Christopher Cox

Translocation of Inhaled Ultrafine Particles to the Brain

Ultrafine particles (UFP, particles <100 nm) are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular effects of particulate matter (PM). Depending on their particle size, inhaled UFP are efficiently deposited in nasal, tracheobronchial, and alveolar regions due to diffusion. Our previous rat studies have shown that UFP can translocate to interstitial sites in the respiratory tract as well as to extrapulmonary organs such as liver within 4 to 24 h postexposure. There were also indications that the olfactory bulb of the brain was targeted. Our objective in this follow-up study, therefore, was to determine whether translocation of inhaled ultrafine solid particles to regions of the brain takes place, hypothesizing that UFP depositing on the olfactory mucosa of the nasal region will translocate along the olfactory nerve into the olfactory bulb. This should result in significant increases in that region on the days following the exposure as opposed to other areas of the central nervous system (CNS). We generated ultrafine elemental 13C particles (CMD = 36 nm; GSD = 1.66) from [13C] graphite rods by electric spark discharge in an argon atmosphere at a concentration of 160 μg/m3. Rats were exposed for 6 h, and lungs, cerebrum, cerebellum and olfactory bulbs were removed 1, 3, 5, and 7 days after exposure. 13C concentrations were determined by isotope ratio mass spectroscopy and compared to background 13C levels of sham-exposed controls (day 0). The background corrected pulmonary 13C added as ultrafine 13C particles on day 1 postexposure was 1.34 μg/lung. Lung 13C concentration decreased from 1.39 μg/g (day 1) to 0.59 μg/g by 7 days postexposure. There was a significant and persistent increase in added 13C in the olfactory bulb of 0.35 μg/g on day 1, which increased to 0.43 μg/g by day 7. Day 1 13C concentrations of cerebrum and cerebellum were also significantly increased but the increase was inconsistent, significant only on one additional day of the postexposure period, possibly reflecting translocation across the blood–brain barrier in certain brain regions. The increases in olfactory bulbs are consistent with earlier studies in nonhuman primates and rodents that demonstrated that intranasally instilled solid UFP translocate along axons of the olfactory nerve into the CNS. We conclude from our study that the CNS can be targeted by airborne solid ultrafine particles and that the most likely mechanism is from deposits on the olfactory mucosa of the nasopharyngeal region of the respiratory tract and subsequent translocation via the olfactory nerve. Depending on particle size, >50% of inhaled UFP can be depositing in the nasopharyngeal region during nasal breathing. Preliminary estimates from the present results show that ∼20% of the UFP deposited on the olfactory mucosa of the rat can be translocated to the olfactory bulb. Such neuronal translocation constitutes an additional not generally recognized clearance pathway for inhaled solid UFP, whose significance for humans, however, still needs to be established. It could provide a portal of entry into the CNS for solid UFP, circumventing the tight blood–brain barrier. Whether this translocation of inhaled UFP can cause CNS effects needs to be determined in future studies.

Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study

INTRODUCTION Exposure to methylmercury (MeHg) before birth can adversely affect childrens neurodevelopment. The most common form of prenatal exposure is maternal fish consumption, but whether such exposure harms the fetus is unknown. We aimed to identify adverse neurodevelopmental effects in a fish-consuming population. METHODS We investigated 779 mother-infant pairs residing in the Republic of Seychelles. Mothers reported consuming fish on average 12 meals per week. Fish in Seychelles contain much the same concentrations of MeHg as commercial ocean fish elsewhere. Prenatal MeHg exposure was determined from maternal hair growing during pregnancy. We assessed neurocognitive, language, memory, motor, perceptual-motor, and behavioural functions in children at age 9 years. The association between prenatal MeHg exposure and the primary endpoints was investigated with multiple linear regression with adjustment for covariates that affect child development. FINDINGS Mean prenatal MeHg exposure was 6.9 parts per million (SD 4.5 ppm). Only two endpoints were associated with prenatal MeHg exposure. Increased exposure was associated with decreased performance in the grooved pegboard using the non-dominant hand in males and improved scores in the hyperactivity index of the Conners teacher rating scale. Covariates affecting child development were appropriately associated with endpoints. INTERPRETATION These data do not support the hypothesis that there is a neurodevelopmental risk from prenatal MeHg exposure resulting solely from ocean fish consumption.

The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group.

Summary. We have reviewed our experience with four of the entities that are included under the generic term chronic myeloid leukaemia (CML), namely the classic Ph+ CGL, both BCR+ and BCR−, aCML and CMML. We have developed a statstical model that confirms that CGL, aCML and CMML can be distinguished from each other with reasonable success employing five quantitative parameters (WBC, percentage immature granulocytes, percentage monocytes, percentage basophils, percentage erythroid precursors in bone marrow) and one qualitative parameter (granulocytic dysplasia). It is hoped that these detailed recommendations will enable investigators to improve their diagnostic accuracy. This should permit more uniform comparisons of molecular biologic and clinical studies.

Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia.

OBJECTIVE To determine whether alterations in second-trimester maternal serum cytokine concentrations can identify women at risk for developing severe, early-onset preeclampsia. METHODS Patients with severe preeclampsia requiring delivery prior to 34 weeks (n = 20) were each matched by gestational age, gravidity, parity, and sample freezing time with three healthy controls who delivered at term (n = 60). By using second-trimester maternal sera originally collected for fetal aneuploidy screening, the concentrations of placental growth factor, vascular endothelial growth factor, granulocyte colony-stimulating factor, endothelin-1, and human chorionic gonadotropin were compared between patients and controls. Logistic regression analysis was used to estimate odds ratios for high versus low (median split) cytokine concentrations with respect to the development of severe, early-onset preeclampsia. Receiver operating characteristic (ROC) curves based on a second logistic regression, using actual cytokine values, were plotted to illustrate reciprocal impact on sensitivity and specificity. RESULTS Placental growth factor and vascular endothelial growth factor levels were significantly lower in patients than in controls. No significant differences were observed for the other cytokines. The odds ratios (with 95% confidence intervals) were 15.54 (3.29, 73.40) for vascular endothelial growth factor and 4.20 (1.35, 13.06) for placental growth factor. Receiver operating characteristic analysis of placental growth factor and vascular endothelial growth factor confirmed that both were useful in discriminating between patients and controls. Models combining both vascular endothelial growth factor and placental growth factor provided the best performance for identifying patients at risk for developing severe, early-onset preeclampsia, according to both odds ratios and ROC analyses. CONCLUSION Combined analysis of placental growth factor and vascular endothelial growth factor is potentially useful as a tool for early identification of patients at risk for developing severe, early-onset preeclampsia.

A Prospective Study of Psychological Predictors of Body Fat Gain Among Children at High Risk for Adult Obesity

OBJECTIVE. Limited data suggest that psychological factors, including binge eating, dieting, and depressive symptoms, may predispose children to excessive weight gain. We investigated the relationship between baseline psychological measures and changes in body fat (measured with dual-energy x-ray absorptiometry) over time among children thought to be at high risk for adult obesity. METHODS. A cohort study of a convenience sample of children (age: 6–12 years) recruited from Washington, DC, and its suburbs was performed. Subjects were selected to be at increased risk for adult obesity, either because they were overweight when first examined or because their parents were overweight. Children completed questionnaires at baseline that assessed dieting, binge eating, disordered eating attitudes, and depressive symptoms; they underwent measurements of body fat mass at baseline and annually for an average of 4.2 years (SD: 1.8 years). RESULTS. Five hundred sixty-eight measurements were obtained between July 1996 and December 2004, for 146 children. Both binge eating and dieting predicted increases in body fat. Neither depressive symptoms nor disturbed eating attitudes served as significant predictors. Children who reported binge eating gained, on average, 15% more fat mass, compared with children who did not report binge eating. CONCLUSIONS. Children’s reports of binge eating and dieting were salient predictors of gains in fat mass during middle childhood among children at high risk for adult obesity. Interventions targeting disordered eating behaviors may be useful in preventing excessive fat gain in this high-risk group.

Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Psychometric assessment of the lung cancer symptom scale

Background. This study continued the development and psychometric testing of the Lung Cancer Symptom Scale (LCSS), a disease‐ and site‐specific instrument primarily measuring the physical and functional dimensions of quality of life for individuals with lung cancer. The instrument contains two scales, one for patients and a counterpart for health professionals as observers.

Placebo-Controlled Study of Divalproex Sodium for Agitation in Dementia

The authors assessed the efficacy, tolerability, and safety of divalproex sodium for the treatment of agitation associated with dementia in a 6-week, randomized study of 56 nursing home patients with agitation and dementia treated with either placebo or individualized doses of divalproex sodium. Participants were blinded to treatment except for a physician-monitor and a pharmacist. When several covariates were taken into account, the drug/placebo difference in Brief Psychiatric Rating Scale Agitation scores became statistically significant (P=0.05). Sixty-eight percent of patients on divalproex were rated as showing reduced agitation on the Clinical Global Impression scale, vs. 52% on placebo (P=0.06 in the adjusted analysis). Side effects occurred in 68% of the divalproex group vs. 33% of the placebo group (P=0.03) and were generally rated as mild. This placebo-controlled study, despite some limitations, suggests possible short-term efficacy, tolerability, and safety of divalproex for agitation in dementia and supports further placebo-controlled studies.

Access to Firearms and Risk for Suicide in Middle-Aged and Older Adults

Elderly white men are at the highest risk for suicide. Firearms are the most common method of suicide used by both men and women in later life, and a greater proportion of older than younger suicide victims use a gun. This psychological autopsy study aimed to test hypotheses concerning the risk for suicide associated with access to and storage of firearms. Subjects included 86 suicide victims age 50 years of age and over and 86 community control subjects individually matched on age, sex, race, and county of residence. Presence of a firearm in the home was associated with increased risk for suicide, even after controlling for psychiatric illness. Elevated risk was accounted for by access to handguns rather than long guns and was more pronounced in men than women. Among subjects who kept a gun in the home, storing the weapon loaded and unlocked were independent predictors of suicide. Findings support the potential benefit for suicide prevention of restricting access to handguns. Education programs for older persons, their families, and healthcare providers concerning the risks of having a gun in the home and reinforcement of rules for safe storage may contribute to reducing the rate of suicide in older people.

Pulmonary Function, Diffusing Capacity, and Inflammation in Healthy and Asthmatic Subjects Exposed to Ultrafine Particles

Particulate air pollution is associated with asthma exacerbations and increased morbidity and mortality from respiratory causes. Ultrafine particles (particles less than 0.1 μ m in diameter) may contribute to these adverse effects because they have a higher predicted pulmonary deposition, greater potential to induce pulmonary inflammation, larger surface area, and enhanced oxidant capacity when compared with larger particles on a mass basis. We hypothesized that ultrafine particle exposure would induce airway inflammation in susceptible humans. This hypothesis was tested in a series of randomized, double-blind studies by exposing healthy subjects and mild asthmatic subjects to carbon ultrafine particles versus filtered air. Both exposures were delivered via a mouthpiece system during rest and moderate exercise. Healthy subjects were exposed to particle concentrations of 10, 25, and 50 μ g/m3, while asthmatics were exposed to 10 μ g/m3. Lung function and airway inflammation were assessed by symptom scores, pulmonary function tests, and airway nitric oxide parameters. Airway inflammatory cells were measured via induced sputum analysis in several of the protocols. There were no differences in any of these measurements in normal or asthmatic subjects when exposed to ultrafine particles at concentrations of 10 or 25 μ g/m3. However, exposing 16 normal subjects to the higher concentration of 50 μ g/m3 caused a reduction in maximal midexpiratory flow rate (−4.34 ± 1.78% [ultrafine particles] vs. +1.08 ± 1.86% [air], p =. 042) and carbon monoxide diffusing capacity (−1.76 ± 0.66 ml/min/mm Hg [ultrafine particles] vs. −0.18 ± 0.41 ml/min/mm Hg [air], p =. 040) at 21 h after exposure. There were no consistent differences in symptoms, induced sputum, or exhaled nitric oxide parameters in any of these studies. These results suggest that exposure to carbon ultrafine particles results in mild small-airways dysfunction together with impaired alveolar gas exchange in normal subjects. These effects do not appear related to airway inflammation. Additional studies are required to confirm these findings in normal subjects, compare them with additional susceptible patient populations, and determine their pathophysiologic mechanisms.

Social Support, Depression, and Functional Disability in Older Adult Primary-Care Patients

OBJECTIVE The authors asked whether social support and depression are independently associated with functional disability and examined the potential role of social support as a moderator in the depression-functional disability association. METHODS Subjects were 305 patients age 60 years and over. Predictor variables were social support, depressive symptoms, and depression diagnosis. Dependent variables were the Instrumental Activities of Daily Living Scale, the Physical Self-Maintenance Scale, and the Physical Functioning subscale of the Medical Outcomes Study 36-Item Short-Form Health Survey. Authors used multiple-regression analyses. RESULTS Depressive symptoms and all dimensions of social support were independently associated with functional disability: the specifics of these relationships varied among types of social support and functional disability. Depression diagnosis was not independently associated with any functional disability measure. Social support (more instrumental help, more perceived satisfaction) moderated some depression diagnosis-functional disability associations, and one depressive symptom-functional disability association. CONCLUSIONS The study hypotheses were partially confirmed. Different dimensions of social support have important and varied roles in the depression-functional disability dynamic. Future research is needed to further specify the complex relationships among depression, social support, and functional disability.