The composite N1 component to gaps in noise.

OBJECTIVE: To indicate whether the double peaked N(1) to gaps in continuous white noise is a composite of onset and offset responses to transients or whether it reflects higher processing such as change or mismatch detection and to assess the role of attention in this process. METHODS: Evoked potentials were recorded to two binaural stimulus types: (1) gaps of different durations randomly distributed in continuous white noise; and (2) click pairs at intervals identical to those between gap onsets and offsets in the continuous noise stimulus. Potentials to these stimuli were recorded while subjects read a text and while detecting gaps in noise or click pairs. RESULTS: Potentials were detected to all click pairs and to gaps of 5 ms or longer, corresponding to the subjects' psychoacoustic gap detection threshold. With long gap durations of 200-800 ms, distinct potentials to gap onset and gap offset were observed. The waveforms to all click pairs and to offsets of long gaps were similar and single-peaked, while potentials to gaps of 10 ms and longer, and potentials to onsets of long gaps were double-peaked, consisting of two N(1) negativities, 60 ms apart, irrespective of gap duration. The first (N(1a)), was more frontal in its distribution and similar to that of clicks. The second (N(1b)) peak's distribution was more central/temporal and its source locations and time course of activity were distinct. No effects of attention on any of the varieties and constituents of N(1) were observed. CONCLUSIONS: Comparing potentials to gap onsets, to click pairs and to gap offsets, suggests that potentials to gap onsets involve not only sound onset/offset responses (N(1), N(1a)) but also the subsequent pre-attentive perception of the cessation of an ongoing sound (N(1b)). We propose that N(1b) is distinct from change or mismatch detection and is associated with termination of an ongoing continuous stimulus. We propose to call it the N(egation)-process. SIGNIFICANCE: A constituent of the N(1) complex is shown to be associated with the pre-attentive perception of termination of an ongoing stimulus and to have distinct scalp distribution and intracranial sources.     

ONSET AND TERMINAL ORIENTING RESPONSES AS A FUNCTION OF TASK DEMANDS

The frequency of response and trials to habituation of the electrodermal onset and terminal orienting response were manipulated as a function of discrimination tasks involving either stimulus content (pitch) or duration. There were no significant differences between the groups on either measure for onset ORs; however, the duration task group demonstrated more TORs and required a greater number of trials to habituate than the content task group. The results, interpreted in terms of the development of cortical models, supported Stern's suggestion that OR and TOR habituation are related to the content and duration of the stimulus respectively.     

Relaxation kinetics of formoterol and salmeterol in the guinea pig trachea in vitro

The mechanisms producing long duration of action for formoterol and salmeterol are not fully understood. The aim of the current study was to examine how the concentration of long and short acting ₂-adrenoceptor agonists affects their relaxation kinetics in airway smooth muscle. Onset (time to peak relaxation) and offset of action (reassertion of reversible relaxation following repeated -adrenoceptor blockade and washout) were measured in the guinea pig trachea precontracted postjunctionally by carbachol 0.3 M in vitro. At 10–1,000% (C _1O–C _1,000) of the maximally effective concentration (C ₁₀₀: 150 nM formoterol, 10 M salbutamol, 30 M salmeterol), salbutamol had a shorter time to peak relaxation than did salmeterol. Formoterol and salmeterol had a similar time to peak relaxation at C ₁₀, but, in contrast to salmeterol, formoterol's time to peak relaxation became markedly shorter and similar to that of salbutamol as the concentration was increased up to C _1,000. Significant reversible reasserted relaxation was demonstrated for salmeterol alone at C ₁₀. At C ₃₀–C _1,000, however, salmeterol produced irreversible relaxation only, in spite of repeated -adrenoceptor blockade by sotalol 10 M followed by washout. In contrast, formoterol produced an increasing reversible reasserted relaxation at C ₃₀–C _1,000. Salbutamol produced significant, reversible reasserted relaxation at C _1,000 only. In conclusion, the concentration determines the onset and offset of action for formoterol and to a lesser extent for salbutamol, but not for salmeterol. To cause sustained action, a submaximally effective concentration is sufficient for salmeterol, whereas formoterol requires a maximally effective concentration. The rank order of concentration dependence for the relaxation kinetics is not paralleled by the rank order of lipophilicity for formoterol, salbutamol, and salmeterol. Therefore, factors other than lipophilicity may also play a role in determining the relationship between concentration and relaxation kinetics for the investigated ₂-agonists. Offprint requests to: Anders Linden, MD, PhD     

No Association Between the Dopamine D2 Receptor Taq I A1 Allele and Earlier Age of Onset of Alcohol Dependence According to Different Specified Criteria

BACKGROUND: The presence of the A1 allele of the dopamine D2 receptor TaqI restriction fragment length polymorphism has been reported to be associated with an earlier age of onset of alcohol dependence as a marker for severity. METHODS: We tested this hypothesis with special regard to the definition of the age of onset of alcoholism in 243 patients with alcohol dependence, according to DSM-IV criteria assessed by the standardized interview Münchner Composite International Diagnostic Interview (M-CIDI), consecutively admitted for detoxification. Additionally, the Addiction Severity Index (ASI) was performed. The TaqIA polymorphism was amplified by polymerase chain reaction (PCR), and the PCR product was digested by the restriction enzyme TaqI. Patients were subsequently divided into an A1 (presence of at least one A1 allele, n = 88) and an A2 group (absence of an A1 allele, n = 155). The following criteria for different definitions of age of onset were used: (1) age of onset of the first occurring symptom necessary for the diagnosis of alcohol dependence according to M-CIDI; (2) age of onset of the last symptom of alcohol dependence according to M-CIDI; (3) age of onset of more than 3 drinking days per week on a regular basis according to ASI; (4) age of onset of more than 3 drinking days-of more than five drinks per drinking day-or at least one binge drinking episode per week on a regular basis according to ASI. RESULTS: The frequency of the A1 allele in our patient sample was 0.208. No statistically significant association between the A1 allele and the age of onset of alcoholism was found. The mean age of onset according to criterion 1 was 30.4 +/- 10.8 years for the A1 group and 30.2 +/- 10.2 years for the A2 group (p = 0.89); for criterion 2, it was 33.3 +/- 10.0 years for the A1 group and 33.9 +/- 10.2 years for the A2 group (p = 0.77); for criterion 3, it was 18.0 +/- 7.5 years for the A1 group and 18.1 +/- 6.1 years for the A2 group (p = 0.92); and for criterion 4, it was 22.3 +/- 9.7 years for the A1 group and 21.8 +/- 8.5 years for the A2 group (p = 0.76). CONCLUSIONS: No association was found between the A1 polymorphism and age at onset of alcohol dependence according to different specified criteria.     

Sleep problems in early childhood and early onset of alcohol and other drug use in adolescence

BACKGROUND: No prospective studies exist on the relationship between sleep problems early in life and subsequent alcohol use. Stimulated by the adult literature linking sleep problems to the subsequent onset of alcohol use disorders in some adults, we examined whether sleep problems in early childhood predicted the onset of alcohol and other drug use in adolescence and whether such a relationship was mediated by other known predictors of this relationship, namely, attention problems, anxiety/depression, and aggression in late childhood. METHODS: This study is part of an ongoing longitudinal study of the development of risk for alcohol and other substance use disorders. Study participants were 257 boys from a community-recruited sample of high-risk families. RESULTS: Mothers' ratings of their children's sleep problems at ages 3 to 5 years significantly predicted an early onset of any use of alcohol, marijuana, and illicit drugs, as well as an early onset of occasional or regular use of cigarettes by age 12 to 14. Additionally, although sleep problems in early childhood also predicted attention problems and anxiety/depression in later childhood, these problems did not mediate the relationship between sleep problems and onset of alcohol and other drug use. CONCLUSIONS: This is, to our knowledge, the first study that prospectively examines the relationship between sleep problems and early onset of alcohol use, a marker of increased risk for later alcohol problems and alcohol use disorders. Moreover, early childhood sleep problems seem to be a robust marker for use of drugs other than alcohol. Implications for the prevention of early alcohol and other drug use are discussed.     

Post-treatment outcomes in a double-blind, randomized trial of sertraline for alcohol dependence

Background: Pharmacotherapy studies in alcohol dependence (AD) are generally of short duration and do not include post‐treatment follow‐up. We examined the durability of treatment effects in a placebo‐controlled trial of sertraline for AD. Methods: As previously reported, patients received 12 weeks of treatment with sertraline (n = 63) or placebo (n = 71), followed by assessments at 3 and 6 months post‐treatment ( Kranzler et al., 2011 , J Clin Psychopharmacol 31:22–30). We examined the main and interaction effects with time of 3 between‐subject factors (medication group, age of onset of AD [late‐onset alcoholics, LOAs, vs. early‐onset alcoholics, EOAs], and the tri‐allelic 5‐HTTLPR genotype) on drinking days (DDs) and heavy drinking days (HDDs). Results: The medication group effect, which was significant during treatment, remained significant during the 3‐month follow‐up period for L’/L’ LOAs, with the sertraline group having fewer DDs than the placebo group (p = 0.027). However, the medication group effect seen in L’/L’ EOAs during treatment was no longer significant (p = 0.48). There were no significant effects in S’ carriers at the 3‐month follow‐up visit, or in either genotype group at the 6‐month follow‐up. Conclusions: The beneficial effects of sertraline observed in LOAs during treatment persisted during the 3‐month post‐treatment period. Additional studies are needed to validate these pharmacogenetic findings, which together with the effects seen during active treatment support the use of sertraline only in LOAs.     

Survey on changes in subjective symptoms,onset/trigger factors,allergic diseases,and chemical exposures in the past decade of Japanese patients with multiple chemical sensitivity

Background

Recently, with rapid changes in the Japanese lifestyle, the clinical condition of patients with multiple chemical sensitivity (MCS) may also have undergone change. Thus, we conducted a new survey for subjective symptoms, ongoing chemical exposures, the prevalence of allergic diseases, and presumed onset/trigger factors in patients with MCS and compared results with those of an old survey from ten years ago.

Maternal dietary ethanol consumption is associated with hypertriglyceridemia in adult rat offspring

BACKGROUND: The consumption of significant amounts of alcohol (ethanol, EtOH) may markedly increase serum triglyceride levels. This study describes a significant increase in fasting serum triglyceride (TG) levels in adult male rats whose mothers consumed EtOH. The hypertriglyceridemia occurred although the offspring never directly consumed EtOH and had consumed only rat chow for the preceding 14 months. Furthermore, both male and female adult offspring had an additional, significant increase in TG levels if their mothers consumed EtOH and experienced stress (restraint) during the pregnancy. METHODS: Harlan-derived Sprague Dawley female rats were dosed during pregnancy with EtOH via a liquid diet, and their offspring were compared with offspring of mothers who were either fed ad libitum or pair-fed the liquid diet without EtOH. At birth, the offspring of EtOH mothers exhibited no visible abnormalities except reduced weight, and all offspring were surrogate fostered within 48 hr of birth to mothers who had consumed commercial rat chow throughout their pregnancy. After weaning, all offspring consumed only commercial rat chow, and they were examined over the next 14 months for changes in triglyceride homeostasis as a function of maternal alcohol intake. RESULTS: Adult male offspring of mothers that consumed EtOH during their pregnancy had significant increases in fasting serum triglycerides associated with an increase in the very low density lipoprotein serum fraction. Acute administration of insulin to the offspring of all maternal dietary groups resulted in a rapid clearing of the serum triglycerides, and there were no differences in basal or heparin-releasable lipoprotein lipase activity between any of the progeny. Castration of the male offspring of EtOH-treated mothers prevented the development of elevated TG levels. Administration of testosterone to littermate female offspring increased circulating TG levels compared with testosterone-treated offspring of pair-fed mothers. EtOH-consuming mothers who also underwent five periods of restraint-induced stress (approximately 10 min each session) produced offspring whose fasting serum TG levels were higher than those whose mothers consumed EtOH but experienced no restraint or who experienced restraint but no EtOH. Maternal stress significantly reduced lipoprotein lipase activity in some offspring treatment groups, but the changes did not correspond to changes in the serum TG levels of the offspring. That is, maternal restraint-induced stress was associated with a loss of heparin-releasable lipoprotein lipase activity by male progeny from pair-fed and EtOH-fed mothers and the female offspring of ad libitum-fed and EtOH-fed mothers. CONCLUSIONS: Although serum triglycerides increased with age in all offspring, the increase was much more pronounced in the progeny of mothers who consumed EtOH during their pregnancy. The hypertriglyceridemia was significantly more pronounced in the male offspring and in female offspring treated with testosterone. Castration of male offspring inhibited the hypertriglyceridemia development, which suggests that male sex hormones may play a role in the development of this condition. Maternal EtOH consumption coupled with maternal restraint-induced stress significantly increased the level of hypertriglyceridemia in both male and female offspring compared with offspring whose mothers experienced restraint but no EtOH or EtOH with no restraint. If this study models the human condition, the results could represent an unrecognized risk factor in a number of adult disease states hypothesized to be associated with hypertriglyceridemia, such as cardiovascular disease, hypertension, and diabetes.     

Health-related services use and the onset of functional disability: 10 year follow-up study

This study aimed to examine the effect of health-related service use on the development of functional disability in an older adult Taiwanese cohort. The sample population consisted of 871 participants without Instrumental Activities of Daily Living (IADL) disabilities, 1061 participants without Activities of Daily Living (ADL) disabilities and 817 participants without IADL and ADL disabilities at baseline. The onset of IADL and ADL disabilities were estimated as the follow-up survey year that these functional disabilities were first noted, or the follow-up survey year that the participant was noted as having died. A Cox proportional hazards model, with time-dependent covariates, was used to analyze the association between the time of onset of the functional disabilities and the health-related service use, after controlling for age, gender, education, marital status and time varying chronic disease status. This study found that an increase in the number of services used by the participants resulted in fewer IADL and ADL disabilities. Furthermore, participants who attended recreational programs, regular health examinations, and who received the information assistance and meal preparation were significantly less likely to develop disabilities. Participants who used one or more services were 55–77% less likely to be IADL disabled, and were 54–81% less likely to be ADL disabled, and were also 59–89% less likely to develop IADL and ADL disabilities as compared to those who used none. In the present study therefore, as the number of health services used increased the likelihood of developing a functional disability decreased.