Sex-difference of multifactorial intervention on cardiovascular and mortality risk in DKD: post-hoc analysis of a randomised clinical trial.

OBJECTIVE: Women with type 2 diabetes experience higher cardiovascular and mortality risk than men possibly because of a sub-optimal cardio-protective treatment. We evaluated whether an intensive multifactorial therapy (MT) produces similar protective effect on development of adverse outcomes in women and men. RESEARCH DESIGN AND METHODS: Nephropathy in Diabetes type 2 study is an open-label cluster randomized trial comparing the effect of Usual Care (UC) or MT of main cardiovascular risk factors (blood pressure < 130/80 mmHg, HbA1c < 7%, LDL < 100 mg/dL, and total cholesterol < 175 mg/dL) on cardiovascular and mortality risk in patients with type 2 diabetes. In this post-hoc analysis, we stratified patients by sex to compare the occurrence of MACEs (primary endpoint) and all-cause death (secondary endpoint) between women (104 MT and 105 UC) and men (103 MT and 83 UC). RESULTS: Achievement of therapeutic goals was similar by sex, with 44% and 47% of women and men in MT achieving at least 3 targets vs. 16% and 20% of women and men in UC. During a median follow-up of 13.0 years, we recorded 262 MACE (48.5% in women) and 189 deaths (53.6% in women). Compared to the UC group, the risk of MACE in the MT group was reduced by 52% in women and by 44% in men (P = 0.11). Conversely, the reduction in mortality risk by MT was greater in women (44% versus 12%, P = 0.019). CONCLUSIONS: MT similarly reduces the risk of MACEs in either sex. This therapeutic approach is associated with a survival advantage in women as compared with men and it may represent an important rationale to motivate physicians in overcoming their therapeutic inertia often encountered in female patients as well as to encourage patients of both sexes at improving their adherence to multidrug therapy.

Application and internal validation of lung ultrasound score in COVID-19 setting: The ECOVITA observational study.

BACKGROUND: The severe acute respiratory syndrome Coronarovirus-2 associated still causes a significant number of deaths and hospitalizations mainly by the development of respiratory failure. We aim to validate lung ultrasound score in order to predict mortality and the severity of the clinical course related to the need of respiratory support. METHODS: In this prospective multicenter hospital-based cohort study, all adult patients with diagnosis of SARS-CoV-2 infection, performed by real-time reverse transcription polymerase chain reaction were included. Upon admission, all patients underwent blood gas analysis and lung ultrasound by expert operators. The acquisition of ultrasound scan was performed on 12 peculiar anatomic landmarks of the chest. Lung ultrasound findings were classified according to a scoring method, ranging 0 to 3: Score 0: normal A-lines. Score 1: multiple separated B-lines. Score 2: coalescent B-lines, alteration of pleural line. Score 3: consolidation area. RESULTS: One thousand and seven patients were included in statistical analysis (male 62.4 %, mean age 66.3). Oxygen support was needed in 811 (80.5 %) patients. The median ultrasound score was 24 and the risk of having more invasive respiratory support increased in relation to higher values score computed. Lung ultrasound score showed negative strong correlation (rho: -0.71) with the P/F ratio and a significant association with in-hospital mortality (OR 1.11, 95 %CI 1.07-1.14; p < 0.001), even after adjustment with the following variables (age, sex, P/F ratio, SpO2, lactate, hypertension, chronic renal failure, diabetes, and obesity). CONCLUSIONS: The novelty of this research corroborates and validates the 12-field lung ultrasound score as tool for predicting mortality and severity clinical course in COVID-19 patients. Baseline lung ultrasound score was associated with in-hospital mortality and requirement of intensive respiratory support and predict the risk of IOT among COVID-19 patients.

Multiparametric correlation of laboratory biomarkers to multiorgan failure outcome in hospitalized COVID-19 patients: a retrospective observational study.

OBJECTIVE: COVID-19 is an extremely contagious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that will keep broadly circulating and evolving. Collected evidence revealed the clinical profile of COVID-19 patients as a potential predictor of their outcome. The aim of this study was to investigate the causal relationship between poor outcomes and laboratory parameters in hospitalized COVID-19 patients, in this sense observing how SARS-CoV-2 infection affects other organs. PATIENTS AND METHODS: We retrospectively evaluated a cohort of 133 patients, positive for SARS-CoV-2, aged between 30 to 94 years, between January 12th and April 25th, 2021. Discharge from the hospital, transferral to the ordinary ward or nursing home, intensive care unit (ICU) admission, and in-hospital mortality were recorded, along with demographic, laboratory and clinical parameters. The whole sample was summarized by median (interquartile range) for quantitative data, and absolute and relative percentage frequencies for qualitative variables. Univariable logistic regression models were performed to assess the association between all the parameters of interest and COVID-19 adverse outcomes, single (in-hospital mortality) and composite (in-hospital mortality and ICU admission). Hence, a multivariable model was fitted to identify potential independent predictors of the composite outcome. The accuracy of the model was assessed through appropriate fitting indices, such as the C-statistic and Hosmer-Lemeshow test. Moreover, to detect multicollinearity, the variance inflation factor (VIF) was used. RESULTS: Our study sample had a median age of 72 years old (59.0-83.0). The most common comorbidities were hypertension (63.7%), cardiovascular disease (41.9%), diabetes (33.6%), and cerebrovascular disease (21.5%); while as the most common symptoms, we observed dry cough (32.5%), dyspnoea (50.8%), and fatigue (29.8%). Totally, 18 patients died during hospitalization (13.5%), 10 required ICU admission (7.5%), 78 (58.6%) were discharged from the hospital, and 27 (20.3%) were transferred to either ordinary wards or nursing homes. We disclosed an association of older age with both composite [OR 1.06, 95% CI 1.02-1.09; p=0.003] and single outcome [OR 1.10, 95% CI 1.04-1.16; p=0.001]. A higher oxygen saturation (SpO2) was associated with a better outcome [OR 0.75, 95% CI 0.60-0.93; p=0.009 and OR 0.76, 95% CI 0.61-0.95, p=0.009]. Among laboratory parameters, higher levels of neutrophils increased the risk of a poor outcome [OR 1.05, 95% CI 1.00-1.10; p=0.043]; while higher levels of lymphocytes seem associated with a better outcome [OR 0.94, 95% CI 0.88-0.99; p=0.043]. Higher levels of creatinine were associated with a higher risk of both adverse outcomes [OR 6.20, 95% CI 2.16-17.81; p<0.001 and OR 19.90, 95% CI 5.07-78.06; p<0.001, respectively]. Higher levels of sodium (Na) were associated with a higher risk of adverse events [OR 1.15, 95% CI 1.03-1.28; p=0.014 and OR 1.14, 95% CI 1.01-1.27]. Similar findings were also observed for C-reactive protein (CRP) levels [OR 1.01, 95% CI 1.00-1.02; p=0.010 and OR 1.01, 95% CI 1.00-1.02; p=0.024]. Conversely, being positive to IgM and IgG decreases the risk of adverse outcomes [IgM: OR 0.33, 95% CI 0.14-0.77; p=0.011 and OR 0.23, 95% CI 0.08-0.66; p=0.006. IgG: OR 0.30 95% CI 0.13-0.72; p=0.007 and OR 0.22 95% CI 0.07-0.66; p=0.007]. Hence, a multivariable model was fitted to identify potential independent laboratory predictors of the composite outcome, with laboratory parameters that showed an association with composite outcome. The model can be considered accurate according to LH-Test and C-statistic [p>0.83, C-stat=0.90]. CONCLUSIONS: Our findings confirm that COVID-19 is a multiorgan disease. In fact, the analysis of laboratory parameters has revealed a strong relationship between poorer outcomes and multiple organ dysfunction, particularly established by higher levels of neutrophils, creatinine, sodium, and CRP. Alongside, cerebrovascular diseases, chronic kidney disease and older age supported this finding. Of note, higher levels of SpO2, and lymphocytes, as well as positivity to IgM and IgG were associated with a lower risk of a poor outcome.

Clinical application of lung ultrasound score on COVID-19 setting: a regional experience in Southern Italy.

OBJECTIVE: We aimed to assess the correlation between LUS Soldati proposed score and clinical presentation, course of disease and the possible need of ventilation support/intensive care. PATIENTS AND METHODS: All consecutive patients with laboratory confirmed SARS-CoV-2 infection and hospitalized in two COVID Centers were enrolled. All patients performed blood gas analysis and lung ultrasound (LUS) at admission. The LUS acquisition was based on standard sequence of 14 peculiar anatomic landmarks with a score between 0-3 based on impairment of LUS picture. Total score was computed with their sum with a total score ranging 0 to 42, according to Soldati LUS score. We evaluated the course of hospitalization until either discharge or death, the ventilatory support and the transition in intensive care if needed. RESULTS: One hundred and fifty-six patients were included in the final analysis. Most of patients presented moderate-to-severe respiratory failure (FiO2 <20%, PaO2 <60 mmHg) and consequent recommendation to invasive mechanic ventilation (CPAP/NIV/OTI). The median ultrasound thoracic score was 28 (IQR 18-36) and most of patients could be ascertained either in a score 2 (40%) or score 3 pictures (24.4%). The bivariate correlation analysis displayed statistically significant and high positive correlations between the LUS score and the following parameters: ventilation (rho=0.481, p<0.001), lactates (rho=0.464, p<0.001), dyspnea (rho=0.398, p=0.001) mortality (rho=0.410, p=0.001). Conversely, P/F (rho= -0.663, p<0.001), pH (rho = -0.363, p=0.003) and pO2 (rho = -0.400 p=0.001) displayed significant negative correlations. CONCLUSIONS: LUS score improve the workflow and provide an optimal management both in early diagnosis and prognosis of COVID-19 related lung pathology.

Methicillin-resistant Staphylococcus aureus: epidemiology and antimicrobial susceptibility experiences from the University Hospital 'Luigi Vanvitelli' of Naples.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the important pathogens worldwide showing resistance to several widely used antibiotics. This has made the treatment of MRSA infections harder, especially due to their prevalence in the hospital setting. We evaluated the antibiotic susceptibility patterns of healthcare-associated MRSA infections with a focus on Vancomycin Intermediate S. Aureus (VISA) and macrolide-licosamide-streptogramin B (MLSB) phenotypes. A total of 417 Staphylococcus aureus (S. aureus) cases were isolated between January 2017 and December 2018, through several clinical specimens collected from the University Hospital 'Luigi Vanvitelli' of Naples. We identified bacterial strains using Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) and antimicrobial susceptibility using Phoenix BD (Becton Dickinson, NJ, USA). Out of the total 417 S. aureus cases, 140 were MRSA (33.6%) and of these, 50% were soft tissue infections. All MRSA and Methicillin sensible S.aureus MSSA isolates were susceptible to linezolid and daptomycin. Two MRSA cases exhibited intermediate resistance to vancomycin and were of constitutive MLSB phenotype. Among the MRSA strains, 11.4% were constitutive and 43.6% were inducible MLSB phenotypes and 8.6% were macrolide-streptogramin B phenotype. This study characterized the epidemiological status, antibiotic resistance patterns, and current prevalent phenotypes of healthcare-associated MRSA. This knowledge can aid clinicians in improving the antimicrobial stewardship program by adapting appropriate guidelines for the proper use of MRSA antibacterial agents.

Relationship between albuminuric CKD and diabetic retinopathy in a real-world setting of type 2 diabetes: Findings from No blind study.

BACKGROUND AND AIMS: Recently, the albuminocentric view of diabetic kidney disease (DKD) in type 2 diabetes (T2DM) has been changing. Therefore, the relationship between diabetic retinopathy (DR) and chronic kidney disease (CKD) has to be addressed according to this new clinical presentation of DKD. The aim of this study was to evaluate, in a real-world setting, the correlation DR-DKD in T2DM. METHODS AND RESULTS: A total of 2068 type 2 diabetic patients enrolled in a multicenter cross-sectional study were investigated. Albuminuric subjects were largely prevalent among subjects with DR (p = 0.019). In the whole study population, no difference in albumin excretion rate (AER) was observed between presence/absence of DR; instead, AER was significantly higher among patients with glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (CKD) (p = 0.009), above all in those with CKD and AER ≥0.03 g/24 h (p = 0.005). Multivariate analysis confirmed that eGFR (O.R. 0.976; 95% C.I.: 0.960-1.028; p < 0.001) and AER (O.R. 1.249; 95% C.I. 1.001-1.619; p = 0.004) were independently associated with DR and HDL-cholesterol (O.R.: 1.042; 95% C.I.: 1.011-1.120; p = 0.014). Additionally, among patients with eGFR <60 mL/min/1.73 m2 and albuminuria, both eGFR and AER significantly varied between those with/without DR (p = 0.012 and p = 0.005, respectively), and this finding was observed among only albuminuric patients. Analogous results were obtained considering DR classification. AER was significantly higher among subjects with either proliferative DR (PDR) or severe nonproliferative DR (NPDR), with regard to mild NPDR (0.498 and 0.938 g/die vs. 0.101 g/die; p < 0.001, respectively). Similar results were obtained in the specular subgroups. CONCLUSION: In T2DM with DKD, the AER seems to be related to the presence of DR. This association is confirmed above all in those with more severe DR.

Perspectives of nuclear diagnostic imaging in diabetic cardiomyopathy.

Diabetic cardiomyopathy is a ventricular dysfunction in the absence of coronary artery disease, valvular or hypertensive heart disease. The mechanisms underlying diabetic cardiomyopathy may involve metabolic disturbances, myocardial fibrosis, small vessel disease, microcirculation abnormalities, cardiac autonomic neuropathy and insulin resistance. Diagnostic problems emerge because no specific disease pattern characterizes the disease and because there may be coexistence in diabetes of coronary artery disease and hypertension as independent but compounding causes of biochemical, anatomical and functional alterations impairing cardiac function. In this paper we will review the role of nuclear imaging today, concentrating on the diagnostic capabilities of radionuclide ventriculography, to study the effect of insulin resistance and, more extensively, gated-single photon emission computed tomography with Tc-99m labelled agents. A broad analysis will be dedicated to: 1) positron emission tomography using perfusion agents, with the potential to quantify resting and stress blood flow and coronary flow reserve; 2) radionuclide procedures evaluating aerobic and anaerobic cardiac metabolism; and 3) cardiac neurotransmission imaging, studying the autonomic neuropathy.

Effect of moderate red wine intake on cardiac prognosis after recent acute myocardial infarction of subjects with Type 2 diabetes mellitus.

BACKGROUND: Oxidative stress and increased inflammation have been reported to be increased in subjects with diabetes and to be involved in the pathogenesis of cardiovascular complications after myocardial infarction (MI). It is well recognized that red wine has antioxidant and anti-inflammatory activities. We examined the effects of moderate red wine intake on echocardiographic parameters of functional cardiac outcome in addition to inflammatory cytokines and nitrotyrosine (oxidative stress marker), in subjects with diabetes after a first uncomplicated MI. METHODS: One hundred and fifteen subjects with diabetes who had sustained a first non-fatal MI were randomized to receive a moderate daily amount of red wine (intervention group) or not (control group). Echocardiographic parameters of ventricular dys-synchrony, circulating levels of nitrotyrosine, tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-18 (IL-18) and C-reactive protein (CRP) were investigated at baseline and 12 months after randomization. RESULTS: After 1 year of diet intervention, concentrations of nitrotyrosine (P < 0.01), CRP (P < 0.01), TNF-alpha (P < 0.01), IL-6 (P < 0.01) and IL-18 (P < 0.01) were increased in the control group compared with the intervention group. In addition, myocardial performance index (P < 0.02) was higher, and transmitral Doppler flow (P < 0.05), pulmonary venous flow analysis (P < 0.02) and ejection fraction (P < 0.05) were lower in the control group, indicating ventricular dys-synchrony. The concentrations of nitrotyrosine, CRP, TNF-alpha and IL-6 were related to echocardiographic parameters of ventricular dys-synchrony. CONCLUSIONS: In subjects with diabetes, red wine consumption, taken with meals, significantly reduces oxidative stress and pro-inflammatory cytokines as well as improving cardiac function after MI. Moderate red wine intake with meals may have a beneficial effect in the prevention of cardiovascular complications after MI in subjects with diabetes.

Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients.

BACKGROUND: Increased intestinal permeability was described in several intestinal auto-immune conditions. There are very few and contradictory reports about type I diabetes mellitus, an auto-immune condition sometimes associated with celiac disease. AIMS: To investigate intestinal permeability in type I diabetes mellitus patients with no concomitant celiac disease, with a comparison to ultra-structural aspects of duodenal mucosa. PATIENTS: 46 insulin dependent diabetes mellitus, non-celiac, patients (18 females and 28 males, mean age 15.8 +/- 5.3 [S.D.] years) were enrolled. The mean duration of the disease was 5.7 years. METHODS: The morphological aspect of the small bowel mucosa, at standard light microscopy and electron transmission microscopy, along with intestinal permeability (by lactulose/mannitol test) were studied. Lactulose and mannitol urinary excretion were determined by means of high performance anion exchange chromatography-pulsed amperometric detection. RESULTS: The lactulose/mannitol ratio was 0.038 [0.005-0.176] (median and range) in 46 patients compared to 0.014 [0.004-0.027] in 23 controls: insulin dependent diabetes mellitus group values being significantly higher than those of the controls (P < 0.0001, Mann-Whitney test). Eight insulin dependent diabetes mellitus patients underwent endoscopy and biopsies were analysed by means of light microscopy and transmission electron microscopy. At the light microscopy level, none of the biopsy samples showed any sign of atrophy nor inflammation, whereas transmission electron microscopy analysis showed remarkable ultra-structural changes in six out of the eight patients. Four parameters were evaluated: height and thickness of microvilli, space between microvilli and thickness of tight junctions. CONCLUSIONS: This alteration of intestinal barrier function in non-celiac type I diabetes mellitus, frequently associated with mucosal ultra-structural alterations, could suggest that a loss of intestinal barrier function can be a pathogenetic factor in a subset of insulin dependent diabetes mellitus patients.

Increased vascular endothelial growth factor mRNA expression in the heart of streptozotocin-induced diabetic rats.

The aim of the present study was to evaluate vascular endothelial growth factor (VEGF), fms-like tyrosine kinase 1 (flt-1), and fetal liver kinase (flk-1) expression in the heart of experimental diabetic rats. Ten young adult male Wistar rats (5 streptozotocin [STZ]-induced diabetic rats, without insulin treatment, and 5 controls) were studied. Ninety days after the induction of diabetes, semiquantitative reverse transcription (RT)-polymerase chain reaction (PCR) coamplification of VEGF/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) transcription was performed. RT-PCR was also performed for VEGF receptors flk-1 and flt-1. VEGF mRNA expression, at 234 bp, was detectable in the heart of the rats and was significantly higher in those with diabetes. Densitometric analysis of PCR products showed that VEGF mRNA levels were meanly 4.8-fold higher in STZ-induced diabetic rats than controls (VEGF/GAPDH densitometric ratio, 3.46 +/- 0.20 v 0.74 +/- 0.10, P <.001). No significant difference was found in flt-1 and flk-1 amplification products between STZ-induced diabetic rats and controls (flt-1/GAPDH densitometric ratio, 0.58 +/- 0.01 v 0.64 +/- 0.05, P>.1; flk-1/GAPDH densitometric ratio, 0.66 +/- 0.10 v 0.7 +/- 0.06, P >.2). The increase in VEGF mRNA expression observed in this experimental diabetic model is in contrast with the typical impairment in collateral vessels of diabetic hearts. This apparent discrepancy might be explained by a resistance of cardiac tissue to VEGF. The lack of mRNA flt-1 and flk-1 overexpression in diabetic hearts could be one of the mechanisms for this resistance.

Effect of treatment with acarbose and insulin in patients with non-insulin-dependent diabetes mellitus associated with non-alcoholic liver cirrhosis.

AIM: Non-insulin-dependent diabetes mellitus (type 2 diabetes) not responding to dietary treatment alone in patients with non-alcoholic liver cirrhosis is characterized by high postprandial hyperglycaemia. The control of postprandial hyperglycaemia in such patients, is generally achieved by the means of progressively higher doses of insulin, with an increasing risk of hypoglycaemia in the late postprandial period. The aim of this study was to evaluate the use of acarbose for the control of postprandial hyperglycaemia in 100 patients with well-compensated liver cirrhosis and type 2 diabetes treated with insulin. METHODS: The study was double blind with randomization of treatments into acarbose (52 patients) vs. placebo (48 patients) with parallel branches over a period of 28 weeks. RESULTS: All patients tolerated the treatments well and no significant variations in liver function tests were observed (< 5% vs. pretreatment). A significant reduction of several parameters was observed only after acarbose treatment: fasting glycaemia (173 +/- 28 vs. 146 +/- 19 mg/dl; p < 0.01), postprandial glycaemia (230 +/- 24 vs. 148 +/- 20 mg/dl; p < 0.01), mean glycaemia (206 +/- 20 vs. 136 +/- 13 mg/dl; p < 0.01), mean variation (180 +/- 14 vs. 51 +/- 10 mg/dl; p < 0.01), HbA1c (8.9 +/- 0.8 vs. 7.2 +/- 0.5; p < 0.05), C-peptide 2 h after a standard meal (4.5 +/- 1.9 vs. 2.8 +/- 1.7 ng/ml; p < 0.05), whereas the parameters did not change significantly after the placebo. After acarbose treatment a significant increase of intestinal voiding/week (+116% vs. +10%; p < 0.01) and a parallel reduction of blood ammonia levels (-52 +/- 9% vs. -9 +/- 5%; P < 0.01) were observed. CONCLUSIONS: The results clearly document the good tolerability and the absence of toxic effects of acarbose on liver, due to the lack of both intestinal absorption and hepatic metabolism of the drug at doses in the therapeutic range. In fact, acarbose increases the peristalsis movements of the gut, stimulates the proliferation of the saccarolytic bacteria and simultaneously reduces the proliferation of proteolytic bacteria, thus resulting active in the reduction of blood ammonia levels. These effects of acarbose may be advantageously exploited in the treatment of type 2 diabetic patients with well-compensated non-alcholic liver cirrhosis.

Effects of insulin-glucose infusion on left ventricular function at rest and during dynamic exercise in healthy subjects and noninsulin dependent diabetic patients: a radionuclide ventriculographic study.

OBJECTIVES: The aim of this study was to evaluate: 1) the effects of insulin administration on left ventricular ejection fraction (LVEF) during exercise, and 2) the eventual impairment of the cardiovascular response to insulin in noninsulin dependent diabetes mellitus. BACKGROUND: Insulin influences the cardiovascular system, but its effect on left ventricular function has yet to be established. METHODS: The effects of normal saline (test A) and insulin-glucose (insulin = 1.7 mU x kg(-1) x min(-1); glucose = 6 mg x kg(-1)min(-1)) (test B) infusions on systolic and diastolic functions at rest and during dynamic exercise were examined by radionuclide ventriculography. Twenty-two noninsulin-dependent diabetic patients and 22 gender, age and body mass index matched healthy subjects were investigated. RESULTS: Both groups had normal scintigraphic parameters at rest and during dynamic exercise. Rest- and stress-LVEF as well as rest- and stress-peak filling rate were significantly (p < 0.001) lower in diabetic than in healthy subjects, both in test A and B. Rest-LVEF was significantly higher during test B than it was in test A only in diabetic subjects (p < 0.01). Stress-LVEF was significantly higher (p < 0.05) during test B than it was in test A, in both groups. Insulin-glucose infusion did not modify rest- and stress-peak filling rate in either group. No difference in left ventricular end diastolic volume and in mean blood pressure was found between test A and B at rest and during exercise in either group. A significant linear correlation between LVEF and the index of insulin sensitivity was found in diabetic patients. CONCLUSIONS: In both normal and diabetic humans, insulin induces a very important rise in LVEF after submaximal work. However, the rise is significantly lower in diabetic than in nondiabetic subjects. The increase in exercise-LVEF on insulin is likely due to an enhancement of ventricular contractility. Insulin resistance could justify the lower angioscintigraphic indexes in diabetic subjects.

Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels.

BACKGROUND & AIMS: Some patients with serum hepatitis C virus (HCV) have persistently normal aminotransferase (ALT) levels and are affected by cirrhosis. This study prospectively evaluated progression of the disease in a group of anti-HCV-positive patients with persistently normal ALT levels. METHODS: Thirty-seven subjects were studied. Each subject underwent liver biopsy at baseline and after 5 years of follow-up. At baseline, serum samples were tested for genotypes and HCV RNA load. ALT levels and serum HCV RNA were tested every other month and every 6 months, respectively. Patients with increased ALT were discharged from the study and treated with IFN. Five years after the end of IFN therapy, a liver biopsy was performed. RESULTS: Liver biopsy at baseline showed chronic hepatitis in 34 patients and normal histology in 3 patients, 2 of whom were negative for HCV RNA and 1 positive. HCV genotypes were distributed as follows: 2a, 56%; 1b, 41%; and 1a, 3%. At the end of 7-year follow-up, 73% of the patients still had normal ALT values. Liver histology after 5 years was comparable to that observed at entry to study. CONCLUSIONS: Most patients with persistently normal ALT serum levels have very mild chronic hepatitis. However, healthy anti-HCV-positive subjects exist. In patients with HCV-related chronic hepatitis associated with persistently normal ALT levels, the grade of disease activity does not increase over years and progression to cirrhosis is slow or absent.

Cochlear dysfunction in type 2 diabetes: a complication independent of neuropathy and acute hyperglycemia.

The effects of type 2 diabetes on evoked otoacoustic emissions (e-OAEs) elicited by clicks in subjects with normal hearing and the involvement of the central (CNS) and peripheral nervous system and acute hyperglycemia were investigated. In study 1, 110 type 2 diabetic patients and 106 control subjects matched for age and gender were investigated by e-OAEs. Central and peripheral neuropathy were evaluated respectively by auditory brainstem responses (ABRs) and according to San Antonio Consensus Conference criteria. In study 2, 10 healthy and 10 type 2 diabetic men matched for age, all with normal e-OAEs, underwent a 5-hour hyperglycemic clamp study. e-OAE tests were performed before and during the hyperglycemic clamp. In study 1, e-OAEs were impaired in 51.8% (57 of 110) of the diabetic subjects, in comparison to 4.7% (five of 106) of the control group (P < .0001). Diabetics with impaired e-OAEs (e-OAEs-), in comparison to those with normal e-OAEs (e-OAEs+), were older (51.0+/-5.8 v 45.1+/-6.0 years, P < .001), had diabetes longer (11.5+/-4.4 v 7.0+/-3.9 years, P < .001), achieved poorer metabolic control as judged by hemoglobin A1c ([HbA1c] 6.9%+/-0.4% v 6.5%+/-0.3%, P < .001), and had more peripheral neuropathy (46% v 23%, P < .02). No difference was observed between e-OAEs- and e-OAEs+ subjects for retinopathy or nephropathy. Nevertheless, when the duration of diabetes was corrected by multiple regression analysis, the correlation between sensorineural damage and peripheral neuropathy lost significance (P = .12). Diabetic groups (e-OAEs+ and e-OAEs-) showed greater latency in waves I, III, and V and greater interwave latency for waves I to V than the control group, but there was no significant difference in ABRs between e-OAEs+ and e-OAEs- subjects. In study 2, there were no significant changes in e-OAE intensities compared with basal values during the entire hyperglycemic clamp in either type 2 diabetic or control subjects. No difference was observed between the two groups at each time of the clamp. Thus, type 2 diabetic subjects show a higher rate of compromised e-OAEs than healthy individuals. The e-OAE dysfunction does not associate with either an injury to the auditory nervous pathway or diabetic microvasculopathy. The apparent interference of peripheral neuropathy in e-OAEs loses significance when corrected for the duration of diabetes.

Short- and long-term treatments with iloprost in diabetic patients with peripheral vascular disease: effects on the cardiovascular risk factor plasminogen activator inhibitor type-1.

OBJECTIVES: Iloprost, an analogue of prostacyclin, is often utilised in subjects with diabetes mellitus complicated by macroangiopathy. METHODS: The effects of iloprost infusion on plasminogen activator inhibitor type-1 (PAI-1), glucometabolic control and cardiovascular equilibrium in patients with type-2 diabetes mellitus and peripheral arterial occlusive disease were investigated. Thirteen (7 men/6 women) normal-weight, normotensive and non-smoker type-2 diabetic patients (63.8 +/- 3.4 years, mean +/- SD) with peripheral arterial occlusive disease, stage-II according to Fontaine classification, were enrolled. Eight (four men/four women) patients underwent three study designs, each separated by a 1-week interval: study I, infusion of iloprost (3 ng kg(-1) min(-1) for 5 h) for 1 day alone (short-term treatment); study II, infusion of saline (for 5 h) for 1 day (control treatment); study III, infusion of iloprost (3 ng kg(-1) min(-1) for 5 h) over a period of 28 days (long-term treatment). The remaining five (three men/two women) patients underwent study IV only, infusion of saline over a period of 28 days (placebo treatment). Plasma levels of glucose, plasminogen, PAI-1 activity and fibrinogen, blood pressure and heart rate were determined in all studies, while plasma insulin levels, blood HbA(1c), walking distance and Winsor index only in studies III and IV. RESULTS: Both short- and long-term treatments with iloprost significantly reduced PAI-1 activity (baseline vs end: 17.4 +/- 1.9 AU/ml vs 15.0 +/- 1.6 AU/ml, P < 0.02; 20.5 +/- 7.6 AU/ml vs 7.9 +/- 2.1 AU/ml, P < 0.002, respectively). Long-term treatment with iloprost significantly increased walking distance (baseline vs end: 325 +/- 41 m vs 496 +/- 52 m, P < 0.0001), but not Winsor index. Neither glucometabolic control nor cardiovascular equilibrium were affected by short- and long-term treatments with iloprost. Control and placebo treatments did not cause any significant modifications in the parameters evaluated. CONCLUSION: If confirmed by further investigations, the results of this pilot study suggest that iloprost, infused for both brief and long periods, is able to reduce the cardiovascular risk factor PAI-1, increases free walking capacity and does not affect glucometabolic control and blood pressure in type-2 diabetic patients complicated by macroangiopathy.