Prodromal frontal/executive dysfunction predicts incident dementia in Parkinson's disease.

To identify the cognitive characteristics predictive of incident dementia in Parkinson's disease (PD), we examined the baseline neuropsychological profiles of 18 initially non-demented patients with PD who met diagnostic criteria for dementia (PDD) at one-year follow-up. PDD participants' baseline neuropsychological test scores were compared to the baseline performance of 18 patients with PD who did not meet criteria for dementia at one-year follow-up (PDND) and 18 normal controls (NC). The three groups were matched on baseline demographic and disease variables. Relative to the PDND group, the incident PDD participants demonstrated significantly poorer performance on digits backward (Wechsler Memory Scale-Revised), word list learning and recognition (California Verbal Learning Test), and perseverative errors on the Wisconsin Card Sorting Test. Each of these baseline neuropsychological variables exhibited adequate diagnostic classification accuracy in predicting PDD and PDND group membership at follow-up. These results suggest that subtle frontal/executive dysfunction is evident during the immediate PDD prodrome and may be of prognostic value in identifying PD patients at risk for dementia. Accordingly, neuropsychological evaluation may facilitate early identification of PDD and thereby inform appropriate dispositional planning.     

Promoting Pneumococcal Immunizations Among Rural Medicare Beneficiaries Using Multiple Strategies

CONTEXT: Vaccine-preventable diseases among adults are major contributing causes of morbidity and mortality in the United States. However, adult immunizations continue to be underutilized in both urban and rural areas. PURPOSE: To evaluate the effectiveness of a community-wide education campaign and mailed reminders promoting pneumococcal immunizations to rural Medicare beneficiaries. METHODS: We implemented a community-wide education campaign, and mailed reminders were sent to Medicare beneficiaries in 1 media market in Montana to increase pneumococcal immunizations. In a second distinct media market, mailed reminders only were sent to beneficiaries. FINDINGS: The proportion of respondents aged 65 years and older aware of pneumococcal immunizations increased significantly from baseline to follow-up among respondents both in the education-plus-reminder (63% to 78%, P = 0.04) and the reminder-only (64% to 74%, P = 0.05) markets. Overall from 1998 to 1999, there was a 3.7-percentage-point increase in pneumococcal immunization claims for Medicare beneficiaries in the education-plus-reminder market and a 1.5-percentage-point increase in the reminder-only market. Medicare beneficiaries sent reminders in the education-plus-reminder market compared to those in the reminder-only market were more likely to have a claim for pneumococcal immunization in 1999 (odds ratio 1.18, 95% confidence interval 1.08 to 1.28). The results suggest that these quality improvement strategies (community education plus reminders and reminders alone) modestly increased pneumococcal immunization awareness and pneumococcal immunization among rural adults. Mailed reminder exposure was associated with an increased prevalence of pneumococcal immunizations between 1998 and 1999 and was augmented somewhat by the education campaign.     

Corticotropin-Releasing Factor Reduces Lipopolysaccharide-Induced Pulmonary Vascular Leak

Previous studies have suggested that corticotropin-releasing factor (CRF) has immunoregulatory effects in addition to its neuroendocrine role. We examined the ability of CRF to inhibit lipopolysaccharide (LPS)-induced pulmonary vascular leak in vivo. Female BALB/C mice were treated with either normal saline (NS) or CRF prior to injection with LPS. Pulmonary vascular leak was inhibited by CRF as assessed by measurement of lung wet-to-dry ratios. The stress-induced increase in serum corticosterone levels in mice injected with LPS alone was not further increased by treatment with CRF. This indicates that the effect of CRF was not mediated centrally by stimulation of endogenous steroid release. Histologic examination of the lungs revealed that leukocyte infiltration was significantly depressed in CRF-treated mice thus confirming the protective effect of CRF. In addition, a modest prolongation of survival was demonstrated in CRF-treated mice following challenge with LPS (p=.08). These data indicate the potential utility of CRF as a modulator of pulmonary vascular leak.     

Anti-leukemia effect of perillyl alcohol in Bcr/Abl-transformed cells indirectly inhibits signaling through Mek in a Ras- and Raf-independent fashion.

PURPOSE: Perillyl alcohol (POH) displays preventive and therapeutic activity against a wide variety of tumor models, and it has been suggested that this might be associated with the ability of POH to interfere with Ras prenylation. POH also selectively induces G(1) arrest and apoptosis in Bcr/Abl-transformed hematopoietic cells. Because signaling through Ras is necessary for Bcr/Abl transformation, we examined whether POH induces its anti-leukemia effect by inhibiting Ras signaling. EXPERIMENTAL DESIGN: The ability of POH to inhibit posttranslational farnesylation and signaling from Ras as well as signaling through the Raf-Mek-Erk cascade was examined in Bcr/Abl-transformed and mock-transformed cells and related to the anti-leukemia effect of POH. RESULTS: POH does not affect Ras prenylation or Ras activity, but it blocks signaling downstream of Ras by reversing the state of activation of the Erk kinase, Mek. POH affects Mek activity only when it is added to intact cells. Treatment of either cell lysates or of purified Mek with POH has no effect on Mek activity. Inhibition of the Mek-Erk pathway seems to be related to the POH anti-leukemia effect for the following reasons: (a) the concentration of POH needed to block the Erk pathway, as well the kinetics with which POH inhibits this signaling cascade, both correlate with the anti-leukemia effect of POH; (b) both U0126 (a specific Mek inhibitor) and POH induce similar anti-leukemia effects; and (c) mock-transformed hematopoietic cells are simultaneously resistant to POH anti-leukemia effects and inhibition of the Mek-Erk pathway. CONCLUSION: Blocking Mek is sufficient to induce growth arrest and apoptosis in Bcr/Abl-transformed cells; therefore, POH represents a novel small molecule inhibitor of Mek that might be effective for treating Bcr/Abl leukemias.     

Characterization of Aerosols of Human Recombinant Deoxyribonuclease I (rhDNase) Generated by Jet Nebulizers

Recombinant human deoxyribonuclease I (rhDNase) is a new therapeutic agent developed to improve clearance of purulent sputum from the human airways. It is delivered by inhalation. Four jet nebulizers, T Up-Draft II (Hudson), Customized Respirgard II (Marquest), Acorn II (Marquest), and Airlife Misty (Baxter), were evaluated in vitro for their ability to deliver aerosols of rhDNase. The aerosols were generated from 2.5-mL aqueous solutions of rhDNase, at concentrations of either 1 or 4 mg/mL. In all experiments, the Pulmo-Aide Compressor (De Vilbiss) was used to supply the air to the nebulizers. Between 20 and 28% of the rhDNase dose initially placed in the nebulizers was delivered to the mouthpiece in the respirable range (1-6 µm). Evaluation of the rhDNase following nebulization in all four devices indicated that there was no loss in enzymatic activity and no increase in aggregation. Circular dichroism spectrophotometry indicated there was no change in either the secondary or the tertiary structure in rhDNase following nebulization. These results show that all four nebulizers are essentially equivalent in their ability to deliver respirable doses of rhDNase in an intact, fully active form. Changing the concentration of the solution in the nebulizer from 4 to 1 mg/mL rhDNase leads to a proportional reduction in the respirable dose delivered to the mouthpiece.     

Moderne Pharmakotherapie bei supraventrikulären und ventrikulären Herzrhythmusstörungen

Currently the pharmacological approach still represents the mainstay in the acute phase of arrhythmia management as well as in the chronic treatment phase of specific entities such as atrial fibrillation. However, non-pharmacological options have recently emerged as frequently used first-line tools for the treatment of various supraventricular and ventricular heart rhythm disturbances. Nevertheless, antiarrhythmic drug treatment is frequently used as a bridging or adjunctive therapy in conjunction with catheter ablation or implantable cardioverter defibrillators. Antiarrhythmic agents constitute a very heterogeneous group prone to various drug interactions and side-effects. Therefore, this article aims to summarise the most important facts and recent findings with regard to appropriate contemporary pharmacological therapy of atrial and ventricular arrhythmias in clinical practice.