Hormone and cytokine circadian alteration in non-small cell lung cancer patients.

Alterations in hormone secretion and cytokine levels have been evidenced in many neoplastic diseases. In this study we have evaluated the circadian profile of growth hormone (GH), insulin-like growth factor-1 (IGF-1), interleukin-2 (IL2), melatonin (MEL) and cortisol (COR) serum levels in non-small cell lung cancer patients. Blood was sampled every 4 h for 24 h in 11 healthy (H) men (ages 35-53 years) and 9 men with stage 2, 3 or 4 non-small cell lung cancer (C) (ages 43-63 years). Serum GH, total IGF1, IL2, MEL and COR were measured and examined for group differences, trends, and rhythm characteristics. 24-h means were significantly higher in C234 vs H for GH, GH/IGF1, IL2 and COR, and lower for IGF1, but IL2 and COR were not different for C23 vs H. A linear regression across 4 groups (H, C2, C3, C4) found a positive trend for COR, GH, GH/IGF1 and IL2, and a negative trend for IGF1. A linear regression run between the 24-h mean levels of GH, IGF1, COR, MEL and IL2 in healthy subjects evidenced a statistically significant positive trend between MEL and GH (R = 0.281, p = 0.022) and in cancer patients showed a statistically significant negative trend between GH and IGF1 (R = 0.332, p = 0.01), COR and IGF1 (R=0.430, p=0.001), and a statistically significant positive trend between the 24-h mean of COR and GH (R = 0.304, p = 0.02). Rhythms in MEL and COR (peaks near 01:00h and 08:00h, respectively) indicated identical synchronization to the light-dark cycle for both groups. A circadian rhythm was detected in GH and GH/IGF1 for C23 and H, with IGF1 and IL2 non-rhythmic in any group. In conclusion, an increasing trend and progressive loss of circadian rhythmicity in GH and GH/IGF1, an increasing trend in cortisol and IL2, and a decreasing trend in IGF1 in C, reflect a complex chain of events that could be involved in progression of neoplastic disease. A therapeutic strategy needs to take into account circadian patterns and complex interactions of the multiple functions that characterize the hormone and cytokine levels in the frame cancer progression.

Alteration of circadian rhythmicity of CD3+CD4+ lymphocyte subpopulation in healthy aging.

The CD4+ T helper/inducer and the CD8+ T suppressor/cytotoxic are major lymphocyte subsets that play a key role in cell-mediated immunity. Aging-related changes of immune function have been demonstrated. The purpose of this study is to analyze the dynamics of variation of these specific lymphocyte subsets in the elderly. In our study cortisol and melatonin serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from fifteen healthy young middle-aged subjects (age range 36-55 years) and fifteen healthy elderly male subjects (age range 67-79 years). A clear circadian rhythm was validated for the time-qualified changes of CD3+ and CD4+ cells with acrophase at night and for the time-qualified changes of CD8+ cells with acrophase at noon in young middle-aged subjects and for the time-qualified changes of CD3+ cells with acrophase at night and for the time-qualified changes of CD8+ cells with acrophase at noon in elderly subjects. No clear circadian rhythm was validated for the time-qualified changes of CD4+ cells in elderly subjects. No statistically significant correlation among lymphocyte subsets was found in elderly subjects. In elderly subjects CD3+ lymphocyte percentage was higher in the photoperiod and in the scotoperiod and cortisol serum level were higher in the scotoperiod in respect to young middle-aged subjects. In the elderly there is an alteration of circadian rhythmicity of T helper/inducer lymphocytes and this phenomenon might contribute to the aging-related changes of immune responses.

Neuro-endocrine correlations of hypothalamic-pituitary-thyroid axis in healthy humans.

Neuro-endocrine hormone secretion is characterized by circadian rhythmicity. Melatonin, GRH and GH are secreted during the night, CRH and ACTH secretion peak in the morning, determining the circadian rhythm of cortisol secretion, TRH and TSH show circadian variations with higher levels at night. Thyroxine levels do not change with clear circadian rhythmicity. In this paper we have considered a possible influence of cortisol and melatonin on hypothalamic-pituitary-thyroid axis function in humans. Melatonin, cortisol, TRH, TSH and FT4 serum levels were determined in blood samples obtained every four hours for 24 hours from ten healthy males, aged 36-51 years. We correlated hormone serum levels at each sampling time and evaluated the presence of circadian rhythmicity of hormone secretion. In the activity phase (06:00 h-10:00 h-14:00 h) cortisol correlated negatively with FT4, TSH correlated positively with TRH, TRH correlated positively with FT4 and melatonin correlated positively with TSH. In the resting phase (18:00 h-22:00 h-02:00 h) TRH correlated positively with FT4, melatonin correlated negatively with FT4, TSH correlated negatively with FT4, cortisol correlated positively with FT4 and TSH correlated positively with TRH. A clear circadian rhythm was validated for the time-qualified changes of melatonin and TSH secretion (with acrophase during the night), for cortisol serum levels (with acrophase in the morning), but not for TRH and FT4 serum level changes. In conclusion, the hypothalamic-pituitary-thyroid axis function may be modulated by cortisol and melatonin serum levels and by their circadian rhythmicity of variation.

Circadian rhythmicity of lymphocyte subpopulations and relationship with neuro-endocrine system.

Lymphocyte subpopulations present circadian variation of some of their subsets, this variation may influence magnitude and expression of the immune responses and may be related to the variation of neuro-endocrine humoral factors. In our study cortisol, melatonin, TRH, TSH, FT4, GH, IGF1 and IL2 serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from 11 healthy male subjects aged 38-55 years. A clear circadian rhythm was validated for cortisol serum levels, CD8, CD16, TcRδ1 with acrophase in the morning and at noon, and for melatonin, TRH, TSH, GH, CD3, CD4, CD4/CD8 ratio, HLA-DR, CD20 and CD25 with acrophase at night. Changes of serum levels of FT4, IGF1 and IL2 did not show circadian rhythmicity. In the photoperiod (06.00-18.00h) and in the scotoperiod (18.00-06.00h) there were significant correlations among the lymphocyte subpopulations and humoral factors studied. The results show that specific lymphocyte subsets present different profiles of nyctohemeral changes and different timed relationships with neuro-endocrine hormones.

Circadian variations of cortisol, melatonin and lymphocyte subpopulations in geriatric age.

A number of age-related changes in the 24-hour hormonal and non-hormonal rhythms have been found in older human beings. Lymphocyte subpopulations present circadian variation of some of their subsets and this variation may influence magnitude and expression of the immune responses. Numerous interactions exist among the nervous, endocrine and immune systems, mediated by neurotransmitters, hormones and cytokines. The aim of this study is to evaluate circadian variations of some endocrine and immune factors in older adults. Cortisol and melatonin serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from ten healthy young and middle-aged subjects and from ten healthy elderly subjects. There was a statistically significant difference between the groups in the observed values of CD20 (higher in young and middle-aged subjects) and CD25 and DR+ T cells (higher in elderly subjects). In the group of young and middle-aged subjects a clear circadian rhythm was validated for the time-qualified changes of all the factors studied. In the group of elderly subjects a number of rhythms were absent or altered. The results of the current study show that aging is associated with enhanced responsiveness of T cell compartment and alterations of circadian rhythmicity.

The hypothalamic-pituitary-thyroid axis and melatonin in humans: possible interactions in the control of body temperature.

OBJECTIVE: Melatonin plays a role in the regulation of biological rhythms, body temperature presents circadian variations with lower levels during nighttime, when melatonin levels are very high, and thyroid hormones influence shiver independent thermogenesis. We have investigated on possible interactions between the hypothalamic-pituitary-thyroid axis and melatonin in the control of body temperature in humans. METHODS: Peripheral blood samples for thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH), free-thyroxine (FT4), melatonin levels determination and body temperature measurements were obtained every four hours for 24-hours starting at 0600 h in a controlled temperature and light-dark environment from ten healthy males, aged 38-65 (mean age +/-s.e. 57.4+/-3.03, mean body mass index +/-s.e. 25.5+/-0.75). We calculated fractional variation and correlation on single time point hormone serum levels and tested whether the time-qualified data series showed consistent pattern of circadian variation. RESULTS: A statistically significant difference was evidenced for the fractional variation of daytime TSH serum levels (0600 h-1000 h vs. 1000 h-1400 h, p=0.01, 1000 h-1400 h vs. 1400 h-1800 h, p=0.0001, 1400 h-1800 h vs. 1800 h-2200 h, p=0.001) and for the fractional variation of FT4 serum levels at 1800 h-2200 h vs. 2200 h-0200 h (p=0.02). FT4 serum levels correlated positively with TRH serum levels at 1000 h (r=0.67, P=0.03) and at 1400 h (r=0.63, p=0.04), negatively with TSH serum levels at 2200 h (r=-0.67, p=0.03), negatively with melatonin serum levels at 2200 h (r=-0.64, p=0.04) and at 0200 h (r=-0.73, p=0.01). TRH serum levels correlated positively with TSH serum levels at 0200 h (r=0.65, p=0.04) and at 0600 h (r=0.64, p=0.04). Body temperature correlated positively with FT4 serum levels at 1000 h (r=0.63, p=0.04) and negatively with melatonin serum levels at 0200 h (r=-0.64, p=0.04). A clear circadian rhythm was validated for body temperature (with acrophase in the morning) and melatonin, TRH and TSH secretion (with acrophase at night), while FT4 serum level changes presented ultradian periodicity (with acrophase in the morning). CONCLUSION: Changes of TSH serum levels are smaller and those of FT4 are greater at night, when melatonin levels are higher, so that the response of anterior pituitary to hypothalamic TRH and of thyroid to hypophyseal TSH may be influenced by the pineal hormone that may modulate the hypothalamic-pituitary-thyroid axis function and influence the circadian rhythm of body temperature.

Immune system alterations in lung cancer patients.

The immune system plays an important role in the defense against neoplastic disease and immune responses show temporal changes related to circadian variations of antibodies, total lymphocytes in the peripheral blood and cell mediated immune responses. In this study we evaluate. lymphocyte subpopulations and interleukin-2 (IL-2) serum levels in peripheral blood samples collected at four-hour intervals for 24-hours starting at 06.00 h from ten healthy subjects aged 65-79 years (mean age +/- s.e. 67.28 +/- 3.11) and from ten subjects suffering from untreated non small cell lung cancer aged 65-78 years (mean age +/- s.e. 68.57 +/- 1.81). Areas under the curve, mean diurnal levels (mean of 06.00-10.00-14.00 h) and mean nocturnal levels (mean of 18.00-22.00-02.00 h) were calculated, and the presence of circadian rhythmicity was evaluate. When we compared AUC values there was a decrease in CD8bright (T suppressor subset) and an increase in CD16 (natural killer cells) and of IL-2 serum levels in cancer patients. When we compared mean diurnal levels, CD8 (T suppressor/cytotoxic subset) and CD8bright levels were lower, and CD16 levels were higher in cancer patients. When we compared mean nocturnal levels, CD16 and CD25 (T and B activated lymphocytes with expression of the a chain of IL-2 receptor) levels were higher, while CD8, CD8bright, CD20 (total B-cells), TcRd1 (epitope of the constant domain of d chain of T-cell receptor 1) and dTcS1 (epitope of the variable domain of d chain of T-cell receptor1) levels were lower in cancer patients. A clear circadian rhythm was validated for the time-qualified changes in CD4, CD20, HLA-DR with acrophase at night, and CD8, CD8 bright, CD8 dim, CD16, TcRd1 and dTcS1 with acrophase in the morning in the control group. A clear circadian rhythm was validated for the time-qualified changes in CD4 with acrophase at night, in the group of cancer patients. Results obtained in our study show that lung cancer is associated with anomalies of proportion and circadian variations of lymphocyte subsets that must be considered when adoptive immunotherapy has to be planned.

Nodular regenerative hyperplasia of the liver: ultrasonographic appearance and echo-guided bioptic diagnosis.

Nodular regenerative hyperplasia of the liver is characterized by multiple and usually small nodules of hyperplastic hepatocytes surrounded by compressed atrophic liver cells. Given the small size of nodules and the preserved framework, the imaging techniques often show a normal liver and blind percutaneous biopsy is misinterpreted. The Authors report two cases of nodular regenerative hyperplasia diagnosed by ultrasound and percutaneous echoguided biopsy.

Cruveilhier-Baumgarten syndrome: an efficient spontaneous portosystemic collateral preventing oesophageal varices bleeding.

The protective role of large spontaneous portosystemic shunts in oesophageal varices bleeding due to portal hypertension in liver cirrhosis is still debated. A series of 20 consecutive patients with haemodynamically efficient collaterals involving the para-umbilical-epigastric venous route (evaluated by Echo-Doppler flowmetry) is reported. All patients presented absent or mild oesophageal varices at endoscopy. During a mean follow-up period of 23.5 months, no patient developed large varices or experienced variceal bleeding. Hepatic encephalopathy was present in 35% of patients. Haemodynamically efficient spontaneous portosystemic shunts may protect cirrhotic patients from the risk of oesophageal varices forming and bleeding. The diversion of large amounts of blood from portal to systemic circulation correlates with the higher trend of hepatic encephalopathy in these patients.

[Bile acids in the therapy of chronic liver diseases]. / Gli acidi biliari nella terapia delle epatopatie croniche.

In the last 10 years, interest about the employment of bile acids, especially of ursodeoxycholic acid (UDCA), in the treatment of chronic liver diseases has increased. The mechanism has not been completely explained yet, but this agent has been thought to act mainly by making bile less toxic for the liver cells, reducing the fraction of hydrophobic detergent bile acids. UDCA is effective in decreasing serum concentrations of liver enzymes in chronic liver diseases, especially in those associated with cholestasis. This effect discloses new perspectives about the employment of this agent, even in association with other drugs, i.e. interferon; however, further investigations will be necessary in order to standardize the use of UDCA in the treatment of chronic liver diseases.

[Recurrent cardiac echinococcosis: a report of a case with multiple intrapericardial cysts]. / Echinococcosi cardiaca recidivante: descrizione di un caso con cisti multiple intrapericardiche.

A case of an isolated recurrent cardiac hydatidosis with multiple intrapericardial cysts is presented. The patient, who underwent 2 previous surgical resection of intramyocardial and pericardial hydatid cysts, presented with atypical chest pain. The ECG and the perfusion scintigraphy with 201-thallium showed a previous lateral myocardial infarction. The diagnosis of recurrent cardiac hydatidosis was made by two-dimensional echocardiography and computed tomography and was confirmed by clinical and biochemical findings.

[Cardiac and metabolic investigations during 24 hour endurance skiing (Pinzolo, Italy)]. / Indagini cardiologiche e metaboliche nel corso di una 24 ore di sci da fondo (Pinzolo, Italia).

In the "24-hour Cross Country Ski Race of Pinzolo" skiers attempt to cover as long as possible distances within 24 hours. Cardiac and metabolic changes of 6 volunteer cross country skiers, aging 29 to 39 years, participating to the individual competition, were analysed. All skiers had negative clinical examination and resting standard 12-lead ECG, except for one who had a midsystolic click on auscultation suggesting the presence of mitral valve prolapse. They were submitted to 48-hour Holter monitoring (HM) going from 3:00 p.m. of the day before the race up to one hour after the end of competition. The period of HM going from 3 p.m. of the day before to 1.00 p.m. of the day of race (one hour before the start) was utilized as control as concerns arrhythmias, ST-T wave and QT interval changes observed during the period of competition. In all 6 skiers, standard 12-lead ECG was again recorded on completion of race. The following serum indexes were obtained in basal conditions and within one hour after the end of race: electrolytes (Na+, K+), Myoglobina (MG) and the enzymes GOT, GPT, LDH, CK and CK-MB. Complete urine analysis was also obtained before and immediately after the race. The distance covered by the skiers ranged from 189 to 260 Km, except for the skier with systolic click who covered 95.7 Km within 12 hour and then retired from the race for acute pain of knee.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of ankylosing spondylitis with hairy cell leukemia: a previously once reported case.

We report a case of ankylosing spondylitis associated with hairy cell leukemia. This is the second observed case (I3) of ankylosing spondylitis with a B-type lymphoproliferative disorder which allows us to make some observations about the pathogenesis of these rare diseases.