Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding.

Tourette syndrome, a chronic tic disorder with autosomal dominant inheritance, exhibits considerable phenotypic variability even within monozygotic twin pairs. The origins of this variability remain unclear. Recent findings have implicated the caudate nucleus as a locus of pathology, and pharmacological evidence supports dopaminergic involvement. Within monozygotic twins discordant for Tourette syndrome severity, differences in D2 dopamine receptor binding in the head of the caudate nucleus predicted differences in phenotypic severity (r = 0.99); this relation was not observed in putamen. These data may link Tourette syndrome with a spectrum of neuropsychiatric disorders that involve associative striatal circuitry.

A strength-endurance index for power grip.

INTRODUCTION: The purpose of this study was to quantify muscle strength and endurance in power grip. METHOD: Workers (74 M and 74 F, 18-72 years) squeezed a dynamometer for a 60 s, 18-cycle test. Initial strength (IS) and final strength (FS) were calculated as the mean peak force for cycles 1-3 and 16-18, respectively. Endurance was defined by the strength decrement index (SDI) where SDI = (IS - FS)/IS x 100. A grip strength-endurance analyzer was constructed from IS and SDI data which were depicted on two parallel, linearly scaled axes. Discrete IS and SDI scores were connected on each axis with a vector. The vector (Vmag) was measured directly from the analyzer and its direction identified from its slope. Integer scales transformed discrete IS and SDI scores into individual strength-endurance performance scores (SEPS). RESULTS: Better than 95% of the sample (n > or = 141) scored within acceptable test ranges defined as the combined sample mean +/- 2SD, for SDI, Vmag and SEPS. Vmag was the best predictor for SEPS. Linear regression for SEPS was SEPS (combined) = 0.09 (Vmag) - 0.29: (SEE = 0.829). The analyzer revealed individual scores outside acceptable ranges for injured and uninjured efforts. CONCLUSION: The development of a power grip strength-endurance analyzer provided a simple method to graph individual power grip performances. Converting strength and endurance scores to integers and summing them (SEPS) provided a simple means to represent individual estimates of power grip strength-endurance performance.

Development of explicit criteria to measure adherence to hypertension guidelines.

Measures of adherence to hypertension guidelines have historically been based on prescription data or physician survey data regarding treatment practices. These methods have limitations that decrease their accuracy. As part of a randomized controlled study testing the effects of pharmacist/physician collaboration on adherence to hypertension guidelines, the investigators and an expert panel developed a JNC 7 measurement tool. The final guideline adherence measurement tool includes 22 explicit criteria in four domains of care. An exploratory factor analysis, conducted to assess the structure of the tool, suggests three underlying treatment dimensions in hypertension care. The adherence measurement tool will allow researchers to link specific elements of care to improved blood pressure control. In addition, use of the tool will provide clinicians with a taxonomy for evaluating practice and describing the effect of improved patient care on patient outcomes.

Urokinase induced fibrinolysis in thromboelastography: a model for studying fibrinolysis and coagulation in whole blood.

BACKGROUND: The contact system (CS) proteins, factor XII and prekallikrein are thought to have roles in blood coagulation and fibrinolysis. Recent research has suggested that the CS proteins might be more important in fibrinolysis and cell function than in coagulation. Most studies on fibrinolysis have used plasma or euglobulin assays, ignoring the influence of cellular elements of blood on the fibrinolytic process. OBJECTIVE AND METHODS: In order to study both coagulation and fibrinolysis in whole blood (WB), we have developed a thromboelastography (TEG) assay to investigate both coagulation and fibrinolysis in the same blood sample. In this assay, named urokinase (UK) induced fibrinolysis in thromboelastography (UKIFTEG), TEG is performed on recalcified citrated WB in the presence of UK. Large variations in Ly60 (percentage lysis 60 min after clot formation) were obtained between different donors with the same UK concentration. The UKIFTEG assay was therefore performed using UK concentrations that gave Ly60 values in the approximate range of 20-40%. RESULTS: The effect of CS activation was investigated in the presence or absence of celite (10 mg mL(-1) blood). Celite shortened the clotting time (CT), and increased Ly60 values. Factor XIIa (FXIIa) and plasma kallikrein (KK) produced concentration dependent reductions in CT (significant at concentrations of 1303 and 2600 ng mL(-1) blood, respectively) and increased Ly60 values (significant at concentrations of 652 and 1300 ng mL(-1) blood, respectively). CONCLUSIONS: Our results show that CS activation and both FXIIa and KK produce reductions in clotting time and enhanced fibrinolysis in UKIFTEG.

The antigenic binding site(s) of antibodies to factor XII associated with the antiphospholipid syndrome.

Phospholipid binding proteins, including factor XII (FXII), are known to be targeted by antiphospholipid antibodies (aPA). Factor XII antibodies (FXIIab) have been described in some patients with the antiphospholipid syndrome (APS) and have been shown to lead to reduced levels of FXII. The antigenic binding site(s) and the pathophysiological effects of FXIIab are unknown. In an attempt to elucidate the binding site of these antibodies, immobilized plasma kallikrein was used to cleave FXII into its 52-kDa heavy-chain (HCFXII) and 28-kDa light-chain (LCFXII) components. Plasma samples from 12 female patients with definite APS and FXIIab were investigated for the presence of antibodies to FXII, HCFXII and LCFXII. All but one patient's plasma reacted to FXII, HCFXII and LCFXII in a similar manner. One patient gave markedly reduced positivity to HCFXII and LCFXII, suggesting that the FXIIab in this patient had a higher affinity for the intact FXII molecule. To further investigate the antigenic binding site(s) of FXII, 150 biotinylated peptides of the known FXII sequence were synthesized using a Multipin(TM) peptide synthesis procedure. The IgG and IgM fractions of the 12 patients' plasma were purified by affinity chromatography. The synthesized peptides were captured on streptavidin plates and individual patients' purified FXIIab assayed against the peptides in a modified enzyme-linked immunosorbent assay (ELISA). Two regions were identified as possible antigenic binding site(s) for FXIIab: one in the growth factor domain and the other in the catalytic domain.

Intrarenal abscess. Report of 14 cases.

Six of 14 patients with renal abscess had prior history of urinary tract infection; initial symptoms included fever and flank pain in 12. A drip-infusion intravenous pyelogram was the most sensitive radiologic test, but selective renal arteriography was most specific. Urine cultures were positive in all 14 patients; blood cultures were positive in nine. Six patients were treated with antibiotics alone and eight required surgery. Of the eight, five had pus-filled cavities, one had multiple stones, one had a renal infarct, and one had a resolving abscess. Of six treated with antibiotics alone, one died of unrelated complications and five have demonstrated no pathological renal condition after three to six years.

Ankle-brachial index and 7-year ischemic stroke incidence: the ARIC study.

BACKGROUND AND PURPOSE: Low ankle-brachial index (ABI), which is the ratio of tibial artery systolic blood pressure to brachial systolic artery pressure, is known to be a measure of lower limb peripheral artery disease as well as a marker for other cardiovascular disease events. The ability of ABI to predict incident ischemic stroke, however, is not established in population-based studies. METHODS: ABI was measured in a cohort of 14 839 black and white men and women aged 45 to 64 years. Stroke incidence was calculated during approximately 7 years of follow-up. RESULTS: A total of 206 incident strokes occurred. Adjusted stroke incidence rates were markedly higher for those in the lowest versus the highest categories of ABI for men, women, blacks, and whites. The proportional hazards regression model, adjusted for age, race, gender, and field center, showed an inverse linear trend between ABI and ischemic stroke incidence (P<0.0001). The lowest group (ABI <0.80) had a hazard ratio of 5.68 (95% CI 2.77 to 11.66). After adjustment for major risk factors in a multivariate model, the hazard ratio in the lowest group was elevated (1.93) but no longer statistically significant (95% CI 0.78 to 4.78). There was, however, still an indication of an overall inverse linear trend between ABI and incident stroke (P=0.03). CONCLUSIONS: Low ABI was strongly associated with increased incidence of ischemic stroke, but the relationship was substantially reduced after adjustment for major cardiovascular risk factors.

Sylvian fissure asymmetries in monozygotic twins: a test of laterality in schizophrenia.

To address prior reports that schizophrenia is associated with loss of normal brain asymmetry and that it might be linked to a defect of a gene controlling cerebral lateralization, we measured on three-dimensional cortical renderings from magnetic resonance imaging (MRI) scans the lengths and angles of the sylvian fissures in 10 normal monozygotic (MZ) twin pairs (n = 10 pairs) and in 10 MZ pairs discordant for schizophrenia (n = 10 pairs). We confirmed in both sets of twins the expected normal asymmetries of length and angle of the sylvian fissure. We also confirmed that the length asymmetry occurs solely in the region of the planum temporale. In the discordant twins, affected and unaffected twins did not differ in asymmetry measures, thus failing to support an association between illness per se and diminished asymmetry. Moreover, the discordant twins as a group did not differ from the normal twins as a group, thus failing to confirm the hypothesis of a genetic association with abnormal asymmetry. The implications of variations in methodology and patient samples are discussed.

Cortical abnormality in schizophrenia: an in vivo application of the gyrification index.

To investigate the hypothesis that patients with schizophrenia exhibit gross cortical abnormalities of developmental origin, we utilized the gyrification index (GI) (ratio of inner to outer cortical contours), a measure of overall cortical folding, in an in vivo magnetic resonance imaging study of young, strongly right-handed male patients and controls. The two groups did not differ with respect to whole-brain volume, age, or handedness. In an examination confined to the left hemisphere, mean GI values were significantly reduced in the patient group in both anterior and posterior regions. Neither age nor length of illness were found to be significant predictors of GI variance in the patients group, suggesting that GI reductions do not result from an ongoing atrophic process. Rather, these results are consistent with the hypothesis of neurodevelopmental abnormalities in schizophrenia that result in an overall reduction in cortical folding.

A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity.

BACKGROUND: Genetic variation of the promoter for the serotonin transporter (5-HTT) gene has been associated with its functional capacity. In vitro, carriers of a short allele (s-carriers) of the 5-HTT promoter display significant reduction in 5-HTT capacity. Dysfunction of 5-HTT has been observed in alcoholic individuals. We assessed whether the allelic constitution of the 5-HTT gene is associated with reduced serotonin transporter availability among alcoholic individuals. METHODS: We genotyped the 5-HTT promoter region and measured the availability of serotonin transporter protein with [I-123]beta-CIT SPECT in the raphe area in 14 abstinent male alcoholic subjects and 8 age-matched control subjects of European American descent. RESULTS: Among control subjects, the ratio of in vivo 5-HTT availability for ll-homozygous individuals relative to s-carriers was comparable to serotonin uptake ratios measured in vitro. There was a significant interaction of diagnosis and 5-HTT promoter genotype on 5-HTT availability (p <.01). Among controls, ll-homozygous individuals displayed a significant increase as compared with s-carriers. The availability of raphe 5-HTT was significantly reduced in ll-homozygous alcoholic individuals and was negatively correlated with their amount of alcohol consumption. Among s-carriers, 5-HTT availability did not differ significantly between control and alcoholic subjects. CONCLUSIONS: Our preliminary findings suggest an association between 5-HTT allelic constitution and in vivo measurements of human serotonin transporter availability, and a potentially selective susceptibility of ll-homozygous individuals to the neurotoxic effects of chronic excessive alcohol consumption.

Sleep-disordered breathing and periodic limb movements in sleep in older patients with schizophrenia.

BACKGROUND: Since the prevalence of both sleep-disordered breathing (SDB) and periodic limb movements in sleep (PLMS) increase with age, we explored whether older schizophrenia patients would have a high incidence of SDB and PLMS. Correlations between sleep and clinical variables were also examined. METHODS: Fifty-two patients (mean age = 59.6 years, SD = 8.9) had their sleep/wake, respiration, and leg movements recorded using a modified Medilog/Respitrace portable recording system plus oximetry. A battery of clinical, psychosocial, and motor disturbance variables were collected by research center staff. RESULTS: Forty-eight percent of these patients had at least 10 respiratory events per hour of sleep. These patients reported more symptoms of daytime sleepiness than patients with fewer than 10 events per hour. The relatively high prevalence of SDB in this group may contribute to overall sleep disturbances, and does not appear to be a result of high body mass index. Only 14% of the patients had at least five limb movements per hour of sleep, suggesting the prevalence of PLMS is much lower than expected in this age group. The number of leg jerks was inversely related to symptoms of tardive dyskinesia. CONCLUSIONS: The disturbance of sleep in these patients may be due, in part, to SDB, but is unlikely due to PLMS.

Superior temporal gyrus volume in schizophrenia: a study using MRI morphometry assisted by surface rendering.

OBJECTIVE: Interpretation of the literature concerning superior temporal gyrus volume in patients with schizophrenia is complicated by methodological variation between studies and by the difficulty of identifying gyral boundaries in serial sections. METHOD: With the aid of three-dimensional cortical renderings, the authors developed a morphometric approach in which information from the cortical surface is incorporated into gyral boundary decisions. Using this technique, they assessed superior temporal gyrus volume in young, right-handed male patients with schizophrenia and in right-handed male comparison subjects. They also compared their technique with existing slice-based morphometric methods by using previously reported subcortical landmarks to define the gyral boundaries. RESULTS: There was no significant main effect of diagnosis and no significant diagnosis-by-hemisphere interaction. Significant leftward laterality was present only among comparison subjects. Leftward superior temporal gyrus laterality did not correlate with leftward laterality of the planum temporale. No significant reduction in superior temporal gyrus volume was revealed in the patients. No significant leftward laterality was detected with the slice-based technique, suggesting that a significant portion of superior temporal gyrus tissue is omitted with this approach. The lack of findings could not be explained by a general absence of morphometric abnormalities in this group of subjects because the patients had significantly larger lateral ventricles. CONCLUSIONS: Significant reduction in the superior temporal gyrus volume was not confirmed in this group of patients with schizophrenia, probably because of the small effect size of this finding. Methodological variation is an important factor in determining superior temporal gyrus volume on magnetic resonance imaging scans.

Reduced central serotonin transporters in alcoholism.

OBJECTIVE: Dysfunction of monoamine uptake mechanisms has been implicated in the pathogenesis of alcohol dependence. The authors explored whether serotonergic dysfunction is associated with anxiety and depression, which increase the risk of relapse in alcoholics. METHOD: The availability of serotonin and dopamine transporters in 22 male alcoholics and 13 healthy male volunteers was measured with the use of [123I] beta-CIT and single photon emission computed tomography, and psychopathological correlates were assessed. RESULTS: A significant reduction (a mean of about 30%) in the availability of brainstem serotonin transporters was found in the alcoholics, which was significantly correlated with lifetime alcohol consumption and with ratings of depression and anxiety during withdrawal. CONCLUSIONS: The findings support the hypothesis of serotonergic dysfunction in alcoholism and in withdrawal-emergent depressive symptoms.

In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates.

OBJECTIVE: Studies on brain serotonin metabolism in human and nonhuman primates have indicated that dysfunction of serotonin transmission may play a role in the biological vulnerability to dependence on alcohol. Among young men, low sensitivity to alcohol intoxication predicts subsequent alcohol abuse and dependence. METHOD: The authors used single photon emission computed tomography and the radioligand [(I)123]beta-CIT ([(I)123]methyl 3beta-(4-iodophenyl) tropane-2-carboxylate) to measure the availability of serotonin transporters in 11 male rhesus monkeys, and the monkeys were genotyped for a functional polymorphism of the serotonin transporter gene. The 11 monkeys had experienced parental separation after birth; their behavior and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in CSF had been assessed regularly. RESULTS: In the 5-year-old monkeys, there was a significant negative correlation between beta-CIT binding to serotonin transporters in the brainstem and 5-HIAA concentrations in CSF. Animals with greater beta-CIT binding and low CSF 5-HIAA concentrations displayed greater aggressiveness and were less sensitive to alcohol-induced intoxication. The genetic constitution of the serotonin transporter promoter gene did not significantly contribute to the availability of brainstem serotonin transporters as measured by beta-CIT binding. CONCLUSIONS: In adult nonhuman primates who underwent early developmental stress, variables indicating a low serotonin turnover rate were associated with behavior patterns similar to those predisposing to early-onset alcoholism among humans.

Efficacy of nonpharmacologic interventions in adults with high-normal blood pressure: results from phase 1 of the Trials of Hypertension Prevention. Trials of Hypertension Prevention Collaborative Research Group.

Phase 1 of the Trials of Hypertension Prevention was conducted in 2182 adults, aged 35-54 y, with diastolic blood pressure of 80-89 mm Hg to test the feasibility and blood pressure-lowering effects of seven nonpharmacologic interventions (weight loss, sodium reduction, stress management, and supplementation with calcium, magnesium, potassium, and fish oil). At 6 and 18 mo, weight loss and sodium reduction were well-tolerated and produced significant declines in systolic and diastolic blood pressures (-2.9/-2.4 and -2.1/-1.2 mm Hg for weight loss and sodium reduction, respectively, at 18 mo). None of the other interventions lowered blood pressure significantly at either the 6- or 18-mo follow-up visits. These results suggest that both weight loss and sodium reduction provide an effective means to prevent hypertension. The long-term effects of both of these interventions are being tested in phase 2 of the trial.

The distribution of cerebral muscarinic acetylcholine receptors in vivo in patients with dementia. A controlled study with 123IQNB and single photon emission computed tomography.

A high-affinity muscarinic receptor antagonist, 123IQNB (3-quinuclidinyl-4-iodobenzilate labeled with iodine 123), was used with single photon emission computed tomography to image muscarinic acetylcholine receptors in 14 patients with dementia and in 11 healthy controls. High-resolution single photon emission computed tomographic scanning was performed 21 hours after the intravenous administration of approximately 5 mCi of IQNB. In normal subjects, the images of retained ligand showed a consistent regional pattern that correlated with postmortem studies of the relative distribution of muscarinic receptors in the normal human brain, having high radioactivity counts in the basal ganglia, occipital cortex, and insular cortex, low counts in the thalamus, and virtually no counts in the cerebellum. Eight of 12 patients with a clinical diagnosis of Alzheimer's disease had obvious focal cortical defects in either frontal or posterior temporal cortex. Both patients with a clinical diagnosis of Pick's disease had obvious frontal and anterior temporal defects. A region of interest statistical analysis of relative regional activity revealed a significant reduction bilaterally in the posterior temporal cortex of the patients with Alzheimer's disease compared with controls. This study demonstrates the practicability of acetylcholine receptor imaging with 123IQNB and single photon emission computed tomography. The data suggest that focal abnormalities in muscarinic binding in vivo may characterize some patients with Alzheimer's disease and Pick's disease, but further studies are needed to address questions about partial volume artifacts and receptor quantification.

Tourette's syndrome: [I-123]beta-CIT SPECT correlates of vocal tic severity.

OBJECTIVE: To examine in vivo the density of brain monoaminergic transporters in Tourette's syndrome (TS). BACKGROUND: TS is a heritable neuropsychiatric disorder characterized by chronic vocal and motor tics and is often associated with obsessive-compulsive symptoms. Hyperstimulation of dopamine receptors and dysfunction of serotonergic transmission have been implicated in its pathogenesis, but direct evidence of involvement of these neurochemical systems has been limited. METHODS: Symptom severity and the availability of presynaptic monoaminergic transporters in the basal ganglia, midbrain, and thalamus were measured using SPECT and the radioligand [I-123]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([I-123]beta-CIT) in 10 patients with TS and in 10 age- and sex-matched normal volunteers. RESULTS: A significant negative correlation was found between a measure of overall tic severity and beta-CIT binding in the midbrain (r = -0.73, p = 0.02) and the thalamus (r = -0.82, p < 0.01). When examined post hoc, these correlations were determined largely by vocal tic severity. No other significant correlations were found between symptom severity and beta-CIT binding in the striatum or cortex. CONCLUSIONS: These findings indicate that serotonergic neurotransmission in the midbrain and serotonergic or noradrenergic neurotransmission in the thalamus may be important factors in the expression of TS and may suggest novel targets for treatment.

In vivo olanzapine occupancy of muscarinic acetylcholine receptors in patients with schizophrenia.

Olanzapine is an atypical antipsychotic with potent antimuscarinic properties in vitro (K(i) = 2-25 nM). We studied in vivo muscarinic receptor occupancy by olanzapine at both low dose (5 mg/dy) and high dose (20 mg/dy) in several regions of cortex, striatum, thalamus and pons by analyzing [I-123]IQNB SPECT images of seven schizophrenia patients. Both low-dose and high-dose olanzapine studies revealed significantly lower [I-123]IQNB binding than that of drug-free schizophrenia patients (N = 12) in all regions except striatum. [I-123]IQNB binding was significantly lower at high-dose than low-dose in the same regions. Muscarinic occupancy by olanzapine ranged from 13% to 57% at 5 mg/dy and 26% to 79% at 20 mg/dy with an anatomical pattern indicating M(2) subtype selectivity. The [I-123]IQNB data indicate that olanzapine is a potent and subtype-selective muscarinic antagonist in vivo, perhaps explaining its low extrapyramidal side effect profile and low incidence of anticholinergic side effects.

Genotype influences in vivo dopamine transporter availability in human striatum.

In vivo availability of striatal dopamine transporter (DAT) protein has been reported to be reduced among alcoholics, and allelic variation of the DAT gene (SLC6A3) has been associated with severity of alcohol withdrawal. We examined the VNTR polymorphism of the 3' untranslated region of SLC6A3 and DAT protein availability in 14 abstinent alcoholics and 11 control subjects. Single photon emission computed tomography (SPECT) and plasma levels of the radioligand [I-123]beta-CIT were used to quantify DAT protein availability. Individuals with the 9-repeat/10-repeat genotype had a mean 22% reduction of DAT protein availability in putamen compared with 10-repeat homozygous individuals (t = 2.14, df = 23, p < .05). Consistent with earlier studies, alcoholism, per se, was not significantly associated with either DAT availability or DAT genotype. These findings suggest that the VNTR polymorphism of the DAT gene effects translation of the DAT protein. This effect may explain a variety of clinical associations that have been reported with this polymorphism.