cas et des recommandations pour une utilisation durable des insectes destinés à l'alimentation humaine et animale.

La cría o producción de insectos con fines de alimentación humana o animal es una actividad incipiente que puede ayudar a responder a la siempre creciente demanda de proteínas y a contener las elevadas tasas de desempleo de África y otras regiones. Para que el sector prospere, no obstante, es preciso reglamentar su cadena de valor a fin de asegurar su sostenibilidad y su inocuidad para el consumidor y el medio ambiente. Aunque unos pocos países africanos, como Kenia, Uganda o Ruanda, tienen promulgadas normas sobre el uso de insectos para la alimentación humana o la producción de piensos, aún hay que redoblar esfuerzos en otros países y formular políticas que ordenen el sector. En todo el planeta se presta hoy una atención sin precedentes a la regulación del sector de los insectos comestibles, un sector que previsiblemente va a recibir cada vez más inversiones. Las cuestiones ligadas a la inocuidad, como la identidad de los insectos que se van a producir, la calidad del substrato o la rastreabilidad impuesta por los países importadores, serán fundamentales para el desarrollo del sector. Los autores analizan las cuestiones reglamentarias, ambientales y de inocuidad que se plantean en relación con la cría y el comercio internacional de insectos comestibles en África, presentan ejemplos concretos y formulan recomendaciones para un uso sostenible de los insectos con fines de alimentación humana o animal.

Caring in the time of COVID-19, longitudinal trends in well-being and mental health in carers in Ireland: Evidence from the Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: The COVID-19 pandemic in 2020 resulted in the older population being asked to remain at home and avoid other people outside their household. This could have implications for both receipt and provision of informal caring. OBJECTIVE: To determine if informal care provision by older carers changed during the first wave of the COVID-19 pandemic from pre-pandemic care and if this was associated with a change in mental health and well-being of carers. DESIGN AND SETTING: Longitudinal nationally representative study of community dwelling adults from The Irish Longitudinal Study on Ageing (TILDA) (Waves 3-COVID-Wave 6). METHODS: We studied a cohort of 3670 adults aged ≥60 in Ireland during the COVID-19 pandemic (July-November 2020) and compared with previous data collections from the same cohort between 2014-2018. Independent variables were caregiving status and caregiving intensity, outcome measures included depressive symptoms (CES-D8), Perceived Stress (PSS4) and Quality of life (CASP12). Mixed models adjusting for socio-demographics and physical health were estimated. RESULTS: Caregiving increased from 8.2% (2014) to 15.4% (2020). Depression, and stress scores increased while quality of life decreased for all participants. Carers reported poorer mental health, and higher caring hours were associated with increased depression and stress and decreased quality of life scores on average, and increased depression was higher for women. CONCLUSIONS: Informal caregiving increased during the pandemic and family caregivers reported increased adverse mental health and well-being and this continued throughout the early months of the pandemic. The disproportionate burden of depression was highest in women providing higher caring hours.

Validation of the 8-item Centre for Epidemiological Studies Depression Scale in a cohort of community-dwelling older people: data from The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: The aim of this study was to validate the 8-item Centre for Epidemiological Studies Depression Scale (CES-D-8) against the 20-item version (CES-D-20) in a large sample of community-dwelling older people. METHODS: Scales were compared for correlation and internal consistency. The ideal cut-off score for the CES-D-8 was determined by comparing scores ranging from 7 to 12 on the CES-D-8 to CES-D-20. RESULTS: 8033 participants were included. The Spearman co-efficient between the scales was 0.8980 indicating high degree of correlation. At a score of 9/24, the sensitivity and specificity of the CES-D-8 were 98 and 83%, respectively. The Cohen's κ for a score of 9 was 0.7855, indicating strong agreement and the ROC area was 0.88. CONCLUSION: When compared to the CES-D-20, the CES-D-8 is a valid and reliable measure of depressive symptoms in community-dwelling older people, and a score of 9 can be used to identify those with clinically significant symptoms.

Evidence-based dentistry can effectively be taught to dental care professional students - A mixed methods study.

BACKGROUND: Little research exists in the teaching of evidence-based dentistry (EBD) to students in the fields of dental hygiene, dental nursing and orthodontic therapy. This study aims to analyse the effect of a 1-day EBD programme on knowledge and confidence whilst also gaining insight into students' experience of the intervention. METHOD: A mixed methods study was utilised with explanatory sequential design. The population consisted of dental hygiene (DH), dental nursing (DN) and orthodontic therapy (OT) students (N = 44). The intervention consisted of a 1-day active learning EBD programme, delivered via group projects and lectures. In the initial quantitative phase, a standardised questionnaire pre- and post -intervention measured changes in confidence for all participants, whilst change in knowledge was measured for DH and OT students only. Following this, focus groups were scheduled for all members of each discipline 3 months post-intervention for DN and 2 months post-intervention for DH and OT students. Semi-structured focus group schedules were drawn up, and groups organised according to the outcomes of quantitative data analysis. Qualitative results were analysed using a deductive adaptation of Burnard's thematic content analysis. RESULTS: Forty-two students took part (94.45%) in this study. Median knowledge scores increased from zero to two of five (P < .001), whilst median confidence score doubled from four to eight of eight (P < .001). Results of thematic content analysis were coincident with quantitative results; however, it also provided constructive feedback regarding design and content of the course. CONCLUSIONS: A 1-day bespoke programme in EBD increased students' confidence and knowledge in EBD skills. However, the findings further suggest that two successive half-day training sessions instead of one full-day training, tied in with coursework that requires the application of the acquired skills, may increase the learning experience further.

Failure to control hypercholesterolaemia in the Irish adult population: cross-sectional analysis of the baseline wave of The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: Hypercholesterolaemia is an important modifiable risk factor for cardiovascular disease (CVD) which requires monitoring and management at a population level. AIMS: This study aims to describe the distribution of serum cholesterol in a community living population of older adults in Ireland and to examine the awareness, treatment and control of hypercholesterolaemia according to CVD risk status. METHOD: This is a cross-sectional study in a nationally representative sample of adults aged 50-79 years (n = 5287). Hypercholesterolaemia was defined as low-density lipoprotein cholesterol (LDL-C) in excess of the recommended CVD risk category target and/or on lipid-lowering medication. RESULTS: This study reports a mean total cholesterol (TC) of 5.1 mmol/L (95% CI 5.0-5.1 mmol/L) and a mean LDL-C of 2.9 mmol/L (95% CI 2.8-2.9 mmol/L) in those aged 50-79 years. In a subgroup aged 50-64 years, 73% (95% CI 71.5-74.5%) were hypercholesterolaemic. LDL-C was controlled to the guideline target in 57% of those with CVD and 49% of those with diabetes. Lack of awareness of hypercholesterolaemia was high across the remainder of the population. CONCLUSION: Despite a substantial reduction in population mean TC from a high of 6.0 mmol/L in the 1980s to 5.1 mmol/L, this study reports a failure to control hypercholesterolaemia to recommended risk-stratified targets in the Irish adult population. Recommendations for policy include continued monitoring of those at highest risk and CVD risk assessment in those perceived to be at low risk in order to inform shared decision making in relation to lifestyle modification and medication management.

Non-Dietary Correlates and Determinants of Plasma Lutein and Zeaxanthin Concentrations in the Irish Population.

OBJECTIVE: To investigate non-dietary correlates and determinants of plasma lutein (L) and zeaxanthin (Z) concentrations in The Irish Longitudinal Study on Ageing (TILDA) sample. DESIGN: Cross-sectional study. SETTING: Community dwelling adults in the Republic of Ireland (ROI). PARTICIPANTS: 3,681 participants aged 50 years and older. MEASUREMENTS: TILDA is a nationally representative prospective cohort study of community dwelling adults aged 50 years and over in the ROI. Demographic and health variables were collected during a face-to-face interview carried out in the home (n=8175), and a substantial proportion of these (n=5035; 62%) also attended a study visit in a health assessment centre. Blood samples collected at baseline (wave 1, the subject of the current study), were analysed for plasma concentrations of L and Z by reversed-phase high performance liquid chromatography, and macular pigment (MP) optical density was also measured (using customized heterochromatic flicker photometry). RESULTS: After excluding participants with eye disease, data from 3,681 participants were available for analysis. For this group of participants, plasma L and Z were inversely and significantly associated with body mass index (BMI), and were positively and significantly associated with MP, total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) (p<0.001, for all). Plasma L and Z were significantly lower in males, current smokers, participants reporting less physical exercise, and participants reporting lower levels of education (p<0.05, for all). Plasma L was significantly higher in participants reporting a family history of age-related macular degeneration (AMD) (p=0.001), and in the group of ≥75 years old (p<0.05). For each of these variables, the significant associations remained after controlling for other potential confounding variables. CONCLUSION: The findings of this large study indicate that plasma concentrations of L and Z were lower in association with indicators of a poor lifestyle (high BMI, tobacco use, and less physical exercise) and in association with lower education, indicating that modifying lifestyle in a positive way is likely to be reflected in higher concentrations of plasma carotenoids, with consequential and putative health benefits.

Polymorphisms in the regulatory region of the porcine MYLPF gene are related to meat quality traits in the Large White breed.

The MYLPF gene encodes fast myosin regulatory light chain, and is a positional and functional candidate gene for meat quality. The aim of this study was to identify associations between SNPs in the promoter region of the porcine MYLPF gene and meat quality traits. A total of 22 SNPs were identified in a population of crossbred animals (n=86) and based on minor allele frequency and proximity to the transcription start site, five SNPs were genotyped in purebred; Large White (n=98), Duroc (n=99) and Pietrain (n=98) pigs. No associations were observed in the Pietrain breed, while the Duroc breed was almost monomorphic for all SNPs. In the Large White breed SNP g-1314A>G and linked SNPS g.-871T>G, g.-566T>C, g.-403C>G were associated with ultimate pH and driploss (P<0.05). This study identified associations between MYLPF and meat quality and highlights the importance of considering the genetic background within gene-assisted selection programmes.

Prevalence and correlates of diagnosed and undiagnosed type 2 diabetes mellitus and pre-diabetes in older adults: Findings from the Irish Longitudinal Study on Ageing (TILDA).

AIMS: The prevalence of type 2 diabetes and pre-diabetes has increased rapidly in recent decades and this trend will continue as the global population ages. This study investigates the prevalence of, and factors associated with, diagnosed and undiagnosed type 2 diabetes mellitus and pre-diabetes in older adults in Ireland. METHODS: Cross-sectional data from 5377 men and women aged 50 and over from Wave 1 of the Irish Longitudinal Study on Ageing (TILDA) was analysed. Diagnosed diabetes was defined using self-reported doctors' diagnosis and medications data. Glycated haemoglobin (HbA1c) analysis was used to identify undiagnosed and pre-diabetes. Age and sex-specific prevalence estimates were generated. Logistic regression was used to investigate the association between diabetes classification and the demographic, health and lifestyle characteristics of the population. RESULTS: The prevalence of diagnosed and undiagnosed type 2 diabetes was 8.6% (95% confidence interval (CI): 7.6-9.5%) and 0.9% (95% CI: 0.6-1.1%) respectively. Diabetes was more prevalent in men than women and increased with age. The prevalence of pre-diabetes was 5.5% (95% CI: 4.8-6.3%) and increased with age. Diabetes and pre-diabetes were independently associated with male sex, central obesity and a history of hypertension, while undiagnosed diabetes was associated with geographic location and medical costs cover. CONCLUSION: Despite high rates of obesity and other undiagnosed health conditions, the prevalence of undiagnosed and pre-diabetes is relatively low in community-dwelling older adults in Ireland. Addressing lifestyle factors in this population may help to further reduce the prevalence of pre-diabetes and improve outcomes for those with a previous diagnosis.

Measuring frailty using self-report and test-based health measures.

BACKGROUND: previously, frailty indices were constructed using mostly subjective health measures. The reporting error in this type of measure can have implications on the robustness of frailty findings. OBJECTIVE: to examine whether frailty assessment differs when we construct frailty indices using solely self-reported or test-based health measures. DESIGN: secondary analysis of data from The Irish LongituDinal study on Ageing (TILDA). SUBJECTS AND METHODS: 4,961 Irish residents (mean age: 61.9 ± 8.4; 54.2% women) over the age of 50 years who underwent a health assessment were included in this analysis. We constructed three frailty indices using 33 self-reported health measures (SRFI), 33 test-based health measures (TBFI) and all 66 measures combined (CFI). The 2-year follow-up outcomes examined were all-cause mortality, disability, hospitalisation and falls. RESULTS: all three indices had a right-skewed distribution, an upper limit to frailty, a non-linear increase with age, and had a dose-response relationship with adverse outcomes. Levels of frailty were lower when self-reported items were used (SRFI: 0.12 ± 0.09; TBFI: 0.17 ± 0.15; CFI: 0.14 ± 0.13). Men had slightly higher frailty index scores than women when test-based measures were used (men: 0.17 ± 0.09; women: 0.16 ± 0.10). CFI had the strongest prediction for risk of adverse outcomes (ROC: 0.64-0.81), and age was not a significant predictor when it was included in the regression model. CONCLUSIONS: except for sex differences, characteristics of frailty are similar regardless of whether self-reported or test-based measures are used exclusively to construct a frailty index. Where available, self-reported and test-based measures should be combined when trying to identify levels of frailty.

Novel variation in the FABP3 promoter and its association with fatness traits in pigs.

This study examines associations between SNPs in the promoter region of the fatty acid binding protein 3 (FABP3) gene and fatness traits in pure bred Large White (n=98), Duroc (n=99) and Pietrain (n=98) populations. In the Large White breed, SNP g.-634 C>A was associated a 27% increase in IMF (%) in the heterozygote (CA) and a 38% increase in the homozygote (CC) relative to the (AA) genotype in the M. semimembranosus (SM) muscle (P=0.02). While the associations observed in this breed were suggestive of significance in both the SM and in the M. longissimus thoracis et lumborum (LTL) (P=0.08), these associations no longer attained significance at thresholds adjusted for multiple testing. In conclusion, SNPs in the FABP3 promoter may contribute to IMF without influencing carcass fatness traits in pigs, however further confirmation of these associations in larger independent populations would be essential before their incorporation into breeding programmes.

Genetic polymorphisms in platelet-related proteins and coronary artery disease: investigation of candidate genes, including N-acetylgalactosaminyltransferase 4 (GALNT4) and sulphotransferase 1A1/2 (SULT1A1/2).

BACKGROUND: Both platelet function and heart disease show strong genetic components, many of which remain to be elucidated. MATERIALS AND METHODS: The roles of candidate polymorphisms in ten platelet-associated genes were compared between 1,237 Acute Coronary Syndrome (ACS) cases (with myocardial infarction and unstable angina) and 386 controls, from an Irish Caucasian population. Additionally, 361 stable angina patients were investigated. Two genes of interest were followed up in a separate Irish study of 1,484 individuals (577 with IHD and 907 unaffected). RESULTS: The GALNT4 (N-acetyl galactosaminyl transferase 4) 506I allele was significantly underrepresented in ACS (OR = 0.66, CI = 0.52-0.84; P = 0.001; P = 0.01 after correction for multiple testing), while the SULT1A1 (Sulphotransferase 1A1) 213H allele was associated with risk of ACS (OR = 1.37, CI = 1.08-1.74; P = 0.01; P = 0.1 after correction for multiple testing). Subsequent genotyping of further SNPs in GALNT4 in the family-based (IHD) group revealed that the 506I allele showed the same trend towards protecting against ACS but the haplotypic test over the four commonest haplotypes was not significant (P = 0.55). In contrast, the SULT1A1/SULT1A2 gene complex showed suggestive haplotypic association in the family-based study (P = 0.07), with the greatest increase in risk conferred by the SULT1A2 235T allele (P = 0.025). CONCLUSION: We have identified two risk genes for cardiovascular disease, one of whose (GALNT4) effects may be on either platelet or endothelial function through modifications of PSGL1 or other important glycosylated proteins. The role of sulphotransferases (SULT1A1/2) in cardiovascular disease requires further exploration. Further validation of cardiovascular risks conferred by both genes in other populations (including gene copy number variation) is warranted.

The impact on coronary artery disease of common polymorphisms known to modulate responses to pathogens.

There are two distinct models to explain how genetic variants contributing to cardiovascular disease may have arisen. Firstly, variants may result from random, initially neutral, mutations whose effects are largely revealed in post-reproductive individuals in industrialized societies. Alternatively, the introduced variants may confer an adaptive advantage in certain circumstances. Resistance to pathogens is one of the strongest selection pressures on human proteins. To determine whether this evolutionary pressure has made a large contribution to heart disease we tested whether seventeen polymorphisms in fourteen innate-immunity genes, with documented evidence of modulating response to pathogens, had an impact on heart disease. Genotyping was performed in 1,598 CAD subjects (ACS or stable angina) and 332 controls. The TLR4 399Ile allele had the greatest impact on ACS risk (uncorrected p = 0.006); however there was no evidence overall that the resistance alleles cumulatively influenced the risk of ACS compared to controls or stable angina patients (p = 0.12, and p = 0.40, respectively). We did note a significant interaction between age at onset of disease and combined resistance allele carriership when the ACS and non-thrombotic, stable angina groups were compared (p = 0.04, 16 d.f.). This suggests that innate immunity factors could have a greater impact on thrombus formation among younger CAD patients.

Activation of apoptotic and inflammatory pathways in dysfunctional donor hearts.

BACKGROUND: Myocardial dysfunction is common after brain death, but the mechanisms remain unclear. Apoptosis is tightly regulated by enzymes termed the caspases. We have investigated the caspases involved in the terminal part of the apoptotic pathway in dysfunctional (nontransplanted) donor hearts and their relation to inflammatory markers and compared them to hearts with good ventricular function (transplanted donors). METHODS: Thirty-one donor hearts assessed for transplantation were examined. Western blotting was used to measure pro-caspase-9, caspase-3, DFF45, the activated nuclease CPAN and poly (ADP-ribose) polymerase, a DNA repair enzyme inactivated by caspase-3. Caspase-3 activity was also measured. Histologic and immunocytochemical analysis for HLA Class II and Real Time polymerase chain reaction for tumor necrosis factor-alpha and interleukin 6 were performed to detect inflammatory activation. RESULTS: Cleaved caspase-9 was higher (5.53+/-0.6 vs. 3.64+/-0.4 O.D. units, P<0.01) in nontransplanted compared with transplanted donors and there was a trend for higher pro-caspase-9 (5.20+/-1.0 vs. 4.22+/-0.4 O.D. units, P=NS). Levels of pro-caspase-3 were higher in nontransplanted (9.66+/-0.5 vs. 5.15+/-0.5 O.D. units, P<0.00001) donors and cleavage products of caspase-3 were elevated in 14 of 14 nontransplanted and 2 of 17 transplanted donors. Intact DFF-45 (8.94+/-0.36 vs. 6.14+/-0.30 O.D. units, P<0.000005), its spliced product (2.38+/-0.35 vs. 0.4+/-0.21 O.D. units, P=0.0001) and the nuclease caspase-activated nuclease (2.01+/-0.3 vs. 0.66+/-0.16 OD units, P=0.001) were higher in nontransplanted donors. The caspase-3 substrate poly (ADP-ribose) polymerase was higher in nontransplanted (1.16+/-0.13 vs. 0.61+/-0.22 O.D. units, P=0.57) donors. CONCLUSIONS: The caspases are elevated in dysfunctional donor hearts compared with hearts with good ventricular function with a possible link to inflammatory activation supporting the concept that brain death causes inflammatory activation which can lead to apoptosis with a possible important effect on function.

Aortic root characteristics of human pulmonary autografts.

BACKGROUND: After pulmonary autograft replacement of the aortic valve and root, the pulmonary artery (PA) wall is subjected to higher pressures. Concern exists that this may lead to structural and functional changes in the implanted autograft and subsequent aortic root dilatation and neoaortic regurgitation. We therefore assessed root dimensions and neoaortic regurgitation, morphological structure, and mechanical behavior in patients who underwent the Ross operation. METHODS AND RESULTS: Seventy-four patients who were randomized to undergo aortic valve replacement with an aortic homograft or a pulmonary autograft were followed up echocardiographically for up to 4 years and had their aortic root dimensions measured at the level of the annulus, sinuses, and sinotubular junction. In a separate series of 18 patients who underwent pulmonary autograft surgery and 8 normal organ donors, samples from the PA and aorta were analyzed for medial wall thickness, distribution of the staining of collagen and elastin, and elastin fragmentation. Finally, stress-strain curves were obtained from samples of the PA and aorta from 9 patients who underwent pulmonary autograft surgery and from 1 patient in whom a 4-month-old autograft was explanted. No patient in either group had aortic dilatation at any level of >20% or more than mild aortic regurgitation at up to 4 years of follow-up. The aortic media was thicker in both autografts and normal donors (P:<0.01), and there was a trend for the PA media to be thicker in the autograft group. Elastic fiber in all aortas showed little or no variation, whereas in the PA, there was considerable variation in fragmentation. Patients with higher preoperative PA pressures tended to have lower fragmentation scores (chi(2) P:<0.01). The lower stiffness modulus, higher stiffness modulus, and maximum tensile strength of the aorta was 34% to 38% higher than that of the PA (P:<0.01); however, the 4-month-old autograft appeared to show adaptation in mechanical behavior. CONCLUSIONS: In our series of patients, there was no significant progressive dilatation of the aortic root. We demonstrated differences in the anatomic structure and mechanical behavior of the PA in vitro and highlighted histological and mechanical modes of adaptation.

Effect of antibiotic pretreatment on immunogenicity of human heart valves and component cells.

BACKGROUND: For many years valves have been sterilized with high-dose antibiotics before implantation, but now there is an increasing trend to using "homovital" valves, which have been exposed to very low dose antibiotics. METHODS: To investigate the immunogenicity of valve tissue, before and after exposure to high- and low-dose antibiotics, peripheral blood mononuclear cells and human allogenic T cells were cocultured with antibiotic-treated valve discs, cultured valve endothelial cells, and fibroblasts. Proliferation was measured by uptake of thymidine labeled with hydrogen 3. RESULTS: Untreated tissue pieces stimulate peripheral blood mononuclear cells (4,080+/-980 cpm) at day 0 with similar results after 1 day in Hank's balanced salt solution (4,272.4+/-1,307 cpm) reducing to 2,442+/-926 cpm after 3 days and 1,111+/-255 cpm after 5 days; antibiotic-treated pieces are less immunogenic after 1 (2,560+/-403 cpm), 3 (1,550+/-60 cpm), 5 (717+/-295 cpm), and 7 days (633+/-174 cpm) in homovital solution, whereas sterilized pieces are not immunogenic (184+/-96 cpm) after only 1 day in strong antibiotics. Histologic analysis showed that this corresponds to a reduction of class I and class II expression by human valve endothelial cells. Human valve endothelial cells but not fibroblasts are capable of causing direct stimulation of CD4+ T cells. However, human valve endothelial cells poorly stimulate CD4+ T cells after incubation in homovital solution for 24 hours. CONCLUSIONS: This study shows that valve tissue is immunogenic and this immunogenicity is mediated mainly by endothelial cells. However, the immunostimulatory potential of the valve can be reduced by incubating the solution in an antibiotic cocktail.

The sigma receptor ligand JO 1784 (igmesine hydrochloride) is neuroprotective in the gerbil model of global cerebral ischaemia.

To assess the effects of the novel sigma receptor ligand JO 1784 ((+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride or igmesine hydrochloride) on behavioural and histological changes following cerebral ischaemia, the gerbil model of cerebral ischaemia was used. Two experiments were carried out. In the first animals were either sham operated, subjected to 5 min of bilateral carotid occlusion or administered JO 1784 (25, 50, 75 or 100 mg/kg p.o.) 1, 24 and 48 h after 5 min bilateral carotid occlusion and histological evaluation carried out 96 h after surgery. In the second experiment the effects of JO 1784 administered at a dose of 100 mg/kg i.p. 30 min, 6, 24 and 48 h post-surgery on home cage activity and nitric oxide (NO) synthase activity in the cortex, hippocampus, cerebellum and brain stem 4 days after surgery was examined. Extensive neuronal death was observed in the CA1 region of 5 min occluded animals. JO 1784 (50, 75 and 100 mg/kg) provided significant protection against this ischaemia-induced cell death (P < 0.03-0.005). In the second experiment a large increase in home cage activity was observed for 5 min occluded animals for 12 h after surgery (P = 0.0018-0.02). A large increase in NO synthase activity was observed in all brain regions for 5 min occluded animals. Post-administration of JO 1784 attenuated the ischaemia-induced hyperactivity and increased NO synthase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of G1-phase arrest induced by ionizing radiation in hematopoietic cells by overexpression of genes involved in the G1/S-phase transition.

D-type cyclins and cyclin-dependent kinase (cdk-4) are likely involved in regulating passage of cells through the G1 phase of the cell cycle. A decrease in the proportion of cells in G1, a relatively radiation-sensitive phase of the cell cycle, should result in increased resistance to ionizing radiation; however, the effect of such overexpression on X-ray-induced G1-phase arrest is not known. Radiation survival curves were obtained at a dose rate of either 8 cGy/min or 1 Gy/min for subclones of the IL-3-dependent hematopoietic progenitor cell line 32D cl 3 expressing transgenes for either cyclin-D1, D2 or D3 or cdk-4. We compared the results to those with overexpression of the transgene for Bcl-2, whose expression enhances radiation survival and delays apoptosis. Cells overexpressing transgenes for each D-type cyclin or Bcl-2 had an increased number of cells in S phase compared to parent line 32D cl 3; however, overexpression of cdk-4 had no effect on cell cycle distribution. Cell death resulting from withdrawal of IL-3 was not affected by overexpression of cyclins D1 and D3 but was delayed by overexpression of D2, cdk-4 or Bcl-2. Flow cytometry 24 h after 5 Gy irradiation demonstrated that overexpression of each G1-phase regulatory transgene decreased the proportion of cells at the G1/S-phase border. Western analysis revealed induction of cyclin-D protein levels by irradiation, but no change in the levels of cdk-4, p53 or p21. There was no significant change in the D0, but a significant increase in the n for cyclin-D or cdk-4 transgene-overexpressing clones at 1 Gy/min (P < 0.017). At a lower dose rate of 8 cGy/min, the n for cyclin or cdk-4-overexpressing clones was also increased (P < 0.07). Thus overexpression of cyclin-D or cdk-4 in hematopoietic cells induces detectable effects on hematopoietic cell radiation biology including a broadening of the shoulder on the radiation survival curve and a decrease in radiation-induced G1/S-phase arrest.