A novel screen for nuclear mitochondrial gene associations with Parkinson's disease

Genetic factors play an important role in the aetiology of Parkinson's disease (PD). We have screened nuclear genes encoding subunits of mitochondrial complex I for associations between single nucleotide polymorphisms (SNPs) and PD. Abnormal functioning of complex I is well documented in human PD. Moreover, toxicological inhibition of complex I can lead to parkinsonism in animals. Thus, commonly occurring variants in these genes could potentially influence complex I function and the risk of developing PD. A sub-set of 70 potential SNPs in 31 nuclear complex I genes were selected and association analysis was performed on 306 PD patients plus 321 unaffected control subjects. Genotyping was performed using the DASH method. There was no evidence that the examined SNPs were significant genetic risk factors for PD, although this initial screen could not exclude the possibility that other disease-influencing variations exist within these genes.

Incorporating nerve-gliding techniques in the conservative treatment of cubital Tunnel syndrome

Objective: To discuss the diagnosis and treatment of a patient with cubital tunnel syndrome and to illustrate novel treatment modalities for the ulnar nerve and its surrounding structures and target tissues. The rationale for the addition of nerve-gliding techniques will be highlighted. Clinical Features: Two months after onset, a 17-year-old female nursing student who had a traumatic onset of cubital tunnel syndrome still experienced pain around the elbow and paresthesia in the ulnar nerve distribution. Electrodiagnostic tests were negative. Segmental cervicothoracic motion dysfunctions were present which were regarded as contributing factors hindering natural recovery. Intervention and Outcomes: After 6 sessions consisting of nerve-gliding techniques and segmental joint manipulation and a home exercise program consisting of nerve gliding and light free-weight exercises, a substantial improvement was recorded on both the impairment and functional level (pain scales, clinical tests, and Northwick Park Questionnaire). Symptoms did not recur within a 10-month follow-up period, and pain and disability had completely resolved. Conclusions: Movement-based management may be beneficial in the conservative management of cubital tunnel syndrome. As this intervention is in contrast with the traditional recommendation of immobilization, comparing the effects of both interventions in a systematic way is an essential next step to determine the optimal treatment of patients with cubital tunnel syndrome.

The antlepileptic Materia Medica of Pedoacus Dioscorides

Since it was written about the middle of the 1st Century AD, and up to comparatively recent times, the great Herbal, or Materia Medica, of Dioscorides provided medicine with its chief source of information about what were then considered therapeutic substances. The work contained data on various materials of botanical, biological and mineral origin which were claimed to provide benefit to sufferers from epilepsy, though often with no clear underlying rationale for their use. Some of these materials continued to be used as antiepileptic remedies over many centuries till they were finally recognised to be without useful effect in the disorder. The longest survivor amongst the Dioscoridean antiepileptic remedies was a rather esoteric one, viz. two stones taken from the belly of a young swallow during the rising phase of the moon and also whilst the swallow's parent birds were absent from the nest. The stones, or one of them, were worn against the skin of the seizure sufferer. The use of the swallow stones for epilepsy was recommended as late as in the writings of Thomas Willis (1675). (C) 2004 Elsevier Ltd. All rights reserved.

Ergot of rye - the first specific for migraine

Over the past decade the various triptan derivatives have been accepted as the most effective available agents for relieving migraine attacks. Prior to that, for a period of half a century, ergotamine was the only 'specific' available for this purpose. In 1918, Stoll had isolated it from the various alkaloids present in extracts of the sclerotia of the fungus Claviceps purpurea (ergot), which grow on rye and, to a lesser extent, on other grasses. By 1925 ergotamine was beginning to be used to treat migraine attacks. However, as ergotamine was present in extracts of ergot, which had been used to treat migraine first, In Italy in 1862, and then by Edward Woakes (11868) in England, and after him by Albert Eulenburg in Germany (1883), the drug had actually come into unrecognised use for the disorder more than half a century before ergotamine itself was known to exist. Unfortunately, because of ergotamine's chemical and pharmacokinetic properties, extracts of ergot of rye were incapable of producing consistent therapeutic results, so that general acceptance that the first specific substance for migraine treatment existed had to wait until pure ergotamine was available for administration. (C) 2003 Elsevier Ltd. All rights reserved.

Leonard Bell Cox (1894-1976) - pioneer of Australian clinical neurology

The name of Leonard Bell Cox (1894-1976) will long be associated with a number of very significant areas in the intellectual and cultural life of the Australian State of Victoria. A quarter of a century after his death, his cultural achievements, and the enduring products of these achievements, continue to be celebrated in his native city, Melbourne. However his enormous contributions in these cultural fields were matched by his perhaps less widely known achievements in medicine, in particular in the neurosciences. In his time he not only pioneered the foundation and progressive development of the speciality of clinical neurology in Australia, but at the same time became a recognised world expert on the pathology of brain tumours.

The application of proteomics to the human alcoholic brain

Alcoholism results in changes in the human brain that reinforce the cycle of craving and dependency, and these changes are manifest in the pattern of expression of proteins in key cells and brain areas. Described here is a proteomics-based approach aimed at determining the identity of proteins in the superior frontal cortex (SFC) of the human brain that show different levels of expression in autopsy samples taken from healthy and long-term alcohol abuse subjects. Soluble protein fractions constituting pooled samples combined from SFC biopsies of four well-characterized chronic alcoholics (mean consumption > 80 g ethanol/day throughout adulthood) and four matched controls (< 20 g/day) were generated. Two-dimensional electrophoresis was performed in triplicate on alcoholic and control samples and the resultant protein profiles analyzed for differential expression. Overall, 182 proteins differed by the criterion of twofold or more between case and control samples. Of these, 139 showed significantly lower expression in alcoholics, 35 showed significantly higher expression, and 8 were new or had disappeared. To date, 63 proteins have been identified using MALDI-MS and MS-MS. The finding that the expression level of differentially expressed proteins is preponderantly lower in the alcoholic brain is supported by recent results from parallel studies using microarray mRNA transcript.

Selective loss of NMDA receptor NR1 subunit isoforms in Alzheimer's disease

Previous work had shown that the ratio of NMDA receptor NR1 subunit mRNA transcripts containing an N-terminal splice cassette to those that do not is markedly lower in regions of the Alzheimer's disease (AD) brain that are susceptible to pathological damage, compared with spared regions in the same cases or homotropic regions in controls. To elucidate the origins of this difference in proportionate expression, we measured the absolute levels of each of the eight NR1 transcripts by quantitative internally standardized RT-PCR assay. Expression of transcripts with the cassette was strongly attenuated in susceptible regions of Alzheimer's brain, whereas expression of non-cassette transcripts differed little from that in controls. The expression of other NR1 splice variants was not associated with pathology relevant to disease status, although some combinations of splice cassettes were well maintained in AD cases. The population profile of NR1 transcripts in occipital cortex differed from the profiles in other brain regions studied. Western analysis confirmed that the expression of protein isoforms containing the N-terminal peptide was very low in susceptible areas of the Alzheimer's brain. Cells that express NR1 subunits with the N-terminal cassette may be selectively vulnerable to toxicity in AD.

Gene expression in profiling in individual cases reveals consistent transcriptional changes in alcoholic human brain

Chronic alcohol exposure induces lasting behavioral changes, tolerance, and dependence. This results, at least partially, from neural adaptations at a cellular level. Previous genome-wide gene expression studies using pooled human brain samples showed that alcohol abuse causes widespread changes in the pattern of gene expression in the frontal and motor cortices of human brain. Because these studies used pooled samples, they could not determine variability between different individuals. In the present study, we profiled gene expression levels of 14 postmortem human brains (seven controls and seven alcoholic cases) using cDNA microarrays (46 448 clones per array). Both frontal cortex and motor cortex brain regions were studied. The list of genes differentially expressed confirms and extends previous studies of alcohol responsive genes. Genes identified as differentially expressed in two brain regions fell generally into similar functional groups, including metabolism, immune response, cell survival, cell communication, signal transduction and energy production. Importantly, hierarchical clustering of differentially expressed genes accurately distinguished between control and alcoholic cases, particularly in the frontal cortex.

Differential expression of N-methyl-D-aspartate receptor NR2 isoforms in Alzheimer's disease

We have previously shown that the expression of NMDA receptor NR1 subunit mRNA splice variants in Alzheimer's disease (AD) brain varies according to regional susceptibility to pathological damage. Here we investigated the expression of the modulatory NR2 subunits of the NMDA receptor using quantitative RT-PCR to assay all NR2 isoforms. Significantly lower expression of NR2A and NR2B transcripts was found in susceptible regions of AD brain, whereas expression of NR2C and NR2D transcripts did not differ from that in controls. Western blot analysis confirmed a lower expression of the NR2A and NR2B isoforms at the protein level. The results suggest that NR2 subunit composition may modulate NMDA receptor-mediated excitotoxicity. NMDA receptor dysfunction might give rise to the regionally selective pattern of neuronal loss that is characteristic of AD.

MMTV-trBrca 1 mice display strain-dependent abnormalities in vaginal development

The breast cancer susceptibility gene Brca1 encodes a large multi-functional protein which is implicated as a caretaker of the genome, through its role in regulation of DNA damage response pathways, including apoptosis. Here we show that in mice expressing a dominant-negative Brca1 transgene on a BALB/c background, vaginal entrance remodeling is inhibited, and that the incidence of this phenotype is increased on a p53 +/- genotype. Given that this developmental process is mediated primarily by apoptosis, we hypothesized that disruption of BRCA1 may confer a resistance to apoptosis in normal epithelial cells. Consistent with this, we show that expression of this transgene in vitro leads to resistance to ionizing radiation induced cell killing in mammary epithelial cells. This is the first time that BRCA1 has been implicated in an apoptosis-mediated normal developmental process.