Active diffraction gratings: development and tests.

We present the realization and characterization of an active spherical diffraction grating with variable radius of curvature to be used in grazing-incidence monochromators. The device consists of a bimorph deformable mirror on the top of which a diffraction grating with laminar profile is realized by UV lithography. The experimental results show that the active grating can optimize the beam focalization of visible wavelengths through its rotation and focus accommodation.

Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep).

BACKGROUND: The effect of hepatitis delta virus (HDV) infection on the clinical course of cirrhosis type B is poorly defined. AIMS: To investigate the impact of HDV status on morbidity and mortality in cirrhosis type B. PATIENTS/METHODS: Retrospective cohort study of 200 Western European patients with compensated cirrhosis type B followed for a median period of 6.6 years. RESULTS: At diagnosis, 20% of patients had antibodies to HDV (anti-HDV); median age was lower in anti-HDV positive cirrhotics (34 v 48 years respectively). Kaplan-Meier five year probability of hepatocellular carcinoma (HCC) was 6, 10, and 9% in anti-HDV positive/HBeAg negative, anti-HDV negative/HBeAg negative, and anti-HDV negative/HBeAg positive cirrhotics respectively; the corresponding figures for decompensation were 22, 16, and 19% and for survival they were 92, 89, and 83% respectively. Cox regression analysis identified age, albumin concentration, gamma-globulin concentration, and HDV status as significant independent prognostic variables. After adjustment for clinical and serological differences at baseline, the risk (95% confidence interval) for HCC, decompensation, and mortality was increased by a factor of 3.2 (1.0 to 10), 2.2 (0.8 to 5.7), and 2.0 (0.7 to 5.7) respectively in anti-HDV positive relative to HDV negative cirrhotic patients. The adjusted estimated five year risk for HCC was 13, 4, and 2% for anti-HDV positive/HBeAg negative, anti-HDV negative/HBeAg negative, and anti-HDV negative/HBeAg positive cirrhotics respectively; the corresponding figures for decompensation were 18, 8, and 14% and for survival 90, 95, and 93% respectively. CONCLUSIONS: HDV infection increases the risk for HCC threefold and for mortality twofold in patients with cirrhosis type B.

Influence of GB virus-C/hepatitis G virus infection on the long-term course of chronic hepatitis B.

AIMS/BACKGROUND: The clinical significance of GB virus-C/hepatitis G virus (GBV-C/HGV) infection in chronic hepatitis B is not well known and its role in the outcome of liver disease was investigated. METHODS: HGV-RNA and antibody to HGV (anti-E2) were studied in 125 patients with chronic hepatitis B (41 with multiple hepatitis virus exposure), 82 asymptomatic HBsAg carriers and 103 healthy adults. RESULTS: In chronic hepatitis B, HGV-RNA was more frequent in patients with HDV infection and/or anti-HCV positivity than in those without (29% vs 6%, p<0.0001), mainly in drug addicts (38%). At diagnosis the overall prevalence of any marker (HGV-RNA plus anti-E2) was similar in chronic hepatitis due to HBV alone (17%), in HBsAg carriers (16%) and in healthy adults (17%) and increased to 58% in those exposed to HDV and/or HCV. During 1-11 years of follow-up, HGV infection persisted in 70% of patients with chronic hepatitis B. About 400% of HGV persistently coinfected patients underwent sustained biochemical remission, whereas continuing disease activity was observed in 80% of patients who cleared HGV-RNA. CONCLUSIONS: In chronic HBV infection the rate of exposure to HGV is similar to that in healthy adults, except for high risk patients. Long lasting HGV coinfection or anti-E2 seroconversion did not modify the course of chronic hepatitis B.

Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP)

OBJECTIVE: The aim of this study was to evaluate the incidence, prognostic factors and clinical significance of delayed clearance of serum HBsAg in compensated cirrhosis B. METHODS: This was a retrospective cohort study of 309 consecutive white patients with biopsy-proved compensated cirrhosis type B. RESULTS: During a mean follow-up of 68 months, HBsAg loss occurred in 32 patients, including 16 (8%) of 196 untreated patients (mean annual incidence 0.8%), 8 (10%) of 82 interferon (IFN) alpha-treated patients and eight patients who had been treated with other antivirals or steroids. The 5-yr probability of HBsAg loss was 4% and 16% for untreated and IFN-treated patients, respectively (p = 0.0001). Cox's regression analysis identified hepatitis B e antigen-positivity at entry as the sole independent prognostic factor for HBsAg loss. Of the 32 patients who lost HBsAg, one (3%) subsequently developed hepatocellular carcinoma (HCC) and died, whereas, among the patients who remained HBsAg-positive, 11% developed HCC and 20% had died. The probability of HCC appearance was lower (p = 0.0137) and survival was longer (p = 0.0006) in patients who cleared HBsAg compared with patients with HBsAg persistence. CONCLUSION: The incidence of HBsAg loss is about 0.8% in cirrhosis type B. Prognostic factors for clearance of HBsAg are initial HBeAg positivity and therapy with alpha interferon. Patients with cirrhosis type B, who lose HBsAg, have a low risk for liver cancer or liver-related death.

Double-blind, randomized controlled trial of interleukin-2 treatment of chronic hepatitis B.

Pilot studies have demonstrated that recombinant interleukin 2 (rIL-2) has an indirect antiviral activity against hepatitis B virus, but the minimal dose of rIL-2 for induction of this effect was not defined. The aim of the study was to ascertain the most efficient dose of rIL-2 for induction of the loss of detectable serum HBV-DNA or a 50% or greater decrease in its level. Thirty-one patients with chronic hepatitis B, hepatitis B e antigen and serum HBV-DNA positive were enrolled in this double-blind randomized controlled trial. Patients were divided: Group I (n = 8) placebo; Group II (n = 7) treated with 0.9 MU of rIL-2 subcutaneously administered daily for 8 weeks; Group III (n = 8) treated with 1.8 MU of rIL-2 under the same schedule; Group IV (n = 8) which received 3.6 MU of rIL-2 under the same conditions. At the end of treatment 25% of the patients in the placebo group, and 13% and 25% in rIL-2 groups III and IV, respectively, had a decrease in HBV-DNA higher than 50% of the basal value. None of the patients lost serum HBV-DNA. Only three patients (one from group II and two from group IV) normalized the ALT levels. Overall, during treatment, ALT levels decreased in the treated groups. This decrease occurred simultaneously with an increase in serum HBV-DNA concentration. Since the response rate in the treated groups was similar to that of the placebo group, rIL-2 is not useful as monotherapy for the treatment of chronic hepatitis B at the doses and schedules used in this study.

Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP).

The aim of this study was to evaluate whether interferon alfa (IFN-alpha) treatment-associated virological and biochemical remission improves survival in a cohort of 90 white patients with compensated cirrhosis caused by hepatitis B (Child A) followed for a mean period of 7 years. Inclusion criteria were biopsy-proven cirrhosis, hepatitis B e antigen (HBeAg) positivity, abnormal serum aminotransferase levels, exclusion of hepatitis delta virus, and absence of complications of cirrhosis. Of the 40 IFN-treated patients, 27 (67%) showed sustained HBeAg loss with alanine aminotransferase (ALT) normalization. Of the 50 untreated patients, 30 (60%) cleared HBeAg, but only 21 (42%) normalized ALT after HBeAg loss. Compared with the untreated patients, IFN-treated patients had similar cumulative rates of HBeAg clearance (P = .48), but higher rates of ALT normalization (P = .016) and of HBsAg loss (P = .028). During follow-up, liver-related death occurred in 8 treated patients, caused by liver failure in 5 and hepatocellular carcinoma (HCC) in 3; all 8 had continued to be HBeAg-positive with elevated ALT. None of the treated patients undergoing remission developed liver-related complications. At univariate analysis, life expectancy was longer in treated patients showing sustained remission than in those who did not (5-year survival: 100% vs. 81%; P = .048). Fourteen untreated patients died (from liver failure in 10 and HCC in 4); all but 3 had continued to be HBeAg-positive with elevated ALT. Cox's model identified age and ALT normalization as the only significant predictors of survival. In conclusion, in patients with HBeAg-positive compensated cirrhosis, virological and biochemical remission following IFN therapy is associated with improved survival.

Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP).

BACKGROUND/AIMS: The role of interferon alfa treatment in improving morbidity endpoints in patients with chronic hepatitis C infection is currently under debate. The aim of this study was to evaluate the effectiveness of interferon in preventing hepatocellular carcinoma and decompensation in cirrhosis type C. METHODS: A retrospective cohort study was carried out on 329 consecutive Caucasian patients with cirrhosis followed for a mean period of 5 years at seven tertiary care university hospitals. Inclusion criteria were biopsy-proven cirrhosis, anti-HCV positivity, abnormal serum aminotransferase levels and absence of complications of cirrhosis. RESULTS: The yearly incidence of hepatocellular carcinoma was 2.3% for 136 untreated patients and 1.0% for 193 patients treated with interferon alfa. The yearly incidence of hepatic decompensation was 5.7 for untreated and 1.5 for the treated patients. Fourteen (7%) of 193 treated patients showed sustained aminotransferase normalization and none of them developed complications of cirrhosis. At enrollment, untreated patients were older and had more severe liver disease than patients treated with interferon. After adjustment for clinical and serologic differences at entry between treated and untreated patients, the 5-year estimated probability of the occurrence of hepatocellular carcinoma was 2.1% and 2.7% and of decompensation was 7% and 11% for treated and untreated cases, respectively. CONCLUSIONS: This analysis did not detect any significant benefit of interferon alfa on morbidity in patients with compensated cirrhosis type C, although it suggests a reduction in complications of cirrhosis for those with a sustained response to therapy, and it indicates the need for better therapies.

Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.

BACKGROUND & AIMS: Few data are available concerning the long-term prognosis of chronic liver disease associated with hepatitis C virus infection. This study examined the morbidity and survival of patients with compensated cirrhosis type C. METHODS: A cohort of 384 European cirrhotic patients was enrolled at seven tertiary referral hospitals and followed up for a mean period of 5 years. Inclusion criteria were biopsy-proven cirrhosis, abnormal serum aminotransferase levels, absence of complications of cirrhosis, and exclusion of hepatitis A and B viruses and of metabolic, toxic, or autoimmune liver diseases. RESULTS: Antibodies against hepatitis C virus were positive in 98% of 361 patients tested. The 5-year risk of hepatocellular carcinoma was 7% and that of decompensation was 18%. Death occurred in 51 patients (13%), with 70% dying of liver disease. Survival probability was 91% and 79% at 5 and 10 years, respectively. Two hundred five patients (53%) were treated with interferon alfa. After adjustment for clinical and serological differences at baseline between patients treated or not treated with interferon, the 5-year estimated survival probability was 96% and 95% for treated and untreated patients, respectively. CONCLUSIONS: In this cohort of patients, life expectancy is relatively long, in agreement with the morbidity data showing a slowly progressive disease.

Hypothalamic control of growth hormone (GH) secretion in type I diabetic men: effect of the combined administration of GH-releasing hormone and hexarelin, a novel GHRP-6 analog.

Insulin dependent (type I) diabetic patients show abnormal growth hormone (GH) secretion. Hexarelin is an analog of GHRP-6 which releases GH in part via somatostatin inhibition. The aim of our study was to evaluate the effects of hexarelin and GHRH, administered either alone or in combination, on GH secretion in 10 type I diabetic and 7 normal men. All the subjects were administered: 1) human GHRH (1-29) NH2 100 micrograms i.v. bolus at 0 min; 2) hexarelin 100 micrograms i.v. bolus at 0 min; 3) hexarelin 100 micrograms + hGHRH 100 micrograms i.v. bolus at 0 min. In type I diabetic patients significantly greater GH responses to GHRH and hexarelin have been observed with normal subjects. Hexarelin caused a significantly (p < 0.05) greater GH response as compared to GHRH in both diabetic and control subjects. After the administration of hexarelin+GHRH, a significant increase in both GH absolute and peak levels as compared to hexarelin or GHRH alone was found in all the subjects. However, the GH responses to the combined stimuli were not significantly different in diabetics as compared to normals; moreover, the interaction of GHRH and hexarelin was synergistic in controls and additive in diabetics. We hypothesize that a reduction in the hypothalamic somatostatin inhibitory tone combined with increased pituitary GH production may be responsible for the pattern of the GH responses to hexarelin and GHRH observed in our type I diabetic patients.

Liver stellate cells in chronic viral hepatitis: the effect of interferon therapy.

BACKGROUND/AIMS: Liver stellate cell proliferation and differentiation into myofibroblast-like cells is related to the development of liver fibrosis. Several cytokines, including interferons, regulate liver stellate cell proliferation and phenotypic modulation. Recent studies indicate that human liver stellate cells express the alpha-isotype of actin, specific to smooth muscle cell differentiation. We aimed to evaluate the expression of alpha-smooth muscle actin-positive liver stellate cells in patients with chronic viral hepatitis and to evaluate whether and how such expression can be modified by alpha-interferon treatment. METHODS: Using immunohistochemistry, and a semi-quantitative scoring method, we evaluated alpha-smooth muscle actin expression in liver stellate cells before and after alpha-interferon therapy in a series of liver biopsies from 44 patients with chronic viral hepatitis. RESULTS: Before therapy, a large number of liver stellate cells expressing alpha-smooth muscle actin were present throughout all acinar zones. A significant reduction in alpha-smooth muscle actin expression by liver stellate cells was demonstrated in biopsies performed after suspending the interferon treatment. The drop in the number of alpha-smooth muscle actin-labelled cells after therapy correlated closely with the improvement in the histological index of activity. CONCLUSIONS: The results suggest a specific effect of interferon on liver stellate cells, possibly related to its anti-inflammatory action.

A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon.

AIMS: The aim of this study was to assess the incidence of fatal, life-threatening side effects and the de novo appearance of non-hepatic morbidity during interferon alfa therapy for chronic viral hepatitis. The relationship of these adverse events to actual total dose and duration of interferon was also evaluated. METHODS: We conducted a retrospective study at 73 Italian centers of 11,241 consecutive patients with chronic viral hepatitis who underwent interferon alfa treatment. RESULTS: Five patients died during interferon therapy due to liver failure (n = 4) or complications arising from sepsis. Life-threatening side effects were observed in eight patients: two cases where depression developed and led to a suicide attempt and six patients with bone marrow suppression (granulocytes < 500/mm3 or platelets < 25,000/mm3). These symptoms and signs completely disappeared after interferon withdrawal. During interferon treatment, 131 patients developed the following de novo non-hepatic disorders: symptomatic thyroid disease (n = 71), impotence (n = 5), systemic autoimmune disease (n = 5), immune-mediated dermatologic disease (n = 14), diabetes mellitus (n = 10), cardiovascular disease (n = 7), psychosis n = 10), seizures (n = 4), peripheral neuropathy (n = 3) and hemolytic anemia (n = 2). Most of these complications are reversible or can be ameliorated. Fatal or life-threatening side effects were not related to actual total dose or duration of interferon alfa, while the majority of patients with de novo non-hepatic morbidity received medium/high doses (> 200 million units) of interferon alfa or were treated for periods longer than 16 weeks (68% and 80%, respectively). CONCLUSIONS: Treatment with interferon alfa may have fatal or life-threatening side effects, their incidence in this study being low (0.04% and 0.07%, respectively) and perhaps no different than in untreated patients with chronic viral hepatitis. Moreover de novo non-hepatic morbidity occurred in 1.2% of patients, and the dose and duration of interferon therapy seem important in determining the frequency of this complication. The development of clinically-overt thyroid disease was most common.

Serum levels of soluble CD30 in chronic hepatitis B virus infection.

There is evidence that both cellular and humoral components of the immune response are required for viral clearance to occur in chronic hepatitis B. Recent studies demonstrated that CD30 molecule, a member of the tumour necrosis factor superfamily of membrane cytokine receptors, is expressed on, and released as a soluble molecule (sCD30) by activated T cells producing T helper 2 (Th2) cytokines, which modulate antibody responses. To better characterize the immunoregulatory mechanisms in chronic hepatitis B virus (HBV) infection, sCD30 values were evaluated by an ELISA in 90 hepatitis B surface (HBsAg)-positive patients with chronic hepatitis, selected on the basis of active viral replication and biochemical activity. At presentation abnormal levels (> 20 U/ml) of sCD30 were detected in 57 (63%) out of 90 patients with chronic hepatitis B, and median value was significantly higher in this group of patients compared with that of healthy HBsAg carriers (26.7 versus 10.5 U/ml, P < 0.000 05) and with normal controls (26.7 versus 3 U/ml P < 0.000 01). Sequential studies of chronic hepatitis B did confirm the association of raised sCD30 levels with the active phase of the illness. On the other hand, a significant decrease was noted when sCD30 levels at diagnosis and after termination of HBV replication and biochemical remission of hepatitis were compared in 10 untreated patients (median, 28 U/ml at entry versus 8 U/ml at remission, P < 0.01) and in six patients responding to interferon-alpha therapy (median, 29.5 U/ml at entry versus 6 U/ml at remission, P < 0.05). The high serum sCD30 levels reported during the active phase of HBsAg-positive chronic hepatitis suggest a certain degree of immune competence of these patients, at least with respect to a Th2-type response. These data are in agreement with recent serologic surveys showing that most chronic hepatitis B patients do demonstrate ongoing humoral immune response to HBV antigens, using novel immunoassays designed to detect antibody in the presence of excess serum viral antigen. Th2 functions that mainly promote humoral immunity to HBV antigens may be critical, in association with a competent virus-specific cytotoxicity, for efficient termination of HBV replication in chronic hepatitis B.

Serum procollagen type III peptide in chronic hepatitis B. Relationship to disease activity and response to interferon-alpha therapy.

The clinical significance of serum procollagen type III peptide, a marker of active fibrogenesis, was evaluated in 110 hepatitis B surface antigen positive patients with chronic hepatitis (32 chronic persistent hepatitis, 60 chronic active hepatitis, and 18 active cirrhosis), selected on the basis of active viral replication and biochemical activity, including 54 cases treated with interferon-alpha. At presentation the procollagen type III peptide level serum was above normal in 48 (44%) of the 110 patients and the median value was significantly higher than that of healthy carriers with normal transaminases and histology (P < 0.000005). Semiquantitative histological evaluation showed a significant correlation between serum procollagen type III peptide levels and necrosis/inflammation in the subgroup of patients with chronic active hepatitis, but no relationship with the score of fibrosis. Among patients treated with interferon-alpha and with increased fibrogenic activity (indicated by high pretreatment serum levels of procollagen type III peptide), peptide levels were significantly decreased when pretreatment levels were compared with those at 12 months after therapy withdrawal, both in responders to interferon (P = 0.022) and non-responders (P = 0.012). However, serum procollagen type III peptide levels normalized in 75% of responders to interferon with sustained serological and histological remission of liver disease, but in only 21% of non-responders (P = 0.02). These results obtained in a well-defined population suggest that serum procollagen type III peptide is a better marker of active fibrogenesis and inflammation than an indicator of the extent of fibrosis, and that interferon may reduce active liver fibrogenesis in chronic hepatitis B independently of its effect on viral replication. However, a consistent proportion (56%) of our chronic hepatitis B patients had normal serum procollagen type III peptide levels at presentation, thus precluding the clinical use of this marker both for diagnosis of liver injury and for monitoring the therapeutic response to interferon.

Clinical evolution of HCV-related chronic hepatitis.

Evolution of HCV positive chronic hepatitis to cirrhosis has been reported to occur in about 30% of patients after five years of follow-up. In contrast, evolution of cirrhosis to decompensation and liver failure is slow, with a survival rate at 5 and 10 years of 91% and 79%, respectively. These findings support the hypothesis that histologic cirrhosis and clinical cirrhosis are different facets of the same disease, the latter developing after a long period of time and being related not only to liver disease per se, but also to other factors only partially identified. During this long-term evolution, extrahepatic manifestations may occur due to the formation of antigen-antibody immunocomplexes, which may eventually lead to death due to renal or cardiac complications.

Hypertension and non-insulin-dependent diabetes. A comparison between an angiotensin-converting enzyme inhibitor and a calcium antagonist.

The effects of the angiotensin-converting enzyme lisinopril were compared with those of the calcium antagonist nifedipine in 162 non-insulin-dependent diabetic hypertensive patients for a 24-week period. In 83 and 79 patients, respectively, lisinopril and slow-release nifedipine produced similar reductions in blood pressure (systolic/diastolic: -16/-13 mmHg supine and -14/-11 mmHg standing after lisinopril; -15/-12 mmHg supine and -14/-11 mmHg standing nifedipine). Fasting and post-prandial plasma glucose, glycosylated haemoglobin and plasma lipids appeared to be unaffected by either agent. Also, 28% of the patients on lisinopril and 30% of those on nifedipine presented microalbuminuria. Both drugs induced a reduction in the albumin excretion rate (AER). The geometric mean x:tolerance factor of the reduction in AER among the 23 microalbuminuric patients on lisinopril (-10.0 x:1.3 micrograms/min) was greater, though not significantly so, than that observed in the 26 on nifedipine (-0.9 x 1.2 micrograms/min). Moreover, lisinopril appeared to be better tolerated than nifedipine in our study population. Microalbuminuria is an important risk factor for cardiovascular mortality in non-insulin-dependent diabetic patients as well as in the general population. To what extent a reduction in the AER could ameliorate diabetic patients is, at present, unknown. Finally, both lisinopril and nifedipine showed a similar antihypertensive effect in these patients which was not associated with significant differences in plasma glucose, insulin or lipid concentrations. The clinical consequences of the insignificant differences in AER remain unclear.

Hexarelin, a novel GHRP-6 analog, counteracts the inhibitory effect of hydrocortisone on growth hormone secretion in acromegaly.

Hexarelin (His-D-2-Methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a GHRP-6 analog with the substitution of D-tryptophan with its 2-methyl derivative. The aim of our study was to ascertain whether hexarelin was able to counteract the glucocorticoid-mediated increase in hypothalamic somatostatin tone and consequent inhibition on serum GH levels in acromegalic patients. Ten patients (5 males, 5 females; age range 27-71 years; BMI range 23.3-35 kg/m2) with active acromegaly underwent: 1) hydrocortisone alone: a bolus iv injection of 100 mg hydrocortisone succinate in 2 mL saline, at time -60 followed by a 120 min iv infusion of 250 mg hydrocortisone succinate in 250 mL saline, from -60 to 60 min; 2) hexarelin+hydrocortisone: a bolus iv injection of hexarelin 100 micrograms, 60 min after initiation of a 2-hour hydrocortisone infusion; 3) hexarelin alone: a bolus iv injection of hexarelin at time 0, 60 min after initiation of a 2-hour saline infusion. The mean GH peak, expressed as percent change with respect to baseline level (mean of -75 and -60 minute samples), after hexarelin (1750 +/- 1157%) did not differ significantly with respect to that observed after hexarelin+hydrocortisone (1120 +/- 770%). After hydrocortisone alone the patients showed a mean decrease in GH levels as compared to baseline levels, of 47 +/- 7%. Our data show that the GH response to hexarelin in acromegaly is resistant to the inhibitor action of an acute and sustained elevation of serum cortisol levels. That hexarelin counteracts the glucocorticoid-mediated inhibition of GH secretion supports the hypothesis of an hexarelin-induced decrease in endogenous somatostatin tone.

Pravastatin-associated myopathy. Report of a case.

A case of acute inflammatory myopathy associated with the use of pravastatin, a new hydrophilic 3-hydroxy-3 methylglutaril coenzyme A reductase inhibitor, is reported. The patient, a 69-year-old man was affected by non-insulin-dependent diabetes mellitus and hypertension. He assumed pravastatin (20 mg/day) because of hypercholesterolemia. He was admitted with acute myopathy of the lower limbs which resolved in a few days after pravastatin discontinuation. A previously unknown hypothyroidism, probably due to chronic autoimmune thyroiditis, was evidenced. Muscle biopsy (left gastrocnemius) revealed a perimysial and endomysial inflammatory infiltrate with a prevalence of CD4+ lymphocytes. While lovastatin and simvastatin have been associated with toxic myopathy, pravastatin-associated myopathy could represent a distinct, inflammatory entity.

Cardiopulmonary performance during exercise in acromegaly, and the effects of acute suppression of growth hormone hypersecretion with octreotide.

We studied 10 adult patients with active acromegaly (4 men and 6 women, mean age 55 +/- 5 years and mean body mass index 27.9 +/- 1.1 kg/m2). Control values for the echocardiographic and exercise studies were obtained from 10 normal subjects matched for sex and age (5 men and 5 women, age 51.1 +/- 3.7 years and body mass index 25.3 +/- 1 kg/m2). Each patient underwent: (1) blood sampling for growth hormone (GH) assay every 3 hours; (2) a 2-dimensional, guided M-mode echocardiographic study; and (3) a cycloergometric exercise test at baseline and after treatment with a portable pump infusing octreotide, 500 micrograms/24 hours subcutaneously. All patients had left ventricular hypertrophy. Systolic function indexes did not significantly differ among normal subjects, whereas baseline Doppler studies showed abnormalities in left ventricular diastolic filling in acromegalic patients. At anaerobic threshold and at maximal exercise, acromegalic subjects sustained a significantly (p < 0.05) decreased workload (54 +/- 23 vs 94 +/- 11 and 87 +/- 37 vs 152 +/- 15 W) compared with control subjects. After octreotide, baseline heart rate (79 +/- 7 vs 87 +/- 8 beats/min, p < 0.05) and serum GH levels significantly decreased compared with levels before administration of octreotide. Systolic and diastolic functional indexes at rest significantly improved after octrotide in acromegalic patients. Both at anaerobic threshold and at maximal exercise, workload and oxygen consumption were significantly increased after octretide administration. Exercise capacity at anaerobic threshold was not significantly different in acromegalic subjects after octreotide when compared with normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of the paradoxical growth hormone inhibitory effect of galanin in acromegaly.

Galanin is a 29-amino acid straight-chain biologically active peptide which has been found to decrease circulating GH levels in some acromegalic patients, whereas is able to increase GH secretion in normal subjects. The aim of our study was to ascertain the incidence, entity and mechanism of the paradoxical GH inhibitory effect of galanin in acromegaly also looking at possible correlations between the GH responses to galanin and the main clinical and biochemical features of the patients. Finally, the effects of either successful or unsuccessful neurosurgical intervention on the GH inhibitory effect of galanin in acromegaly were investigated. A series of 23 consecutive patients with active acromegaly seen at the Endocrine Section of the Department of Internal Medicine of the University of Brescia (Italy) between 1991 and 1994 was examined. The acromegalic patients were subdivided in group 1 (i.e. patients who were 1) untreated, 2) evaluated before surgery, and 3) not cured after surgery and radiotherapy) and group 2 (i.e. surgically cured). All patients were submitted at least once to the following biochemical and radiological evaluations: 1) baseline serum insulin-like growth factor-I and PRL samples, 2) iv infusion of synthetic porcine galanin (500 micrograms in 100 mL saline) from -10 to 30 min, 3) iv bolus injection of TRH (200 micrograms) at time zero, 4) oral glucose tolerance test (75 g glucose, orally) at time zero, and 5) magnetic resonance of the pituitary sella. Adenomatous tissue obtained during neurosurgery in four patients was cultured in vitro, and the effect of the addition of galanin in the culture medium on GH secretion was tested. During galanin infusion in 19 of 21 group 1 patients, serum GH levels were lower with respect to baseline (range of GH decrease, -6.2 to -85.4% with respect to basal levels). During galanin infusion, no reductions in GH levels were observed in the acromegalic patients cured after neurosurgery (group 2); on the contrary, 6 of 7 patients displayed a normal stimulatory response to galanin (range of GH increase, +120-1533.3% of the basal level). A significant correlation between the percent decrease in GH levels after galanin treatment and the percent increase after TRH was found in group 1 patients (r = -0.783; P < 0.05). In three of the four adenomas examined, galanin determined a clear decrease in GH secretion (mean nadir, 63.3 +/- 12% of the baseline secretion rate). In conclusion, we demonstrated that the large majority of numerous patients with active acromegaly show a decrease in serum GH levels after galanin administration.(ABSTRACT TRUNCATED AT 400 WORDS)