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.     

Nonagenarian Siblings and Their Offspring Display Lower Risk of Mortality and Morbidity than Sporadic Nonagenarians: The Leiden Longevity Study

OBJECTIVES: To compare the risk of mortality of nonagenarian siblings with that of sporadic nonagenarians (not selected on having a nonagenarian sibling) and to compare the prevalence of morbidity in their offspring with that of the offsprings' partners.
DESIGN: Longitudinal (mortality risk) and cross-sectional (disease prevalence).
SETTING: Nationwide sample.
PARTICIPANTS: The Leiden Longevity Study consists of 991 nonagenarian siblings derived from 420 Caucasian families, 1,365 of their offspring, and 621 of the offsprings' partners. In the Leiden 85-plus Study, 599 subjects aged 85 were included, of whom 275 attained the age of 90 (sporadic nonagenarians).
MEASUREMENTS: All nonagenarian siblings and sporadic nonagenarians were followed for mortality (with a mean±standard deviation follow-up time of 2.7±1.4 years and 3.0±1.5 years, respectively). Information on medical history and medication use was collected for offspring and their partners.
RESULTS: Nonagenarian siblings had a 41% lower risk of mortality ( P <.001) than sporadic nonagenarians. The offspring of nonagenarian siblings had a lower prevalence of myocardial infarction (2.4% vs 4.1%, P =.03), hypertension (23.0% vs 27.5%, P =.01), diabetes mellitus (4.4% vs 7.6%, P =.004), and use of cardiovascular medication (23.0% vs 28.9%, P =.003) than their partners.
CONCLUSION: The lower mortality rate of nonagenarian siblings and lower prevalence of morbidity in their middle-aged offspring reinforce the notion that resilience against disease and death have similar underlying biology that is determined by genetic or familial factors.     

Basal cerebral blood flow is dependent on the nitric oxide pathway in elderly but not in young healthy men

OBJECTIVE: Brain perfusion is tightly regulated over a wide range of blood pressures by local regulation of cerebral blood flow (CBF). Ageing is associated with impaired CBF and impaired nitric oxide mediated vasodilator responses. The role of nitric oxide in the regulation of basal CBF in young and older subjects was investigated, using the nitric oxide synthase inhibitor L-NMMA as pharmacological tool. METHODS: We used a gradient echo phase-contrast magnetic resonance imaging technique to investigate the role of nitric oxide in the regulation of cerebral blood flow in young (25+/-7.1 years; n=8) and old (78+/-6.6 years; n=7) volunteers. The study was performed in a double-blinded fashion and consisted of two study days. On one day the effects of the intravenously infused L-NMMA on CBF and blood pressure was measured and on the other day the effects of a matching placebo. RESULTS: Basal CBF was significantly lower in old compared to young subjects (590+/-20 vs 704+/-20 ml/min), while the cerebral vascular resistance (CVR) levels were significantly higher (0.15+/-0.01 (arbitrary units) vs 0.12+/-0.01, respectively). Infusion of L-NMMA significantly increased mean arterial pressure in both groups (2.8+/-1.2 mmHg; p=0.02 in the young and in the old subjects 5.6+/-1.1 mmHg; p<0.001). Infusion of L-NMMA significantly decreased CBF (49+/-12 ml/min; p<0.001) and increased CVR (0.02+/-0.004; p<0.001) in the old subjects but did not significantly influence cerebral circulation in the young subjects. CONCLUSION: We conclude that compared to young subjects, in old people CBF is impaired, and dependent on the intactness of the nitric oxide pathway.     

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.     

Preexisting cardiopulmonary disease attenuating the atrial natriuretic peptide response. Results in patients with acute respiratory failure.

The purpose of this study was to evaluate the pathophysiologic role of atrial natriuretic peptide (ANP) as a pulmonary artery vasodilator in patients with acute respiratory failure receiving artificial ventilation. Twenty-one consecutive patients were studied, 12 without and 9 with preexisting cardiopulmonary disease. Pulmonary artery plasma ANP levels were significantly higher than the levels obtained in the superior vena cava and radial artery. Plasma ANP levels correlated significantly with the plasma levels of its second messenger, guanosine 3',5'-cyclic monophosphate (cGMP). In the 12 patients without prior cardiopulmonary disease, plasma ANP levels correlated significantly with mean pulmonary arterial pressure (MPAP). This correlation was not found in the nine patients with preexisting cardiopulmonary disease. The cGMP/ANP ratio, indicating the biologic effect of ANP, was also higher in the patients without preexisting cardiopulmonary disease. These results are compatible with clearance and vasodilator activity of ANP in the pulmonary vascular bed, but only in patients without preexisting cardiopulmonary disease.     

MUSHROOM BODY INFLUENCE ON LOCOMOTOR ACTIVITY AND CIRCADIAN RHYTHMS IN DROSOPHILA MELANOGASTER

Whether or not mechanisms underlying circadian locomotor rhythms and learning are related anatomically through the mushroom bodies (MBs) was investigated by monitoring behavioral rhythmicity in flies with MB lesions induced by chemical ablation and by mutations in five different genes. All flies tested were later examined histologically to assess (1) MB neuroanatomy, and (2) the condition of the putative pacemaker cells -- the ventral Lateral Neurons (LN v s) and their terminals that project to the vicinity of the MB calyces. All groups of flies had normal rhythms except for mushroom body miniature ( mbm ; only in a wild-type Berlin genetic background) and mushroom body defect ( mud ). MB ablation had no effect on the gender-specific differences in the rhythmic activity profile that are typical of wild-type flies. However, ablated males had a slightly longer period than untreated males and were more active under constant dark conditions. LN v s and their arborization patterns appeared normal in MB-ablated and in most mutant flies. Activity defects of mbm flies were attributed to genetic background rather than to the mutation alone. Misrouted LN v projections and ～14% arrhythmia of mud flies were uncorrelated and attributed to pleiotropy rather than to specific effects of MB lesions. Our results imply that MBs are not involved in circadian activity rhythms but that they do have an inhibitory effect on activity levels of male flies.     

The influence of clan structure on the genetic variation in a single Ghanaian village

Socioeconomic and cultural factors are thought to have an important role in influencing human population genetic structure. To explain such population structure differences, most studies analyse genetic differences among widely dispersed human populations. In contrast, we have studied the genetic structure of an ethnic group occupying a single village in north-eastern Ghana. We found a markedly skewed male population substructure because of an almost complete lack of male gene flow among Bimoba clans in this village. We also observed a deep male substructure within one of the clans in this village. Among all males, we observed only three Y-single-nucleotide polymorphism (SNP) haplogroups: E1b1a*-M2, E1b1a7a*-U174 and E1b1a8a*-U209, P277, P278. In contrast to the marked Y-chromosomal substructure, mitochondrial DNA HVS-1 sequence variation and autosomal short-tandem repeats variation patterns indicate high genetic diversities and a virtually random female-mediated gene flow among clans. On the extreme micro-geographical scale of this single Bimoba village, correspondence between the Y-chromosome lineages and clan membership could be due to the combined effects of the strict patrilocal and patrilineal structure. If translated to larger geographic scales, our results would imply that the extent of variation in uniparentally inherited genetic markers, which are typically associated with historical migration on a continental scale, could equally likely be the result of many small and different cumulative effects of social factors such as clan membership that act at a local scale. Such local scale effects should therefore be considered in genetic studies, especially those that use uniparental markers, before making inferences about human history at large.     

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.     

C-reactive protein is a strong but nonspecific risk factor of fatal stroke in elderly persons

An elevated level of C-reactive protein is a strong predictor of cardiovascular events in elderly persons. Whether C-reactive protein has direct adverse vascular effects or is a marker of aspecific systemic inflammation remains to be determined. The aim of this study was to investigate the relation between C-reactive protein and the occurrence of fatal strokes in elderly persons. In the Leiden 85-Plus Study, a population-based prospective follow-up study, we studied the levels of C-reactive protein in 80 participants who died from stroke within the first 5 years of follow-up. Levels of C-reactive protein were determined in serum samples at baseline. Levels of C-reactive protein were also determined in 82 control subjects who survived for the first 5 years of follow-up and in 83 participants who died from noncardiovascular causes. Mortality risks were estimated with logistic regression and adjusted for differences in age, sex, smoking, medication, total cholesterol, history of diabetes or hypertension, and previous cardiovascular events. Levels of C-reactive protein at baseline were 2-fold higher in subjects who died from stroke than in control subjects (median 5.7 versus 2.7 mg/L, P<0.005). The levels of C-reactive protein in subjects who died from stroke or from noncardiovascular causes were similar (median 5.7 versus 4.9 mg/L, P=0.7). The risk of death from stroke as well as from noncardiovascular causes increased linearly up to 10-fold in subjects with the highest levels of C-reactive protein at baseline (P<0.001). The levels of C-reactive protein were lower when more time had elapsed between blood sampling and time of death during follow-up (P=0.01). C-reactive protein is a strong but nonspecific risk factor of fatal stroke in old persons. The data do not support the idea that C-reactive protein has direct vascular effects that underlie fatal cerebrovascular disease.