Michael Brimacombe

Leukocyte telomere dynamics: longitudinal findings among young adults in the Bogalusa Heart Study.

Leukocyte telomere length (LTL) is ostensibly a biomarker of human aging. Cross-sectional analyses have found that LTL is relatively short in a host of aging-related diseases. These studies have also provided indirect estimates of age-dependent LTL shortening. In this paper, the authors report findings of the first comprehensive longitudinal study of 450 whites and 185 African Americans in Louisiana (aged 31.4 and 37.4 years at baseline (1995–1996) and follow-up (2001–2006) examinations, respectively) participating in the Bogalusa Heart Study. Rate of change in LTL was highly variable among individuals, with some displaying a paradoxical gain in LTL during the follow-up period. The most striking observation was that age-dependent LTL shortening was proportional to LTL at baseline examination. At both baseline and follow-up examinations, African Americans had longer LTLs than whites, and smokers had shorter LTLs than nonsmokers. The longer LTL in African Americans than in whites explained in part the faster rate of LTL shortening observed among African Americans. These findings underscore the complexity of leukocyte telomere dynamics in vivo and suggest that determinants in addition to the “end-replication problem” contribute to telomere shortening in vivo.

Telomere Length and Mortality: A Study of Leukocytes in Elderly Danish Twins

Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality analysis in 548 same-sex Danish twins (274 pairs) aged 73-94 years, of whom 204 pairs experienced the death of one or both co-twins during 9-10 years of follow-up (1997-2007). From the terminal restriction fragment length (TRFL) distribution, the authors obtained the mean TRFL (mTRFL) and the mean values of the shorter 50% (mTRFL(50)) and shortest 25% (mTRFL(25)) of TRFLs in the distribution and computed the mode of TRFL (MTRFL). They analyzed the proportions of twin pairs in which the co-twin with the shorter telomeres died first. The proportions derived from the intrapair comparisons indicated that the shorter telomeres predicted the death of the first co-twin better than the mTRFL did (mTRFL: 0.56, 95% confidence interval (CI): 0.49, 0.63; mTRFL(50): 0.59, 95% CI: 0.52, 0.66; mTRFL(25): 0.59, 95% CI: 0.52, 0.66; MTRFL: 0.60, 95% CI: 0.53, 0.67). The telomere-mortality association was stronger in years 3-4 than in the rest of the follow-up period, and it grew stronger with increasing intrapair difference in all telomere parameters. Leukocyte telomere dynamics might help explain the boundaries of the human life span.

Autism Spectrum Disorders: Concurrent Clinical Disorders

Individuals with autism spectrum disorder are heterogeneous in clinical presentation, concurrent disorders, and developmental outcomes. This study characterized the clinical co-occurrences and potential subgroups in 160 children with autism spectrum disorders who presented to The Autism Center between 1999 and 2003. Medical and psychiatric co-occurrences included sleep disorders, epilepsy, food intolerance, gastrointestinal dysfunction, mood disorder, and aggressive and self-injurious behaviors. Sleep disorders were associated with gastrointestinal dysfunction (P < .05) and mood disorders (P < .01). Food intolerance was associated with gastrointestinal dysfunction (P = .001). Subjects with mood disorder tended to develop aggressive or self-injurious behaviors (P < .05). Developmental regression was not associated with increased co-occurrence of medical or psychiatric disorders. Medical co-occurrence did not present as a risk factor for psychiatric co-occurrence, and vice versa. These results showed a high prevalence of multiple medical and psychiatric co-occurrences. There may be common pathophysiologic mechanisms resulting in clinical subgroups of autism spectrum disorders. Recognition of the co-occurrence of concurrent disorders may provide insight into the therapeutic strategy.

Offspring's Leukocyte Telomere Length, Paternal Age, and Telomere Elongation in Sperm

Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offsprings LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offsprings LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18–94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (<30 years) and older (>50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offsprings LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study.

Reduced cardiac parasympathetic activity in children with autism

Many of the clinical symptoms of autism suggest autonomic dysfunction. The aim of this study was to measure baseline cardiovascular autonomic function in children with autism using the NeuroScope, a device that can measure this brainstem function in real-time. Resting cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), mean arterial blood pressure (MAP), diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR) were recorded in three different groups of children. The symptomatic group (n = 15) consisted of those with autism who exhibited symptoms or signs of autonomic dysfunction. The asymptomatic group (n = 13) consisted of children with autism but without symptoms or signs of autonomic dysfunction and the healthy children were in the control group (n = 17) [corrected]. The CVT and CSB were significantly lower in association with a significant elevation in HR, MAP and DBP in all children with autism compared with the healthy controls. Further more, the levels of CVT and CSB were lower in the symptomatic than in the asymptomatic group. The levels of CVT and CSB were not related to age in all the three groups. These results suggest that there is low baseline cardiac parasympathetic activity with evidence of elevated sympathetic tone in children with autism whether or not they have symptoms or signs of autonomic abnormalities.

The association of autism diagnosis with socioeconomic status

Background: In 2007 the Centers for Disease Control and Prevention (CDC) reported a higher prevalence of autism spectrum disorder (ASD) in New Jersey, one of the wealthiest states in the United States, than in other surveillance regions. Objective: To examine the association of socioeconomic status (SES) with ASD prevalence. Methods: Information on eight-year-olds with ASD from four counties was abstracted from school and medical records. US Census 2000 provided population and median household income data. Results: 586 children with ASD were identified: autism prevalence was 10.2/1000, higher in boys than girls (16 vs. 4/1000); higher in white and Asian non-Hispanics than in black non-Hispanics and Hispanics (12.5, 14.0, 9.0, and 8.5/1000, respectively); and higher (17.2/1000 (95% CI 14.0–21.1)) in tracts with median income >US

Where the O2 goes to: preservation of human fetal oxygen delivery and consumption at high altitude

90,000 than in tracts with median income ≤US

Maternal oxygen delivery is not related to altitude- and ancestry-associated differences in human fetal growth.

30,000 (7.1 (95% CI 5.7–8.9)). Number of professional evaluations was higher, and age at diagnosis younger, in higher income tracts (p < .001), but both measures spanned a wide overlapping range in all SES levels. In multivariable models race/ethnicity did not predict ASD, but the prevalence ratio was 2.2 (95% CI 1.5–3.1) when comparing highest with lowest income tracts. Conclusions: In the US state of New Jersey, ASD prevalence is higher in wealthier census tracts, perhaps due to differential access to pediatric and developmental services.

Comorbidity and mortality following hip fracture: a population-based cohort study

Fetal growth is decreased at high altitude (> 2700 m). We hypothesized that variation in fetal O2 delivery might account for both the altitude effect and the relative preservation of fetal growth in multigenerational natives to high altitude. Participants were 168 women of European or Andean ancestry living at 3600 m or 400 m. Ancestry was genetically confirmed. Umbilical vein blood flow was measured using ultrasound and Doppler. Cord blood samples permitted calculation of fetal O2 delivery and consumption. Andean fetuses had greater blood flow and oxygen delivery than Europeans and weighed more at birth, regardless of altitude (+208 g, P < 0.0001). Fetal blood flow was decreased at 3600 m (P < 0.0001); the decrement was similar in both ancestry groups. Altitude‐associated decrease in birth weight was greater in Europeans (−417 g) than Andeans (−228 g, P < 0.005). Birth weight at 3600 m was > 200 g lower for Europeans at any given level of blood flow or O2 delivery. Fetal haemoglobin concentration was increased, decreased, and the fetal / curve was left‐shifted at 3600 m. Fetuses receiving less O2 extracted more (r2= 0.35, P < 0.0001). These adaptations resulted in similar fetal O2 delivery and consumption across all four groups. Increased umbilical venous O2 delivery correlated with increased fetal O2 consumption per kg weight (r2= 0.50, P < 0.0001). Blood flow (r2= 0.16, P < 0.001) and O2 delivery (r2= 0.17, P < 0.001) correlated with birth weight at 3600 m, but not at 400 m (r2= 0.04, and 0.03, respectively). We concluded that the most pronounced difference at high altitude is reduced fetal blood flow, but fetal haematological adaptation and fetal capacity to increase O2 extraction indicates that deficit in fetal oxygen delivery is unlikely to be causally associated with the altitude‐ and ancestry‐related differences in fetal growth.

Leukocyte telomere length is associated with HDL cholesterol levels: The Bogalusa heart study.

Fetal growth is reduced at high altitude, but the decrease is less among long‐resident populations. We hypothesized that greater maternal uteroplacental O2 delivery would explain increased fetal growth in Andean natives versus European migrants to high altitude. O2 delivery was measured with ultrasound, Doppler and haematological techniques. Participants (n= 180) were pregnant women of self‐professed European or Andean ancestry living at 3600 m or 400 m in Bolivia. Ancestry was quantified using ancestry‐informative single nucleotide polymorphims. The altitude‐associated decrement in birth weight was 418 g in European versus 236 g in Andean women (P < 0.005). Altitude was associated with decreased uterine artery diameter, volumetric blood flow and O2 delivery regardless of ancestry. But the hypothesis was rejected as O2 delivery was similar between ancestry groups at their respective altitudes of residence. Instead, Andean neonates were larger and heavier per unit of O2 delivery, regardless of altitude (P < 0.001). European admixture among Andeans was negatively correlated with birth weight at both altitudes (P < 0.01), but admixture was not related to any of the O2 transport variables. Genetically mediated differences in maternal O2 delivery are thus unlikely to explain the Andean advantage in fetal growth. Of the other independent variables, only placental weight and gestational age explained significant variation in birth weight. Thus greater placental efficiency in O2 and nutrient transport, and/or greater fetal efficiency in substrate utilization may contribute to ancestry‐ and altitude‐related differences in fetal growth. Uterine artery O2 delivery in these pregnancies was 99 ± 3 ml min−1, ∼5‐fold greater than near‐term fetal O2 consumption. Deficits in maternal O2 transport in third trimester normal pregnancy are unlikely to be causally associated with variation in fetal growth.