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Erythropoiesis is affected during deep saturation dives. The mechanism should be related to a downregulation of serum Erythropoietin (s-EPO) concentration or to a toxic effect of the hyperbaric hyperoxia. We evaluated s-EPO and other haematological parameters in 6 scuba divers before, during and after a 14-days guinness saturation dive (8-10 m). Athletes were breathing air at 1.8-2 ATA, under the control of a team of physicians. Serum parameters were measured before diving (T0) and: 7 days (T1), 14 days (T2) after the beginning of the dive and 2 h (T3) and 24 h (T4) after resurfacing. Hgb, and many other haematological parameters did not change whereas Ht, s-EPO, the ratio between s-EPO predicted and that observed and reticulocytes (absolute, percent) declined progressively from T0 to T3. At T4 a significant rise in s-EPO was observed. Hgb did not vary but erythropoiesis seemed to be affected as s-EPO and reticulocyte counts showed. All these changes were statistically significant. The experiment, conducted in realistic conditions of dive length, oxygen concentration and pressure, allows us to formulate some hypotheses about the role of prolonged hyperbarism on erythropoiesis. The s-EPO rise, 24 h after resurfacing, is clearly documented and related to the "Normobaric Oxygen Paradox". This evidence suggests interesting hypotheses for new clinical applications such as modulation of s-EPO production and Hgb content triggered by appropriate O₂ administration in pre-surgical patients or in some anemic disease., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Shear stress triggers conformational stretching of von Willebrand factor (VWF), which is responsible for its self-association and binding to the platelet receptor glycoprotein (GP)Ibα. This phenomenon supports primary hemostasis under flow. Type 2B VWF natural mutants are considered to have increased affinity for platelet GPIbα., Objectives: To assess the mechanism responsible for the enhanced interaction of the p.R1306W VWF mutant with the platelet receptor., Methods: The interaction of GPIbα with wild-type (WT) and p.R1306W VWF multimers and A1-A2-A3 constructs was investigated with surface plasmon resonance spectroscopy. Analysis of the static VWF conformation in solution was performed with dynamic light scattering spectroscopy. The shear stress-induced self-association of VWF multimers was investigated with atomic force microscopy (AFM) over a 0-60 dyn cm(-2) range., Results: WT VWF did not interact with GPIbα under static conditions, whereas the mutant at ~ 2 μg mL(-1) already bound to the receptor. By contrast, the WT and p.R1306W-A1-A2-A3 constructs showed comparable affinities for GPIbα (Kd  ~ 20 nm). The hydrodynamic diameter of resting R1306W VWF multimers was significantly greater than that of the wild type (210 ± 60 nm vs. 87 ± 22 nm). At shear forces of < 14 dyn cm(-2) , the p.R1306W multimers rapidly changed conformation, entering a regime of self-aggregation, which, in contrast, was induced for WT VWF by shear forces of > 30 dyn cm(-2) . Mechanical stretching AFM experiments showed that p.R1306W multimers needed less energy per length unit (~ 10 pN) to be stretched than the WT protein., Conclusions: The increased affinity of p.R1306W VWF for GPIbα arises mostly from higher sensitivity to shear stress, which facilitates exposure of GPIbα binding sites., (© 2013 International Society on Thrombosis and Haemostasis.)

Background: Vascular calcification and osteoporosis share similar etiopathogenetic mechanisms. Vitamin K2 deficiency could be responsible of the so called "calcium paradox", that is the lack of calcium in the bone and its storage in the vessel wall. These events may have clinically relevant consequences, such as cardiovascular accidents, and bone fractures., Aim: To review the biological function of vitamin K2 metabolism, the main factors related to its deficiency and the consequent clinical significance., Discussion: Vitamin K2 is essential for the function of several proteins, involved in the maintenance of the normal structure of arterial wall, osteoarticular system, teeth, and for the regulation of cell growth. It has been demonstrated to have a pivotal role in the inhibition of vascular foci of calcification, and in the regulation of calcium deposition in the bone. Vitamin K2 deficiency is often subclinic in a large part of healthy population. This deficiency is related to the interaction of various factors, such as the reduced dietary intake, the alteration of intestinal absorption or production, with a possible role of intestinal microbiota and the increased consumption at the vessel wall., Conclusions: Vitamin K2 deficiency has recently been recognized as a protagonist in the development of vascular calcification and osteoporosis. Data reported so far are promising and, dietary supplementation seems a useful tool to contrast these diseases. However, large studies or solid clinical correlations regarding vitamin K2 deficiency and its pathologic consequences are needed to confirm these preliminary experiences.

Purpose: Appetite in patients on chronic hemodialysis (HD) may be constantly very good/good or fair/poor or may fluctuate up and down over time. When constantly fair/poor, appetite has been shown to be associated with older age, more comorbidities, and more hospitalizations; however, it is unknown if it predicts survival. The aim of the present study was to assess appetite monthly for 6 months in patients on chronic HD and to determine if the course of appetite over time predicts mortality., Methods: Ninety-two HD patients were evaluated at baseline for appetite, nutritional and inflammatory markers, comorbid conditions, and Charlson's comorbidity index. Appetite assessment was repeated monthly for 6 consecutive months. Survival in relation with the course of appetite over time was determined., Results: Appetite was constantly very good/good in 45 patients (Group 1), fair/poor/very poor in 30 (Group 2), and fluctuated in 17 (Group 3). Twenty-seven (29.3 %) patients died after a mean period of 28 ± 13 months. Overall, the mean survival time was 42.1 ± 1.2 months. For Groups 1, 2, and 3, the mean survival time was 46.1 ± 0.92, 37.9 ± 2.5, and 39.1 ± 3.7 months, respectively (p < 0.0001). After multivariate logistic regression analysis, the course of appetite over time was not found to be an independent risk factor for mortality., Conclusions: The course of appetite over time does not seem to predict mortality in patients on chronic hemodialysis. Considering that the study included a relatively small number of patients, larger similar studies are desirable.

Background: α-Dystroglycan (α-DG) is heavily glycosylated within its central mucin-like domain. The glycosylation shell of α-dystroglycan is known to largely influence its functional properties toward extracellular ligands. The structural features of this α-dystroglycan domain have been poorly studied so far. For the first time, we have attempted a recombinant expression approach in E. coli cells, in order to analyze by biochemical and biophysical techniques this important domain of the α-dystroglycan core protein., Results: We expressed the recombinant mucin-like domain of human α-dystroglycan in E. coli cells, and purified it as a soluble peptide of 174 aa. A cleavage event, that progressively emerges under repeated cycles of freeze/thaw, occurs at the carboxy side of Arg461, liberating a 151 aa fragment as revealed by mass spectrometry analysis. The mucin-like peptide lacks any particular fold, as confirmed by its hydrodynamic properties and its fluorescence behavior under guanidine hydrochloride denaturation. Dynamic light scattering has been used to demonstrate that this mucin-like peptide is arranged in a conformation that is prone to aggregation at room temperature, with a melting temperature of ~40°C, which indicates a pronounced instability. Such a conclusion has been corroborated by trypsin limited proteolysis, upon which the protein has been fully degraded in less than 60 min., Conclusions: Our analysis indirectly confirms the idea that the mucin-like domain of α-dystroglycan needs to be extensively glycosylated in order to reach a stable conformation. The absence/reduction of glycosylation by itself may greatly reduce the stability of the dystroglycan complex. Although an altered pattern of α-dystroglycan O-mannosylation, that is not significantly changing its overall glycosylation fraction, represents the primary molecular clue behind currently known dystroglycanopathies, it cannot be ruled out that still unidentified forms of αDG-related dystrophy might originate by a more substantial reduction of α-dystroglycan glycosylation and by its consequent destabilization.

Background: The aim of this study was to evaluate the relationship among time of recovery after hemodialysis (TIRD) and the demographic, social, clinical and laboratory characteristics of hemodialysis patients of a Mediterranean country., Methods: One hundred hemodialysis patients were invited to answer the following question: "How long does it take you to recover from a dialysis session?" Demographic, clinical (Charlson Comorbidity Index [CCI], Mini-Mental State Examination [MMSE] and Geriatric Depression Scale [GDS]) and laboratory variables were recorded, and fatigue qualities (FQs) were assessed through 5 questions: Do you feel tired much of the time? (general); Do you feel that life is empty? (emotional); Do you have trouble concentrating? (cognitive); Do you have difficulty sleeping? (sleepiness); Do you have muscle weakness? (weakness); and Do you feel full of energy? (lack of energy)., Results: The means ± SD of TIRD was 205.5 ± 198.6 minutes: 79 patients reported a TIRD

Study Objective: To determine the effect of positive end-expiratory pressure (PEEP) on the respiratory system and on cardiac function., Design: Prospective randomized study., Setting: Operating room., Patients: 60 ASA physical status 1 women scheduled for pelvic laparoscopic surgery., Interventions: Patients were ventilated normally during surgery; PEEP was modified depending on patient group allocation. Group A was the control group and did not receive PEEP. Group B received PEEP 5 cmH2O and Group C received PEEP 10 cmH2O., Measurements: Respiratory parameters measured were partial pressure of arterial oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), and end-tidal carbon dioxide tension (ETCO2). Cardiac parameters measured were left ventricular end-diastolic volume index (LVEDVI), ie, ratio of LVEDV/body surface area (BSA; [LVEDVI = end-diastolic volume [EDV]/BSA); left ventricular (LV) systolic function, tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) fractional area change (FAC), RV dimensions in the apical 4-chamber view, tracing basal and mid-cavity minor dimensions and longitudinal dimension, cardiac index, systolic pulmonary artery pressure (PASP), and systolic RV pressure (RVSP). Respiratory and cardiac measurements were recorded at T0 (baseline); T1 (after anesthesia induction, before pneumoperitoneum induction); at 10 (T2), 20 (T3), and 30 (T4) minutes after CO2 insufflation; and at the end of surgery (T5)., Main Results: Ventilation with PEEP at 10 cm H2O led to significant improvement in both respiratory and cardiac parameters. A reduction in pulmonary vascular resistance and enhanced washout of expiratory CO2 occurred. Ten and, to a lesser extent, 5 cm H2O of PEEP decreased LV stroke work., Conclusions: Ventilation with PEEP (up to 10 cm H2O) recruits the hypoventilated areas of the lungs and reduces cardiac afterload., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Cinacalcet is a new effective treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients (HP), but the alterations of parathyroid gland (PTG) hyperplasia determined by cinacalcet and vitamin D have not been extensively investigated in humans., Methods: We performed histological analyses of 94 PTGs removed from 25 HP who underwent parathyroidectomy (PTx) because of SHPT refractory to therapy with vitamin D alone (group A=13 HP and 46 PTGs) or associated with cinacalcet (group B=12 HP and 48 PTGs). The number, weight, the macroscopic cystic/hemorrhagic changes, and type of hyperplasia of PTG (nodular=NH, diffuse=DH) were assessed. In randomly selected HP of group A (4 HP and 14 PTGs) and group B (4 HP and 15 PTGs), the labeling index of cells positive to Ki-67 and TUNEL and the semiquantitative score of immunohistochemistry staining of vitamin D receptor, calcium-sensing receptor, and vascular endothelial growth factor-α (VEGF-α) were measured in the entire PTGs and in the areas with DH or NH., Results: The number and weight of single and total PTG of each HP were similar in the two groups as well as the number of PTG with macroscopic cystic/hemorrhagic areas. TUNEL, Ki-67, and VEGF-α scores were higher in NH than in DH areas., Conclusion: This observational study of a highly selected population of HP, submitted to PTx because SHPT refractory to therapy, shows that the macroscopic, microscopic, and immunochemistry characteristics of PTG in HP who received or did not receive cinacalcet before PTx did not differ significantly.

Epidemiological studies suggest that n-3 polyunsaturated fatty acid (n-3 FA) deficiency is a risk factor for bipolar disorders (BDs). The aim of this study was to determine whether such a deficit does exist in patients with BD and to characterize the overall plasma fatty acid (FA) profile in these patients. Using gas chromatography/mass spectrometry, we measured fasting plasma levels of 15 FAs in 42 patients diagnosed with BD according to DSM-IV criteria and in 57 age- and gender-matched healthy controls. Plasma docosahexaenoic acid (DHA) levels were significantly decreased in bipolar patients (p < 0.001 versus healthy controls). Compared with controls, patients had higher plasma levels of all other FAs, including arachidonic acid (AA, p < 0.001), alpha-linolenic acid (ALA, p < 0.001), and eicosapentaenoic acid (EPA) (p < 0.001). Although in the present study we observed significant DHA deficits in the plasma of bipolar patients our findings do not support the therapeutic use of ALA and/or EPA supplementation. DHA may provide a basis for possible pharmacological intervention in psychiatric disorders at the level of second messengers linked to the phosphatidylinositol cycle. Finally, measurement of FA levels in plasma seems to be more reliable and reproducible than assays of erythrocyte FA content., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Acute kidney injury (AKI) is a common complication among hospitalized patients. The aim of this study was to evaluate the utility of blood neutrophil gelatinase-associated lipocalin (NGAL) assessment as an aid in the early risk evaluation for AKI development in admitted patients., Methods: This is a multicenter Italian prospective emergency department (ED) cohort study in which we enrolled 665 patients admitted to hospital from the ED., Results: Blood NGAL and serum creatinine (sCr) were determined at ED presentation (T0), and at: 6 (T6), 12 (T12), 24 (T24) and 72 (T72) hours after hospitalization. A preliminary assessment of AKI by the treating ED physician occurred in 218 out of 665 patients (33%), while RIFLE AKI by expert nephrologists was confirmed in 49 out of 665 patients (7%). The ED physician's initial judgement lacked sensitivity and specificity, overpredicting the diagnosis of AKI in 27% of the cohort, while missing 20% of those with AKI as a final diagnosis., Conclusions: Our study demonstrated that assessment of a patient's initial blood NGAL when admitted to hospital from the ED improved the initial clinical diagnosis of AKI and predicted in-hospital mortality. Blood NGAL assessment coupled with the ED physician's clinical judgment may prove useful in deciding the appropriate strategies for patients at risk for the development of AKI.See related commentary by Legrand et al., http://ccforum.com/content/17/2/132.

Background: Monitoring of tacrolimus (TAC) concentrations in transplanted patients is necessary to ensure effective immunosuppression and to avoid adverse side effects. The fully automated analysis of TAC by the affinity column-mediated immunoassay (ACMIA), which does not require a precipitation step, may represent an efficient alternative to liquid chromatography-tandem mass spectrometry (LC-MS/MS), including in the clinically urgent situation. The aim of this work was to compare the analytical performances of ACMIA with those of LC-MS/MS and to evaluate the influence of hematological parameters, time posttransplant, and type of transplant on the results obtained from routine blood samples., Methods: Performance characteristics of ACMIA were evaluated using quality control materials and samples spiked with TAC from the International Proficiency Testing Scheme. One hundred and fifty-eight whole-blood samples from patients who received a liver (n = 55) or kidney (n = 14) transplant were assayed by ACMIA and LC-MS/MS, and hematologic, biochemical, and demographic data were collected. Univariate and multivariate statistical analyses were also performed to assess associations between the interassay differences with clinical and laboratory parameters., Results: For artificially spiked samples, the average difference between results obtained by ACMIA and LC-MS/MS was 0.24 ± 0.51 ng/mL (2.91 ± 7.03%). Crosschecking of calibrators and controls by both methods was in accordance with the nominal concentrations of TAC. The lower limit of quantification of ACMIA was found to be 3.0 ng/mL. The results with the 2 methods using routine samples from the transplant recipients correlated well (Spearman's r = 0.90). However, the ACMIA method demonstrated a positive mean bias of 1.78 ng/mL in comparison with LC-MS/MS. Multivariate analysis showed that liver transplant and albumin plasma concentrations significantly and independently affected ACMIA results (P = 0.033 and P = 0.001, respectively). Samples from liver transplant recipients early postsurgery were associated with a larger method bias than those from renal transplant recipients., Conclusions: Results obtained by ACMIA must be interpreted cautiously, particularly at lower TAC concentrations. Patients with low plasma concentrations of albumin are likely to display higher concentrations of TAC compared with LC-MS/MS in the early postsurgery period.

We aimed to assess the relationship among fatigue qualities (FQ) and the association of FQ with various characteristics of chronic hemodialysis (HD) patients. In 68 HD patients, we assessed the Charlson Comorbidity Index (CCI), the Geriatric Depression Scale score (GDS), the Mini Mental Status Examination (MMSE), and measured the laboratory parameters. In addition, patients answered to six questions about FQ (Tiredness: Do you feel tired much of the time? Emotional: Do you feel that life is empty? Cognitive: Do you have trouble concentrating? Sleepiness: Have you had difficulty sleeping in the past month? Weakness: Have you had muscle weakness in the past month? Lack of energy: Do you feel full of energy?). At least one FQ was reported by 62 patients. Muscle weakness (61.7%) was the most frequent and cognitive fatigue (22%) the least. Physical FQ were all more common than the mental ones. Correlation between the two mental FQ (emotional and cognitive) was 0.381 (p = 0.002). Six patients reported none of the FQ, 20 one FQ, 13 two FQ, and 29 three or more FQ. CCI and GDS were associated with all FQ and MMSE with all FQ but sleepiness. Patients reporting ≥3 FQ were older, had more comorbidities, more symptoms of depression, and a lower MMSE score. At multivariate linear regression analysis, the GDS was the only significant predictor of the number of FQ. HD patients report a variety of qualities of fatigue and the number of FQ is independently associated with symptoms of depression., (© 2012 The Authors. Hemodialysis International © 2012 International Society for Hemodialysis.)

Background: Neurohumoral, immunologic and metabolic alteration characterize surgical procedures in relation with the intensity of injury, the total operating time and the anesthetic technique. We, therefore, compared the effects of desflurane versus sevoflurane anesthesia on intra and postoperative release of the stress hormones and inflammatory cytokines., Methods: Fifty Caucasian women undergoing laparoscopic surgery for benign ovarian cysts were randomized to receive inhaled anesthesia with desflurane (DES group; N.=25) or sevoflurane (SEVO group; N.=25), with fentanyl bolus and remifentanil infusion. Plasma levels of noradrenaline, adrenaline, ACTH and cortisol were measured preoperatively (T1), 30 minutes after the beginning of surgery (T2), and 30 minutes, 2 and 4 hours after the end of surgery (T3, T4, T5 respectively). Interleukin 6 (IL-6), glucose and C-reactive protein (CRP) were measured at T1, T2,T3, T4, T5 and 12 hours after the end of surgery (T6)., Results: An increase of catecholamines during (T2) and immediately after surgery (T3) was observed in both groups. However, adrenaline and noradrenaline levels were significantly higher in the DES group compared to the SEVO group. Despite a drop of cortisol concentration was observed in both groups, only in the DES group there was a significant difference intraoperatively as compared to the baseline levels and to the SEVO group. While, the consequent increase of ACTH was significantly higher in the SEVO group at T2-T4. The preoperatory levels were restored at T5. Glucose, IL-6, CRP levels and postoperative pain did not show significant differences in timing within the same group and comparing DES vs SEVO group., Conclusion: In the present study we demonstrated that desflurane and sevoflurane produced a different stress response in the setting of laparoscopic surgery. The greater release of catecholamines during desflurane anesthesia could have adverse effects in patients with pre-existing cardiovascular disease. In low stress surgery desflurane, as compared to sevoflurane, was associated with a better control of intraoperative cortisol and ACTH response (T2). Moreover, the ACTH secretion resulted attenuated also postoperatively (T3-T4). Both gases did not influence the plasmatic levels of Il-6, CRP and glucose.

Objective: A high-risk location--defined as the tumor margin being less than 5 mm from large vessels or vital structures--represents a well-known limitation and contraindication for radiofrequency ablation of hepatocellular carcinoma (HCC) nodules. The aim of this study was to verify whether HCC nodule location negatively affected the outcome of percutaneous laser ablation in terms of its primary effectiveness, safety, and ability to prevent local tumor progression., Materials and Methods: The medical records and radiologic examinations of 164 cirrhotic patients (90 men, 74 women; mean age ± SD, 68.6 ± 8.3 years) with 182 HCC nodules 4 cm or smaller (mean diameter ± SD, 2.7 ± 0.78 cm) that had been treated by laser ablation between 1996 and 2008 were retrospectively analyzed. One hundred six patients had 116 nodules in high-risk sites (high-risk group), whereas 58 patients had 66 tumors located elsewhere (standard-risk group)., Results: The overall median follow-up was 81 months (range, 6-144 months). The initial complete ablation rate per nodule did not significantly differ between the high-risk group and the standard-risk group (92.2% vs 95.5%, respectively; p = 0.2711). Rates of major complications (high-risk group vs standard-risk group, 1.9% [including one death] vs 0%) and minor complications (5.6% vs 1.0%) were not statistically different between the two groups. Only side effects were recorded significantly more often in high-risk patients than in standard-risk patients (31.5% vs 19.8%; p = 0.049). There was no significant difference in either cumulative incidence of local tumor progression (p = 0.499) or local tumor progression-free survival (p = 0.499, log rank test) between the high-risk group and the standard-risk group., Conclusion: When laser ablation is used to treat small HCC nodules, tumor location does not have a significant negative impact on the technique's primary effectiveness or safety or on its ability to achieve local control of disease.

Background: Ketorolac tromethanime is a non steroidal anti inflammatory drug and its efficacy on acute pain control after abdominal surgery has been well documented. It has a rapid onset and it can be given both for intra operative and for post operative pain management., Aim: In this study we aimed to evaluate if there were any differences in relieving post operative pain when Ketorolac was administered with continuous infusion or if it was given at prearranged times., Patients and Methods: 80 ASA I patients, scheduled for major gynecological surgery, were randomly assigned to 2 groups: group A patients were connected after surgical incision with a 24h analgesic infusor (2 ml/h) containing morphine (0.02 mg/kg/h) and Ketorolac (90 mg). Group B patients were connected after surgical incision with a 24h analgesic infusor (2 ml/h) containing morphine (0.02 mg/kg/h) at first and Ketorolac was then given in bolus after surgical incision and then every 8 hours for the first 24 hours. Post-operative pain scores were assessed using the Visual Analogue Scale (VAS) every 8 hours for 24 h. For a VAS value greater than 6, patients received Tramadol 100 mg., Results: Post-operative pain scores showed a better pain relief for patients in the group B. Furthermore, the requirements of rescue analgesic were less in the group B [Tramadol was used for only 8 patients] than in the group A [Tramadol was used for 31 patients]. No adverse effects were registered in both groups. , Conclusions: For post-operative pain Ketorolac administration at prearranged times, every 8 hours, offers greater benefits in respect to its continuous infusion.

Background: We recently demonstrated that pneumoperitoneum affects diastolic echocardiographic findings in healthy women scheduled for gynaecologic laparoscopy. No reports have been conducted in order to assess the echocardiographic consequences in hypertensive subjects during laparoscopic procedures., Aim: The aim of this study was to evaluate Left Ventricular filling pressures in hypertensive women with and without diastolic dysfunction, combining the tissue Doppler imaging technique and the plasmatic levels of amino terminal proBNP., Materials and Methods: Doppler recordings of mitral inflow, tissue Doppler imaging of mitral annulus and N-terminal-proBNP plasmatic levels were obtained in 40 hypertensive women with or without diastolic dysfunction. Measurements were executed in awake patients (T0), after the induction of anesthesia (T1), 10 and 20 minutes after the creation of the pneumoperitoneum (T2 and T3, respectively) and at the end of the surgery (T4). Furthermore, we collected the last blood sample after 12 hours (T5)., Results: The E/Ea ratio for the evaluation of left ventricular filling pressures were higher in the diastolic dysfunction group than in the non diastolic dysfunction and significantly increased after pneumoperitoneum. Pneumoperitoneum increased the plasmatic levels of natriuretic peptide in both groups. At the end of the procedure we did not observe any further significant alteration., Conclusions: Pneumoperitoneum produces a consistent increase of ventricular filling pressures in a population of hypertensive patients with and without diastolic dysfunction. Moreover, there is a significant but transient rise in NT-proBNP after gas insufflation in both groups, most accentuated in the diastolic dysfunction group.

Background: Little is known about the course of the symptoms of depression/anxiety and the factors predictive of such courses in hemodialysis (HD) patients. This study aimed at evaluating the possible changes of Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HARS) over time, and factors associated with such changes in HD patients., Methods: We screened 110 patients for study participation. Of these, 30 were excluded because of dialytic vintage <6 months, alcohol/substance abuse, inability to answer to the questionnaires, diagnosis of psychotic or neurological disorders or recent stressful life events. Eighty patients were included in the study and BDI, HARS, Charlson Comorbidity Index, SF-36 Vitality Subscale, Mini-Mental State Examination (MMSE), routine laboratory parameters, C-reactive protein (CRP) and interleukin-6 were measured at baseline. The 18-month course of BDI and HARS was measured in patients with baseline BDI ≤14., Results: At baseline, 42 patients had BDI >14 and 38 patients ≤14. In patients with BDI ≤14, the BDI decreased/remained stable in 19 and increased in 19. Patients with increased BDI had lower baseline MMSE (22.6 ± 2.6 vs. 25.9 ± 2.7, p=0.004) and higher baseline serum CRP (6.07 ± 4.2 vs. 1.64 ± 1.59, p=0.003). At multivariate analysis the relationship between BDI changes and MMSE and serum CRP was statistically significant. In 25 patients, the HARS decreased/remained stable, while in 13 it increased. Characteristics of the 2 groups of patients did not differ significantly., Conclusions: In a meaningful proportion of HD patients, symptoms of depression worsen over time, and CRP and MMSE are independent predictors of such change.

Background: Ablation of the normal hepatic parenchyma surrounding the tumor (ablative margin [AM]) is necessary to prevent local tumor progression., Purpose: To assess the prognostic value of the ablative margin in patients with HCC ≤4 cm treated with US-guided laser ablation., Material and Methods: A cohort of 116 patients (53 women and 63 men, age range 42-82 years) with 132 HCC nodules ≤4 cm completely ablated by US-guided laser ablation was retrospectively analyzed. Rates of local tumor progression were compared using different ablative margin cut-offs (≥2.5, 5.0, 7.5, and 10.0 mm). Survival probability curves were obtained with the Kaplan-Meier method., Results: The mean period of follow-up was 42 months (range 3-114 months). Local tumor progression was identified in 24 out of 132 lesions (18%), with an average time to progression of 24 months (range 6-36 months). A significant difference in local tumor progression was observed only if the ablative margin was ≥7.5 mm (7% vs. 23%, P = 0.020). Survival curves of patients with or without an ablative margin ≥7.5 mm were not different (P = 0.665; mean survival time 43.8 ± 3.1 and 46.8 ± 6.1 for an AM < or ≥7.5 mm, respectively)., Conclusion: An ablative margin ≥7.5 mm turned out to be useful in preventing local tumor progression but did not affect long-term survival in patients with HCC ≤4 cm treated with laser ablation.

Bilirubin-IX-alpha (BR) is the final product of heme metabolism through the heme oxygenase/biliverdin reductase (HO/BVR) system. Previous papers reported on the microbicidal effects of the HO by-products biliverdin-IX-alpha, carbon monoxide and iron, through either direct or indirect mechanisms. In this paper the evidence of a virucidal effect of BR against human herpes simplex virus type 1 (HSV-1) and the enterovirus EV71 was provided. Bilirubin-IX-alpha, at concentrations 1-10 μM, close to those found in blood and tissues, significantly reduced HSV-1 and EV71 replication in Hep-2 and Vero cell lines, respectively. Bilirubin-IX-alpha inhibited viral infection of Hep-2 and Vero cells when given 2 h before, concomitantly and 2 h after viral infection. Furthermore, BR retained its antiviral activity even complexed with a saturating concentration of human serum-albumin. Moreover, 10 μM BR increased the formation of nitric oxide and the phosphorylation of c-Jun N-terminal kinase in Vero and Hep-2 cell lines, respectively, thus implying a role of these two pathways in the mechanism of antiviral activity of the bile pigment. In conclusion, these results support the antiviral effect of BR against HSV-1 and enterovirus in vitro, and put the basis for further basic and clinical studies to understand the real role of BR as an endogenous antiviral molecule.

Objective: We aimed at evaluating the association between appetite and symptoms of depression and anxiety, cognitive dysfunction, fatigue, and comorbidities in patients on hemodialysis (HD)., Design: A cross-sectional study was conducted., Setting: The study was conducted in an outpatient HD service of a tertiary level academic hospital., Patients: A total of 90 patients on HD were evaluated for appetite (during the past week, how would you rate your appetite?), symptoms of depression (Beck Depression Inventory [BDI]) and anxiety (Hamilton Anxiety Rating Scale [HARS]), cognitive dysfunction (Mini Mental State Examination [MMSE]), and comorbidities (Charlson Comorbidity Index)., Main Outcome Measure: Relationship between appetite and symptoms of depression and/or anxiety, cognitive dysfunction, and comorbidities was assessed., Results: In 43 patients, the appetite was very good/good (group 1), in 22, it was fair (group 2), and in 25, it was poor/very poor (group 3). Mean and median BDI were significantly higher in group 3 as well as the percentage of patients with BDI ≥16. Mean and median HARS and the percentage of patients with HARS >13 were significantly higher in group 3. MMSE was significantly lower in group 3 as well as the percentage of patients with MMSE ≤23. Multiple linear regression analysis showed a dependence of appetite by age and BDI (P = .007 and P = .002, respectively)., Conclusions: Anorexia is associated with older age and symptoms of depression in patients on HD., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: A high frequency of blue eyes and fair skin are reported in northern European Caucasians with type 1 diabetes (T1D). Also there is an inverse relationship between latitude and T1D incidence. We determined whether iris colour and skin pigmentation are risk factors in a Caucasian population living in two Mediterranean regions located at the same latitude with higher ultraviolet B irradiance, but with different T1D incidence., Methods: We studied iris colour in 281 consecutive subjects with T1D and 298 controls. Skin type was evaluated by melanin quantification., Results: In Lazio, blue eyes and fair skin type are significantly more common in T1D subjects than in controls (21 versus 9%, p = 0.002; 50 versus 35%, p < 0.001, respectively). In Sardinia, the frequency of blue eyes in T1D subjects is twice that in controls (5.8 versus 2.6% and significantly higher when compared to the expected calculated frequency in the entire population). By logistic regression analysis, only blue eyes are independent and significant predictors of T1D [odds ratio for blue eyes = 2.2; 95% confidence interval (1.1-4.4), p = 0.019]., Conclusions: As previously shown in a Caucasian population from northern Europe, blue eyes and a trend for fair skin increase the risk for T1D also in a Caucasian population born and residing in a Mediterranean region (Continental Italy). This finding may be relevant for explaining different T1D incidence as prevalence of blue eyes differ substantially between northern and southern European Caucasians., (Copyright © 2011 John Wiley & Sons, Ltd.)

Flow-mediated dilation (FMD) is a widely used tool to investigate endothelial function. However, FMD assessment may cause mechanical damage to the arterial endothelium. In this study we investigated the effect of FMD assessment on endothelial function. We studied 20 healthy subjects (26 ± 6 years; 12 males). FMD was assessed by measuring brachial artery dilation in response to hyperemia after 5 min of forearm cuff inflation. Subjects were studied on 2 subsequent days. On day 1 they underwent two consecutive FMD measures, with the second test (FMD2) performed 15 min after the first test (FMD1). On day 2, the subjects were randomized to receive either placebo (saline) or intravenous L: -arginine (10 g in 20 min). At the end of the infusion, patients underwent two consecutive FMD measures following the same protocol as on day 1. Asymmetric dimethyl-arginine (ADMA) serum levels were assessed on day 2 before FMD1 and FMD2. On day 1, FMD2 was lower than FMD1 in both groups (placebo 6.47 ± 2.1 vs. 7.86 ± 1.8%, P < 0.01; arginine 6.13 ± 2.6 vs. 7.76 ± 2.7%, P < 0.01). On day 2, a significant reduction of FMD was observed during FMD2 compared to FMD1 in the placebo group (5.82 ± 1.7 vs. 7.44 ± 2.2%, P < 0.001), but not in the arginine group (7.19 ± 1.5 vs. 7.27 ± 1.5, P = 0.67). ADMA levels significantly increased compared to baseline after FMD1 (0.59 ± 0.12-0.91 ± 0.64 μmol/l, P = 0.036), with similar changes in the two groups. FMD assessment induces a significant impairment of endothelial function. An increase of endogenous NO synthesis inhibitors seems responsible for the phenomenon that is reversed by L: -arginine administration.

Objective: Previous studies have shown a high cardiovascular risk in patients with autoimmune diseases, such as type 1 diabetes mellitus (T1DM). Conversely, few data are available about patients with celiac disease (CD). The aim of our study was to assess carotid intima-media thickness (c-IMT), in patients with T1DM, CD or both (T1DM+CD) as compared with age- and sex-matched healthy individuals (H)., Methods: We enrolled 120 patients, 30 with T1DM, 30 with CD, 30 with T1DM+CD and 30 H. Clinical, metabolic and anthropometric data were collected. All T1DM patients were on insulin while all CD patients were on a gluten-free diet. c-IMT was evaluated by high frequency linear digital ultrasound., Results: c-IMT was significantly greater in patients with T1DM+CD than in patients with T1DM or CD (P<0.001 for both), while no difference was found between T1DM and CD. Moreover, c-IMT was greater in CD than in H (P<0.001). Glycemic control and disease duration were similar between T1DM+CD and T1DM. Lipid and anthropometric parameters were similar among groups. Furthermore, in a pooled multivariate analysis, only age and disease type were significantly correlated with c-IMT (P<0.001 for both)., Conclusion: Our study demonstrates that celiac patients have greater c-IMT as compared with healthy individuals. Thus, non-invasive monitoring of c-IMT in CD might be useful in preventing cardiovascular disease. Moreover, patients with T1DM+CD show more severe subclinical atherosclerosis as compared with those presenting T1DM or CD only, suggesting that the association of these autoimmune diseases might accelerate the atherosclerotic process., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: Cognitive impairment is relatively common in end-stage renal disease patients on chronic hemodialysis, but the course of cognitive function deterioration in hemodialysis patients is essentially unknown. The present study aimed to evaluate if changes in Mini Mental State Examination (MMSE) over time in hemodialysis (HDP) and elderly (EP) patients differ significantly and determine the variables associated with such possible changes., Methods: In 80 HDP and 160 EP, the MMSE was assessed at baseline and after 1 year. Patients were stratified at baseline and at 1 year into three groups according to the MMSE: normal cognitive function >23; mild-moderate cognitive dysfunction: 18-23; severe cognitive dysfunction: <18. Univariate and multivariate analyses were performed to determine the variables associated with MMSE change over time, Results: One-year median reduction of MMSE was greater in HDP (from 24 to 21) than in EP (from 26 to 25) (P<.0001). A higher percentage of HDP than EP switched from normal to mild-moderate or severe MMSE group (P<.0001). At baseline, MMSE was negatively correlated with hypertension (P=.013), angina (P=.007) and Beck Depression Inventory (P=.041) and positively correlated with education (P=.017) and male gender (P=.015). No factors were found to be significantly associated with change of MMSE between baseline and month 12 in HDP., Conclusion: One-year MMSE reduction was greater in HDP that in EP. No factors were associated with MMSE reduction in HDP. However, it remains likely that cardiovascular comorbidities and low haemoglobin levels are related to such decline., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: The cardiac left ventricle responds to pressure overloads with mechanisms culminating in irreversible structural/functional cardiac alterations (left ventricular hypertrophy and/or diastolic dysfunction), inducing myocardial cells to secrete natriuretic peptides (NT-proBNP) antagonists of the renin-angiotensin-aldosterone system. The aim of this study was to evaluate the diagnostic accuracy of serum NT-proBNP levels in order to detect structural/functional cardiac diseases assessed by echocardiography., Methods: A total of 126 consecutive newly diagnosed, never before treated, hypertensive patients (30-67 years) were enrolled, and clinical, echocardiography parameters and biochemical data were collected. Our reference was the presence of structural/functional cardiac disease (CSFD) and our index text was the serum NT-proBNP levels., Results: NT-proBNP levels in CSFD patients were ~2 times higher than in non-CSFD subjects (median 61 vs 29 ng/L, n=50 and 76, respectively); in addition, 60% of CSFD subjects (only 14% of which with pathological levels, >125 ng/L), and 30% without CSFD showed NT-proBNP concentrations higher than 50 ng/L. However, ROC curves demonstrated a low specificity (38%) (calculated at 90% sensitivity at a cut-off of 22.5 ng/L)., Discussion: NT-proBNP levels, as a screening tool for cardiac structural/functional disease, appear to be limited, because of the low specificity. However, the strong association between its concentration and the establishment of irreversible cardiac hypertrophy prompts successive studies aimed to ascertain the use of its serum levels as an early alert indicator of disease severity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

In the PREdiction of DIabetes from CApillary blood glucose (PREDICA) study, we propose a novel approach based on multiple capillary blood glucose (CBG) measurements, assuming that weekly measurements performed for 2 months may be an efficient strategy to screen for diabetes. We studied 538 Caucasian subjects (247 men and 291 women) without a history of diabetes, consecutively recruited by 50 GPs from the Italian provinces of Rome and Frosinone. Subjects were asked to perform 8 fasting glucose and 8 post-prandial glucose measurements during a frame time of 2 months (Glucometer Accu-chek AVIVA Roche Diagnostics). Study subjects were 55 ± 9 years old (range 22-77 years of age), 50% were overweight and 16% obese. Fifty-eight percent of subjects have performed 13 to 16 CBG measurements during the study, 68% of subjects have performed at least 5 out of 8, both fasting and post-prandial measurements. Among 492 subjects who had at least two fasting measurements, 63.6% had normal glucose levels, 25.4% showed IFG, and 11.0% were diabetic. Considering post-prandial measurements, 74.2% had normal glucose levels, 23.0% had IGT, and 2.8% were diabetic. Combined IFG + IGT was detected in 7% of study subjects, while in 0.8% diagnosis of diabetes was confirmed with both fasting and post-prandial measurements. In this study, we found a high adherence to a novel screening strategy based on self-glucose monitoring in the general population. Our results show that multiple CBG measurements may represent a simple and efficient method for diabetes screening.

Background: We aimed to evaluate the relationship between serum leptin and the leptin/body mass index (BMI) ratio with prevalent cardiovascular disease (CVD), and their influence on all-cause and CVD-related mortality in patients on hemodialysis (HD)., Methods: 118 stable HD patients (50 women, median [interquartile range] age, 65.1 [54.7-72.2] years) were studied. All patients had baseline measurement of serum leptin concentrations. Relationships between leptin and all-cause and CVD mortality were studied by means of survival analysis and Cox regression analysis., Results: The leptin/BMI ratio was similar in patients with and without CVD at baseline (0.65 [0.29-2.23] vs. 0.68 [0.29-1.49] ng·m2/ml·kg, respectively, NS). Multiple logistic regression analysis showed that there was not an independent association between leptin/BMI ratio and prevalent CVD. During the follow-up time, 52 (44.1%) patients died. CVD was the cause of death in 27 out of 52 (51.9%) deceased patients. Survival analysis and Cox proportional multivariate regression analysis showed that there were no significant relationships between leptin levels or the leptin/BMI ratio and all-cause and CVD-related mortality., Conclusion: These results do not support that, in stable HD patients, serum leptin concentrations and the leptin/BMI ratio are related with prevalent CVD. Leptin/BMI ratio seems not to be a risk factor for mortality in these patients.

Macromolecules and cells exposed to blood flow in the circulatory tree experience hydrodynamic forces that affect their structure and function. After introducing the general theory of the effects of shear forces on protein conformation, selected examples are presented in this review for biological macromolecules sensitive to shear stress. In particular, the biochemical effects of shear stress in controlling the von Willebrand Factor (VWF) conformation are extensively described. This protein, together with blood platelets, is the main actor of the early steps of primary haemostasis. Under the effect of shear forces >30 dyn/cm², VWF unfolding occurs and the protein exhibits an extended chain conformation oriented in the general direction of the shear stress field. The stretched VWF conformation favors also a process of self aggregation, responsible for the formation of a spider web network, particularly efficient in the trapping process of flowing platelets. Thus, the effect of shear stress on conformational changes in VWF shows a close structure-function relationship in VWF for platelet adhesion and thrombus formation in arterial circulation, where high shear stress is present. The investigation of biophysical effects of shear forces on VWF conformation contributes to unraveling the molecular interaction mechanisms involved in arterial thrombosis., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Von Willebrand factor (VWF) is a large multimeric adhesive glycoprotein, with complex roles in thrombosis and hemostasis, present in circulating blood and in secretory granules of endothelial cells and platelets. High shear stress triggers conformational changes responsible for both binding to the platelet receptor glycoprotein GpIb and its self-association, thus supporting the formation of platelet plug under flow. Ristocetin also promotes the interaction of VWF with GpIb and is able to induce platelet aggregation, and thus is largely used to mimic this effect in vitro. In this research paper, we followed the time course of VWF self-association in solution induced by ristocetin binding by light scattering and at the same time we collected atomic force microscopy images to clarify the nature of the assembly that is formed. In fact, this process evolves initially through the formation of fibrils that subsequently interact to form supramolecular structures whose dimensions would be capable of trapping platelets even in the absence of any degree of shear stress or interaction with external surfaces. This intrinsic property, that is the ability to self-aggregate, may be involved in some pathological settings that have been revealed in clinical practice.

Objective: We investigated whether supplementation of the active form of vitamin D (calcitriol) in recent-onset type 1 diabetes can protect beta-cell function evaluated by C-peptide and improve glycemic control assessed by A1C and insulin requirement., Research Design and Methods: Thirty-four subjects (aged 11-35 years, median 18 years) with recent-onset type 1 diabetes and high basal C-peptide >0.25 nmol/l were randomized in a double-blind trial to 0.25 microg/day calcitriol or placebo and followed-up for 2 years., Results: At 6, 12, and 24 months follow-up, A1C and insulin requirement in the calcitriol group did not differ from the placebo group. C-peptide dropped significantly (P < 0.001) but similarly in both groups, with no significant differences at each time point., Conclusions: At the doses used, calcitriol is ineffective in protecting beta-cell function in subjects (including children) with recent-onset type 1 diabetes and high C-peptide at diagnosis.

Cinacalcet efficacy is limited in severe secondary hyperparathyroidism (SHPT) and its effect on parathyroid gland (PTG) volume and morphology have not been sufficiently investigated. We evaluated the effect of cinacalcet treatment for one year on the laboratory parameters of calcium-phosphorus metabolism and PTG ultrasound (US) patterns in hemodialysis (HD) patients with severe SHPT and US results indicative of nodular hyperplasia. Thirteen HD patients with severe SHPT (intact parathyroid hormone >700 pg/mL), US/scintigraphic evidence of at least one PTG with a diameter >7 mm, and high surgical risk or refusal of surgery were included. The patients were treated with cinacalcet. The initial dose of 30 mg was increased up to 180 mg once daily. At baseline and after one year of cinacalcet treatment a neck US was performed, providing data on 22 parathyroid glands in eight patients. The mean diameter at baseline and at one year was 12.6 +/- 5.9 and 13.0 +/- 5.3 mm, respectively (P = 0.46). Similarly, the mean volume at baseline and at one year was 513.4 +/- 416.3 and 556.8 +/- 480.8 mm(3), respectively (P = 0.18). The US structural score remained unchanged in 16 parathyroid glands and increased in 6 (P < 0.03), while the vascular score remained unchanged in 16 parathyroid glands and decreased in 6 (P = 0.25). Thus it can be concluded that cinacalcet treatment for one year in HD patients with severe SHPT is not associated with significant changes in parathyroid gland US patterns.

In the recent decades, oxidative stress has become focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence from research on several diseases show that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on this research, the emerging concept is that oxidative stress is the "final common pathway", through which risk factors of several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell-cell homeostasis. In this review, we discuss the role of oxidative stress in the pathogenesis of insulin resistance and beta-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes, and in the pathogenesis of diabetic vascular complications, the leading cause of death in diabetic patients.

Objective: Little is known about the demographic, clinical and laboratory variables which may be correlated with symptoms of depression and anxiety in hemodialysis (HD) patients. The present study aimed at evaluating such correlation in HD patients treated at a single HD center in a Mediterranean country., Methods: Eighty HD patients were assessed for depression and anxiety with the Beck Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale (HARS). The scores of BDI and HARS were correlated with demographic, clinical and laboratory variables., Results: Based on the Beck Depression Inventory, 38 patients had no symptoms of depression and 42 had symptoms of depression. Based on the HARS, three patients had no symptoms of anxiety and 38 had mild symptoms of anxiety, whereas moderate or severe symptoms of anxiety were present in 39 patients. In univariate analysis, BDI score correlated significantly with age, the Charlson Comorbidity Index, SF-36 Vitality Subscale, Mini-Mental Status Examination, creatinine, albumin, plasma 25-hydroxy vitamin D and interleukin-6 (IL-6) levels. HARS score correlated significantly with age, Charlson Comorbidity Index, SF-36 Vitality Subscale and parathyroid hormone (PTH) levels. In the multivariate analysis, a direct and an inverse correlation between BDI and IL-6 [P=.042, OR=1.31 (95% CI=1.01-1.71)] and creatinine [P=.050, OR=0.73 (95% CI=0.54-1.00)] was observed. With regard to HARS, only a direct correlation with Charlson Comorbidity Index [P<.001, OR=1.55 (95% CI=1.22-1.96)] was found., Conclusion: Although numerous demographic, clinical and laboratory variables correlated with BDI and HARS in univariate analysis, the multivariate regression analysis showed only a direct correlation between BDI and IL-6 [P=.042, OR=1.31 (95% CI=1.01-1.71)] and an inverse correlation between BDI and creatinine [P=.050, OR=0.73 (95% CI=0.54-1.00)] and a direct correlation between HARS and the Charlson Comorbidity Index [P<.001, OR=1.55 (95% CI=1.22-1.96)]., (Copyright 2010 Elsevier Inc. All rights reserved.)

The levothyroxine suppressive efficacy in benign thyroid nodules treatment is well described in uninodular non-toxic goiter, whereas only few controlled trials enrolled patients with multinodular disease. The aim of the present study is to evaluate the short term effects of levothyroxine treatment in never treated, pre-menopausal women affected by thyroid multinodular disease. Seventy-one pre-menopausal women with thyroid multinodular disease, still presenting normal TSH levels, from Latina area were randomly assigned to a levothyroxine treated or control group. Biochemical and ultrasonography evaluations of thyroid were monitored at the enrollment and after 6, 12 and 24 months of treatment. In the levothyroxine treated group, after 1 year of treatment, thyroid and dominant nodule volume and number of nodules >0.5 mL significantly decreased from a median of 12.0 to 9.8 mL (p <0.001), from 1.0 to 0.5 mL (p <0.001) and from 0.5 to 0, respectively. Conversely, in the control group significant augmented values of these parameters were observed (p =0.007, p <0.001 and p <0.001, respectively). Furthermore, these observations were also confirmed by results obtained after a 24 months follow-up period. Our data support previous observations on the clinical usefulness of L-T(4) treatment in preventing thyroid and nodule volume and nodule numbers growth. These findings confirm the tendency of benign nodular disease toward progression and the efficacy of TSH suppression in preventing its evolution by means of removing the major growth factor for thyroid nodules still responsive to physiological stimuli.

Aims: To explore the role of asymmetric-dimethyl-L-arginine (ADMA), an endogenous nitric oxide synthetases (NOS) inhibitor, and nitrite/nitrate (NOx) in the pathogenesis of oxidative stress in early stages of type 1 diabetes mellitus., Methods: We measured in 99 female subjects with uncomplicated type 1 diabetes (duration disease <10 years) and in 44 sex-matched controls (comparable for age, smoking habit, diet and physical activity) plasma levels of NOx, glycosylated haemoglobin (HbA1c), glucose, uric acid, total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides and serum ADMA., Results: Type 1 diabetic subjects have higher levels of glycemia, HbA1c, LDL cholesterol and NOx, but lower ADMA and serum uric acid (UA), compared with the control group; no further differences were found. A significant linear and inverse correlation was found between NOx and ADMA levels (R(2)=0.237, p<0.001)., Conclusions: This study suggests a reduced ADMA inhibition of NOS as possible mechanism involved in the pathogenesis of oxidative stress in female subjects with a short duration and uncomplicated type 1 diabetes.

Background and Objective: Several reports concerning the haemodynamic changes during gynaecologic laparoscopy have been published so far, and the effects of head-down tilt and pneumoperitoneum have not been clearly separated. However, its main effect seems to be an increase in systemic vascular resistance. We investigated how the augmented afterload can affect diastolic function., Methods: : Our study involved 20 healthy women, classified as having ASA status I: 10 undergoing laparoscopic hysterectomy and 10 undergoing conventional open hysterectomy. Measurements were made in awake patients and after induction of anaesthesia and then repeated after carbon dioxide insufflation and head-down positioning and at the end of surgery. Diastolic function was primarily studied by transthoracic echocardiography., Results: We observed that pneumoperitoneum caused a significant reduction in stroke volume, cardiac output and left ventricular end-diastolic volume; the diastolic filling times showed a progressive reduction in the E-velocity (the velocity of early mitral inflow, corresponding to the ventricular passive filling phase, measured by pulsed-wave Doppler), a prolonged deceleration time and an augmented isovolumetric relaxation time. After head-down tilting, stroke volume, cardiac output and left ventricular end-diastolic volume increased in both laparoscopic hysterectomy and conventional open hysterectomy groups., Conclusion: We have found that pneumoperitoneum has important effects on left ventricular volumes, causing a drop in left ventricular end-diastolic volume; it also affects diastolic function with a delay in deceleration time and isovolumetric relaxation time without any effects on intracavitary pressures.

Von Willebrand factor (VWF) is a multimeric glycoprotein present in circulating blood and in secretory granules of endothelial cells and platelets. VWF is sensitive to hydrodynamic shear stress that promotes conformational changes, rendering it able to interact with subendothelial proteins and platelets, thus promoting primary haemostasis. Likewise, the binding of the glycopeptide antibiotic ristocetin to VWF triggers hemostatically relevant conformational transitions. These changes reveal both the interaction site for platelet receptor GpIbalpha and the Tyr1605-Met1606 peptide bond, which is cleaved by the regulatory metalloprotease ADAMTS-13. In this study we investigated by a combined approach of light scattering spectroscopy and turbidimetry the ability of VWF to self-associate in solution in the presence of ristocetin and in the absence of any protein adsorbing surface. Micro- and macro-aggregates induced by ristocetin, have been characterized under static conditions in the early stage of formation and on a longer time scale (up to 10 h). These findings show that VWF multimers form supramolecular structures favoring platelet trapping not only under high shear stress or interaction with external surfaces, but also in solution under static conditions when the conformational state of the protein is changed only by chemical potential of allosteric effectors.

Background/aims: Prognostic scores currently used in cirrhotic patients do not include thrombotic risk factors (TRFs). Predicting factors of portal vein thrombosis (PVT) development are still unknown. We wanted to describe TRFs as a function of liver disease severity using the MELD score and assess the role of local and systemic TRFs as predictors of PVT development in cirrhotic patients., Methods: One hundred consecutive patients with liver cirrhosis were included in the study. TRFs, D-dimers, MELD score, portal vein patency and flow velocity were evaluated in all subjects at baseline and every 6 months thereafter. Variables able to predict PVT development within 1 year were identified by means of multiple logistic regression., Results: The plasma levels of protein C and antithrombin were lower and the concentration of D-dimers was higher in patients with advanced disease. Plasma levels of antithrombin, protein C and protein S resulted significantly lower in PVT group at univariate analysis, but reduced portal vein flow velocity was the only variable independently associated with PVT development., Conclusions: Lower concentrations of natural coagulation inhibitors are frequently detected in patients with liver cirrhosis. A reduced portal flow velocity seems to be the most important predictive variable for PVT development in patients with cirrhosis.

Objective: Charcot neuroarthropathy is a disabling complication of diabetes. Although its pathogenesis remains unknown, we suppose that genetics may play a relevant role., Research Design and Methods: We performed a case-control study with 59 subjects with diabetic Charcot neuroarthropathy (Ch group), 41 with diabetic neuropathy without Charcot neuroarthropathy (ND group), and 103 healthy control subjects (H group) to evaluate the impact of two single nucleotide polymorphisms (SNPs) of the osteoprotegerin gene (G1181C and T245G) on the risk of Charcot neuroarthropathy., Results: Regarding the SNPs of G1181C, we found a significant linkage between the G allele and Charcot neuroarthropathy (Ch vs. ND, odds ratio [OR] 2.32 [95% CI 1.3-4.1], P = 0.006; Ch vs. H, 2.10 [1.3-3.3], P = 0.002; and ND vs. H, 0.90 [0.7-1.9], P = 0.452); similarly, we found a linkage with the G allele of T245G (Ch vs. ND, 6.25 [2.2-19.7], P < 0.001; Ch vs. H, 3.56 [1.9-6.7], P = 0.001; and ND vs. H, 0.54 [0.6-5.7], P = 0.304), supporting a protective role for the allele C and T, respectively. For this reason we investigated the frequency of the protective double homozygosis CC + TT (7% in Ch) that was significantly lower in Ch compared with H (0.18 [0.06-0.5], P = 0.002) and with ND (0.17 [0.05-0.58], P = 0.006), whereas there was no difference between H and ND (1.05 [0.43-2.0], P = 0.468). In a multivariate logistic backward regression model, only weight and the lack of CC and TT genotypes were independently associated with the presence of Charcot neuroarthropathy., Conclusions: This is the first study that shows an association between genetic regulation of bone remodeling and Charcot neuroarthropathy.

Bilirubin-IX-alpha (BR) is an endogenous molecule with a strong antioxidant feature due to its ability to scavenge free radicals. In this paper, we demonstrated that BR, at concentrations close to those found within the cell (0.1-2.5 microM), acted as a denitrosylating agent and increased the release of nitric oxide from S-nitrosoglutathione (GSNO) and S-nitrosocysteine (SNOC) (2.5 microM). The complexation of BR with saturating concentrations of human serum albumin (HSA, 2.5 microM) did not further increase nitric oxide release from GSNO and SNOC. At concentrations similar to those reached in plasma (5-20 microM), BR denitrosylated S-nitroso-HSA (2.5 microM), the main circulating S-nitrosothiol, and this effect was potentiated by the complexation of BR with saturating HSA (20 microM). Furthermore, the product(s) of the reaction between nitric oxide and BR were identified. Ultraviolet and mass spectrometry analysis revealed that nitric oxide binds to BR forming a N-nitroso derivative (BR-nitric oxide) with extinction coefficients of 1.393 mM(-1)cm(-1) and 2.254 mM(-1)cm(-1) in methanol and NaOH, respectively. The formation of BR-nitric oxide did not occur only in a reconstituted system, but was confirmed in rat fibroblasts exposed to pro-oxidant stimuli. These results provided novel insights on the antioxidant characteristic of BR through its interaction with nitric oxide, a gaseous neurotransmitter with a well-known dual effect, namely neuroprotective under physiological conditions or neurotoxic if produced in excess, and proposed BR-nitric oxide as a new biomarker of oxidative/nitrosative stress.

Ultrasonography-guided fine needle aspiration (FNA) and fine needle non-aspiration (FNNA) biopsy were performed consecutively on 104 patients (mean age 50 +/- 15 years) affected by multinodular and uninodular goiter. Both techniques were executed on the same patients in the same clinical session beginning with the first (FNA) on half of the patients (randomly selected) and vice versa. The cytological findings on cell samples were divided into four groups: colloidal (benign), follicular (suspicious), malignant, and inadequate. The overall cytologic findings obtained with the two techniques were as follows (FNA % vs FNNA %): inadequate, 16.3% vs 5.8%; colloidal, 69.2% vs 76.9%; follicular, 9.6% vs 10.5%; and malignant, 4.8% vs 6.7%. A statistically significant difference between FNA and FNNA cytology was found only on the number of inadequate results (p = 0.015). Interestingly, the frequency of inadequate specimens for FNNA showed a significantly different distribution depending on the sequence (first or second) in which the technique was executed. In conclusion, FNA and FNNA are useful and cost-effective techniques for the pre-operative assessment of patients with thyroid nodules. However, due probably to its minimally invasive procedure, FNNA produces specimens of better quality and reduces inadequate results. For these reasons FNNA should be preferable to FNA for the cytological evaluation of thyroid nodules.

Objective: The aim of the study was to evaluate the effects of an intensive rehabilitation programme on thyroid metabolism, the relationship between disability and thyroid hormone level, and the occurrence of nonthyroidal illness syndrome (NTIS) before and after rehabilitation., Design, Subjects and Measurements: This was a clinical prospective study. Orthopaedic surgery patients (n = 82) were classified into two groups: patients in whom early active mobilization and walking were possible (walking group, WG, n = 45), and patients in whom these were not recommended (nonwalking group, NWG, n = 37). Levels of free T3 (fT3), fT4, TSH and rT3 were measured before and after surgery, and then at 1, 3, 7, 14 and 30 days from the beginning of rehabilitation. Personal, nutritional and clinical data were acquired for all patients. The Barthel Index (BI) was used to assess disability before and after rehabilitation., Results: Immediately after surgery, both groups of patients showed a significant decrease in mean fT3 concentrations and a significant increase in rT3; mean fT4 values decreased significantly only in NWG patients. Once rehabilitation had been completed, fT3 and rT3 levels returned to baseline values in WG patients. In NWG patients mean fT3 and fT4 levels continued to decrease significantly and rT3 values remained significantly high until the end of rehabilitation. NTIS occurred in 38% of the NWG patients. No significant changes in TSH levels were observed in either group. Finally, we observed a direct correlation between fT3 levels and the BI in WG patients., Conclusions: Our data suggest that early patient mobilization and physical activity during an active and intensive rehabilitation programme induce recovery of thyroid function and avoid occurrence of NTIS.

Inflammation is involved in the pathophysiologic process of atherosclerosis, a frequent complication of type 2 diabetes. The purpose of our study was to investigate the effect of pioglitazone on systemic inflammatory markers and activation of circulating monocytes in type 2 diabetic patients through the dosage of IL-6. Twenty-four metformin-treated patients, in good glycemic control, were randomized to add pioglitazone for 8 weeks or to continue their previous treatment. Blood samples were collected before and at the end of the study to evaluate: serum levels of high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6 and leukocyte activation. IL-6 production of circulating monocytes after LPS stimulation was similar at baseline and showed a 54% reduction in pioglitazone-group at 8 weeks (9.1 pg/mL, range 0.0-24.3, P=0.04 vs. baseline) while, in controls, did not change at 8 weeks (16.9 pg/mL, range 1.5-58.8). Treatment with pioglitazone, associated with metformin, showed a reduction of IL-6 monocyte production after their in vitro activation with LPS.

The main objective of this study is to assess the course of peroneal mononeuropathy (PM). The study design includes Clinical and Prospective study. The setting involves neurophysiological Service. From November 2002 to January 2004, we enroled 69 consecutive patients and prospectively followed up 49 patients with multiple measurements. Comparison was made between follow-up and baseline values, and baseline factors were used to predict the PM evolution in multiple regression analysis. At follow-up, we observed a significant improvement of all clinical, neurophysiological and disability measurements, and physical aspects of quality of life (QoL). Greater muscle strength of tibialis anterior and higher conduction velocity of peroneal nerve at baseline were seen to be positive prognostic factors. A better evolution of mental aspects of QoL was observed in the subacute group and in younger patients, while a better physical evolution in QoL was observed in women. Rehabilitation is ambiguously associated with a better Deambulation Index but lower ratings in mental aspects of QoL. In conclusion, PM shows a positive spontaneous course and rehabilitation seems to help the recovery of deambulation. Further studies on the effects of conventional rehabilitation are needed.

Objective: In this study, we evaluated the modifications of nasal function in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]) by active anterior rhinomanometry (AAR) to understand if involvement of the nasal nervous system and microcirculation could be detected in nasal mucosa., Method: We studied 35 nonsmoking IDDM patients without diabetic complications, nasal pathology, or septal deviation. We measured serum levels of nitric oxide (NO) and nasal airway in three conditions: basal, supine, and after decongestion (phenylephrine hydrochloride 0.25 mg spray) by means of rhinomanometry, determining inspiratory total resistance and nasal airflow. The rhinomanometric results of the IDDM patients were compared with those of control normal subjects. In the IDDM patients, neuropathy was evaluated according to standardized procedures, including the vibration perception threshold test, cardiovascular autonomic tests, conduction velocity test, and fundoscopic examination., Results: The NO serum level was significantly higher in IDDM patients (12.5 +/- 3.8) compared with normal controls (4.8 +/- 1.4). The AAR results showed that in IDDM patients, inspiratory total resistance in the basal (0.82 +/- 0.4 Pa/cm3) and supine (0.94 +/- 0.7 Pa/cm3) positions and after decongestion (0.59 +/- 0.2 Pa/cm3) were increased compared with the control group in three conditions (basal, 0.52 +/- 0.2 Pa/cm3; supine, 0.58 +/- 0.3 Pa/cm3; after decongestion, 0.48 +/- 0.2 Pa/cm3). After decongestion, there was a greater decrease in nasal resistance in diabetic patients than in normal subjects., Conclusion: Nasal function is involved in IDDM, rhinomanometry can also be considered an important test in the evaluation of this involvement in patients without other signs of diabetic neuropathy, and an increase in NO could partially explain these alterations.

The zinc-protease a disintegrin-like and metalloprotease with thrombospondin type I repeats (ADAMTS13) cleaves the Tyr(1605)-Met(1606) peptide bond of von Willebrand factor (VWF), avoiding the accumulation of ultra large VWF multimers. Hydrolysis by ADAMTS13 of a VWF analog (Asp(1596)-Arg(1668) peptide, fluorescence energy transfer substrate [FRETS]-VWF73) was investigated by a fluorescence quenching method (FRETS method) from 15 degrees C to 45 degrees C and pH values from 4.5 to 10.5. The catalysis was influenced by two ionizable groups, whose pK(a) values were equal to 6.41 +/- 0.08 (ionization enthalpy = 32.6 +/- 1.7 kJ/mol) and 4 +/- 0.1 (ionization enthalpy = 3.8 +/- 0.4 kJ/mol), whereas these values were equal to 6 +/- 0.1 and 4.1 +/- 0.1, respectively, in Co(2+)-substituted ADAMTS13. The catalytic process of FRETS-VWF73 hydrolysis showed negative activation entropy (-144 kJ/mol), suggesting that the transition state becomes more ordered than the ground state of the reactants. The k(cat)/K(m) values were not linearly correlated with temperature, as expression of change of the kinetic "stickiness" of the substrate. The Met(1606)-Arg(1668) peptide product acted as hyperbolic mixed-type inhibitor of FRETS-VWF73 hydrolysis. Asp(1653), Glu(1655), Glu(1660), Asp(1663), together with the hydrophilic side chain of Thr(1656) were shown to form a "hot spot" in the VWF A2 sequence, which drives the molecular recognition and allosteric regulation of binding to ADAMTS13. The interaction of the Met(1606)-Arg(1668) region of VWF with ADAMTS13 involves basic residues of the protease and is thus progressively inhibited at pH values >8.50. A molecular model of the FRETS-VWF73 showed that the substrate can fit into the active site only if ADAMTS13 assumes a C-like shape and, interacting with the acidic 1653-1668 region of VWF, properly orients the Tyr(1605)-Met(1606) peptide bond for the cleavage by the zinc-aquo complex in the active site.

Purpose: Usefulness of rapid intraoperative parathyroid hormone assay (RI-PTH) for diagnosis of multiglandular disease during parathyroidectomy is still debated., Materials and Methods: Two hundred seven patients were selected for focused parathyroidectomy for a suspicious single adenoma. RI-PTH results were interpreted on the basis of our criteria for prediction of multiglandular disease (a < 50% drop from the highest pre-excision level and/or a T20 concentration higher than reference range and/or >7.5 ng/L higher than the T10). The results of these criteria were compared with the Miami Criterion (MC)., Results: One hundred ninety-seven uniglandular disease and ten multiglandular disease were found. Our criteria identified all but one patient with multiglandular disease (false positive (FP) rate 0.5%; specificity 90%). On the basis of MC, RI-PTH monitoring would have resulted in five FP results, with a specificity of 50%., Conclusions: Despite the higher rate of unnecessary bilateral exploration, our criteria results in a lower FP, markedly reducing the risk of missing multiglandular disease.

Background: Aims of the present study were to examine the anthropometrical and metabolic characteristics of the Filipino population migrant to the Southern European city of Rome, Italy., Methods: A cross-sectional study was carried out in the city of Rome. Three hundred thirty-five Filipinos (95 M/240 F, mean age: 44.0+/-9.8 years, mean residence in Italy: 12.9+/-6.3 years) were studied. Data were collected by standardized questionnaires; anthropometrical parameters, arterial pressure, and fasting capillary blood glucose (FCG) were measured., Results: Abdominal obesity was found in 52.5%, and BMI >or= 25 kg/m(2) in 44.5% of subjects. History of type 2 diabetes mellitus (T2DM) and hypertension were reported by 6.0 and 9.0% of subjects, respectively. Impaired fasting glucose was found in 13.1%, and FCG >or= 110 mg/dl in 18.5% of subjects. Altered systolic and/or diastolic blood pressure was found in 34.3% of subjects. About three-fourths of subjects were unaware of being diabetic and/or hypertensive. Years of Italy residence showed a direct significant correlation with the degree of changes in alimentary behaviours (rho=0.18, p=0.001), and with weight gain (rho=0.27, p<0.001). Multivariate analysis showed only age and waist circumference to be associated with both diabetes and hypertension., Conclusions: In the present study, the first to examine the metabolic disorders in a migrant Filipino population resident in Rome, a high prevalence of obesity, diabetes, and hypertension was found. The alarming results emerging from this study should be seriously considered by public health practitioners and decision makers, and made known to the Filipinos resident in Europe.

Primary Objective: To evaluate the effects of rehabilitation on disability and quality of life (QoL) in patients with chronic stroke., Research Design: This is an observational, prospective and multidimensional study., Methods and Procedures: Sixty-six consecutive inpatients were enrolled. A rehabilitation programme of 2 months consisting of six exercise periods per week was performed. An impairment of cognitive function was the exclusion criteria for patient enrolment., Main Outcomes and Results: European Stroke Scale, Barthel Index, Modified Rankin Scale, Deambulation Index and SF-36 were performed both before and after rehabilitation. A short-term follow-up (2 months after discharge) was performed by phone administration of SF-36. Significant improvement in clinical and disability measurements was observed after rehabilitation. For QoL, a significant improvement was observed both in physical function and in social function immediately after rehabilitation. At follow-up the social function improvement was maintained, while physical function improvement was lost., Conclusions: The data show that rehabilitation in patients with chronic stroke lessens disability and improves physical and social function and that repeated cycles of treatment are needed to maintain the level of improvement reached.