https://www.cns.nyu.edu/~david/courses/sm12/Readings/Tracey_Mantya-Neuron2007.pdf

The Cerebral Signature for Pain Perception and Its Modulation

Background: Melatonin shows poten-tial oncostatic action,and light expo-sure during night suppresses melatoninproduction. There is little information,however,about the direct effect ofnight work on the risk of cancer. Weinvestigated the effect of night work inbreast cancer. Methods: We examinedthe relationship between breast cancerand working on rotating night shiftsduring 10 years of follow-up in 78562women from the Nurses’ Health Study.Information was ascertained in 1988about the total number of years duringwhich the nurses had worked rotatingnight shifts with at least three nightsper month. From June 1988 throughMay 1998,we documented 2441 inci-dent breast cancer cases. Logistic re-gression models were used to calculaterelative risks (RRs) and 95% confi-dence intervals (CIs),adjusted for con-founding variables and breast cancerrisk factors. All statistical tests weretwo-sided. Results: We observed a mod-erate increase in breast cancer riskamong the women who worked 1–14years or 15–29 years on rotating nightshifts (multivariate adjusted RR = 1.08[95% CI = 0.99 to 1.18] and RR = 1.08[95% CI = 0.90 to 1.30],respectively).The risk was further increased amongwomen who worked 30 or more yearson the night shift (RR = 1.36; 95% CI =1.04 to 1.78). The test for trend was sta-tistically significant ( P = .02).Conclu-sions: Women who work on rotatingnight shifts with at least three nightsper month,in addition to days and eve-nings in that month,appear to have amoderately increased risk of breastcancer after extended periods of work-ing rotating night shifts. [J Natl CancerInst 2001;93:1563–8]The suprachiasmatic nucleus in the hy-pothalamus, one of the most importantphysiologic determinants of alertness andperformance, drives a circadian pace-maker in mammals, with an intrinsic pe-riod averaging 24 hours. Light is the pri-mary stimulus to disrupt and reset thispacemaker, which is expressed in chang-ing melatonin rhythms. Light exposure atnight may, therefore, be related to a vari-ety of behavioral changes and associatedhealth problems not yet well explored.Studies (1)have suggested an increasedrisk of coronary heart disease among ro-tating night shift workers, not fully ex-plained by an increased prevalence ofcoronary risk factors. Others have linkednight work to an increased breast cancerrisk among women (2).Melatonin, the “hormone of the dark-ness,” has only recently gained substantialattention from the scientific communitywith regard to its potential oncostatic ac-tions and its possible effect on breast can-cer risk (3–10).Melatonin serum levels inhumans decrease when people are ex-posed to light at night (11).Suppressedserum melatonin levels might enhance tu-mor development (12).Observationalstudies (2,13–15)are compatible with aneffect of melatonin on breast cancer risk,reporting meaningful increases in breastcancer risk among postmenopausal womenexposed to shiftwork. Recently, a tumor-promoting effect of light exposure wasdemonstrated on chemically induced tu-mors in rodents (16).To date, melatoninhas been shown to be oncostatic for a va-riety of tumor cells in experimental car-cinogenesis (17–26).The evidence of arelation between melatonin and oncogen-esis in humans is conflicting (27),butthe majority of reports indicate protectiveaction (28).Several mechanisms have been hy-pothesized to explain an association be-tween melatonin and breast cancer. Cohenet al. (29)proposed that loss of pinealfunction and the resulting decreased mel-atonin serum levels may increase repro-ductive hormone levels and, in particular,estradiol levels, thereby increasing thegrowth and proliferation of hormone-sensitive cells in the breast. More recentresearch focuses on potential mechanismsthrough which melatonin is directly onco-static. Melatonin is believed to have anti-mitotic activity by affecting directly hor-mone-dependent proliferation throughinteraction with nuclear receptors (4).An-other explanation is that melatonin in-creases the expression of the tumor sup-pressor gene p53 (3).Cells lacking p53have been shown to be genetically un-stable and thus more prone to tumors (30).Breast cancer is the most common can-cer among women in the United States.To date, the relationship between nightwork and breast cancer risk has not beenevaluated in prospective cohort studies. Acausal link between the two would be ofpublic health importance, because smallchanges in shift patterns may create a sub-stantial decrease of disease burden amongwomen.In this report, we evaluate the relation-ship between night work, as a surrogatefor light exposure at night, and breastcancer risk in a large prospective cohortof premenopausal and postmenopausalwomen. Our analysis is based on 10 yearsof follow-up in 78562 women participat-ing in the Nurses’ Health Study.

Rotating Night Shifts and Risk of Breast Cancer in Women Participating in the Nurses' Health Study

The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions.

A 28-year-old woman presents with a 7-month history of recurrent, crampy pain in the left lower abdominal quadrant, bloating with abdominal distention, and frequent, loose stools. She reports having had similar but milder symptoms since childhood. She spends long times in the bathroom because she is worried about uncontrollable discomfort and fecal soiling if she does not completely empty her bowels before leaving the house. She feels anxious and fatigued and is frustrated that her previous physician did not seem to take her distress seriously. Physical examination is unremarkable except for tenderness over the left lower quadrant. How should her case be evaluated and treated?

/pdf/irritable-bowel-syndrome-4cbjzv3crp.pdf

Irritable bowel syndrome

Since poly-ADP ribose was discovered over 40 years ago, there has been significant progress in research into the biology of mono- and poly-ADP-ribosylation reactions. During the last decade, it became clear that ADP-ribosylation reactions play important roles in a wide range of physiological and pathophysiological processes, including inter- and intracellular signaling, transcriptional regulation, DNA repair pathways and maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis. ADP-ribosylation reactions are phylogenetically ancient and can be classified into four major groups: mono-ADP-ribosylation, poly-ADP-ribosylation, ADP-ribose cyclization, and formation of O-acetyl-ADP-ribose. In the human genome, more than 30 different genes coding for enzymes associated with distinct ADP-ribosylation activities have been identified. This review highlights the recent advances in the rapidly growing field of nuclear mono-ADP-ribosylation and poly-ADP-ribosylation reactions and the distinct ADP-ribosylating enzyme families involved in these processes, including the proposed family of novel poly-ADP-ribose polymerase-like mono-ADP-ribose transferases and the potential mono-ADP-ribosylation activities of the sirtuin family of NAD+-dependent histone deacetylases. A special focus is placed on the known roles of distinct mono- and poly-ADP-ribosylation reactions in physiological processes, such as mitosis, cellular differentiation and proliferation, telomere dynamics, and aging, as well as “programmed necrosis” (i.e., high-mobility-group protein B1 release) and apoptosis (i.e., apoptosis-inducing factor shuttling). The proposed molecular mechanisms involved in these processes, such as signaling, chromatin modification (i.e., “histone code”), and remodeling of chromatin structure (i.e., DNA damage response, transcriptional regulation, and insulator function), are described. A potential cross talk between nuclear ADP-ribosylation processes and other NAD+-dependent pathways is discussed.

https://mmbr.asm.org/content/mmbr/70/3/789.full.pdf

Nuclear ADP-Ribosylation Reactions in Mammalian Cells: Where Are We Today and Where Are We Going?

Tonic pain response in mice: effects of sex, season and time of day.

Diurnal variations in tonic pain reactions in mice.

Treatment with the cytotoxic antitumor drug cyclophosphamide is highly effective in mice bearing Lewis lung carcinoma, causing the absence of macroscopically detectable tumors at necroscopy after sacrifice. When the effects of the treatment on survival are determined, a significant increase in survival time and in the proportion of long-term survivors is observed. When restraint stress is further applied, tumors develop in all of the mice treated with cyclophosphamide, and survival time and the fraction of long-term survivors are significantly reduced. Flow cytometry of splenic T-lymphocyte subsets in normal mice indicates a significant decrease in the number of CD3+, CD4+, and CD8+ subsets after treatment with cyclophosphamide and after application of restraint stress; the interaction of the two treatments is significant for CD3+ and marginally significant for CD4+ subsets. The attenuation by restraint stress which was observed for the effects of cyclophosphamide on the presence of tumors at necroscopy and for the survival of the treated mice might thus be interpreted as follows: restraint stress attenuates the immune functions of the host directed toward the weakly immunogenic tumor, an effect which, in the absence of restraint stress, interacts effectively with the cytotoxic action of cyclophosphamide toward tumor cells. The results obtained using this animal model thus indicate that experimental stress reduces the therapeutic efficacy of a cytotoxic antitumor drug; experimental and clinical implications are discussed.

Restraint stress reduces the antitumor efficacy of cyclophosphamide in tumor-bearing mice.

Diurnal variations in tonic pain reactions have been described in mice tested in Spring, but the underlying mechanisms are still unknown. We tested the potential role of melatonin, a key hormone in the control of neuro-endocrine circadian rhythms. The experiments were performed in male CBA/J mice housed under controlled temperature, humidity, and light (12/12 dark/light cycle) conditions, during the Light (7-10a.m.) or Dark (7-10p.m.) phases of the diurnal cycle. In a first group of experiments, animals were either pretreated with i.p. saline (controls) or with the melatonin receptor antagonist, luzindole (30 mg/kg), before the s.c. injection of a dilute formalin solution into a hindpaw. In control animals, pain-related behavioral reactions (licking and flinching) were higher in the evening (Dark) than in the morning (Light), both during the first (0-10 min) and the second (11-55 min) phase of the response to s.c. formalin. In animals pre-treated with luzindole, no diurnal changes occurred, pain reactions in the Dark being similar to those of the Light Control group. In a second group of experiments, artificial pinealectomy, obtained by exposing animals to continuous light for 48 h, also reduced pain reactions in the evening to levels comparable to those in the morning. Receptor autoradiography showed lower binding availability at spinal cord level in mice sacrificed during the Dark, as expected from the circadian pattern of melatonin secretion. A further significant decrease of melatonin receptor binding was induced by noxious stimulation. These results suggest a proalgesic role of endogenous melatonin in tonic pain.

Diurnal changes of tonic nociceptive responses in mice: evidence for a proalgesic role of melatonin.

Melatonin decreases bone marrow and lymphatic toxicity of adriamycin in mice bearing TLX5 lymphoma

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