Erythrocyte viscoelastic recovery after liver transplantation in a cirrhotic patient affected by spur cell anaemia.

In physiological conditions, red blood cells (RBCs) are capable of dramatic deformations when passing through the microvasculature. This extreme deformability is closely related to the RBC biconcave shape, to the fluidic nature of the haemoglobin and the cell membrane structure, primarily consisting of a phospholipid bilayer with an underlying two-dimensional spectrin network. In many pathological and inflammatory conditions, the shape and the extreme deformability of erythrocytes appear to be significantly altered. These findings have stimulated intense research towards the search and validation of novel erythrocyte-based mechanical biomarkers, useful for disease diagnosis and therapy monitoring. In this study, we investigated with Atomic Force Microscopy (AFM) the mechanical properties of erythrocytes obtained from a 68 years old cirrhotic man diagnosed with spur cell anaemia and cold agglutinated disease, before and after liver transplantation. Mechanical changes are compared with ultrastructural alterations as studied by scanning electron microscopy and discussed according to confocal fluorescence microscopy results, showing possible alterations induced by the cirrhotic environment at the level of the RBCs cytoskeletal organisation and lipidic composition. Taken together, the results here presented show that liver transplantation not only contributes to restoring the proper RBC morphology, but it also induces recovery of the physiological viscous behaviour of cells, further stressing the relevance of viscous and dissipative forces in determining the RBC biomechanical response.

Towards 100 channel dense wavelength division multiplexing with 100GHz spacing on silicon.

A 1 by 4 wavelength division multiplexer with 0.5nm bandwidth and no free spectral range limitation is demonstrated on silicon. The device utilizes wide bandwidth filters cascaded with ring resonators in order to select specific ring resonator modes and route each resonant mode to a separate port. This technology will enable dense wavelength division multiplexing covering the C - and L - bands with up to 100 10GB/s channels separated by 100GHz to be implemented for optical interconnects applications. A 1 by 4 wavelength division multiplexer with 3dB channel bandwidths as small as 0.5nm and 1dB insertion loss are demonstrated with 16dB inter-channel crosstalk suppression. A second wavelength division multiplexer scheme with four channels, each spaced 0.5nm apart without any free spectral range limitations is also demonstrated using wide bandwidth filters centered at the same wavelength to select resonances from four different ring resonators with slightly different widths.

Silicon nanophotonic devices for chip-scale optical communication applications [Invited].

This paper reviews recent work in the area of silicon photonic devices and circuits for monolithic and heterogeneous integration of circuits and systems on a chip. In this context, it presents fabrication results for producing low-loss silicon waveguides without etching. Resonators and add-drop distributed filters utilizing sidewall modulation fabricated in a single lithography and etching step are demonstrated. It also presents an optical pulse compressor that monolithically integrates self-phase modulation and anomalous dispersion compensation devices on a silicon chip. As an example of heterogeneous integration, we demonstrate vertical emitting metallo-dielectric nanolasers integrated onto a silicon platform. Future research directions toward large-scale photonic circuits and systems on a chip also are discussed.

Single-step multimodal locoregional treatment for unresectable hepatocellular carcinoma: balloon-occluded percutaneous radiofrequency thermal ablation (BO-RFA) plus transcatheter arterial chemoembolization (TACE).

PURPOSE: This study was undertaken to evaluate the feasibility, safety and efficacy of a new combined single-step therapy in patients with unresectable multinodular unilobar hepatocellular carcinoma (HCC), with at least one lesion >3 cm, with balloon-occluded radiofrequency ablation (BO-RFA) plus transcatheter arterial chemoembolization (TACE) of the main lesion and TACE of the other lesions. The second purpose of our study was to compare the initial effects in terms of tumour necrosis of this new combined therapy with those obtained in a matched population treated with TACE alone in a singlestep treatment in our centre in the previous year. METHODS AND MATERIALS: This pilot study was approved by the institutional review board, and informed consent was obtained from all patients. Ten consecutive patients with multinodular (two to six nodules) unilobar unresectable HCC and with a main target lesion >3 cm (range, 3.5-6 cm) not suitable for curative therapy were enrolled in our single-centre multidisciplinary pilot study. The schedule consisted of percutaneous RFA (single 3-cm monopolar needle insertion) of the target lesion during occlusion of the hepatic artery supplying the tumour, followed by selective TACE, plus lobar TACE for other lesions (450-mg carboplatin and lipiodol plus temporary embolisation with SPONGOSTAN). Adverse events and intra- and periprocedural complications were clinically assessed. Early local efficacy was evaluated on 1-month follow-up multiphasic computed tomography (CT) on the basis of the Modified Response Evaluation Criteria in Solid Tumors (m-RECIST). A separate evaluation of target lesions in terms of enhancement, necrotic diameter and presence and distribution of lipiodol uptake was also performed. RESULTS: No major complications occurred. Overall technical success, defined as complete devascularisation of all nodules during the arterial phase, was achieved in seven of 10 patients, with three cases of partial response (persistence of small hypervascular nodules). When considering only target lesions, technical success was obtained in all patients, with a nonenhancing area corresponding in shape to the previously identified HCC (necrotic diameter, 3.5-5 cm) and with circumferential peripheral lipiodol uptake (safety margin) of at least 0.5 cm (0.5-1.3cm). CONCLUSIONS: TACE and BO-RFA, plus TACE in a singlestep approach seems to be a safe and effective combined therapy for treating advanced, unresectable HCC lesions, allowing a high rate of complete local response to be achieved in large lesions also.

Elderly patients with multimorbidity in the home setting: umbrella review on therapeutic non-adherence causes.

OBJECTIVE: The elderly population is the most at risk regarding adherence, especially in the coexistence of multiple diseases. This study aims to detect factors contributing to therapeutic non-adherence in elderly patients in home settings. MATERIALS AND METHODS: A review protocol was developed to conduct the umbrella review using the methodological framework of the Richardson et al study. The search strategy was developed in December 2022 to conduct a systematic search and to perform an Umbrella Review of systematic reviews, meta-analyses and integrative reviews published from 2012 to 2022 in English. RESULTS: A total of 26,038 articles were identified and screened. 18 relevant articles were included in the study. CONCLUSIONS: Therapeutic adherence in elderly patients with comorbidities in polypharmacotherapy at home is a significant problem in public health and health care. Several factors of non-adherence have been identified in the studies reviewed, confirming that the problem is multifactorial. Reducing the number of medications prescribed would appear optimal, although often not possible, as this has been seen to have an immediate positive impact. A multidisciplinary approach makes it possible not to fragment care, ensuring positive feedback on therapeutic adherence.

Project for interventional Oncology LArge-database in liveR Hepatocellular carcinoma - Preliminary CT-based radiomic analysis (POLAR Liver 1.1).

OBJECTIVE: The objective of this study is to find a contrast-enhanced CT-radiomic signature to predict clinical incomplete response in patients affected by hepatocellular carcinoma who underwent locoregional treatments. PATIENTS AND METHODS: 190 patients affected by hepatocellular carcinoma treated using focal therapies (radiofrequency or microwave ablation) from September 2018 to October 2020 were retrospectively enrolled. Treatment response was evaluated on a per-target-nodule basis on the 6-months follow-up contrast-enhanced CT or MR imaging using the mRECIST criteria. Radiomics analysis was performed using an in-house developed open-source R library. Wilcoxon-Mann-Whitney test was applied for univariate analysis; features with a p-value lower than 0.05 were selected. Pearson correlation was applied to discard highly correlated features (cut-off=0.9). The remaining features were included in a logistic regression model and receiver operating characteristic curves; sensitivity, specificity, positive and negative predictive value were also computed. The model was validated performing 2000 bootstrap resampling. RESULTS: 56 treated lesions from 42 patients were selected. Treatment responses were: complete response for 26 lesions (46.4%), 18 partial responses (32.1%), 10 stable diseases (17.9%), 2 progression diseases (3.6%). Area-Under-Curve value was 0.667 (95% CI: 0.527-0.806); accuracy, sensitivity, specificity, positive and negative predictive values were respectively 0.66, 0.85, 0.50, 0.59 and 0.79. CONCLUSIONS: This contrast-enhanced CT-based model can be helpful to early identify poor responder's hepatocellular carcinoma patients and personalize treatments.

Severe giant cell arteritis associated with essential thrombocythaemia.

Giant-cell arteritis (GCA) is a chronic vasculitis of the elderly usually involving the ophthalmic arteries, which can result in visual loss. High platelet counts may have some pathogenic significance in the obstruction of the ophthalmic circulation and a few cases of associated essential thrombocythaemia and GCA have been described. Here we report a case of severe temporal arteritis associated with essential thrombocythaemia.

Transarterial chemoembolization (TACE) for unresectable HCC: a new life begins?

BACKGROUND AND OBJECTIVES: To provide an overview on the loco-regional therapy performed by transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC), either as sole, either as neoadjuvant to surgery or bridge therapy to orthotopic liver transplantation (OLT). EVIDENCE AND INFORMATION SOURCES: The current review is based on an analysis of the current literature and the caseload experience of the Authors on this topic. STATE OF THE ART: Chemoembolization combines de-arterialization of the tumor and selective delivery of chemotherapeutic agents into tumor's feeding vessels during angiography. Tumor ischemia raises the drug concentration compared to infusion alone and extends the retention of the chemotherapeutic drug. As locoregional therapy, TACE allows a complete local tumor control of 25-35% and permits an increase of survival in patients with intermediate HCC according to Barcelona-Clinic Liver Cancer (BCLC) classification. Excellent results were also achieved by combined therapies, such as with percutaneous ethanol injection or radiofrequency ablation, as neoadjuvant therapy prior to liver resection and in some circumstances as a bridging tool before liver transplantation. PERSPECTIVES: Drug eluting beads are microspheres that can be loaded with doxorubicin and induce toxic and ischemic necrosis with the same device; that allows an increase of drug selectively exposed to tumor cells and simultaneously a reduction of systemic toxicity. Tumor embolization induces a neoangiogenic reaction with a significant growth of adiacent satellites, so the association with sorafenib has a strong rationale for a combined therapy and is currently under investigation. CONCLUSIONS: Today TACE is the standard of care for treatment of intermediate hepatocellular carcinoma. To get the best performance it should be tailored according to the individual patient's condition.

Mediterranean diet and the prevention of non-alcoholic fatty liver disease: results from a case-control study.

OBJECTIVE: Few studies report that Mediterranean dietary (MD) pattern has a beneficial role in the progression of non-alcoholic fatty liver disease (NAFLD). Evidence on its potential effect on the onset of disease are, however, scanty. With our study, we evaluated whether MD affects the risk of NAFLD with a large case-control study performed in Italy. PATIENTS AND METHODS: Three hundred and seventy-one cases of NAFLD and 444 controls were questioned on the demographic data and their dietary habits before diagnosis. Additionally, information about lifestyles and other related diseases, such as hypertension and diabetes mellitus were collected. The MD adherence was assessed using a pre-defined Mediterranean Diet Score (MDS). Odds ratios (OR) and 95% confidence intervals (CI) were obtained using a multiple logistic regression model. RESULTS: A high adherence to the MD is significantly associated with decreased risk of NAFLD (OR: 0.83 95% CI: 0.71-0.98). When the different MD components were examined separately, higher legumes consumption (OR: 0.62 95% CI: 0.38-0.99) and high fish consumption (OR 0.38 95% CI: 0.17-0.85) were reported to be protective against NAFLD. CONCLUSIONS: Our study shows that a high adherence to the MD decreases the risk of NAFLD.

The diagnostic performance of PIVKA-II in metabolic and viral hepatocellular carcinoma: a pilot study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a primary liver tumor derived from metabolic or viral chronic hepatitis, with few treatment options in advanced cases. New biomarkers that allow improving diagnosis and staging are widely desired. Here, we aim to evaluate the performance of Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) in combination with α-fetoprotein (AFP), in the diagnosis of HCC in patients with metabolic or viral hepatitis. PATIENTS AND METHODS: We enrolled 60 HCC patients (20 metabolic and 40 viral) and 20 healthy subjects (HS) as negative controls. PIVKA-II, AFP, Matrix metalloproteinase-9 (MMP-9) and Fibroblast growth factor (FGF) serum levels were assessed by immunoassays. RESULTS: AFP and PIVKA-II levels were obviously higher in patients than in HS. AFP displayed a better diagnostic performance than PIVKA-II for viral HCC while PIVKA-II was better for metabolic HCC. The combination of the two biomarkers did not improve the discriminating ability. CONCLUSIONS: PIVKA-II may be considered an independent predictor of macrovascular invasion from HCC cells and it can be used to better stratify HCC patients and should be evaluated in prospective studies for early detection of advanced HCC in metabolic subjects.

Celiac disease in the 21st century: issues of under- and over-diagnosis.

Until the 1960s celiac disease (CD) or sprue was considered a pediatric disease that was rarely diagnosed in adulthood. Thanks to greater awareness of the disease and the availability of improved diagnostic tools (above all, sophisticated endoscopic techniques and the development of reliable serological markers), the prevalence of CD in Western countries has been increasing steadily, and it is now recognized as a common disorder, even in adults. However, many cases of this disease still go undiagnosed, especially among the elderly and in patients with atypical clinical presentations (which are by no means uncommon). On the other hand, the frequency of unfounded diagnoses of CD is also on the rise. This reflects a tendency toward exclusively symptomatic diagnosis as well as the growing use of invalidated tests for CD (e.g., the cytotoxic test, the sublingual or subcutaneous provocation/neutralization test, etc.). As a result, public healthcare spending is being increased in several countries (Italy included) by the growing number of prescriptions for gluten-free diets. This editorial discusses the problems of under- and over-diagnosis of CD and provides an algorithm for management of suspected cases designed to minimize both problems with particular importance to morphologic aspects of small bowel (also in electron microscopy), in basal conditions or in gluten-free diets.

Gastrointestinal amyloidosis: a case of chronic diarrhoea.

Amyloidosis is a rare disease caused by extracellular deposits of insoluble fibrillar proteins in various organs and tissues. There are different forms of amyloidosis distinguished by the type of protein fibrils, by the sites of deposition and by associated conditions. Gastrointestinal involvement is common both in primary and secondary amyloidosis, while isolated gastrointestinal amyloidosis is rare. We describe a case of AL amyloidosis with a gastrointestinal involvement and restrictive cardiomiopathy. A 64 year old woman came to our attention with a history of chronic diarrhoea and weight loss, associated with dysphagia, dry mouth, xerophtalmia, chronic gastritis and depression. Clinical diagnosis has been difficult because of aspecificity of symptoms that mimed other more common diseases, like gastro-paresis, epigastric discomfort, gastric or duodenal ulcers, perforation, malabsorption, intestinal pseudo-obstruction. There is an important risk of misunderstanding and diagnostic delay. Indeed in this patient a diagnosis of irritable colon syndrome was erroneously established two years before admission in our hospital. Therefore gastrointestinal amyloidosis should be considered among differential diagnoses of chronic diarrhoea and weight loss when other more common diseases have been excluded.

[The treatment of hepatocellular carcinoma: an update]. / Il trattamento dell'epatocarcinoma oggi.

Hepatocellular carcinoma (HCC) is the third most frequent cause of death from cancer with an increasing incidence in the world. Hepatic cirrhosis is the main risk factor for the development of this tumor, present in more than 80% of cases. The prognosis of this tumor is still poor and appears to be strictly related to liver residual function and tumor extension. A regular surveillance program was defined to increase early detection of tumor in cirrhotic patients when curative treatment could be applied. Liver transplantation and liver resection offer a high rate of positive response when applied in a early stage of the disease; locoregional therapies are effective, palliative options for patients with unresectable HCC: transarterial chemoembolisation being the only with a proven positive impact on survival. Several prognostic systems are proposed in the last years to stratify patients in different risk groups and to identify those who could achieve the best survival benefit from different therapeutic strategies: the Okuda system, the Cancer of the Liver Italian Program and the Barcelona Clínic Liver Cancer are the most widely used, but there is no consensus to which is the best in predicting outcome most accurately.

Evaluation of microbial contamination of air in two haematology departments equipped with ventilation systems with different filtration devices.

BACKGROUND: Nosocomial infections (NI) are above all due to health-care workers practices, but also the contamination of the environment could lead to their rise in health-care facilities. Introduction. In the last years, the incidence of NI has increased due to a substantial rise in the number of immuno-compromised patients. These patients are often gathered in hospital areas declared at "high risk" of infection such as Hematology and Bone Marrow Transplant ward. In this study, we evaluated microbial contamination of the air in two divisions with high risk patients, focusing on the validity of the air system with correlation to the presence or not of the HEPA absolute filters. METHODS: An environmental surveillance study has been carried out in two Divisions of Haematology, in two different Hospitals. Investigations have been performed by sampling air and by analyzing bacterial and fungal growth on microbiology plates after an incubation period. RESULTS: Unit A, without HEPA filters in the ventilation systems, showed a gradual increase in the bacterial load 20 and 60 days after cleaning of the ventilation system. Mycetes and Aspergilli were not present in basal conditions, at 20 or 60 days after decontamination. Unit B, equipped with HEPA filters placed at the inlet vents, showed extremely low values of the bacterial load either in basal conditions or upon inspection 60 days after cleaning. No mycetes were present. DISCUSSION: From the results obtained, it was evident that following the cleaning operation, the quality of the air is excellent in both types of equipment, since no mycetes were present and the bacterial load was < 20 CFU/mc in all the sites tested. However, although in subsequent controls mycetes were absent in both types of equipment, a great difference in the suspended bacterial load was found: Unit B was close to sterility whereas in Unit A a progressive increase was observed.

Acute HEV hepatitis: clinical and laboratory diagnosis.

OBJECTIVE: Hepatitis E Virus (HEV) is probably the most common cause of acute hepatitis worldwide. It has been regarded for a long time as a disease limited to developing countries. Recently, the refinement of diagnostic techniques, on the one hand, and migratory flows, on the other hand, have also led to the identification of an increased number of HEV infections in industrialized countries. Four HEV genotypes have been identified across the world, with different epidemiological burdens and a wide range of clinical presentations. Here, we report a case series of acute HEV hepatitis observed in the last three years in our hospital. PATIENTS AND METHODS: We performed a search for HEV IgM and IgG in all subjects admitted for acute hepatitis without evidence of other possible infectious, toxic or metabolic causes of liver damage. In subjects with HEV IgM positivity, the search for HEV-RNA was performed. RESULTS: We diagnosed eight acute HEV infections: 2 epidemic and 6 sporadic forms. HEV-RNA was detected in serum in 2 cases. CONCLUSIONS: HEV infection appears to be a cause of acute hepatitis that we must keep in mind even in developed countries.

Contrast-enhanced ultrasound assessment of arterial vascularization of small nodules arising in the cirrhotic liver.

BACKGROUND AND AIM: Aim of this study was to compare contrast-enhanced ultrasound and multi-detector row computed tomography in detecting arterial hypervascularity in small cirrhotic nodules. PATIENTS AND METHODS: Sixty-two nodules (41 measuring 1.0-2.0 cm, 21 measuring 2.1-3.0 cm) found in 55 cirrhotic patients were examined with both methods. Lesions displaying arterial hypervascularity with washout in the portal/venous phase on both studies were considered hepatocellular carcinomas and treated; all other nodules were subjected to ultrasound-guided fine-needle biopsy. RESULTS: The larger nodules (2.1-3.0 cm) included 19 hepatocellular carcinomas (90%), 1 macroregenerative nodule type I and 1 macroregenerative nodule type II; 35 (87%) of the smaller nodules were hepatocellular carcinomas, 2 were macroregenerative nodules type I, 2 macroregenerative nodules type II and 2 hemangiomas. The two studies yielded concordant findings for 54 nodules (87%), including 46 hypervascular on both examinations and 8 that were consistently hypovascular. Two of the latter nodules were hepatocellular carcinomas. The other eight nodules displayed arterial hypervascularity on only one of the studies. Six of these (75%) were hepatocellular carcinomas, including five that were negative in the contrast-enhanced ultrasound study. CONCLUSION: Computed tomography and contrast-enhanced ultrasound show high agreement in the vascular classification of small nodules detected by ultrasound in cirrhotic livers, although the former technique was slightly more sensitive in the detection of arterial hypervascularization.

13C-methionine breath tests for mitochondrial liver function assessment.

13C-methionine breath test has been proposed as a non-invasive tool for the assessment of human hepatic mithocondrial function. Two methionine breath labeled with 13C in differents point of his molecular structure have been used for breath test analisys. Aim of this study was to compare two differently 13C-labeled methionines in the evaluation of mitochondrial oxidation in basal conditions and after an acute oxidative stress. 15 healthy male subjects (mean age 30.5 +/- 3.1) received [methyl-13C]-methionine dissolved in water. Breath samples were taken at baseline and and 10, 20, 30, 45, 60, 75, 90, 105 and 120 minutes after the ingestion of the labeled substrate. Forthy-eight hours later, subjects underwent the same test 30 minutes after ethanol ingestion (0,3 g/kg of body weight). Seven-day later, subjects underwent breath test using (L-methionine-1-13COOH) as substrate, in basal condition and after ethanol ingestion. At basal condition, the cumulative percentage of 13CO2 recovered in breath during the test period (%cum-dose) was higher using L-methionine-1-13COOH than [methyl-13C]-methionine (10.25 +/- 1.0 vs 4.07 +/- 0.8; p < 0.01). After ethanol ingestion, % cum dose was significantly decreased at 60 and 120 minutes with both methionines (120 min: 10.25 +/- 1.0 vs 5.03% +/- 1.8; < 0.01 and 4.07 +/- 0.8 vs 2.16% +/- 0.9; p < 0.01, respectively). However, %cum-dose during L-methionine-1-13C-breath test was significantly lower than that observed during methyl-13C-methionine breath test (120 minutes: 5.03% +/- 1.8 vs 2.16% +/- 0.9; p < 0.01). In conclusion, breath test based on L-methionine-1-13COOH seems to show a greater reliability when compared to [methyl-13C]-methionine to assess mitochondrial function because a larger amount of labeled carbon that reaches the Krebs' cicle.

Mild hepatitis at recommended doses of acetaminophen in patients with evidence of constitutionally enhanced cytochrome P450 system activity.

Acetaminophen (paracetamol) is used throughout the world for pain relief and antipyresis in both children and adults. In many countries, it can be purchased without a medical prescription and it is also a common component of a number of over-the-counter remedies for colds, influenza and the like. Fasting, malnutrition and use of alcohol and/or other drugs are thought to play causal roles in hepatotoxicity associated with recommended doses of acetaminophen although liver injury provoked by therapeutic doses has also been observed in the absence of these factors. We describe two patients who experienced subclinical hepatotoxic reactions after taking acetaminophen at therapeutic doses. The results of an antipyrine metabolism test suggest the presence of constitutional hyperactivity of the cytochrome P450-dependent mixed function oxidative system in both patients. We hypothesize that the latter contributed to the hepatotoxicity and that it may play a role in idiosyncratic reactions to this drug.

Safety and efficacy profile of G-CSF therapy in patients with acute on chronic liver failure.

BACKGROUND/AIM: We aimed to evaluate safety and efficacy of granulocyte-colony stimulating factor treatment in patients with acute on chronic liver failure and the effect of granulocyte-colony stimulating factor on the expression level of CXCR4, vascular endothelial growth factor receptor and very late activation antigen 4. METHODS: Twenty-four patients with acute on chronic liver failure were randomised to receive standard therapy, standard therapy+granulocyte-colony stimulating factor (5 microg/kg/day for 6 days) and standard therapy+granulocyte-colony stimulating factor (15 microg/kg/day s.c. for 6 days). Data on CD34+cell mobilisation were compared to age-matched peripheral blood haematopoietic stem cell donors treated with granulocyte-colony stimulating factor. On day third of treatment, the expression level of CXCR4, vascular endothelial growth factor receptor and very late activation antigen 4 was analysed in mobilised CD34+ cells. RESULTS: CD34 cell count increased after the second day of granulocyte-colony stimulating factor injection in both treatment groups compared to the linear increase observed in control. After the fifth day the increase was significantly higher in healthy donors versus patients with acute on chronic liver failure. A decrease in the expression of CXCR4, very late activation antigen 4 and vascular endothelial growth factor receptor compared to premobilisation values was observed. No major side effects were observed. CONCLUSIONS: Granulocyte-colony stimulating factor treatment is able to induce CD34 mobilisation in patients with acute on chronic liver failure. The expression pattern of CXCR4, very late activation antigen 4 and vascular endothelial growth factor receptor suggests that these molecules are involved in the granulocyte-colony stimulating factor-induced stem cell mobilisation.