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Chronic hepatitis B (CHB) is the leading cause of hepatocellular carcinoma (HCC) globally. We described and evaluated the outcomes of patients with CHB‐HCC in Canada. In this retrospective cross‐sectional cohort study, data were analysed from CHB mono‐infected subjects seen between 1 January 2012 and 31 December 2022, and entered the Canadian Hepatitis B Network Registry. Descriptive analysis and chi‐squared modelling were used to compare cohorts, followed by multivariable survival analysis regarding survival post‐diagnosis. Statistical analyses were completed in R version 2.2. Of the 6711 patients with CHB who met inclusion criteria, 232 (3.5%) developed HCC. Compared with the CHB cohort, the majority of CHB‐HCC cohort were male, SEA and HBeAg negative and born in endemic area (80% vs. 56%, 73% vs. 55%, 84% vs. 54%, 64% vs. 40% and all p < 0001). Overall, median HBV DNA level was log 2.54 (IQR: 0–4.04). Advanced liver disease, defined as minimum Fibrosis stage F3, was seen in 9.4% of overall cohort, but 92% of HCC cohort. At diagnosis, median tumour size was 2.5 cm (IQR: 1.7–4.0) and mean tumour number was 1.33 (SD: 1.33), with 81% of patients BCLC 0‐A. Fifty‐three per cent of patients were diagnosed with HCC as part of surveillance protocols. The survival rate after HCC diagnosis was 78.7%, during the median follow‐up of 52.9 months (IQR: 17–90). In multivariable analysis, survival was significantly correlated with diagnosis through the screening programme. In this large cohort of patients with CHB‐HCC, the majority of patients were detected with early‐stage HCC and received treatment with curative intent, resulting in strong survival rates. [ABSTRACT FROM AUTHOR]

Objectives: Current guidelines recommend use of a diagnostic algorithm to assess disease severity in cases of suspected nonalcoholic fatty liver disease (NAFLD). We applied this algorithm to HIV‐monoinfected patients. Methods: We analysed three prospective screening programmes for NAFLD carried out in the following cohorts: the Liver Disease in HIV (LIVEHIV) cohort in Montreal, the Modena HIV Metabolic Clinic (MHMC) cohort and the Liver Pathologies in HIV in Palermo (LHivPa) cohort. In the LIVEHIV and LHivPa cohorts, NAFLD was diagnosed if the controlled attenuation parameter (CAP) was ≥ 248 dB/m; in the MHMC cohort, it was diagnosed if the liver/spleen Hounsfield unit (HU) ratio on abdominal computerized tomography scan was < 1.1. Medium/high‐risk fibrosis category was defined as fibrosis‐4 (FIB‐4) ≥ 1.30. Patients requiring specialist referral to hepatology were defined as either having NAFLD and being in the medium/high‐risk fibrosis category or having elevated alanine aminotransferase (ALT). Results: A total of 1534 HIV‐infected adults without significant alcohol intake or viral hepatitis coinfection were included in the study. Of these, 313 (20.4%) patients had the metabolic comorbidities (obesity and/or diabetes) required for entry in the diagnostic algorithm. Among these patients, 123 (39.3%) required specialist referral to hepatology, according to guidelines. A total of 1062 patients with extended metabolic comorbidities (any among obesity, diabetes, hypertension and dyslipidaemia) represented most of the cases of NAFLD (79%), elevated ALT (75.9%) and medium/high‐risk fibrosis category (75.4%). When the algorithm was extended to these patients, it was found that 341 (32.1%) would require specialist referral to hepatology. Conclusions: According to current guidelines, one in five HIV‐monoinfected patients should undergo detailed assessment for NAFLD and disease severity. Moreover, one in ten should be referred to hepatology. Expansion of the algorithm to patients with any metabolic comorbidities may be considered. [ABSTRACT FROM AUTHOR]

The crack density within a fault's damage zone is thought to vary as seismic rupture is approached, as well as in the postseismic period. Moreover, external stress loads, seasonal or tidal, may also change the crack density in rocks, and all such processes can leave detectable signatures on seismic attenuation. Here we show that attenuation time histories from the San Andreas Fault at Parkfield are affected by seasonal loading cycles, as well as by 1.5–3‐year periodic variations of creep rates, consistent with Turner et al. (2015, https://doi.org/10.1002/2015JB011998), who documented a broad spectral peak, between 1.5 and 4 years, of the spectra calculated over the activity of repeating earthquakes, and over InSAR time series. After the Parkfield main shock, we see a clear modulation between seismic attenuation correlated to tidal forces. Opposite attenuation trends are seen on the two sides of the fault up to the M6.5 2003 San Simeon earthquake, when attenuation changed discontinuously, in the same directions of the relative trends. Attenuation increased steadily of over one year on the SW side of the San Andreas Fault, until the San Simeon earthquake, whereas it decreased steadily on the NE side of the San Andreas Fault, roughly for the six months prior to the event. Random fluctuations are observed up to the 2004 M6 Parkfield main shock, when rebounds in opposite directions are observed, in which attenuation decreased on the SW side, and increased on the NE side. Key Points: Seismic attenuation fluctuates with periods related to solid tides and seasonal loading, indicating strong sensitivity to stress changesAttenuation on the opposite sides of the San Andreas Fault shows mirror‐like anomalies before and after the 2004 Parkfield main shockEarthquake‐induced damage increases the sensitivity of seismic attenuation to periodic stress fluctuations [ABSTRACT FROM AUTHOR]

During the last 20 years, three seismic sequences affected the Apenninic belt (central Italy): Colfiorito (1997–1998), L'Aquila (2009), and Amatrice Visso‐Norcia Campotosto (2016–2017). They lasted for a long time, with a series of moderate‐to‐large earthquakes distributed over 40‐ to 60‐km‐long Apenninic‐trending segments. Their closeness in space and time suggested to study their aftershock sequences to highlight similarities and differences. Aftershock space migration and the distribution of aftershock interarrival times were studied. Mathematical Morphology and nonparametric statistics were applied to reduce the effect of spatial noise. Parametric analysis in time domain and spectral analysis were performed. Two different types of aftershock sequences were found. The L'Aquila sequence presented a continuous and periodic temporal variation (period ≃120 days) of aftershock activity center along the sequence axis, while the other two sequences showed a piecewise continuous pattern and a shorter duration. We also found two different types of temporal evolution of the mean radial distance between the aftershock hypocenters and the one of a reference event corresponding to the start of a large and fast increase of daily energy release. One type was well described by a simple exponential model, while a power law model was more appropriate for the other one. Furthermore, in the first case, the aftershock interarrival time was very well fitted by an exponential model, while noticeable deviations were present in the other case. A possible explanation was provided in terms of the local geological and hydrogeological properties, which depend on the region location with respect to the Ancona‐Anzio tectonic lineament. Key Points: Two different temporal patterns of aftershock migration along sequence axis were foundThe type of pattern is possibly correlated with the local lithological and hydrogeological properties [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is particularly dangerous in systemic lupus erythematosus (SLE), being a problem both for the differential diagnosis with disease flare and for the management of SLE flare with immunosuppressive drugs. We report on four cases of SLE with concomitant CMV infection, having some common clinical and laboratory characteristics. Our data suggest that lupus patients presenting with symptoms such as fever, diarrhea, and respiratory symptoms, alone or in combination, and laboratory evidence of leukopenia, elevated transaminases, and hyponatremia, especially in the setting of recent immunosuppressive treatments, should be screened for CMV. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical and serological features of a prospectively followed cohort of early diagnosed systemic lupus erythematosus (SLE) patients during a one-year follow-up period. Methods: SLE patients with disease duration less than 12 months were consecutively enrolled in a multicentre, prospective study. At study entry and then every 6 months, a large panel of data was recorded. Results: Of 260 patients enrolled, 185 had at least 12 months of follow-up; of these, 84.3% were female, 92.4% were Caucasians. Mean diagnostic delay was about 20 months; higher values of European Consensus Lupus Activity Measurement (ECLAM) and of organs/systems involved were both associated with shorter diagnostic delay. Clinical and serological parameters improved after study entry. However, patients' quality of life deteriorated and cardiovascular risk factors significantly increased. About one-third of patients with active disease at study entry went into remission (ECLAM=0). Negative predictors for remission were: oral ulcers, arthritis, low C4, anti-SSB (Ro) antibodies and therapy with mycophenolate. There was a widespread use of glucocorticoids both at baseline and during follow-up. Conclusion: Clinical symptoms and serological parameters improve during the first period after diagnosis. However, patients' quality of life deteriorates. The widespread use of glucocorticoids is probably the reason for the early significant increase of some cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

We propose a new iterative procedure to find the best time for re-initialization of meta-heuristic algorithms to solve combinatorial optimization problems. The sequence of algorithm executions with different random initializations evolves at each iteration by either adding new independent executions or extending all existing ones up to the current maximum execution time. This is done on the basis of a criterion that uses a surrogate of the algorithm failure probability, where the optimal solution is replaced by the best so far one. Therefore, the new procedure can be applied in practice. We prove that, with probability one, the maximum time of current executions of the proposed procedure approaches, as the number of iterations diverges, the optimal value minimizing the expected time to find the solution. We apply the new procedure to several Traveling Salesman Problem instances with hundreds or thousands of cities, whose solution is known, and to some instances of a pseudo-Boolean problem. As base algorithm, we use different versions of an Ant Colony Optimization algorithm or a Genetic Algorithm. We compare the results from the proposed procedure with those from the base algorithm. This comparison shows that the failure probability estimated values of the new procedure are several orders of magnitude lower than those of the base algorithm for equal computational cost. [ABSTRACT FROM AUTHOR]

Summary: Background: Infants born small‐for‐gestational‐age (SGA) who develop post‐natal weight catch‐up are at risk for insulin resistance, central adiposity and cardiovascular disease in later life, even in the absence of overweight. Objective: In young (age 3–6 years) non‐obese SGA children, we assessed arterial health (as judged by intima‐media thickness [IMT]) and abdominal fat distribution (subcutaneous, visceral, preperitoneal and hepatic components by magnetic resonance imaging [MRI] and/or ultrasound [US]) besides a selection of endocrine markers. Methods: Comparisons of measures in SGA (n = 27) vs. appropriate‐for‐GA (AGA) children (n = 19) of similar height, weight and body mass index. Longitudinal outcomes (age 3–6 years) were carotid IMT (cIMT); fasting glucose, circulating insulin, IGF‐I and high‐molecular‐weight (HMW) adiponectin; abdominal fat partitioning by US. Cross‐sectional outcomes (age 6 years) were aortic IMT (aIMT) and abdominal fat partitioning by MRI. Results: At 3 and 6 years, cIMT and IGF‐I results were higher and HMW adiponectin lower in SGA than AGA children; at 6 years, SGA subjects had also a thicker aIMT and more pre‐peritoneal and hepatic fat, and were less insulin sensitive (all P values between <0.05 and <0.0001). cIMT correlated positively with pre‐peritoneal fat, particularly at 6 years. Post‐SGA status and weight gain in early childhood (between 3 and 6 years) were independent predictors of cIMT at 6 years, explaining 48 % of its variance. Conclusion: SGA children aged 3–6 years were found to have a thicker intima‐ media and more pre‐peritoneal and hepatic fat than AGA children of comparable size. [ABSTRACT FROM AUTHOR]

Introduction: Infant anthropometry and body composition have been previously assessed to gauge the impact of intrauterine growth restriction (IUGR) at birth, but the interplay between prenatal Doppler measurements and postnatal development has not been studied in this setting. The present investigation was performed to assess the significance of prenatal Doppler findings relative to postnatal anthropometrics and body composition in IUGR newborns over the first 12 months of life. Patients and Methods: Consecutive cases of singleton pregnancies with suspected IUGR were prospectively enrolled over 12 months. Fetal biometry and prenatal Doppler ultrasound examinations were performed. Body composition was assessed by absorptiometry at ages 10 days, and at 4 and12 months. Results: A total of 48 pregnancies qualifying as IUGR were studied. Doppler parameters were normal in 26 pregnancies. The remaining 22 deviated from normal, marked by an Umbilical Artery Pulsatility Index (UA-PI) >95th centil or Cerebro-placental ratio (CPR) <5th centile. No significant differences emerged when comparing anthropometry and body composition at each time point, in relation to Doppler findings. Specifically, those IUGR newborns with and without abnormal Doppler findings had similar weight, length, body mass index, lean and fat mass, and bone mineral content throughout the first 12 months of life. In a separate analysis, when comparing IUGR newborns by Doppler (abnormal UA-PI vs. abnormal CPR), anthropometry and body composition did not differ significantly. Conclusions: Infants with IUGR maintain a pattern of body composition during the first year of life that is independent of prenatal Doppler findings. Future studies with larger sample sizes and correlating with hormonal status are warranted to further extend the phenotypic characterization of the various conditions now classified under the common label of IUGR. [ABSTRACT FROM AUTHOR]

Background Systemic lupus erythematosus (SLE) is an autoimmune disease with a high degree of variability at onset that is problematic for a correct and prompt diagnosis. We undertook this project with the purpose of collecting an inception cohort of Italian patients with recent-onset SLE, in order to obtain information on the main clinical and serological characteristics at the beginning of the disease. In this first report we describe the characteristics of this cohort at study entry. Methods All patients with a diagnosis of SLE (1997 ACR criteria) and a disease duration less than 12 months were consecutively enrolled between 1 January 2012 and 31 December 2013 in a multicentre prospective study. Information on clinical and serological characteristics at study entry and then every six months was collected into a specific electronic database. Statistical analysis was performed by means of the Openstat program. Results Among 122 patients enrolled (103 F) 94.3% were Caucasians. Mean age (SD) of patients at study entry was 37.3 (14.3) years, mean age at disease onset was 34.8 (14.3) years, mean age at diagnosis was 36.9 (14.3) years, and mean disease duration was 2.9 (3.9) months. The frequency of the manifestations included in the 1997 ACR criteria was as follows: ANA 97.5%, immunologic disorders (anti-dsDNA, anti-Sm, antiphospholipid antibodies) 85.2%, arthritis 61.8%, haematologic disorders 55.7%, malar rash 31.1%, photosensitivity 29.5%, serositis 27%, renal disorders 27%, oral/nasal ulcers 11.5%, neurologic disorders 8.2%, and discoid rash 5.7%. The cumulative frequency of mucocutaneous symptoms was 77.8%. At enrolment, autoantibody frequency was: ANA 100%, anti-dsDNA 83.6%, anti-SSA 28%, anticardiolipin 24.5%, anti-nRNP 20.4%, anti-beta2GPI 17.2%, lupus anticoagulant 16.3%, anti-Sm 16%, and anti-SSB 13.1%. Conclusions In this paper we describe the main clinical and serological characteristics of an Italian inception cohort of patients with recent-onset SLE. At disease onset, mucocutaneous manifestations, arthritis and haematologic manifestations were the most frequent symptoms; ANA, anti-dsDNA and complement reduction were the most frequent laboratory findings. Our data confirm that the diagnosis of SLE is a challenging one, and that SLE is a severe disease even at onset, since the majority of patients require at least a hospitalization before the diagnosis. [ABSTRACT FROM AUTHOR]

Background/Objective:Fibroblast growth factor 19 (FGF19) and 21 (FGF21) have been linked to obesity and type 2 diabetes in adults. We assessed the circulating concentrations of these factors in human neonates and infants, and their association with the endocrine-metabolic changes associated to prenatal growth restraint.Subjects/Methods:Circulating FGF19 and FGF21, selected hormones (insulin, insulin-like growth factor I and high- molecular-weight (HMW) adiponectin) and body composition (absorptiometry) were assessed longitudinally in 44 infants born appropriate- (AGA) or small-for-gestational-age (SGA). Measurements were performed at 0, 4 and 12 months in AGA infants; at 0 and 4 months in SGA infants; and cross-sectionally in 11 first-week AGA newborns.Results:Circulating FGF19 and FGF21 surged >10-fold in early infancy from infra- to supra-adult concentrations, the FGF19 surge appearing slower and more pronounced than the FGF21 surge. Whereas the FGF21 surge was of similar magnitude in AGA and SGA infants, FGF19 induction was significantly reduced in SGA infants. In AGA and SGA infants, cord-blood FGF21 and serum FGF19 at 4 months showed a positive correlation with HMW adiponectin (r=0.49, P=0.013; r=0.43, P=0.019, respectively).Conclusions:Our results suggest that these early FGF19 and FGF21 surges are of a physiological relevance that warrants further delineation and that may extend beyond infancy. [ABSTRACT FROM AUTHOR]

Aims/hypothesis Glucagon-like peptide 1 (GLP-1) is a major incretin, mainly produced by the intestinal L cells, with beneficial actions on pancreatic beta cells. However, while in vivo only very small amounts of GLP-1 reach the pancreas in bioactive form, some observations indicate that GLP-1 may also be produced in the islets. We performed comprehensive morphological, functional and molecular studies to evaluate the presence and various features of a local GLP-1 system in human pancreatic islet cells, including those from type 2 diabetic patients. Methods The presence of insulin, glucagon, GLP-1, proconvertase (PC) 1/3 and PC2 was determined in human pancreas by immunohistochemistry with confocal microscopy. Islets were isolated from non-diabetic and type 2 diabetic donors. GLP-1 protein abundance was evaluated by immunoblotting and matrix-assisted laser desorption–ionisation-time of flight (MALDI–TOF) mass spectrometry. Single alpha and beta cell suspensions were obtained by enzymatic dissociation and FACS sorting. Glucagon and GLP-1 release were measured in response to nutrients. Results Confocal microscopy showed the presence of GLP-1-like and PC1/3 immunoreactivity in subsets of alpha cells, whereas GLP-1 was not observed in beta cells. The presence of GLP-1 in isolated islets was confirmed by immunoblotting, followed by mass spectrometry. Isolated islets and alpha (but not beta) cell fractions released GLP-1, which was regulated by glucose and arginine. PC1/3 (also known as PCSK1) gene expression was shown in alpha cells. GLP-1 release was significantly higher from type 2 diabetic than from non-diabetic isolated islets. Conclusions/interpretation We have shown the presence of a functionally competent GLP-1 system in human pancreatic islets, which resides in alpha cells and might be modulated by type 2 diabetes. [ABSTRACT FROM AUTHOR]

Prenatal growth restraint, if followed by postnatal overweight, confers risk for adult disease including diabetes. The mechanisms whereby neonatal nutrition may modulate such risk are poorly understood. We studied the effects of nutrition (breast-feeding [BRF] vs. formula-feeding [FOF]) on weight partitioning and endocrine state (as judged by high-molecular-weight [HMW] adiponectin and IGF-I) of infants born small for gestational age (SGA). Body composition (by absorptiometry), HMW adiponectin, and IGF-I were assessed at birth and 4 months in BRF infants born appropriate for gestational age (AGA; n = 72) and SGA infants receiving BRF (n = 46) or FOF (n = 56), the latter being randomized to receive a standard (FOF1) or protein-rich formula (FOF2). Compared with AGA-BRF infants, the catchup growth of SGA infants was confined to lean mass, independently of nutrition. Compared with AGA-BRF infants, SGA-BRF infants had normal HMW adiponectin and IGF-I levels at 4 months, whereas SGA-FOF infants had elevated levels of HMW adiponectin (particularly SGA-FOF1) and IGF-I (particularly SGA-FOF2). In conclusion, neonatal nutrition seems to influence endocrinology more readily than body composition of SGA infants. Follow-up will disclose whether the endocrine abnormalities in SGA-FOF infants can serve as early markers of an unfavorable metabolic course and whether they may contribute to design early interventions that prevent subsequent disease, including diabetes. [ABSTRACT FROM AUTHOR]

Summary OTHER THEMES PUBLISHED IN THIS IMMUNOLOGY IN THE CLINIC REVIEW SERIES Metabolic diseases, host responses, cancer, autoinflammatory diseases, allergy. Type 1 diabetes mellitus (T1DM) is a multi-factorial immune-mediated disease characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically susceptible individuals. Epidemiological evidence has also documented the constant rise in the incidence of T1DM worldwide, with viral infections representing one of the candidate environmental risk factors identified by several independent studies. In fact, epidemiological data showed that T1DM incidence increases after epidemics due to enteroviruses and that enteroviral RNA can be detected in the blood of >50% of T1DM patients at the time of disease onset. Furthermore, both in-vitro and ex-vivo studies have shown that viruses can infect pancreatic beta cells with consequent effects ranging from functional damage to cell death. [ABSTRACT FROM AUTHOR]

Summary. Hepatic iron overload has been described in chronic hepatitis C as a cofactor affecting fibrosis progression. Data in patients with chronic hepatitis B infection are scarce. We investigated hepatic iron deposits and serum iron indices in 205 consecutive patients with hepatitis B and compensated liver disease. Mean age of the patients was 42.4 ± 12.4 years and 72.5% were males. Coinfection with hepatitis delta virus (HDV) was present in 8.8%. At least one of the serum iron indices was elevated in 41.5% of cases. Hepatic iron deposits were detected in 35.1% of patients, most of them being minimal (grade I) (59.7%) or mild (grade II) (27.8%). Variables significantly associated with hepatic iron deposits were male gender ( P = 0.001), serum ferritin ( P = 0.008), γGT ( P = 0.05) and alkaline phosphatase ( P = 0.05) levels. By multivariate analysis hepatic iron deposits correlated with serum ferritin [odds ratio (OR) 1.2, 95% confidence interval (CI) 1.05-1.4, P = 0.002]. Presence of mild-moderate (grades II and III) hepatic iron deposits could be excluded with high negative predictive value (90%) when serum ferritin was within normal values. A significant correlation between coinfection with HDV and hepatic iron deposits was also found (OR 4.23, 95% CI 1.52-11.82, P = 0.003). When compared to monoinfected cases, HDV positive patients had more elevated γGT ( P = 0.03), more advanced fibrosis and more severe iron deposits ( P < 0.0001). In conclusion, in well-compensated chronic hepatitis B infection, hepatic iron deposits and elevation of serum iron indices are common, especially in male gender and in patients coinfected with HDV. As HBV/HDV liver disease is generally more rapidly progressive than that caused by HBV monoinfection, we speculate that iron overload may be one of the factors contributing to the severity of liver disease. [ABSTRACT FROM AUTHOR]

Summary. Chronic hepatitis C represents a major cause of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications. Formation and accumulation of fibrosis in the liver is the common pathway that leads to evolutive liver disease. Precise staging of liver fibrosis is essential for patient management in clinical practice because the presence of bridging fibrosis represents a strong indication for antiviral therapy, while cirrhosis requires a specific follow-up. Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis, but it has limitations: it is invasive, costly and prone to sampling errors. Recently, blood markers and instrumental methods have been proposed for the noninvasive assessment of liver fibrosis in hepatitis C. However, international guidelines do not recommend the widespread use of noninvasive methods for liver fibrosis in clinical practice. This is because of, in some cases, unsatisfactory accuracy and incomplete validation of others. Some studies suggest that the effectiveness of noninvasive methods for assessing liver fibrosis may increase when they are combined, and a number of sequential and synchronous algorithms have been proposed for this purpose, with the aim of reducing rather than substituting liver biopsies. This may represent a rational and reliable approach for implementing noninvasive assessment of liver fibrosis in clinical practice. It could allow more comprehensive first-line screening of liver fibrosis in hepatitis C than would be feasible with liver biopsy alone. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2012; 35: 92-104 Summary Background Preliminary data suggest that performance of non-invasive markers for liver fibrosis in hepatitis C may improve when combined. Three algorithms based on the combination of Fibrotest, Forns' index and AST-to-platelet ratio (APRI) have been proposed: Sequential Algorithm for Fibrosis Evaluation (SAFE biopsy); Fibropaca algorithm; Leroy algorithm. Aim To compare three algorithms to diagnose significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4). Methods A total of 1013 HCV monoinfected cases undergoing liver biopsy were consecutively enrolled in seven centres. Fibrotest, APRI and Forns' index were measured at the time of liver biopsy, considered the reference standard. Results Overall, performance of combination algorithms was significantly higher than the single non-invasive methods ( P < 0.0001). SAFE biopsy and Fibropaca algorithm saved a significantly higher number of liver biopsies than the single methods ( P < 0.0001). For ≥F2, Fibropaca algorithm saved more biopsies than SAFE biopsy (51.7% vs. 43.8%, P = 0.0003), but with lower accuracy (87.6% vs. 90.3%, P = 0.05). Regarding F4, the number of saved liver biopsies did not differ between SAFE biopsy and Fibropaca algorithm (79.1% vs. 76.2%, P = 0.12). However, SAFE biopsy showed a lower accuracy when compared with Fibropaca algorithm (91.2% vs. 94%, P = 0.02). As to Leroy algorithm, although it showed a good performance for ≥F2 (93.5% accuracy), it saved less liver biopsies than SAFE biopsy and Fibropaca algorithm (29.2% vs. 43.8% and 51.7% respectively, P < 0.0001). Conclusions SAFE biopsy and the Fibropaca algorithm have excellent performance for liver fibrosis in hepatitis C, allowing a significant reduction in the need for liver biopsies. They can be useful in clinical practice and for large-scale screening. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2011; 34: 1202-1216 Summary Background Performance of non-invasive fibrosis biomarkers may be influenced by aetiology of chronic liver disease (CLD) and the stages of hepatic fibrosis, but large-scale studies are pending. Aim To investigate the effect of aetiogy and stages of hepatic fibrosis on the performance of fibrosis biomarkers. Methods A total of 2411 patients with compensated CLD (HCV = 75.1%, HBV = 10.5%, NASH = 7.9%, HIV/HCV = 6.5%) were consecutively enrolled in 9 centres. APRI, Forns'index, Lok index, AST-to-ALT ratio, Fib-4, platelets and Fibrotest-Fibrosure were tested against liver biopsy, considered the gold standard. The effect of the stages of hepatic fibrosis to diagnose significant fibrosis and cirrhosis (≥F2 and F4 respectively) was investigated through difference between advanced and non-advanced fibrosis stages (DANA). Performance was expressed as observed area under the ROC curve (ObAUROC) and AUROC adjusted for DANA (AdjAUROC). Results Performance of APRI and Fibrotest-Fibrosure was higher than other biomarkers. In all aetiologies, AdjAUROC was higher than ObAUROC. APRI showed its best performance in HCV monoinfected cases, with an AdjAUROC of 0.77 and 0.83 for ≥F2 and F4 respectively. In HBV and non-alcoholic steatohepatitis (NASH) patients, its performance was poor (AdjAUROC <0.70). Performance of Fibrotest-Fibrosure was good in all aetiologies for both ≥F2 and F4 (AdjAUROC >0.73), except for ≥F2 in NASH (AdjAUROC = 0.64). Performance of all biomarkers was reduced in HCV cases with normal ALT. Conclusions Aetiology is a major factor influencing the performance of liver fibrosis biomarkers. Even after correction for DANA, APRI and Fibrotest-Fibrosure exhibit the best performance. However, liver biopsy is not replaceable, especially to diagnose ≥F2 and in HCV carriers with normal ALT. [ABSTRACT FROM AUTHOR]

Background Hedgehog pathway plays an important role during pancreas development, when its inactivation is crucial to assure expression of pancreatic marker genes involved in the organ formation and to assure an appropriate organogenesis. Patched1 (Ptch1) is a transmembrane receptor of hedgehog pathway which has a key role in this process. In fact, heterozygous Ptch1 mutant (ptc+/−) mice are affected by an impaired glucose tolerance accompanied by reduced islet function. In the light that the cell distribution of Ptch1 receptor within the endocrine pancreas has not yet been established, we aimed at identifying the pancreatic endocrine cell subset(s) expressing such molecule. Methods Double immunostaining for Ptch1 and pancreatic hormones insulin, glucagon and somatostatin on pancreatic paraffin sections of C57BL/6J mice and human non-diabetic multiorgan donors was performed and analysed using confocal microscopy. In addition, diabetes was experimentally induced in mice by intraperitoneal injection of streptozotocin. Quantitative real-time polymerase chain reaction after laser-capture microdissection of different islets from frozen pancreatic murine tissue sections was also performed. Results Ptch1 receptor was detected only in somatostatin-positive delta cells both in mice and in human pancreas; in mice its expression was not affected by streptozotocin treatment. A significant increase of Ptch1 mRNA expression levels in the islet periphery versus the islet core was observed by quantitative real-time polymerase chain reaction, in accord with immunohistochemical observations. Conclusion Our data show a delta-cell-specific expression of Ptch1 receptor in murine and human pancreas. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A major drawback of asymmetric incremental sheet forming (AISF) is the long cycle time. AISF is known in general as forming of a sheet metal by only one small forming zone. The developed concepts presented in this paper aim at decreasing the main process time by applying several forming zones on the part through multiple tools working in parallel. By the use of a systematic design process, four major structural tooling concepts were invented. Those variants were compared to each other by a cost-utility analysis. As a result, a prototype with two tools was produced to fasten the AISF process. [ABSTRACT FROM AUTHOR]

Objective: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. Patients and methods: Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up. Results: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed. Conclusion: The data confirm that a LD IVCY regimen followed by AZA—the “Euro-Lupus regimen”—achieves good clinical results in the very long term. [ABSTRACT FROM PUBLISHER]

Genetic, environmental, and hormonal factors contribute to disease susceptibility in systemic lupus erythematosus. Among environmental factors, infectious agents play a major role. When considering the complex relationship between genetic predisposition and infections in the pathogenesis of systemic lupus erythematosus, we have to consider that infectious agents can interact with the immune system in several ways. For example, molecular mimicry, altered apoptosis of the host cells, exposure of as yet masked antigens to the immune system by a given microorganism, and direct viral invasion of immunocompetent cells are all mechanisms that may give rise to dysfunction of the immune system; in addition, some genetically determined deficit of the immune system, such as complement deficiency or deficit of mannose binding lectine, may cause insufficient clearance of infectious agents, whose persistence in the host may determine autoimmunity. Finally, evidence has been emerging suggesting that the production of autoantibodies, by infected B-lymphocytes, may be drawn by altered expression of particular microRNA in these cells. In this paper, we review some of the distinct scenarios that can account for the role of infectious agents, acting on a genetically prone host, in determining systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Understanding the pathogenesis of systemic lupus erythematosus (SLE) remains a considerable challenge. Multiple abnormalities of both the innate and adaptive immune system have been described and, furthermore, immunological dysfunction precedes clinical presentation by many years. There is a strong genetic basis to SLE, which means that genetic studies can play a key role in furthering our understanding of this disease. Because susceptibility variants are present from birth and are unaffected by the course of the disease, or by its treatment, genetic analysis is, perhaps uniquely, capable of identifying fundamental, causative, disease mechanisms. In this article, we review our SLE immunogenetic studies performed in collaboration with the European Working Party on Systemic Lupus Erythematosus. By considering the results of our research and the recent advances obtained by genome-wide associations' studies, we can begin to understand how dysregulation at a number of key immunological steps may predispose to the development of SLE. [ABSTRACT FROM AUTHOR]

This article focuses on the realization of a simple and kinematic tool setup for incremental sheet metal forming. It allows achieving a similar geometrical accuracy like a full specific support, but minimizes the tool setup and increases the process flexibility at the same time. In incremental sheet metal forming different process variants are in use. The simplest one is the single point incremental forming process which works with a single forming tool and does not require any support. The partially supported incremental forming process uses a simple tool setup for a static support of the sheet when forming only in local areas. In the fully supported incremental forming process a specific die is used which includes the geometry of the part to be manufactured. Here, a good geometrical accuracy can be achieved, but expensive and specific tools are needed for the support. In the full kinematic incremental forming process both the forming tool and the supporting tool move synchronously in three axes. This process is very flexible regarding the part geometry and promises a good accuracy. However, the mechanical setup is very complex and requests a specialized machine. The setup described in this article includes a kinematic support which can be mounted on a conventional milling machine. The presented dynamic support consists of an exchangeable support tool, which is fixed on a rotating plate. During the incremental forming process the dynamic support moves synchronously with the forming tool. This way, a flexible forming with simple tools and low costs is realized. The parts manufactured by the Dyna-Die have been compared to parts which were produced using a full and a partial static support as well as without any support. The discussion of the results completes this contribution. [ABSTRACT FROM AUTHOR]

In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Few studies investigated noninvasive markers of liver fibrosis in hepatitis C virus (HCV) patients with normal alanine aminotrasferase (NALT). Eighty HCV patients with NALT and 164 HCV patients with elevated alanine aminotrasferase (EALT) who underwent a diagnostic liver biopsy were evaluated for AST-to-platelet ratio, Forns’ index, AST-to-ALT ratio (AAR), Fibrotest and the recently proposed Fibroindex, using liver histology as reference standard. The primary end-point was the detection of significant fibrosis (≥F2). Performance of noninvasive markers was expressed as specificity, sensitivity and positive (PPV) and negative (NPV) predictive value, accuracy and area under the receiver operating characteristic curve (AUROC). All noninvasive markers for liver fibrosis tested showed a poorer performance in NALT group than in EALT group. Overall, Fibrotest had the best performance in NALT group, as showed by AUROC of 0.70 and 73.5% accuracy. Performance of AAR, Forns’ index and Fibroindex was poor in NALT group and it was significantly lower than in EALT group for Forns and Fibroindex (AUROC 0.6 vs 0.76 and 0.58 vs 0.74, respectively, P = 0.05). In NALT patients, PPV was high for all noninvasive markers (>87%) except for AAR, while NPV was low (<65%), thus none of them was able to reliably exclude significant fibrosis. In conclusion, performance of noninvasive-markers is significantly reduced in HCV patients with NALT. Liver biopsy may still be needed for many of these cases to correctly stage liver fibrosis. Specific noninvasive tools and possibly combination of markers should be developed and validated in this clinical setting. [ABSTRACT FROM AUTHOR]

Background Pegylated interferon (PEG-IFN) alpha2b is currently used as a once weekly injection in combination with ribavirin for the treatment of chronic hepatitis C. Aim To test whether twice half-dose weekly administration may improve the virological response in difficult-to-treat hepatitis C virus-1 patients. Methods Thirty patients were treated with 1.5 μg/kg of PEG-IFN alpha2b given once weekly for 48 weeks (group A) and were compared with 30 patients treated with the same dose of PEG-IFN alpha2b divided in twice weekly doses of 0.75 μg/kg for the initial 4 weeks (group B). All patients were hepatitis C virus-1 positive and received weight-based ribavirin (800–1400 mg/daily). Results Weekly twice half-dose administration of PEG-IFN alpha2b for the first 4 weeks was associated with lower rates of biochemical and virological response at all time points compared with a once weekly schedule, and with significantly higher rates of in-therapy breakthrough leading to significantly lower rates of end of therapy response (week 48). The rate of sustained virological response was of 56.7% in group A and 36.7% in group B. Conclusions Weekly twice half-dose administration of PEG-IFN alpha2b is not superior to the standard once weekly schedule, and might be less efficacious. [ABSTRACT FROM AUTHOR]

Genetic variation in the interferon regulatory factor 5 (IRF5) gene affects systemic lupus erythematosus (SLE) susceptibility. However, association is complex and incompletely defined. We obtained fourteen European sample collections with a total of 1383 SLE patients and 1614 controls to better define the role of the different IRF5 variants. Eleven polymorphisms were studied, including nine tag single nucleotide polymorphisms (SNPs) and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility (rs10488631, P<10−17) and protection (rs729302, P<10−6). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression, a splice variant with a different exon 1 and a longer proline-rich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5′ side of the gene. In conclusion, our results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, we have found evidence for epistasis between known functional polymorphisms for the susceptibility effect.Genes and Immunity (2007) 8, 429–438. doi:10.1038/sj.gene.6364407; published online 14 June 2007 [ABSTRACT FROM AUTHOR]

We obtained eight collections of DNA samples from ethnically matched systemic lupus erythematosus (SLE) patients and controls from five European countries totaling 783 patients and 1210 controls. A highly significant cline in the frequency of the PD1.3 A allele was found among controls but not among SLE patients. The frequency of the PD1.3 A allele increased from the Northeast to the Southwest of Europe. The cline was clearly apparent (P=1.2 × 10−6) when data from controls of other five SLE susceptibility studies were included in the analysis. This variation has severely biased SLE association studies owing to the lack of parallel changes in SLE patients. As a consequence, the PD1.3 A allele was more common in SLE patients than in controls in the Northeast and Center of Europe, similar to controls in Southeast Europe, and less frequent than in the controls in the Southwest of the Continent. This dissociation in allele frequencies between SLE patients and controls in different subpopulations indicated that programmed cell death 1 variation and disease susceptibility are not independent but the type of relationship is currently unclear. As allele frequency clines are common in other polymorphisms their impact in genetic epidemiology studies should be carefully considered.Genes and Immunity (2007) 8, 138–146. doi:10.1038/sj.gene.6364370; published online 18 January 2007 [ABSTRACT FROM AUTHOR]

In Fricke-agarose gels, an accurate determination of the spatial dose distribution is hindered by the diffusion of ferric ions. In this work, a model was developed to describe the diffusion process within gel samples of finite length and, thus, permit the reconstruction of the initial spatial distribution of the ferric ions. The temporal evolution of the ion concentration as a function of the initial concentration is derived by solving Fick's second law of diffusion in two dimensions with boundary reflections. The model was applied to magnetic resonance imaging data acquired at high spatial resolution (0.3 mm) and was found to describe accurately the observed diffusion effects. [ABSTRACT FROM AUTHOR]

Hepatic iron has been described in hepatitis C virus (HCV) infection as an important cofactor of disease outcome. The mechanisms leading to hepatic iron deposits (HIDs) in HCV patients are partially understood. We investigated HIDs in the liver biopsies of a consecutive series of 242 HCV-infected patients with well-compensated liver disease. Serum ferritin was elevated in 20.7% and transferrin saturation in 19.0%, while 38.8% had stainable HIDs indicating that serum markers of systemic iron overload have low sensitivity in predicting HIDs in hepatitis C. A cut-off value of serum ferritin (350 μg/L in females and 450 μg/L in males) had good negative predictive value in excluding presence of mild–moderate HIDs (grade II–III). Hepatic iron deposits correlated by multivariate analysis with serum ferritin [odds ratio (OR) 1.008, 95% confidence interval (CI) 1.005–1.011] and albumin (OR 1.15, 95% CI 1.02–1.297). Hepatic iron deposits were more frequent in HCV-3-infected cases than in other genotypes ( P = 0.027) while raised serum iron indices were more frequent in non-HCV-3 genotypes ( P = 0.02). Furthermore, advanced fibrosis (F3–F4 by METAVIR) was more frequent in non-HCV-3 genotypes ( P = 0.04). In HCV-3 cases there was a close association between HIDs and severe (grade II–III) steatosis ( P < 0.00001). These results indicate that in well-compensated chronic hepatitis C HIDs are strongly associated with HCV-3 and viral-induced hepatic steatosis, while in the presence of other genotypes they might merely reflect a more advanced stage of liver disease and/or a systemic iron overload. Serum ferritin could identify a subgroup of patients in which the need of venesection could be excluded without liver biopsy. [ABSTRACT FROM AUTHOR]

Prenatal growth restraint associates with the risk for later diabetes, particularly if such restraint is followed by postnatal formula-feeding (FOF) rather than breast-feeding (BRF). Circulating incretins can influence the neonatal programming of hypothalamic setpoints for appetite and energy expenditure, and are thus candidate mediators of the long-term effects exerted by early nutrition. We have tested this concept by measuring (at birth and at age 4 months) the circulating concentrations of glucagon-like peptide-1 (GLP-1) in BRF infants born appropriate-for-gestational-age (AGA; n=63) and in small-for-gestational-age (SGA) infants receiving either BRF (n=28) or FOF (n=26). At birth, concentrations of GLP-1 were similar in AGA and SGA infants. At 4 months, pre-feeding GLP-1 concentrations were higher than at birth; SGA-BRF infants had GLP-1 concentrations similar to those in AGA-BRF infants but SGA-FOF infants had higher concentrations. In conclusion, nutrition appears to influence the circulating GLP-1 concentrations in SGA infants and may thereby modulate long-term diabetes risk. [ABSTRACT FROM AUTHOR]