Anatomic Versus Non-anatomic Liver Resection for Intrahepatic Cholangiocarcinoma: A Systematic Review and Patient-Level Meta-Analysis.

BACKGROUND: The current standard treatment for intrahepatic cholangiocarcinoma (ICC) involves complete liver resection with negative surgical margins and lymphadenectomy, followed by adjuvant chemotherapy. Debate is ongoing regarding the necessity of systematic anatomic resection (AR). This study aimed to summarize existing literature to determine whether AR leads to better oncologic outcomes than non-AR for patients with resectable ICC. METHODS: A systematic literature review (PubMed, Embase, and Google Scholar) was performed until December 2023. Only studies comparing the oncologic outcomes of AR and non-AR for ICC using propensity score matching or inverse probability of treatment weighting were considered. A meta-analysis of aggregated data for perioperative variables and a reconstructed patient-level meta-analysis for survival data were performed. RESULTS: Five articles were gathered (n = 930 patients after matching: 465 AR/465 non-AR patients). The overall survival (OS) rates were higher in the AR group than in the non-AR group at 1, 3, and 5 years (71.5%, 46.1% and 34.3% vs. 63.6%, 32.9%, and 24.8%, respectively; hazard ratio [HR] 0.74; 95% CI 0.63-0.87; P < 0.001). The same results were observed for the disease-free survival (DFS) rates (58.3%, 33.4%, and 24.5% for AR vs. 45.6%, 23.1%, and 17.4% for non-AR; HR 0.74; 95% CI 0.63-0.86; P < 0.001). The results were confirmed in the two-stage meta-analysis for OS (HR 0.73; P < 0.001) and DFS (HR 0.73; P < 0.001). No differences were observed between the two approaches in terms of operative time, intraoperative blood loss, overall and major morbidity, and hospital length of stay. CONCLUSIONS: By pooling the available evidence, the current study demonstrated that AR for ICC patients is associated with better OS and DFS without any negative impact on postoperative outcomes.

Influence of stimuli emotional features and typicality on memory performance: insights from a virtual reality context.

The present study tested the influence of stimuli emotional valence, emotional arousal, and typicality on memory recollection in three groups of participants exposed to the same environment through different modalities: in vivo exposure (i.e., real-life), 3D virtual reality (i.e., VR), and 2D pictures. Context-related free-recall, recognition accuracy, and recognition confidence were analyzed. The results showed that memory performance was best in the real-life modality, and participants in the VR and 2D pictures modalities performed comparably. Interesting effects of stimuli emotional valence and typicality emerged: in the VR and 2D pictures modalities, positive items were better recalled than negative items; typicality was relevant only in the real-life modality, with less common objects within the explored setting (i.e., an office) recalled more often. Furthermore, recognition accuracy and confidence were significantly higher in the real-life modality than in the VR and 2D pictures modalities. Further research is needed to support the creation of VR environments that are sufficiently comparable to real-life contexts in order to obtain higher ecological validity in studies of cognitive performance. In particular, the impact of stimuli typicality and emotional valence in VR contexts should be investigated to gain insight into how these features might improve memory recall in virtual scenarios.

Assessing teratogenic risks of gadolinium in freshwater environments: Implications for environmental health.

Gadolinium (Gd) is among the rare earth elements extensively utilized in both industrial and medical applications. The latter application appears to contribute to the rise in Gd levels in aquatic ecosystems, as it is excreted via urine from patients undergoing MRI scans and often not captured by wastewater treatment systems. The potential environmental and biological hazards posed by gadolinium exposure are still under investigation. This study aimed to assess the teratogenic risk posed by a gadolinium chelate on the freshwater cnidarian Hydra vulgaris. The experimental design evaluated the impact of pure Gadodiamide (25 µg/l, 50 µg/l, 100 µg/l, 500 µg/l) and its commercial counterpart compound (Omniscan®; 100 µg/l, 500 µg/l, 782.7 mg/l) at varying concentrations using the Teratogenic Risk Index (TRI). Here we showed a moderate risk (Class III of TRI) following exposure to both tested formulations at concentrations ≥ 100 µg/l. Given the potential for similar concentrations in aquatic environments, particularly near wastewater discharge points, a teratogenic risk assessment using the Hydra regeneration assay was conducted on environmental samples collected from three rivers (Tiber, Almone, and Sacco) in Central Italy. Additionally, chemical analysis of field samples was performed using ICP-MS. Analysis of freshwater samples revealed low Gd concentrations (≤ 0.1 µg/l), despite localized increases near domestic and/or industrial wastewater discharge sites. Although teratogenic risk in environmental samples ranged from high (Class IV of TRI) to negligible (Class I of TRI), the low Gd concentrations, particularly when compared to higher levels of other contaminants like arsenic and heavy metals, preclude establishing a direct cause-effect relationship between Gd and observed teratogenic risks in environmental samples. Nevertheless, the teratogenic risks observed in laboratory tests warrant further investigation.

External validation of scores predicting postoperative fistula after pancreatogastrostomy for pancreatoduodenectomy reconstruction. A single center experience.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) is the most frequent complication of pancreatic surgery and can be fatal. Selection and stratification of patients according to the risk of POPF are important for the perioperative management. Predictive metrics have been developed and validated in pancreatojejunostomy. Aim of this study is to assess whether the most used prognostic scores can be predictive of fistula following Wirsung-pancreaticogastrostomy (WPG) for pancreatoduodenectomy (PD)reconstruction. METHOD: This single-center prospective observational study included 212 PDs between January 2008 and October 2022 with a standardized WPG. All component variables of the six scores were separately validated in our cohort. The overall predictive ability of the six fistula scores was measured and compared with the receiver operating characteristics curves (ROC) method and expressed by the area under the ROC-curve (AUC). Univariate and multivariate logistic regression analyses were performed considering all risk factors in the scores in order to identify variables independently correlated with POPF in the WPG. RESULTS: CR-POPF occurred in 36 of 212 (17 %) patients. All scores showed poor prognostic stratification for the development of CR-POPF. The occurrence of CR-POPF was associated with nine factors: male gender (p = 0.003); BMI (kg/m2) (p = 0.005); ASA (%) (p = 0.003); Soft pancreatic texture (%) (p = 0.003), Pathology (p = 0.008); MPD (p = 0.011); EBL (mL) (p = 0.021); Preop. Bilirubin (mg/dl) (p = 0.038); Preop. Glucose (mg/dl) (p = 0.0369). Male gender (OR: 5.54, CI 1.41-21.3) and soft consistency of the remnant pancreas (OR: 3.83, CI 1.14-12.8) were the only independent prognostic factors on multivariate analysis. CONCLUSIONS: Our study including exclusively pancreatogastrostomies failed to validate the most used predictive scores for POPF. We found that only male gender and soft pancreatic texture are associated with POPF. Specific predictive scores following pancreatogasgtrostomy are needed.

Iron Saturation Drives Lactoferrin Effects on Oxidative Stress and Neurotoxicity Induced by HIV-1 Tat.

The Trans-Activator of Transcription (Tat) of Human Immunodeficiency Virus (HIV-1) is involved in virus replication and infection and can promote oxidative stress in human astroglial cells. In response, host cells activate transcription of antioxidant genes, including a subunit of System Xc- cystine/glutamate antiporter which, in turn, can trigger glutamate-mediated excitotoxicity. Here, we present data on the efficacy of bovine Lactoferrin (bLf), both in its native (Nat-bLf) and iron-saturated (Holo-bLf) forms, in counteracting oxidative stress in U373 human astroglial cells constitutively expressing the viral protein (U373-Tat). Our results show that, dependent on iron saturation, both Nat-bLf and Holo-bLf can boost host antioxidant response by up-regulating System Xc- and the cell iron exporter Ferroportin via the Nuclear factor erythroid 2-related factor (Nrf2) pathway, thus reducing Reactive Oxygen Species (ROS)-mediated lipid peroxidation and DNA damage in astrocytes. In U373-Tat cells, both forms of bLf restore the physiological internalization of Transferrin (Tf) Receptor 1, the molecular gate for Tf-bound iron uptake. The involvement of astrocytic antioxidant response in Tat-mediated neurotoxicity was evaluated in co-cultures of U373-Tat with human neuronal SH-SY5Y cells. The results show that the Holo-bLf exacerbates Tat-induced excitotoxicity on SH-SY5Y, which is directly dependent on System-Xc- upregulation, thus highlighting the mechanistic role of iron in the biological activities of the glycoprotein.

Laparoscopic Left Hepatectomy for Hepatocellular Carcinoma Recurrence Following Liver Transplantation.

BACKGROUND: Despite the successful oncological results of liver transplantation, patients with hepatocellular carcinoma (HCC) can develop tumor recurrence. When technically feasible, liver resection represents the preferred treatment for recurrent HCC, even in the setting of transplanted patients. Recent progresses in minimally invasive liver resections have pushed the surgical community to attempt more challenging cases. We report a full laparoscopic left hepatectomy for HCC recurrence on transplanted liver. METHODS: A routine follow-up computed tomography (CT) scan of a 53-year-old male who previously underwent an orthotopic liver transplantation for alcoholic-related liver disease showed a 3 cm HCC in segment 4 in close relationship with the peripheral portion of the left portal pedicle. A full laparoscopic left hepatectomy was performed using an extrahepatic intraglissonean approach. RESULTS: Operative time was 332 min and blood loss was 100 mL. The patient had an uneventful postoperative recovery and was discharged home after 3 days. CONCLUSIONS: Laparoscopic liver resection on transplanted patients is feasible. Challenging clinical scenarios should only be attempted in referral centers and after an appropriate learning curve.1-8.

Detecting faking-good response style in personality questionnaires with four choice alternatives.

Deliberate attempts to portray oneself in an unrealistic manner are commonly encountered in the administration of personality questionnaires. The main aim of the present study was to explore whether mouse tracking temporal indicators and machine learning models could improve the detection of subjects implementing a faking-good response style when answering personality inventories with four choice alternatives, with and without time pressure. A total of 120 volunteers were randomly assigned to one of four experimental groups and asked to respond to the Virtuous Responding (VR) validity scale of the PPI-R and the Positive Impression Management (PIM) validity scale of the PAI via a computer mouse. A mixed design was implemented, and predictive models were calculated. The results showed that, on the PIM scale, faking-good participants were significantly slower in responding than honest respondents. Relative to VR items, PIM items are shorter in length and feature no negations. Accordingly, the PIM scale was found to be more sensitive in distinguishing between honest and faking-good respondents, demonstrating high classification accuracy (80-83%).

An integrated approach for chemical water quality assessment of an urban river stretch through Effect-Based Methods and emerging pollutants analysis with a focus on genotoxicity.

The impact of emerging chemical pollutants, on both status and functionality of aquatic ecosystems is worldwide recognized as a relevant issue of concern that should be assessed and managed by researchers, policymakers, and all relevant stakeholders. In Europe, the Reach Regulation has registered more than 100.000 chemical substances daily released in the environment. Furthermore, the effects related to the mixture of substances present in aquatic ecosystems may not be predictable on the basis of chemical analyses alone. This evidence, coupled with the dramatic effects of climate changes on water resources through water scarcity and flooding, makes urgent the application of innovative, fast and reliable monitoring methods. In this context, Effect-Based Methods (EBMs) have been applied in the urban stretch of the Tiber River (Central Italy) with the aim of understanding if detrimental pressures affect aquatic environmental health. In particular, different eco-genotoxicological assays have been used in order to detect genotoxic activity of chemicals present in the river, concurrently characterized by chemical analysis. Teratogenicity and embryo-toxicity have been studied in order to cover additional endpoints. The EBMs have highlighted the presence of diffuse chemical pollution and ecotoxicological effects in the three sampling stations, genotoxicological effects have been also detected through the use of different tests and organisms. The chemical analyses confirmed that in the aquatic ecosystems there is a diffuse presence, even at low concentrations, of emerging contaminants such as pharmaceuticals, not routinely monitored pesticides, personal care products, PFAS. The results of this study can help to identify an appropriate battery of EBMs for future studies and the application of more appropriate measures in order to monitor, mitigate or eliminate chemical contamination and remediate its adverse/detrimental effects on the ecosystem health.

Liver transplantation for sickle cell disease: a systematic review.

BACKGROUND: Sickle cell disease is a group of autosomal recessive disorders characterised by haemolytic anaemia. Liver is one of the most affected organs, ranging from liver tests alterations to acute liver failure for which liver transplantation is the only life-saving treatment. METHODS: This study aims to make a systematic review of the current literature to evaluate indications, timing, and results of liver transplantation for patients affected by SCD. RESULTS: Twenty-nine patients in total were reported worldwide until 2018, the average patient age is 28.7 (0.42-56), all patients have a pre-transplant diagnosis of SCD. Cirrhosis at transplantation was present in six-teen (n = 16, 55.1%) patients. In ten patients (n = 10, 34.5%), acute liver failure arises from healthy liver and presented sickle cell intrahepatic cholestasis. Eleven patients (n = 11, 39.2%) died, three (n = 3, 10.7%) in the first postoperative month, and seven (n = 7, 25%) in the first year. Mean follow-up was 27 months (range: 7-96), one-year overall survival was 48.7%. DISCUSSION: Liver transplantation for SCD has been increasingly reported with encouraging results. Indications are presently reserved for acute liver failure arising both in healthy liver and end-stage liver disease.

The Role of Salvage Transplantation in Patients Initially Treated With Open Versus Minimally Invasive Liver Surgery: An Intention-to-Treat Analysis.

Despite gaining wide consensus in the management of hepatocellular carcinoma (HCC), minimally invasive liver surgery (MILS) has been poorly investigated for its role in the setting of salvage liver transplantation (SLT). A multicenter retrospective analysis was carried out in 6 Italian centers on 211 patients with HCC who were initially resected with open (n = 167) versus MILS (n = 44) and eventually wait-listed for SLT. The secondary endpoint was identification of risk factors for posttransplant death and tumor recurrence. The enrolled patients included 211 HCC patients resected with open surgery (n = 167) versus MILS (n = 44) and wait-listed for SLT between January 2007 and December 2017. We analyzed the intention-to-treat survival of these patients. MILS was the most important protective factor for the composite risk of delisting, posttransplant patient death, and HCC recurrence (OR, 0.26; 95% confidence interval [CI], 0.11-0.63; P = 0.003). MILS was also the only independent protective factor for the risk of post-SLT patient death (OR, 0.29; 95% CI, 0.09-0.93; P = 0.04). After propensity score matching, MILS was the only independent protective factor against the risk of delisting, posttransplant death, and HCC recurrence (OR, 0.22; 95% CI, 0.07-0.75; P = 0.02). On the basis of the current analysis, MILS seems protective over open surgery for the risk of delisting, posttransplant patient death, and tumor recurrence. Larger prospective studies balancing liver function and tumor stage are strongly favored to better clarify the beneficial effect of MILS for HCC patients eventually referred to SLT.

Validation of the AFP model as a predictor of HCC recurrence in patients with viral hepatitis-related cirrhosis who had received a liver transplant for HCC.

BACKGROUND & AIMS: The AFP model was shown to be superior to the Milan criteria for predicting hepatocellular carcinoma (HCC) recurrence after liver transplantation in a French population. Our aim was to test the AFP model in a non-French, post-hepatitic cirrhosis-based population of HCC candidates. METHODS: 574 patients transplanted for HCC in four Italian centers were studied. AFP score was assessed at the last evaluation before liver transplantation (LT). Probabilities of recurrence and survival were estimated by the log-rank test or competing risk analysis and compared according to the AFP model. RESULTS: 24.7% patients were beyond Milan criteria. HCC complicated hepatitis C virus (HCV) and hepatitis B virus (HBV) cirrhosis in 58.7% and 24% of the cases, respectively. Five-year probabilities of recurrence differed according to AFP score ⩽2 vs. >2 in the whole population (13.2±1.8% vs. 49.8±8.7%, p<0.001, HR=4.98), in patients within Milan criteria (12.8±2.0% vs. 32.4±12.1%, p=0.009, HR=3.51), beyond Milan criteria (14.9±4.2% vs. 58.9±11.5%, p<0.001, HR=4.26), HCV patients (14.9±2.5% vs. 67.6±14.7%, p<0.001, HR=6.56) and HBV patients (11.6±3.4% vs. 34.3±12.5%, p=0.012, HR=3.49). By net reclassification improvement analysis AFP score significantly improved prediction of non-recurrence compared to Milan criteria. Overall five-year survival rates according to AFP score ⩽2 or >2 were 71.7±2.2% vs. 42.2±8.3% (p<0.001, HR=2.14). CONCLUSIONS: The AFP model identifies HCC candidates at low risk of recurrence, otherwise excluded by Milan criteria in a population with a predominance of post-hepatitic-related HCC. The AFP score can be proposed for selection of HCC candidates in programs with a high proportion of viral/HCV-related cirrhosis. LAY SUMMARY: Selection criteria for liver transplantation of patients affected with hepatocellular carcinoma (HCC) are based on the Milan criteria, which have been shown to be too restrictive, precluding access to liver transplantation for some patients who might be cured by this operation. Recently, a French group of researchers developed a new selection model called the AFP model, or AFP score, allowing some patients with HCC not meeting Milan criteria to be transplanted with excellent results. In the present work, the AFP score was tested in a population of non-French patients transplanted for HCC occurring mainly on post-hepatitic (HCV or HBV) cirrhosis. The results confirm that in this specific population, as in the original French population of patients, the AFP model better selects patients with HCC eligible for transplantation, compared to Milan criteria. We conclude that the AFP score, which has been officially adopted by the French organization for Organ Sharing for HCC patients, can also be implemented in countries with an important burden of HCC occurring on post-hepatitic cirrhosis.

Yttrium-90 Radioembolization for Hepatocellular Carcinoma Prior to Liver Transplantation.

BACKGROUND: Liver transplantation (LT) is a well-established procedure for hepatocellular carcinoma (HCC) within the Milan criteria. Yttrium-90 microspheres radioembolization (Y90-RE) has shown to be an effective and safe treatment of primary liver tumors. We retrospectively evaluate the efficacy of the Y90-RE in patients with HCC prior to LT. METHODS: From January 2002 to December 2015, 365 patients were transplanted at the San Camillo Hospital Center. One hundred forty-three patients were transplanted for HCC, and in 22 cases the patients were treated with Y90-RE before LT. RESULTS: Three patients were treated with Y90-RE within the Milan criteria, and 19 patients were out of criteria before Y90-RE. Four patients had an increasing MELD score between Y90-RE and LT. On the other hand, alpha-fetoprotein decreases after Y90-RE treatment in all cases. No patient death was observed in Y90-RE procedure or at LT. In 78.9 % of cases, a successful downstaging was observed, and in 100 % of cases bridging was achieved. From Y90-RE treatment overall survival was 43.9 months. From LT, overall mean survival was 30.2 months with a free survival of 29.6 months. The overall survival after LT analysis between the patients treated with Y90-RE and patients without was not significant (p = 0.113). Free survival analysis was not significant (p = 0.897) between the two populations. CONCLUSIONS: We successfully performed LT in patients after Y90-RE treatment both as bridging and downstaging for HCC and obtained a similar overall and free survival of LT for HCC within Milan criteria. Y90-RE becomes a real option to provide curative therapy for patients who traditionally are not considered eligible for surgery.

The Hydra regeneration assay reveals ecological risks in running waters: a new proposal to detect environmental teratogenic threats.

The regenerative ability of Hydra vulgaris was tested as potential biomarker for the development of a new eco-toxicological index. The test is based on the regeneration rate and the aberration frequency of the columna (body and adhesive foot) after separation from head and tentacles by a bistoury. Particularly, 45 columnae were submerged in the rearing solution (that is Hydra medium) to have control, and 285 in potential contaminated waters to have treatments, collected from 19 sites along 10 rivers in central Italy. ANCOVA and chi-square tests were used to compare values from each site to a laboratory control. Subsequently the values on regeneration rate and aberration frequency were inserted in a double entry matrix, where the match of the two entries in the matrix provides the score of the proposed Teratogenic Risk Index (TRI). Each score corresponded to one of the 5 teratogenic risk classes, to which a risk level was associated: from 1 (no risk) to 5 (very high risk). On the whole, 32% of the studied sites were classified as no teratogenic risk while the remaining showed a variable risk level from low to very high. This study proposed for the first time an early warning system to detect the presence of teratogens in running waters, providing a rapid and cost-effective evaluation method. Therefore, TRI may contribute to initiate adequate measures to manage riverine habitats, and to monitor the running water teratogenic status. Specifically, this index may provide the opportunity to identify the disturbance sources and then to drive the decisions, together with competent authorities, on the catchment and landscape management and on the possible use of waters for urban, agricultural, and industrial activities, since they may show significant effects on the human health.

Shell fluctuating asymmetry in the sea-dwelling benthic bivalve Mytilus galloprovincialis (Lamarck, 1819) as morphological markers to detect environmental chemical contamination.

Investigations on asymmetries showed that deviations from perfect bilateral symmetry are interpreted as environmental changes inducing developmental instability. Since morphological abnormalities increase with pollution, deformations may be considered indicators of the organism exposition to pollution. Therefore, the onset of asymmetry in otherwise normally symmetrical traits has been used as a measure of some stresses as well. In this context, we studied how marine pollution affects the valve morphological alterations in the mussel Mytilus galloprovincialis. We used 180 specimens (30 per site) from the aquaculture area of Goro (River Po delta, northern Adriatic Sea), translocated, and released within 50 × 50 × 50 cm cages in five sites: two disturbed and one undisturbed near Naples (eastern Tyrrhenian Sea), and one disturbed and one undisturbed near Siracusa (western Ionian Sea). Disturbed sites were stressed by heavy industrialization and heavy tankers traffic of crude and refined oil, and were defined basing on sediment contamination. In particular, by the cone-beam computed tomography we obtained 3D virtual valve surfaces to be analyzed by the geometric morphometric techniques. Specifically, we focused the levels of the shell shape fluctuating asymmetry in relation to the degrees of marine pollution in different sites of the Tyrrhenian Sea. The Mahalanobis distances (interpreted as proxy of the individual shape asymmetry deviation from the mean asymmetry) significantly regressed with the sediment contamination gradient. Indeed, although the left-right differences were normally distributed in each studied site, the individual asymmetry scores (IAS) significantly varied amongst the investigated sites. IAS showed higher values in disturbed areas than those of undisturbed ones in both Tyrrhenian and Ionian Sea. Our results are consistent with past studies on molluscans and other taxa, demonstrating some detrimental effects of chemicals on organisms, although the investigated morphological marker did not discriminate the real disturbance source. Our findings indicate that the mussels act as a prognostic tool for sea pollution levels driving detrimental effects on benthic community.

Massive pelvic recurrence of uterine leiomyomatosis with intracaval-intracardiac extension: video case report and literature review.

BACKGROUND: Uterine leiomyomas represent the gynecological neoplasm with the highest prevalence worldwide. This apparently benign pathological entity may permeate into the venous system causing the so-called intravenous leiomyomatosis of the uterus (IVL). IVL may seldom extend to large caliber veins and reach the right cardiac chambers or pulmonary arteries and cause signs of right sided congestive heart failure and sudden death. Due to its low incidence, however, IVL with intracardiac extension is often misdiagnosed resulting in deferred treatment. No consensus has been obtained regarding the standard surgical approach to be used for this rare condition. We describe the case of a massive pelvic recurrence of uterine leiomyomatosis with intracardiac extension and provide a review of the literature, analyzing management and surgical outcomes. CASE PRESENTATION: We present the case of a 46-year-old premenopausal woman presenting with lower-extremity edema, recurrent syncopes and a history of subtotal hysterectomy for multiple uterine fibroids. She was diagnosed with pelvic recurrence of uterine leiomyomatosis and IVL with cardiac involvement. A two-stage surgical excision of the intracardiac-intracaval mass and pelvic leiomyomatosis was performed. The patient had an uneventful recovery and no evidence of recurrence was observed on follow-up. CONCLUSIONS: By virtue of the rarity of the present pathology, awareness is widely scarce and diagnosis is often delayed. Early recognition is difficult due to initial aspecific and subtle clinical manifestations. Nevertheless, suspicion should be held high in premenopausal women with known history of uterine leiomyomata, presenting with cardiovascular symptoms and evidence of a free-floating mass within the right cardiac chambers. In-depth imaging is crucial for defining its anatomical origin and relations. Prompt surgical treatment with radical excision of pelvic and intravenous leiomyomatosis guarantees favorable outcomes and excellent prognosis with low rates of recurrence, whereas delayed diagnosis and treatment exposes to increased risk of congestive heart failure and sudden death.

Amyloid ß peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation.

BACKGROUND: Amyloid ß (Aß)-induced vascular dysfunction significantly contributes to the pathogenesis of Alzheimer's disease (AD). Aß is known to impair endothelial nitric oxide synthase (eNOS) activity, thus inhibiting endothelial nitric oxide production (NO). METHOD: In this study, we investigated Aß-effects on heat shock protein 90 (HSP90) interaction with eNOS and Akt in cultured vascular endothelial cells and also explored the role of oxidative stress in this process. RESULTS: Treatments of endothelial cells (EC) with Aß promoted the constitutive association of HSP90 with eNOS but abrogated agonist (vascular endothelial growth factor (VEGF))-mediated HSP90 interaction with Akt. This effect resulted in blockade of agonist-mediated phosphorylation of Akt and eNOS at serine 1179. Furthermore, Aß stimulated the production of reactive oxygen species in endothelial cells and concomitant treatments of the cells with the antioxidant N-acetyl-cysteine (NAC) prevented Aß effects in promoting HSP90/eNOS interaction and rescued agonist-mediated Akt and eNOS phosphorylation. CONCLUSIONS: The obtained data support the hypothesis that oxidative damage caused by Aß results in altered interaction of HSP90 with Akt and eNOS, therefore promoting vascular dysfunction. This mechanism, by contributing to Aß-mediated blockade of nitric oxide production, may significantly contribute to the cognitive impairment seen in AD patients.

JCV-specific T-cells producing IFN-gamma are differently associated with PmL occurrence in HIV patients and liver transplant recipients.

Aim of this work was to investigate a possible correlation between the frequency of JCV-specific T-cells and PML occurrence in HIV-infected subjects and in liver transplant recipients. A significant decrease of JCV-specific T-cells was observed in HIV-PML subjects, highlighting a close relation between JCV-specific T-cell immune impairment and PML occurrence in HIV-subjects. Interestingly, liver-transplant recipients (LTR) showed a low frequency of JCV-specific T-cells, similar to HIV-PML subjects. Nevertheless, none of the enrolled LTR developed PML, suggesting the existence of different immunological mechanisms involved in the maintenance of a protective immune response in LTR.