title: Circadian variation in multiple sclerosis of oxidative stress marker of DNA damage. A potential cancer marker?
abstract: OBJECTIVE
  To investigate circadian rhythm (CR) of urinary creatinine and 8-hydroxy-2-deoxyguanosine (8-OHdG) in patients with Multiple Sclerosis (MS) and to present concentrations of this DNA damage marker, 5 years prior to mastectomy, in one MS study subject, and 2 years prior to biopsy confirmed a carcinoma (CA) of the prostate in one non-MS subject.
  
  
  METHODS
  Eleven subjects with MS (6 women 36-52 years of age and 5 men 51-68 years) volunteered for this study, carried out at Edward Hines Jr., Medical Center. Subjects were offered a general hospital diet (2400 cal in total/24h) at 16:30h, 07:30h and 13:00h. The dark (sleep) phase of the light-dark cycle extended from 22:30h to 06:30h with brief awakening for sampling at 01:00h, and 04:00h. Urine samples were collected for consecutive 3h spans beginning at 16:00-19:00h and were analyzed for creatinine and 8-OHdG. Twelve men (including 3 with type 2 diabetes) provided 21 profiles according to the same protocol used for comparison. In addition, 10 healthy women provided 24h urine samples. Statistical analysis of data was performed using the Single-Cosinor and Population-Mean Cosinor.
  
  
  RESULTS
  A CR was detected for creatinine in healthy men (p < 0.001) but not for MS patients. Urinary creatinine concentrations were lower in MS women than in healthy women (p = 0.015) and were lower in MS women than in men healthy or with MS (p < 0.001): Women; MS 655 +/- 76; H 1381 +/- 316; Men, MS 1830 +/- 285; H 1532 +/- 265 mg/24h vol. A CR was evident in 8-OHdG in MS (p = 0.007) and in non-MS subjects (p < 0.001) with highest values occurring at about 16:45h. The average concentrations of 8-OHdG in MS patients were similar to those in healthy subjects: Women, MS 589 +/- 125; H 794 +/- 318; Men, MS 504 +/- 156; H 591 +/- 134 picomoles/kg bw/24h vol. The 8-OHdG concentrations of a MS patient, later diagnosed with breast cancer, were found to exceed the upper 95% prediction limit in health. An increased 8-OHdG level was also noted in a non-MS subject who 2 years later received a biopsy-confirmed diagnosis of prostate CA.
  
  
  CONCLUSIONS
  Despite the small number of subjects in this study, a statistically significant CR was documented for 8-OHdG in urine of subjects with MS. Interestingly, the increased concentrations of DNA damage marker, the 8-OHdG, 5 years prior to mastectomy and the 2 years prior to affirmative diagnosis of prostate CA, could be the most significant clinical observations of this study. Follow-up studies of a larger population of subjects would, thus, be required to ascertain the predictive validity of such challenging observation.
authors.affiliation: Edward Hines Jr. Medical Center, Hines, IL 60141, USA. Eugene.Kanabrocki@med.va.gov
authors.forename: E L
authors.initials: EL
authors.lastname: Kanabrocki
authors.forename: M D
authors.initials: MD
authors.lastname: Ryan
authors.forename: D
authors.initials: D
authors.lastname: Murray
authors.forename: R W
authors.initials: RW
authors.lastname: Jacobs
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Hurder
authors.forename: N C
authors.initials: NC
authors.lastname: Friedman
authors.forename: G
authors.initials: G
authors.lastname: Siegel
authors.forename: B
authors.initials: B
authors.lastname: Eladasari
authors.forename: B A
authors.initials: BA
authors.lastname: Nemchausky
authors.forename: G
authors.initials: G
authors.lastname: Cornelissen
authors.forename: F
authors.initials: F
authors.lastname: Halberg
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000652:urine*; D016022:Case-Control Studies; D002940:Circadian Rhythm; D003404:Creatinine / Q000652:urine*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D009103:Multiple Sclerosis / Q000378:metabolism / Q000652:urine*; D018384:Oxidative Stress; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003404:Creatinine; D003849:Deoxyguanosine