Current classification structures for dementia may not be adequate in diabetes, where mixed pathogenesis is likely. Further research into the mechanisms of cognitive impairment in Type 2 DM may allow us to challenge the concept of dementia, at least in these patients, as an irremediable disease.

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We identified two novel heteroplasmic mitochondrial DNA point mutations in the gene encoding the ND5 subunit of complex I: a 12770A-->G transition identified in a patient with MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and a 13045A-->C transversion in a patient with a MELAS/Leber's hereditary optic neuropathy/Leigh's overlap syndrome. Biochemical analysis of muscle homogenates showed normal or very mildly reduced complex I activity. Histochemistry was normal. Our observations add to the evidence that mitochondrial ND5 protein coding gene mutations frequently associate with the MELAS phenotype, and it highlights the role of complex I dysfunction in MELAS.

Mitochondrial encephalomyopathy and lactic acidosis with strokelike episodes (MELAS) is a severe young onset stroke disorder without effective treatment. We have identified a MELAS patient harboring a 13528A3 G mitochondrial DNA (mtDNA) mutation in the Complex I ND5 gene. This mutation was homoplasmic in mtDNA from patient muscle and nearly homoplasmic (99.9%) in blood. Fibroblasts from the patient exhibited decreased mitochondrial membrane potential (⌬ m ) and increased lactate production, consistent with impaired mitochondrial function. Transfer of patient mtDNA to a new nuclear background using transmitochondrial cybrid fusions confirmed the pathogenicity of the 13528A3 G mutation; Complex I-linked respiration and ⌬ m were both significantly reduced in patient mtDNA cybrids compared with controls. Inhibition of the adenine nucleotide translocase or the F 1 F 0 -ATPase with bongkrekic acid or oligomycin caused a loss of potential in patient mtDNA cybrid mitochondria, indicating a requirement for glycolytically generated ATP to maintain ⌬ m . This was confirmed by inhibition of glycolysis with 2-deoxy-Dglucose, which caused depletion of ATP and mitochondrial depolarization in patient mtDNA cybrids. These data suggest that in response to impaired respiration due to the mtDNA mutation, mitochondria consume ATP to maintain ⌬ m , representing a potential pathophysiological mechanism in human mitochondrial disease.Mitochondrial respiration is fundamental to the well being of most mammalian cells, since it provides the central mechanism that couples fuel and oxygen consumption to ATP synthesis. The mitochondrial respiratory chain resides at the inner membrane and consists of five multimeric enzyme complexes: I (NADH:ubiquinone oxidoreductase), II (succinate:ubiquinone oxidoreductase), III (ubiquinol:cytochrome c oxidoreductase), IV (cytochrome c oxidase), and V (F 1 F 0 -ATPase). Electrons donated from the tricarboxylic acid cycle to Complexes I and II are utilized by Complexes I, III, and IV to pump protons from the matrix to the intermembrane space. The resulting electrochemical potential gradient, normally expressed as a mitochondrial membrane potential (⌬ m ), 2 provides the energy to drive ATP synthesis by Complex V (1, 2).Mitochondria contain their own unique, double-stranded, circular genome, which encodes the 13 essential protein subunits of the respiratory complexes. It also encodes the 12 and 16 S rRNAs and the 22 tRNAs specific for mitochondrial protein synthesis. Mutations in mitochondrial DNA (mtDNA) are associated with a wide variety of multisystemic degenerative diseases (3). Aspects of central nervous system and muscle function are usually affected, whereas a number of mutations are also variably associated with deafness, diabetes, and optic nerve atrophy or retinal degeneration (2, 4). In many cases, the pathogenic mtDNA mutation associated with the respiratory defect has been assigned, but it is still unclear why different mtDNA mutations result in such a wide array of clinical phenotypes.Mitochondr...

Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including beta-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK ( P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.

The mitochondrial diseases encompass a diverse group of disorders that can exhibit various combinations of clinical features. Defects in mitochondrial DNA (mtDNA) have been associated with these diseases, and studies have been able to assign biochemical defects. Deficiencies in mitochondrial oxidative phosphorylation appear to be the main pathogenic factors, although recent studies suggest that other mechanisms are involved. Reactive oxygen species (ROS) generation has been implicated in a wide variety of neurodegenerative diseases, and mitochondrial ROS generation may be an important factor in mitochondrial disease pathogenesis. Altered apoptotic signaling as a consequence of defective mitochondrial function has also been observed in both in vitro and in vivo disease models. Our current understanding of the contribution of these various mechanisms to mitochondrial disease pathophysiology will be discussed.

The evidence suggests that there is a potential benefit in using phlebotonics in treating haemorrhoidal disease as well as a benefit in alleviating post-haemorrhoidectomy symptoms. Outcomes such as bleeding and overall symptom improvement show a statistically significant beneficial effect and there were few concerns regarding their overall safety from the evidence presented in the clinical trials.However methodological limitations were encountered. In order to enhance our conclusion further, more robust clinical trials which take into account these limitations will need to be performed in the future.

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