Hepatitis B immunity in teenagers vaccinated as infants: an Italian 17-year follow-up study.

We assessed the persistence of hepatitis B surface antigen antibody (anti-HBs) and immune memory in a cohort of 571 teenagers vaccinated against hepatitis B as infants, 17 years earlier. Vaccinees were followed-up in 2003 and in 2010 (i.e. 10 years and 17 years after primary vaccination, respectively). When tested in 2003, 199 vaccinees (group A) had anti-HBs <10 mIU/mL and were boosted, 372 (group B) were not boosted because they had anti-HBs ≥10 mIU/mL (n = 344) or refused booster (n = 28) despite anti-HBs <10 mIU/mL. In 2010, 72.9% (416/571) of participants had anti-HBs ≥10 mIU/mL (67.3% in group A vs. 75.8% in group B; p 0.03). The geometric mean concentrations (GMCs) were similar in both groups. Between 2003 and 2010, anti-HBs concentrations in previously boosted individuals markedly declined with GMC dropping from 486 to 27.7 mIU/mL (p <0.001). Fifteen vaccinees showed a marked increase of antibody, possibly due to natural booster. In 2010, 96 individuals (37 of group A and 59 of group B) with anti-HBs <10 mIU/mL were boosted; all vaccinees of the former group and all but two of the latter had an anamnestic response. Post-booster GMC was higher in group B (895.6 vs. 492.2 mIU/mL; p 0.039). This finding shows that the immune memory for HBsAg persists beyond the time at which anti-HBs disappears, conferring long-term protection.

Hepatitis E: a puzzling double-faced disease.

Viral hepatitis type E is highly endemic in many developing countries, where large water-borne epidemics caused by viral genotype 1 and - to a lesser degree - by genotype 2 cyclically occur, resulting in high morbidity and mortality, especially among pregnant women. In developed countries, the disease is usually diagnosed in travelers coming back from endemic countries, but an increasing number of sporadic locally acquired hepatitis cases caused by genotype 3 and 4 have recently been reported. The wide-spread distribution of HEV3 and HEV4 in domestic pigs, wild boars, deer, as well as in other mammals, suggests that infections caused by these genotypes may have a zoonotic source. HEV3 infection can evolve to chronic infection in immunosuppressed patients; in addition, it may be associated with neurological disorders and extrahepatic manifestations. Two recently developed recombinant vaccines have proved to be safe and effective. One of such vaccines has recently been licensed for use in China.

Vitamin D deficiency in septic patients at ICU admission is not a mortality predictor.

BACKGROUND: Vitamin D is involved in immune regulation in humans. Vitamin D serum deficiency is reported to be common in hospitalized patients, especially among Intensive Care Unit (ICU) patients. Our aim was to evaluate the relationship between vitamin D levels in septic patients and outcome. METHODS: A total of 170 patients were studied, of which 92 were severe sepsis/septic shock patients, and 72 were major trauma patients, as an age-matched control group. Exclusion criteria were: age <18 years (y), malnutrition state, pregnancy, breast feeding, chemotherapy, immunotherapy, pathologies affecting bone and calcium metabolism, vitamin D metabolism derangement for therapy, hematological and solid malignancies, and HIV. Vitamin D levels were measured by radioimmunoassay at admission. RESULTS: Median vitamin D levels at admission to ICU were 10.1 ng/mL in the sepsis group and 18.4 ng/mL in the trauma group (P<0.0001). In univariate analysis, mortality rate in septic patients was significantly correlated with age, gender, SAPS II, vitamin D level at admission, duration of mechanical ventilation, and ICU/hospital length of stay, however, the multivariate logistic regression model confirmed significance only for age. CONCLUSION: In our cohort, septic patients showed a significantly lower vitamin D level than trauma patients in comparison to age cohort patients with the same demographic/clinical characteristics, but no clear relationship between vitamin D level and outcome was found. Further studies with larger samples are needed to clarify the prognostic role of vitamin D and nutraceutical interventions in critically ill patients.

Bioequivalence of vildagliptin/metformin fixed-dose combination tablets and a free combination of vildagliptin and metformin in healthy subjects.

OBJECTIVE: To assess the bioequivalence of vildagliptin/metformin fixed-dose combination tablets (at doses of 50/500, 50/850 and 50/1,000 mg) with free combination of the individual drugs in healthy subjects. METHODS: The pharmacokinetics of vildagliptin and metformin following administration of a fixed-dose combination tablet of vildagliptin/metformin at doses of 50/500 mg (Study I), 50/850 mg (Study II) and 50/1,000 mg (Study III) compared with administration of the individual drugs as free combinations were investigated. All three studies were open-label, single-center, randomized, two-period, two-treatment crossover studies in healthy subjects. RESULTS: Pharmacokinetic parameters (AUC(0-infinity), C(max), t(max), t(1/2) and CL/F) for vildagliptin and metformin across the three studies were similar whether vildagliptin and metformin were administered as a single fixed-dose combination tablet (vildagliptin/metformin 50/500, 50/850 or 50/1,000 mg) or as the respective individual tablets. The point estimates and 90% CI of the geometric mean ratios for vildagliptin and metformin C(max), AUC(0-t), and AUC(0-infinity) were all within the predefined bioequivalence range of 0.80 - 1.25. Administration of the vildagliptin/metformin combination tablets was well tolerated; the incidence of adverse events was similar to that observed with the respective free combinations of vildagliptin and metformin, and the most common individual adverse events were mild gastrointestinal events, which are commonly observed with metformin treatment. CONCLUSIONS: The fixed-dose combination tablet of vildagliptin/metformin is bioequivalent to administration of the individual drugs as a free combination at dose levels of 50/500, 50/850 and 50/1,000 mg and is well tolerated. Consequently, the fixed-dose combination tablets are considered therapeutically equivalent and exchangeable to the free combination in clinical practice. Furthermore, the fixed-dose combination tablets are expected to enhance convenience and thereby improve compliance and improve glycemic control for patients with Type 2 diabetes on both medications.

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia.

AIMS/HYPOTHESIS: This study sought first to compare the pharmacodynamics and pharmocokinetics of two rapid-onset, rapidly-reversible insulinotropic agents, nateglinide and repaglinide, in pre-diabetic Cynomolgus monkeys and second to use these agents to assess the metabolic effects of early insulin secretion on prandial glucose control. METHODS: First, equipotent doses of nateglinide (20 mg/kg) and repaglinide (0.1 mg/kg) or vehicle were given intragastrically to overnight-fasted ketamine-anesthetized pre-diabetic Cynomolgus monkeys and samples were obtained for measurement of plasma glucose, insulin, glucagon, NEFA and drug concentrations. Second, nateglinide, repaglinide or vehicle were administered 10 min before a glucose-supplemented liquid meal and prandial glucose and insulin profiles were compared. RESULTS: Although oral administration of nateglinide and repaglinide elicited similar maximum increments of plasma insulin (+403 and +448 pmol/l, respectively), the effects of nateglinide were more rapidly manifest and less prolonged. With nateglinide, insulin increased within 10 min and returned to baseline within 50 min. After repaglinide, the first increase occurred at 30 min and insulin concentrations remained increased for 3.5 h post-dose. When given 10 min before a meal, nateglinide increased early, but not total insulin release (AUC(0-210)=108 vs 150 nmol/l min for nateglinide and vehicle, respectively) and reduced prandial glucose excursions by 78%. Repaglinide increased total insulin release (AUC(0-210)=298 nmol/l min) and reduced glucose excursions by 53%. CONCLUSION/INTERPRETATION: Nateglinide is more rapid-acting and rapidly-reversible than is repaglinide. By restoring a more physiologic insulin profile, nateglinide is more effective than repaglinide in controlling prandial glucose excursions with less hyperinsulinaemia.

[Tumor markers in the diagnosis of pancreatic cancer]. / I marcatori tumorali nella diagnosi del carcinoma pancreatico.

The difficulty in an early diagnosis of pancreatic cancer is in the absence of early symptoms due to lower limit of detection of the actual imaging techniques. Clinical symptoms like weight loss, abdominal pain and jaundice indicate an advanced cancer stage. Today 50% of pancreatic tumors are diagnosed in advanced metastatic stage and only 20-30% show resectable cancer. Ultrasound and determination of a mucine like antigen as CA 19-9, CA 50 and CA 195 seem to allow an earlier diagnosis with a higher rate of resective surgery and a prolonged survival for these patients. The mucines are high molecular weight glycoproteins consistent of a backbone protein to which oligosaccarides are attached. The linkage of carbohydrate to the peptide is termed O-glycosidic and involves the hydroxylic groups of serine or threonine with N-acetylglucosamine. Only the backbone proteins are genetically determined (genes MUC). The gangliosides are the same or derivative of Lewis antigen. CA 19-9, CA 50 and CA 195 are assays directed to different epitopes probably present on the same mucinous antigen. These epitopes are not present in different mucines as CA 15-3, CA 125 and TAG 72. Recently other two mucines are emploied CA 242 and CAM 17.1 but they are not better than CA 19-9. The use of a "triplet" of tumor markers as CA 19-9, CA 125 and CEA is the best diagnostic tool for cancer of pancreas in an "integrated" use with ultrasonographic evaluation of the lesion. CA 19-9 permits differential diagnosis from neuroendocrine tumor or pancreatitis, the values of CA 125 and CEA are useful in the evaluation of the stage, resectability and prognosis of pancreatic cancer. The recent use of CA19-9 for the evaluation of radiochemotherapy in preoperative management of the patient is a mode of a well known application of tumor markers in a kinetic evaluation of the tumor for the radicality of therapy, follow-up, recurrence and the effectiveness of the palliative therapy.

High maternal serum alpha-fetoprotein levels during the 2nd trimester of pregnancy: diagnostic approach.

The limit of the classic diagnostic protocols following the evidence of high maternal serum alpha-fetoprotein levels is represented by the high number of amniocenteses performed and that, in the most part of cases, give false negative results. Now days the introduction of high resolution ecographic equipments allows to us, in many cases, to clarify the diagnostic without further examinations. The Authors propose a diagnostic protocol that include the execution of high resolution ultrasound at the second withdrawal of serum alpha-fetoprotein, limiting the use of amniocentesis only when is necessary to determine the fetal karyotype. An high sensibility diagnostic system with a favourable cost/benefit ratio results from this approach.

[Use of antimyosin monoclonal antibodies in the diagnosis of acute myocardial infarct. Comparison with other imaging technics and in vivo kinetics study]. / Impiego degli anticorpi monoclonali antimiosina nella diagnosi di infarto miocardico acuto. Confronto con altre tecniche di imaging e studio della cinetica in-vivo.

Labelled monoclonal antimyosin antibodies have been proposed for the diagnostic imaging of acute myocardial infarction (AMI). In order to verify in the clinical practice the theoretical advantages of this new approach, we performed planar imaging with a commercial kit of 111In-antimyosin (111In-AM) in 17 patients admitted to our Coronary Care Unit with the diagnosis of AMI. The results were compared with the echocardiographic assessment of AMI and, in 9 subjects, also with 99mTc-pyrophosphate (99mTc-PYP) scintigraphy. Furthermore, the in-vivo kinetics of 111In-AM was investigated in 11 patients (blood pool activity curve; column gel-chromatography of the injected compound and patient serum). 111In-AM images showed a myocardial uptake in 16/17; 99mTc-PYP scintigraphy in 7/9. The site of AMI was correctly identified by 111In-AM in 14/17, was mistaken in one and impossible to evaluate in another (diffuse uptake pattern). AMI extent, qualitatively assessed in 111In-AM images was consonant with echocardiography in 8/17 and with 99mTc-PYP in 5 of 9 subjects studied also with this method. An apparent underestimation, in comparison with echocardiography was found in 2 cases, whilst an overestimation was seen in 5 cases. One patient was also underestimated in comparison with 99mTc-PYP. 111In-AM images showed a poor quality, with considerable liver, bone marrow, kidney and blood pool activity and therefore low target to background ratio. In-vivo kinetics was characterized by a slow clearance from the blood pool.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute antiarrhythmia treatment with amiodarone and blood levels of thyroid hormones]. / Trattamento antiaritmico acuto con amiodarone e livelli ematici degli ormoni tiroidei.

Amiodarone has a good antiarrhythmic effect administered either acutely or chronically. Since the antiarrhythmic effect of chronically administered amiodarone has been thought to be dependent on a depression of thyroid function, we studied the peripheral hormonal pattern of 10 euthyroid patients with ventricular arrhythmias who had been responsive to the acute intravenous administration of the drug (10 mg/Kg). During the first 12 hours following the drug administration, reverse T3, free T3 and free T4 values and QTc duration were unchanged. Therefore the antiarrhythmic effect of amiodarone when acutely administered has no correlation with thyroid hormone serum changes.

Vasoactive factors in the mechanism of renal sodium handling in cirrhotics: the effect of acute plasma expansion.

Twenty cirrhotic patients with ascites, divided into two groups of 10 each, according to their daily urinary sodium excretion (sodium retainers and sodium excretors) and given a diet of 75 mEq of sodium daily, underwent acute plasma volume expansion with 1,000 ml of 10% dextran in saline, infused through a catheter located in the right atrium. Even if a significant increase in sodium excretion was observed in both groups (p less than 0.001 in sodium excretors and p less than 0.05 in sodium retainers), plasma expansion did not reverse sodium retention in sodium retainers. A significant increase in creatinine clearance was found only in sodium retainers (p less than 0.02). Basal plasma renin activity and plasma aldosterone were elevated only in a few patients of both groups. The renin-angiotensin-aldosterone system was highly responsive to plasma expansion. Sodium retainers, who showed an ineffective natriuretic response after expansion, were able to suppress both plasma renin activity and plasma aldosterone in an analogous manner to the sodium-excreting group. This result lends strong support to the concept that the elevated aldosterone level in cirrhosis is not the major determinant of sodium retention. The kallikrein-kinin system was responsive to volume stimulus, since a decrease in kallikrein excretion was noted. It was significant in sodium retainers (p less than 0.05). Plasma PGE1,2 levels were significantly higher in sodium retainers than in controls. This may suggest that there is an activation of the intrarenal prostaglandin system, which could play a protective role against renal ischaemia. After volume expansion, PGE1,2 increased, but not significantly. Octopamine appeared unrelated to sodium excretion and unresponsive to volume stimulus. Endotoxins did not seem to be involved in renal sodium handling. Plasma volume expansion seemed effective in inducing a reduction of vasoconstrictor and sodium-retaining factors, such as the renin-angiotensin-aldosterone system. It is possible to suggest that volume expansion could increase PGE1,2. Plasma volume expansion produced different rates of sodium excretion in the two groups of patients and this suggests that impaired sodium handling in cirrhosis could, to some extent, be independent of effective plasma volume.

[Thyroid function in patients chronically treated with amiodarone]. / La funzione tiroidea nel corso del trattamento cronico con amiodarone.

The effects of Amiodarone (1000-1400 mg/week, for a period ranging from 3 to 24 months) on thyroid gland function were studied in 45 patients with heart disease, using a new method of free thyroid hormone assay. Forty-four untreated patients and 11 normal subjects were used as controls. In treated patients the prevalence of dysthyroidism was 22,2% (15,6% hypothyroidism and 6,6% hyperthyroidism); the onset of dysthyroidism ranged from 20 days to 2 years after the beginning of treatment. In control patients the prevalence of dysthyroidism was 4,4% (2,2% hypothyroidism and 2,2% hyperthyroidism). In patients with hypothyroidism (TSH greater than 7 microunits/ml) T4 levels were generally low, while T3, fT4 and fT3 levels were normal. In treated patients with hyperthyroidism (fT3 greater than 5,3 pg/ml and fT4 greater than 16 pg/ml) T4 values were high, while T3 concentrations were in the normal range. In Amiodarone-treated euthyroid patients, mean T4, fT4 and rT3 values were significantly (p less than 0,01) higher than those of control subjects; TSH levels were normal in all the groups studied. These data suggest that Amiodarone can exert both a direct effect on the thyroid gland and the peripheral metabolism of thyroid hormones. The action on the thyroid gland is suggested by the high prevalence of dysthyroidism in Amiodarone-treated patients and by the high levels of T4 and fT4 observed in patients who did not show dysthyroidism. The action on the peripheral hormonal metabolism seems to be proved by the high levels of rT3 and by the prolongation of QTc interval.

Plasma hormone assay in pregnancy.

This paper reports the results obtained with various hormonal parameters (HPL, E3, alpha-FP) in evaluating fetal wellbeing during pathologic pregnancies. The expression of hormonal parameters in terms of standard deviation (S.D.) provides a constant endocrine index throughout pregnancy, independently of the adopted parameter. Such methodology reduces error and simplifies interpretation of data. The hormonal index is important not only for reliable diagnosis of a pathologic situation, but also because of its simple interpretation for clinical and practical purposes.

Functional renal alterations in chronic liver diseases.

83 patients with chronic active hepatitis (CAH), 38 of them with cirrhosis, were studied and compared with 10 control subjects suffering from chronic persistent hepatitis (CPH). Tubular acidosis frequently was found in our cases. Renal plasma flow and glomerular filtration rate were significantly decreased in CAH when compared with CPH. Selective renal arteriography showed evident decrease of arterial flow in the outer cortex. Selective renal scan with 99mTc microspheres of human albumin showed a frequent escape of the tracer from the kidney to the lung. PGE1 and PGE2 levels appeared higher in the renal artery than in the vein and were significantly more elevated in 9 cases with cirrhosis vs. 13 controls. These results suggest the frequent functional impairment of the kidney also in the early stages of CAH, with an increase of PGE levels and an opening of intrarenal shunts.