Dynamical interactions reconfigure the gradient of cortical timescales.

The functional organization of the brain is usually presented with a back-to-front gradient of timescales, reflecting regional specialization with sensory areas (back) processing information faster than associative areas (front), which perform information integration. However, cognitive processes require not only local information processing but also coordinated activity across regions. Using magnetoencephalography recordings, we find that the functional connectivity at the edge level (between two regions) is also characterized by a back-to-front gradient of timescales following that of the regional gradient. Unexpectedly, we demonstrate a reverse front-to-back gradient when nonlocal interactions are prominent. Thus, the timescales are dynamic and can switch between back-to-front and front-to-back patterns.

Visuospatial working memory abilities in children analyzed by the bricks game task (BGT).

The study of the development of visuospatial memory processes is useful for devising personalized educational interventions as well as for understanding the changes in cognitive functioning in an era characterized by technological progress. The present research is aimed at investigating spatial working memory ability in children that attended the first three years of primary school by means of the Brick Game Task (BGT), a novel visuospatial working memory test. BGT is a small-scale ecological test inspired by behavioral walking tasks with nine white bricks in different spatial configurations as well as to Corsi Block-Tapping test.228 Italian children (121 F; mean age: 7.22 ± 1.18) were assigned to three groups based on the primary school class attended: Group 1 (N = 85; 40 F; mean age 6.18 ± .5), Group 2 (N = 61; 36 F; mean age 7.2 ± .83), and Group 3 (N = 82; 44 F; mean age 8.32 ± .94). All participants were asked to complete the Digit Span test, the Corsi Block-Tapping test, and to explore the three spatial configurations of the BGT with the form of Matrix, M-BGT, Cluster, CL-BGT, Cross, CR-BGT.MANOVA revealed a main significant effect for Group (F12,434 = 15.06; p < .0001) indicating that the group of older obtained a better global executive performance than 1 and 2 groups. Multiple linear regression indicated that Corsi Block-Tapping test performance and Age significantly predicted the M-BGT score. Moreover, Corsi Block-Tapping test and Digit Span significantly predicted the CL-BGT performance, showing how a higher score results in a better CL- BGT performance. Finally, Corsi Block-Tapping test, Digit Span, and Age were positively associated with the CR- BGT performance. The present findings evidenced that novel BGT is a sensible visuospatial working memory task suggesting thus its use to assess the children's executive performance in ecological way. These results open to the development of personalized educational interventions.

Whole-Brain Propagation Delays in Multiple Sclerosis, a Combined Tractography-Magnetoencephalography Study.

Two structurally connected brain regions are more likely to interact, with the lengths of the structural bundles, their widths, myelination, and the topology of the structural connectome influencing the timing of the interactions. We introduce an in vivo approach for measuring functional delays across the whole brain in humans (of either sex) using magneto/electroencephalography (MEG/EEG) and integrating them with the structural bundles. The resulting topochronic map of the functional delays/velocities shows that larger bundles have faster velocities. We estimated the topochronic map in multiple sclerosis patients, who have damaged myelin sheaths, and controls, demonstrating greater delays in patients across the network and that structurally lesioned tracts were slowed down more than unaffected ones. We provide a novel framework for estimating functional transmission delays in vivo at the single-subject and single-tract level.SIGNIFICANCE STATEMENT This article provides a straightforward way to estimate patient-specific delays and conduction velocities in the CNS, at the individual level, in healthy and diseased subjects. To do so, it uses a principled way to merge magnetoencephalography (MEG)/electroencephalography (EEG) and tractography.

Role of cytosolic calcium-dependent phospholipase A2 in Alzheimer's disease pathogenesis.

Phospholipases (PLA2s) are a superfamily of enzymes characterized by the ability to specifically hydrolyze the sn-2 ester bond of phospholipids generating arachidonic acid, utilized in inflammatory responses, and lysophospholipids involved in the control of cell membrane remodeling and fluidity. PLA2s have been so far considered a crucial element in the etiopathogenesis of several neurological diseases such as cerebral ischemia, multiple sclerosis, Parkinson's disease, and Alzheimer's disease (AD). In AD, the role of beta-amyloid (Aß) fragments is well established although still more elusive are the molecular events of the cascade that from the Aß accumulation leads to neurodegeneration with its clinical manifestations. However, it is well known that inflammation and alteration of lipid metabolism are common features of AD brains. Findings obtained from in vitro studies, animal models, and human brain imaging analysis point towards cPLA2 as a key molecule in the onset and maintenance of the neurodegenerative mechanism(s) of AD. In this review, we have focused on the molecular and biological evidence of the involvement of cPLA2s in the pathogenesis of AD. An insight into the molecular mechanism(s) underlying the action and the regulation of cPLA2 is of tremendous interest in the pharmaceutical and biotechnology industry in developing selective and potent inhibitors able to modulate the onset and/or the outcome of AD.

Frontal Behavioural Inventory in the differential diagnosis of dementia.

OBJECTIVE: To evaluate diagnostic properties of the Frontal Behavioural Inventory (FBI) in patients suffering from different forms of dementia. METHODS: The FBI was administered with other psychometric tests investigating cognitive performances and behavioral scales to the caregivers of 35 patients with the frontal variant of frontotemporal dementia (fv-FTD), 22 patients with Alzheimer's disease (AD) and 15 with vascular dementia (VaD). All patients were comparable for degree of dementia severity and level of executive impairment. RESULTS: The FBI showed high concurrent validity, internal consistency and good inter-rater and test-retest reliability. The discriminant validity was also very high. A new FBI cut-off score of 23 gave 97% sensitivity and 95% specificity in distinguishing fv-FTD from non-FTD patients. Conversely, the Neuropsychiatic Inventory (NPI) score was unable to differentiate fv-FTD from AD. CONCLUSIONS: The FBI is a neurobehavioral tool suitable to distinguish fv-FTD from other forms of dementia also when data from cognitive testing or other behavioral scales fail to support the differential diagnosis.

Diagnosis of benign and malignant portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma: color Doppler US, contrast-enhanced US, and fine-needle biopsy.

BACKGROUND: We assessed the role of contrast-enhanced ultrasound (CEUS) in the differential diagnosis between benign and malignant portal vein thrombosis in patients who had cirrhosis with hepatocellular carcinoma (HCC). METHODS: Fifty-four consecutive patients who had cirrhosis, biopsy-proved HCC, and thrombosis of the main portal vein and/or left/right portal vein on US were prospectively studied with color Doppler US (CDUS) and CEUS. CEUS was performed at low mechanical index after intravenous administration of a second-generation contrast agent (SonoVue, Bracco, Milan, Italy). Presence or absence of CDUS signals or thrombus enhancement on CEUS were considered diagnostic for malignant or benign portal vein thrombosis. Twenty-eight patients also underwent percutaneous portal vein fine-needle biopsy (FNB) under US guidance. All patients were followed-up bimonthly by CDUS. Shrinkage of the thrombus and/or recanalization of the vessels on CDUS during follow-up were considered definitive evidence of the benign nature of the thrombosis, whereas enlargement of the thrombus, disruption of the vessel wall, and parenchymal infiltration over follow-up were considered consistent with malignancy. CDUS, CEUS, and FNB results were compared with those at follow-up. RESULTS: Follow-up (4 to 21 months) showed signs of malignant thrombosis in 34 of 54 patients. FNB produced a true-positive result for malignancy in 19 of 25 patients, a false-negative result in six of 25 patients, and a true-negative result in three of three patients. CDUS was positive in seven of 54 patients. CEUS showed enhancement of the thrombus in 30 of 54 patients. No false-positive result was observed at CDUS, CEUS, and FNB. Sensitivities of CDUS, CEUS, and FNB in detecting malignant thrombi were 20%, 88%, and 76% respectively. Three patients showed negative CDUS and CEUS and positive FNB results; follow-up confirmed malignant thrombosis in these patients. One patient showed negative CDUS, CEUS, and FNB findings. However, follow-up of the thrombus showed US signs of malignancy. Another FNB confirmed HCC infiltration of the portal vein. CONCLUSION: CEUS seems to be the most sensitive and specific test for diagnosing malignant portal vein thrombosis in patients with cirrhosis.

Non-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in South Italy.

BACKGROUND/AIMS: In the absence of other causes, obesity increases the risk of liver disease. We evaluated the prevalence and degree of metabolic and hepatic abnormalities associated with non-alcoholic fatty liver disease (NAFLD) in type II-III obesity in a metropolitan area of South Italy. METHODS: 187 (81 M, 106 F) young adult non-diabetic obese patients, age range 18-50 years (mean 31.9 +/- 8.8), body mass index (BMI) > or =30 (mean 47.5 +/- 9.6), consecutively admitted from January 2000 to April 2003 to the Obesity Outpatients Clinic entered into the study. Patients were divided into two groups: (1) BMI 30.0-39.9, and (2) BMI> or =40. Ultrasound detected liver steatosis was classified as: (I) mild; (II) moderate, and (III) severe. RESULTS: All patients, except 4, showed a variable degree of steatosis: mild was more frequent among females, severe steatosis present only in grade III obesity, with higher prevalence in males than in females (p < 0.001). Mean serum transaminases, in particular alanine aminotransferase (ALT), increased according to BMI and degree of steatosis. Homeostasis Model Assessment (HOMA) index, ferritin and fibrinogen levels increased with BMI, particularly in severe steatosis. In group 2, patients with BMI> or =40 showed a positive correlation between ferritin, aspartate aminotransferase (AST) (r = 0.46, p < 0.018), ALT (r = 0.41, p < 0.036) and gamma-glutamyltransferase (gammaGT) (r = 0.51, p < 0.007), between serum triglycerides (TG) and AST (r = 0.28, p < 0.036), ALT (r = 0.30, p < 0.02) and between HOMA and ALT (r = 0.30, p < 0.03) and gammaGT (r = 0.35, p < 0.012). In group 2 patients with severe steatosis the prevalence of metabolic syndrome according to Adult Treatment Panel III (ATP III) was 40%. CONCLUSION: These data suggest that, in young adult non-diabetic grade III obese patients, fatty liver is always present and strictly related to insulin resistance which, in the presence of severe liver steatosis, is also related to serum ferritin.

A clinical-morphological study on cholestatic presentation of nonalcoholic fatty liver disease.

To determine the association among the clinical, biochemical, and histological features of cholestasis, we analyzed all the relevant data of the patients recorded in our non-alcoholic fatty liver disease (NAFLD) database. We selected 20 NAFLD patients with abnormal transaminase levels, with both alkaline phosphatase >500 U/L and gamma-glutamyl transpeptidase >250 U/L. Their histological features were compared with those of a group of patients with NAFLD matched for sex, age, and body mass index and of a group of patients matched for sex, body mass index and histological NAFLD grading/staging. Cases and controls satisfied, on histology, the criteria for NASH. The presence of cholestasis in our patients was correlated with injury of the bile duct epithelium, characterized by cholangitis, swelling, variable bile duct loss, and bile stasis. Compared to NAFLD patients of similar age, sex, and body mass index, the cholestatic group had total and severe histological liver impairment. When we analyzed the group of patients histologically identified on the basis of identical stage and grade severity, we could not find any evidence of significant bile damage, compared to cases, despite the control group's significantly older age. NAFLD patients with biochemical cholestasis have a histological picture of bile damage; they have more advanced histological impairment than patients matched for age, sex and body mass index.

Clinical presentation and prevalence of spontaneous bacterial peritonitis in patients with cryptogenic cirrhosis and features of metabolic syndrome.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) may progress to cirrhosis. The prevalence and clinical relevance that spontaneous bacterial peritonitis may have in complicating ascites due to NASH-related cirrhosis have yet to be defined. METHODS: Among 611 cases of cirrhosis-associated ascites, 45 patients with cryptogenic cirrhosis were retrospectively identified. Of these, 36 patients and a control group of subjects with viral- associated ascites were followed up and compared in a case control study. Information on the onset of ascites, with or without spontaneous bacterial peritonitis, history of risk factors for multimetabolic syndrome, and serological and ascitic laboratory data were compared between groups. RESULTS: Spontaneous bacterial peritonitis occurred significantly more often in patients with cryptogenic cirrhosis than in equally symptomatic viral controls. The prevalence of obesity, diabetes and spontaneous bacterial peritonitis was significantly higher in patients with cryptogenic cirrhosis. Although liver function was similar in both groups, cryptogenic cirrhosis patients had lower aminotransferase levels. Multivariate analysis identified diabetes, juvenile obesity and spontaneous bacterial peritonitis as independent factors associated with ascites due to cryptogenic cirrhosis. CONCLUSIONS: Features suggestive of NASH are more frequently observed in patients with ascites and cryptogenic cirrhosis than in age- and sex-matched ascitic patients with well-defined viral etiology. Ascites may be a presenting symptom of NASH-related cirrhosis, and affected patients have a twofold greater risk of spontaneous bacterial peritonitis.

[How to prevent saphenous nerve injury. A personal modified technique for the stripping of the long saphenous vein]. / Come prevenire le lesioni del nervo safeno. Una tecnica personale modificata per lo stripping della grande safena.

BACKGROUND: In literature the incidence of paresthesia caused by long stripping (LS) of the saphenous vein (SV) varies widely. Best results have been reported with the invagination technique by Van Der Stricht. However, this technique is associated with a high incidence of vein rupture and incomplete stripping. The aim of this study is to test a personal technique to avoid the SV rupture and to reduce the incidence of saphenous nerve injury. METHODS: Sixty-eight patients underwent LS of the SV from groin to ankle under monolateral spinal anesthesia on a one-day surgery basis using a personal technique combining external and invaginated saphenous stripping. All patients underwent a clinical re-evalutation 1, 3, 6, 12, 24 and 48 months after the operation. RESULTS: No intraoperative complications were recorded. Stripping of the long saphenous vein was complete in all cases without any rupture of the veins. Only one postoperative hematoma of the leg (1.5%) which was naturally reabsorbed, was recorded; four patients (5.9%) had transitory saphenous nerve injury. Permanent saphenous nerve damage was found in only one of 68 patients (1.5%). All the patients were discharged on the day of operation and we did not register any prolonged hospitalization. CONCLUSIONS: The result of our approach was a very low postoperative complication rate (1.5% of permanent neurological damage) without any rupture of the vein.

Low daily dosage of interferon for 1 year after HCV-related end-therapy response. A randomized-controlled study.

This randomized controlled study involved 236 1b genotype (121 males) naive patients with chronic hepatitis C. After a course of interferon (IFN)-alpha2b plus ribavirin for 6 or 12 months, 117 (49.5%) of the end-therapy responders were equally divided into two groups and were assigned to receive either low daily doses of IFN-alpha2b (1.5 MU) 'consolidation therapy' (59 patients) for 1 year or no further treatment (58 patients). At the end of the follow-up period (6 months), the number of sustained responders in the consolidation group (83%) was significantly higher than in the control group (37.9%). The predicting factors of both end-therapy response and sustained response were the classic ones and a lower GGT/ALT ratio (GGT: gamma-glutamyl transpeptidase; ALT: alanine aminotransferase). The strongest predictors of sustained response alone were consolidation therapy and the longer period on combined treatment (12 vs 6 months). Consolidation therapy was better tolerated than the previously prescribed combined therapy in terms of side effects. In conclusion, genotype 1b naive end-therapy responders to usual combined therapy, after a period of daily consolidation therapy with a low dosage of IFN without ribavirin, achieved a better rate of sustained response than the control group.

Influence of age and menopausal status on pathologic and biologic features of breast cancer.

The distribution of the main prognostic factors in different age groups was evaluated in 1226 patients operated on for primary breast cancer, in order to identify those influenced by age and/or menopausal status. Patients were divided into the following groups: 1) 40 years of age and under; 2) premenopausal over 40 years of age; 3) postmenopausal under 75 years of age and 4) 75 years of age and over. Our findings showed that the youngest patients had the worst prognostic pattern, which improves as age increases and is the best in patients over 75 years of age. Some of the parameters investigated (tumour size, histologic and nuclear grade, tumour infiltrating lymphocytes, p53 and Ki 67) were found to be influenced by age, some (necrosis and oestrogen receptors) were influenced by menopausal status and/or age, some (vascular invasion, ploidy, S-phase and progesterone receptors) showed significant differences in different age groups but there was no consistent relation with patient age or menopausal status, and others (node status, ErbB2/Neu and Cathepsin D) were not influenced by age or menopause.

[Blood tumor markers in patients with lung cancer]. / Marcatori tumorali sierici in pazienti con cancro del polmone.

Over the past years, a number of serum components have been confirmed as useful biological markers of lung cancer. Although none have been sensitive or specific enough to enable early diagnosis, they do seem to facilitate the monitoring and prediction of disease prognosis. We studied tumor markers in 66 patients with lung cancer: serum levels of ferritin, carcinoembryonic antigen (CEA), alpha-fetoprotein (alpha-FP); tissue polypeptide antigen (TPA), cytocheratin fragment 19, 21-1 (CYFRA 21-1) and carbohydrate antigen 125 (CA 125) levels were measured and correlated to tumor stage and histological type. Postulating a specificity of 95% versus benign diseases of the lung, we confirmed the following diagnostic sensitivity for the markers: ferritin = 39.3%; CEA = 42.4%; alpha-FP = 5.1%; TPA = 57.5%; CYFRA 21-1 = 65.1%; CA 125 = 46.9%. CYFRA 21-1 showed significantly higher sensitivity in non small cell lung cancer patients than in those with small cell lung cancer (Wilcoxon, p = 0.02). Moreover since survival time was significantly shorter in patients with high serum CYFRA 21-1, these levels seemed to be correlated with the prognosis.

Outpatient surgery of varices of the lower limbs: experience of 2,568 cases at four universities.

Outpatient surgery of varices of the lower limbs is currently considered a viable alternative to traditional surgery with hospitalization. This paper reports the experience of 4 university groups (Padua, Modena, Verona, Milan), where outpatient treatment has been used since 1987. From June 1987 to June 1992, 2,568 lower limb varices were treated in this way. Different techniques of anaesthesia were used (local infiltration, combined local and general, general, subarachnoid). In all cases, crossectomy was combined with short or long saphenous stripping. There were no intra- or perioperative deaths, and only limited morbidity. Postoperative hospitalization was required in only 2 cases: for hemorrhaging of the inguinal wound in one case, and headache 2 days after spinal anaesthesia in the other. In 2 separate samples of 100 patients, 88 and 89 indicated satisfaction with the surgical treatment. In conclusion, outpatient surgery of varices can be based on the same techniques as in-patients treatment. The risks of surgery and anaesthesia in specialised centres are very limited, with scope for a variety of anaesthetic techniques according to facilities available. Patients satisfaction is high.

[Echo-sclerotherapy in the management of varices of the lower extremities]. / La sclerosi ecoguidata nel trattamento delle varici degli arti inferiori.

Sclerotherapy has been used with satisfactory results, for several years in the treatment of varicose veins. Nevertheless sometimes sclerosis can be incomplete because of the morphology of lower limbs or because the varicose disease is not clinically evident. In addition, sclerotherapy can give rise to severe complications due to intrarterial or extraluminal injections. In order to exceed this limits, some authors suggested to use a new technique, the echosclerotherapy, which was presented for the first time in Strasburg 1989 by Knight and Vin. Echosclerotherapy is a good help for traditional sclerotherapy, especially when it is applied in the sclerosis of the short saphenous veins, of perforating veins or in unfavourable anatomical situations. From May to November 1993 at the Second Surgical Department of Padua University, 31 patients, 29 women and 3 men, have been treated by echosclerotherapy. 25 patients had great saphenous varicose veins; 3 patients had varices due to perforating veins of the popliteal fossa and 3 patients varices due to Hunter perforating veins. In 48.4% of cases we obtained a complete sclerosis of the vessel; in 38.7% a stump remained near the sapheno-femoral junction of about two centimeters; in one case the treatment was not completed and in one case remained a stump of ten centimeters. Only in two cases Echosclerotherapy was not able to obtain sclerosis. None of the patients had major complications and nobody had deep vein thrombosis. If we consider our results altogether we can say that in 87% of cases we had good results.(ABSTRACT TRUNCATED AT 250 WORDS)

Steady state pharmacokinetics of idebenone in patients with moderate hepatic impairment.

The kinetics of idebenone (45 mg twice daily p.o.) in 6 Caucasian chronic hepatopathic patients without portal hypertension were studied. The pharmacokinetic parameters were evaluated both for single (day 1) and multiple (day 10) administrations. These 6 patients showed a first order bi-compartimental kinetic curve for idebenone and for its metabolites, superimposable on the curves obtained from healthy volunteers. The C(max) parameters, tmax and bioavailability confirm the absence of accumulation. On day 12, 48 h after the last administration (performed on day 10), there was no evidence of residual drug. One of these patients was being treated with diuretics (chlorthalidone) and with perfusion fluids, including 5% glucose, and no interference was shown between the two drugs. There is no evidence of any particular side effect or alteration of the haematochemical parameters that could be thought to be drug related. This study confirms that idebenone at the dose of 90 mg/day p.o. administered to hepatopathic patients does not cause accumulation or toxicity.

Steady-state pharmacokinetics of idebenone in patients with moderate renal impairment.

Idebenone (45 mg twice daily) was administered to 7 patients with moderate renal impairment (creatinine clearance 21-40 ml/min) for 10 days. Standard pharmacokinetic parameters were computed on day 1 (single administration) and on day 10. On day 1 the mean of the maximum plasma concentration values (C(max)) was 364 ng/ml (standard deviation (S.D.) 100); time to C(max) (t(max)) was in the range of 1-2 h for 6 patients and 12 h for the remaining patient: the mean was 3 h (S.D. 3.99); the mean area under the plasma concentration vs. time curve (AUC) was 3005 ng h/ml (S.D. 1152). On day 10 the mean C(max) was 531 ng/ml (S.D. 355.3), the mean t(max) was 0.07 h (S.D. 0.19), the mean AUC was 3167 ng/ml (S.D. 2944) and the mean elimination half-life (t(1/2)) was 4.9 h (S.D. 1.1). Idebenone metabolites (QS-4, QS-6 and QS-10) showed a kinetic profile similar to the parent compound, with pharmacokinetic parameters comparable to idebenone for QS-4 and lower than idebenone for QS-6 and QS-10. Idebenone was metabolized and easily excreted and no accumulation was observed for the compound and its metabolites. No significant modification of the biohumoral indexes and vital signs and no adverse reactions were observed.