The metabolic anatomy of tremor in Parkinson's disease

OBJECTIVE: To identify regional metabolic brain networks related specifically to the presence of tremor in PD. BACKGROUND: The pathophysiology of parkinsonian tremor is unknown. Because tremor in PD occurs mainly in repose, we used resting state PET with 18F-fluorodeoxyglucose (FDG) to identify specific metabolic brain networks associated with this clinical manifestation. METHODS: We studied two discrete groups of eight PD patients with and without tremor using FDG/PET. Both patient groups were matched for gender, age, and Unified Parkinson Disease Rating Scale ratings for akinesia and rigidity. Ten normal volunteer subjects served as controls. RESULTS: Network analysis with the Scaled Subprofile Model was performed in two steps. 1) We computed the expression of the PD-related pattern (PDRP) identified by us previously in each of the PD patients and control subjects. Although PDRP subject scores were abnormally elevated in the combined PD cohort (p < 0.005), these values did not differ in the PD patient groups with and without tremor (p = 0.36). 2) We used SSM to analyze the data from the combined PD cohort comprising both patient groups. We found that PD patients with tremor were characterized by increased expression of a metabolic network comprising the thalamus, pons, and premotor cortical regions. Subject scores for this pattern were elevated in the tremor group compared with the atremulous patient group and the normal control group (p < 0.005). CONCLUSIONS: The findings suggest that PD patients with tremor are characterized by distinct increases in the functional activity of thalamo-motor cortical projections. Modulation of this functional anatomic pathway is likely to be the mechanism for successful interventions for the relief of parkinsonian tremor.     

Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.     

Effects of antipsychotic treatment on polysomnographic measures in schizophrenia: a replication and extension

OBJECTIVE: The authors sought to replicate and extend previous observations of improvement in some EEG sleep measures during the course of antipsychotic treatment in schizophrenia patients. METHOD: Fourteen medication-free patients with schizophrenia underwent 2 nights of sleep EEG monitoring before and after 3-4 weeks of treatment with clinically determined doses of haloperidol or thiothixene. RESULTS: Measures of sleep continuity improved consistently. REM latency increased, although five of 14 patients continued to exhibit short REM latencies (less than 60 minutes). Stage 3 sleep increased during neuroleptic treatment, while stage 4 sleep did not change. CONCLUSIONS: These data demonstrate partial improvement of some but not all EEG sleep measures in schizophrenic patients through the course of neuroleptic treatment. They suggest that shortened REM latency and disturbed sleep continuity might represent reversible state abnormalities, while reduced slow-wave sleep may represent a more persistent trait abnormality in schizophrenia.     

Measurement of pulmonary resistance and dynamic compliance with airway obstruction

We compared four algorithms by using least squares regression for determination of pulmonary resistance and dynamic elastance in subjects with emphysema, normal subjects, and subjects with asthma before and after bronchoconstriction. The four methods evaluated include 1) a single resistance and elastance, 2) separate resistances and elastances for each half breath, 3) separate inspiratory and expiratory resistances with a single elastance, and 4) separate inspiratory and expiratory resistances, an expiratory volume interaction term, and a single elastance. All methods gave comparable results in normal and asthmatic subjects. We found expiratory resistance was larger than inspiratory resistance in normal and asthmatic subjects during control conditions, but inspiratory resistance was higher than expiratory resistance in subjects who experienced severe bronchoconstriction in response to methacholine. In subjects who are flow limited, method 2 gives a higher inspiratory resistance than would be computed by assuming that the elastic pressure-volume curve passes through the zero-flow points. Methods 1 and 3 overestimate dynamic elastance and inspiratory resistance. Method 4 appears to identify flow limitation and dynamic hyperinflation and gives a good measure of inspiratory resistance and dynamic elastance.     

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival

The EMS1 and CCND1 genes at chromosome 11q13 are amplified in about 15% of primary breast cancers but appear to confer different phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene amplification (P = 0.0061), whereas cyclin D1 mRNA overexpression was not (P = 0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P = 0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P = 0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically significant (P = 0.0951). In marked contrast there was a significant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P = 0.030). A potential explanation for this difference was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without effect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age > 50 years (P = 0.0001), postmenopausal status (P = 0.0008), lymph node negativity (P = 0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene amplification, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer different phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene amplification.