Differential relationships between parent-child DXA and pQCT bone measures: Results from the Southampton Women's Survey.

AIM: To investigate the associations between indices of bone health in childhood and corresponding parental measures. METHODS: The Southampton Women's Survey characterised 12,583 non-pregnant women aged 20-34 years; 3158 subsequently had singleton live births. In a subset, dual-energy X-ray absorptiometry (DXA) measurements of bone area (BA), bone mineral content (BMC) and areal bone mineral density (aBMD) lumbar spine and total hip were obtained in the parent/offspring (aged 8-9 years) trios. Another subset of children (aged 6-7 years), and their parents, had peripheral quantitative computed tomography (pQCT; 4% and 38% tibia) measures. Using multivariable linear regression we examined relationships between mother/father and offspring, adjusting for parental age, habitual walking speed and education; offspring age and sex; and the corresponding bone measure in the other parent (ß-coefficients (95%CI) unit/unit for each bone measure). RESULTS: Data were available for 260 trios with DXA and 99 with pQCT. There were positive associations for BA, BMC and aBMD between either parent and offspring. Mother-child associations were of greater magnitude than father-child; for example, mother-child aBMD (ß = 0.26 g·cm-2/g·cm-2 (0.21,0.32)) and father-child aBMD (ß = 0.16 g·cm-2/g·cm-2 (0.11,0.21)), P-difference in ß = 0.007. In the subset with pQCT there was a positive association for mother-offspring 4% tibial total area (ß = 0.33 mm2/mm2 (0.17,0.48)), but little evidence of a father-offspring association (ß = -0.06 mm2/mm2 (-0.17,0.06)). In contrast offspring 38% cortical density was more strongly associated with this measure in fathers (ß = 0.48 mg·cm-3/mg·cm-3 (0.15,0.82)) than mothers (ß = 0.27 mg·cm-3/mg·cm-3 (-0.03,0.56)). In general mother-father differences were attenuated by adjustment for height. CONCLUSIONS: Whilst offspring bone measures are independently associated with those of either parent, the magnitude of the association is often greater for maternal than paternal relationships. These findings are consistent with an in utero influence on offspring growth but might also reflect genetic and/or epigenetic parent of origin effects. SUMMARY: In an established parent-offspring cohort, associations between parent and offspring bone indices were generally greater in magnitude for mother-offspring than father-offspring relationships.

Electrophysiological investigation of reward anticipation and outcome evaluation during slot machine play.

Slot machines are a popular form of gambling, offering a tractable way to experimentally model reward processes. This study used a 3-reel slot paradigm to assess psychologically distinct phases of reward processing, reflecting anticipation, and early- and late-stage outcome processing. EEG measures of winning, nearly missing (a losing outcome revealed at the final, third reel), and "totally" missing (a losing outcome revealed earlier, at the second reel) were collected from healthy adults (n=54). Condition effects were evaluated in: i) event-related potential (ERP) components reflecting anticipatory attention (stimulus preceding negativity, SPN) and outcome processing (reward positivity, RewP and late-positive potential, LPP) and ii) total power and phase synchrony of theta and delta band oscillations. Behaviorally, trial initiation was fastest after a near miss outcome and slowest after a winning outcome. As expected, a significant SPN was observed for possible wins (AA) vs. total misses (AB), consistent with reward anticipation. Larger win (AAA) vs. near miss (AAB) amplitudes were observed for the RewP; LPP amplitudes were largest for wins (AAA), intermediate for near misses (AAB), and smallest for total misses (ABC), reflecting significant early (RewP) and late-stage (LPP) outcome processing effects. There was an effect of reel position on the RewP, with larger amplitude in the final reel (AAA-AAB) relative to the 2nd-reel locked difference waves (AA-AB). Across all outcomes, near misses elicited the largest and most phase-synchronized theta responses, while wins elicited larger and more phase-synchronized delta responses than total misses, with delta band measures not distinguishing between near misses and wins. . Phase locking measures contrasting win vs. near miss delta and theta synchronization, within time windows corresponding to ERP measurements, covaried with RewP, but not SPN or LPP, amplitude. Lastly, EEG measures showed differential relationships with age and self-reported consummatory pleasure. In the context of slot machine play, where reward anticipation and attainment place minimal demands on effort and skill, ERP and time-frequency methods capture distinct neurophysiological signatures of reward anticipation and outcome processing.

Exploring individual differences in task switching: Persistence and other personality traits related to anterior cingulate cortex function.

Anterior cingulate cortex (ACC) is involved in cognitive control and decision-making but its precise function is still highly debated. Based on evidence from lesion, neurophysiological, and neuroimaging studies, we have recently proposed a critical role for ACC in motivating extended behaviors according to learned task values (Holroyd and Yeung, 2012). Computational simulations based on this theory suggest a hierarchical mechanism in which a caudal division of ACC selects and applies control over task execution, and a rostral division of ACC facilitates switches between tasks according to a higher task strategy (Holroyd and McClure, 2015). This theoretical framework suggests that ACC may contribute to personality traits related to persistence and reward sensitivity (Holroyd and Umemoto, 2016). To explore this possibility, we carried out a voluntary task switching experiment in which on each trial participants freely chose one of two tasks to perform, under the condition that they try to select the tasks "at random" and equally often. The participants also completed several questionnaires that assessed personality trait related to persistence, apathy, anhedonia, and rumination, in addition to the Big 5 personality inventory. Among other findings, we observed greater compliance with task instructions by persistent individuals, as manifested by a greater facility with switching between tasks, which is suggestive of increased engagement of rostral ACC.

Progressive multifocal leukoencephalopathy associated with infliximab.

A 69-year-old female with seropositive rheumatoid arthritis presented with progressive cognitive decline following treatment with infliximab and methotrexate. Cranial MRI showed non-enhancing white matter signal abnormality consistent with demyelination was seen in the antero-inferior left frontal lobe extending into the frontal opercular white matter and into the left temporal lobe white matter. Similar appearances were seen in the inferomedial right frontal lobe. Brain biopsy showed histological changes consistent with progressive multifocal leukoencephalopathy. The cerebrospinal fluid polymerase chain reaction was negative but brain tissue polymerase chain reaction was positive for JC virus. This case highlights the association of infliximab with progressive multifocal leukoencephalopathy in a patient with known seropositive rheumatoid arthritis.

Placental size at 19 weeks predicts offspring bone mass at birth: findings from the Southampton Women's Survey.

OBJECTIVES: In this study we investigate the relationships between placental size and neonatal bone mass and body composition, in a population-based cohort. STUDY DESIGN: 914 mother-neonate pairs were included. Placental dimensions were measured via ultrasound at 19 weeks gestation. Dual X-ray absorptiometry (DXA) was performed on the neonates within the first two weeks of life. RESULTS: We observed positive relationships between placental volume at 19 weeks, and neonatal bone area (BA; r = 0.26, p < 0.001), bone mineral content (BMC; r = 0.25, p < 0.001) and bone mineral density (BMD; r = 0.10, p = 0.001). Thus placental volume accounted for 6.25% and 1.2% of the variation in neonatal BMC and BMD respectively at birth. These associations remained after adjustment for maternal factors previously shown to be associated with neonatal bone mineral accrual (maternal height, smoking, walking speed in late pregnancy, serum 25(OH) vitamin D and triceps skinfold thickness). CONCLUSIONS: We found that placental volume at 19 weeks gestation was positively associated with neonatal bone size and mineral content. These relationships appeared independent of those maternal factors known to be associated with neonatal bone mass, consistent with notion that such maternal influences might act through modulation of aspects of placental function, e.g. utero-placental blood flow or maternal nutrient concentrations, rather than placental size itself. Low placental volume early in pregnancy may be a marker of a reduced postnatal skeletal size and increased risk of later fracture.

Epigenetic influences in the developmental origins of osteoporosis.

Osteoporosis is a major public health problem due to consequent fragility fractures; data from the UK suggest that up to 50% of women and 20% men aged 50 years will have an osteoporosis-related fracture in their remaining lifetime. Skeletal size and density increase from early embryogenesis through intrauterine, infant, childhood and adult life to reach a peak in the third to fourth decade. The peak bone mass achieved is a strong predictor of later osteoporosis risk. Epidemiological studies have demonstrated a positive relationship between early growth and later bone mass, both at peak and in later life, and also with reduced risk of hip fracture. Mother-offspring cohorts have allowed the elucidation of some of the specific factors in early life, such as maternal body build, lifestyle and 25(OH)-vitamin D status, which might be important. Most recently, the phenomenon of developmental plasticity, whereby a single genotype may give rise to different phenotypes depending on the prevailing environment, and the science of epigenetics have presented novel molecular mechanisms which may underlie previous observations. This review will give an overview of these latter developments in the context of the burden of osteoporosis and the wider data supporting the link between the early environment and bone health in later life.

Secular trends in the incidence of hip and other osteoporotic fractures.

Osteoporosis constitutes a major public health problem through its association with age-related fractures, most notably those of the proximal femur. Substantial geographic variation has been noted in the incidence of hip fracture throughout the world, and estimates of recent incidence trends have varied widely. Studies in the published literature have reported an increase, plateau, and decrease in age-adjusted incidence rates for hip fracture among both men and women. Accurate characterisation of these temporal trends is important in predicting the health care burden attributable to hip fracture in future decades. We therefore conducted a review of studies worldwide, addressing secular trends in the incidence of hip and other fractures. Studies in western populations, whether in North America, Europe or Oceania, have generally reported increases in hip fracture incidence through the second half of the last century, but those continuing to follow trends over the last two decades have found that rates stabilise with age-adjusted decreases being observed in certain centres. In contrast, some studies suggest that the rate is rising in Asia. This synthesis of temporal trends in the published literature will provide an important resource for preventing fractures. Understanding the reasons for the recent declines in rates of hip fracture may help understand ways to reduce rates of hip fracture worldwide.

Reduced cortical bone density with normal trabecular bone density in girls with Turner syndrome.

SUMMARY: This study of 22 girls with Turner syndrome (TS) demonstrates a reduction in bone mineral apparent density (BMAD) at the femoral neck along with a reduction in cortical bone density at the radius (with sparing of trabecular bone). These findings may account for the increased fracture risk noted in this population. INTRODUCTION: Increased fracture risk is a feature of TS; however, the reasons for this are unclear. Little is known regarding cortical and trabecular bone mineral density (BMD) in TS. We have addressed this by measurement of volumetric bone mineral density (vBMD) using peripheral quantitative computed tomography (pQCT). METHODS: We studied 22 females with TS and 21 females without TS; mean ages 12.7 and 12.9 years, respectively. Bone mass measurements were made by dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femur and pQCT of the radius. BMAD was calculated from DXA values. We utilized published reference data to generate Z-scores for both populations. RESULTS: The mean BMAD Z-score at the lumbar spine was not significantly different in individuals with TS compared to the controls. At the femoral neck, individuals with TS had a significantly lower BMAD Z-score compared to the controls (-1.32 vs. -0.14, p = 0.001). At the distal radius, total vBMD Z-score and trabecular vBMD Z-score were not significantly different between the TS group and controls. A significant reduction in cortical vBMD at the proximal radius was noted in the TS group however (-2.58 vs. -1.38, p = 0.02). There was also a trend towards reduced cortical thickness at this site in the TS group (Z-score -2.89 vs. -1.73, p = 0.08). DISCUSSION: TS is associated with reduced BMAD at the femoral neck; pQCT data suggests that cortical density is reduced with sparing of trabecular bone. This differential of cortical and trabecular BMD may predispose to fracture.

The effects of hormone replacement therapy on autoimmune disease: rheumatoid arthritis and systemic lupus erythematosus.

Autoimmune diseases are generally more common in women than men; however, there is no simple explanation for this. Sex hormones, especially estrogen (but also prolactin and testosterone), play important roles in these diseases. Estrogens are generally considered to enhance autoimmunity and have multiple effects on the immune system through various cell types and molecular pathways. There is much evidence supporting the role of estrogen in the pathogenesis of systemic lupus erythematosus (SLE): the disease occurs much more frequently in women, especially during the years of child-bearing potential, and commonly flares during pregnancy. The relationship between estrogen and the development of SLE is complex, however. Exogenous estrogens have been historically avoided in women with SLE due to the widely held view that they could activate disease and their use remains controversial. Current evidence from prospective trials suggests that there may be a small increased risk of mild/moderate flares in women with SLE taking hormone replacement therapy (HRT), but the risk of major flare does not appear to be increased. In rheumatoid arthritis, HRT does not appear to be associated with an increased risk of disease flare and may actually improve disease activity. In all individuals with autoimmune disease, the risk of venous thrombosis associated with oral HRT is an important factor that should also be considered.

Lung cancer mortality at a UK tin smelter.

BACKGROUND: An earlier study of mortality among male former employees at a tin smelter in Humberside, UK, had identified excess mortality from lung cancer, which appeared to be associated with occupational exposure. AIMS: The aim of the present study was to investigate the relationship between lung cancer mortality and quantitative measures of exposure. METHODS: Using available records of occupational hygiene measurements, we established exposure matrices for arsenic, cadmium, lead, antimony and polonium-210 ((210)Po), covering the main process areas of the smelter. We established work histories from personnel record cards for the previously defined cohort of 1462 male employees. Three different methods of extrapolation were used to assess exposures prior to 1972, when no measurement results were available. Lung cancer mortality was examined in relation to cumulative inhalation exposure by Poisson regression analysis. RESULTS: No significant associations could be found between lung cancer mortality and simple cumulative exposure to any of the substances studied. When cumulative exposures were weighted according to time since exposure and attained age, significant associations were found between lung cancer mortality and exposures to arsenic, lead and antimony. CONCLUSIONS: The excess of lung cancer mortality in the cohort can most plausibly be explained if arsenic is the principal occupational carcinogen (for which the excess relative risk diminishes with time since exposure and attained age) and if there is a contribution to excess mortality from an enhanced prevalence of smoking within the cohort. The implications of the dose-response for arsenic exposure for risk estimation merit further consideration.

Evidence for hierarchical error processing in the human brain.

Human goal-directed behavior depends on multiple neural systems that monitor and correct for different types of errors. For example, tracking errors in continuous motor tasks appear to be processed by a system involving posterior parietal cortex, whereas errors in speeded response and trial-and-error learning tasks appear to be processed by a system involving frontal-medial cortex. To date, it is unknown whether there is a functional relationship between the posterior and frontal error systems. We recorded the event-related brain potential from participants engaged in a tracking task to investigate the role of the frontal system in continuous motor control. Our results demonstrate that tracking errors elicit temporally distinct error-related event-related brain potentials over frontal and posterior regions of the scalp, suggesting an interaction between the subcomponents of a hierarchically organized system for error processing. Specifically, we propose that the frontal error system assesses high-level errors (i.e. goal attainment) whereas the posterior error system is responsible for evaluating low-level errors (i.e. trajectory deviations during motor control).

Mortality experience of male workers at a UK tin smelter.

BACKGROUND: Between 1937 and 1991, Capper Pass and Sons Limited operated a tin smelter complex in North Humberside, UK, at which employees were potentially exposed to a number of substances, including lead, arsenic, cadmium and natural series radionuclides. Decommissioning and site clearance continued until 1995. Between 1967 and 1995 the company was a subsidiary of Rio Tinto plc. AIMS: The aim was to identify any significant excess, or deficits, in mortality among former employees that might be attributable to factors associated with occupation. METHODS: We defined a cohort of 1462 males who had been employed for at least 12 months between 1/11/1967 and 28/7/1995, followed-up through to 31/12/2001. The mortality of the cohort was compared against that expected for both national and regional populations. RESULTS: Mortality from all causes and all cancers did not differ from that expected. Mortality from ischaemic heart disease showed a deficit and mortality from lung cancer showed a statistically significant excess. Mortality from smoking related diseases other than lung cancer showed a non-significant deficit. CONCLUSIONS: The pattern of lung cancer mortality is consistent with the hypothesis that the risk of lung cancer has been enhanced by occupational exposure to one or more carcinogens, the effect of which diminishes with time since exposure. The deficit in ischaemic heart disease may be attributed to a protective effect from manual labour. The results provide no evidence for attribution of other excess or deficits in mortality to factors associated with employment.

Protein translocation machineries of peroxisomes.

Targeting of peroxisomal matrix and membrane proteins is performed by distinct transport machineries and requires the concerted action of at least 23 peroxins. Cargo recognition takes place in the cytosol and the multiple binding sites for peroxisomal signal sequence receptors at the peroxisomal membrane reflect the existence of an import cascade where the cargo-loaded receptors successively interact with different components of the import machinery. These interactions are likely to trigger conformational changes of the proteins within the import cascade which are required for the consecutive steps of peroxisomal protein import: docking, translocation, cargo release and receptor recycling.

Why is there an ERN/Ne on correct trials? Response representations, stimulus-related components, and the theory of error-processing.

The ERN or Ne is a component of the event-related brain potential that occurs when human subjects make errors in reaction time tasks. It is observed in response-locked averages, time-locked to the execution of the incorrect response. Recent research has reported that this component is present on correct response trials, thereby challenging the idea that the component is specifically related to error-processing. In this paper, we argue that the ERN or Ne observed on correct trials can be attributed to one or both of two factors: either there is error-processing on correct trials, and/or the response-locked averages used to derive the ERN/Ne are contaminated by negative components evoked by the stimulus. For this reason, there is no reason to abandon theories that relate the ERN/Ne to error-processing.

The use of the fluorescein disappearance test in the management of childhood epiphora.

PURPOSE. The fluorescein disappearance test (FDT) is reported to be an objective measure of lacrimal outflow in congenital non-canalisation of the nasolacrimal system. We introduced FDT into our evaluation of children with epiphora to investigate its sensitivity/specificity with regard to symptoms in a prospective study. We also examined the FDT against findings at syringing and probing (S&P) and persistence or resolution of symptoms on follow-up. METHODS. Over a period of 16 months, 88 consecutive children (median age 12 months; range 2.5-192) with epiphora were reviewed and FDT measured at 5 and 10 minutes; 66 FDT were evaluated for inter-observer variation in a masked fashion. S&P were scheduled on the basis of symptoms, abnormal FDT and age "1 year. Normal FDT prompted review. Younger children were observed for natural history and possible resolution with repeat FDT. Equivocal symptoms and normal FDT initiated discharge and telephone review. RESULTS. Inter-observer correlation coefficient = 0.86. Sensitivity/specificity of FDT was 76/76% at 5 minutes and 63/89% at 10 minutes, respectively. In patients under 1 year of age undergoing follow-up (29 patients; 38 eyes) FDT at 10 minutes correctly predicted persistence of symptoms in 65% and resolution in 66% of eyes (follow-up 3-14 months; mean 6); 23 patients (mean age 27 months; range 12-72) underwent S&P with positive surgical findings in 20 (87%). On review, symptoms had improved in 64% eyes (20/31). CONCLUSION. FDT at 5 minutes is an objective measure of symptoms with high inter-observer agreement and agreement with surgical findings. FDT read at 10 minutes may be useful to indicate the persistence or resolution of symptoms and guide patient management.

A SNARE complex mediating fusion of late endosomes defines conserved properties of SNARE structure and function.

Sets of SNARE proteins mediate membrane fusion by assembling into core complexes. Multiple SNAREs are thought to function in different intracellular trafficking steps but it is often unclear which of the SNAREs cooperate in individual fusion reactions. We report that syntaxin 7, syntaxin 8, vti1b and endobrevin/VAMP-8 form a complex that functions in the fusion of late endosomes. Antibodies specific for each protein coprecipitate the complex, inhibit homotypic fusion of late endosomes in vitro and retard delivery of endocytosed epidermal growth factor to lysosomes. The purified proteins form core complexes with biochemical and biophysical properties remarkably similar to the neuronal core complex, although each of the four proteins carries a transmembrane domain and three have independently folded N-terminal domains. Substitution experiments, sequence and structural comparisons revealed that each protein occupies a unique position in the complex, with syntaxin 7 corresponding to syntaxin 1, and vti1b and syntaxin 8 corresponding to the N- and C-terminal domains of SNAP-25, respectively. We conclude that the structure of core complexes and their molecular mechanism in membrane fusion is highly conserved between distant SNAREs.

The R-SNARE endobrevin/VAMP-8 mediates homotypic fusion of early endosomes and late endosomes.

Endobrevin/VAMP-8 is an R-SNARE localized to endosomes, but it is unknown in which intracellular fusion step it operates. Using subcellular fractionation and quantitative immunogold electron microscopy, we found that endobrevin/VAMP-8 is present on all membranes known to communicate with early endosomes, including the plasma membrane, clathrin-coated pits, late endosomes, and membranes of the trans-Golgi network. Affinity-purified antibodies that block the ability of endobrevin/VAMP-8 to form SNARE core complexes potently inhibit homotypic fusion of both early and late endosomes in vitro. Fab fragments were as active as intact immunoglobulin Gs. Recombinant endobrevin/VAMP-8 inhibited both fusion reactions with similar potency. We conclude that endobrevin/VAMP-8 operates as an R-SNARE in the homotypic fusion of early and late endosomes.

Fusion of endosomes involved in synaptic vesicle recycling.

Recycling of vesicles of the regulated secretory pathway presumably involves passage through an early endosomal compartment as an intermediate step. To learn more about the involvement of endosomes in the recycling of synaptic and secretory vesicles we studied in vitro fusion of early endosomes derived from pheochromocytoma (PC12) cells. Fusion was not affected by cleavage of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins synaptobrevin and syntaxin 1 that operate at the exocytotic limb of the pathway. Furthermore, fusion was inhibited by the fast Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid but not by the slow Ca(2+) chelator EGTA. Endosome fusion was restored by the addition of Ca(2+) with an optimum at a free Ca(2+) concentration of 0.3 x 10(-6) M. Other divalent cations did not substitute for Ca(2+). A membrane-permeant EGTA derivative caused inhibition of fusion, which was reversed by addition of Ca(2+). We conclude that the fusion of early endosomes participating in the recycling of synaptic and neurosecretory vesicles is mediated by a set of SNAREs distinct from those involved in exocytosis and requires the local release of Ca(2+) from the endosomal interior.

Error-related scalp potentials elicited by hand and foot movements: evidence for an output-independent error-processing system in humans.

The error-related negativity (ERN) is a fronto-centrally distributed component of the event-related brain potential (ERP) that occurs when human subjects make errors in a variety of experimental tasks. In the present study, we recorded ERPs from 128 scalp electrodes while subjects performed a choice reaction time task using either their hands or feet. We applied the brain electric source analysis technique to compare ERNs elicited by hand and foot errors. The scalp distributions of these error potentials suggest that they share the same neural generator and, therefore, that the ERN process is output-independent. Together with other findings, the results are consistent with the hypothesis that the ERN is generated within the anterior cingulate cortex and is elicited by the activation of a generic error-processing system.