Baseline metabolic disturbances and the twenty-five years risk of incident cancer in a Mediterranean population.

BACKGROUND AND AIMS: Obesity is predictive of metabolic syndrome (metS), type 2 diabetes, cardiovascular (CV) disease and cancer. The aim of the study is to assess the risk of incident cancer connected to obesity and metS in a Mediterranean population characterized by a high prevalence of obesity. METHODS AND RESULTS: As many as 1133 subjects were enrolled in two phases and followed for 25 years (859 subjects) or 11 years (274 subjects) and incident cancer was registered in the follow-up period. Anthropometric measures and biochemical parameters were filed at baseline and evaluated as predictors of incident cancer by measuring hazards ratios (HR) using multivariate Cox parametric hazards models. Best predictive threshold for metabolic parameters and metS criteria were recalculated by ROC analysis. Fasting Blood Glucose >5.19 mmol/L [HR = 1.58 (1.0-2.4)] and the TG/HDL ratio (log10) (Males > 0.225, Females > 0.272) [HR = 2.44 (1.3-4.4)] resulted independent predictors of survival free of cancer with a clear additive effect together with age classes [45-65 years, HR = 2.47 (1.3-4.4), 65-75 years HR = 3.80 (2.0-7.1)] and male gender [HR = 2.07 (2.3-3.1)]. CONCLUSIONS: Metabolic disturbances are predictive of cancer in a 25 years follow-up of a Mediterranean population following a traditional Mediterranean diet. The high prevalence of obesity and metS and the observed underlying condition of insulin resistance expose this population to an increased risk of cardiovascular disease and cancer despite the healthy nutritional habits.

Curcumin induces apoptosis in human neuroblastoma cells via inhibition of AKT and Foxo3a nuclear translocation.

Neuroblastoma (NB) is one of the most frequent extracranial solid tumors in children. It accounts for 8-10% of all childhood cancer deaths, and there is a need for development of new drugs for its treatment. Curcumin (diferuloylmethane), a major active component of turmeric (Curcuma longa), has been shown to exert anti-tumor activity on NB, but the specific mechanism by which curcumin inhibits cancer cells proliferation remains unclear. In the present study, we investigated the anti-proliferative effect of curcumin in human LAN5 NB cells. Curcumin treatment causes a rapid increase in reactive oxygen species and a decrease in the mitochondrial membrane potential-events leading to apoptosis activation. Furthermore, curcumin induces decrease in haet shock protein (Hsp)60 and hexokinase II mitochondrial protein levels and increase in the pro-apoptotic protein, bcl-2 associated death promoter (BAD). Moreover, we demonstrate that curcumin modulates anti-tumor activity through modulation of phosphatase and tensin homolog deleted on chromosome 10 and consequential inhibition of the survival Akt cell-signaling pathway. Inhibition of Akt causes its translocation into the cytoplasm and import of Foxo3a into the nucleus where it activates the expression of p27, Bim, and Fas-L pro-apoptotic genes. Together, these results take evidence for considering curcumin as a potential therapeutic agent for patients with NB.

Increased expression of IL-19 in the epithelium of patients with chronic rhinosinusitis and nasal polyps.

BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammation of the nose and of the paranasal sinuses. The involvement of the respiratory epithelium in the mechanisms of CRS is poorly understood. AIMS: Among proteins expressed by nasal epithelial cells in CRS, IL-19 may have key functions. We here aimed to determine the expression and regulation of IL-19. METHODS: Nasal biopsies from normal subjects (n = 12), subjects with CRS but without nasal polyps (NP) (CRSsNP, n = 12) and with CRS with NP (CRSwNP, n = 15) were collected. Human Asthma Gene Array and real-time PCR were used to evaluate gene expression, western blot analysis and immunohistochemistry for protein expression. Results for IL-19 were confirmed by real-time PCR. The constitutive and stimulated (LPS, TGF ß) expression of IL-19 and cell proliferation were evaluated in a nasal epithelial cell line (RPMI 2650). RESULTS: Human Asthma Gene Array showed an increased IL-19 gene expression in NP from patients with CRS in comparison with normal subjects. Real-time PCR confirmed the IL-19 mRNA up-regulation in patients with CRSwNP and showed an up-regulation of IL-19, at lower extent, in patients with chronic rhinosinusitis without nasal polyps (CRSsNP) in comparison with normal subjects. Western blot analysis confirmed that IL-19 is increased also at protein level in patients with CRSwNP in comparison with normal subjects. In NP, IL-19 is highly expressed in the metaplastic nasal epithelium when compared to normal or hyperplastic epithelium. LPS stimulation increased IL-19 expression, and recombinant IL-19 increased cell proliferation in nasal epithelial cells. CONCLUSIONS: IL-19 is overexpressed in the epithelium in CRSwNP and increases epithelial cell proliferation.

Immune-inflammatory responses and oxidative stress in Alzheimer's disease: therapeutic implications.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and oxidative stress. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. Irrespective of the source and mechanisms that lead to the generation of reactive oxygen species, mammalian cells have developed highly regulated inducible defence systems, whose cytoprotective functions are essential in terms of cell survival. When appropriately activated, each one of these systems has the possibility to restore cellular homeostasis and rebalance redox equilibrium. Increasing evidence, support the notion that reduction of cellular expression and activity of antioxidant proteins and consequent augment of oxidative stress are fundamental causes for ageing processes and neurodegenerative diseases., including AD. The better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, hence for its prevention and drug therapy. Accordingly, two lines of preventive therapeutics can be outlined, the first based on anti-inflammatory drugs, the second one on anti-oxidative properties.

Pro-inflammatory gene variants in myocardial infarction and longevity: implications for pharmacogenomics.

Inflammation and genetics play an important role in the pathogenesis of coronary heart disease (CHD). However, despite the increasing appreciation of the role of genetics in CHD and myocardial infarction (MI) pathogenesis, pharmacogenomic approaches to uncover drug target have not been extensively explored. Cyclo-oxygenases (COXs) and 5-lipoxygenase (5-LO) are the key enzymes in the conversion of arachidonic acid to prostaglandins (PG) and leukotrienes (LT) and are implicated in a wide variety of inflammatory disorders, including atherosclerosis. In fact, PGE2 activates Matrix Metallo-proteinases whereas LTB4 is a chemoactractant for monocytes and activates gene expression in inflammatory cells. We have tested the hypothesis that anti-inflammatory variants of these genes confer genetic resistance to MI and conversely favour longevity. So, we analyzed MI patients, age-related controls and centenarians. The pro-inflammatory alleles of COX-2 and 5-LO were overrepresented in MI and under-represented in centenarians whereas age-related controls displayed intermediate values. MI is a multifactorial disease, hence MI might be the result of a cumulative effect which contributes with different timing to achieve a threshold where the chance to develop the diseases is very high. In particular, differences in inflammatory status can contribute to the chance of developing a risk phenotype. However, these studies might contribute to the determination of a risk profile which may allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug.

Relapses of hyperthyroidism in patients treated with radioiodine for nodular toxic goiter: relation to thyroid autoimmunity.

Relapses of hyperthyroidism after treatment with radioiodine for uni- or multi-nodular goiter may be accompanied by the appearance of TSAb. However, this phenomenon has only emerged from one retrospective study on Northern European patients, in which it was not possible to determine whether TSAb also appeared in treated patients who did not relapse. The present study aimed to assess the appearance, immunogenic nature and clinical characteristics of hyperthyroidism relapse after treatment with 131I for nodular toxic goiter in patients from the Mediterranean area. A retrospective study was performed on 76 consecutive patients, born and resident in Sicily and aged 56-80 yr at diagnosis, who were treated with radioiodine. Serum aliquots obtained from the patients before 131I treatment and during a follow-up of 36-144 months were assayed for TSAb and TPOAb. The clinical charts of the patients were also re-examined. Twenty-six out of 76 patients (36.8%) had a hyperthyroidism relapse after a first treatment with 131I. Eight of the 26 (30.7%) also relapsed after the second treatment. Three out of 26 (11.5%) relapsed after a third treatment. The 50 patients who required only one treatment and the 18 who relapsed only once were all TSAb-negative at baseline, while 3/8 (37.5%) who relapsed also after the second treatment were already TSAb-positive at baseline. TSAb became positive in 3/18 patients (16.7%) who relapsed once, and in 4/8 (50.0%) of those who relapsed after a second treatment. One of these 7 TSAb-positive relapsers was also already TPOAb-positive at baseline and another became TPOAb-positive after treatment. The presence of circulating TSAb in 3/76 (3.9%) patients before treatment for toxic goiter more probably points to a diagnosis of Marine-Lenhart's syndrome. In contrast, the de novo appearance of TSAb in the presence of hyperthyroidism relapse in 4/76 (5.3%) patients suggests the development of a Graves'-like disease after radioiodine treatment. This occurrence does not seem to have precise ethnic grounds, since the incidence we observed in Mediterranean patients was similar to that previously reported in Northern European patients.

Glycemic homeostasis in chronic viral hepatitis and liver cirrhosis.

OBJECTIVES: This study aimed at investigating the respective impacts of virus-related chronic hepatitis (CH) and liver cirrhosis (LC) on glycemic homeostasis, with reference to grading and/or staging of liver disease and to contribution of the two main responsible viruses. MATERIAL AND METHODS: The glycometabolic features of 82 patients with CH (B-related 16, and C-related 66) and 145 with LC (B-related 24, and C-related 121) were evaluated. RESULTS: Impaired glucose tolerance (IGT) was detected in 9 (11.0%) and diabetes mellitus (DM) in 6 (7.3%) of the CH patients [(P<0.05 vs controls, in both cases; respective odds ratios (95% CI): 2.6 (1.1-6.3), and 4.0 (1.2-13.2)]. IGT was detected in 86 (59.3%) and DM in 34 (23.4%) of the LC patients [(P=0.000 vs controls, in both cases; respective odds ratios: 10.0 (7.0-14.4), and 5.5 (3.5-8.5)]. The odds ratios for the prevalence of IGT and DM in the LC patients were 11.8 (5.2-27.5) and 3.9 (1.5-10.8), compared with the CH patients. In the CH patients, glycometabolic failure was significantly related to age (P=0.026), but not to grading and staging, and in the LC patients to Pugh-Child score (P=0.037). IGT was found in 17/40 (42.5%) HBV-related patients and in 13/40 (32.5) matched HCV-related patients. DM was found in 9/40 (22.5%) HBV-related patients and in 10/40 (25.0%) HCV-related matched patients, without significant difference in the respective proportions. CONCLUSION: The prevalence of DM associated to virus-related CH is on average four times higher than in the general population, independently of the histopathological picture of disease. Virus-related LC further increases the prevalence of both IGT and DM, independently of sex and age, but in relationship with the severity of disease. HBV and HCV infections do not appear to have a different impact on glycemic homeostasis.

Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridemic patients.

In order to assess the efficacy of gemfibrozil on lipid and haemostatic parameters in patients with plurimetabolic syndrome, a multicenter double-blind placebo controlled, parallel study was carried out in 56 patients with primary hypertriglyceridemia and glucose intolerance. These patients had elevated PAI activity and antigen and t-PA antigen levels at rest and after venous occlusion. Gemfibrozil reduced plasma triglyceride levels (P<0.001), whereas it increased free fatty acids (P<0.05) and high density lipoprotein cholesterol levels (P<0.05). In those patients reaching normalization of plasma triglyceride levels (triglyceride reduction > or =50%) (n=15), insulin levels (P<0.05) as well as the insulin resistance index were reduced by gemfibrozil treatment, suggesting an improvement of the insulin resistance index in this patient subgroup. Gemfibrozil treatment did not affect plasma fibrinolysis or fibrinogen levels, despite marked reduction of plasma triglycerides and improvement of the insulin sensitivity associated with triglyceride normalization.

Serum and fecal pancreatic enzymes in beta-thalassemia major.

CONCLUSION: This study, using indirect tests, demonstrated that exocrine pancreatic function is impaired in a proportion of patients with beta-thalassemia major (TM), though this impairment is generally mild or moderate. BACKGROUND: Impaired structure and function of the exocrine pancreas has been reported in patients with Beta-thalassemia major. METHODS: In this study we measured fecal fats and serum and fecal pancreatic enzymes in 30 patients (13 M, 17 F) with TM, mean age 22.1 yr (range 14-39) and compared them with those of a matched group of healthy controls. Results were correlated with age, serum ferritin, blood transfusion, and various nutritional parameters. Enzymes assays included: serum pancreatic amylase (PA), lipase (L), trypsin (T), fecal chymotrypsin (FCT), and fecal elastase (FE). RESULTS: No patient was positive for steatorrhea. Comparison of the mean values showed a significant difference only for FE (p < 0.002). Using only the fecal tests as a reference, we found that 12 patients had FE values below the cutoff limit; of these, five had values between 100 and 185 micrograms/g, three between 50 and 99 micrograms/g and four below 50 micrograms/g. Ten patients had FCT values below the cutoff limit; seven presented impairment in both tests and six of them had FE values below 100 micrograms/g (including four diabetics). No correlations were found between enzyme values and mean serum ferritin values or mean blood consumption over the previous 3 yr. No correlation was found between FE and FCT levels or between enzymes and age.

Prospective study on thyroid autoimmunity and dysfunction related to chronic hepatitis C and interferon therapy.

This study was designed to assess patients with chronic hepatitis C (CHC) for the presence of thyroid autoimmunity and dysfunction, to evaluate the risk of thyroid disorders associated with interferon (IFN) therapy, and to survey the outcome of possible treatment-related thyroid injury. Out of 104 consecutive untreated patients (30 women and 74 men; mean age, 52.7 years), 8 (7.7%) were found seropositive for thyroid autoantibodies (ThyAb), whereas seropositivity in healthy controls was 1/98 (1.3%). The relative increase in risk of developing thyroid autoimmunity associated with CHC was 760% (95% CI, 220-1300%). No patients had abnormalities of thyroid function tests, but on IFN treatment, 3/3 patients showed a rapid over-range rise in circulating thyrotropin, which returned to normal after therapy discontinuation. In the other 5 seropositive patients who refused treatment, thyroid function remained normal. Out of the 58 initially seronegative patients who consented to IFN treatment, 9 (15.5%) developed thyroid autoimmunity. Seven of them (77.7%) had thyroid dysfunction: hypothyroidism in 4 cases, transient thyrotoxicosis in 2 cases. The last patient developed TSH-receptor antibodies and Graves' disease, requiring methimazole therapy. Thyroid function recovered in the former 6 cases following IFN discontinuation. In the 28 initially seronegative patients who refused IFN and participated in a preliminary tauroursodeoxycholic acid trial, antithyroglobulin antibodies alone appeared in one case, but no thyroid dysfunction was observed. The relative risk of thyroid autoimmune disorder associated with IFN therapy was 342% (28-636%). The patients with CHC were unlikely to develop thyroid dysfunction in the absence of IFN therapy, in spite of being ThyAb seropositive. Moreover, a considerable proportion of seronegative patients, when IFN-treated, developed thyroid autoimmunity and then thyroid dysfunction. Both in seropositive and seronegative patients immediate IFN discontinuation normalized thyroid function and hormone replacement therapy was not necessary.

Effectiveness of cascade filtration plasmapheresis in two patients affected by familial hypercholesterolemia.

Hypercholesterolemia has been recognised as a primary risk factor for coronary heart disease. Reduction of plasma levels of total and LDL cholesterol has been shown to decrease coronary atherosclerosis. Plasmapheresis represents an useful non-pharmacological tool to treat severe hypercholesterolemias. We have evaluated the effectiveness of a system of plasmapheresis using a cascade filtration method in two young male subjects (aged 16 and 26 years) with homozygous familial hypercholesterolemia. Both showed severe coronary atherosclerosis as determined by angiography. Procedures were performed at intervals of 7 days in each case. We observed a mean reduction of plasma levels of total cholesterol of 59.5% (range 31.0-75.5%); LDL-cholesterol, 61.6% (range 32.6-77.1%); triglycerides, 48.1%; HDL-cholesterol, 31.1%; apo A-I, 30.8%; and apo B, 57.6%. We also noted a reduction of other parameters, such as fibrinogen (49.9%) and Lp(a) (59.9%). At the end of each procedure about 8 g of cholesterol was removed from the total body pool. A decrease of total proteins (26.9%) and albumin (19.6%) was also observed, but this was completely restored before the next apheresis (1 week). These data show the effectiveness of the removal of LDL in a cascade filtration system, which obtains results not very different from other more selective methods. The lack of selectivity is not much of a problem, since it also reduces other risk factors such as Lp(a) and fibrinogen.

Subclinical hypothyroidism resulting from autoimmune thyroiditis in female patients with endogenous depression.

Thyroid function and presence of thyroid autoantibodies were assessed in a group of 75 consecutive female patients with mood disturbances and in a group of 38 healthy women of similar age recruited as controls. Nine patients suffered from major (endogenous) depression and 66 from minor (neurotic) depression. The individual patients had normal values of circulating thyroid hormones. Nevertheless, endogenously depressed patients had total serum triiodothyronine (M +/- SE = 1.49 +/- 0.09 nmol/l) and both total (83.9 +/- 4.3 nmol/l) and free serum thyroxine (13.9 +/- 1.1 pmol/l) lower than in the group of minor depressed and in the group of controls (p < 0.01, in both comparison). The median value of serum thyrotropin was 5.22 mU/l in the major depressed patients versus 1.72 mU/l in the minor depressed and 1.69 mU/l in the controls. Thyroid function test results in the minor depressed group did not significantly differ from those in the controls. Five of the 9 endogenously depressed patients were subclinically hypothyroid, while none of the 66 patients with minor depressive disorder showed thyroid dysfunction. Antibodies against thyroglobulin and/or thyroid peroxidase were positive in all the 5 endogenously depressed women with subclinical hypothyroidism, revealing a symptomless autoimmune thyroiditis, which was also confirmed by ultrasonography in all cases and histopathologically demonstrated in one case. None of the endogenously depressed women without thyroid dysfunction and none of the 66 minor depressives were seropositive for thyroid autoantibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Deficient pulsatile thyrotropin secretion in the low-thyroid-hormone state of severe non-thyroidal illness.

Twenty-four-hour thyrotropin (TSH) profiles in eight severely ill patients were compared with those of six healthy subjects. The profiles were assessed using the cosinor method to evaluate circadian variations and using the Pulsar algorithm to analyze episodic secretion. In the normal subjects, the typical periodicity of TSH secretion showed a mean level in the rhythm (mesor) of 2.03 mU/l. The amplitude (half the extent of rhythmic change in the cycle) was 0.58 mU/l; the acrophase (the delay from midnight (0 degrees) of the highest level in the rhythm) was -9.9 degrees. In contrast, severely ill patients showed only slight and anticipated elevations of serum TSH levels (mesor 0.93 mU/l, amplitude 0.22 mU/l, acrophase +82.4 degrees). Moreover, whereas the episodic TSH secretion in healthy individuals consisted of 5-8 pulses/24 h, mainly clustered around midnight, only one pulse of reduced amplitude was detected in two of the eight severely ill patients and no pulses in the other six. Since earlier studies have indicated that the loss of TSH pulsatility is associated with the relative insensitivity of the thyrotrophs to low thyroid hormone levels and our analytical procedures have demonstrated that 24 h pulsatile pattern of TSH closely overlapped with baseline TSH secretion, it seems reasonable to assume that low-thyroid-hormone state, deficient pulsatile TSH secretion and altered nyctohemeral TSH periodicity do not coincide by chance, but that there is a causal relationship between such abnormalities in severely ill patients.

Transient neonatal hypercholesterolemia. Lack of relationships with dehydroepiandrosterone sulfate.

In order to obtain new information about the relationship between transient neonatal hypercholesterolemia and adrenal gland function, we have studied 39 healthy babies found hypercholesterolemic at birth and 39 healthy controls with normal cholesterol levels. The results of this study have shown that levels of dehydroepiandrosterone sulfate in cord blood were not significantly different in the hypercholesterolemic subjects compared with normolipidemic controls (1.4 +/- 0.5 micrograms/dl vs 1.3 +/- 0.5 mu/dl). Moreover correlations between this hormone and levels of total and LDL-cholesterol were not only not statistically significant but even positive (respectively r = +0.207 and +0.195). These data suggest that dehydroepiandrosterone sulfate measurements in cord blood do not give any further information about transient neonatal hypercholesterolemia.

Lipoprotein (a) levels in end-stage renal failure and renal transplantation.

Some previous studies have documented an increase in lipoprotein (a) [Lp(a)] levels in renal diseases. Here, we report data in subjects with end-stage renal failure treated with hemodialysis (HD) or with continuous ambulatory peritoneal dialysis (CAPD) and in renal transplant recipients (RTR), compared with a group of normolipidemic controls (C). Lp(a) levels were significantly increased in HD and CAPD patients in comparison with C, while they were only slightly increased in RTR. Both HD and CAPD patients showed Lp(a) levels higher than in RTR, but no difference was found between the subjects of the two dialysis procedures. The prevalence of Lp(a) levels > 25 mg/dl was significantly higher in HD and CAPD patients, but not in RTR, in comparison with C. Moreover, Lp(a) levels did not change after HD. When patients were divided according to their fasting lipid levels in normolipidemics and hyperlipoproteinemics, no difference was found for Lp(a) levels in any group. Mechanisms underlying the increase in Lp(a) levels in these patients are not known. It is possible to suggest an active role of the kidney in the Lp(a) metabolism or that uremic plasma contains some factors affecting Lp(a) metabolism.

Lp(a) levels in patients undergoing aorto-coronary bypass surgery.

The aims of this study were to evaluate plasma lipid, apoprotein and Lp(a) levels in patients with severe coronary atherosclerosis undergoing aorto-coronary bypass surgery (BP) and to relate these parameters to the involvement of one or more vessels. Seventy-seven male patients and 77 cardiovascular disease-free controls, matched for sex, age and body weight were studied. Higher triglyceride and apo B levels with lower HDL-cholesterol and apo A-I levels were found in BP patients in comparison with the controls. Lp(a) levels were slightly, but not significantly, increased. Moreover BP patients presented a significantly higher prevalence of HDL-cholesterol levels below 35 mg dl-1 (49.3% vs 22.1%) and Lp(a) levels above 70 mg dl-1 (10.4% vs 1.3%) than the controls. When patients were divided according to the number of coronary vessels involved (one, two or three), no significant difference was found, with a trend to increase in Lp(a) mean levels and in prevalence of Lp(a) levels above 30 and 70 mg dl-1 in more severely diseased patients. These results suggest that patients with severe coronary artery disease undergoing aorto-coronary bypass surgery show low HDL-cholesterol levels with high triglyceride levels. Moreover Lp(a) levels above 70 mg dl-1 are highly associated with severe coronary vessel stenosis.

Alterations in circadian rhythm of serum thyrotropin in critically ill patients.

To evaluate the 24-h pattern of serum thyrotropin (TSH) in critically ill patients, we measured serum concentrations of TSH in blood samples collected every 2 h for 24 h from nine patients (six with malignancy, two with liver cirrhosis, one with chronic renal failure), who had subnormal levels of both triiodothyronine (T3) and thyroxine (T4), in the absence of history, symptoms or signs of thyroid disease. Analysis of the data, performed using a second-order inferential statistical methodology for rhythmometry (cosinor method), demonstrated that critically ill patients still had daily oscillations of serum TSH which significantly adapted to the function approximating the circadian rhythms (R2 = 74.3%). However, the mean level (mesor) in the rhythm of the patients was found to be significantly lower than that of healthy subjects (0.96 vs 2.18 mU/l); the amplitude of rhythmical daily variations also was lower in patients than in healthy subjects (0.23 vs 0.56 mU/l), even though the amplitude/mesor ratio was similar (23% vs 26%). Lastly, the highest level in the TSH rhythm of the patients was found to be in the late afternoon, in contrast to healthy subjects, who had a TSH surge after midnight. Although these alterations are consistent with the existence of a dysregulation at suprahypophyseal level in critically ill patients, it remains to be established whether the state of low T3 and T4 may be ascribed to anomalous circadian rhythm of TSH.

Pituitary resistance to thyroid hormone action with preserved circadian rhythm of thyrotropin in a postmenopausal woman.

We assessed the 24-h behavior of circulating TSH and the dopaminergic control on TSH release in a postmenopausal woman, who had elevated levels of serum thyroid hormones and an inappropriately high concentration of serum TSH, indicating pituitary resistance to thyroid hormone action. The patient was found to have a daily profile of serum TSH similar to that of normal subjects, except for the persistently elevated 24 h levels, suggesting that alterations in thyroid hormone negative feedback control did not affect substantially circadian TSH rhythm. The acute administration of a dopamine antagonist drug (metoclopramide) resulted in a markedly elevated peak of serum TSH, similar both in the morning and in the evening. The chronic administration of a dopamine agonist drug (bromocriptine) reduced basal and TRH-stimulated TSH, restored circadian TSH variations to lower levels, and normalized other thyroid function tests. Although the metoclopramide test results confirmed the existence of an increased dopaminergic inhibitory tone in nonneoplastic inappropriate secretion of TSH, the outcome of bromocriptine treatment indicated that the dopaminergic control over TSH release was not enough in this case of PRTH.

Prospective study on thyroid function anomalies in severely ill patients.

Patients with severe non-thyroidal illness (NTI) often evidence concomitant anomalies in thyroid function (TF). In order to shed light on the implications of these anomalies and/or changes and disease course, we monitored TF changes in a selected cohort of 45 patients with serious NTI (21 with liver cirrhosis, 15 with renal failure and 9 with malignancy) from April 1985 to October 1989. TF test results on admission were as follows: all patients had normal thyroid stimulating hormone (TSH) levels; 16 patients had no TF abnormalities; 28 had decreased serum triiodothyronine (T3) and increased serum reverse triiodothyronine (rT3) levels, (8 of them had low serum free T3 values as well); 1 patient had subnormal level of both T3 and thyroxine (T4). Fifteen (53.5%) of the 28 subjects with initial low T3 sustained a subsequent decline in total and free serum T4 to subnormal levels; in 13 of these patients the drop occurred shortly before death. Patients in critical condition with below normal serum T4 also had decreased serum TSH concentrations: the so-called "low T3 and low T4 syndrome" might thus result from decreased TSH concentrations: due to failure of the usual feedback mechanism. Eighteen patients (40%) had died by the end of the study period. The mortality rate was 89% in patients with initial T3 level less than 0.40 nmol/L. This finding leads us to the hypothesis that initial low T3 levels in NTI patients are indicative of a poor prognosis.