Biomedical subjects

Farhad F Shadan

Publications and source records attributed to Farhad F Shadan.

4 recordsLinked to original sources

PubMed2006

Circadian tempo: a paradigm for genome stability?

Circadian clocks are molecular time-keeping systems that underlie daily biological rhythms in anticipation of the changing light and dark cycles. These clocks mediate daily rhythms in physiology and behavior that are thought to confer an adaptive advantage for organisms. It is hypothesized that cell cycle checkpoints are gated to an intrinsic circadian clock to protect DNA from diurnal exposure to mutagens (e.g.; UV radiation peaks with daylight and dissolved genotoxins that fluctuate with feeding periods). It is proposed that DNA replication arrest in response to genotoxic stress is a likely basis for the evolution of circadian-gated DNA replication. This protective mechanism is highly conserved and can be traced along the evolutionary time-line to the early prokaryotes, unicellular eukaryotes and viruses. Peak DNA repair capacity is normally synchronous to the crest of mutagenic stress as they oscillate with respect to time. Mutator phenotypes with increased vulnerability to genotoxic stress may therefore develop when the circadian pattern of cell cycle control, DNA repair or apoptotic response are phase-shifted relative to the rhythm of mutagenic stress. The accumulating mutations would lead to accelerated aging, genome instability and neoplasia. The proposed model delineates areas of research with potentially profound implications for carcinogenesis.

Aging↗

PubMed2006

A circadian model for viral persistence.

Persistently infecting DNA viruses depend heavily on host cell DNA synthesis machinery. Replication of cellular and viral DNA is inhibited by mutagenic stress. It is hypothesized that diurnal regulation of viral DNA replication may occur at the level of cell cycle checkpoints and DNA repair, to protect DNA from exposure to UV light or other mutagens. This highly conserved mechanism is traced back to viruses that persist in prokaryotes and eukaryotes. Inhibition of viral DNA replication and the cell cycle in response to UV light may represent a functional building block in the evolution of circadian-gated DNA replication. Viral DNA replication appears to be closely linked to the circadian clock by interaction of viral promoters, early viral proteins and transcription factors. It is proposed here that under certain conditions viral oncogene expression is phase-shifted relative to that of tumor suppressor and DNA repair genes. The resulting desynchrony of checkpoint controls and DNA repair from diurnal genotoxic exposure produces cyclic periods of suboptimal response to DNA damage. This temporal vulnerability to genotoxic stress produces a "mutator phenotype" with inherent genome instability. The proposed model delineates areas of research with implications for viral pathogenesis and therapeutics.

Cell Cycle↗

PubMed2006

Melatonin effects on luteinizing hormone in postmenopausal women: a pilot clinical trial NCT00288262.

BACKGROUND: In many mammals, the duration of the nocturnal melatonin elevation regulates seasonal changes in reproductive hormones such as luteinizing hormone (LH). Melatonin's effects on human reproductive endocrinology are uncertain. It is thought that the same hypothalamic pulse generator may both trigger the pulsatile release of GnRH and LH and also cause hot flashes. Thus, if melatonin suppressed this pulse generator in postmenopausal women, it might moderate hot flashes. This clinical trial tested the hypothesis that melatonin could suppress LH and relieve hot flashes. METHODS: Twenty postmenopausal women troubled by hot flashes underwent one week of baseline observation followed by 4 weeks of a randomized controlled trial of melatonin or matched placebo. The three randomized treatments were melatonin 0.5 mg 2.5-3 hours before bedtime, melatonin 0.5 mg upon morning awakening, or placebo capsules. Twelve of the women were admitted to the GCRC at baseline and at the end of randomized treatment for 24-hour sampling of blood for LH. Morning urine samples were collected twice weekly to measure LH excretion. Subjective responses measured throughout baseline and treatment included sleep and hot flash logs, the CESD and QIDS depression self-ratings, and the SAFTEE physical symptom inventory. RESULTS: Urinary LH tended to increase from baseline to the end of treatment. Contrasts among the 3 randomized groups were statistically marginal, but there was relative suppression combining the groups given melatonin as contrasted to the placebo group (p < 0.01 one-tailed, Mann-Whitney U = 14). Similar but not significant results were seen in blood LH. There were no significant contrasts among groups in hot flashes, sleep, depression, or side-effect measures and no significant adverse effects of any sort. CONCLUSION: The data are consistent with the hypothesis that melatonin suppresses LH in postmenopausal women. An effect related to the duration of nocturnal melatonin elevation is suggested. Effects of melatonin on reproductive endocrinology should be studied further in younger women and in men. Larger studies of melatonin effects on postmenopausal symptoms would be worthwhile.

Journal Article↗

PubMed2004

Zolpidem for postanoxic spasticity.

A 28-year-old male sustained anoxic brain damage following aborted cardiac arrest, and subsequently developed severe muscular rigidity and spasticity involving all extremities. The spasticity was refractory to the standard regimens used for spastic hypertonia. Zolpidem dramatically inhibited muscular rigidity, spasticity, and dystonic posturing in a dose-dependent manner, resulting in a sustained improvement of his global performance over four years. The authors postulate a central mechanism of action by selective inhibition of GABAergic inhibitory neurons, and suggest a controlled clinical study to investigate the potential efficacy of zolpidem in relieving spasticity related to postanoxic brain injury.

Adult↗