Expression of melatonin receptors in triple negative breast cancer (TNBC) in African American and Caucasian women: relation to survival.

In the normal rodent breast, the pineal hormone melatonin controls the development of ductal and alveolar tissue. Melatonin counteracts tumor occurrence and tumor cell progression in vivo and in vitro in animal and human breast cancer cell cultures. It acts predominantly through its melatonin MT1 receptor. Our aim was to investigate the presence or absence of the MT1 melatonin receptor in the aggressive triple negative group of human breast carcinoma (TNBC) and its possible relationship to the course of the disease. A total of 167 patients with a ER-, PR-, Her-2/neu- phenotype in which tissue for receptor studies was available were examined. The MT1 receptor immunostain was evaluated semiquantitatively as staining intensity (0, 1, 2, 3), percentage of stained cells and the weighted index (WI) (staining intensity times percentage of stained cells). A score of WI < 60 was regarded as "negative". There was a striking difference in incidence of MT1 positivity and staining intensity between carcinomas in African American (AA) and Caucasian (C) women. The AA showed a higher incidence of MT1 negative tumors (41/84 = 48.8 % in AA, 6/51 = 11.8 % in C) and a lower average WI. MT1 positivity in TNBC was associated with a lower stage and a smaller tumor size at time of diagnosis. In multivariable survival analysis, MT1 negative TNBC in all cases regardless of race showed a significantly higher hazard ratio for disease progression, shorter progression free survival, and disease-related death, and shorter OS. This was especially pronounced in the AA group but did not reach statistical significance in the smaller group of C alone. These results suggest that melatonin or a melatonin receptor agonist may be useful biologic additions in the treatment of some forms of TNBC, especially in AA who generally show a more aggressive course of their disease.

Acute exposure to 50-Hz magnetic fields increases interleukin-6 in young healthy men.

Some epidemiologic studies have suggested that extremely low frequency magnetic fields might affect human health and, in particular, that the incidence of certain types of cancer might increase among individuals living or working in environments exposed to such fields. This study is part of a broad study we conducted in humans. The study presented here was designed to look for possible effects of acute exposure to 50-Hz magnetic fields (10 µT) on the interleukin 1 beta (IL-1ß), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA), and the interleukin-2 receptor (IL-2R) production. Thirty-two young men (20-30 years old) were divided into two groups (sham-exposed or control group and exposed group) of 16 subjects each. All subjects participated in two 24-h experiments to evaluate the effects of both continuous and intermittent (1 h "off" and 1 h "on" with the field switched "on" and "off" every 15 s) exposure to linearly polarized magnetic fields. The subjects were exposed to the magnetic field from 2300 to 0800 while recumbent. Blood samples were collected during each session at 11:00, 17:00, 22:00, 01:00, 04:00, 06:00, and 08:00. Results showed that exposure to 50-Hz magnetic fields (10 µT) significantly increases IL-6 when subjects were exposed to an intermittent magnetic field. However, no effect has been observed on interleukin IL-1ß, IL-2, IL-1RA, and IL-2R.

Considerations of circadian impact for defining 'shift work' in cancer studies: IARC Working Group Report.

Based on the idea that electric light at night might account for a portion of the high and rising risk of breast cancer worldwide, it was predicted long ago that women working a non-day shift would be at higher risk compared with day-working women. This hypothesis has been extended more recently to prostate cancer. On the basis of limited human evidence and sufficient evidence in experimental animals, in 2007 the International Agency for Research on Cancer (IARC) classified 'shift work that involves circadian disruption' as a probable human carcinogen, group 2A. A limitation of the epidemiological studies carried out to date is in the definition of 'shift work.' IARC convened a workshop in April 2009 to consider how 'shift work' should be assessed and what domains of occupational history need to be quantified for more valid studies of shift work and cancer in the future. The working group identified several major domains of non-day shifts and shift schedules that should be captured in future studies: (1) shift system (start time of shift, number of hours per day, rotating or permanent, speed and direction of a rotating system, regular or irregular); (2) years on a particular non-day shift schedule (and cumulative exposure to the shift system over the subject's working life); and (3) shift intensity (time off between successive work days on the shift schedule). The group also recognised that for further domains to be identified, more research needs to be conducted on the impact of various shift schedules and routines on physiological and circadian rhythms of workers in real-world environments.

Schedule shifts, cancer and longevity: good, bad or indifferent?

Prompted by a recent report of the possible carcinogenic effect of shiftwork focusing on the disruption of circadian rhythms, we review studies involving shifts in schedule implemented at varying intervals in unicells, insects and mammals, including humans. Results indicate the desirability to account for a broader-than-circadian view. They also suggest the possibility of optimizing schedule shifts by selecting intervals between consecutive shifts associated with potential side-effects such as an increase in cancer risk. Toward this goal, marker rhythmometry is most desirable. The monitoring of blood pressure and heart rate present the added benefit of assessing cardiovascular disease risks resulting not only from an elevated blood pressure but also from abnormal variability in blood pressure and/or heart rate of normotensive as well as hypertensive subjects.

Chronobiology of hemostasis and inferences for the chronotherapy of coagulation disorders and thrombosis prevention.

The hemostatic system in its multiple components displays an intricate organization in time which is characterized by circadian (approximately 24-hour), circaseptan (approximately 7-day), menstrual (approximately monthly), and circannual (approximately yearly) bioperiodicities. The interaction of the rhythms of the variables participating in hemostasis determine transient risk states of thromboembolic events, including myocardial infarction and stroke, and of hemorrhage and hemorrhagic events, each with a unique timing. The circadian staging of the rhythms in vascular, cellular, and coagulation factors that favors blood coagulation and thrombosis coincides with the daily minimum in fibrinolytic activity; as a result there is elevated risk in the morning of acute myocardial infarction and stroke. Similar hemostatic rhythms may determine the epidemiology of thromboembolic and hemorrhagic events during the week, month and year. This article focuses on the large-amplitude circadian rhythms operative in the hemostatic system. Their implication for preventive and curative pharmacotherapy of hemostatic disorders is presented, with discussion of related problems.

Chronobiology in the endocrine system.

Biological signaling occurs in a complex web with participation and interaction of the central nervous system, the autonomous nervous system, the endocrine glands, peripheral endocrine tissues including the intestinal tract and adipose tissue, and the immune system. All of these show an intricate time structure with rhythms and pulsatile variations in multiple frequencies. Circadian (about 24-hour) and circannual (about 1-year) rhythms are kept in step with the cyclic environmental surrounding by the timing and length of the daily light span. Rhythmicity of many endocrine variables is essential for their efficacy and, even in some instances, for the qualitative nature of their effects. Indeed, the continuous administration of certain hormones and their synthetic analogues may show substantially different effects than expected. In the design of drug-delivery systems and treatment schedules involving directly or indirectly the endocrine system, consideration of the human time organization is essential. A large amount of information on the endocrine time structure has accumulated, some of which is discussed in this review.

Possible linkage between the ability to change the period (tau) of the prolactin and cortisol rhythms in women and breast cancer risk.

The 24 h profiles of plasma hormone concentrations are rhythmic. The circadian period (tau) changes in development, with seasons, and in women with different stages of the menstrual cycle. It is known that the rhythms of prolactin and cortisol are sensitive to environmental time cues, such as changes in day length and phase; however, the importance of these changes is not yet understood. This study investigates whether there is a relation between the ability of a subject to respond to external cues that are associated with seasonal changes causing alteration of the rhythm's periods in cortisol and prolactin and the epidemiologically determined susceptibility to breast cancer. It is shown that the rhythmic output pattern of prolactin and cortisol in vivo is generated by more than one oscillator and structured by more than one rhythmic component. Each cohort of American women, classified on an epidemiologic basis as high risk (HR) or low risk (LR) to develop breast cancer, expresses different rhythmic output patterns of both variables, suggesting that the genetic background as defined by the risk state is related to differences in the circadian time structure, including the ability of the subject to change the rhythm's tau. The LR cohort exhibited a statistically significant change between seasons in the rhythm's tau of both the prolactin and cortisol patterns. In contrast, the HR cohort showed no change in the rhythm's tau between seasons for prolactin and cortisol patterns. These results show that in human beings, the presence of a circannual rhythm in the circadian time structure or the ability to adapt the circadian rhythmic pattern of these variables to external cues, such as seasons, is related to the partly genetically determined risk state to develop breast cancer and may be of importance for human health.

Risk of obesity in male shift workers: A chronophysiological approach.

AIMS: Why are some healthy male shift workers (SWers) overweight [body mass index (BMI) >25 and <30] if not obese (BMI >30)? Seven risk factors potentially causing overweight and obesity were evaluated, namely (1) age, (2) physical/sports activity, (3) length of exposure to shift work (SW), (4) speed of shift rotation, (5) tolerance to SW, (6) internal desynchronization of circadian rhythms and (8) night eating (nocturnal nibbling). "New" as well as "old" data, acquired from longitudinal and individual time series of 5-56 days recording span, were reanalyzed. The data were analyzed from a set of field studies of 67 SWers and 53 non-shift workers (non-SWers). To estimate the respective weight of these factors, a multiple regression analysis (MRA) was used among other statistical tools. A similar age-related increase in BMI was validated (with p < 0.001) in both SWers and non-SWers. However, in SWers, desynchronization of rhythms increases the effect of age on BMI. Length of exposure to SW, tolerance to SW and speed of rotation do not seem to play a role as risk factors. Major effects are likely to relate to a sedentary lifestyle (lack of regular physical or sport activities) (MRA with p < 0.01), as well as, presumably, to a nocturnal nibbling of carbohydrates, which mimics the night eating syndrome.

Biological rhythms, medication safety, and women's health.

Biological processes and functions in women are well organized in time, as evidenced by the expression of ultradian (high frequency), circadian ( approximately 24-hour), circamensual ( approximately monthly), and circannual ( approximately yearly) rhythms and by the changes that occur with menarche, reproduction, and menopause. Attributes of women's circamensual structure have been explored in depth, particularly with regard to fertility/infertility and birth control. However, the role of 24-hour and other rhythms in health, disease, and treatment has been little studied. The symptom intensity of a variety of chronic medical conditions is rhythmic, as is the risk of severe events, such as stroke and myocardial infarct (MI). Improving the safety, efficacy, and preventive qualities of medications requires the understanding of how rhythms impact drug pharmacokinetics and pharmacodynamics. The therapeutic and adverse effects of prescription and nonprescription medications widely used by women can vary markedly with the (circadian) time of administration. Circadian rhythm-dependent differences in the safety of medications are particularly relevant to pregnant women; laboratory animal studies show that the fetal toxicity of various treatments varies not only with developmental stage but also with circadian time. Rhythm-dependent differences in the actions of medications are also of great importance to perimenopausal and postmenopausal women, who are advised to ingest prescribed pharmacotherapy for osteopenia and osteoporosis in the morning to minimize the risk of adverse effects and, as a consequence, may elect to take other medications at times not recommended in the instructions for their use. Medication trials must be comprehensive and representative of women and men of different life stages, ethnicities, and likely times (morning vs. evening) of drug use.

Circadian variation in stroke onset: identical temporal pattern in ischemic and hemorrhagic events.

Stroke is the culmination of a heterogeneous group of cerebrovascular diseases that is manifested as ischemia or hemorrhage of one or more blood vessels of the brain. The occurrence of many acute cardiovascular events--such as myocardial infarction, sudden cardiac death, pulmonary embolism, critical limb ischemia, and aortic aneurysm rupture--exhibits prominent 24 h patterning, with a major morning peak and secondary early evening peak. The incidence of stroke exhibits the same 24 h pattern. Although ischemic and hemorrhagic strokes are different entities and are characterized by different pathophysiological mechanisms, they share an identical double-peak 24 h pattern. A constellation of endogenous circadian rhythms and exogenous cyclic factors are involved. The staging of the circadian rhythms in vascular tone, coagulative balance, and blood pressure plus temporal patterns in posture, physical activity, emotional stress, and medication effects play central and/or triggering roles. Features of the circadian rhythm of blood pressure, in terms of their chronic and acute effects on cerebral vessels, and of coagulation are especially important. Clinical medicine has been most concerned with the prevention of stroke in the morning, when population-based studies show it is of greatest risk during the 24 h; however, improved protection of at-risk patients against stroke in the early evening, the second most vulnerable time of cerebrovascular accidents, has received relatively little attention thus far.

Diurnal and twenty-four hour patterning of human diseases: cardiac, vascular, and respiratory diseases, conditions, and syndromes.

Various medical conditions, disorders, and syndromes exhibit predictable-in-time diurnal and 24 h patterning in the signs, symptoms, and grave nonfatal and fatal events, e.g., respiratory ones of viral and allergic rhinorrhea, reversible (asthma) and non-reversible (bronchitis and emphysema) chronic obstructive pulmonary disease, cystic fibrosis, high altitude pulmonary edema, and decompression sickness; cardiac ones of atrial premature beats and tachycardia, paroxysmal atrial fibrillation, 3rd degree atrial-ventricular block, paroxysmal supraventricular tachycardia, ventricular premature beats, ventricular tachyarrhythmia, symptomatic and non-symptomatic angina pectoris, Prinzmetal vasospastic variant angina, acute (non-fatal and fatal) incidents of myocardial infarction, sudden cardiac arrest, in-bed sudden death syndrome of type-1 diabetes, acute cardiogenic pulmonary edema, and heart failure; vascular and circulatory system ones of hypertension, acute orthostatic postprandial, micturition, and defecation hypotension/syncope, intermittent claudication, venous insufficiency, standing occupation leg edema, arterial and venous branch occlusion of the eye, menopausal hot flash, sickle cell syndrome, abdominal, aortic, and thoracic dissections, pulmonary thromboembolism, and deep venous thrombosis, and cerebrovascular transient ischemic attack and hemorrhagic and ischemic stroke. Knowledge of these temporal patterns not only helps guide patient care but research of their underlying endogenous mechanisms, i.e., circadian and others, and external triggers plus informs the development and application of effective chronopreventive and chronotherapeutic strategies.

Diurnal and twenty-four hour patterning of human diseases: acute and chronic common and uncommon medical conditions.

The symptom intensity and mortality of human diseases, conditions, and syndromes exhibit diurnal or 24 h patterning, e.g., skin: atopic dermatitis, urticaria, psoriasis, and palmar hyperhidrosis; gastrointestinal: esophageal reflux, peptic ulcer (including perforation and hemorrhage), cyclic vomiting syndrome, biliary colic, hepatic variceal hemorrhage, and proctalgia fugax; infection: susceptibility, fever, and mortality; neural: frontal, parietal, temporal, and occipital lobe seizures, Parkinson's and Alzheimer's disease, hereditary progressive dystonia, and pain (cancer, post-surgical, diabetic neuropathic and foot ulcer, tooth caries, burning mouth and temporomandibular syndromes, fibromyalgia, sciatica, intervertebral vacuum phenomenon, multiple sclerosis muscle spasm, and migraine, tension, cluster, hypnic, and paroxysmal hemicranial headache); renal: colic and nocturnal enuresis and polyuria; ocular: bulbar conjunctival redness, keratoconjunctivitis sicca, intraocular pressure and anterior ischemic optic neuropathy, and recurrent corneal erosion syndrome; psychiatric/behavioral: major and seasonal affective depressive disorders, bipolar disorder, parasuicide and suicide, dementia-associated agitation, and addictive alcohol, tobacco, and heroin cravings and withdrawal phenomena; plus autoimmune and musculoskeletal: rheumatoid arthritis, osteoarthritis, axial spondylarthritis, gout, Sjögren's syndrome, and systemic lupus erythematosus. Knowledge of these and other 24 h patterns of human pathophysiology informs research of their underlying circadian and other endogenous mechanisms, external temporal triggers, and more effective patient care entailing clinical chronopreventive and chronotherapeutic strategies.

Circadian and ultradian (12 h) variations of skin blood flow and barrier function in non-irritated and irritated skin-effect of topical corticosteroids.

The skin is the organ that receives the greatest exposure to light and shows a high-amplitude circadian rhythm in epidermal cell proliferation. We have previously demonstrated that the skin barrier function has a significant circadian rhythm. Corticosteroids (CS) are the most commonly used topical treatment in dermatology. Time-dependent differences in their efficacy and side-effects would be of considerable interest. The aims of the current study were to examine time-dependent cycles in the effect of topical CS application in healthy and irritated skin on skin blood flow and its relationship to barrier function. Twenty clinically healthy, diurnally active subjects were examined at eight and nine time points over a 24 or 28 h span respectively, using non-invasive skin bioengineering techniques of laser Doppler imaging, a transepidermal water loss (TEWL) device and a skin thermometer in a 28 h session. The results of this current study demonstrate circadian and ultradian (12 h) variations in skin blood flow. A significant correlation was found between skin temperature and skin blood flow but not with TEWL. Circadian and ultradian rhythms are maintained during treatment with high-potency and mid-potency CS in healthy skin. These rhythms persist during stratum corneum disruption with and without CS application.

Chronoastrobiology: proposal, nine conferences, heliogeomagnetics, transyears, near-weeks, near-decades, phylogenetic and ontogenetic memories.

"Chronoastrobiology: are we at the threshold of a new science? Is there a critical mass for scientific research?" A simple photograph of the planet earth from outer space was one of the greatest contributions of space exploration. It drove home in a glance that human survival depends upon the wobbly dynamics in a thin and fragile skin of water and gas that covers a small globe in a mostly cold and vast universe. This image raised the stakes in understanding our place in that universe, in finding out where we came from and in choosing a path for survival. Since that landmark photograph was taken, new astronomical and biomedical information and growing computer power have been revealing that organic life, including human life, is and has been connected to invisible (non-photic) forces, in that vast universe in some surprising ways. Every cell in our body is bathed in an external and internal environment of fluctuating magnetism. It is becoming clear that the fluctuations are primarily caused by an intimate and systematic interplay between forces within the bowels of the earth--which the great physician and father of magnetism William Gilbert called a 'small magnet'--and the thermonuclear turbulence within the sun, an enormously larger magnet than the earth, acting upon organisms, which are minuscule magnets. It follows and is also increasingly apparent that these external fluctuations in magnetic fields can affect virtually every circuit in the biological machinery to a lesser or greater degree, depending both on the particular biological system and on the particular properties of the magnetic fluctuations. The development of high technology instruments and computer power, already used to visualize the human heart and brain, is furthermore making it obvious that there is a statistically predictable time structure to the fluctuations in the sun's thermonuclear turbulence and thus to its magnetic interactions with the earth's own magnetic field and hence a time structure to the magnetic fields in organisms. Likewise in humans, and in at least those other species that have been studied, computer power has enabled us to discover statistically defined endogenous physiological rhythms and further direct effects that are associated with these invisible geo- and heliomagnetic cycles. Thus, what once might have been dismissed as noise in both magnetic and physiological data does in fact have structure. And we may be at the threshold of understanding the biological and medical meaning and consequences of these patterns and biological-astronomical linkages as well. Structures in time are called chronomes; their mapping in us and around us is called chronomics. The scientific study of chronomes is chronobiology. And the scientific study of all aspects of biology related to the cosmos has been called astrobiology. Hence we may dub the new study of time structures in biology with regard to influences from cosmo- helio- and geomagnetic rhythms chronoastrobiology. It has, of course, been understood for centuries that the movements of the earth in relation to the sun produce seasonal and daily cycles in light energy and that these have had profound effects on the evolution of life. It is now emerging that rhythmic events generated from within the sun itself, as a large turbulent magnet in its own right, can have direct effects upon life on earth. Moreover, comparative studies of diverse species indicate that there have also been ancient evolutionary effects shaping the endogenous chronomic physiological characteristics of life. Thus the rhythms of the sun can affect us not only directly, but also indirectly through the chronomic patterns that solar magnetic rhythms have created within our physiology in the remote past. For example, we can document the direct exogenous effects of given specific solar wind events upon human blood pressure and heart rate. We also have evidence of endogenous internal rhythms in blood pressure and heart rate that are close to but not identical to the period length of rhythms in the solar wind. These were installed genetically by natural selection at some time in the distant geological past. This interpretive model of the data makes the prediction that the internal and external influences on heart rate and blood pressure can reinforce or cancel each other out at different times. A study of extensive clinical and physiological data shows that the interpretive model is robust and that internal and external effects are indeed augmentative at a statistically significant level. Chronoastrobiological studies are contributing to basic science--that is, our understanding is being expanded as we recognize heretofore unelaborated linkages of life to the complex dynamics of the sun, and even to heretofore unelaborated evolutionary phenomena. Once, one might have thought of solar storms as mere transient 'perturbations' to biology, with no lasting importance. Now we are on the brink of understanding that solar turbulences have played a role in shaping endogenous physiological chronomes. There is even documentation for correlations between solar magnetic cycles and psychological swings, eras of belligerence and of certain expressions of sacred or religious feelings. Chronoastrobiology can surely contribute to practical applications as well as to basic science. It can help develop refinements in our ability to live safely in outer space, where for example at the distance of the moon the magnetic influences of the sun will have an effect upon humans unshielded by the earth's native magnetic field. We should be better able to understand these influences as physiological and mechanical challenges, and to improve our estimations of the effects of exposure. Chronoastrobiology moreover holds great promise in broadening our perspectives and powers in medicine and public health right here upon the surface of the earth. Even the potential relevance of chronoastrobiology for practical environmental and agricultural challenges cannot be ruled out at this early stage in our understanding of the apparently ubiquitous effects of magnetism and hence perhaps of solar magnetism on life. The evidence already mentioned that fluctuations in solar magnetism can influence gross clinical phenomena such as rates of strokes and heart attacks, and related cardiovascular variables such as blood pressure and heart rate, should illustrate the point that the door is open to broad studies of clinical implications. The medical value of better understanding magnetic fluctuations as sources of variability in human physiology falls into several categories: 1) The design of improved analytical and experimental controls in medical research. Epidemiological analyses require that the multiple sources causing variability in physiological functions and clinical phenomena be identified and understood as thoroughly as possible, in order to estimate systematic alterations of any one variable. 2) Preventive medicine and the individual patients'care. There are no flat 'baselines', only reference chronomes. Magnetic fluctuations can be shown statistically to exacerbate health problems in some cases. The next step should be to determine whether vulnerable individuals can be identified by individual monitoring. Such vulnerable patients may then discover that they have the option to avoid circumstances associated with anxiety during solar storms, and/or pay special attention to their medication or other treatments. Prehabilitation by self-help can hopefully complement and eventually replace much costly rehabilitation. 3) Basic understanding of human physiological mechanisms. The chronomic organization of physiology implies a much more subtle dynamic integration of functions than is generally appreciated. All three categories of medical value in turn pertain to the challenges for space science of exploring and colonizing the solar system. The earth's native magnetic field acts like an enormous umbrella that offers considerable protection on the surface from harsh solar winds of charged particles and magnetic fluxes. The umbrella becomes weaker with distance from the earth and will offer little protection for humans, other animals, and plants in colonies on the surface of the moon or beyond. Thus it is important before more distant colonization is planned or implemented to better understand those magnetism-related biological- solar interactions that now can be studied conveniently on earth. (ABSTRACT TRUNCATED)

Chronobiology of the mammalian response to ionizing radiation. Potential applications in oncology.

Ionizing radiation from all sources under appropriate conditions leads to cell death and tissue damage. It is used in cancer treatment under the assumption of a higher radiosensitivity of the fast dividing tumor cells as compared with adjacent host tissues. The radiosensitivities of proliferating host tissues like bone marrow and gastrointestinal lining epithelium are dose limiting. Since these host tissues and many tumors show circadian and other periodicities in their cell proliferation, the timing of radiation treatment according to host and/or tumor rhythms is expected to improve the toxic/therapeutic ratio of the treatment. The experimental data on the chronobiology of radiation exposure show circadian rhythmicity in radiation response after whole body irradiation in mice and rats with highest toxicity in light-dark 12h:12h synchronized animals during their daily activity span. Bone marrow toxicity as well as gastrointestinal epithelial damage show circadian rhythms in part due to radiation damage to the stem cells involved and especially in the intestine also due to damage to the microvasculature. Chronoradiotherapy of malignant tumors seems promising, alone or in combination with response modifiers, provided the host and potential tumor rhythms can be monitored.

Health and performance factors in health care shift workers.

OBJECTIVES: To assess the impact of shift work on health care workers. SUBJECTS AND METHODS: A cross-sectional study assessed health and performance markers of 188 day and night shift nonphysician health care workers. RESULTS: Night-shift workers were more likely to report difficulty with routine orders, lower energy levels, unpredictable work schedules, and sleep disturbance but no difference with injuries or motor vehicle crashes. A classification of day shift, night shift without unpredictable schedule or sleep problems, and night shift with unpredictable schedule or sleep problems revealed a trend of increased difficulty with routine orders, suggesting a "dose response effect." CONCLUSIONS: Findings suggest an association with night shift health care workers and adverse health and performance markers. A "higher-risk" subgroup may benefit from targeted interventions to reduce potential adverse effects from shift work and improve health care delivery.

Salivary CA130 with and without unilateral autonomic parotid denervation of rats fed different diets.

BACKGROUND: Tumor markers such as CA130 can be determined in human whole saliva. Saliva represents an attractive body fluid for longitudinal studies. MATERIALS AND METHODS: CA130 was determined in parotid saliva from 8 rats fed different diets, with or without autonomic denervation. RESULTS: CA130 could be determined in parotid saliva of rats, irrespective of diet and/or autonomic denervation. Whether the numerical decrease in CA130 observed after autonomic denervation is statistically significant requires further work. CONCLUSIONS: Since salivary CA130 has been shown to decrease following treatment with anti-cancer drugs in humans, the ability to determine this tumor marker in rat saliva opens new opportunities for optimizing cancer chronotherapy in the experimental laboratory.

Incorporation of titanium mesh in orbital and midface reconstruction.

Several authors have demonstrated the safety and effectiveness of titanium in orbital reconstruction. One question posed by clinicians is what happens to large pieces of titanium in communication with the paranasal sinuses or nasal-oral-pharyngeal area. This question becomes increasingly relevant as titanium is used to reconstruct extensive defects for which the destruction of bony architecture requires the placement of mesh in proximity to these areas. The objective of this study was to examine the gross and histologic soft-tissue response to large segments of titanium mesh in the setting of orbital and midface reconstruction, particularly when exposed to the nasal-oral-pharyngeal area and paranasal sinuses. In this study, large segments of titanium mesh were used in eight patients to reconstruct orbital and midface defects, with direct communication between the mesh and nasal-oral-pharyngeal area and paranasal sinuses. Four patients had suffered self-inflicted gunshot wounds; as a result, much of their midface was missing, including the inferior and medial orbital floor, maxilla, nose, naso-orbital-ethmoid complex, and hard palate. Extensive sheets of titanium mesh were used to reconstruct their medial and inferior orbital walls, nasal bridge, and maxilla. In the fifth patient, titanium mesh was used to reconstruct the maxilla after resection of a squamous cell carcinoma of the nasolacrimal duct. In the sixth and seventh patients, mesh was used to reconstruct the nasal bridge after severely comminuted nasal fractures resulted in the loss of bone and mucosa. Finally, the eighth patient had titanium mesh used to replace cocaine-induced bone loss involving the left medial orbital floor and wall and part of the maxilla. On gross examination by either endoscopy or direct inspection, all eight patients had rapid soft-tissue incorporation of the titanium mesh. Initial examination typically revealed budding of soft tissue through mesh interstices, followed by progressive incorporation. One patient's mesh was covered in only 15 days. Two patients underwent biopsies of this newly formed soft tissue. One had biopsies performed at 3, 15, and 31 months after the original operation. Biopsy examination at 3 months revealed incorporation of the titanium with fibrous soft tissue covered by ciliated respiratory epithelium, goblet cells, and squamous epithelium with metaplasia. In addition, the dense, acute inflammation present at 3 months evolved into mild, chronic inflammation at 31 months. The second patient had a single biopsy 4 months after secondary orbital reconstruction for delayed enophthalmos. Biopsy examination revealed a fibrous soft-tissue sheath lined by squamous epithelium with metaplasia. Again, mild chronic inflammation was present within the soft tissue. This study provides evidence of titanium's compatibility with soft tissue. The mesh underwent progressive incorporation with soft tissue that was then resurfaced by indigenous cells, including respiratory epithelia and goblet cells. This phenomenon occurred despite communication with the nasal-oral-pharyngeal area and paranasal sinuses.

Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation.

Shift work that includes a nighttime rotation has become an unavoidable attribute of today's 24-h society. The related disruption of the human circadian time organization leads in the short-term to an array of jet-lag-like symptoms, and in the long-run it may contribute to weight gain/obesity, metabolic syndrome/type II diabetes, and cardiovascular disease. Epidemiologic studies also suggest increased cancer risk, especially for breast cancer, in night and rotating female shift workers. If confirmed in more controlled and detailed studies, the carcinogenic effect of night and shift work will constitute additional serious medical, economic, and social problems for a substantial proportion of the working population. Here, we examine the possible multiple and interconnected cancer-promoting mechanisms as a consequence of shift work, i.e., repeated disruption of the circadian system, pineal hormone melatonin suppression by exposure to light at night, sleep-deprivation-caused impairment of the immune system, plus metabolic changes favoring obesity and generation of proinflammatory reactive oxygen species.

[2013 Ambulatory blood pressure monitoring recommendations for the diagnosis of adult hypertension, assessment of cardiovascular and other hypertension-associated risk, and attainment of therapeutic goals (summary). Joint recommendations from the International Society for Chronobiology (ISC), American Association of Medical Chronobiology and Chronotherapeutics (AAMCC), Spanish Society of Applied Chronobiology, Chronotherapy, and Vascular Risk (SECAC), Spanish Society of Atherosclerosis (SEA), and Romanian Society of Internal Medicine (RSIM)]. / Recomendaciones 2013 para el uso de la monitorización ambulatoria de la presión arterial para el diagnóstico de hipertensión en adultos, valoración de riesgo cardiovascular y obtención de objetivos terapéuticos (resumen). Recomendaciones conjuntas de la International Society for Chronobiology (ISC), American Association of Medical Chronobiology and Chronotherapeutics (AAMCC), Sociedad Española de Cronobiología Aplicada, Cronoterapia y Riesgo Vascular (SECAC), Sociedad Española de Arteriosclerosis (SEA) y Romanian Society of Internal Medicine (RSIM).

Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime office measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers. Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive decrease by therapeutic intervention in the asleep BP mean is the most significant predictor of CVD event-free interval. The 24 h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information pertaining to the features of the 24 h BP pattern. Persons with the same 24 h BP mean may display radically different 24 h BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of individuals by comparing office with either the 24 h or awake BP mean as "masked normotensives" (elevated clinic BP but normal ABPM), which should replace the terms of "isolated office" or "white-coat hypertension", and "masked hypertensives" (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of compelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lower by 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male and female high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and/or past CVD events. In the adult population, the combined prevalence of masked normotension and masked hypertension is >35%. Moreover, >20% of "normotensive" adults have a non-dipper BP profile and, thus, are at relatively high CVD risk. Clinic BP measurements, even if supplemented with home self-measurements, are unable to quantify 24 h BP patterning and asleep BP level, resulting in potential misclassification of up to 50% of all evaluated adults. ABPM should be viewed as the new gold standard to diagnose true hypertension, accurately assess consequent tissue/organ, maternal/fetal, and CVD risk, and individualize hypertension chronotherapy. ABPM should be a priority for persons likely to have a blunted nighttime BP decline and elevated CVD risk, i.e., those who are elderly and obese, those with secondary or resistant hypertension, and those diagnosed with diabetes, CKD, metabolic syndrome, and sleep disorders.