Ascitic complement system in ovarian cancer

Ovarian cancer spreads intraperitoneally and forms fluid, whereby the diagnosis and therapy often become delayed. As the complement (C) system may provide a cytotoxic effector arm for both immunological surveillance and mAb-therapy, we have characterised the C system in the intraperitoneal ascitic fluid (AF) from ovarian cancer patients. Most of the AF samples showed alternative and classical pathway haemolytic activity. The levels of C3 and C4 were similar to or in the lower normal range when compared to values in normal sera, respectively. However, elevated levels of C3a and soluble C5b-9 suggested C activation in vivo. Malignant cells isolated from the AF samples had surface deposits of C1q and C3 activation products, but not of C5b-9 (the membrane attack complex; MAC). Activation could have become initiated by anti-tumour cell antibodies that were detected in the AFs and/or by changes on tumour cell surfaces. The lack of MAC was probably due to the expression of C membrane regulators CD46, CD55 and CD59 on the tumour cells. Soluble forms of C1 inhibitor, CD59 and CD46, and the alternative pathway inhibitors factor H and FHL-1 were present in the AF at concentrations higher than in serum samples. Despite the presence of soluble C inhibitors it was possible to use AF as a C source in antibody-initiated killing of ovarian carcinoma cells. These results demonstrate that although the ovarian ascitic C system fails as an effective immunological surveillance mechanism, it could be utilised as an effector mechanism in therapy with intraperitoneally administrated mAbs, especially if the intrinsic C regulators are neutralised

Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types

Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus

The pedunculopontine nucleus (PPN) is a part of the mesencephalic locomotor region and is thought to be important for the initiation and maintenance of gait. Lesions of the PPN induce gait deficits, and the PPN has therefore emerged as a target for deep brain stimulation for the control of gait and postural disability. However, the role of the PPN in gait control is not understood. Using extracellular single-unit recordings in awake patients, we found that neurons in the PPN discharged as synchronous functional networks whose activity was phase locked to alpha oscillations. Neurons in the PPN responded to limb movement and imagined gait by dynamically changing network activity and decreasing alpha phase locking. Our results indicate that different synchronous networks are activated during initial motor planning and actual motion, and suggest that changes in gait initiation in Parkinson's disease may result from disrupted network activity in the PPN

A door-to-door survey to estimate the prevalence of Parkinsonism in Pakistan

Suliman Khan,1 Ghulam Nabi,2 Muhammad Naeem,3 Liaqat Ali,4 Peter A Silburn,1,5 George D Mellick1 1Clinical Neuroscience Group, Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia; 2Department of Animal Sciences, 3Department of Biotechnology, Quaid-i-Azam University, Islamabad, 4Saidu Medical College, Saidu Sharif Swat Khyber Pakhtunkhwa, Pakistan; 5The University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia Introduction: Parkinson’s disease (PD) occurs in all races and cultures, and population-related differences in frequency may provide etiological clues. The present study was designed to explore the prevalence of PD and Parkinsonism in Pakistan, the world’s sixth most populous country, for which no published prevalence data are available.Methods: We conducted a three-phase door-to-door survey in two districts of the Khyber Pakhtunkhwa province of Pakistan, to assess the prevalence of PD and Parkinsonism in a sample of 4,000 individuals aged 50 years and above.Results: We identified 14 cases of Parkinsonism, eleven with a diagnosis of idiopathic PD. The overall prevalence estimates were 1.7/100 (95% confidence interval [CI]: 0.9-2.46) for Parkinsonism and 1.28/100 (95% CI: 0.6-1.94) for PD in persons aged 65 years and above. The age-standardized prevalence of PD (aged 65 years and above), normalized to the USA population in 2000, was 1.33/100, which is similar to that observed in other human populations. Of the total 14 cases, five were newly diagnosed and four had a family history of PD.Conclusion: The estimated prevalence rates in Pakistan are similar to those observed in other human populations. The frequency of familial Parkinsonism is also equivalent to previous estimates. Keywords: Parkinsonism, Parkinson’s disease, door-to-door surve

Haplotype analysis of the PARK 11 gene, GIGYF2, in sporadic Parkinson's disease

Familial Parkinsonism (PARK) genes are strong candidates for conferring susceptibility to common forms of PD. However, most studies to date have provided little evidence that their common variants substantially influence disease risk. Recently, mutations were described in the gene, GIGYF2 (TNRC15), located at the PARK11 locus (2q37.1). Here, we use a haplotype tagging approach to examine common variation in the GIGYF2 gene and PD risk. PD cases (n = 568) and age and gender-matched control subjects (n = 568) were recruited from three specialist movement disorder clinics in Brisbane (Australia) and the Australian electoral roll. Twelve tagging SNPs were assessed in all subjects and haplotype and genotype associations were explored. Overall our findings suggest that common genetic variants of GIGYF2 do not significantly affect sporadic PD risk in Australian Caucasians

The parkin gene S/N167 polymorphism in Australian Parkinson's disease patients and controls

This study determined the frequencies of a G-to-A transition (S/N167) polymorphism in exon 4 of the parkin gene in Australian Parkinson's disease patients and control subjects. The genotype of each subject was determined using the polymerase chain reaction and restriction-fragment-length-polymorphism analysis. Overall, the A allele was significantly less common in the Parkinson's disease group (1.7%) compared with the control group (3.8%, OR = 0.43, 95% CI = 0.19-1.00, P < 0.05), although the frequency in the young onset Parkinson's disease group (6.6%) was not significantly different to controls. The A allele is less common in Australian Caucasian subjects compared to Japanese Parkinson's disease patients and appears to be under-represented in older-onset Parkinson's disease. <(c)> 2001 Elsevier Science Ltd. All rights reserved

The impact of low-frequency stimulation of the pedunculopontine nucleus region on reaction time in parkinsonism

Objectives: Attentional augmentation and enhanced motor function are potential mechanisms by which stimulation of the region of the pedunculopontine nucleus (PPN) may improve gait in parkinsonism. Here, the authors assess the impact of stimulation of this region on attentional and motor aspects of reaction task performance in patients with parkinsonism. Methods: Eleven patients implanted with PPN stimulators underwent computerised assessment of simple, choice and digit vigilance reaction tasks. Patients were assessed 'off medication' during stimulation at different frequencies (0 Hz, 5 Hz, 10 Hz and 'therapeutic' 20-35 Hz). There were two primary endpoints: 'Speed of Reaction' (sum of the mean task reaction times) and 'Accuracy of Reaction' (reflecting omissions and percentage of correct responses). Baseline performance was compared with age- and sex-matched healthy controls. Clinical effects of stimulation were assessed using the Unified Parkinson's Disease Rating Scale and a falls frequency scale. Results: Compared with healthy controls, subjects had significant deficits in 'Speed of Reaction' and in all mean task reaction times. 'Accuracy of Reaction' was not different from healthy controls and did not improve with stimulation. 'Speed of Reaction' significantly improved with stimulation at therapeutic frequencies (20e35 Hz). Of the individual tasks, only simple reaction time improved significantly. Simple reaction time distribution analysis revealed a general speeding of responses rather than a selective reduction in outliers. Acute PPN stimulation improved gait and balance but not akinesia scores. Chronic PPN stimulation significantly improved falls frequency. Falls score improvement significantly correlated with changes to simple reaction time with therapeutic stimulation. Conclusion: The pattern of reaction time improvement with stimulation of the PPN area suggests a benefit on motor performance, rather than augmentation of attention