An alternative clinical postural stability test for patients with Parkinson’s disease

We compared the sensitivity and consistency of a new Push and Release Test versus the Pull Test (item 30 of the Unified Parkinson’s Disease Rating Scale; UPDRS) as clinical measures of postural stability. Subjects with Parkinson’s disease and age-matched control subjects participated in 3 protocols investigating: (1) the sensitivity and specificity of the two tests related to the subjects’ balance confidence, as measured by the Activities-specific Balance Confidence (ABC) scale, (2) the inter-rater reliability of the two tests, and (3) the consistency of the perturbation forces applied to the subjects by each balance test. As a test for concurrent validity, the balance tests were also compared with the subjects’ retrospective reports of fall frequency. Compared with the Pull Test, the Push and Release Test was more sensitive to subjects with low balance confidence, but less specific for subjects with high balance confidence. The inter-rater correlations were higher with the Push and Release Test. Examiners applied more consistent perturbation forces to the subjects with the Push and Release Test than with the Pull Test. The Push and Release Test correlated better with self-reported falls. Therefore, the Push and Release Test provided a more sensitive and consistent test of postural stability than the Pull Test. Received in revised form: 2 March 2006     

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease

OBJECTIVE: Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open-label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin). METHODS: Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15 microg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and (18)F-dopa uptake. RESULTS: At 6 months, mean percentage changes in "off" UPDRS motor score were -10.0% and -4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, -23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean (18)F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension). INTERPRETATION: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased (18)F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.     

High affinity germinal center B cells are actively selected into the plasma cell compartment

A hallmark of T cell-dependent immune responses is the progressive increase in the ability of serum antibodies to bind antigen and provide immune protection. Affinity maturation of the antibody response is thought to be connected with the preferential survival of germinal centre (GC) B cells that have acquired increased affinity for antigen via somatic hypermutation of their immunoglobulin genes. However, the mechanisms that drive affinity maturation remain obscure because of the difficulty in tracking the affinity-based selection of GC B cells and their differentiation into plasma cells. We describe a powerful new model that allows these processes to be followed as they occur in vivo. In contrast to evidence from in vitro systems, responding GC B cells do not undergo plasma cell differentiation stochastically. Rather, only GC B cells that have acquired high affinity for the immunizing antigen form plasma cells. Affinity maturation is therefore driven by a tightly controlled mechanism that ensures only antibodies with the greatest possibility of neutralizing foreign antigen are produced. Because the body can sustain only limited numbers of plasma cells, this "quality control" over plasma cell differentiation is likely critical for establishing effective humoral immunity.     

A psychopharmacological treatment algorithm for generalised anxiety disorder (GAD)

Generalised anxiety disorder (GAD) is defined as excessive and uncontrollable worry and anxiety about everyday life situations. It is a chronic disorder, and is associated with substantial somatisation, high rates of comorbid depression and other anxiety disorders, and significant disability. The evidence base for pharmacotherapy and psychotherapy has continued to grow, and a wide range of drug choices for GAD now exists. Current guidelines for GAD generally restrict themselves to presentation of the evidence for various treatments, which, as a result, generally do not offer detailed discussion or recommendation of strategies beyond the first level of treatment, or take into account the individual circumstances of the patient. Thus, there is a lack of algorithm-based treatment guidelines for GAD. Our aim is, therefore, to present an algorithm for the psychopharmacologic management of GAD, intended for all clinicians who treat patients with GAD, where issues of pharmacotherapy are under consideration. We also hope that these GAD algorithms and other guidelines can help to identify high-priority areas that need further study. In this algorithm, we provide a sequenced approach to the pharmacotherapy of GAD, taking into account salient symptomatology and comorbidity, levels of evidence and extent of response. Special issues, including comorbidity, insomnia, suicidality, substance abuse, treatment adherence, pregnancy and lactation, cross-cultural issues, use of medication in the elderly, psychosocial treatment and dosing issues are also addressed.     

Levodopa Slows Progression of Parkinson’s Disease. External Validation by Clinical Trial Simulation

Purpose To externally validate the model predictions of a DATATOP cohort analysis through application of clinical trial simulation with the study design of the ELLDOPA trial. Methods The stochastic pharmacokinetic-pharmacodynamic and disease progress model was developed from the large DATATOP cohort of patients followed for 8 years. ELLDOPA was designed to detect a difference between placebo and levodopa treated arms in the total Unified Parkinson’s Disease Rating Scale (UPDRS) taken at baseline and following 2 weeks levodopa washout after 40 weeks of treatment. The total UPDRS response was simulated with different assumptions on levodopa effect (symptomatic with/without disease modifying capability) and washout speed of symptomatic effect. Results The observed results of ELLDOPA were similar to the model predictions assuming levodopa slows disease progression and has a slow washout of symptomatic effect. Conclusions This simulation work confirmed the conclusion of the DATATOP analysis finding that levodopa slows disease progression. The simulation results also showed that a dose-related increased rate of progression in Parkinson’s disease, obscured by symptomatic benefit, is very unlikely. Finally, the simulation results also shown that 2 weeks washout period was not adequate to completely eliminate the symptomatic benefits of levodopa.     

腋路臂丛阻滞麻醉行小儿上肢手术

1．1 对象 小儿上肢手术120(男82,女38)例,为急诊或择期手术病例．,年龄2～13(平均5．5)岁,手术时间1～4h．术前常规检查出凝血时间、血常规及ECG。