Long-term albumin improves the outcomes of patients with decompensated cirrhosis and diabetes mellitus: Post hoc analysis of the ANSWER trial.

Type-2 diabetes mellitus is a frequent comorbidity of cirrhosis independently associated with cirrhosis-related complications and mortality. This post hoc analysis of the ANSWER trial database assessed the effects of long-term human albumin (HA) administration on top of the standard medical treatment (SMT) on the clinical outcomes of a subgroup of 85 outpatients with liver cirrhosis, uncomplicated ascites and insulin-treated diabetes mellitus type 2 (ITDM). Compared to patients in the SMT arm, the SMT + HA group showed a better overall survival (86% vs. 57%, p = .016) and lower incidence rates of paracenteses, overt hepatic encephalopathy, bacterial infections, renal dysfunction and electrolyte disorders. Hospital admissions did not differ between the two arms, but the number of days spent in hospital was lower in the SMT + HA group. In conclusion, in a subgroup of ITDM outpatients with decompensated cirrhosis and ascites, long-term HA administration was associated with better survival and a lower incidence of cirrhosis-related complications.

Correction and Prevention of Hyponatremia in Patients With Cirrhosis and Ascites: Post Hoc Analysis of the ANSWER Study Database.

INTRODUCTION: We assessed the impact of long-term albumin administration to hyponatremic patients with ascites enrolled in the ANSWER trial. METHODS: The normalization rate of baseline hyponatremia and the 18-month incidence rate of at least moderate hyponatremia were evaluated. RESULTS: The hyponatremia normalization rate was higher with albumin than with standard medical treatment (45% vs 28%, P = 0.042 at 1 month). Long-term albumin ensured a lower incidence of at least moderate hyponatremia than standard medical treatment (incidence rate ratio: 0.245 [CI 0.167-0.359], P < 0.001). DISCUSSION: Long-term albumin administration improves hyponatremia and reduces episodes of at least moderate hyponatremia in outpatients with cirrhosis and ascites.

On-treatment serum albumin level can guide long-term treatment in patients with cirrhosis and uncomplicated ascites.

BACKGROUND & AIMS: The ANSWER study reported that long-term albumin administration in patients with cirrhosis and uncomplicated ascites improves survival. During treatment, serum albumin increased within a month and remained stable thereafter. In this post hoc analysis, we aimed to determine whether on-treatment serum albumin levels could guide therapy. METHODS: Logistic regression was used to assess the association between baseline serum albumin and mortality, as well as to determine on-treatment factors associated with mortality and to predict the achievement of a given on-treatment serum albumin level. Survival was assessed by Kaplan-Meier estimates and second-order polynomial regression. Patients whose on-treatment serum albumin remained below normal were compared with a subset of patients from the control arm matched by principal score. RESULTS: Baseline serum albumin was closely associated with 18-month mortality in untreated patients; albumin treatment almost effaced this relationship. On-treatment serum albumin and MELD-Na at month 1 were the sole independent variables associated with mortality. Second-order polynomial regression revealed that survival improved in parallel with increased 1-month on-treatment serum albumin. Kaplan-Meier estimations showed that any value of 1-month on-treatment serum albumin (0.1 g/dl intervals) in the range 2.5-4.5 g/dl discriminated patient survival. In the normal range of serum albumin, the best discriminant value was 4.0 g/dl. Compared to untreated patients, survival even improved in patients whose on-treatment serum albumin remained below normal. CONCLUSION: Baseline serum albumin per se should not guide the decision to start albumin therapy. Conversely, 1-month on-treatment serum albumin levels are strongly associated with outcomes and could guide the use of albumin - 4.0 g/dl being the target threshold. However, even patients whose serum albumin remains below normal benefit from long-term albumin administration. LAY SUMMARY: The ANSWER study has shown that long-term albumin administration improves survival and prevents the occurrence of major complications in patients with cirrhosis and ascites. This study shows that the achievement of these beneficial effects is related to a significant increase in serum albumin concentration. Even though the best results follow the achievement of a serum albumin concentration of 4 g/dl, a survival benefit is also achieved in patients who fail to normalise serum albumin.

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.

BACKGROUND: Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. METHODS: We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008-000625-19, and ClinicalTrials.gov, number NCT01288794. FINDINGS: From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40-0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3-4 non-liver related adverse events. INTERPRETATION: In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. FUNDING: Italian Medicine Agency.

Vision loss due to atypical bilateral edema of the optic nerve in a patient with hereditary angioedema: A case report.

PURPOSE: To describe a rare case of vision loss due to bilateral edema of the optic nerve in a patient with Hereditary Angioedema, treated with prophylactic C1-esterase inhibitor. METHODS: A 60-year-old Caucasian male affected by Hereditary Angioedema with unknown genetic defect (HAE- UNK) was admitted to our hospital presenting bilateral vision loss (best corrected visual acuity of 20/32 in the right eye and hand motion in the left eye) during an HAE attack. Intravenous administration of C1- esterase inhibitor (C1-INH, 1500 IU, Berinert, CSL Behring) determined the resolution of facial and periorbital swelling, however visual impairment persisted, in contrast with previous attacks experienced by the patient. Fundus examination revealed a vital optic disc without papilledema in both eyes. Magnetic resonance imaging (MRI) of the head and orbits showed bilateral edema of the optic nerve sheath. Treatment with intravenous and oral steroids was ineffective. Subsequently, a prophylactic treatment strategy with subcutaneous C1-esterase inhibitor was started (7000 IU every four days). RESULTS: Complete regression of edema of the optic nerves was observed by imaging at two months of follow-up after chronic treatment with C1-esterase inhibitor (7000 IU every four days). Complete restoration of visual acuity was achieved (BCVA 20/20 in both eyes) and multimodal imaging of the optic nerves demonstrated the absence of anatomical and functional damage. CONCLUSION: Patients affected by HAE may show atypical presentation with edema of the optic nerves without involvement of the optic nerve head. They may significantly benefit from prophylactic and chronic treatment with C1-esterase inhibitor.

Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement.

Mental health problems frequently occur in chronic infection with the hepatitis C virus (HCV) and during antiviral treatment with pegylated interferon-alpha (PegIFNα) and ribavirin. Depression is one of the most important complications during antiviral treatment of chronic hepatitis C infection. However, an increased prevalence of depression, fatigue, and cognitive disturbances has also been reported in untreated HCV-positive patients. Patients with psychiatric disorders or drug addiction also have an increased risk of HCV infection. Furthermore, because of possible drug-drug interactions, new antivirals administered together with PegIFNα and ribavirin may complicate psychiatric side effect management, even if no specific psychiatric adverse events are known so far for these new drugs. The European liver patient's organization (ELPA) organised a European expert conference to review the literature and develop expert recommendations for the management of mental health problems in HCV infected patients. This paper results from the output of the 2011 EASL meeting and subsequent dialogue with patient groups and relevant experts in Europe. It summarises the current knowledge of HCV infection and the brain; prevalence, course, and neurobiology of IFN-α associated psychiatric side effects; possible risk factors for IFN-α associated depression and suicide attempts; psychiatric management of HCV infected patients before and during antiviral treatment; prevention of IFN- α associated psychiatric side effects; and psychiatric aspects of the new antivirals. The summarised current knowledge about mental health changes before and during antiviral treatment should improve interdisciplinary management of HCV infected patients.

Patients with unrecognized peripheral arterial disease (PAD) assessed by ankle-brachial index (ABI) present a defined profile of proinflammatory markers compared to healthy subjects.

BACKGROUND: Many studies have postulated that atherosclerosis should be considered as an inflammatory disease. In addition, some studies have focused on the relationship between inflammation and peripheral arterial disease (PAD). OBJECTIVE: Define the plasma levels of soluble markers, including the proinflammatory cytokine interleukin-6 (IL-6), the anti-inflammatory cytokine transforming growth factor-ß1 (TGF-ß1), the endothelial-specific adhesion factor (E-selectin) and two proteinases involved in extracellular matrix degradation (matrix metalloproteinases-2 and -9, MMP-2, and MMP-9) in previously unrecognized patients with peripheral artery disease (PAD) and non-PAD controls. RESULTS: Significantly higher levels of IL-6, E-selectin and MMP-2/MMP-9 and significantly reduced levels of TGF-ß1 were found in PAD patients (ankle-brachial index, ABI⩽0.9) compared to non-PAD control subjects (1.4>ABI>0.9). CONCLUSION: The results demonstrated the subjects with unrecognized PAD (ABI⩽0.9) show a characteristic phlogistic pattern differently from healthy subjects and it strongly supports the pivotal role played by inflammatory and immunological mechanisms in the initiation and progression of the atherosclerotic process in peripheral arteries. These biomarkers could be helpful to screen the susceptibility for the diseases in peripheral arteries.

Carotid intima-media thickness and liver histology in hemodialysis patients with nonalcoholic Fatty liver disease.

The prevalence of atherosclerotic cardiovascular disease in chronic hemodialysis (HD) patients has been demonstrated to be higher than in healthy people. Severe liver fibrosis is strongly associated with early carotid atherosclerosis and it might reduce the survival of patients who undergo both renal replacement therapy and transplantation. We wanted to assess whether nonalcoholic fatty liver disease (NAFLD) was associated with altered intima-media thickness (IMT) in HD patients as an independent marker of subclinical atherosclerosis. We enrolled 42 patients undergoing HD and 48 patients with normal renal function, all of them with high levels of aminotransferases and an ultrasonographic diagnosis of liver steatosis. The control group consisted of 60 healthy subjects. Laboratory tests for inflammatory and oxidative markers, ultrasonographic liver evaluation, carotid IMT measurement, and liver biopsy were performed. Different degrees of fibrosis were detected in our study cohort. Worse liver histopathological scores and higher plasmatic levels of C-reactive protein, reactive oxygen species, and vascular cell adhesion molecule-1 were found in HD patients. Carotid IMT was significantly higher (p < 0.005) in patients with histological steatosis. HD patients may develop active and progressive chronic hepatitis faster than patients with normal renal function and the thickness of their carotid intima-media might be markedly increased. These two conditions seem to be independent on classical risk factors and on metabolic syndrome. They might be related to the high levels of oxidants and to the inflammatory state, which are typical of patients undergoing HD. Independently related with the traditional risk factors for cardiovascular disease, nonspecific inflammation and oxide-reductive imbalance may play an important role in the progression of NAFLD and atherosclerotic disease in HD patients.

The Relationship between Body Dissatisfaction and Eating Disorder Symptoms in Young Women Aspiring Fashion Models: The Mediating Role of Stress.

It is widely recognized that body dissatisfaction is an important public health concern. In the past, being a fashion model was almost synonymous with anorexia/bulimia, and even today, there are cases of eating disorders in young women whose ambition is to become a top model. Moreover, stress can play a substantial role within ill health via related behaviors such as smoking, substance abuse, and inappropriate eating. In our study, we examined 112 aspiring fashion models aged between 15 and 24 years (M = 19.5, SD = 2.08) from 32 different countries of the world during an international contest, and 100 students (control group), aged between 16 and 22 years (M = 18.6, SD = 1.39). The purpose of this cross-sectional study was to examine whether stress mediated the relationship between body dissatisfaction and eating disorders. The study included the administration of stress and self-efficacy and the locus of control dimensions, body (image) dissatisfaction, and eating attitude disorder. Results indicated higher scores on body dissatisfaction, stress level, and eating attitudes disorder among the group of fashion models compared to the control. Mediational analyses showed that body dissatisfaction was partially mediated by stress level on eating disorders. Especially in the aspiring fashion models, there are often many possibilities that competitive stress causes candidates to exacerbate attempts to maintain their body weight below normal weight/height parameters. These results indicated that appropriate intervention for the management of stress level could possibly defend against the negative impact of body dissatisfaction on eating disorder symptoms. The presence of skilled health workers in the field of nutrition and psychology can be extremely important in the field of fashion to maintain an adequate quality of life.

A multidisciplinary therapeutic approach for reducing the risk of psychiatric side effects in patients with chronic hepatitis C treated with pegylated interferon α and ribavirin.

GOALS: To evaluate the effectiveness of psychiatric counseling in reducing the rate of development of psychiatric side effects of antiviral therapy with interferon-α and ribavirin among study participants compared with standard clinical monitoring alone. BACKGROUND: Interferon-α is used to treat chronic hepatitis C. Interferons may induce adverse events that usually, but not always, reverse within a few days after the end of therapy. STUDY: Two hundred eleven patients with chronic hepatitis C, genotype 1b were treated with peginterferon and ribavirin for 48 weeks in a prospective trial. Two groups were randomly created. Group A was interviewed by a team of gastroenterologists, psychiatrists, and psychologists and treated with psychotherapy once a month. Group B was monitored once a month according to a conventional protocol that did not include psychotherapy. SVR (sustained viral response), severe psychiatric symptom onset, and mood progression were assessed (P calculated using Fisher exact test, Friedman test, Dunn posttest, and Mann-Whitney U-test). RESULTS: At baseline, there was no difference in depressive symptoms or liver histologic score between the 2 groups. The onset rate of severe psychiatric manifestations was 4.7% (Group A) and 16.1% (Group B) between the 24th and 36th weeks (P<0.01). Fifteen participants in Group A and 39 in Group B required antidepressants and benzodiazepines (P<0.05). CONCLUSIONS: Patients can develop depressive symptoms during interferon therapy. Multidisciplinary medical treatment with psychiatric counseling provided during the treatment of chronic hepatitis C may contribute to the decrease or prevent the higher rates of depression associated with interferon treatment.

Epoetin alpha improves the response to antiviral treatment in HCV-related chronic hepatitis.

BACKGROUND: The conventional antiviral treatment of chronic hepatitis related to hepatitis C virus (HCV) often leads to anemia. In this case, it is necessary to reduce ribavirin dose or stop treatment, thus reducing the rate of sustained virological response. AIM: We investigated whether epoetin alpha administration improves treatment adherence and leads to higher percentage of response at the end of therapy and sustained virological response. METHODS: Two hundred and fourteen individuals with genotype 1b HCV-related chronic hepatitis underwent treatment with pegylated (peg)-interferon alpha-2A 180 µg once weekly and ribavirin 1,000-1,200 mg/day; 174 were responders. Forty individuals completed treatment with no hemoglobin reduction; 134 developed anemia during therapy. Anemic responders were distributed randomly into two groups: group 1 continued therapy with epoetin alpha addiction; group 2 continued antiviral therapy with ribavirin reduction only. RESULTS: Patients in group 1 achieved better control of hemoglobin levels (13.8 ± 1.2 g/dl at the end of therapy) than those in group 2 (11.5 ± 0.8 g/dl). Sustained virological response was 59.7% in group 1 compared with 34.4% in group 2 (p<0.01). CONCLUSIONS: In patients with 1b HCV-related chronic hepatitis who develop anemia during antiviral treatment, administration of epoetin alpha increases hemoglobin levels and the end-of-treatment rate and sustains virological response by improving treatment adherence.

Drug rash with eosinophilia and systemic signs syndrome in a patient with multiple sclerosis.

INTRODUCTION: Drug rash with eosinophilia and systemic signs (DRESS) syndrome is defined by the triad of fever, dermatitis, and internal organ involvement, characteristically occurring with a delay of 3 to 8 weeks after the initiation of treatment with the associated drug. We describe a case of DRESS syndrome in a patient with multiple sclerosis (MS), characterized by a very high eosinophilia and cholestatic hepatitis. CASE SUMMARY: A 44-year-old white woman with primary progressive MS receiving a multidrug of PO baclofen 75 mg/d, PO piracetam 3 g/d, and IV mitoxantrone 10 mg administered once a month presented to the Multiple Sclerosis Center, University of Catania, Catania, Italy. Eight weeks after the introduction of the latter 2 drugs, the patient had clinical and histological signs of severe cholestatic syndrome followed by hypereosinophilia. All treatments were stopped on admission. Laboratory tests (serologic viral markers, autoantibody pattern antinuclear autoantibodies, antismooth muscle autoantibodies, antimitochondrial autoantibodies, antineutrophil-cytoplasmic autoantibodies, antiliver-kidney-microsomes), abdomen ultrasound, and magnetic resonance cholangiopancreatography did not reveal a cause of the cholestatic syndrome. A liver biopsy was performed because of the persistence of the clinical signs. A Naranjo rating of 4 suggested that mitoxantrone was possibly associated with the occurrence of DRESS. Six months after the first symptoms of DRESS appeared, laboratory tests were normal. Although there are few diagnostic methods for confirming an adverse drug hypersensitivity reaction, a skin prick test suggested a marked positivity for mitoxantrone at all concentrations (100%, 50%, 10%). During the first 72 hours, reaction was characterized by skin edema, erythema, and itchiness in the site of inoculation of the drug. The local reaction started to regress after 72 hours, with a complete restitution ad integrum in 6 days. A blue discoloration of skin remained for an additional 13 days. CONCLUSION: We report a case of DRESS syndrome possibly associated with mitoxantrone in a patient with MS.

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks.

BACKGROUND: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). OBJECTIVE: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). METHODS: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). RESULTS: A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. CONCLUSIONS: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.

Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue.

Fatigue is one of the conditions most frequently complained by the elderly. There are few effective treatment options for patients with chronic fatigue syndrome. To determine the efficacy, tolerability and impact on the fatigue, as well as on cognitive and functional status of elderly subjects with acetyl L-carnitine (ALC), 96 aged subjects (>70 years, range 71-88) were investigated (50 females and 46 males; mean age 76.2+/-7.6 and 78.4+/-6.4 years, respectively). They met four or more of the Holmes major criteria or at least six of Fukuda minor criteria. Fatigue was measured with the Wessely and Powell [Wessely, S., Powell, R., 1989. Fatigue syndromes: a comparison of chronic postviral fatigue with neuromuscular and affective disorders. J. Neurol. Neurosurg. Psychiatry 52, 940-948] scores, with the fatigue severity scale. At the end of the treatment, we observed a decrease of physical fatigue: 6.2 (p<0.001), of mental fatigue: 2.8 (p<0.001), of severity fatigue: 21.0 (p<0.001) and improvements in functional status: 16.1 (p<0.001) and cognitive functions: 2.7 (p<0.001). By the end of the treatment, significant differences between the two groups were found for the following parameters: muscle pain -27% versus -3% (p<0.05); prolonged fatigue after exercise: 51% versus -4% (p<0.0001); sleep disorders: 28% versus 4% (p<0.05); physical fatigue: 7 versus -0.5 (p<0.0001); mental fatigue: -3.3 versus 0.6 (p<0.0001); fatigue severity scale: -22.5 versus 1.2 (p<0.0001); functional status 17.1 versus 0.6 (p<0.0001); mini mental state examination (MMSE) improvements: 3.4 versus 0.5 (p<0.0001). Our data show that administering ALC may reduce both physical and mental fatigue in elderly and improves both the cognitive status and physical functions.

Oxidative stress, nitric oxide, endothelial dysfunction and tinnitus.

To assess whether pathogenic endothelial dysfunction is involved in acute idiopathic tinnitus we enrolled 44 patients and 25 healthy volunteers. In blood from the internal jugular vein and brachial vein we determined malonaldehyde, 4-hydroxynonenal, myeloperoxidase, glutathione peroxidase, nitric oxide, L-arginine and L-ornitine, thrombomodulin (TM) and von Willebrand factor (vWF) activity during tinnitus and asymptomatic period. Higher plasma concentrations of oxidative markers and L-arginine, and lower nitric oxide and L-ornitine levels were observed in jugular blood of patients with tinnitus, there being a significant difference between brachial and jugular veins. TM and vWF activity were significantly higher in patients' jugular blood than in brachial blood. Our results suggest oxidant, TM, vWF activity production are increased and nitric oxide production reduced in brain circulation reflux blood of patients with acute tinnitus. These conditions are able to cause a general cerebro-vascular endothelial dysfunction, which in turn induce a dysfunction of microcirculation in the inner ear.

A randomised, controlled clinical trial evaluating changes in therapeutic efficacy and oxidative parameters after treatment with propionyl L-carnitine in patients with peripheral arterial disease requiring haemodialysis.

OBJECTIVE: We explored the efficacy of intravenous therapy with propionyl L-carnitine in patients with both peripheral arterial disease (PAD) and chronic renal insufficiency requiring haemodialysis. METHODS: The trial was a randomised, double-blind, placebo-controlled trial. Sixty-four patients on haemodialysis (32 per treatment arm) with chronic renal insufficiency and PAD were assigned to receive either intravenous propionyl L-carnitine 600 mg or placebo 3 times weekly for 12 months. The main outcome measures were the ankle/brachial index (ABI), plasma malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations, and the plasma nitrite/nitrate ratio (NO(2)/NO(3)); these were measured at baseline and at 6 and 12 months. RESULTS: Significant increases in ABI were observed in the propionyl L-carnitine group, whereas in the placebo group the reverse trend was seen. In patients treated with propionyl L-carnitine, significant progressive decreases were seen in plasma MDA, 4-HNE and the NO(2)/NO(3) ratio from baseline. In the placebo-treated group, only weakly significant or no differences were seen. CONCLUSION: Intravenous administration of propionyl L-carnitine to haemodialysis patients with PAD improves both haemodynamic flow and the oxidative profile.

Behaviour of some indicators of oxidative stress in postmenopausal and fertile women.

OBJECTIVE: Unsaturated fatty acids are known to have a crucial role in the pathogenesis of atherosclerosis. They are very sensitive to oxidation caused by excess free oxygen radicals and the consequent oxidative status, and it is well known that lipid and lipoprotein metabolism is markedly altered in postmenopausal women. Oxidative stress is involved in the pathophysiology of atherosclerosis and our study aim was to assess the presence of such stress in postmenopausal women. DESIGN: One hundred and one women were enrolled in the study. Fifty were fertile (32.5+/-1.1 years) with regular menses and fifty-one were postmenopausal women (52.1+/-1.3 years). None of the study cohort had ever used hormone replacement therapy. Malonaldehyde (MDA), 4-hydroxynenal (4-HNE), oxidized lipoproteins (ox LDL) and glutathione peroxidase (GSH-PX) values were determined as we believe they reveal oxidative stress. RESULTS: MDA, 4-HNE and ox LDL concentrations were higher in postmenopausal than fertile women (p<0.001), while GSH-PX concentrations were significantly higher in fertile women than in postmenopausal subjects (p<0.001). CONCLUSIONS: Our data revealed the presence of oxidative stress in postmenopausal women.

Psychiatric symptoms induced by antiviral therapy in chronic hepatitis C: comparison between interferon-alpha-2a and interferon-alpha-2b.

BACKGROUND AND OBJECTIVE: Interferon-alpha treatment is associated with a large number of adverse effects. Depressive symptoms are not unexpected, and potentially dangerous psychiatric adverse effects can induce life-threatening conditions. We compared the incidence of depressive symptoms in patients with chronic hepatitis C during treatment with pegylated interferon-alpha-2a (IFNalpha-2a) and pegylated interferon-alpha-2b (IFNalpha-2b). PATIENTS AND DESIGN: We randomly divided 186 subjects with chronic hepatitis C into two treatment groups: group A, treated with IFNalpha-2a, and group B, treated with IFNalpha-2b. Treatment was continued for up to 48 weeks. Liver biopsy and hepatitis C virus RNA assay were carried out in all patients. Depressive symptoms and the prevalence of psychiatric adverse effects during treatment with IFN were evaluated using the Hamilton Depression Rating Scale, the Zung Self-Rating Depression Scale, and the Structured Clinical Interview for Diagnostic and Statistic Manual-IV axis disorders. RESULTS: At baseline 53% of subjects in group A and 57% of subjects in group B presented with depressive symptoms; at 12 weeks we found a high incidence of depressive symptoms in both groups (group A 61% and group B 65%) and three cases of life-threatening psychiatric symptoms (i.e. psychosis and delirium requiring discontinuation of antiviral therapy and admission to a psychiatric unit) in group A. CONCLUSIONS: Long-term administration of IFN can be associated with serious psychiatric adverse effects. It is very important that psychiatric symptoms are diagnosed early in IFN treatment so to improve treatment compliance and prevent fatal and/or life-threatening adverse events, as were documented in some subjects treated with IFNalpha-2a in our study.

Plasma Levels of Inflammatory Biomarkers in Peripheral Arterial Disease: Results of a Cohort Study.

Previous research analyzed the level of plasma inflammatory markers in patients with coronary disease, but very few studies have evaluated these markers in patients with peripheral arterial disease (PAD). The objective of this study was to investigate the plasma levels of inflammatory markers in patients with PAD and in healthy controls. The following plasma levels of biomarkers were measured in 80 patients with PAD (mean age 68 ± 5 years) and in 72 healthy participants (mean age 67 ± 6 years): interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), L-selectin (LS), neopterin (N), P-selectin (PS), E-selectin (ES), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and matrix metalloproteinase 2 (MMP-2), and 9 (MMP-9). Significantly higher levels of IL-6 (P < .001), TNF-α (P < .0001), ES (P < .0001), LS (P < .0001), PS (P < .0001), ICAM-1 (P < .001), VCAM-1 (P < .001), N (P < .001), MMP-2 (P < .001), and MMP-9 (P < .005) were found in the patients with PAD. Patients with PAD show a inflammation marker profile different from that of control participants. Reducing the high plasma levels of inflammatory markers could be a new therapeutic approach both for the prevention and the treatment of PAD.