Twenty-Four-Hour Patterns in Occurrence and Pathophysiology of Acute Cardiovascular Events and Ischemic Heart Disease

The scientific literature clearly establishes the occurrence of cardiovascular (CV) accidents and myocardial ischemic episodes is unevenly distributed during the 24?h. Such temporal patterns result from corresponding temporal variation in pathophysiologic mechanisms and cyclic environmental triggers that elicit the onset of clinical events. Moreover, both the pharmacokinetics and pharmacodynamics of many, though not all, CV medications have been shown to be influenced by the circadian time of their administration, even though further studies are necessary to better clarify the mechanisms of such influence on different drug classes, drug molecules, and pharmaceutical preparations. Twenty-four-hour rhythmic organization of CV functions is such that defense mechanisms against acute events are incapable of providing the same degree of protection during the day and night. Instead, temporal gates of excessive susceptibility exist, particularly in the morning and to a lesser extent evening (in diurnally active persons), to aggressive mechanisms through which overt clinical manifestations may be triggered. When peak levels of critical physiologic variables, such as blood pressure (BP), heart rate (HR), rate pressure product (systolic BP?×?HR, surrogate measure of myocardial oxygen demand), sympathetic activation, and plasma levels of endogenous vasoconstricting substances, are aligned together at the same circadian time, the risk of acute events becomes significantly elevated such that even relatively minor and usually harmless physical and mental stress and environmental phenomena can precipitate dramatic life-threatening clinical manifestations. Hence, the delivery of CV medications needs to be synchronized in time, i.e., circadian time, in proportion to need as determined by established temporal patterns in risk of CV events, and in a manner that averts or minimizes undesired side effects. (Author correspondence: prf@unife.it)     

Knowledge and Attitudes of American Physicians and Public About Medical Chronobiology and Chronotherapeutics. Findings of Two 1996 Gallup Surveys

Two Gallup telephone interview surveys were conducted during 1996 of 320 American primary care physicians and 1011 adults to assess their knowledge and attitudes about medical chronobiology and chronotherapeu-tics. Of the doctors, 88% claimed to possess at least some familiarity with the concept of chronobiology and circadian rhythms; however, many were not often able to identify correctly the time of day or night when common medical conditions and events most likely occur or worsen. Furthermore, a significant number of doctors believed that chronotherapies, special dosage forms that proportion medications during the day and night in synchrony to need with reference to 24h patterns in the intensity of symptoms and risk of severe medical events, were already being marketed in the United States for angina pectoris, hypertension, respiratory allergies, and other medical conditions even though this was not the case at the time of the survey. On the other hand, the doctors were relatively unaware of those chronotherapies that actually did exist to treat asthma and peptic ulcer disease. American adults also lacked knowledge of temporal patterns in disease and were seldom able to identify the clock time when asthma and myocardial infarction are of greatest risk or when blood pressure is highest. Although neither the American physicians nor adults possessed knowledge of these facts, both had a strong positive attitude toward the concept of chronotherapeutics. Overall, the findings of these Gallup surveys indicate that a massive educational effort is necessary immediately to ensure new developments in medical chronobiology and chronotherapeutics are correctly comprehended and properly incorporated by physicians into clinical medicine and wisely utilized by patients.     

(Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis

Introduction  

Both cardiovascular disease and osteoporosis are important causes of morbidity and mortality in the elderly. The co-occurrence of cardiovascular disease and osteoporosis prompted us to review the evidence of an association between cardiovascular (CV) disease and osteoporosis and potential shared common pathophysiological mechanisms.     

The endogenous circadian pacemaker imparts a scale-invariant pattern of heart rate fluctuations across time scales spanning minutes to 24 hours

Heartbeat fluctuations in mammals display a robust temporal structure characterized by scale-invariant/fractal patterns. These scale-invariant patterns likely confer physiological advantage because they change with cardiovascular disease and these changes are associated with reduced survival. Models of physical systems imply that to produce scale-invariant patterns, factors influencing the system at different time scales must be coupled via a network of feedback interactions. A similar cardiac control network is hypothesized to be responsible for the scale-invariant pattern in heartbeat dynamics, although the essential network components have not been determined. Here is shown that scale-invariant cardiac control occurs across time scales from minutes to approximately 24 h, and that lesioning the mammalian circadian pacemaker (suprachiasmatic nucleus; SCN) completely abolishes the scale-invariant pattern at time scales>or approximately 4 h. At time scales相似文献   

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.     

Temporal Aspects of the Pathophysiology of Human Ulcer Disease

In this paper, a peptic ulcer is considered from the perspective that it is representative of a heterogeneous group of multifactorial determined or influenced disorders having a common pathomorphologic expression. This heterogeneity involves several pathophysiological attributes, including both functional (including secretory and motility events and their respective driving mechanisms) and morphologic alterations that relate to mucosal resistance. Patients with duodenal ulcer (DU) have been observed to exhibit alterations, in comparison to normal subjects, in the circadian rhythm characteristics of several gastrointestinal functions. Prominent among these are altered amplitudes of several circadian-organized gastric variables, such as intragastric pH, gastrin, pepsinogen and gastric mitotic index. With respect to any given variable, a reduced group amplitude (a measure of one-half the peak-trough difference of a 24-hr rhythm) could signify an increased dispersion of acrophases (the location of the peak of a circadian rhythm along the 24-hr time scale) reflecting interindividual variation in synchronization schedules, sleep-wake patterns, or chronobiologic alterations. A reduced interindividual amplitude further supports the concept of the heterogeneity of peptic disease. A decrease in the intraindividual amplitude of certain gastric rhythms implies an altered temporal pattern over the 24 hr. This is consistent with the hypothesis of a decrease in the amount of time available for recovery of a given function or set of integrated functions, and hence, increased susceptibility to mucosal injury. Normal high-amplitude variation in gastrointestinal functioning over the 24 hr appears to be required for natural restoration of the gut.     

Temporal Aspects of the Pathophysiology of Human Ulcer Disease

In this paper, a peptic ulcer is considered from the perspective that it is representative of a heterogeneous group of multifactorial determined or influenced disorders having a common pathomorphologic expression. This heterogeneity involves several pathophysiological attributes, including both functional (including secretory and motility events and their respective driving mechanisms) and morphologic alterations that relate to mucosal resistance. Patients with duodenal ulcer (DU) have been observed to exhibit alterations, in comparison to normal subjects, in the circadian rhythm characteristics of several gastrointestinal functions. Prominent among these are altered amplitudes of several circadian-organized gastric variables, such as intragastric pH, gastrin, pepsinogen and gastric mitotic index. With respect to any given variable, a reduced group amplitude (a measure of one-half the peak-trough difference of a 24-hr rhythm) could signify an increased dispersion of acrophases (the location of the peak of a circadian rhythm along the 24-hr time scale) reflecting interindividual variation in synchronization schedules, sleep-wake patterns, or chronobiologic alterations. A reduced interindividual amplitude further supports the concept of the heterogeneity of peptic disease. A decrease in the intraindividual amplitude of certain gastric rhythms implies an altered temporal pattern over the 24 hr. This is consistent with the hypothesis of a decrease in the amount of time available for recovery of a given function or set of integrated functions, and hence, increased susceptibility to mucosal injury. Normal high-amplitude variation in gastrointestinal functioning over the 24 hr appears to be required for natural restoration of the gut.     

Ambulatory blood pressure monitoring in the prediction of cardiovascular events and effects of chronotherapy: rationale and design of the MAPEC study

Ambulatory blood pressure (BP) measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post-prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (non-dipper pattern) or even reversed (riser pattern). This is clinically relevant because the non-dipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia, and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the specific circadian BP pattern of each patient. All previous trials that have demonstrated an increased cardiovascular risk in non-dipper as compared to dipper patients have relied on the prognostic significance of a single ABPM baseline profile from each participant without accounting for possible changes in the BP pattern during follow-up. Moreover, the potential benefit (i.e., reduction in cardiovascular risk) associated with the normalization of the circadian BP variability (conversion from non-dipper to dipper pattern) from an appropriately envisioned treatment strategy is still a matter of debate. Accordingly, the MAPEC (Monitorización Ambulatoria de la Presión Arterial y Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study was designed to investigate whether the normalization of the circadian BP profile toward more of a dipper pattern by chronotherapeutic strategies (i.e., specific timing during the 24 h of BP-lowering medications according to the 24 h BP pattern) reduces cardiovascular risk. The prospective MAPEC study investigates 3,000 diurnally active men and women >/=18 yrs of age. At inclusion, BP and wrist activity are measured for 48 h. The initial evaluation also includes a detailed medical history, an electrocardiogram, and screening laboratory blood and urine tests. The same evaluation procedure is scheduled yearly or more frequently (quarterly) if treatment adjustment is required for BP control. Cardiovascular morbidity and mortality are thus evaluated on the basis of changes in BP during follow-up. The MAPEC study, now on its fourth year of follow-up, investigates the potential decrease in cardiovascular, cerebrovascular, and renal risk from the proper modeling of the circadian BP profile by the timed administration (chronotherapy) of antihypertensive medication, beyond the reduction of clinic-determined daytime or ABPM-determined 24 h mean BP levels.     

Ambulatory Blood Pressure Monitoring in the Prediction of Cardiovascular Events and Effects of Chronotherapy: Rationale and Design of the MAPEC Study

Ambulatory blood pressure (BP) measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post‐prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (non‐dipper pattern) or even reversed (riser pattern). This is clinically relevant because the non‐dipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia, and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the specific circadian BP pattern of each patient. All previous trials that have demonstrated an increased cardiovascular risk in non‐dipper as compared to dipper patients have relied on the prognostic significance of a single ABPM baseline profile from each participant without accounting for possible changes in the BP pattern during follow‐up. Moreover, the potential benefit (i.e., reduction in cardiovascular risk) associated with the normalization of the circadian BP variability (conversion from non‐dipper to dipper pattern) from an appropriately envisioned treatment strategy is still a matter of debate. Accordingly, the MAPEC (Monitorización Ambulatoria de la Presión Arterial y Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study was designed to investigate whether the normalization of the circadian BP profile toward more of a dipper pattern by chronotherapeutic strategies (i.e., specific timing during the 24 h of BP‐lowering medications according to the 24 h BP pattern) reduces cardiovascular risk. The prospective MAPEC study investigates 3,000 diurnally active men and women ≥18 yrs of age. At inclusion, BP and wrist activity are measured for 48 h. The initial evaluation also includes a detailed medical history, an electrocardiogram, and screening laboratory blood and urine tests. The same evaluation procedure is scheduled yearly or more frequently (quarterly) if treatment adjustment is required for BP control. Cardiovascular morbidity and mortality are thus evaluated on the basis of changes in BP during follow‐up. The MAPEC study, now on its fourth year of follow‐up, investigates the potential decrease in cardiovascular, cerebrovascular, and renal risk from the proper modeling of the circadian BP profile by the timed administration (chronotherapy) of antihypertensive medication, beyond the reduction of clinic‐determined daytime or ABPM‐determined 24 h mean BP levels.     

Short-term complexity of cardiac autonomic control during sleep: REM as a potential risk factor for cardiovascular system in aging

Introduction

Sleep is a complex phenomenon characterized by important modifications throughout life and by changes of autonomic cardiovascular control. Aging is associated with a reduction of the overall heart rate variability (HRV) and a decrease of complexity of autonomic cardiac regulation. The aim of our study was to evaluate the HRV complexity using two entropy-derived measures, Shannon Entropy (SE) and Corrected Conditional Entropy (CCE), during sleep in young and older subjects.

Methods

A polysomnographic study was performed in 12 healthy young (21.1±0.8 years) and 12 healthy older subjects (64.9±1.9 years). After the sleep scoring, heart period time series were divided into wake (W), Stage 1–2 (S1-2), Stage 3–4 (S3-4) and REM. Two complexity indexes were assessed: SE(3) measuring the complexity of a distribution of 3-beat patterns (SE(3) is higher when all the patterns are identically distributed and it is lower when some patterns are more likely) and CCE_min measuring the minimum amount of information that cannot be derived from the knowledge of previous values.

Results

Across the different sleep stages, young subjects had similar RR interval, total variance, SE(3) and CCE_min. In the older group, SE(3) and CCE_min were reduced during REM sleep compared to S1-2, S3-4 and W. Compared to young subjects, during W and sleep the older subjects showed a lower RR interval and reduced total variance as well as a significant reduction of SE(3) and CCE_min. This decrease of entropy measures was more evident during REM sleep.

Conclusion

Our study indicates that aging is characterized by a reduction of entropy indices of cardiovascular variability during wake/sleep cycle, more evident during REM sleep. We conclude that during aging REM sleep is associated with a simplification of cardiac control mechanisms that could lead to an impaired ability of the cardiovascular system to react to cardiovascular adverse events.     

24‐Hour,Weekly, and Annual Patterns in Traumatic and Non‐Traumatic Surgical Pediatric Emergencies

24 h patterns with high frequency components in the incidence of pediatric trauma were validated and quantified in one of our earlier studies. Herein, we further explored the temporal—high frequency, 24 h, weekly (7 d), hemi‐weekly (3.5 d), and annual – patterns in traumatic (1990–1997; n=15,110 events) and non‐traumatic pediatric surgical emergencies (PSE) (1992–2001; n=5,593 events) as well as automobile accidents (AA) (1990–1997; n=67,712) in the County of Vaud, Switzerland. The latter served as a reference system of human adult activity and risk. Two‐way ANOVA, χ2, correlation, and cosinor analyses were used as statistical tools. A 24 h pattern, reproducible from year to year, was validated in traumatic and non‐traumatic PSE and AA. The 24 h patterns were not correlated and differed from one another in terms of their acrophase (peak time) and amplitude. A gender‐related difference was found only in the non‐traumatic time series for weekly (7 d) and hemi‐weekly (3.5 d) patterns. The latter were detected in boys but not girls. No statistically significant difference was found in the acrophase and amplitude between boys and girls in the temporal patterns of other periods. An annual pattern was validated in automobile accidents (acrophase: 4th of September ±37 d (SD)) and pediatric trauma (acrophase: 14th of June ±10 d), but not in non‐traumatic PSE. These results suggest that environmental modulations differ between the incidence of traumatic and non‐traumatic PSE. Presumably, the two phenomena involve different aspects of the temporal organization and/or different levels of susceptibility of a set of biological rhythms to environmental factors.     

The gene expression profile of preclinical autoimmune arthritis and its modulation by a tolerogenic disease-protective antigenic challenge

Introduction  

Autoimmune inflammation is a characteristic feature of rheumatoid arthritis (RA) and other autoimmune diseases. In the natural course of human autoimmune diseases, it is rather difficult to pinpoint the precise timing of the initial event that triggers the cascade of pathogenic events that later culminate into clinically overt disease. Therefore, it is a challenge to examine the early preclinical events in these disorders. Animal models are an invaluable resource in this regard. Furthermore, considering the complex nature of the pathogenic immune events in arthritis, microarray analysis offers a versatile tool to define the dynamic patterns of gene expression during the disease course.     

Temporal trends in cardiovascular demand in EMS: Weekday versus weekend differences

Diagnosed cardiovascular disease has well-reported temporal patterns, with demand distribution peaks in the late morning and greater case numbers on Mondays and in winter. We aimed to report temporal patterns of presumptive cardiovascular disease cases as determined after emergency medical services (EMS) assessment and to characterize the demand distribution by day of the week. We conducted a secondary analysis of all Ambulance Victoria cases in metropolitan Melbourne (Victoria, Australia) between January 2008 and December 2011. Analyzed data included time of call, incident mechanism, location type, final assessment (paramedic “diagnosis”) and patient age. We employed Poisson’s regression to analyze case numbers and trigonometric regression to quantify distribution patterns. The 182?983 cases of presumptive cardiovascular disease observed during the study period constituted 15.2% of total demand. The median age of persons attended was 72 (IQR 57–82) and there was an almost even split between genders (51% female). Peak numbers of most cardiovascular case types occurred between 09:00 and 11:00; the only exception was acute pulmonary edema, which had peak case numbers at 06:00. Trigonometric regression showed distinct time of day distribution patterns, which did not alter by season. Although weekend day demand was lower than on Mondays, due to a different distribution pattern, these differences were not constant over the 24-hour period. There were up to 27% fewer cases at 09:00 and up to 2.8% more cases at 01:00 on weekends compared to Mondays. We have shown that examination of presumptive cardiovascular disease using not only case counts but also demand distribution patterns allows for a greater understanding of ambulance demand. Monday might be the most frequent day for cardiovascular cases but different patterns of demand occur on weekends. Increased knowledge of when different types of cases are most likely to occur will help inform EMS planning, including paramedic capacity and resources.     

A seasonal periodicity in relapses of multiple sclerosis? A single-center,population-based,preliminary study conducted in Bologna,Italy

Background  

Temporal, i.e., 24-hour, weekly, and seasonal patterns in the occurrence of acute cardiovascular and cerebrovascular events are well documented; however, little is known about temporal, especially seasonal, variation in multiple sclerosis (MS) and its relapses. This study investigated, by means of a validated chronobiological method, whether severe relapses of MS, ones requiring medical specialty consultation, display seasonal differences, and whether they are linked with seasonal differences in local meteorological variables.     

Nitrite and nitric oxide metabolism in peripheral artery disease

Peripheral artery disease (PAD) represents a burgeoning form of cardiovascular disease associated with significant clinical morbidity and increased 5 year cardiovascular disease mortality. It is characterized by impaired blood flow to the lower extremities, claudication pain and severe exercise intolerance. Pathophysiological factors contributing to PAD include atherosclerosis, endothelial cell dysfunction, and defective nitric oxide metabolite physiology and biochemistry that collectively lead to intermittent or chronic tissue ischemia. Recent work from our laboratories is revealing that nitrite/nitrate anion and nitric oxide metabolism plays an important role in modulating functional and pathophysiological responses during this disease. In this review, we discuss experimental and clinical findings demonstrating that nitrite anion acts to ameliorate numerous pathophysiological events associated with PAD and chronic tissue ischemia. We also highlight future directions for this promising line of therapy.     

24-hour, weekly, and annual patterns in traumatic and non-traumatic surgical pediatric emergencies

24 h patterns with high frequency components in the incidence of pediatric trauma were validated and quantified in one of our earlier studies. Herein, we further explored the temporal—high frequency, 24 h, weekly (7 d), hemi-weekly (3.5 d), and annual - patterns in traumatic (1990-1997; n=15,110 events) and non-traumatic pediatric surgical emergencies (PSE) (1992-2001; n=5,593 events) as well as automobile accidents (AA) (1990-1997; n=67,712) in the County of Vaud, Switzerland. The latter served as a reference system of human adult activity and risk. Two-way ANOVA, χ2, correlation, and cosinor analyses were used as statistical tools. A 24 h pattern, reproducible from year to year, was validated in traumatic and non-traumatic PSE and AA. The 24 h patterns were not correlated and differed from one another in terms of their acrophase (peak time) and amplitude. A gender-related difference was found only in the non-traumatic time series for weekly (7 d) and hemi-weekly (3.5 d) patterns. The latter were detected in boys but not girls. No statistically significant difference was found in the acrophase and amplitude between boys and girls in the temporal patterns of other periods. An annual pattern was validated in automobile accidents (acrophase: 4th of September ±37 d (SD)) and pediatric trauma (acrophase: 14th of June ±10 d), but not in non-traumatic PSE. These results suggest that environmental modulations differ between the incidence of traumatic and non-traumatic PSE. Presumably, the two phenomena involve different aspects of the temporal organization and/or different levels of susceptibility of a set of biological rhythms to environmental factors.     

Norepinephrine kinetics in the rat with tail-suspension-induced central hypervolemia,as a model of cardio-vascular deconditioning

Tail-suspension (TS) in the rat represents an interesting experimental condition to mimic, on Earth, the microgravity-induced cardiovascular deconditioning although the rat's profile of response is partially different from human's. To investigate underlying pathophysiological mechanisms, we have speculated on a decreased activity of the sympathetic system, (sigma S) triggered by the increase of the central venous pressure (CVP) induced by TS. Thus a decreased activity of the sigma S could account, at least partly, for the deconditioning of the cardiovascular system. The sympathetic activity (sigma A) was evaluated through measurement of the norepinephrine (NE) kinetics in rats that were tail-suspended for either 6, 24 or 48 hours. Neither NE spillover rate nor metabolic clearance rate were changed during TS, as compared to control. Thus, TS for a short period of time in the rat is unlikely to trigger a decrease of the sigma A.     

Endothelial cell senescence in aging-related vascular dysfunction

Increased cardiovascular disease in aging is partly a consequence of the vascular endothelial cell (EC) senescence and associated vascular dysfunction. In this contest, EC senescence is a pathophysiological process of structural and functional changes including dysregulation of vascular tone, increased endothelium permeability, arterial stiffness, impairment of angiogenesis and vascular repair, and a reduction of EC mitochondrial biogenesis. Dysregulation of cell cycle, oxidative stress, altered calcium signaling, hyperuricemia, and vascular inflammation have been implicated in the development and progression of EC senescence and vascular disease in aging. A number of abnormal molecular pathways are associated with these underlying pathophysiological changes including Sirtuin 1, Klotho, fibroblast growth factor 21, and activation of the renin angiotensin-aldosterone system. However, the molecular mechanisms of EC senescence and associated vascular impairment in aging are not completely understood. This review provides a contemporary update on molecular mechanisms, pathophysiological events, as well functional changes in EC senescence and age-associated cardiovascular disease. This article is part of a Special Issue entitled: Genetic and epigenetic regulation of aging and longevity edited by Jun Ren & Megan Yingmei Zhang.     

Cardiovascular disease in systemic sclerosis - an emerging association?

Microvascular disease is a prominent feature of systemic sclerosis (SSc) and leads to Raynaud's phenomenon, pulmonary arterial hypertension, and scleroderma renal crisis. The presence of macrovascular disease is less well established, and, in particular, it is not known whether the prevalence of coronary heart disease in SSc is increased. Furthermore, in terms of cardiac involvement in SSc, there remains conjecture about the relative contributions of atherosclerotic macrovascular disease and myocardial microvascular disease. In this review, we summarize the literature describing cardiovascular disease in SSc, discuss the pathophysiological mechanisms common to SSc and atherosclerosis, and review the surrogate markers of cardiovascular disease which have been examined in SSc. Proposed mediators of the vasculopathy of SSc which have also been implicated in atherosclerosis include endothelial dysfunction, a reduced number of circulating endothelial progenitor cells, and an increased number of microparticles. Excess cardiovascular risk in SSc is suggested by increased arterial stiffness and carotid intima thickening and reduced flow-mediated dilatation. Cohort studies of adequate size are required to resolve whether this translates into an increased incidence of cardiovascular events in patients with SSc.     

Induction of Olfaction and Cancer-Related Genes in Mice Fed a High-Fat Diet as Assessed through the Mode-of-Action by Network Identification Analysis

The pathophysiological mechanisms underlying the development of obesity and metabolic diseases are not well understood. To gain more insight into the genetic mediators associated with the onset and progression of diet-induced obesity and metabolic diseases, we studied the molecular changes in response to a high-fat diet (HFD) by using a mode-of-action by network identification (MNI) analysis. Oligo DNA microarray analysis was performed on visceral and subcutaneous adipose tissues and muscles of male C57BL/6N mice fed a normal diet or HFD for 2, 4, 8, and 12 weeks. Each of these data was queried against the MNI algorithm, and the lists of top 5 highly ranked genes and gene ontology (GO)-annotated pathways that were significantly overrepresented among the 100 highest ranked genes at each time point in the 3 different tissues of mice fed the HFD were considered in the present study. The 40 highest ranked genes identified by MNI analysis at each time point in the different tissues of mice with diet-induced obesity were subjected to clustering based on their temporal patterns. On the basis of the above-mentioned results, we investigated the sequential induction of distinct olfactory receptors and the stimulation of cancer-related genes during the development of obesity in both adipose tissues and muscles. The top 5 genes recognized using the MNI analysis at each time point and gene cluster identified based on their temporal patterns in the peripheral tissues of mice provided novel and often surprising insights into the potential genetic mediators for obesity progression.