Serum triiodothyronine levels and inflammatory cytokine production capacity

Increasing evidence suggests that pro-inflammatory cytokines are at play in lowering peripheral thyroid hormone levels during critical illness. Conversely, thyroid hormones have been suggested to enhance production of inflammatory cytokines. In view of these considerations, we hypothesized a mutual association between triiodothyronine and pro-inflammatory cytokines. Therefore we evaluated the relation between both circulating and induced inflammatory markers and serum thyroid function parameters in the Leiden 85-plus Study. We found that higher circulating levels of inflammatory markers were associated with lower levels of free serum triiodothyronine. In turn, higher serum free triiodothyronine levels were related to higher production capacity of pro-inflammatory cytokines after stimulation with lipopolysaccharide. By combining in vivo and ex vivo data, we were able to demonstrate for the first time the existence of a potential feedback mechanism between thyroid function and immune production capacity. We conclude that maintenance of normal thyroid function might be important for a preserved immune response in elderly human populations.     

The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding?

OBJECTIVE: In order to determine whether screening of thyroid function is justified in patients with hypercholesterolaemia, we determined the prevalence of subclinical hypothyroidism at different levels of total plasma cholesterol in middle-aged men and women. DESIGN AND METHODS: 1200 participants were selected from a population based cross sectional study on risk factors for cardiovascular diseases. The participants were divided into three groups: total plasma cholesterol < 5 mmol/l, total plasma cholesterol 5-8 mmol/l, total plasma cholesterol > 8 mmol/l. Each group was comparable in size and sex distribution. Subclinical hypothyroidism was defined as plasma TSH levels higher than 4 mU/l, in the presence of normal free thyroxine (FT4(4)) concentration. RESULTS: Plasma samples of a total of 1191 participants were analyzed. The overall prevalence of subclinical hypothyroidism was 1.9% in men and 7.6% in women of middle age. In women the prevalence of subclinical hypothyroidism increased from 4.0 percent in the lowest, to 10.3 percent in the highest cholesterol stratum (P = 0.02). In men, the mean prevalence was 1.8 percent and roughly similar in the various strata. After age correction, an increase of 1 mU/l TSH in women was associated with an increase of 0.09 mmol/l total plasma cholesterol (95% confidence interval (CI) 0.02-0.16 mmol/l). A similar trend was found in men (0.16 mmol/l, 95% CI -0.02-0.34 mmol/l). CONCLUSIONS: In the population, the prevalence of subclinical hypothyroidism is up to 10 percent in middle aged women with high levels of total plasma cholesterol and may justify case-finding. In these women approximately 0.5 mmol/l of total plasma cholesterol can be attributed to the subclinical thyroid dysfunction. In men a similar correlation between thyroid dysfunction and total plasma cholesterol is seen, but the prevalence of thyroid dysfunction is considerably lower.     

NAL1 allele from a rice landrace greatly increases yield in modern indica cultivars

Increasing crop production is essential for securing the future food supply in developing countries in Asia and Africa as economies and populations grow. However, although the Green Revolution led to increased grain production in the 1960s, no major advances have been made in increasing yield potential in rice since then. In this study, we identified a gene, SPIKELET NUMBER (SPIKE), from a tropical japonica rice landrace that enhances the grain productivity of indica cultivars through pleiotropic effects on plant architecture. Map-based cloning revealed that SPIKE was identical to NARROW LEAF1 (NAL1), which has been reported to control vein pattern in leaf. Phenotypic analyses of a near-isogenic line of a popular indica cultivar, IR64, and overexpressor lines revealed increases in spikelet number, leaf size, root system, and the number of vascular bundles, indicating the enhancement of source size and translocation capacity as well as sink size. The near-isogenic line achieved 13–36% yield increase without any negative effect on grain appearance. Expression analysis revealed that the gene was expressed in all cell types: panicles, leaves, roots, and culms supporting the pleiotropic effects on plant architecture. Furthermore, SPIKE increased grain yield by 18% in the recently released indica cultivar IRRI146, and increased spikelet number in the genetic background of other popular indica cultivars. The use of SPIKE in rice breeding could contribute to food security in indica-growing regions such as South and Southeast Asia.The world’s population is expected to surpass 9 billion in 2050 (http://esa.un.org/unpd/ppp/index.htm). Most of this increase will occur in the developing countries of Asia and Africa. By 2035, a 26% increase in rice production will be essential to feed the rising population (1, 2). Rice (Oryza sativa L.) is a staple food of more than 3 billion people, mainly in Asia. Predominantly, indica cultivars are grown in southern China, Southeast Asia, and South Asia, occupying approximately 70% of the rice-producing area in the world, whereas japonica cultivars are grown mainly in East Asia (3, 4). Because of urbanization and industrialization, an increase in the yield of indica cultivars is a pressing need in Southeast and South Asia (5). Additionally, good grain quality (influencing market value) and high yield are essential for the adoption of new cultivars in local areas (6).The grain yield of rice is determined by spikelet number per panicle, panicle number per plant, grain weight, and spikelet fertility. Although many quantitative trait loci (QTLs) for yield components have been identified (www.gramene.org), few have so far been isolated. To date, at least nine genes or loci for yield-related traits in rice have been isolated from natural variation: Gn1a and APO1 for number of grains (7–9); GS3, GW2, and qSW5 for grain size (10–12); DEP1 and WFP for panicle architecture (13, 14); SCM2 for strong culm (15); and Ghd7 for late heading and number of grains (16). APO1, SCM2, and DEP1 increased grain yield in a japonica genetic background in field experiments (9, 13, 15). However, no novel cloned gene has been reported to increase grain yield in indica cultivars (17). Here, we identified a gene in a tropical japonica landrace and used the allele to increase the grain yield of modern indica cultivars at the crop level through a breeding concept developed by International Rice Research Institute (IRRI) breeders more than 20 y ago.In 1989, a breeding program for New Plant Type (NPT) rice was launched at IRRI to increase the yields of modern indica cultivars by using genetic material from tropical japonica landraces (18). Several Indonesian tropical japonica landraces—which are characterized by large panicles, large leaves, a vigorous root system, thick stems, and few unproductive tillers—have been used in international breeding programs. However, despite these features, the NPT cultivars yield less than modern indica cultivars, mainly because of low grain fertility and low panicle number (19, 20). To genetically dissect and elicit the valuable traits of NPT cultivars, we backcrossed the NPT cultivars including YP9 (IR68522-10-2-2) against modern indica cultivar IR64 to develop introgression lines (ILs) (Fig. S1). BC₃-derived ILs, which had favorable yield-related traits and few undesirable traits, were selected by field observation (21). Using the ILs, we identified 21 QTLs for yield components such as total spikelet number per panicle (TSN), grain weight, and panicle number. Among the QTLs, qTSN4, for high TSN, was commonly detected on the long arm of chromosome 4 in five NPT lines derived from different tropical japonica cultivars (22). Additionally, a near-isogenic line (NIL) for qTSN4 from YP9, derived from tropical japonica landrace Daringan with an IR64 genetic background, had more spikelets per panicle and more branches than IR64.In this study, we isolated the gene for qTSN4 through map-based cloning to facilitate its use in breeding. The phenotypic effects of the gene were validated in transgenic plants and by expression analysis. To confirm the effect on practical grain yield in the field, we evaluated yield and related traits by using NILs with genetic backgrounds of popular indica cultivars.     

Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways

In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from long-lived sibships collected in the Leiden Longevity Study and 1,670 younger population controls. We analyzed 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes using four self-contained pathway tests (PLINK set-based test, Global test, GRASS and SNP ratio test). Although we observed small differences between the results of the different pathway tests, they showed consistent significant association of the IIS and TM pathway SNP sets with longevity. Analysis of gene SNP sets from these pathways indicates that the association of the IIS pathway is scattered over several genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG), while the association of the TM pathway seems to be mainly determined by one gene (POT1). In conclusion, this study shows that genetic variation in genes involved in the IIS and TM pathways is associated with human longevity.     

Common chronic diseases and general impairments as determinants of walking disability in the oldest-old population

OBJECTIVES: Walking disability affects older people's autonomy and well-being. We investigated the relative effect of common chronic diseases and general impairments on walking disability in the general oldest-old population. DESIGN: Population-based cohort study. SETTING: Leiden 85-plus Study, the Netherlands. PARTICIPANTS: Five hundred ninety-nine persons aged 85, response rate 87%. MEASUREMENTS: Walking disability was assessed using a 6-meter walking test. Persons with a walking time below the 25th percentile and those who were physically unable to perform the walking test were categorized as having a walking disability. Information on common chronic diseases was obtained from records of subjects' general practitioners and pharmacies. General impairments were assessed with functional tests and standardized questions during face-to-face interviews. We expressed the effect of common chronic diseases and general impairments as the population attributable risk (PAR), indicating how much disability can be prevented when the identified risk factor is eliminated from the population. RESULTS: One hundred ninety-two persons (33%) had a walking disability. This disability was highly associated with poor mobility in daily life, recurrent falls, and poor well-being (all P <.001). Of the common chronic diseases, stroke, angina pectoris, diabetes mellitus, and hip fracture but not arthritis contributed most (PARs from 6% to 15%) to walking disability in the population at large. General impairments had higher prevalence rates and higher PARs than common chronic diseases. Cognitive impairment, depressive symptoms, and dizziness upon rising contributed most (PARs between 22 to 27%) to walking disability. In multivariate regression analyses of all common chronic diseases and general impairments, associations remained significant. CONCLUSION: Within the general oldest-old population, general impairments contribute more substantially to walking disability than do common chronic diseases. The diagnosed diseases did not explain the impairments that led to walking disability. Especially in the oldest old, clinicians should focus not merely on common chronic diseases but particularly on general impairments as targets for diagnostic analysis and treatment to decrease walking disability.     

Relevance of underlying disease and bacterial vacA and cagA status on the efficacy of Helicobacter pylori eradication

AIM: To study the effects of Helicobacter pylori associated diseases and the bacterial vacA and cagA statuses on the efficacy of H. pylori eradication. METHODS: A prospective study in a consecutive series of outpatients of a gastroenterological institution and of a primary practice. A series of 146 H. pylori positive patients with peptic ulcer disease (PUD; n = 40) or nonulcer dyspepsia (NUD; n = 106) were evaluated. H. pylori vacA genotpyes and cagA status were determined directly in gastric biopsy specimens by polymerase chain reaction. The patients were treated with triple-therapy regimens consisting of a proton pump inhibitor and two antibiotics twice daily for 7 days. Reevaluation of H. pylori was determined 4-5 weeks later by endoscopy or 13C urea breath test. RESULTS: 123 patients completed the study. In 8 patients, colonization with two or more H. pylori strains was found. The overall cure rate was 84.6% (104/123). The eradication rates were significantly higher in patients with PUD (94.4%, 34/36) than in those with NUD (81.6%, 71/87; p < 0.05). In patients with cagA-positive H. pylori strains, the eradication rate was 89.0% (73/82) as compared with 78.8% (26/33) in those with cagA-negative strains (p = 0.15). The vacA genotype had no effect on the efficacy of H. pylori eradication. CONCLUSION: Using 1-week triple-therapy regimens, treatment of H. pylori infection is more effective in patients with PUD than in those with NUD.     

“Dog ear” formation after double-stapled low anterior resection as a risk factor for anastomotic disruption

PURPOSE: The aim of this study was to investigate the possible deleterious effect of the lateral intersecting margins (so-called dog ears) on anastomotic disruption after experimentally performed double-stapled anastomoses. METHODS: Two groups of double-stapled side-to-end anastomoses were performed using pig small intestines. Group A consisted of 35 circular anastomoses and Group B of 32 double-stapled anastomoses with a bilateral dog ear. In both groups bursting pressures were tested using a water-filled, pressure-controlled automatic pumping system (Hamou Endomat®), and special attention was paid to the location(s) in the anastomoses were the disruption(s) occurred. RESULTS: In Group A bursting pressures were significantly higher than in Group B (median pressure, 90vs. 60 mmHg;P<0.001, Mann-WhitneyU test). Remarkably, in Group B in 13 cases (42 percent) the first disruption occurred at the corner of a dog ear. CONCLUSIONS: We conclude that the lateral intersections of double-stapled anastomoses are a structural weak spot and that the currently most often applied double-stapled anastomosis is a less effective type of anastomosis than a complete circular one. Resolving this technical problem might help to reduce the number of anastomotic disruptions after low anterior resections.Equipment supplied by Ethicon Endosurgery-Johnson & Johnson, the Netherlands.Presented at the meeting of the Dutch Surgical Society, Leiden, the Netherlands, November 27, 1998.