Parkinson's disease: cognition, pulmonary function and muscle strength

Parkinson's disease is a slowly progressive disease: the cause is still unknown. The symptoms can range from tremor, rigidity, bradykinesia, postural instability and autonomic dysfunction to cognitive disturbances. The pathophysiological mechanism for most of these symptoms is the degeneration of the nigrostriatal tract, leading to a shortage of dopamine in the striatum. Levodopa given orally, can be an effective drug for most of these symptoms, but not all symptoms respond equally. In addition, the progression of the disease continues in spite of levodopa treatment. Longterm levodopa treatment can lead to considerable side-effects. In the early phases of the disease amantadine and anti-cholinergics are to be preferred above levodopa. However, anticholinergics do have a reputation of side-effects with regard to cognitive function, since acetylcholine is an important neurotransmitter for systems involved in memory functions

The course of neuropathy after cessation of cisplatin treatment, combined with Org 2766 or placebo

Peripheral neuropathy is an important and disabling side-effect of cisplatin treatment. A new drug, Org 2766, has been found to prevent this neuropathy up to 1 month after treatment. A group of 18 patients with ovarian cancer, who participated in an earlier randomized study with placebo or Org 2766, together with cisplatin and cyclophophamide, were thereafter prospectively followed up to 2 years after discontinuation of treatment to monitor the development of neurological signs and symptoms and vibration perception threshold (VPT). Exploratory, descriptive data analysis shows that between 1 and 4 months after the last cycle the average sum score for neurological signs and symptoms and VPT had deteriorated compared with 1 month after treatment. Thereafter a gradual but incomplete improvement was seen between 4-12 and 12-24 months after treatment. These changes were seen in all patients regardless of previous treatment with Org 2766 or placebo, but deterioration was less pronounced in patients previously treated with Org 2766. These results suggests that treatment with Org 2766 to prevent a cisplatin-induced neuropathy should possibly be continued up to 4 months after the last cycle of cisplatin

Breakpoint mapping of 13 large parkin deletions/duplications reveals an exon 4 deletion and an exon 7 duplication as founder mutations

Early-onset Parkinson’s disease (EOPD) has been associated with recessive mutations in parkin (PARK2). About half of the mutations found in parkin are genomic rearrangements, i.e., large deletions or duplications. Although many different rearrangements have been found in parkin before, the exact breakpoints involving these rearrangements are rarely mapped. In the present study, the exact breakpoints of 13 different parkin deletions/duplications, detected in 13 patients out of a total screened sample of 116 EOPD patients using Multiple Ligation Probe Amplification (MLPA) analysis, were mapped using real time quantitative polymerase chain reaction (PCR), long-range PCR and sequence analysis. Deletion/duplication-specific PCR tests were developed as a rapid and low cost tool to confirm MLPA results and to test family members or patients with similar parkin deletions/duplications. Besides several different deletions, an exon 3 deletion, an exon 4 deletion and an exon 7 duplication were found in multiple families. Haplotype analysis in four families showed that a common haplotype of 1.2 Mb could be distinguished for the exon 7 duplication and a common haplotype of 6.3 Mb for the deletion of exon 4. These findings suggest common founder effects for distinct large rearrangements in parkin

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

The treatment of early Parkinson's disease: levodopa rehabilitated

Many clinicians regard levodopa as a last resort in the symptomatic treatment of Parkinson's disease. Here we critically review the arguments that are typically used to postpone the start of levodopa for as long as possible. We will point out that most concerns are invalid. Levodopa remains the most effective and best tolerated Parkinson's drug to date, and should have an important role in all therapeutic strategies, both as monotherapy in early Parkinson's disease and as part of combination therapy in advanced disease. Regardless of disease stage, the choice of a particular drug should not be driven by fear of long term complications but by the clinical condition of the patient at the time, with an emphasis on functioning in everyday life and any comorbidity. A 'phobia' for levodopa—or, indeed, for any other antiparkinsonian medication—is unacceptable according to current evidence

Managing Parkinson's disease with continuous dopaminergic stimulation

The pathophysiology of Parkinson's disease is marked by the loss of dopaminergic neurons, which leads to striatal dopaminergic deficiency. This causes resting tremor, hypokinesia, rigidity, bradykinesia, and loss of postural reflexes. Most current treatments for Parkinson's disease aim to restore striatal dopamine signaling by increasing the supply of dopamine with oral levodopa (L-dopa), stimulating dopamine receptors directly using dopamine agonists, or inhibiting the reuptake of endogenous dopamine. L-dopa is standard therapy for patients with Parkinson's disease. However, with continued treatment and disease progression, the response to oral dopaminergic drugs becomes unstable and motor fluctuations emerge, including off periods and dyskinesia. Direct duodenal-administered infusible L-dopa/carbidopa is effective for the management of refractory motor fluctuations in some patient populations. However, enteral infusions cannot mimic the function of the normal dopaminergic brain, and around-the-clock constant-rate administration carries the risk of causing refractory off periods associated with severe immobility and hyperpyrexia. Subthalamic nucleus (STN) deep brain stimulation (DBS) is also a promising treatment. DBS passes a high-frequency electrical current into the target area, mimicking the effect of lesioning the stimulated area. However, this treatment requires invasive surgery and is appropriate for a limited segment of the patient population. This supplement provides a rationale for the use of continuous dopaminergic receptor stimulation and offers guidelines on the individualization of treatment decisions, with special focus on continuous L-dopa infusion and STN DBS, Erik Wolters, MD, PhD, offers an introduction to the impact of continuous L-dopa infusion. Andrew J. Lees, MD, FRCP, provides an overview of the physiologic response to L-dopa and reviews clinical pharmacologic studies of intravenous and intraduodenal L-dopa. Jens Volkmann, MD, discusses selection criteria for STN DBS and duodenal L-dopa/carbidopa infusion. Teus van Laar, MD, Phl), and Ad Hovestadt, MD, discuss the first data from a Dutch cohort study of duodenal L-dopa/carbidopa