Correlation between pentosidine and endothelin-1 in subjects undergoing chronic hemodialysis.

Advanced glycation end-products (AGEs), which accumulate in the blood and tissues of patients with chronic renal failure (CRF) undergoing chronic hemodialysis, play an important role in the pathogenesis of uremic complications. Endothelin 1 (ET1), a 21-amino acid peptide with vasoconstricting and mitogenic properties, is an important factor in the endothelial dysfunction occurring in uremia. The circulating levels of both AGEs and ET1 have been reported to be increased in chronic renal failure. In the present study we evaluated the possible relationship between pentosidine and ET1 plasma levels in CRF patients undergoing chronic hemodialysis treatment. The plasma concentrations of "free" and bound pentosidine (HPLC methods) and endothelin-1 (RIA method) were measured before the hemodialysis session in 40 nondiabetic CRF patients (22 males and 18 females; 54+/-3 years) on chronic hemodialysis for at least 1 year. Forty age- and sex-matched normal subjects served as a control group. In hemodialyzed patients, the overall pentosidine residues and pentosidine-free adduct plus pentosidine-free adduct bound reversibly to protein levels (24.9+/-2.04 pmol/mg protein and 110.5+/-5.9 pmol/ml, respectively) were significantly higher than those recorded in normal subjects (2.0+/-0.2 pmol/mg protein and 0.7+/-0.2 pmol/ml, respectively ). Endothelin-1 was also significantly (p<0.01) increased in CRF patients (10.6+/-0.4 pmol/ml in CRF patients and 2.7+/-0.3 pmol/ml in normal subjects). A significant positive correlation (p<0.01) was seen between "total" pentosidine (pentosidine residues and pentosidine-free adduct plus pentosidine-free adduct bound reversibly to protein) levels and endothelin-1 plasma values. The correlation between pentosidine and endothelin-1 provides further evidence that some AGEs exert a detrimental effect on the vascular endothelium, thereby contributing to the hypertension and other cardiovascular damage seen in CRF patients.

Endothelin-1 plasma levels in cluster headache.

BACKGROUND AND OBJECTIVE: A role for endothelin-1, a potent vasoconstrictor peptide, in some cerebrovascular diseases has been proposed. To obtain preliminary data about peripheral concentrations of endothelin-1 in acute cluster headache, we measured the plasma endothelin-1 secretory pattern in 10 men with cluster during and independent of a headache attack. METHODS: We collected blood samples for plasma endothelin-1 determinations at 0, 15, 30, 45, 60, 90, and 120 minutes during a cluster attack and closely monitored blood pressures. We repeated the same sampling during an asymptomatic period. RESULTS: The mean values of plasma endothelin-1 (before a cluster headache, 3.3 +/- 0.3 pg/mL) significantly increased (F = 2.578, P < .05) during an attack, reaching their peak at 30 minutes (5.0 +/- 0.5 pg/mL, P < .05). We found no significant variations in mean arterial pressure. CONCLUSION: Endothelin-1 may play a role in the pathophysiology of cluster attacks. The increase in plasma observed during cluster attacks may be linked to alterations in systemic hemodynamics and vascular tone.

Endocrine abnormalities and outcome of ischaemic stroke.

Multiple endocrine abnormalities have been reported in stroke patients. In the past few years, it has been claimed that some of these abnormalities may play a role in worsening the neurological deficit and the outcome of stroke. Several mechanisms have been hypothesised, including a direct effect on the development of neuronal cell death, vasospasm, and development of brain edema. In this brief review, we discuss the current knowledge concerning the role of endothelin-1, arginine vasopressin, and cortisol in the pathogenesis of stroke. Finally, we discuss the possibility that leptin, the OB gene product, may be the link of some of these endocrine abnormalities, and that its abnormal secretion during stroke may contribute to the eating disorders and poor nutritional status often seen in these patients.

Twenty-four-hour endothelin-1 secretory pattern in stroke patients.

Endothelin-1 (ET-1) is a potent and long-acting vasoconstrictor peptide, which may play a role in the pathophysiology of a number of diseases. Controversial data exist on its role in human ischemic stroke. In order to ascertain whether changes in ET-1 plasma levels occur in ischemic stroke, plasma ET-1 levels and mean arterial pressure were determined in 15 patients at their first ischemic cerebral infarction and in 15 control subjects, over a 24-hour period. In stroke patients, mean 24-hour plasma ET-1 levels (4.9+/-0.5 ng/L) were higher (P< 0.05) than in control subjects (3.2+/-0.3 ng/L), and correlated with the mean size of the lesion, but not with the severity score of the neurological deficit. These results support the hypothesis that ET-1 levels reflect an indicator function for the amount of damaged cerebral tissue rather than a pathophysiological role.

Evaluation of the secretory pattern of plasma arginine vasopressin in stroke patients.

Arginine vasopressin (AVP) may play a role in the development of ischemic brain edema and/or cerebral vasospasm. Data available on AVP plasma levels in ischemic stroke are few and discordant. In order to ascertain whether changes in AVP plasma levels occur in ischemic stroke, plasma AVP levels, plasma osmolality and mean arterial pressure were determined in 24 patients with unprecedented ischemic cerebral infarction and in 15 controls over a 24-hour period. In stroke patients, mean 24-hour plasma AVP levels (7.2 +/- 0.8 ng/l) were higher (p < 0.05) than in control subjects (2.4 +/- 0.3 ng/l), and correlated with the severity score of the neurologic deficit and the mean size of the lesion. In patients with a more severe neurologic deficit, the mean 24-hour plasma AVP levels (8.7 +/- 1.0 ng/l) were higher than in patients with a less severe neurologic deficit (5.2 +/- 0.8 ng/l). Data indicate that in ischemic stroke an increased AVP secretion occurs independently of osmotic or baroreceptorial mechanisms. The possibility that AVP may play a role in neuronal cell damage following cerebral ischemia warrants further attention.

Leptin has no role in determining severity of steatosis and fibrosis in patients with chronic hepatitis C.

OBJECTIVE: The presence of steatosis is a common histological finding in patients with chronic hepatitis C (CHC). The causes of the severity of this condition are not yet clear, although both metabolic and viral factors supposedly are involved. In this study our aim was to examine the possible influence that leptin levels, hepatitis C virus (HCV) RNA levels, and hepatitis G virus (HGV) infection have on the severity of steatosis and on the presence and degree of fibrosis in patients with CHC. METHODS: One hundred eighty-two CHC patients with histological findings of steatosis were chosen from among a cohort of patients referred to our center for staging of liver disease. Among them 48 CHC patients were accurately selected so as to rule out possible confounding factors for the presence of steatosis (diabetes mellitus, hyperlipemia, obesity, alcohol). Leptin levels, HCV RNA levels, and HCV genotype, and the presence of HGV RNA were assessed in these patients and related to histological findings. RESULTS: We found that leptin levels in CHC patients were similar to those in healthy subjects. No relationship was found between leptin levels and severity of steatosis. HCV RNA levels, HCV genotype, and the presence of HGV infection were no different among CHC patients with various degrees of steatosis. Leptin was not related to different degrees of fibrosis, whereas higher viral load was the only parameter associated to higher fibrosis scores. CONCLUSIONS: These findings suggest that the degree of steatosis in patients with CHC does not seem to depend on serum leptin levels or on viral factors, at least as far as HCV viremia and genotype and HGV infection are concerned. The severity of fibrosis does not seem to be influenced by leptin levels, whereas HCV viral load does seem to play some role.

Serum leptin levels in patients with viral chronic hepatitis or liver cirrhosis.

BACKGROUND/AIM: Serum levels of leptin, the adipocyte-derived hormone regulating food intake and energy expenditure in mammals, have been found to be increased in cirrhotic patients. The aim of the present study was to investigate leptin serum level in relation to anthropometric features and liver function in patients with viral chronic hepatitis or liver cirrhosis. METHODS: Serum leptin levels were determined by radioimmunoassay in 30 male and 10 female patients with chronic hepatitis, in 42 male and 10 female patients with liver cirrhosis, and in four respective control groups. Liver function was evaluated by the monoethylglycinexylidide formation test. Body mass index and body fat mass were estimated by weight, height and skinfold thickness measurements. RESULTS: Compared with controls, absolute serum leptin levels were significantly (p<0.01) lower in chronic hepatitis patients and similar in cirrhotic patients. Leptin serum levels were significantly (p<0.05) higher in cirrhotic than in chronic hepatitis patients. When expressed in relation to body fat mass, the above differences persisted; however, cirrhotic females showed significantly (p<0.05) higher serum leptin values than controls. Serum leptin values correlated negatively (p<0.01) with monoethylglycinexylidide serum values in all groups of patients. CONCLUSIONS: In patients with chronic viral liver disease, serum leptin levels tend to increase as liver function worsens. This may reflect a decline in the ability to downregulate energy expenditure as an adaptation to anorexia and/or to defective substrate utilisation due to liver disease and may negatively influence body weight homeostasis in these patients.

Leptin levels in nonalcoholic steatohepatitis and chronic hepatitis C.

BACKGROUND/AIMS: Leptin is a peptide which regulates food intake and energy expenditure. Moreover, it is involved in the homeostasis of body composition and is linked to the regulation of insulin signaling, thus playing an important role in liver fat storage. Steatosis is a common finding in chronic hepatitis C, and both viral and metabolic factors have been suggested to explain the presence of this histological characteristic. In order to study leptin in chronic liver disease characterized by the presence of steatosis, we evaluated its serum levels in patients with nonalcoholic steatohepatitis (NASH), in chronic hepatitis C (CHC) patients with no histological findings of steatosis, and CHC patients with steatosis but no risk factors for its development. METHODOLOGY: We studied 6 male patients with NASH whose diagnosis was made on the basis of histological findings and clinical criteria. From among a cohort of 170 CHC patients we put together 2 groups of 6 male patients each (with or without steatosis at liver biopsy examination), who had no risk factors for NASH. Male patients were chosen in order to avoid gender influence on leptin levels. Further criteria for admission were similar impairment of liver metabolic function as assessed by the monoethylglycinexylidide (MEGX) test and, in patients with CHC, similar body mass index (BMI) and histological staging. Moreover, we evaluated leptin/BMI ratio, in order to rule out BMI influence on leptin levels. Leptin levels were assessed by means of radioimmunoassay. RESULTS: We found that BMI was higher in NASH compared to CHC (27.2 +/- 2.9 vs. 23.9 +/- 1.8; p = 0.01). Analysis of serum leptin levels showed an increasing trend starting from patients with CHC without steatosis (3.2 +/- 0.4 ng/ml), through CHC patients with steatosis (4.2 +/- 0.7 ng/ml) up to patients with NASH (5.7 +/- 2 ng/ml), although the differences observed were not statistically significant. Moreover, the ratio of leptin to BMI also followed the same trend showing increasing values (CHC without steatosis = 0.04 +/- 0.02; CHC patients with steatosis = 0.17 +/- 0.03; NASH = 0.203 +/- 0.07). Leptin levels and BMI showed a significant relationship (n = 18; r = 0.60; p < 0.01). CONCLUSIONS: The increasing trend observed in leptin serum levels among the different groups of patients showed that in chronic liver disease characterized by the presence of steatosis, leptin signaling is preserved. Moreover, CHC factors different from the metabolic ones should be investigated in order to explain the presence of steatosis. Further studies on broader groups of patients are needed to verify these preliminary results.

Twenty-four-hour variation in serum leptin in the elderly.

To investigate the possibility that the aging process may affect the diurnal variation in serum leptin in humans, serum leptin levels were measured by a sensitive radioimmunoassay method in 12 elderly (aged 72 to 87 years) and 10 middle-aged (35 to 50 years) lean male subjects. Fasting blood samples (4 mL) were drawn at 8:00 AM, and then every 4 hours until 10:00 PM and every 2 hours from 12:00 midnight to 8:00 AM of the next morning. Circadian rhythmicity analysis was performed using the cosinor method. In elderly subjects, serum leptin levels showed a significant diurnal rhythm, which was similar to that observed in controls. Single cosinor analysis showed a significant rhythm in eight of 12 elderly subjects and in all middle-aged subjects but one. Compared with middle-aged subjects, similar mesor mean values (7.8 +/- 1.0 v 8.1 +/- 0.8 ng/mL) but a decreased amplitude (1.4 +/- 0.3 v 2.3 +/- 0.2 ng/mL) and an earlier acrophase (11:56 PM v 2:04 AM) were observed in the elderly. The data demonstrate that the diurnal variation in serum leptin is generally preserved in the elderly. However, the amplitude of leptin diurnal excursion undergoes a reduction with advancing age. It can be speculated that the blunted diurnal variation in serum leptin observed in the elderly may result in an alteration of the afferent signal in the adipose tissue-central nervous system homeostatic loop.

Somatostatin release in response to glucose is impaired in chronic renal failure.

In order to evaluate somatostatin (SRIH) secretion in uremia, plasma SRIH concentrations were determined in basal conditions and after an oral glucose tolerance test (OGTT) in 14 non-dialysed patients with chronic renal failure (CRF), seven of whom had normal glucose tolerance (NGT) and seven impaired glucose tolerance (IGT). Plasma insulin, C-peptide and glucagon and blood glucose concentrations were also evaluated. The results were compared with those obtained in a group of age- and sex-matched normal subjects. In CRF patients, plasma SRIH fasting values (8.6 +/- 0.6 and 7.8 +/- 0.6 pmol/L in NGT and IGT patients, respectively) were comparable to those recorded in controls (7.7 +/- 0.5 pmol/L). SRIH response to OGTT, evaluated as area under curves (AUC) above basal, was similar in both groups of CRF patients (412.9 +/- 84.5 and 415.6 +/- 51.9 pmol/L per min), and significantly lower than in controls (660.1 +/- 58.5 pmol/L per min). Data indicate that chronic uremia induces a loss of SRIH secretory cell responsiveness to glucose. A possible effect of impaired SRIH secretion on glucose metabolism in CRF is discussed.

Oxidative stress in subjects affected by celiac disease.

In order to study the role of oxidative stress in celiac disease, protein carbonyl groups, thiobarbituric acid-reactive substance and pentosidine were evaluated in the plasma of nine patients with asymptomatic celiac disease and in a control group (n = 25). Plasma alpha-tocopherol, retinol and lipids were determined in the same samples. The levels of markers of oxidative stress derived from both protein (carbonyl groups) and lipids (thiobarbituric acid-reactive substances) were significantly higher in celiac disease patients, whereas lipoproteins and alpha-tocopherol were significantly lower. These data indicate that in celiac disease, even when asymptomatic, a redox imbalance persists; this is probably caused by an absorption deficiency, even if slight. Dietary supplementation with antioxidant molecules may offer some benefit and deserves further investigation.

Inter-organ leptin exchange in humans.

To assess the individual role of splanchnic organs, kidney, and peripheral tissues on leptin metabolism, leptin exchange across the splanchnic bed, kidney, and leg has been evaluated by the arterio-venous technique in post-absorptive non-obese subjects. Leptin levels in the hepatic and renal veins were significantly lower (p < 0.001), while femoral vein levels were consistently greater (p < 0.05) than in the artery. The fractional extraction of leptin, namely the percentage of arterial leptin extracted, was greater in splanchnic organs (16%) than in the kidney (9.5%). Urinary excretion of leptin was undetectable in most subjects, indicating that leptin is degraded within the kidney. There was no correlation between fractional extraction of leptin and glomerular filtration rate, whereas leptin fractional extraction was directly related to renal plasma flow (p = 0.017). Renal leptin clearance was about 50% of the glomerular filtration rate. Our data demonstrate that both splanchnic organs and the kidney cooperate in the disposal of leptin, while peripheral tissues add significant amounts of leptin to the circulation. In non-obese subjects the contribution of the kidney to whole body clearance is no more than 50%. The removal of leptin by the kidney depends on renal plasma flow but not on glomerular filtration rate or filtered leptin.

Plasma somatostatin response to an oral test meal in liver transplant patients.

Ten liver transplant patients were studied in basal conditions and after ingestion of a standard mixed test meal. Control groups included 10 normal subjects, 10 patients with nonalcoholic liver cirrhosis, and seven kidney transplant patients. Plasma somatostatin, blood glucose, and plasma insulin, C-peptide, and glucagon were determined before and 15, 30, 45, 60, 90, 120, and 180 minutes after the start of the meal. In liver transplant patients, basal somatostatin and insulin levels were significantly lower than in cirrhotics and were comparable to those recorded in controls and in kidney transplant patients. The time course of the somatostatin secretory response after the meal was similar in any group, but the increase, evaluated as the incremental area above baseline, was significantly higher in liver transplant patients than in controls and cirrhotics and comparable to that recorded in kidney transplant patients. Insulin incremental areas were also lower than in cirrhotics and comparable to those recorded in controls and kidney transplant patients. The data suggest that in liver transplant patients an increased somatostatin response to a meal may be related to a relative beta-cell secretory defect, which in turn seems consequent to immunosuppressive treatment.

Evaluation of beta-endorphin secretion in patients suffering from episodic cluster headache.

In order to obtain data regarding peripheral levels of beta-endorphin in head pain syndromes, we evaluated the plasma beta-endorphin secretory pattern in 12 adult male patients suffering from cluster headache. Blood samples were drawn every 2 hours for a 24-hour period, and in addition at 30-minute intervals for 120 minutes during cluster attacks. The same sampling was repeated during an asymptomatic period. Cluster headache patients showed no significant beta-endorphin circadian rhythm and a delayed acrophase during cluster periods compared with that recorded in the remission period and in normal subjects. Eighteen cluster headache attacks were recorded during the study day, 13 (72%) of which were followed by a significant increase in beta-endorphin levels. No correlation was found between beta-endorphin maximum net increase and intensity and/or duration of pain. These data suggest the hypothesis of a temporary alteration of beta-endorphin circadian secretion, probably related to involvement of neural structures controlling biorhythm pacemakers.

Crohn's-like colitis in glycogen storage disease Ib: a case report.

Association between glycogen storage disease type Ib and Crohn's like disease is rare. We present one such case. A young woman with glycogen storage disease type Ib underwent a right hemicolectomy for stenosis and a blind fistulous tract. The histological picture of the resected bowel was consistent with the diagnosis of Crohn's like disease. A leak in the entero-colostomy occurred during medical treatment with steroids, sulfasalazine, and methronidazole. Partial ileal and colonic resection and a new anastomosis were then performed. Recombinant human colony-stimulating factor (300 mcg/die subcutaneously) was then started. The neutrophils promptly increased to a normal range, and the neutrophil function tests improved. The postoperative course was uneventful and the patient did not have a relapse of the bowel disease.

Effect of the 5-HT3 receptor antagonist ondansetron on plasma AVP secretion: a study in cancer patients.

The aim of the present study was to investigate the effects of a serotonin subtype 3 receptor antagonist, ondansetron, on arginine vasopressin secretion in humans. Plasma vasopressin concentrations were determined in 24 breast cancer patients undergoing adjuvant chemotherapy, before and after ondansetron intravenous (i.v.) administration. Ondansetron (8 mg i.v. at time 0 and 8 mg po at time 240 min) was administered alone in 12 patients and afterwards in combination with chemotherapy in all patients. No changes in hormone levels were found after ondansetron alone and in 17 patients who did not claim nausea and/or emesis after chemotherapy. In seven patients who experienced nausea and /or emesis, vasopressin levels significantly (P < 0.01) increased (from 6.3 +/- 0.9 ng/L in basal conditions to 15.1 +/- 3.3 ng/L at 10 h; P < 0.05 vs baseline). The results suggest the possibility that in humans, serotoninergic mechanisms, which modulate vasopressin secretion, may involve the activation of the serotonin receptors recognised by ondansetron.

Raised plasma arginine vasopressin concentrations during cluster headache attacks.

To obtain data about peripheral concentrations of arginine vasopressin in head pain syndromes, the plasma arginine vasopressin secretory pattern in 12 adult male patients with cluster headache was evaluated. Blood samples for plasma arginine vasopressin and osmolality determinations were collected before, and at 15, 30, 45, 60, 90, and 120 minutes during a cluster attack. Blood pressure was also monitored. The same sampling was repeated during an asymptomatic period. During cluster attacks, the mean values of plasma arginine vasopressin before an attack (2.3 (0.1) ng/l) significantly increased, reaching their peak at 45 minutes (4.8 (0.5) ng/l; P < 0.01 v baseline). No significant variations were found in mean arterial pressure and plasma osmolality. These data suggested involvement of neurotransmitter mechanisms regulating arginine vasopressin secretion and a possible role of arginine vasopressin in vasomotor phenomena accompanying cluster attacks.

Lichen planus induced by interferon-alpha-2a therapy for chronic active hepatitis C.

OBJECTIVE: To report the development of hepatitis C virus (HCV)-positive chronic active hepatitis with lichen planus in a patient during interferon treatment. DESIGN: Case report and literature review. PATIENT: A 64-year-old anti-HCV and HCV-RNA-positive woman. INTERVENTIONS: The patient received interferon-alpha-2a treatment for histologically proven chronic active hepatitis. RESULTS: Four months after the start of treatment the patient developed multiple cutaneous lesions on her hands, feet and back. A skin biopsy led to the diagnosis of lichen planus. The withdrawal of interferon was followed by a marked improvement in the cutaneous lesions, but not complete regression. CONCLUSION: This case shows that HCV-positive patients with chronic active hepatitis may develop lichen planus during interferon therapy.

Plasma beta-endorphin levels and glucose tolerance in patients with chronic renal failure.

In order to examine the role of endogenous opioid peptides on glucose metabolism in uraemic patients, plasma concentrations of beta-endorphin, glucose, insulin and C-peptide were determined before and during an oral glucose tolerance test (OGTT) in nine non-dialysed patients with chronic renal failure (CRF). The results are compared with those obtained in a group of age-matched normal subjects. In CRF patients, plasma beta-endorphin fasting values (16.0 +/- 1.9 pmol/l) were significantly higher than those of the controls (6.6 +/- 0.6 pmol/l) and significantly correlated with the degree of renal function impairment. After glucose load, plasma beta-endorphin in CRF patients tended to decline, whereas in normal subjects increased. The fasting and the mean OGTT plasma beta-endorphin values negatively correlated with insulin initial response to glucose, insulin and C-peptide mean OGTT values, but not with glucose OGTT mean values. Data indicate that chronic uraemia induces a significant increase in circulating plasma beta-endorphin levels, with a loss of opioid system responsiveness to glucose. The possibility that this hyper-endorphinism may have a biological importance at least as a contributory factor of impaired glucose tolerance in uraemia may be suggested.