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.

Previous studies have reported seasonal variation in peptic ulcer disease (PUD), but few large-scale, population-based studies have been conducted.

To verify whether a seasonal variation in cases of PUD (either complicated or not complicated) requiring acute hospitalization exists, we assessed the database of hospital admissions of the region Emilia Romagna (RER), Italy, obtained from the Center for Health Statistics, between January 1998 and December 2005. Admissions were categorized by sex, age (<65, 65-74, > or = 75 yrs), site of PUD lesion (stomach or duodenum), main complication (hemorrhage or perforation), and final outcome (intended as fatal outcome: in-hospital death; nonfatal outcome: patient discharged alive). Temporal patterns in PUD admissions were assessed in two ways, considering a) total counts per single month and season, and b) prevalence proportion, such as the monthly prevalence of PUD admissions divided by the monthly prevalence of total hospital admissions, to assess if the temporal patterns in the raw data might be the consequence of seasonal and annual variations in hospital admissions per se in the region. For statistical analysis, the chi2 test for goodness of fit and inferential chronobiologic method (Cosinor and partial Fourier series) were used.

Of the total sample of PUD patients (26,848 [16,795 males, age 65 +/- 16 yrs; 10,053 females, age 72 +/- 15 yrs, p < 0.001)], 7,151 were < 65 yrs of age, 8,849 between 65 and 74 yrs of age, and 10,848 > or = 75 yrs of age. There were more cases of duodenal (DU). (89.8%) than gastric ulcer (GU) (3.6%), and there were 1,290 (4.8%) fatal events. Data by season showed a statistically difference with the lowest proportion of PUD hospital admissions in summer (23.3%) (p < 0.001), for total cases and rather all subgroups. Chronobiological analysis identified three major peaks of PUD hospitalizations (September-October, January-February, and April-May) for the whole sample (p = 0.035), and several subgroups, with nadir in July. Finally, analysis of the monthly prevalence proportions yielded a significant (p = 0.025) biphasic pattern with a main peak in August-September-October, and a secondary one in January-February.

A seasonal variation in PUD hospitalization, characterized by three peaks of higher incidence (Autumn, Winter, and Spring) is observed. When data corrected by monthly admission proportions are analyzed, late summer-autumn and winter are confirmed as higher risk periods. The underlying pathophysiologic mechanisms are unknown, and need further studies. In subjects at higher risk, certain periods of the year could deserve an appropriate pharmacological protection to reduce the risk of PUD hospitalization.

Liver cirrhosis is the most common cause of portal hypertension which may end in serious bleeding from gastro-esophageal varices. Recent studies have demonstrated a daily pattern of acute upper gastrointestinal bleeding in patients with liver cirrhosis evidenced by one or two peaks throughout the day.

The assessment of the circadian rhythm of acute variceal bleeding with the possible participation of circadian changes of the fibrinolytic parameters.

The study included 264 patients with liver cirrhosis and upper gastrointestinal bleeding in addition to 20 healthy subjects as a control group. A series of hemostatic tests and parameters including prothrombin (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), Factors II, V, VII, IX, X, XI, platelets counts and fibrinolytic parameters assessement were completed in 60 patients in addition to the control group. The fibrinolytic activity was assessed by estimation of plasminogen, tissue plasminogen activator antigen (tPA: Ag) and plasminogen activator inhibitor antigen (PAI-1: Ag) at hour 09:00 and hour 17:00. The hemostatic tests and liver function tests were assessed once at hour 09.00.

We observed statistically significant two time peaks of upper gastrointestinal bleeding at hour 04:00 and hour 17:00 with a peak of the fibrinolytic parameter, tissue plasminogen activator antigen, with the night peak of bleeding. A significant correlation between the levels of fibrinolytic parameters and hemostatic factors as well as liver function tests were detected.

There are two time peaks of upper gastrointestinal bleeding with a temporal association between the night peak and a relative hyperfibrinolytic state.

Variceal bleeding carries a high-mortality rate in patients with liver cirrhosis. Since coagulation and fibrinolysis are abnormal in these patients we evaluated whether or not abnormalities of these haemostasis systems were independently related to mortality.

Global coagulation, coagulation activation and fibrinolysis measurements were performed in 43 cirrhotics bleeding from esophageal varices at baseline and during follow-up and in 43 non-bleeding cirrhotic patients at baseline only.

Baseline measurements of coagulation activation and fibrinolysis were more impaired in bleeders. In bleeders, prothrombin time, tissue type plasminogen activator antigen and D-dimer plasma levels were persistently more abnormal in patients who died. High-D-dimer, infection, Child-Pugh C class and MELD score >or=17 were the significant predictors of death at univariate analysis. Two different multivariate analyses to assess the independent prognostic value of these variables, one including the Child-Pugh class, the other including MELD, were performed. Independent predictors of death were high-D-dimer and infection, but not Child-Pugh class, in the former; MELD and infection, but not D-dimer, in the latter.

Beside infection, high-D-dimer is a stronger predictor of death as compared to Child-Pugh C class, but not to a MELD score >or=17.

Over activity of the fibrinolytic system (hyperfibrinolysis) occurs in cirrhosis and has been shown to correlate with the risk of variceal hemorrhage. We have developed a model for assessing acute tissue plasminogen activator (t-PA) release in vivo in man. The aims of the study were to assess the contribution of basal and stimulated t-PA release to hyperfibrinolysis in patients with alcoholic cirrhosis.

Bilateral forearm blood flow and plasma fibrinolytic variables were measured in 8 patients with biopsy proven alcohol induced cirrhosis, ascites and portal hypertension, and 8 age and sex matched healthy controls during infusion of bradykinin (100-900 pmol/min; endothelium-dependent vasodilator that releases t-PA) followed by sodium nitroprusside (SNP 2-8 microg/min; a control endothelium-independent vasodilator).

Baseline plasma t-PA antigen concentrations were higher in patients (14+/-2 vs 9+/-1 ng/mL; p<0.05) whereas plasma plasminogen activator inhibitor type-1 (PAI-1) antigen concentrations were similar (59+/-16 vs 55+/-11 ng/mL; p=NS). This resulted in an increased t-PA activity (3+/-1 vs 0+/-0 IU/mL; p<0.05) and reduced PAI-1 activity (9+/-2 vs 21+/-2 AU/mL; p<0.05) indicating a relative deficiency of PAI-1 in patients with cirrhosis. Bradykinin and SNP caused dose-dependent vasodilatation (p<0.001 for both) that did not differ between the two groups. Bradykinin caused a similar release of t-PA antigen (p<0.05 for both) in both patients and controls (24+/-17 vs 23+/-7 ng/100 mL/min; p=ns) without affecting PAI-1 concentrations. Local t-PA activity was increased in patients following acute stimulated t-PA release (5+/-1 vs 3+/-1 IU/mL; p<0.05). SNP caused no significant change in fibrinolytic parameters.

Patients with alcoholic cirrhosis have a higher basal plasma t-PA activity because of a failure to increase plasma concentrations of its inhibitor, PAI-1. Furthermore, despite releasing normal amounts of t-PA acutely, higher t-PA activity remained due to the relative deficiency of PAI-1. This suggests that the pathogenesis of hyperfibrinolysis in alcoholic cirrhosis is the result of a relative PAI-1 deficiency and enhanced basal t-PA release.

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.

To examine the relationship of both the unstimulated and the postprandial portal blood flow (PVF) to the time of day and to determine its intra-individual reproducibility over time in patients with liver cirrhosis.

In 24 cirrhotic patients, 27 PVF measurements were performed during 24 h on day 0 and day 7 using Doppler ultrasound. Three standard liquid meals were given orally. On day 7, the baseline hepatic venous pressure gradient (HVPG) was also measured.

Circadian area under the time curve of PVF was highly reproducible within individuals (r=0.959, p<0.001). It did not correlate with HVPG. Cosinor analysis showed a significant circadian rhythm of PVF (acrophase at 11:44 and amplitude of 9.44%). Maximal postprandial increase in PVF was significantly higher in the morning than at noon or in the evening.

PVF is subject to a circadian rhythm and postprandial portal hyperemia shows a diurnal variability. Both are highly reproducible.

Several studies have suggested the existence of seasonal variation in the incidence of upper gastrointestinal bleeding (UGB). However, the role of climatic factors has not been elucidated. The aim of the present study was to investigate the role of these factors in the incidence of UGB secondary to esophageal varices (EV), gastric ulcer (GU), and duodenal ulcer (DU).

Based on the use of the Minimum Data Set and the International Classification of Diseases, cases of endoscopically-confirmed UGB secondary to EV, GU and DU were retrospectively included (1998-2001). The incidence of UGB was correlated with daily climatic factors (temperature, atmospheric pressure, humidity, direction and speed of wind) in Jerez de la Frontera (Spain) during the study period.

A total of 499 patients were included (GU = 192, DU = 199, EV = 108). No significant differences were found in the monthly or seasonal incidence of UGB. Episodes of UGB were grouped according to the climatic conditions present on the day of admission. No significant relationship was found between UGB and any of the daily climatic factors studied.

The results of our study do not support the existence of a seasonal pattern in the incidence of UGB secondary to GU, DU or EV and allow us to conclude that, in our geographical area, these factors are not involved in episodes of bleeding.

Long-acting somatostatin analogues have been suggested as an alternative to propranolol for the prevention of variceal rebleeding.

To compare the effectiveness of lanreotide SR, a new depot formulation injected once-weekly, and propranolol in reducing circadian portal blood flow (PVF) and meal-stimulated hepatic venous pressure gradient (HVPG) in patients with liver cirrhosis.

Patients were randomized to receive either lanreotide SR intramuscularly (30 mg once weekly, n=12) or propranolol (n=12) orally. Hemodynamic measurements were performed on day 0 and on day 21 after a 3-week period of drug administration, while patients received three standard oral liquid test meals. On each study day 27 PVF measurements were performed over 24 h and eight measurements of HVPG during the first postprandial period.

Propranolol was more effective than lanreotide SR in reducing baseline HVPG (-21.9 vs. -13.6%, P=0.04) and meal-stimulated HVPG (-16.6 vs. -3.8%, P=0.04). Propranolol reduced circadian PVF significantly by 9.3% (P=0.03) but not lanreotide SR.

Long-term treatment with propranolol reduced baseline and postprandial HVPG and circadian PVF, while lanreotide SR did not. The results of our study do not encourage clinical testing of lanreotide SR 30 mg for the prevention of variceal haemorrhage.

The circadian variation in portal blood pressure and in the diurnal incidence of variceal bleeding is well known, but the seasonal variation in variceal bleeding is still controversial. This report analyzes the seasonal variations in mortality and hospitalizations due to variceal bleeding in the French population.

All the deaths due to variceal bleeding that occurred from 1987 to 1996 (N = 13,514) and all adults discharged from French public hospitals for variceal bleeding from 1995 to 1997 (N = 17,026) were examined retrospectively. Cumulated monthly averages were expressed as the percentage above or below the average monthly value during the entire study period.

Deaths due to variceal bleeding in France occurred with a clear annual periodicity and peaked in winter (December/January), both in the overall population and in subgroups defined by age and sex, except for women. The distribution of cumulative monthly deaths differed by 24%, with a peak (14% above average) in December and a trough (10% below average) in July (Roger's test: p < 0.001). Hospitalizations for variceal bleeding in French public hospitals followed a similar seasonal pattern (p < 0.001) with a winter-spring predominance (4% to 7% from December through April), except in patients aged 15-49 yr. There was a short sharp peak of mortality in early winter in French public hospitals. The seasonality of hospitalization and death increased markedly with age.

A better understanding of these age- and sex-specific seasonal patterns would allow to improve pharmacological protection measures, disease management, and educational strategies.

Variceal bleeding, whose triggering mechanisms are largely unknown, occurs with a circadian rhythmicity, with 2 peaks, one greater, in the evening, and one smaller, in the early morning. We assessed some clotting and hemodynamic parameters, possibly involved in variceal hemorrhage, over a 24-hour period, at 4-hour intervals, in 16 patients with cirrhosis and esophageal varices and in 9 controls. At each time interval, tissue plasminogen activator (tPA) and tPA inhibitor-1 (PAI-1) antigens and activities and total euglobulin fibrinolytic activity were determined and portal-vein flow velocity, volume, and congestion index were measured by duplex-Doppler. Significant circadian rhythms were searched for by least-squares and cosinor methods. tPA activity showed a circadian rhythm in cirrhosis, with a peak of 2.85 times the trough value, calculated at 18:42, and remained over 2.5-fold until shortly after 22:00. Total fibrinolytic activity showed a similar pattern, which was statistically significant also in controls. tPA and PAI antigens also showed significant circadian rhythm both in controls and cirrhotics, with higher values in the morning. Among the portal hemodynamic parameters only the congestion index showed significant rhythmic changes and only in cirrhosis, with the highest values in the late evening, but with limited diurnal excursion (+/- 5.5%). In conclusion, we showed the existence of a circadian rhythm of fibrinolysis in cirrhosis, whose temporal distribution might suggest a role of fibrinolysis in variceal hemorrhage on the basis of the comparison to the known chronorisk of variceal bleeding.