Medial temporal lobe atrophy ratings in a large 75-year-old population-based cohort: gender-corrected and education-corrected normative data.

OBJECTIVES: To find cut-off values for different medial temporal lobe atrophy (MTA) measures (right, left, average, and highest), accounting for gender and education, investigate the association with cognitive performance, and to compare with decline of cognitive function over 5 years in a large population-based cohort. METHODS: Three hundred and ninety 75-year-old individuals were examined with magnetic resonance imaging of the brain and cognitive testing. The Scheltens's scale was used to assess visually MTA scores (0-4) in all subjects. Cognitive tests were repeated in 278 of them after 5 years. Normal MTA cut-off values were calculated based on the 10th percentile. RESULTS: Most 75-year-old individuals had MTA score ≤2. Men had significantly higher MTA scores than women. Scores for left and average MTA were significantly higher in highly educated individuals. Abnormal MTA was associated with worse results in cognitive test and individuals with abnormal right MTA had faster cognitive decline. CONCLUSION: At age 75, gender and education are confounders for MTA grading. A score of ≥2 is abnormal for low-educated women and a score of ≥2.5 is abnormal for men and high-educated women. Subjects with abnormal right MTA, but normal MMSE scores had developed worse MMSE scores 5 years later. KEY POINTS: • Gender and education are confounders for MTA grading. • We suggest cut-off values for 75-year-olds, taking gender and education into account. • Males have higher MTA scores than women. • Higher MTA scores are associated with worse cognitive performance.

Longitudinal relationships among depressive symptoms, cortisol, and brain atrophy in the neocortex and the hippocampus.

OBJECTIVE: Depression is associated with accelerated aging and age-related diseases. However, mechanisms underlying this relationship remain unclear. The aim of this study was to longitudinally assess the link between depressive symptoms, brain atrophy, and cortisol levels. METHOD: Participants from the Betula prospective cohort study (mean age = 59 years, SD = 13.4 years) underwent clinical, neuropsychological and brain 3T MRI assessments at baseline and a 4-year follow-up. Cortisol levels were measured at baseline in four saliva samples. Cortical and hippocampal atrophy rates were estimated and compared between participants with and without depressive symptoms (n = 81) and correlated with cortisol levels (n = 49). RESULTS: Atrophy in the left superior frontal gyrus and right lingual gyrus developed in parallel with depressive symptoms, and in the left temporal pole, superior temporal cortex, and supramarginal cortex after the onset of depressive symptom. Depression-related atrophy was significantly associated with elevated cortisol levels. Elevated cortisol levels were also associated with widespread prefrontal, parietal, lateral, and medial temporal atrophy. CONCLUSION: Depressive symptoms and elevated cortisol levels are associated with atrophy of the prefrontal and limbic areas of the brain.

White matter changes in familial Alzheimer's disease.

BACKGROUND: Familial Alzheimer's disease (FAD) resulting from gene mutations in PSEN1, PSEN2 and APP is associated with changes in the brain. OBJECTIVE: The aim of this study was to investigate changes in grey matter (GM), white matter (WM) and the cerebrospinal fluid (CSF) in FAD. SUBJECTS: Ten mutation carriers (MCs) with three different mutations in PSEN1 and APP and 20 noncarriers (NCs) were included in the study. Three MCs were symptomatic and seven were presymptomatic (pre-MCs). METHODS: Whole-brain GM volume as well as fractional anisotropy (FA) and mean diffusivity (MD) using voxel-based morphometry and tract-based spatial statistics analyses, respectively, were compared between MCs and NCs. FA and MD maps were obtained from diffusion tensor imaging. RESULTS: A significant increase in MD was found in the left inferior longitudinal fasciculus, cingulum and bilateral superior longitudinal fasciculus in pre-MCs compared with NCs. After inclusion of the three symptomatic MCs in the analysis, the regions became wider. The mean MD of these regions showed significant negative correlation with the CSF level of Aß42, and positive correlations with P-tau181p and T-tau. No differences were observed in GM volume and FA between the groups. CONCLUSIONS: The results of this study suggest that FAD gene mutations affect WM diffusivity before changes in GM volume can be detected. The WM changes observed were related to changes in the CSF, with similar patterns previously observed in sporadic Alzheimer's disease.

Practical cut-offs for visual rating scales of medial temporal, frontal and posterior atrophy in Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Atrophy in the medial temporal lobe, frontal lobe and posterior cortex can be measured with visual rating scales such as the medial temporal atrophy (MTA), global cortical atrophy - frontal subscale (GCA-F) and posterior atrophy (PA) scales, respectively. However, practical cut-offs are urgently needed, especially now that different presentations of Alzheimer's disease (AD) are included in the revised diagnostic criteria. AIMS: The aim of this study was to generate a list of practical cut-offs for the MTA, GCA-F and PA scales, for both diagnosis of AD and determining prognosis in mild cognitive impairment (MCI), and to evaluate the influence of key demographic and clinical factors on these cut-offs. METHODS: AddNeuroMed and ADNI cohorts were combined giving a total of 1147 participants (322 patients with AD, 480 patients with MCI and 345 control subjects). The MTA, GCA-F and PA scales were applied and a broad range of cut-offs was evaluated. RESULTS: The MTA scale showed better diagnostic and predictive performances than the GCA-F and PA scales. Age, apolipoprotein E (ApoE) ε4 status and age at disease onset influenced all three scales. For the age ranges 45-64, 65-74, 75-84 and 85-94 years, the following cut-offs should be used. MTA: ≥1.5, ≥1.5, ≥2 and ≥2.5; GCA-F, ≥1, ≥1, ≥1 and ≥1; and PA, ≥1, ≥1, ≥1 and ≥1, respectively, with an adjustment for early-onset ApoE ε4 noncarrier AD patients (MTA: ≥2, ≥2, ≥3 and ≥3; and GCA-F: ≥1, ≥1, ≥2 and ≥2, respectively). CONCLUSIONS: If successfully validated in clinical settings, the list of practical cut-offs proposed here might be useful in clinical practice. Their use might also (i) promote research on atrophy subtypes, (ii) increase the understanding of different presentations of AD, (iii) improve diagnosis and prognosis and (iv) aid population selection and enrichment for clinical trials.

The influence of negative life events on hippocampal and amygdala volumes in old age: a life-course perspective.

BACKGROUND: Psychosocial stress has been related to changes in the nervous system, with both adaptive and maladaptive consequences. The aim of this study was to examine the relationship of negative events experienced throughout the entire lifespan and hippocampal and amygdala volumes in older adults. METHOD: In 466 non-demented old adults (age range 60-96 years, 58% female), hippocampal and amygdala volumes were segmented using Freesurfer. Negative life events and the age at which these events occurred were assessed by means of a structured questionnaire. Using generalized linear models, hippocampal and amygdala volumes were estimated with life events as independent variables. The statistical analyses were adjusted for age, gender, intracranial volume, lifestyle factors, cardiovascular risk factors, depressive symptoms, and cognitive functioning. RESULTS: Total number of negative life events and of late-life events, but not of early-life, early-adulthood, or middle-adulthood events, was related to larger amygdala volume. There were interactions of early-life events with age and gender. Participants who reported two or more early-life events had significantly smaller amygdala and hippocampal volumes with increasing age. Furthermore, smaller hippocampal volume was found in men who reported two or more early-life events, but not in women. CONCLUSIONS: These results suggest that the effect of negative life events on the brain depends on the time when the events occurred, with the strongest effects observed during the critical time periods of early and late life.

The association between biomarkers in cerebrospinal fluid and structural changes in the brain in patients with Alzheimer's disease.

BACKGROUND: Biochemical changes in the cerebrospinal fluid (CSF) could reflect pathophysiological processes in Alzheimer's disease (AD). However, it is still not clear how these processes correlate with grey matter (GM) volume and microstructural changes in the brain. OBJECTIVE: To assess the relationship between CSF biomarkers and structural brain changes in AD. DESIGN AND SETTING: Cross-sectional study in a memory clinic-based sample. SUBJECTS: A total of 78 subjects were included in the study: 22 with subjective cognitive impairment (SCI), 35 with mild cognitive impairment (MCI) and 21 with AD. MAIN OUTCOME MEASURES: Voxel-wise correlations between CSF biomarkers, including ß-amyloid42 (Aß42), tau phosphorylated at position threonine 181 and total tau protein, and GM volume, self-diffusion fractional anisotropy (FA) and mean diffusivity (MD) maps using voxel-based morphometry and tract-based spatial statistical analyses. FA and MD maps were obtained using diffusion tensor imaging. RESULTS: In the whole sample (patients with SCI, MCI and AD), there was positive correlation between GM volume and Aß42 concentration, and negative correlation with total tau protein. Higher FA was only related to higher concentration of Aß42. MD showed significant negative correlation with Aß42 and positive correlation with T-tau levels. The majority of brain regions with significant correlation with CSF biomarkers overlapped with the default mode network and extended to the adjacent white matter. CONCLUSIONS: Early AD pathological changes can be detected with voxel-based morphometric analysis and diffusion tensor imaging measurements. Furthermore, there was an association between CSF AD biomarkers and structural brain changes in areas related to the default mode network.

Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut-offs.

BACKGROUND: Visual assessment of medial temporal lobe atrophy (MTA; range 0-4, from no atrophy to increasing atrophy of the choroid fissure, temporal horns and hippocampus) is a sensitive radiological marker of Alzheimer's disease (AD). One of the critical elements for visual MTA assessment is the cut-off score that determines deviation from normality. METHODS: In this study, we assessed the sensitivity and specificity of different MTA cut-off scores to classify control subjects, individuals with mild cognitive impairment (MCI) and AD patients from two large independent cohorts, AddNeuroMed and Alzheimer's Disease Neuroimaging Initiative. Of note, we evaluated the effects of clinical, demographic and genetic variables on the classification performance according to the different cut-offs. RESULTS: A cut-off of ≥1.5 based on the mean MTA scores of both hemispheres showed higher sensitivity in classifying patients with AD (84.5%) and MCI subjects (75.8%) who converted to dementia compared to an age-dependent cut-off. The age-dependent cut-off showed higher specificity or ability to correctly identify control subjects (83.2%) and those with MCI who remained stable (65.5%). Increasing age, early-onset disease and absence of the ApoE ε4 allele had a stronger influence on classifications using the ≥1.5 cut-off. Above 75 years of age, an alternative cut-off of ≥2.0 should be applied to achieve a classification accuracy for both patients with AD and control subjects that is clinically useful. CONCLUSION: Clinical, demographic and genetic variables can influence the classification of MTA cut-off scores, leading to misdiagnosis in some cases. These variables, in addition to the differential sensitivity and specificity of each cut-off, should be carefully considered when performing visual MTA assessment.

Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol.

BACKGROUND: The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects. METHODS: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis. RESULTS: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year. CONCLUSIONS: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma-tocopherols and tocotrienols-as indirect indicators of AD pathology, and the utility of a multimodality approach.

An MRI-based index to measure the severity of Alzheimer's disease-like structural pattern in subjects with mild cognitive impairment.

BACKGROUND: Structural magnetic resonance imaging (MRI) is sensitive to neurodegeneration and can be used to estimate the risk of converting to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). Brain changes in AD and prodromal AD involve a pattern of widespread atrophy. The use of multivariate analysis algorithms could enable the development of diagnostic tools based on structural MRI data. In this study, we investigated the possibility of combining multiple MRI features in the form of a severity index. METHODS: We used baseline MRI scans from two large multicentre cohorts (AddNeuroMed and ADNI). On the basis of volumetric and cortical thickness measures at baseline with AD cases and healthy control (CTL) subjects as training sets, we generated an MRI-based severity index using the method of orthogonal projection to latent structures (OPLS). The severity index tends to be close to 1 for AD patients and 0 for CTL subjects. Values above 0.5 indicate a more AD-like pattern. The index was then estimated for subjects with MCI, and the accuracy of classification was investigated. RESULTS: Based on the data at follow-up, 173 subjects converted to AD, of whom 112 (64.7%) were classified as AD-like and 61 (35.3%) as CTL-like. CONCLUSION: We found that joint evaluation of multiple brain regions provided accurate discrimination between progressive and stable MCI, with better performance than hippocampal volume alone, or a limited set of features. A major challenge is still to determine optimal cut-off points for such parameters and to compare their relative reliability.

Suppressive effects of a quinoxaline-analogue (Rob 803) on pathogenic immune mechanisms in collagen-induced arthritis.

The anti-arthritic effects of the synthetic compound 9-chloro-2,3 dimethyl-6-(N,N-dimetylamino-2-oxoethyl)-6H-indolo[2,3-b] quinoxaline (Rob 803) was evaluated by treating Dark Agouti rats with collagen-induced arthritis using three different protocols. Daily subcutaneous treatment with 40 mg/kg/day of Rob 803 from the day of immunization and 14 days forward suppressed arthritis severity significantly and delayed the onset of clinical arthritis. In contrast, similar treatment initiated when individual rats had developed clinical disease (at a score of 2 points) did not suppress disease. Oral treatment with 35 mg/kg/day of Rob 803 from the day of immunization and 21 days forward resulted in a trend towards disease suppression. In vitro analysis of rats treated subcutaneously with Rob 803 revealed an inhibition of T cell proliferation but no effect on the generation of an anti-CII immunoglobulin G response. Further in vitro analysis demonstrated that Rob 803 also inhibited the generation of nitric oxide in macrophages, although at higher concentrations than needed for inhibitory effects on T cell proliferation. Thus we report that early subcutaneous administration of the synthetic substance Rob 803 has anti-rheumatic effects that are probably mediated by affecting the proliferative capacity of lymph node T cells. Rob 803 should be considered as a new candidate substance for anti-rheumatic treatment.

Acid-base analysis of individuals following two weight loss diets.

OBJECTIVE: To examine the effects of low-carbohydrate, ketogenic (LCKD) and low-fat (LFD) diets on acid-base status. DESIGN: Prospective analysis of volunteers from two clinical trials. PARTICIPANTS: Subset of 39 volunteers from a randomized trial comparing the effects of an LCKD with an LFD, and a single-arm trial of an LCKD. SETTING: Outpatient research clinic. INTERVENTION: LCKD (initially <20 g of carbohydrate daily) or LFD (<30% of energy from fat, 500-1000 kcal energy reduction) instruction. MEASUREMENTS: Arterial blood gas analysis, serum chemistries (electrolytes, urea nitrogen/creatinine, glucose, ketone bodies, lactate), anion gap, and urine ketone bodies measured at weeks 0, 2, 8, and 24. RESULTS: Participants had a mean (+/-standard deviation) age of 43.5+/-9.3 years; 28 (72%) were female, 29 (74%) were Caucasian. Using linear mixed-model analysis to examine blood test changes from baseline to 24 weeks, the LFD group experienced a decrease in arterial blood pH from a mean of 7.43 at week 0 to 7.40 at week 24 (P=0.03), and the LCKD group experienced a decrease from 7.42 at week 0 to 7.40 at week 24 (P=0.01). The lowest pH measurements observed were 7.34 in the LFD group and 7.37 in the LCKD group. Although serum bicarbonate appeared to decrease from baseline at weeks 2 and 8 in the LCKD group, the change at 24 weeks was not statistically significant in either diet group, and only four of 131 (two of 92 from the LCKD group) measurements were less than 22 mmol/l. The proportion of participants with elevated urine and serum ketone body levels rose in the LCKD group only, was highest at week 2, and decreased over the subsequent time points. CONCLUSION: In individuals following an LCKD or an LFD, blood pH decreased mildly and the LCKD group experienced a small, transient decrease in serum bicarbonate in conjunction with mild ketosis. This suggests that an LCKD induced a mild compensated metabolic acidosis, but no individual showed evidence of significant metabolic derangement.

The nicotine patch in smoking cessation. A randomized trial with telephone counseling.

BACKGROUND: This study was conducted to determine the efficacy of the nicotine patch in smoking cessation when combined with self-help materials, three brief visits, and telephone counseling. METHODS: One hundred fifty-nine healthy volunteers who smoked at least one pack of cigarettes per day and desired to quit smoking were enrolled in a double-blind trial with 6-week treatment and 6-month follow-up periods. After review of self-help materials, subjects were randomly assigned to regimens of nicotine or placebo patches. Subjects wore two patches per day for 4 weeks (25 mg of nicotine per 24 hours), then one patch per day for 2 weeks. Return visits were at the ends of weeks 4 and 6. Telephone counseling was given during weeks 1, 2, 3, and 5. Abstinence at 6 weeks was defined as zero cigarettes smoked for the previous 28 days, verified by exhaled carbon monoxide less than 8 ppm at 4 weeks and 6 weeks. Abstinence at 3 and 6 months was defined as self-report of zero cigarettes since the previous contact, verified by carbon monoxide value at 6 months. RESULTS: Abstinence rates at 6 weeks, 3 months, and 6 months were 29.5%, 21.8%, and 20.5% in the active group, and 8.8%, 3.8%, and 2.5% in the placebo group (P < or = .001 for each comparison), respectively. Skin irritation was the main side effect, causing 1.3% to drop out. CONCLUSION: The nicotine patch is efficacious in smoking cessation over a 6-month period, when combined with only self-help materials, three brief visits, and telephone counseling.

Smoking behavior on the first day of a quit attempt predicts long-term abstinence.

BACKGROUND: The nicotine patch has been widely used for smoking cessation, but not all smokers quit using the patch. Knowing which smokers are likely to succeed with the nicotine patch may improve the efficiency of nicotine patch use. OBJECTIVE: To identify predictors of smoking abstinence using baseline characteristics, smoking behavior, and withdrawal symptoms. METHODS: Using 2 randomized clinical trials of pharmacologic treatment, brief counseling, and quit date formats in the outpatient research clinic setting, predictors of smoking cessation were derived in 1 sample (n = 159), then prospectively validated in an independent sample (n = 48). Subjects smoked 1 pack of cigarettes per day or more and were motivated to quit smoking. Self-report of abstinence at 6 months verified by exhaled carbon monoxide of 8 ppm or less was used. RESULTS: Abstinence at 6 months was 24% in the derivation set and 25% in the validation set. Using logistic regression, a model containing quit date abstinence (odds ratio, 10.6; 95% confidence interval [CI], 2.9-38.7) and baseline nicotine dependence (odds ratio, 0.75; 95% CI, 0.6-1.0 per unit increase in Fagerstrom score) provided the optimal predictive ability and was validated in the independent set. Quit date abstinence improved the likelihood of 6-month abstinence by 4.1 over baseline (95% CI, 2.6-6.4) for low-nicotine-dependent smokers and 1.2 (95% CI, 0.6-2.2) for high-nicotine-dependent smokers. Quit date smoking altered the likelihood of 6-month abstinence by 0.2 (95% CI, 0.0-0.8) for low-dependent smokers and 0.1 for high-dependent smokers (95% CI, 0.0-0.6). CONCLUSIONS: Abstinence on the quit date and low-nicotine dependence improve the likelihood of smoking abstinence at 6 months. Smoking on the quit date may be an indication for postponing the cessation attempt or adjusting the therapy for smoking cessation.

Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes.

There is great interest in blood-based markers of Alzheimer's disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of 1129 proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n = 195), and regional brain volumes (n = 34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q < 0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD.

Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone.

OBJECTIVE: To evaluate concurrent administration of mecamylamine (nicotine antagonist) with nicotine skin patch treatment for smoking cessation. METHODS: This was a randomized, double-blind, placebo-controlled trial. Forty-eight healthy smokers who smoked at least one pack per day were studied at an outpatient smoking cessation research clinic. The subjects ranged in age from 20 to 40 years. Intervention with the nicotine skin patch (6 to 8 weeks) plus oral mecamylamine (2.5 to 5 mg twice a day for 5 weeks) was compared to nicotine patch plus placebo. Mecamylamine treatment began 2 weeks before smoking cessation. The primary outcome was continuous abstinence through 7 weeks after cessation (1 week after treatment), confirmed by expired air carbon monoxide measurements. Secondary measures included point abstinence at 7 weeks, continuous abstinence at 6- and 12-month follow-up, and self-reported withdrawal symptoms. RESULTS: The continuous abstinence rate at 7 weeks was three times higher in the mecamylamine condition: 50% versus 16.7%, p = 0.015. Point abstinence at 7 weeks was 58% for mecamylamine versus 29% for placebo, p = 0.044. At follow-up, continuous abstinence remained higher for mecamylamine: 37.5% versus 12.5% at 6 months (p = 0.046) and 37.5% versus 4.2% at 12 months (p = 0.004). Mecamylamine also significantly reduced craving for cigarettes, negative affect, and appetite. CONCLUSIONS: Agonist-antagonist therapy, consisting of the nicotine patch with oral mecamylamine, may substantially improve current smoking cessation treatment.

Airway sensory replacement combined with nicotine replacement for smoking cessation. A randomized, placebo-controlled trial using a citric acid inhaler.

STUDY OBJECTIVE: This study was conducted to determine if the combination of airway sensory replacement and nicotine replacement improves 10-week smoking abstinence rates over nicotine replacement alone. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Outpatient research clinic. PARTICIPANTS: One hundred healthy volunteers who smoked at least one pack of cigarettes per day and desired to quit smoking. INTERVENTIONS: Subjects received either citric acid (n = 41) or lactose placebo (n = 59) inhalers to cope with smoking urges for 10 weeks. All subjects received self-help materials and nicotine patches for 6 weeks. Return visits were at weeks 1, 4, 6, and 10. Abstinence was defined as zero cigarettes smoked since the quit date verified by exhaled carbon monoxide < or = 8 ppm at all return visits. Inhaler effects were measured by a standardized questionnaire. MEASUREMENTS AND RESULTS: The primary outcome of continuous abstinence at the end of the 10-week treatment period was 19.5% (95% confidence interval [CI] = 7.4 to 31.6%) for the citric acid group vs 6.8% (95% CI = 0.4 to 13.2%) for the lactose group (p = 0.05). Relief from craving and short-term abstinence increased as airway sensations from the inhaler also increased. Abstinence at 10 weeks for subjects receiving strong airway sensations from the inhalers was 33.3% (95% CI = 14.5 to 52.1%). At 6 months, there was no difference in abstinence between the treatment groups (0% vs 5.1%, p = 0.20). CONCLUSIONS: When combined with the nicotine patch, the citric acid inhaler improved 10-week smoking abstinence over lactose inhaler. The combination of airway sensory replacement and nicotine replacement may prove beneficial for smoking cessation.

Moraxella catarrhalis-induced purulent otitis media in the rat middle ear. Structure, protection, and serum antibodies.

To study the effects of viable and heat-killed Moraxella catarrhalis bacteria on the middle ear mucosa and to evaluate the protection after whole-cell immunizations, Sprague-Dawley rats were challenged and rechallenged with four different M. catarrhalis strains. The animals were monitored by clinical observations, bacterial and histological samples from middle ears, and serum IgG levels. Only viable bacteria at a high concentration induced purulent otitis media, which was culture positive in 58% of the cases on day 4. The infection was characterized by a mild acute reaction lasting otomicroscopically about 8 days, together with quantitative and qualitative changes of the goblet cells. Structurally the mucosal effects of the heat-killed bacteria were less pronounced in the early phase compared to the viable bacteria, but similar at the end of the experiment at 6 months. The intrabullar and subcutaneous immunizations evoked an IgG antibody response in all animals, and the protection rate after immunization was 50% or more. The induced protection was not strain-specific. The study showed the rat to be a possible alternative for the study of different aspects of M. catarrhalis otitis media, an infection that is clinically and structurally different from that elicited by Streptococcus pneumoniae and Haemophilus influenzae in the rat.

Naltrexone blockade of nicotine effects in cigarette smokers.

RATIONALE: The role of endogenous opiate systems in cigarette smoking remains unclear. In laboratory animals, opiate antagonists block many of the effects of nicotine, but in humans they do not consistently alter smoking behavior. OBJECTIVE: This study explored the effects of naltrexone, alone and in combination with nicotine, on smoking behavior. METHODS: In a double-blind, double-dummy, within-subjects design, 19 regular smokers received four treatments of 1 week duration: naltrexone tablet (50 mg) plus placebo skin patch, placebo tablet plus nicotine skin patch (21 mg/24 h), naltrexone tablet plus nicotine skin patch, and placebo tablet plus placebo skin patch. During each treatment, subjects rated their responses to nicotine-containing and denicotinized cigarettes in the laboratory, and to their own brand of cigarette smoked ad libitum outside the laboratory. RESULTS: Pretreatment with the nicotine patch attenuated smoking-induced decreases in craving, negative affect, and rates of ad lib smoking, and potentiated the aversiveness of a cigarette. Naltrexone reversed these effects of the nicotine patch, and produced negative effects on mood. CONCLUSIONS: The blockade of nicotine's effects by naltrexone supports a role for opioid mechanisms in cigarette smoking.

Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction.

An understanding of drug addiction requires knowledge of the effective drug concentrations to which receptors in the nervous system are exposed. It has often been thought that smoking of abused substances such as nicotine or cocaine produces much higher drug concentrations in the arterial blood than those achieved following any other route of administration. However, to date no studies have sampled arterial blood following cigarette smoking with the rapidity necessary to evaluate this hypothesis. We measured arterial plasma nicotine concentrations in samples collected every 5 s from 13 cigarette smokers during cigarette smoking and during administration of nicotine by intravenous injections. Our results show that, for both routes of administration, concentrations of nicotine in arterial blood were more than 10 times lower than expected. Thus, the delivery of nicotine into arterial blood is substantially slower than would be predicted if nicotine were absorbed as rapidly as has generally been assumed. A plausible explanation of these results is that lung uptake of nicotine considerably slows the entry of nicotine into the systemic circulation, as has been shown for other amines. These results have significant implications for theories of addiction to nicotine as well as other drugs such as cocaine that may be subject to binding by lung tissue.