Aggressive gastric carcinoma producing alpha-fetoprotein: a case report and review of the literature.

A 65-year-old man presented to our hospital with abdominal pain, dyspepsia and anorexia. Laboratory tests showed an altered liver function and abdomen ultrasonography revealed multiple liver nodules, suspected to be metastatic lesions. Serous tumor markers were elevated and a very high level of alpha-fetoprotein was found. Computer tomography confirmed the hepatic lesions and disclosed a thickening of the lesser curvature of the gastric wall. A subsequent endoscopy showed an ulcer on the lesser curvature. Biopsies taken from the gastric ulcer and the liver nodule revealed an adenocarcinoma, both of gastric origin. Shortly after the diagnosis, the patient's condition worsened and he died only 15 days later. This case report illustrates how alpha-fetoprotein-producing gastric adenocarcinomas have a high incidence of venous and lymphatic invasion and a rapid hepatic spread with a very poor prognosis.

Madelung disease : report of a case and review of the literature.

Madelung disease is a rare disorder characterized by the presence of multiple, symmetric, nonencapsulated fatty accumulations diffusely involving the cheeks, the neck, the upper trunk, the shoulder girdle area, and the upper extremities. The cause of this syndrome is unknown, but it has been associated with alcoholism in 60% to 90% of -patients. The long-term lipomatous deposits are often large and cosmetically deforming, and the upper aerodigestive tract and great veins may be compressed. We report the case of a man with MD, involving the cervical and upper dorsal -regions, who underwent surgical treatment at our Department.

The transcriptional regulators, the immune system and the the circadian clock.

The immune system function oscillates with a 24-hour period driving circadian rhythmicity of immune responses. A circadian timing system comprising central and peripheral oscillators entrains body rhythmicity of physiology and behavior to environmental cues by means of humoral signals and autonomic neural outputs. In every single cell an oscillator goes ticking through a molecular clock operated by transcriptional/translational feedback loops driven by the rhythmic expression of circadian genes. This clock gene machinery steers daily oscillations in the regulation of immune cell activity, driving the periodicity in immune system function. The transcriptional networks that regulate temporal variation in gene expression in immunocompetent cells and tissues respond to diverse physiological clues, addressing well-timed adjustments of transcription and translation processes. Nuclear receptors comprise a unique class of transcriptional regulators that are capable of gauging hormones, metabolites, endobiotics and xenobiotics, linking ligand sensing to transcriptional responses in various cell types through switching between coactivator and corepressor recruitment. The expression of coregulators is highly responsive to physiological signals, and plays an important role in the control of rhythmic patterns of gene expression, optimizing the switch between nycthemeral patterns, and synchronizing circadian rhythmicity with changing physiological demands across the light-dark cycle. The nuclear receptors and transcription factors expressed in the immune components contribute to the cross-talk between the circadian timing system, the clock gene machinery and the immune system, influencing transcriptional activities and directing cell-type specific gene expression programs linked to innate and adaptive immune responses.

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.

A timetable of 24-hour patterns for human lymphocyte subpopulations.

Specific lymphocyte cell surface molecules involved in antigen recognition and cell activation present different circadian patterns, with peaks and troughs reflecting a specific time-related compartment of immune cell function. In order to study the dynamics of variation in expression of cytotoxic lymphocyte cell surface molecules that trigger immune responses, several lymphocyte cell surface clusters of differentiation (CD) and antigen receptors, analyses were performed on blood samples collected every 4 h for 24 h from eleven clinically-healthy men. Assays for serum melatonin (peaking at night) and cortisol (peaking near awakening) confirmed 24-h synchronization of the subjects to the light-dark schedule. A significant (p≤0.05) circadian rhythm could be demonstrated for six of the 10 lymphocyte subpopulations, with midday peaks for CD8+dim (T cytotoxic cells, 11:15 h), gammadeltaTCR (gamma-delta T cell receptor-expressing cells, 11:33 h), CD8+ (T suppressor/cytotoxic cells, 12:08 h), and for CD16+ (natural killer cells, 12:59 h), and peaks during the night for CD4+ (T helper/inducer cells, 01:23 h) and CD3+ (total T cells, 02:58 h). A borderline significant rhythm (p = 0.056) was also observed for CD20+ (total B cells), with a peak late in the evening (23:06 h). Acrophases for 3 subsets, CD8+bright (T suppressor cells, 15:22 h), HLA-DR+ (B cells and activated T cells, 23:06 h) and CD25+ (activated T lymphocytes with expression of the alpha chain of IL2 receptor, 23:35 h), where a 24-h rhythm could not be definitively determined, nevertheless provide information on the location of their highest values and possible physiological significance. Thus, specific lymphocyte surface molecules present distinctly-timed profiles of nyctohemeral changes that indicate a temporal (i.e., circadian) organization of cellular immune function, which is most likely of physiological significance in triggering and regulating immune responses. Such a molecular cytotoxic timetable can potentially serve as a guide to sampling during experimental, diagnostic, therapeutic and/or other medical procedures.

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.

Change of γδTCR-expressing T cells in healthy aging.

A mature T-cell lineage with the capacity to proliferate in response to receptor-mediated signals and to display non-major histocompatibility complex (MHC)-restricted cytolysis expresses a CD3-associated heterodimer made up of the protein encoded by the T-cell receptor (TCR) gamma-gene. We investigated the possible differences in lymphocyte subpopulations between healthy young-middle-aged and elderly subjects, focusing attention on γδ-TCR-expressing cells. The study was carried out on fifteen healthy young-middle-aged male subjects (age range 36-55 years) and fifteen healthy elderly male subjects (age range 67-79 years). Lymphocyte subpopulations were analyzed in blood samples collected every four hours for 24 hours. The presence of circadian rhythmicity on absolute counts was validated to evaluate the periodicity of variation, and the fractional variation between single time point values was calculated to evaluate the dynamics of variation. In the group of young and middle-aged subjects a clear circadian rhythm was validated for the time-qualified changes of all the lymphocyte subpopulations (CD3, CD4, CD4/CD8 ratio, CD20, CD25 and HLA-DR with acrophase at night, CD8, CD16 and TcR γδ with acrophase at noon). In the group of elderly subjects a clear circadian rhythm was validated for the nyctohemeral changes of CD3, CD8, CD4/CD8 ratio, CD16, CD25. There was a statistically significant difference for the Midline Estimating Statistic of Rhythm (MESOR) of CD3 (p=0.001), CD25 (p=0.003) and γδ-TCR-expressing cells (p=0.004), higher in the elderly, and for the MESOR of HLA-DR (p=0.002) and CD20 (p=0.002) higher in the young and middle-aged subjects. There was a statistically significant difference between the groups in the fractional variation of TcR γδ-expressing cells between 18:00h and 22:00h values (higher in elderly subjects, p=0.007). In conclusion, specific lymphocyte subsets present different levels and different profiles of nyctohemeral changes in healthy young-middle aged in respect to elderly subjects, since B cells are decreased, whereas CD25 and γδ -TCR-bearing cells are higher in the elderly, but the rhythm and the dynamics of variation of this lymphocyte subset is severely altered and this phenomenon might contribute to the onset of age-related variations of the immune responses.

Prophylactic surgery in Lynch syndrome.

Lynch syndrome (LS) is caused by a germline mutations in DNA mismatch repair genes and is a dominantly inherited syndrome, responsible for 2-5% of all colorectal cancer (CRC) cases. Mutation carriers have a 60-85% risk of developing CRC. With the increasing use of genetic predisposition testing, patients and health care providers must decide on cancer risk-reduction strategies. The cancers observed in families with LS are diagnosed at an unusually early age and may be multiple. The decision about which surgery is suitable should be made on the basis of patient factors and preferences, with special emphasis on age, comorbidity, sphincteric function, and the ability of the patient to cope with intensive surveillance. Colectomy decreases the risk of second CRC significantly. The estimated lifetime risk for endometrial adenocarcinoma is 40-60% in women with LS, and the mean age at diagnosis is around 50 years. This risk equals or exceeds the risk of CRC. The optimal management of the elevated risk for cancer in carriers of mutations for hereditary nonpolyposis colorectal cancer is unclear. Patients who are gene mutation carriers should receive counseling about colectomy, and if women, prophylactic hysterectomy and bilateral oophorectomy.

Hypothalamus-hypophysis-thyroid axis function in healthy aging.

There is an increased frequency of dysthyroidism in elderly people. We investigated whether there are differences among healthy young middle-aged and elderly people in the 24 hour secretory profiles of TRH, TSH and free thyroxine. The study was carried out on fifteen healthy young, middle-aged subjects (range 36-55 years, mean age±s.e. 44.1±1.7) and fifteen healthy elderly subjects (range 67-79 years, mean age±s.e. 68.5±1.2). TRH, TSH and free thyroxine serum levels were measured in blood samples collected every four hours for 24 hours. The area under the curve (AUC), the mean of 06:00h-10:00h-14:00h and the mean of 18:00h-22:00h-02:00h hormone serum levels and the presence of circadian rhythmicity were evaluated. A normal circadian rhythmicity was recognizable for TRH and TSH in young, middle-aged subjects and for TSH in elderly subjects. Elderly subjects presented lower TSH levels, whereas there was no statistically significant difference in TRH and free thyroxine serum levels between young, middle-aged and elderly subjects. Aging is associated with an altered TSH secretion.

WITHDRAWN: Neuroendocrine axes function in healthy aging: Evaluation of predictive and manipulable blood serum indexes.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.biomag.2010.09.002. The duplicate article has therefore been withdrawn.

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.

Liver failure complicating segmental hepatic ischaemia induced by a PTFE-coated TIPS stent.

The use of polytetrafluoroethylene (PTFE)-covered prostheses improves trans-jugular intrahepatic porto-systemic shunt (TIPS) patency and decreases the incidence of clinical relapses and re-interventions. Therefore, the improvement provided by covered stents might expand the currently accepted recommendations for TIPS use. Stent-related occlusion of the hepatic vein with consequent ischaemia of the corresponding liver parenchyma emerges as a novel complication reported in at least 5% of patients implanted with coated stents. However, this complication was reported to be mild, without signs or symptoms of liver failure, and self-limiting. We report a case of segmental liver ischaemia following PTFE-covered stent placement resulting in a marked impairment in liver function in a patient with hepatitis C virus cirrhosis implanted because of refractory oesophageal bleeding, thus expanding the severity range of this new procedural complication. Moreover, we discuss the possible involvement of additional pathogenetic mechanisms other than out-flow obstruction in the onset of coated-stent induced congestive liver ischaemia.

Adiponectin and the cardiovascular system: from risk to disease.

Adiponectin is known to play a role in fatty acid and glucose metabolism through a change in insulin sensitivity and activation of fuel oxidation by AMP-activated protein kinase. Adiponectin can be considered an important factor able to modulate the adipovascular axis which, through genomic and environmental influences, affects the cardiovascular risk milieu, from the pre-metabolic syndrome-- through the metabolic syndrome--to the overt atherosclerotic process and its clinical manifestations. Hypoadiponectinaemia can be viewed as an early sign of a complex cardiovascular risk factor predisposing to the atherosclerosis process as well as a contributing factor accelerating the progress of the atherosclerotic plaque. In addition, adiponectin per se holds a protective role thanks to its anti-inflammatory and antiatherogenic properties. The early identification of patients "at cardiovascular risk" means in the current practice to search for indexes of metabolic derangements and pro-inflammatory status (adiponectin) from adolescence and childhood.

ADMA correlates with portal pressure in patients with compensated cirrhosis.

BACKGROUND: Chronic liver diseases are frequently complicated by portal hypertension, an important component of which is the increased intrahepatic vascular resistance, in part related to endothelial dysfunction. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is an established mediator and marker of endothelial dysfunction. We therefore investigated the possible implication of ADMA in chronic liver diseases-induced portal hypertension. MATERIALS AND METHODS: We studied 39 consecutive patients with compensated hepatitis C virus (HCV) related chronic liver diseases. All patients underwent hepatic venous pressure gradient (HVPG) measurement, and simultaneous blood sampling from the hepatic vein and the pulmonary artery, for ADMA and nitrite/nitrate (NOx) plasma level determinations. RESULTS: A positive correlation between HVPG and ADMA concentrations in hepatic veins (ADMA-h) was found (r = 0.77, P < 0.0001). Moreover, a negative correlation between HVPG and NOx concentrations in the hepatic veins (NO-h) (r = -0.50, P = 0.005), and between ADMA-h and NO-h was observed (r = -0.40, P = 0.02). ADMA concentrations in pulmonary artery (ADMA-p) (0.55 +/- 0.13 micromol L(-1)) were significantly higher than in hepatic veins (0.47 +/- 0.09 micromol L(-1)) (P < 0.0001). CONCLUSIONS: These results suggest that ADMA may play a pathophysiological role in portal hypertension by contributing to the relative intrahepatic NO deficiency typical of endothelial dysfunction.

CHRONOBIOLOGY OF HIGH BLOOD PRESSURE.

BIOCOS, the project aimed at studying BIOlogical systems in their COSmos, has obtained a great deal of expertise in the fields of blood pressure (BP) and heart rate (HR) monitoring and of marker rhythmometry for the purposes of screening, diagnosis, treatment, and prognosis. Prolonging the monitoring reduces the uncertainty in the estimation of circadian parameters; the current recommendation of BIOCOS requires monitoring for at least 7 days. The BIOCOS approach consists of a parametric and a non-parametric analysis of the data, in which the results from the individual subject are being compared with gender- and age-specified reference values in health.Chronobiological designs can offer important new information regarding the optimization of treatment by timing its administration as a function of circadian and other rhythms.New technological developments are needed to close the loop between the monitoring of blood pressure and the administration of antihypertensive drugs.

Circasemidian rather than circadian variation of circulating osteoprotegerin in clinical health.

Osteoprotegerin (OPG) serves as a soluble decoy receptor for RANKL to inhibit osteoclast formation and activity. Hormones such as PTH and glucocorticoids have been reported to decrease OPG concentrations, while estrogens, transforming growth factor b, related bone morphogenic factor and thrombopoietin reportedly enhance the OPG production in the osteoblastic and bone stromal cells. Since bone turnover shows a prominent circadian rhythm in laboratory animals and humans, with bone resorption increasing at night, we investigated the time structure of circulating OPG concentrations in a group of nine healthy subjects (six women and three men; in the age range of 26-49 years). Blood samples for OPG determination were collected every 4 h for 24 h on the same day, starting at 08:00 in the morning. Data were analyzed by inferential statistical procedures, including the single and population-mean cosinor. A 12-h component was found to characterize serum OPG concentrations (P = 0.038) with peak concentrations around noon and midnight. No statistically significant circadian rhythm of OPG concentrations could be found by cosinor in our study population. The mean 24-h OPG concentration was higher in women than in men (mean +/- S.E.: 3.13 +/- 0.44 vs. 1.94 +/- 0.26 pmol/l, Student t = 2.325, P = 0.053). Since PTH concentrations also exhibit a bimodal pattern along the 24-h scale, PTH may be tested as a putative determinant of the observed changes in serum concentrations of osteoprotegerin.

Chronomics, neuroendocrine feedsidewards and the recording and consulting of nowcasts--forecasts of geomagnetics.

A multi-center four-hourly sampling of many tissues for 7 days (00:00 on April 5-20:00 to April 11, 2004), on rats standardized for 1 month in two rooms on antiphasic lighting regimens happened to start on the day after the second extremum of a moderate double magnetic storm gauged by the planetary geomagnetic Kp index (which at each extremum reached 6.3 international [arbitrary] units) and by an equatorial index Dst falling to -112 and -81 nT, respectively, the latter on the first day of the sampling. Neuroendocrine chronomes (specifically circadian time structures) differed during magnetically affected and quiet days. The circadian melatonin rhythm had a lower MESOR and lower circadian amplitude and tended to advance in acrophase, while the MESOR and amplitude of the hypothalamic circadian melatonin rhythm were higher during the days with the storm. The circadian parameters of circulating corticosterone were more labile during the days including the storm than during the last three quiet days. Feedsidewards within the pineal-hypothalamic-adrenocortical network constitute a mechanism underlying physiological and probably also pathological associations of the brain and heart with magnetic storms. Investigators in many fields can gain from at least recording calendar dates in any publication so that freely available information on geomagnetic, solar and other physical environmental activity can be looked up. In planning studies and before starting, one may gain from consulting forecasts and the highly reliable nowcasts, respectively.