Can reduced folic acid and vitamin B12 levels cause deficient DNA methylation producing mutations which initiate atherosclerosis?

Atherosclerosis of the vascular system has classically been attributed to elevated serum cholesterol concentrations. Recently, it has been found that reduced serum levels of folic acid, vitamin B12, and vitamin B6 are related to the etiology of atherosclerosis and coronary heart disease. These deficiencies lead to inadequate production of S-adenosyl-methionine, creating a condition of hypomethylation. It is hypothesized that this causes hypomethylation of the DNA in cells in the arterial intima resulting in mutation and proliferation of smooth-muscle cells which lead to the formation of atheroma. It is further hypothesized that such action can be reversed by supraphysiological doses of these three vitamins to reduce or remove existing atheroma. It is recommended that all patients suffering from atherosclerosis and having deficiencies of any of these three vitamins and/or an elevation of serum homocysteine receive supplementation to prevent worsening of their condition.     

Pathogenic mitochondrial tRNA mutations – Which mutations are inherited and why?

Mitochondrial transfer RNA (mt-tRNA) mutations are the commonest mitochondrial (mtDNA) mutations to cause human disease. The majority of mt-tRNA mutations are heteroplasmic and while some exhibit maternal transmission within families, many others are only seen as sporadic mutations. Using the available clinical, biochemical and genetic data from published pathogenic mt-tRNA mutations, we have explored several different factors thought to influence the transmission of mt-tRNA mutations. Our data show that the most important factor in predicting whether a mutation is transmitted to offspring is whether the mt-tRNA mutation is selected against in a rapidly replicating tissue such as blood. This suggests that those mt-tRNA mutations which exert a major phenotype in dividing cells are unlikely to be inherited. This is entirely compatible with recent observations on the mitochondrial genetic bottleneck in early development and has important implications for families with mt-tRNA disease. © 2009 Wiley-Liss, Inc.     

How do MYBPC3 mutations cause hypertrophic cardiomyopathy?

It is well established that MYBPC3 mutations are the most common cause of hypertrophic cardiomyopathy, accounting for about half of identified mutations. However, when compared with mutations in other myofibrillar proteins that cause hypertrophic cardiomyopathy, MYBPC3 mutations seem to be the odd one out. The most striking characteristic of HCM mutations in MYBPC3 is that many are within introns and are predicted to cause aberrant splicing leading to a frameshift and a premature chain termination, yet the truncated peptides have never been identified in human heart tissue carrying these mutations. Instead of expression of a poison peptide we consistently observe haploinsufficiency of MyBP-C in MYBPC3 mutant human heart muscle. In this review we investigate the mechanism for MyBP-C haploinsufficiency and consider how this haploinsufficiency could cause hypertrophic cardiomyopathy.     

Does prohibitin expression regulate sperm mitochondrial membrane potential, sperm motility, and male fertility?

Prohibitin (PHB) is a highly conserved major sperm mitochondrial membrane protein whose absence in somatic cells is associated with mitochondrial membrane depolarization and increased generation of reactive oxygen species (ROS). Our recent findings suggest that high levels of oxidants in human semen may contribute to male infertility and that sperm motility could be the earliest and most sensitive indicator of oxidative damage. Based on PHB's roles in mitochondrial sub-compartmentalization and respiratory chain assembly, we examine sperm PHB expression and mitochondrial membrane potential (MITO) in infertile men with poor sperm motility (asthenospermia, A) and/or low sperm concentrations (oligoasthenospermia, OA). Here, we demonstrate that MITO is significantly lower in sperm from A and OA subjects than in normospermic (N) subjects; the decrease is more severe for OA than for A subjects. PHB expression is also significantly lower in sperm from A and OA subjects. Significantly positive correlations are found among PHB expression, MITO, and sperm motility in normospermic, asthenospermic, and oligoasthenospermic subjects. Collectively, our observations lead to the hypothesis that PHB expression is an indicator of sperm quality in infertile men, and that it regulates sperm motility via an alteration in MITO and increased ROS levels.     

Can phages cause Alzheimer’s disease?

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with progressive dementia. Multiple processes have been implicated in AD, notably including abnormal beta-amyloid production, tau hyperphosphorylation and neurofibrillary tangles (NFTs), synaptic pathology, oxidative stress, inflammation, protein processing or misfolding, calcium dyshomeostasis, aberrant reentry of neurons into the cell cycle, cholesterol synthesis, and effects of hormones or growth factors. The complexity of the disease, which affects numerous molecules, cells, and systems and impedes attempts to determine which alterations are specifically associated with early pathology. Chlamydia pneumoniae is an obligate intracellular bacterium. Infection with this organism has been suggested to be a risk factor for AD. C. pneumoniae has two phages phiCPAR39 and phage related to phiCPG1. HYPOTHESIS: we propose that these two phages by entering into mitochondria of chlamydia's host cell can work as slow viruses and can initiate AD.     

Is mitochondrial DNA depletion involved in Alzheimer's disease?

Several studies have suggested that mitochondrial metabolism disturbances and mitochondrial DNA (mtDNA) abnormalities may contribute to the progression of the pathology of Alzheimer's disease (AD).In this study we have investigated whether the amount of mtDNA is modified in different brain regions (cerebellum, hippocampus and frontal cortex) of confirmed AD necropsies and in blood of living AD patients. We used a real-time PCR method to analyse the mtDNA relative abundance in brain regions from 12 AD and seven controls and from a group of blood samples (17 living AD patients and 11 controls). MtDNA from blood samples together with hippocampus and cerebellum brain areas did not show differences between controls and AD. However, AD patients showed a 28% decrease in the amount of mtDNA in the frontal cortex when compared to controls for this specific area. Since frontal cortex is a severely affected region in AD, our results support the hypothesis that mitochondrial defects may play a role in the pathogenesis of AD.     

More evidence for non-maternal inheritance of mitochondrial DNA?

Background: A single case of paternal co-transmission of mitochondrial DNA (mtDNA) in humans has been reported so far. Objective: To find potential instances of non-maternal inheritance of mtDNA. Methods: Published medical case studies (of single patients) were searched for irregular mtDNA patterns by comparing the given haplotype information for different clones or tissues with the worldwide mtDNA database as known to date—a method that has proved robust and reliable for the detection of flawed mtDNA sequence data. Results: More than 20 studies were found reporting clear cut instances with mtDNAs of different ancestries in single individuals. As examples, cases are reviewed from recent published reports which, at face value, may be taken as evidence for paternal inheritance of mtDNA or recombination. Conclusions: Multiple types (or recombinant types) of quite dissimilar mitochondrial DNA from different parts of the known mtDNA phylogeny are often reported in single individuals. From re-analyses and corrigenda of forensic mtDNA data, it is apparent that the phenomenon of mixed or mosaic mtDNA can be ascribed solely to contamination and sample mix up.     

Can nuchal cord cause transient increased nuchal translucency thickness?

When detected in a first trimester scan, an increased thickness of nuchal translucency (NT) may be associated with chromosomal, cardiac or genetic disorders. However, less attention has been devoted to the outcome of those fetuses who have confirmed normal anatomies and karyotyping, but have abnormal first trimester scans. Thus, a challenging new issue is how to counsel such cases of transient increased NT in which the translucency rapidly vanishes with no evidence of other underlying abnormalities. Two cases of transient increased thickness of NT are reported. In both, a nuchal cord was ultrasonographically demonstrated and a thorough work-up revealed chromosomally and anatomically normal fetuses. The pathophysiological theories behind these observations and their significance are discussed. Based on these observations, we suggest that transvaginal sonography combined with Doppler flow studies should be utilized for the presize detection of cord patterns to accomplish the work-up in cases of increased NT.     

Can oral levofloxacin cause of flexor digitorum profundus rupture?

Fluoroquinolones are broad-spectrum antibacterial agents. Reports of Achilles tendon rupture as a possible side effect of the quinolones have been previously presented but mechanism of the side effect of the medication is still unknown. Tendon rupture in the forearm associated with fluoroquinolone use has not been reported. We present a patient who underwent levofloxacin treatment for skin infections and subsequently developed left small finger flexor digitorum profundus rupture. We propose that this rupture may be related to the side effect of the medication. If it is, clinicians have to be aware of possible tendon ruptures in the upper extremity due to side effects of quinolones and patients have to be informed about it.     

Can traditional “cupping” treatment cause a stroke?

The case study of a patient who developed haemorrhagic stroke after ‘cupping’ to the cervical area is presented. We consider the various manners in which cupping might induce haemorrhagic or ischemic stroke with particular reference to the relevant pathologies of the major cervical arteries. The other possible causes due to the induced cupping stresses are also examined using a computer based simulation study. Cupping of the cervical area may cause a haemorrhagic stroke by an acute rise in blood pressure. The tensile radial stresses generated by cupping may potentially facilitate the development of a dissection in the presence of an intimal tear. Moreover, the possible presence of micro-inclusions can intensify the local stress concentration for a thin cap.     

Do cell junction protein mutations cause an airway phenotype in mice or humans?

Cell junction proteins connect epithelial cells to each other and to the basement membrane. Genetic mutations of these proteins can cause alterations in some epithelia leading to varied phenotypes such as deafness, renal disease, skin disorders, and cancer. This review examines if genetic mutations in these proteins affect the function of lung airway epithelia. We review cell junction proteins with examples of disease mutation phenotypes in humans and in mouse knockout models. We also review which of these genes are expressed in airway epithelium by microarray expression profiling and immunocytochemistry. Last, we present a comprehensive literature review to find the lung phenotype when cell junction and adhesion genes are mutated or subject to targeted deletion. We found that in murine models, targeted deletion of cell junction and adhesion genes rarely result in a lung phenotype. Moreover, mutations in these genes in humans have no obvious lung phenotype. Our research suggests that simply because a cell junction or adhesion protein is expressed in an organ does not imply that it will exhibit a drastic phenotype when mutated. One explanation is that because a functioning lung is critical to survival, redundancy in the system is expected. Therefore mutations in a single gene might be compensated by a related function of a similar gene product. Further studies in human and animal models will help us understand the overlap in the function of cell junction gene products. Finally, it is possible that the human lung phenotype is subtle and has not yet been described.     

Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hürthle cell tumors

In an attempt to progress in the understanding of the relationship of mitochondrial DNA (mtDNA) alterations and thyroid tumorigenesis, we studied the mtDNA in 79 benign and malignant tumors (43 Hürthle and 36 non-Hürthle cell neoplasms) and respective normal parenchyma. The mtDNA common deletion (CD) was evaluated by semiquantitative polymerase chain reaction. Somatic point mutations and sequence variants of mtDNA were searched for in 66 tumors (59 patients) and adjacent parenchyma by direct sequencing of 70% of the mitochondrial genome (including all of the 13 OXPHOS system genes). We detected 57 somatic mutations, mostly transitions, in 34 tumors and 253 sequence variants in 59 patients. Follicular and papillary carcinomas carried a significantly higher prevalence of non-silent point mutations of complex I genes than adenomas. We also detected a significantly higher prevalence of complex I and complex IV sequence variants in the normal parenchyma adjacent to the malignant tumors. Every Hürthle cell tumor displayed a relatively high percentage (up to 16%) of mtDNA CD independently of the lesion's histotype. The percentage of deleted mtDNA molecules was significantly higher in tumors with D-loop mutations than in mtDNA stable tumors. Sequence variants of the ATPase 6 gene, one of the complex V genes thought to play a role in mtDNA maintenance and integrity in yeast, were significantly more prevalent in patients with Hürthle cell tumors than in patients with non-Hürthle cell neoplasms. We conclude that mtDNA variants and mtDNA somatic mutations of complex I and complex IV genes seem to be involved in thyroid tumorigenesis. Germline polymorphisms of the ATPase 6 gene are associated with the occurrence of mtDNA CD, the hallmark of Hürthle cell tumors.