Trajectories of adherence to mood stabilizers in patients with bipolar disorder.

BACKGROUND: Nonadherence with mood stabilizers is a major problem that negatively impacts the course of bipolar disorder. Medication adherence is a complex individual behavior, and adherence rates often change over time. This study asked if distinct classes of adherence trajectories with mood stabilizers over time could be found, and if so, which patient characteristics were associated with the classes. METHODS: This analysis was based on 12 weeks of daily self-reported data from 273 patients with bipolar 1 or II disorder using ChronoRecord computer software. All patients were taking at least one mood stabilizer. The latent class mixed model was used to detect trajectories of adherence based on 12 weekly calculated adherence datapoints per patient. RESULTS: Two distinct trajectory classes were found: an adherent class (210 patients; 77%) and a less adherent class (63 patients; 23%). The characteristics associated with the less adherent class were: more time not euthymic (p < 0.001) and female gender (p = 0.016). No other demographic associations were found. CONCLUSION: In a sample of motivated patients who complete daily mood charting, about one quarter were in the less adherent class. Even patients who actively participate in their care, such as by daily mood charting, may be nonadherent. Demographic characteristics may not be useful in assessing individual adherence. Future research on longitudinal adherence patterns in bipolar disorder is needed.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Imaging findings in MR imaging-guided focused ultrasound treatment for patients with essential tremor.

BACKGROUND AND PURPOSE: MR imaging-guided focused sonography surgery is a new stereotactic technique that uses high-intensity focused sonography to heat and ablate tissue. The goal of this study was to describe MR imaging findings pre- and post-ventralis intermedius nucleus lesioning by MR imaging-guided focused sonography as a treatment for essential tremor and to determine whether there was an association between these imaging features and the clinical response to MR imaging-guided focused sonography. MATERIALS AND METHODS: Fifteen patients with medication-refractory essential tremor prospectively gave consent; were enrolled in a single-site, FDA-approved pilot clinical trial; and were treated with transcranial MR imaging-guided focused sonography. MR imaging studies were obtained on a 3T scanner before the procedure and 24 hours, 1 week, 1 month, and 3 months following the procedure. RESULTS: On T2-weighted imaging, 3 time-dependent concentric zones were seen at the site of the focal spot. The inner 2 zones showed reduced ADC values at 24 hours in all patients except one. Diffusion had pseudonormalized by 1 month in all patients, when the cavity collapsed. Very mild postcontrast enhancement was seen at 24 hours and again at 1 month after MR imaging-guided focused sonography. The total lesion size and clinical response evolved inversely compared with each other (coefficient of correlation = 0.29, P value = .02). CONCLUSIONS: MR imaging-guided focused sonography can accurately ablate a precisely delineated target, with typical imaging findings seen in the days, weeks, and months following the treatment. Tremor control was optimal early when the lesion size and perilesional edema were maximal and was less later when the perilesional edema had resolved.

Cell cycle times of short-term cultures of brain cancers as predictors of survival.

Tumour cytokinetics estimated in vivo as potential doubling times (T(pot) values) have been found to range in a variety of human cancers from 2 days to several weeks and are often related to clinical outcome. We have previously developed a method to estimate culture cycle times of short-term cultures of surgical material for several tumour types and found, surprisingly, that their range was similar to that reported for T(pot) values. As T(pot) is recognised as important prognostic variable in cancer, we wished to determine whether culture cycle times had clinical significance. Brain tumour material obtained at surgery from 70 patients with glioblastoma, medulloblastoma, astrocytoma, oligodendroglioma and metastatic melanoma was cultured for 7 days on 96-well plates, coated with agarose to prevent proliferation of fibroblasts. Culture cycle times were estimated from relative (3)H-thymidine incorporation in the presence and absence of cell division. Patients were divided into two groups on the basis of culture cycle times of < or =10 days and >10 days and patient survival was compared. For patients with brain cancers of all types, median survival for the < or =10-day and >10-day groups were 5.1 and 12.5 months, respectively (P=0.0009). For 42 patients with glioblastoma, the corresponding values were 6.5 and 9.0 months, respectively (P=0.03). Lower grade gliomas had longer median culture cycle times (16 days) than those of medulloblastomas (9.9 days), glioblastomas (9.8 days) or melanomas (6.7 days). We conclude that culture cycle times determined using short-term cultures of surgical material from brain tumours correlate with patient survival. Tumour cells thus appear to preserve important cytokinetic characteristics when transferred to culture.

The heritability of plasma homocysteine, and the influence of genetic variation in the homocysteine methylation pathway.

BACKGROUND: The extent of genetic influence on plasma homocysteine, a risk factor for ischaemic heart disease, is uncertain. Many association studies have investigated common polymorphisms and their role in hyperhomocysteinaemia, but only the thermolabile variant of methylene tetrahydrofolate reductase (MTHFR) has shown an association (small but robust). AIM: To estimate the heritability of plasma homocysteine and the contributions of well-studied common SNPs in the three main candidate genes in the homocysteine methylation pathway. DESIGN: Twin study. METHODS: We studied 216 monozygotic and 790 dizygotic pairs of twins; all were women. Blood was collected after overnight fasting for measurement of homocysteine, folate, vitamin B12, and extraction of DNA. Heritability was estimated by structural modelling, including correction for known environmental influences, particularly serum folate. The frequency of a common coding SNP in MTHFR and methionine synthase (MTR), and two coding SNPs in methionine synthase reductase (MTRR) were measured in dizygotic twins by ABI 7700 Sequence Detection, and the contribution of each to homocysteine variance was determined. RESULTS: The heritability of homocysteine was 57% (95%CI 51-63%). The highest contribution to homocysteine was serum folate, accounting for 10.13% of variance. This was twice the total genetic contribution of 4.56%, and only the C1763T SNP of MTRR showed significant association with homocysteine. DISCUSSION: Homocysteine has one of the highest heritabilities of common risk factors for ischaemic heart disease. This is not accounted for by the commonly studied SNPs in MTHFR, MTR and MTRR.

Epidemic spread of adenovirus type 4-associated acute respiratory disease between U.S. Army installations.

A large outbreak of adenovirus type 4-associated acute respiratory disease (ARD) occurred at Fort Jackson, South Carolina, in 1997. A laboratory-based ARD surveillance program was initiated at Fort Gordon, Georgia, where advanced individual training was heavily populated with Fort Jackson soldiers. Adenovirus type 4 was isolated from 50% of 147 trainees hospitalized with ARD. Most (88%) introduced cases were in trainees from Fort Jackson.

A genome-wide search for susceptibility loci to human essential hypertension.

We undertook a systematic search of the entire human genome with the affected sibling-pair model to identify major susceptibility loci to essential hypertension. Affected nuclear families (n=263) were recruited and divided according to definite or probable genetic contribution to hypertension depending on number of hypertensive siblings. The largest nuclear families were first screened with a set of microsatellite markers. Regions on the genome with P<0.05 were tested against the second set of smaller families. An exclusion map was generated to identify regions in which hypertension-causing genes are unlikely to reside. Sibling-pair linkage analysis identified a single locus on chromosome 11q (P<0.004) in the first pass. A second pass with nuclear families that had only affected sibling pairs was, as expected, insufficient to support linkage to 11q. Multipoint exclusion-linkage analysis showed that 3 genetic loci are necessary to explain familial aggregation of essential hypertension. Our preliminary findings suggest that no single region within the human genome contains genes with a major contribution to essential hypertension. We show that the disease is indeed polygenic, with each gene providing a relatively small risk. Our exclusion map will help future investigators to concentrate on areas likely to contain these genes. The region on chromosome 11 is the first to point to a new candidate gene for hypertension that has arisen out of a genome search, but replication of these results at a higher significance is necessary before positional cloning can be justified.

Large, persistent epidemic of adenovirus type 4-associated acute respiratory disease in U.S. army trainees.

In May 1997, a large, persistent epidemic of adenovirus type 4-associated acute respiratory disease began at Fort Jackson, South Carolina, the largest army basic training center. The epidemic lasted until December and declined when vaccine administration resumed. More than 1,000 male and female trainees were hospitalized; 66.1% of those hospitalized had an adenovirus type 4 isolate.

A common variant of the endothelial nitric oxide synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK.

BACKGROUND: Endothelium-derived nitric oxide (NO) is synthesised from L-arginine by endothelial nitric oxide synthase (eNOS) encoded by the NOS 3 gene on chromosome 7. Because reduced NO synthesis has been implicated in the development of coronary atherosclerosis, which has a heritable component, we hypothesised that polymorphisms of NOS 3 might be associated with increased susceptibility to this disorder. METHODS AND RESULTS: Single-strand conformation polymorphism analysis of NOS 3 identified a G-->T polymorphism in exon 7 of the gene which encodes a Glu-->Asp amino acid substitution at residue 298 of eNOS. We investigated the relationship between this Glu(298)-->Asp variant and atherosclerotic coronary artery disease (CAD) using 2 independent case-controlled studies. In the first study (CHAOS), cases consisted of 298 unrelated patients with positive coronary angiograms and controls were 138 unrelated healthy individuals ascertained through a population health screen. In the second study (CHAOS II), the cases were 249 patients with recent myocardial infarction (MI), and a further 183 unrelated controls. There was an excess of homozygotes for the Asp298 variant among patients with angiographic CAD, and among patients with recent MI when compared with their respective controls (35.9% versus 10.2%, P<0.0001 in CHAOS, and 18.1% versus 8.7%, P<0.02 in CHAOS II). In comparison to Glu(298) homozygotes, homozygosity for Asp(298) was associated with an odds ratio of 4.2 (95% CI, 2.3 to 7.9) for angiographic CAD and 2.5 (95% CI, 1.3 to 4.2) for MI. CONCLUSIONS: Homozygosity for a common NOS 3 polymorphism (894 G-->T) which encodes a Glu298-->Asp amino acid substitution in eNOS is a risk factor for angiographic CAD and recent MI in this population.

Expression of the alpha- and beta-subunits of the stimulatory and inhibitory G-proteins in beta 1-adrenoceptor-blocked and non-beta-adrenoceptor-blocked human atrium.

1. Chronic beta 1-adrenoceptor blocker therapy induces hyperresponsiveness of the beta 2-adrenoceptor in human atrium. To investigate whether the beta 2-adrenoceptor sensitization induced by beta 1-adrenoceptor blockade is associated with altered gene expression of G-proteins, which couple the receptors to adenylate cyclase, we determined the mRNA expression of the alpha- and beta-subunits of the stimulatory G-protein, Gs, and inhibitory G-protein, Gi, in human right atrial appendage by polymerase chain reaction and by enhanced chemiluminescence Northern blot analysis. 2. The polymerase chain reaction revealed bands of predicted size of Gs alpha, both short form and long form, all three Gi alpha subtypes and three G beta subtypes. In Northern blots, the digoxigenin-labelled antisense cRNA probe specific for Gi alpha 2 hybridized to a predominant band at 2.3 kb, whereas the Gi alpha 3 cRNA probe detected a message of 1.8 kb in total RNA extracted from human atrium. The cRNA probe encoding Gs alpha revealed one major band at 1.9 kb and one minor band at 1.7 kb. The G beta cRNA probes detected messages of 3.4 kb for G beta 1, 1.8 kb for G beta 2 and 1.9 kb for G beta 3 in human atrium. 3. The mRNA levels of Gs alpha in beta 1-adrenoceptor-blocked atria (n = 12) were not significantly different from those in non-beta-adrenoceptor-blocked atria (n = 12), nor were there any significant differences in the Gi alpha 2 mRNA levels between atria from patients treated with beta 1-adrenoceptor blockers and untreated patients. The ratios of 1.9-kb Gs alpha mRNA to 1.7-kb Gs alpha mRNA and of 1.9-kb Gs alpha mRNA to 2.3-kb Gi alpha 2 mRNA in beta 1-adrenoceptor-blocked patients were almost identical to those in non-beta-adrenoceptor-blocked patients. Neither G beta 1 mRNA nor G beta 2 mRNA expression in beta 1-adrenoceptor-blocked atria differed significantly from that in non-beta-adrenoceptor-blocked atria. 4. We conclude that the previously observed sensitization following beta 1-adrenoceptor-blockade of beta 2-adrenoceptors in human atria is unlikely to be mediated by altered gene expression of the alpha- and beta-subunits of G-proteins.