Short term air pollution exposure during pregnancy and associations with maternal immune markers.

BACKGROUND: Air pollution exposure during pregnancy has been associated with numerous adverse pregnancy, birth, and child health outcomes. One proposed mechanism underlying these associations is maternal immune activation and dysregulation. We examined associations between PM2.5 and NO2 exposure during pregnancy and immune markers within immune function groups (TH1, TH2, TH17, Innate/Early Activation, Regulatory, Homeostatic, and Proinflammatory), and examined whether those associations changed across pregnancy. METHODS: In a pregnancy cohort study (n = 290) in Rochester, New York, we measured immune markers (using Luminex) in maternal plasma up to 3 times during pregnancy. We estimated ambient PM2.5 and NO2 concentrations at participants' home addresses using a spatial-temporal model. Using mixed effects models, we estimated changes in immune marker concentrations associated with interquartile range increases in PM2.5 (2.88 µg/m3) and NO2 (7.82 ppb) 0-6 days before blood collection, and assessed whether associations were different in early, mid, and late pregnancy. RESULTS: Increased NO2 concentrations were associated with higher maternal immune markers, with associations observed across TH1, TH2, TH17, Regulatory, and Homeostatic groups of immune markers. Furthermore, the largest increases in immune markers associated with each 7.82 ppb increase in NO2 concentration were in late pregnancy (e.g., IL-23 = 0.26 pg/ml, 95% CI = 0.07, 0.46) compared to early pregnancy (e.g., IL-23 = 0.08 pg/ml, 95% CI = -0.11, 0.26). CONCLUSIONS: Results were suggestive of NO2-related immune activation. Increases in effect sizes from early to mid to late pregnancy may be due to changes in immune function over the course of pregnancy. These findings provide a basis for immune activation as a mechanism for previously observed associations between air pollution exposure during pregnancy and reduced birthweight, fetal growth restriction, and pregnancy complications.

Effects of short-term increases in personal and ambient pollutant concentrations on pulmonary and cardiovascular function: A panel study analysis of the Multicenter Ozone Study in oldEr subjects (MOSES 2).

BACKGROUND: The cardiovascular effects of ozone exposure are unclear. Using measurements from the 87 participants in the Multicenter Ozone Study of oldEr Subjects (MOSES), we examined whether personal and ambient pollutant exposures before the controlled exposure sessions would be associated with adverse changes in pulmonary and cardiovascular function. METHODS: We used mixed effects linear regression to evaluate associations between increased personal exposures and ambient pollutant concentrations in the 96 h before the pre-exposure visit, and 1) biomarkers measured at pre-exposure, and 2) changes in biomarkers from pre-to post-exposure. RESULTS: Decreases in pre-exposure forced expiratory volume in 1 s (FEV1) were associated with interquartile-range increases in concentrations of particulate matter ≤2.5 µm (PM2.5) 1 h before the pre-exposure visit (-0.022 L; 95% CI -0.037 to -0.006; p = 0.007), carbon monoxide (CO) in the prior 3 h (-0.046 L; 95% CI -0.076 to -0.016; p = 0.003), and nitrogen dioxide (NO2) in the prior 72 h (-0.030 L; 95% CI -0.052 to -0.008; p = 0.007). From pre-to post-exposure, increases in FEV1 were marginally significantly associated with increases in personal ozone exposure (0.010 L; 95% CI 0.004 to 0.026; p = 0.010), and ambient PM2.5 and CO at all lag times. Ambient ozone concentrations in the prior 96 h were associated with both decreased pre-exposure high frequency (HF) heart rate variability (HRV) and increases in HF HRV from pre-to post-exposure. CONCLUSIONS: We observed associations between increased ambient PM2.5, NO2, and CO levels and reduced pulmonary function, and increased ambient ozone concentrations and reduced HRV. Pulmonary function and HRV increased across the exposure sessions in association with these same pollutant increases, suggesting a "recovery" during the exposure sessions. These findings support an association between short term increases in ambient PM2.5, NO2, and CO and decreased pulmonary function, and increased ambient ozone and decreased HRV.

Multicenter Ozone Study in oldEr Subjects (MOSES): Part 2. Effects of Personal and Ambient Concentrations of Ozone and Other Pollutants on Cardiovascular and Pulmonary Function.

INTRODUCTION: The Multicenter Ozone Study of oldEr Subjects (MOSES) was a multi-center study evaluating whether short-term controlled exposure of older, healthy individuals to low levels of ozone (O3) induced acute changes in cardiovascular biomarkers. In MOSES Part 1 (MOSES 1), controlled O3 exposure caused concentration-related reductions in lung function with evidence of airway inflammation and injury, but without convincing evidence of effects on cardiovascular function. However, subjects' prior exposures to indoor and outdoor air pollution in the few hours and days before each MOSES controlled O3 exposure may have independently affected the study biomarkers and/or modified biomarker responses to the MOSES controlled O3 exposures. METHODS: MOSES 1 was conducted at three clinical centers (University of California San Francisco, University of North Carolina, and University of Rochester Medical Center) and included healthy volunteers 55 to 70 years of age. Consented participants who successfully completed the screening and training sessions were enrolled in the study. All three clinical centers adhered to common standard operating procedures and used common tracking and data forms. Each subject was scheduled to participate in a total of 11 visits: screening visit, training visit, and three sets of exposure visits consisting of the pre-exposure day, the exposure day, and the post-exposure day. After completing the pre-exposure day, subjects spent the night in a nearby hotel. On exposure days, the subjects were exposed for 3 hours in random order to 0 ppb O3 (clean air), 70 ppb O3, and 120 ppm O3. During the exposure period the subjects alternated between 15 minutes of moderate exercise and 15 minutes of rest. A suite of cardiovascular and pulmonary endpoints was measured on the day before, the day of, and up to 22 hours after each exposure.In MOSES Part 2 (MOSES 2), we used a longitudinal panel study design, cardiopulmonary biomarker data from MOSES 1, passive cumulative personal exposure samples (PES) of O3 and nitrogen dioxide (NO2) in the 72 hours before the pre-exposure visit, and hourly ambient air pollution and weather measurements in the 96 hours before the pre-exposure visit. We used mixed-effects linear regression and evaluated whether PES O3 and NO2 and these ambient pollutant concentrations in the 96 hours before the pre-exposure visit confounded the MOSES 1 controlled O3 exposure effects on the pre- to post-exposure biomarker changes (Aim 1), whether they modified these pre- to post-exposure biomarker responses to the controlled O3 exposures (Aim 2), whether they were associated with changes in biomarkers measured at the pre-exposure visit or morning of the exposure session (Aim 3), and whether they were associated with differences in the pre- to post-exposure biomarker changes independently of the controlled O3 exposures (Aim 4). RESULTS: Ambient pollutant concentrations at each site were low and were regularly below the National Ambient Air Quality Standard levels. In Aim 1, the controlled O3 exposure effects on the pre- to post-exposure biomarker differences were little changed when PES or ambient pollutant concentrations in the previous 96 hours were included in the model, suggesting these were not confounders of the controlled O3 exposure/biomarker difference associations. In Aim 2, effects of MOSES controlled O3 exposures on forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were modified by ambient NO2 and carbon monoxide (CO), and PES NO2, with reductions in FEV1 and FVC observed only when these concentrations were "Medium" or "High" in the 72 hours before the pre-exposure visit. There was no such effect modification of the effect of controlled O3 exposure on any other cardiopulmonary biomarker.As hypothesized for Aim 3, increased ambient O3 concentrations were associated with decreased pre-exposure heart rate variability (HRV). For example, high frequency (HF) HRV decreased in association with increased ambient O3 concentrations in the 96 hours before the pre-exposure visit (-0.460 ln[ms2]; 95% CI, -0.743 to -0.177 for each 10.35-ppb increase in O3; P = 0.002). However, in Aim 4 these increases in ambient O3 were also associated with increases in HF and low frequency (LF) HRV from pre- to post-exposure, likely reflecting a "recovery" of HRV during the MOSES O3 exposure sessions. Similar patterns across Aims 3 and 4 were observed for LF (the other primary HRV marker), and standard deviation of normal-to-normal sinus beat intervals (SDNN) and root mean square of successive differences in normal-to-normal sinus beat intervals (RMSSD) (secondary HRV markers).Similar Aim 3 and Aim 4 patterns were observed for FEV1 and FVC in association with increases in ambient PM with an aerodynamic diameter ≤ 2.5 µm (PM2.5), CO, and NO2 in the 96 hours before the pre-exposure visit. For Aim 3, small decreases in pre-exposure FEV1 were significantly associated with interquartile range (IQR) increases in PM2.5 concentrations in the 1 hour before the pre-exposure visit (-0.022 L; 95% CI, -0.037 to -0.006; P = 0.007), CO in the 3 hours before the pre-exposure visit (-0.046 L; 95% CI, -0.076 to -0.016; P = 0.003), and NO2 in the 72 hours before the pre-exposure visit (-0.030 L; 95% CI, -0.052 to -0.008; P = 0.007). However, FEV1 was not associated with ambient O3 or sulfur dioxide (SO2), or PES O3 or NO2 (Aim 3). For Aim 4, increased FEV1 across the exposure session (post-exposure minus pre-exposure) was marginally significantly associated with each 4.1-ppb increase in PES O3 concentration (0.010 L; 95% CI, 0.004 to 0.026; P = 0.010), as well as ambient PM2.5 and CO at all lag times. FVC showed similar associations, with patterns of decreased pre-exposure FVC associated with increased PM2.5, CO, and NO2 at most lag times, and increased FVC across the exposure session also associated with increased concentrations of the same pollutants, reflecting a similar recovery. However, increased pollutant concentrations were not associated with adverse changes in pre-exposure levels or pre- to post-exposure changes in biomarkers of cardiac repolarization, ST segment, vascular function, nitrotyrosine as a measure of oxidative stress, prothrombotic state, systemic inflammation, lung injury, or sputum polymorphonuclear leukocyte (PMN) percentage as a measure of airway inflammation. CONCLUSIONS: Our previous MOSES 1 findings of controlled O3 exposure effects on pulmonary function, but not on any cardiovascular biomarker, were not confounded by ambient or personal O3 or other pollutant exposures in the 96 and 72 hours before the pre-exposure visit. Further, these MOSES 1 O3 effects were generally not modified, blunted, or lessened by these same ambient and personal pollutant exposures. However, the reductions in markers of pulmonary function by the MOSES 1 controlled O3 exposure were modified by ambient NO2 and CO, and PES NO2, with reductions observed only when these pollutant concentrations were elevated in the few hours and days before the pre-exposure visit. Increased ambient O3 concentrations were associated with reduced HRV, with "recovery" during exposure visits. Increased ambient PM2.5, NO2, and CO were associated with reduced pulmonary function, independent of the MOSES-controlled O3 exposures. Increased pollutant concentrations were not associated with pre-exposure or pre- to post-exposure changes in other cardiopulmonary biomarkers. Future controlled exposure studies should consider the effect of ambient pollutants on pre-exposure biomarker levels and whether ambient pollutants modify any health response to a controlled pollutant exposure.

The genome of the simian and human malaria parasite Plasmodium knowlesi.

Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or 'hypnozoite' in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome and other sequenced Plasmodium genomes. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.

Latent factor regression models for grouped outcomes.

We consider regression models for multiple correlated outcomes, where the outcomes are nested in domains. We show that random effect models for this nested situation fit into a standard factor model framework, which leads us to view the modeling options as a spectrum between parsimonious random effect multiple outcomes models and more general continuous latent factor models. We introduce a set of identifiable models along this spectrum that extend an existing random effect model for multiple outcomes nested in domains. We characterize the tradeoffs between parsimony and flexibility in this set of models, applying them to both simulated data and data relating sexually dimorphic traits in male infants to explanatory variables.

Associations and costs of parental symptoms of psychiatric distress in a multi-diagnosis group of children with special needs.

BACKGROUND: Families supporting children with complex needs are significantly more distressed and economically disadvantaged than families of children without disability and delay. What is not known is the associations and costs of parental psychiatric distress within a multi-diagnosis group of special needs children. METHODS: In this cross-sectional survey, families were identified from the Children's Treatment Network. Families were eligible if the child was aged 0-19 years, resided in Simcoe/York, and if there were multiple family needs (n = 429). RESULTS: Some 42% of surveyed parents exhibited symptoms (mild to severe) of psychiatric distress. The presence of these symptoms was associated with reports of poorer social support, family dysfunction, greater adverse impact of the child's situation on the family, poorer child behaviour, unfavourable parenting styles and poorer child psychosocial functioning. The severity of the child's physical dysfunction was not related to parents/guardians most knowledgeable symptoms of psychiatric distress. Total parent costs were higher and children's uses of primary care services were higher in parents with symptoms of psychiatric distress. CONCLUSION: Parent symptoms of psychiatric distress are a significant societal concern in families with complex needs children. Children's rehabilitation efforts need to incorporate parental mental health assessment and treatment into existing programmes. This could lead to decreases in direct and indirect healthcare utilisation costs.

Associations between maternal inflammation during pregnancy and infant birth outcomes in the Seychelles Child Development Study.

PROBLEM: Markers of maternal inflammation may determine infant birth outcomes. METHOD OF STUDY: Maternal serum samples were collected at 28 weeks gestation (n = 1418) in the Seychelles Child Development Study Nutrition Cohort 2 and analyzed for immune markers by MSD multiplex assay, including cytokines from the Th1 (IFN-γ, IL-1ß, IL-2 and TNF-α) and Th2 (IL-4, IL-5, IL-10) subsets, with IL-6, MCP-1, TARC, sFlt-1 and VEGF-D. Associations of log-transformed immune markers with birthweight, length, head circumference and gestational age were assessed by multiple linear regression models, which were adjusted for maternal age, BMI, parity, child sex, gestational age and socioeconomic status. RESULTS: Neither total Th1, Th2 nor Th1:Th2 were significantly associated with any birth outcome. However, the angiogenesis marker VEGF-D was predictive of a lower birthweight, (ß = -0.058, P = 0.017) and birth length (ß = -0.088, P = 0.001) after adjusting for covariates. Higher concentrations of CRP were predictive of a lower birthweight (ß = -0.057, P = 0.023) and IL-2 (ß = 0.073, P = 0.009) and the chemokine MCP-1 (ß = 0.067, P = 0.016) were predictive of a longer gestational age. CONCLUSIONS: In our cohort of healthy pregnant women, we found no evidence for associations between the Th1 or Th2 inflammatory markers with birth outcomes. However, VEGF-D and CRP appear to predict lower birthweight and IL-2 and MCP-1 a longer gestation. Greater understanding is required of the variation in these immune markers at different gestational stages, as well as the factors which may regulate their balance in healthy pregnancy. n = 233.

Arts for the Blues - a new creative psychological therapy for depression: a pilot workshop report.

INTRODUCTION: Research over the last decade has identified both strengths and limitations in the use of routinely prescribed psychological therapies for depression. More recently, a focus on how creative art therapies and 'arts on prescription' are developing a growing recognition of their potential additional therapeutic mechanisms for depression. AIM: In an attempt to develop a new therapeutic intervention for depression, this research aligned both the evidence base surrounding the arts on prescription movement, collating these with client-reported helpful factors and preferences for therapeutic interventions. METHODS: We developed a framework for a new pluralistic 'meta-approach' of therapy for depression, based on; an interdisciplinary thematic synthesis of active ingredients, considered specific features implemented in therapy, and client-reported helpful factors considered to be the broad features or experiences in therapy from both talking therapies and creative approaches. This framework contributed to the development of a pilot workshop entitled Arts for the Blues - A New Creative Psychological Therapy for Depression. An outline of, and evaluation from this workshop is presented in this article. Workshop participants were recruited via a voluntary workshop taking place at a North West Higher Education Institution Arts and Health conference ( N = 15). RESULTS: The workshop was evaluated using quantitative measures, with results indicating around a 70% overall satisfaction, followed up with qualitative commentary around areas of good practice and areas for development. These included the positive reflection on the application of creative arts and the multimodal nature of the approach, while others reflected on the potential overwhelming nature of utilising multimodal methods for individuals with depression. CONCLUSION: Overall feedback from the pilot workshop is discussed in relation to prior research, giving credence to the potential for incorporating arts into therapy.

A negative regulatory element with properties similar to those of enhancers is contained within an Alu sequence.

A negative regulatory element has been found within a member of the African green monkey Alu family of interspersed repeated sequences. This "reducer" element decreased transcription in both directions from a cellular simian virus 40-like bidirectional promoter independently of both orientation and position. The reducer was not promoter specific since it also decreased expression from the simian virus 40 early and human beta-globin promoters. In addition, the reducer decreased transcription from a polymerase III promoter. The reducer was contained in 38 base pairs of an Alu family member and interacted specifically with a monkey cell nuclear protein.

Early age at smoking initiation and tobacco carcinogen DNA damage in the lung.

BACKGROUND: DNA adducts formed as a consequence of exposure to tobacco smoke may be involved in carcinogenesis, and their presence may indicate a high risk of lung cancer. To determine whether DNA adducts can be used as a "dosimeter" for cancer risk, we measured the adduct levels in nontumorous lung tissue and blood mononuclear cells from patients with lung cancer, and we collected data from the patients on their history of smoking. METHODS: We used the 32P-postlabeling assay to measure aromatic hydrophobic DNA adducts in nontumorous lung tissue from 143 patients and in blood mononuclear cells from 54 of these patients. From the smoking histories, we identified exposure variables associated with increased DNA adduct levels by use of multivariate analyses with negative binomial regression models. RESULTS/ CONCLUSIONS: We found statistically significant interactions for variables of current and former smoking and for other smoking variables (e.g., pack-years [number of packs smoked per day x years of smoking] or years smoked), indicating that the impact of smoking variables on DNA adduct levels may be different in current and former smokers. Consequently, our analyses indicate that models for current and former smokers should be considered separately. In current smokers, recent smoking intensity (cigarettes smoked per day) was the most important variable. In former smokers, age at smoking initiation was inversely associated with DNA adduct levels. A highly statistically significant correlation (r=.77 [Spearman's correlation]; two sided P<.001) was observed between DNA adduct levels in blood mononuclear cells and lung tissue. IMPLICATIONS: Our results in former smokers suggest that smoking during adolescence may produce physiologic changes that lead to increased DNA adduct persistence or that young smokers may be markedly susceptible to DNA adduct formation and have higher adduct burdens after they quit smoking than those who started smoking later in life.

Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung carcinoma.

Traditionally, non-small cell lung cancer (NSCLC) has been evaluated as a unique entity in genotyping studies. However, recent biological data suggest that different NSCLC subtypes, specifically adenocarcinomas (AC) and squamous cell carcinomas (SCC), differentially alter cancer behavior. Several studies have associated a p53 polymorphism at codon 72 with NSCLC susceptibility. This study investigated whether different p53 genotypes altered the overall risk of developing AC versus SCC. Polymorphisms in metabolizing enzymes, together with prolonged exposure to tobacco carcinogens, can result in accumulation of DNA damage; these effects may potentiate the effects of subtle differences in p53 function. Thus, interactions between polymorphisms of p53 and either GSTM1 or GSTT1 were also evaluated. We analyzed 1168 incident lung cancer cases and 1256 control subjects using multiple logistic regression. Histological data were available for 1144 cases (98%): 585 with AC, 284 with SCC, and 275 with other histological subtypes (large cell, small cell, mixed, and other). An increase in the NSCLC risk posed by the p53 Pro allele (versus Arg/Arg) was seen in AC compared with controls [adjusted odds ratio (OR), 1.36; 95% confidence interval (CI), 1.1-1.7] but not in SCC (adjusted OR, 1.04; 95% CI, 0.8-1.4). Among AC and SCC cancer patients, individuals with the GSTM1-null genotype had an OR of 1.80 (95% CI, 1.1-2.8; case-only analysis) of having AC versus SCC if they also carried a p53 Pro allele. We conclude that different genotype combinations of p53 and GSTM1 increase the risk of developing specific histological subtypes of NSCLC.

Phthalate exposure and semen quality in fertile US men.

Several experimental and observational studies have demonstrated the antiandrogenicity of several phthalates. However, there is limited evidence of an association between phthalate exposure in adult life and semen quality. The aim of this study was to examine phthalate exposure during adulthood in relation to semen quality in fertile US men. This multi-center cross-sectional study included 420 partners of pregnant women who attended a prenatal clinic in one of five US cities during 1999-2001. Nine phthalate metabolites [mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP)], as well as mono-n-butyl phthalate (MBP) and mono-isobutyl phthalate (MiBP), mono (three carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP), and monoethyl phthalate (MEP)] were measured in urine collected at the same time as the semen sample. We regressed natural log-transformed (ln) sperm concentration, ln(total sperm count), ln(total motile sperm count), percent motile spermatozoa, and percent spermatozoa with normal morphology on each of the nine natural log-transformed metabolite concentrations and on the molar-weighted sum of DEHP metabolites in separate models. We fit unadjusted models and models that adjusted for confounders determined a priori. In unadjusted models, ln(MiBP) was significantly and positively associated with motility and ln(MBzP) significantly negatively associated with ln(total sperm count). In adjusted linear models, urinary metabolite concentrations of DEHP, DBP, DEP, and DOP were not associated with any semen parameter. We found an inverse association between ln(MBzP) concentrations and sperm motility (ß = -1.47, 95% CI: -2.61, -0.33), adjusted for ln(creatinine concentration), geographic location, age, race, smoking status, stress, recent fever, time from sample collection and time to complete analysis. Several sensitivity analyses confirmed the robustness of these associations. This study and the available literature suggest that impacts of adult exposure to phthalates at environmental levels on classical sperm parameters are likely to be small.

The NAD(P)H:quinone oxidoreductase 1 gene polymorphism and lung cancer: differential susceptibility based on smoking behavior.

We conducted a hospital-based case-control study of 814 lung cancer patients and 1123 controls to examine the association of the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene polymorphism with lung cancer susceptibility. Using PCR-RFLP genotyping assay techniques, we analyzed DNA samples to detect the variant forms of the NQO1 gene in exon 6 on chromosome 16q. We examined the relationship between lung cancer odds and NQO1 genotypes after adjusting for age, gender, and smoking behavior using generalized additive modeling. We found no overall association between NQO1 genotypes and lung cancer susceptibility, regardless of age, gender, family history of cancer, or histological cell type. However, our data demonstrated that in both former and current smokers, there was an association between NQO1 genotypes and lung cancer susceptibility that was dependent upon cigarette smoking duration and smoking intensity. For both current and former smokers, smoking intensity was more important in predicting cancer risk than smoking duration for all of the genotypes. Among former smokers, individuals with the T/T genotype were predicted to have a greater cancer risk than those with the C/C genotype for smoking durations up to 37 years. The predicted cancer risk for former smokers with the C/T versus T/T genotype depended on both smoking intensity and smoking duration. Our results support the concept that differential susceptibility to lung cancer is a function of both an inheritable trait in NQO1 metabolism and individual smoking characteristics.

The interaction between microsomal epoxide hydrolase polymorphisms and cumulative cigarette smoking in different histological subtypes of lung cancer.

Microsomal epoxide hydrolase (mEH) is involved in the metabolism of environmental and tobacco carcinogens. Smaller studies found inconsistent results in the relationship between mEH polymorphisms and lung cancer risk. We investigated the two polymorphisms of mEH in 974 Caucasian lung cancer patients and 1142 controls using PCR-RFLP techniques. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between mEH genotypes and lung cancer risk. The adjusted odds ratio (OR) of the very low activity genotype versus that of other genotypes combined was 1.00 [95% confidence interval (CI), 0.74-1.34]. However, gene-environment interaction analyses revealed that the ORs decreased as cumulative smoking (defined as square root of pack-years) increased. When pack-years = 0, the OR was 1.89 (95% CI, 1.08-3.28). When pack-years = 28.5, the OR was 1.00 (95% CI, 0.76-1.32), and when pack-years = 80, the OR decreased to 0.65 (95% CI, 0.42-1.00). When cases were stratified according to histological subtypes, the interaction between mEH genotype and cumulative smoking was statistically significant (P < 0.01) for the 222 squamous cell carcinoma cases, whereas it was not significant (P = 0.18) for the 432 adenocarcinoma cases. In conclusion, cumulative cigarette smoking plays a pivotal role in the association between mEH polymorphisms and lung cancer risk, altering the direction of risk (in the case of the very low activity genotype) from a risk factor in nonsmokers to a relatively protective factor in heavy smokers.

Superior oblique myokymia: quantitative description of the eye movement.

We studied superior oblique myokymia (intermittent uniocular microtremor) using magnetic scleral search coils. The monocular disorder consisted of both phasic and tonic components consistent with the primary, secondary, and tertiary actions of the superior oblique muscle. These observations support the hypothesis of a disorder restricted to the superior oblique motor unit.

Epileptic gaze deviation and nystagmus.

We studied a patient with stereotyped focal seizures characterized by leftward conjugate eye- and head-turning followed by nystagmus. Eye deviation was associated with the appearance of seizure activity, recorded over the right temporo-occipital scalp, that did not spread frontally. The initial eye deviation consisted of a staircase of small saccades. The subsequent nystagmus showed rightward decreasing-velocity exponential slow phases and normal leftward quick phases. Saccadic eye movements due to seizures may occur via projections from posterior cortical areas as well as from the frontal eye fields.

Hyperactive vestibulo-ocular reflex in cerebellar degeneration: pathogenesis and treatment.

We studied a patient with a cerebellar degeneration and hyperactive vestibulo-ocular reflex (VOR). He complained of oscillopsia and blurred vision with head movement. A twofold increase in VOR gain (peak eye velocity/peak head velocity) at high frequencies was associated with a VOR time constant of 6 seconds (low normal). Visual cancellation ("suppression") of the VOR and smooth pursuit were also abnormal. We hypothesized that his high VOR gain was due to dysfunction of olivocerebellar projections. Physostigmine reduced his VOR gain, consistent with the hypothesis that these projections are cholinergic.

Effects of retinal image stabilization in acquired nystagmus due to neurologic disease.

We studied the effects of variable amounts of artificial retinal image stabilization (RIS) upon oscillopsia and visual acuity in eight patients with acquired nystagmus due to neurologic disease. We measured horizontal and vertical eye movements with the magnetic search coil technique and used these electronic signals to control the position of a visual stimulus on a screen in front of the patient. We also used an optical device to stabilize images of the real world upon the retina. During electronic stabilization, RIS was progressively increased until oscillopsia was abolished; this was achieved in all eight patients and corresponded to retinal image drift of 5 degrees/sec or less. In five patients with downbeat nystagmus, further increases in RIS caused the oscillopsia to reappear, but in the opposite direction. Electronic stabilization also improved visual acuity in four of five patients; the limitation of improvement could be related to coexistent visual system defects. Using electronic feedback, we could measure the range of RIS that any individual required to abolish oscillopsia; from this measurement, the components of the optical device that were best suited to provide a stable field of vision could be calculated.

Slow saccades and hypometria in anticonvulsant toxicity.

We report a patient with abnormal saccades in association with anticonvulsant toxicity (phenytoin 27.5 micrograms/ml, phenobarbital 18.8 micrograms/ml). The patient looked toward visual targets either with multiple, small, hypometric saccades or with single slow saccades. These abnormalities resolved when anticonvulsant levels returned to therapeutic range. Thus, slow saccades may be clinical evidence of anticonvulsant toxicity.