Mitochondrial disorders share common cellular consequences: (1) decreased ATP production; (2) increased reliance on alternative anaerobic energy sources; and (3) increased production of reactive oxygen species. The purpose of the present study was to determine the effect of a combination therapy (creatine monohydrate, coenzyme Q(10), and lipoic acid to target the above-mentioned cellular consequences) on several outcome variables using a randomized, double-blind, placebo-controlled, crossover study design in patients with mitochondrial cytopathies. Three patients had mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), four had mitochondrial DNA deletions (three patients with chronic progressive external ophthalmoplegia and one with Kearns-Sayre syndrome), and nine had a variety of other mitochondrial diseases not falling into the two former groups. The combination therapy resulted in lower resting plasma lactate and urinary 8-isoprostanes, as well as attenuation of the decline in peak ankle dorsiflexion strength in all patient groups, whereas higher fat-free mass was observed only in the MELAS group. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction. Future studies with larger sample sizes in relatively homogeneous groups will be required to determine whether such combination therapies influence function and quality of life.

We examined the effects of increased levels of thioredoxin 1 (Trx1) on resistance to oxidative stress and aging in transgenic mice overexpressing Trx1 [Tg(TRX1)(+/0)]. The Tg(TRX1)(+/0) mice showed significantly higher Trx1 protein levels in all the tissues examined compared with the wild-type littermates. Oxidative damage to proteins and levels of lipid peroxidation were significantly lower in the livers of Tg(TRX1)(+/0) mice compared with wild-type littermates. The survival study demonstrated that male Tg(TRX1)(+/0) mice significantly extended the earlier part of life span compared with wild-type littermates, but no significant life extension was observed in females. Neither male nor female Tg(TRX1)(+/0) mice showed changes in maximum life span. Our findings suggested that the increased levels of Trx1 in the Tg(TRX1)(+/0) mice were correlated to increased resistance to oxidative stress, which could be beneficial in the earlier part of life span but not the maximum life span in the C57BL/6 mice.

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Purpose-Unexplained clinical conditions share common features, such as pain, fatigue, disability out of proportion to physical examination findings, inconsistent laboratory abnormalities, and an association with stress and psychosocial factors. In this literature review, we examine the extent of the overlap among urological and non-urological unexplained clinical conditions characterized by pain, note the limitations of previous research, and suggest several possible explanatory models.Materials & Methods-Using hallmark symptoms and syndromes as search terms, a search of 12 databases identified 1,037 full-length published articles in 8 languages from 1966 to April, 2008. The search focused on the overlap of chronic pelvic pain, interstitial cystitis, painful bladder syndrome, chronic prostatitis/chronic pelvic pain syndrome, or vulvodynia, with fibromyalgia, chronic fatigue syndrome, temporomandibular disorder, or irritable bowel syndrome. Information on authorship, type of case and control groups, eligibility criteria, case definitions, study methods, and major findings were abstracted.Results-The literature suggests considerable comorbidity between urological and non-urological unexplained clinical conditions. The most robust evidence for overlap was for irritable bowel syndrome and urological unexplained syndromes, with some estimates of up to 79% comorbidity between chronic pelvic pain and symptoms of irritable bowel syndrome. However, most studies were limited by methodological problems, such as varying case definitions and selection of control subjects. None of the authors have any conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript.Dr. Buchwald has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ms. Bullones Rodriguez made substantial contributions to the conception and design, acquisition of data, analysis and interpretation, drafting of the manuscript, and technical support. Dr. Afari made substantial contributions to conception and design, acquisition of data, analysis and interpretation, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and obtaining funding. Dr. Buchwald made substantial contributions to conception and design, critical revision of the manuscript, obtaining funding, and supervision. Conclusions-Overlap between urological and selected non-urological unexplained clinical conditions is substantial. Future research should focus on using standardized definitions and rigorously designed and well-controlled studies to further assess comorbidity, clarify the magnitude of the association, and examine common pathophysiological mechanisms. NIH Public Access