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• In our cohort, individuals with MASLD showed increased levels of homocysteine (Hcy). • High Hcy levels characterize increased risk for metabolic-associated steatotic liver disease (MASLD) development even when accounting for potentially confounding variables like age and sex. • Identifying patients with hyperhomocysteinemia could help clinicians targeting patients at increased risk of MASLD. Homocysteine (Hcy) levels are elevated in different conditions, including cardiovascular diseases (CVD), diabetes, and metabolic-associated steatotic liver disease (MASLD). In this observational retrospective study, we analyzed Hcy levels in a population of 901 outpatients, considering its putative etiological role in MASLD. A total of 901 outpatients underwent physical and biochemical evaluations. Abdominal and carotid ultrasound were performed to assess liver steatosis, carotid intima-media thickness (IMT) and presence of atherosclerotic plaque. Hyperhomocysteinemia (HHcy) was identified in 140 subjects (16 %). Patients with HHcy showed glucose metabolism impairment (p < 0.001), altered lipid profile (p < 0.001), low Vitamin D levels (p < 0.0001), increased cardiovascular risk (p < 0.001). We then investigated the relationship between Hcy and MASLD (OR=3.6, p < 0.0001), finding that the relationship remained significant also when accounting for confounding variables (age, sex) (OR=3.2, p < 0.0001). Hcy values were significantly higher (p < 0.0001) in patients with MASLD (n = 78, 29.4 ± 10.1μmol/l) compared to those without MASLD (20.4 ± 4.8 1μmol/l). Furthermore, in MASLD patients we found a direct correlation between Hcy level and waist circumference (r = 0.3, p < 0.001) and an inverse correlation with both HDL-c (r =-0.4, p < 0.001) and Vitamin D levels (r =-0.24, p < 0.05). Our data suggest an intriguing scenario whereby HHcy is present in patients with MASLD and is associated to lower vitamin D and altered glucose and lipid profile. Thus, considering Hcy levels may help clinicians with the management of patients with increased MASLD risk. [ABSTRACT FROM AUTHOR]

Through the lenses of Entrepreneurial Event Theory and the Affective Processing Principle, this study aims to explore the interplay between cognition and emotion in the entrepreneurship education-entrepreneurial intention link, exploring the specific role of fear, conceptualized as a negative, avoidance-oriented, emotion. A moderation- mediation empirical model was tested on a sample of Italian University students. The results of the study discovered significant interactions. Fear decreases all the direct and mediating relations, suggesting that an assessment of the importance of emotions in the students' learning and decision-making processes is a vital issue that entrepreneurship scholars are advised to take into account to foster the formation of intentional behavior. Theoretical advancements and implications for academics, professors, and students will be finally discussed. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by the presence of hepatic steatosis, detected on ultrasonography (US) imaging or histology, and at least one of criteria for Metabolic Syndrome diagnosis. Simple non-invasive tests (NITs) have been proposed as an acceptable alternative when US and biopsy are not available or feasible but have not been validated for MASLD. In this observational study, we investigated the reliability of NITs for MASLD detection and whether sex-differences in screening methods should be considered. Methods: We included 1069 individuals (48% males and 52% females) who underwent their first clinical examination for Metabolic Syndrome in the period between January 2015 and December 2022. Liver steatosis was detected through US and anthropometric and clinical parameters were recorded. Results: Liver steatosis was detected in 648 patients and MASLD was diagnosed in 630 subjects (355 males; 275 females). Women with MASLD showed better metabolic profile and lower prevalence of Metabolic Syndrome criteria than men. Among NITs, Fatty Liver Index (FLI) showed the best ability for detection of MASLD, with a cut-off value of 44 (AUC = 0.82). When considering the two sexes for MASLD detection via FLI, despite no substantial differences regarding FLI correlations with metabolic biomarkers except for age, women showed marked lower FLI cut-off value (32; AUC = 0.80) than men (60; AUC = 0.80). Conclusions: In this study, we found that FLI is the best non-invasive predictor of both liver steatosis and MASLD. The finding that in women FLI cut-off value for MASLD detection is 50% lower than in men suggests the need of a sex-specific personalized program of screening and prevention of dysmetabolism-related liver diseases, despite outwardly healthy biomarkers profile. Plain English Summary: Fatty liver disease is caused by the accumulation of fat into the liver and it is associated to increased risk of chronic diseases. Diagnosis of fatty liver is based on biopsy or ultrasound assessment but when these procedures are not available or feasible also some non-invasive scores have been showed to be reliable measures of this condition. In this study we compared the use of ultrasound and non-invasive scores to assess liver steatosis and associated metabolic disease, finding that Fatty Liver Index (FLI) is the best score for these diagnosis. Surprisingly, in women FLI cut-off value is 50% lower than in men, suggesting that different sex-specific factors may come into play in the development and evolution of liver steatosis. Thus, we suggest the need of a sex-specific personalized program of screening and prevention of dysmetabolism-related liver diseases. Highlights: Simple non-invasive tests (NITs) have been proposed to assess liver steatosis and fibrosis but have not been validated for MASLD, a disease that shows different features and prevalence in the two sexes; We show here that Fatty liver Index (FLI) is the best NIT for predicting MASLD and that its cut-off value is 50% lower in women than in men; We suggest the need of a sex-specific personalized program of screening and prevention of dysmetabolism-related liver diseases, despite outwardly healthy biomarkers profile. [ABSTRACT FROM AUTHOR]

Forensic autopsy is an important tool for the proper management of non-natural deaths in minors. However, it seems that autopsy in minors is a practice which may not be performed routinely. In this framework, we conducted a study analyzing autopsies of minors (under 18 years of age in Italy) performed at the Institute of Forensic Medicine in Milan in the period 2001–2019. For the period 2015–2019, we extrapolated all deaths due to non-natural causes in minors to investigate how many and which of these deaths were not subjected to forensic autopsy. Of the total, 344 minors (235 males and 109 females) underwent autopsies, with an overall downward trend of about 80% since 2004. Most autopsies occurred between the ages of 0 and 1 year, and the fewest between the ages of 5 and 9 years. The place of death was home in most cases, and accidental death was most common, followed by natural death, suicide, and homicide, with prevalence varying by age group. Blunt force trauma predominated among accidental death in all age groups, followed by asphyxia. Similar findings were observed for suicides, although there was a more differentiated pattern for suicides between the ages of 15 and 17 years. Among homicides, blunt force trauma, asphyxia, and gunshot wounds were fairly evenly distributed across all age groups. Between 2015 and 2019, a total of 86 minors died of a non-natural cause, and a forensic autopsy was performed in only 33 cases (38%). Our data shows that fewer and fewer autopsies are being performed over the last years, which indicates a dangerous lack of forensic investigation of children and adolescent deaths, with enormous implications for prevention of child abuse. [ABSTRACT FROM AUTHOR]

Background: In forensic pathology, asphyxia presents a problem as frequently as it is thorny and challenging. Some knowledge in forensic pathology is still considered to be traditionally acquired and is not critically assessed with modern statistical or technical tools. In this study, we seek to examine the injuries that are considered to be typical of cases of hanging (neck lesions, haemorrhages, and pleural and epicardial petechiae). Methods: We evaluated whether there was, indeed, a statistically significant association between these injuries and deaths from hanging as compared to non-hanging deaths. We collected 399 cases (32 deaths by hanging and 367 cases of non-hangings), built contingency tables and performed chi-square tests for each variable (lesion) examined; we also analysed this association in various subgroups of the sample (according to sex, age and weight ranges). Results: Our results did not deviate from the expected outcome based on traditional knowledge, although they do provide a more detailed demonstration and clarification of traditional knowledge regarding this topic. Conclusions: These findings provide valuable insights for future discussion, examination and deepening of knowledge that is traditionally accepted but often undersupported in the literature. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), specifically liver steatosis and fibrosis with steatohepatitis (NASH), is often associated with visceral adiposopathy, whose pathogenetic features have been proposed as tumorigenic triggers. We performed a prospective analysis in 653 metabolic women to reveal any conditions that may predict and concur to cancer development during a 8-years period of follow-up. Among clinical and biochemical variables, only AST and non-invasive liver fibrosis scores (AARPRI, APRI, FIB-4, mFIB4) significantly distinguished cancer-developer women (n = 62, 9.5%) from those who did not develop cancer (p < 0.001). In ROC analysis, these scores also showed good sensitivity and specificity in differentiating women who developed cancer (all p < 0.001). We then calculated OR for these indexes finding that increased AARPRI was associated with the highest risk (OR = 6, p < 0.001) of gynaecological cancers development. We further validated these cut-off values in women who had developed other types of cancer, confirming that AARPRI is able to identify the risk for cancer development (OR = 5, p < 0.001). Our findings support the hypothesis that NAFLD, more than obesity per se, is directly associated with the clinical and pathogenic metabolic scenario of gynaecological cancers and encourage the use of liver fibrosis indexes to detect risk of cancer onset in women. Preventing adiposopathy and NAFLD through lifestyle and therapies may represent an instrumental strategy for cancer prevention and/or co-treatment in oncology. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), specifically liver steatosis and fibrosis with steatohepatitis (NASH), is often associated with visceral adiposopathy, whose pathogenetic features have been proposed as tumorigenic triggers. We performed a prospective analysis in 653 metabolic women to reveal any conditions that may predict and concur to cancer development during a 8-years period of follow-up. Among clinical and biochemical variables, only AST and non-invasive liver fibrosis scores (AARPRI, APRI, FIB-4, mFIB4) significantly distinguished cancer-developer women (n = 62, 9.5%) from those who did not develop cancer (p < 0.001). In ROC analysis, these scores also showed good sensitivity and specificity in differentiating women who developed cancer (all p < 0.001). We then calculated OR for these indexes finding that increased AARPRI was associated with the highest risk (OR = 6, p < 0.001) of gynaecological cancers development. We further validated these cut-off values in women who had developed other types of cancer, confirming that AARPRI is able to identify the risk for cancer development (OR = 5, p < 0.001). Our findings support the hypothesis that NAFLD, more than obesity per se, is directly associated with the clinical and pathogenic metabolic scenario of gynaecological cancers and encourage the use of liver fibrosis indexes to detect risk of cancer onset in women. Preventing adiposopathy and NAFLD through lifestyle and therapies may represent an instrumental strategy for cancer prevention and/or co-treatment in oncology. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), specifically liver steatosis and fibrosis with steatohepatitis (NASH), is often associated with visceral adiposopathy, whose pathogenetic features have been proposed as tumorigenic triggers. We performed a prospective analysis in 653 metabolic women to reveal any conditions that may predict and concur to cancer development during a 8-years period of follow-up. Among clinical and biochemical variables, only AST and non-invasive liver fibrosis scores (AARPRI, APRI, FIB-4, mFIB4) significantly distinguished cancer-developer women (n = 62, 9.5%) from those who did not develop cancer (p < 0.001). In ROC analysis, these scores also showed good sensitivity and specificity in differentiating women who developed cancer (all p < 0.001). We then calculated OR for these indexes finding that increased AARPRI was associated with the highest risk (OR = 6, p < 0.001) of gynaecological cancers development. We further validated these cut-off values in women who had developed other types of cancer, confirming that AARPRI is able to identify the risk for cancer development (OR = 5, p < 0.001). Our findings support the hypothesis that NAFLD, more than obesity per se, is directly associated with the clinical and pathogenic metabolic scenario of gynaecological cancers and encourage the use of liver fibrosis indexes to detect risk of cancer onset in women. Preventing adiposopathy and NAFLD through lifestyle and therapies may represent an instrumental strategy for cancer prevention and/or co-treatment in oncology. [ABSTRACT FROM AUTHOR]

Altered expression of circular RNAs (circRNAs) has previously been investigated in breast cancer. However, little is known about the effects of drugs on their regulation and relationship with the cognate linear transcript (linRNA). We analyzed the dysregulation of both 12 cancer-related circRNAs and their linRNAs in two breast cancer cell lines undergoing various treatments. We selected 14 well-known anticancer agents affecting different cellular pathways and examined their impact. Upon drug exposure circRNA/linRNA expression ratios increased, as a result of the downregulation of linRNA and upregulation of circRNA within the same gene. In this study, we highlighted the relevance of identifying the drug-regulated circ/linRNAs according to their oncogenic or anticancer role. Interestingly, VRK1 and MAN1A2 were increased by several drugs in both cell lines. However, they display opposite effects, circ/linVRK1 favors apoptosis whereas circ/linMAN1A2 stimulates cell migration, and only XL765 did not alter the ratio of other dangerous circ/linRNAs in MCF-7. In MDA-MB-231 cells, AMG511 and GSK1070916 decreased circGFRA1, as a good response to drugs. Furthermore, some circRNAs might be associated with specific mutated pathways, such as the PI3K/AKT in MCF-7 cells with circ/linHIPK3 correlating to cancer progression and drug-resistance, or NHEJ DNA repair pathway in TP-53 mutated MDA-MB-231 cells. [ABSTRACT FROM AUTHOR]

Many animals learn to recognize conspecifics after an early experience with them through sexual imprinting. For brood parasitic birds, it is not possible to develop conspecific recognition using cues provided by their foster parents. One solution is that a unique species-specific signal triggers the learning of additional aspects of the conspecific's phenotype. It has been proposed that for brood parasitic cowbirds, this signal is an innate vocalization, the chatter. This vocalization might act in a cross-modal learning process through which juveniles that listen to the song learn to recognize the visual characteristics of the song's producer. We trained two groups of juvenile shiny cowbirds (Molothrus bonariensis). In one group, individuals listened to the chatter or a heterospecific call while they observed a stuffed model of the corresponding species. In the other group, individuals listened to the call of one species (cowbird or heterospecific) while they observed the stuffed model of the other species. In the preference test, juveniles chose the model associated with the chatter, regardless of whether the model was a cowbird or a heterospecific. These results show how the auditory system through a species-specific signal can lead to cross-modal learning of visual cues allowing conspecific recognition in brood parasitic cowbirds. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we investigated human genes encoding circular RNAs (circRNAs) in order to shed light on their functional role, which is still under debate. We identified 183 genes encoding circRNAs differentially expressed in cancer tissues with a novel coding potential. Our data suggest that circRNAs might directly affect cellular and systemic processes in cancer by generating novel members of the human proteome. circRNAs constitute a novel class of RNA, generally considered as non-coding RNAs; nonetheless, their coding potential has been under scrutiny. In this work, we systematically explored the predicted proteins of more than 160,000 circRNAs detected by exome capture RNA-sequencing and collected in the MiOncoCirc pan-cancer compendium, including normal and cancer samples from different types of tissues. For the functional evaluation, we compared their primary structure and domain composition with those derived from the same linear mRNAs. Among the 4362 circRNAs potentially encoding proteins with a unique primary structure and 1179 encoding proteins with a novel domain composition, 183 were differentially expressed in cancer. In particular, eight were associated with prognosis in acute myeloid leukemia. The functional classification of the dysregulated circRNA-encoded polypeptides showed an enrichment in the heme and cancer signaling, DNA-binding, and phosphorylation processes, and disclosed the roles of some circRNA-based effectors in cancer. [ABSTRACT FROM AUTHOR]

Discovering novel risk and prognostic factors for COVID-19 may help not only in reducing severity and mortality but also in creating targeted therapies considering patients' individual features. Liver fibrosis is considered a complication in Non-alcoholic Fatty Liver Disease (NAFLD), it is a feature of steatohepatitis (NASH), and it has already been related to an increased risk for a wide range of diseases. Here, we aimed to define if any parameter assessing metabolic status has predictive power in identifying inpatients at risk for poorer prognosis and an increased mortality from COVID-19. This retrospective study was conducted at the Sub-Intensive Medicine Care Unit of the Presidio Maxi-Emergenze Fiera del Levante, Azienda Ospedaliero-Universitaria Policlinico di Bari, Italy. We evaluated 271 inpatients with moderate-to-severe SARS-CoV-2-related respiratory failure by comparing biochemical features and non-invasive liver fibrosis scores among discharged, transferred to Intensive Care Units (ICU) and non-survivor patients. Moreover, by performing ROC curves, we defined cut-off values to predict mortality and disease severity for each score. We found that non-invasive scores of liver fibrosis, obtained at day of admission, such as AAR (p < 0.001), FIB-4 and mFIB-4, FORNS, and AARPRI (p < 0.05) strongly predict not only in-hospital mortality but also the length of hospitalization and eventual admission to ICU. FIB-4 was the best score to identify non-survivor patients (sensitivity of 80% and specificity of 63%) and predict the need for ICU or mortality (71% of sensitivity and 65% of specificity), with a cut-off value of 1.94. Therefore, we present the predictive power and the cut-off values of several liver fibrosis scores here for disease severity and mortality in SARS-CoV-2 in-patients and we proposed the use of the present scores to identify ab initio the clinical therapeutic and diagnostic protocols for high-risk patients. [ABSTRACT FROM AUTHOR]

• The KLB rs17618244 variant increases the risk of ballooning and lobular inflammation in children with NAFLD. • KLB plasma levels are lower in carriers of the rs17618244 minor A allele. • KLB plasma levels are associated with lobular inflammation, ballooning and fibrosis. • KLB mutant induces intracellular lipid accumulation in HepG2 and Huh7. • KLB mutant causes upregulation of lipotoxic and proinflammatory genes. Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined. We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant. The KLB rs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression. In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes. Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is a common herpesvirus that may cause asymptomatic infection or various diseases, such as mononucleosis, lymphoproliferative disorders and several cancers. Our objective was to estimate the prevalence of EBV among patients hospitalized in "Luigi Vanvitelli" University Hospital in the last 10 years. Our results showed that EBV seroprevalence in our geographical area was 65%. Seroprevalence increased gradually with age with no significant difference between females (49.42%) and males (50.58%). The seropositivity for primary infection was higher in patients about 5 years old, while seropositivity for past infection was predominant in patients of about 35 years old. These results underline that children in our country are still exposed to EBV. The development and the deeper use of an EBV vaccine in the early years of life could represent the solution for this infection. [ABSTRACT FROM AUTHOR]

The interpretation of cranial base injuries has never been investigated from a purely anthropological perspective. Very little exists in forensic literature in order to interpret the significance of cranial base fractures. We analyzed 296 cases of deaths due to skull–brain injuries. The frequency of vault fractures was 75.7% and that of base fractures was 91.9%. We observed the distribution of cases of death according to manner of death and manner of injury and number of fossae involved. These observations were analytically compared to different variables (age, sex, manner of injury, and mode of injury). The study presented the proportion of base fractures associated with vault fractures, and the frequency of absence of base fracture in subjects with no vault fractures. Interesting associations of base fractures to age and manner of death are shown. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Due to the high incidence of post-operative recurrence after current treatments, the identification of new and more effective drugs is required. In previous years, new targetable genes/pathways involved in HCC pathogenesis have been discovered through the help of high-throughput sequencing technologies. Mutations in TP53 and β-catenin genes are the most frequent aberrations in HCC. However, approaches able to reverse the effect of these mutations might be unpredictable. In fact, if the reactivation of proteins, such as p53 in tumours, holds great promise as anticancer therapy, there are studies arguing that chronic activation of these types of molecules may be deleterious. Thus, recently the efforts on potential targets have focused on actionable mutations, such as those occurring in the gene encoding for focal adhesion kinase (FAK). This tyrosine kinase, localized to cellular focal contacts, is over-expressed in a variety of human tumours, including HCC. Moreover, several lines of evidence demonstrated that FAK depletion or inhibition impair in vitro and in vivo HCC growth and metastasis. Here, we provide an overview of FAK expression and activity in the context of tumour biology, discussing the current evidence of its connection with HCC development and progression. [ABSTRACT FROM AUTHOR]

Increased intracranial pressure (ICP) secondary to severe brain injury is common. Increased ICP is commonly encountered in malignant middle cerebral artery ischemic stroke, traumatic brain injury, subarachnoid hemorrhage, and intracerebral hemorrhage. Multiple interventions—both medical and surgical—exist to manage increased ICP. Medical management is used as first-line therapy; however, it is not always effective and is associated with significant risks. Decompressive hemicraniectomy is a surgical option to reduce ICP, increase cerebral compliance, and increase cerebral blood perfusion when medical management becomes insufficient. The purpose of this review is to provide an up-to-date summary of the use of decompressive hemicraniectomy for the management of refractory elevated ICP in malignant middle cerebral artery ischemic stroke, traumatic brain injury, subarachnoid hemorrhage, and intracerebral hemorrhage. [ABSTRACT FROM AUTHOR]

Plastic Bag Suffocation is a rare cause of death in developed countries and almost unknown in the rest of the world. This study aims to retrospectively evaluate cases of PBS _asphyxia in Milan's Department of Legal Medicine from 1993 to 2013. Cases were selected from the database of 21,472 autopsies performed in the considered timeframe. One hundred and one cases were considered to be cases of Plastic Bag Suffocation, comprised of 100 suicides, no accidental events and 1 homicide. The most relevant elements pertaining to this type of death were evaluated for both the corpses and the crime scenes. From this study the typical PBS victim is an adult male, aged 52.3 years on average, depressed or afflicted by chronic or terminal diseases, and found at home. In 42.6% of cases, the victims were found with the plastic bag still positioned over their head, fastened by tying. Also common among these cases are drugs, alcohol and chemical abuses. According to the collected data, it is impossible to outline a pathognomonic detrimental background that leads to this cause of death. Crime scene investigation is, therefore, the one and only technical resource for evaluating these cases. [ABSTRACT FROM AUTHOR]

The inflammatory involvement of vital organs may represent a dangerous and life-threatening situation: in particular, the inflammation of the myocardial tissue of the heart may lead to severe consequences since the clinical history of the disease may be completely asymptomatic, any clinical sign may be lacking, thus preventing correct diagnosis and treatment. This may occur even in the case of myocarditis and may lead to unexpected death whose cause can be assessable only by means of a thorough histopathological examination. The article reports the case of 61-year old female who developed a flu-like syndrome with very few symptoms, followed by sudden death in three weeks. The autopsy and following histopathological investigations identified the cause of death in a post-viral lymphocytic myocarditis, probably related to the previous infectious disease, and alternative causes (as arrhythmic ventricular dysplasia, vasculitis, sarcoidosis and giant cell myocarditis) were excluded. The exclusive location in the right ventricle was a peculiar finding. The case highlights the importance of the myocardium of the right ventricle, a tissue which is often less considered even in histopathological surveys. The exclusive location of myocarditis in the right ventricle is a rare event but in this case fully responsible for death. [ABSTRACT FROM AUTHOR]

Introduction: A cadaver in water sets a relevant issue for the forensic pathologist, concerning the differential diagnosis between homicide, suicide, accidental event, and natural death in water. In the present study, the drowning suicides in a non-coastal territory are analyzed, discussing the main diagnostic difficulties, the preventive intervention, and the strategies for outlining the profile of a 'mean victim' that is at risk of committing suicide by drowning. Methods: The cases of drowning suicide were extrapolated by the database of the 21,472 autopsies performed at the Civic Morgue of Milan, in the period between 1993 and 2013. Results: Drowning represents the fifth cause of suicide registered in Milan for the study period, with 139 cases (3.8 % of all suicides). Victims were mainly elderly males (61-80 years old) with a history of psychiatric diseases in pharmacological therapy; they committed suicide mainly during summer, in the rivers. The diatoms test was positive in 82 cases (59 %) and highlighted typical taxa of fresh water. Alcohol and illicit drugs were not noticed, at high levels. Conclusion: Drowning suicide occurs even in a non-coastal territory, far from the sea, if there is an easy access to the water: specifically, many natural and artificial waterways in the Milan district represent a high-risk factor predisposing the drowning suicide. [ABSTRACT FROM AUTHOR]

Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 × 1012 vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine) in FIX inhibitor-prone HB dogs. Two naïve HB dogs showed sustained expression of FIX-Padua with an 8- to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached ∼200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB. [ABSTRACT FROM AUTHOR]

Co‐parasitism is ubiquitous and has important consequences for the ecology and evolution of wild host populations. Studies of parasite co‐infections remain limited in scope, with few experimental tests of the fitness consequences of multiple parasites, especially in natural populations.We measured the separate and combined effects of Philornis seguyi nest flies and shiny cowbirds Molothrus bonariensis on the fitness of a shared host, the chalk‐browed mockingbird (Mimus saturninus) in Argentina.Using a two‐factor experimental approach, we manipulated the presence of nest flies and cowbirds in mockingbird nests and assessed their effects on mockingbird haemoglobin levels, begging and provisioning rates, body size, and fledging success. We also monitored rates of nest predation in relation to parasitism by flies and cowbirds.Nest flies reduced the haemoglobin concentration, body size, and fledging success of mockingbirds, likely because mockingbirds did not compensate for parasitism by begging more or feeding their nestlings more. Cowbirds also reduced the fledging success of mockingbirds, even though they had no detectable effect on haemoglobin or body size. Nests with cowbirds, which beg more than mockingbirds, attracted more nest predators. There was no significant interaction between the effects of flies and cowbirds on any component of mockingbird fitness. The combined effects of nest flies and cowbirds were strictly additive.In summary, we show that nest flies and cowbirds both reduce host fitness, but do not have interactive effects in co‐parasitized nests. Our results further suggest that predators exacerbate the effects of nest flies and cowbirds on their hosts. Our study shows that the fitness consequences of co‐parasitism are complex, especially in the context of community‐level interactions. [ABSTRACT FROM AUTHOR]

A common form of violence against women is sexual coercion on the part of their husbands/partners, the uncontrollable effects of which can lead to extreme consequences, as in the case of uxoricide examined in this report. It involved a 59-year-old female alcoholic, under observation on the part of social services as the possible victim of abuse by her husband, an amputee with a transtibial prosthesis. The woman had never admitted to her social workers that her husband was abusing her. One night, she was admitted to hospital in a state of hemorrhagic shock due to massive vaginal bleeding, but despite treatment, she died 20 min after arrival. The anatomical-pathological examination conducted by the hospital revealed serious genital lesions which warranted reporting the case to the Judicial Authorities, who arranged for a forensic autopsy. The cause of death was identified as acute meta-hemorrhagic anemia in a cirrhotic woman, secondary to a large, irregular vaginal lesion involving both the vaginal wall and the soft perivaginal tissues as well as the medium and small urogenital vascular branches. To identify the foreign body used to inflict this injury, a scanning electron microscope and energy dispersive X-ray spectrometer (SEM-EDS) were used. This revealed tiny splinters of wood in the vaginal tissues examined. In addition to the genetic-forensic techniques used, this finding allowed the investigators to identify the husband's prosthetic limb as the instrument of sexual coercion. The report describes a particular case of marital rape that resulted in uxoricide, in which the overall concordance of the investigations carried out played a fundamental role in identifying the offending body and, consequently, the murderer. [ABSTRACT FROM AUTHOR]

Three elastin model peptides containing the repetitive motif –VGVXGVG–, where X corresponds to (2S)-proline (Pro), (2S,4R)-4-hydroxy-proline (Hyp) and (2S,4R)-4-methoxy-proline (Mop), were synthesized in order to define the effect of the introduction of an electronegative group on the conformation and self-assembling properties of the peptides. Circular dichroism, NMR and FT-IR spectroscopies evidenced outstanding differences at molecular and supramolecular level. This work constitutes the basis for the proper design of elastin-inspired drugs with tailored conformational properties. [ABSTRACT FROM AUTHOR]

The article provides information related to the pathogenesis of atherosclerosis. According to several clinical and experimental studies it is detected that increased levels of low-density lipoprotein cholesterol in serum causes arthrosclerosis. It is mentioned that the diseases is associated with the endothelial dysfunction and infiltration of immune cells. It is discussed that pathogenetic and etiologic factors of both environmental and genetic origin promotes the outcomes of disease.

Abstract: The clinical transplantation outcome is related to both effects of immunological and non immunological factors degenerating into hyperacute, acute and chronic rejection. Modern immunosuppressive treatments have resolved most events linked to acute rejection while long-term survival still remains the major problem after heart transplantation. The goal of personalized immunosuppressive therapy is to prevent rejection without inducing toxic effects. The aim of future studies could be to clarify the pathogenesis of chronic rejection and develop new and less toxic therapeutic approaches to induce “tolerance” to the graft without major side effects. [Copyright &y& Elsevier]

Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors. Although the CXCR4/SDF-1 pathway is well characterized, the transcription factors executing the effector function of this signaling are poorly understood. The multifunctional Yin Yang 1 (YY1) protein is highly expressed in different types of cancers and may regulate some cancer-related genes. The network involving CXCR4/ YY1 and neoangiogenesis could play a major role in cancer progression. In this study we have shown that YY1 forms an active complex with HIF-la at VEGF gene promoters and increases VEGF transcription and expression observed by RT-PCR, ELISA, and Western blot using two different antibodies against VEGFB. Long-term treatment with T22 peptide (a CXCR4/SDF-1 inhibitor) and YY1 silencing can reduce in vivo systemic neoangiogenesis (P < 0.01 and P < 0.05 vs. control, respectively) during metastasis. Moreover, using an in vitro angiogenesis assay, we observed that YY1 silencing led to a 60% reduction in branches (P < 0.01) and tube length (P < 0.02) and a 75% reduction in tube area (P < 0.001) compared with control cells. A similar reduction was observed using T22 peptide. We demonstrated that T22 peptide determines YY1 cytoplasmic accumulation by reducing its phosphorylation via downregulation of AKT, identifying a crosstalk mechanism involving CXCR4/YY1. Thus, YY1 may represent a crucial molecular target for antiangiogenic therapy during cancer progression. [ABSTRACT FROM AUTHOR]

The integration of a fast tool servo (FTS) with piezoelectric actuation on a diamond turning machine (DTM) is presented. The intent of this research is to monitor improvements in surface quality in the areas of surface roughness and waviness observed in the facing of an aluminum work piece. Performance is compared between the utilization of a polynomial controller with position feedback of the tool, a repetitive controller that uses position feedback of the tool in conjunction with position feedback of the spindle face via and eddy current probe, and legacy performance of the DTM with no active control methodology. [Copyright &y& Elsevier]

Growth and alginate production by Azotobacter vinelandii DSM576 as a function of initial ammonium sulphate concentration (0.45–1.05 g l-1) and agitation speed (300–700 rpm) were studied in batch fermentations at controlled pH. The time course of growth, alginate production and substrate consumption and the effect of nitrogen concentration and agitation speed on kinetic parameters and on maximum alginate molecular weight (MW) was modelled using empirical equations. The kinetics of growth, alginate production and polymerization were deeply affected by agitation speed and, to a lesser extent, by inorganic nitrogen concentration. Average and maximum specific growth rate and maximum alginate MW all increased with agitation speed, and were higher at intermediate ammonium sulphate concentration. Maximum alginate MW (>250,000) was obtained at high agitation speed (600–700 rpm) and alginate depolymerization was limited or did not occur at all when the agitation speed was higher than 500 rpm, while at 400 rpm depolymerization significantly reduced the alginate. However, alginate yield was negatively affected by increasing agitation speed. A good compromise between alginate yield (>2 g l-1) and quality (MW>250,000) was obtained with agitation speed of 500–600 rpm and 0.75–0.90 g l-1 of ammonium sulphate. Journal of Industrial Microbiology & Biotechnology (2000) 25, 242–248. [ABSTRACT FROM AUTHOR]

In the human genome, there are about 600 ultra-conserved regions (UCRs), long DNA sequences extremely conserved in vertebrates. We performed a large-scale study to quantify transcribed UCR (T-UCR) and miRNA levels in over 6000 cancer and normal tissue samples to find possible correlation between these kinds of regulatory molecules. Our analysis evidenced several non-coding RNAs showing negative co-regulation with miRNAs; among them, we focused on miR-221 to investigate any relationship with its pivotal role in the cell cycle. We have chosen breast cancer as model, using two cell lines with different phenotypes to carry out in vitro treatments with siRNAs against T-UCRs. Our results demonstrate that the expression of uc.183, uc.110, and uc.84 T-UCRs is mutually exclusive with miR-221 and is engaged in the regulation of CDKN1B expression. In addition, tests with a set of anticancer drugs, including BYL719, AZD5363, AZD8055, AZD7762, and XL765, revealed the modulation of specific T-UCRs without alteration of miR-221 levels. [ABSTRACT FROM AUTHOR]

Simple Summary: We systematically reviewed the recent scientific publications describing the role of microRNAs in the regulation of drug resistance in colon cancer. To clarify the intricate web of resulting genetic and biochemical interactions, we used a machine learning approach aimed at creating: (i) networks of validated miRNA/target interactions involved in drug resistances and (ii) drug-centric networks, from which we identified the major clusters of proteins affected by drugs used in the treatment of colon cancer. Finally, to facilitate a high-level interpretation of these molecular interactions, we determined the cellular pathways related with drug resistance and regulated by the miRNAs in colon cancer. Drug resistance is one of the major forces driving a poor prognosis during the treatment and progression of human colon carcinomas. The molecular mechanisms that regulate the diverse processes underlying drug resistance are still under debate. MicroRNAs (miRNAs) are a subgroup of non-coding RNAs increasingly found to be associated with the regulation of tumorigenesis and drug resistance. We performed a systematic review of the articles concerning miRNAs and drug resistance in human colon cancer published from 2013 onwards in journals with an impact factor of 5 or higher. First, we built a network with the most studied miRNAs and targets (as nodes) while the drug resistance/s are indicated by the connections (edges); then, we discussed the most relevant miRNA/targets interactions regulated by drugs according to the network topology and statistics. Finally, we considered the drugs as nodes in the network, to allow an alternative point of view that could flow through the treatment options and the associated molecular pathways. A small number of microRNAs and proteins appeared as critically involved in the most common drugs used for the treatment of patients with colon cancer. In particular, the family of miR-200, miR34a, miR-155 and miR-17 appear as the most relevant microRNAs. Thus, regulating these miRNAs could be useful for interfering with some drug resistance mechanisms in colorectal carcinoma. [ABSTRACT FROM AUTHOR]

The kinetics of growth and alginate production from glucose in a nitrogen and phosphate-rich medium by Azotobacter vinelandii DSM576 were studied in a laboratory fermenter at pH 7 and 35°C. Batch fermentations were carried out both without control of dissolved oxygen concentration (DO) and at 1, 2, 5 and 10% DO. Although growth was faster at higher DO, maximum biomass concentration was lower. No alginate was produced at 10% DO. Alginate production was faster at 5 and 2% DO but higher alginate concentrations and yields were obtained without DO control. Alginate production was growth-associated at 5% DO, but significant amounts of alginate were produced after growth had stopped at lower DO values. In fermentations without DO control the molecular weight of the polymer reached a maximum (11-17.6 × 10[SUP4]) when specific growth rate was between 0.02 and 0.04 h[SUP-1] and residual concentration of ammoniacal nitrogen was between 0.01 and 0.02 g L[SUP-1] and then sharply decreased. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI)-related inflammatory diseases, including polymyositis (PM) and dermatomyositis (DM), in patients suffering from neoplastic disorders represent a medical challenge. The treatment of these conditions has taken on new urgency due to the successful and broad development of cancer-directed immunological-based therapeutic strategies. While primary and secondary PM/DM phenotypes have been pathophysiologically characterized, a rational, stepwise approach to the treatment of patients with ICI-related disease is lacking. In the absence of high-quality evidence to guide clinical judgment, the available data must be critically assessed. In this literature review, we examine partially neglected immunological and clinical findings to obtain insights into the biological profiles of ICI-related PM/DM and potential treatment options. We show that differential diagnosis is essential to stratifying patients according to prognosis and therapeutic impact. Finally, we provide a comprehensive assessment of druggable targets and suggest a stepwise patient-oriented approach for the treatment of ICI-related PM/DM. [ABSTRACT FROM AUTHOR]

Background: Real-world data on the use of lipid-lowering therapy (LLT) in clinical practice show that about 80% of (very) high-cardiovascular (CV)-risk patients disregard the 2019 European Society of Cardiology (ESC) Guidelines' recommendations on dyslipidemias. The availability of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9mAb) should reduce this gap. Our aim was to provide data on PCSK9mAb use in clinical practice, investigating the achievement of the ESC Guidelines' recommendations in the real world. Methods: Between April 2018 and December 2022, patients who started on PCSK9mAb therapy (140 mg of evolocumab or 75 mg or 150 mg of alirocumab, subcutaneous injection every 2 weeks) were included in a prospective registry. Our cohort consisted of 256 patients: 95 (37.1%) were women (mean age: 65.43 ± 11.12 yrs), 53 (20.7%) were at high CV risk, and 203 (79.3%) were at very high CV risk. Results: After one year of PCSK9mAb treatment, nearly 60% of patients demonstrated full adherence to the ESC Guidelines' recommendations, defined as achieving at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C) levels along with reaching LDL-C target levels (≤55 and ≤70 mg/dL for very high and high risk, respectively). Concomitant high-dose statin therapy emerged as the primary predictor of LDL-C target attainment. Heterozygous familial hypercholesterolemia (HeFH), statin intolerance, and female gender were associated with a significant lower probability of achieving LDL-C target levels. Conclusions: Our analysis confirms that PCSK9mAb treatment is safe and effective, enabling 60% of our cohort to fully achieve the LDL-C guideline recommendations. The use of high-intensity statins emerged as a significant predictor of efficacy. Conversely, familial hypercholesterolemia and female gender were identified as predictors of therapeutic failure. Hence, it is crucial to address disparities in cardiovascular disease prevention between genders and to enhance strategies for managing elevated LDL-C in HeFH patients. [ABSTRACT FROM AUTHOR]

The problem raised by the authors of the Commentary is certainly of considerable importance and calls for great caution when diagnosing cranial base fractures. 1 Crudele GDL, Merelli VG, Vener C, Milani S, Cattaneo C. The frequency of cranial base fractures in lethal head trauma. 2 Hu J, Zheng N, Liang M. Commentary on: Crudele GDL, Merelli VG, Vener C, Milani S, Cattaneo C. The frequency of cranial base fractures in lethal head trauma.. J Forensic Sci doi: 10.1111/1556-4029.14149. [Extracted from the article]

Background: Nebulin is a critical thin filament-binding protein that spans from the Z-disk of the skeletal muscle sarcomere to near the pointed end of the thin filament. Its massive size and actin-binding property allows it to provide the thin filaments with structural and regulatory support. When this protein is lost, nemaline myopathy occurs. Nemaline myopathy causes severe muscle weakness as well as structural defects on a sarcomeric level. There is no known cure for this disease. Methods: We studied whether sarcomeric structure and function can be improved by introducing nebulin's Z-disk region into a nebulin-deficient mouse model (Neb cKO) through adeno-associated viral (AAV) vector therapy. Following this treatment, the structural and functional characteristics of both vehicle-treated and AAV-treated Neb cKO and control muscles were studied. Results: Intramuscular injection of this AAV construct resulted in a successful expression of the Z-disk fragment within the target muscles. This expression was significantly higher in Neb cKO mice than control mice. Analysis of protein expression revealed that the nebulin fragment was localized exclusively to the Z-disks and that Neb cKO expressed the nebulin fragment at levels comparable to the level of full-length nebulin in control mice. Additionally, the Z-disk fragment displaced full-length nebulin in control mice, resulting in nemaline rod body formation and a worsening of muscle function. Neb cKO mice experienced a slight functional benefit from the AAV treatment, with a small increase in force and fatigue resistance. Disease progression was also slowed as indicated by improved muscle structure and myosin isoform expression. Conclusions: This study reveals that nebulin fragments are well-received by nebulin-deficient mouse muscles and that limited functional benefits are achievable. [ABSTRACT FROM AUTHOR]

Two letters to the editor are presented in response to the article "The Dea[r]th of Human Understanding," by Neville Holmes in the October 2008 issue. Two responses from Neville Holmes to two letters to the editor about his article "The Dea[r]th of Human Understanding," in the October 2008 issue is also presented.

SARS-CoV-2 and its variants cause CoronaVIrus Disease 19 (COVID-19), a pandemic disease. Hematological malignancies increase susceptibility to severe COVID-19 due to immunosuppression. Anti-SARS-CoV-2 neutralizing antibodies protect against severe COVID-19. This retrospective real-life study aimed to evaluate seropositivity and neutralizing antibody rates against SARS-CoV-2 and its Omicron BA.1 variant in hematological patients. A total of 106 patients with different hematologic malignancies, who have mostly received three or more vaccine doses (73%), were included in this study. Serum was collected between May and June 2022. The primary endpoint was anti-SARS-CoV-2 antibody response against ancestral (wild type; wt) and Omicron BA.1 virus, defined as a neutralizing antibody titer ≥ 1:10. Adequate neutralizing antibody response was observed in 75 (71%) and 87 (82%) of patients for wt and Omicron BA.1 variants, respectively. However, patients with B-cell lymphoproliferative disorders and/or those treated with anti-CD20 monoclonal antibodies in the prior 12 months showed a lower seropositivity rate compared to other patients against both Omicron BA.1 variant (73% vs 91%; P = 0.02) and wt virus (64% vs 78%; P = 0.16). Our real-life experience confirmed that full vaccination against SARS-CoV-2 induces adequate neutralizing antibody protection for both the wt virus and Omicron BA.1 variants, even in hematological frail patients. However, protective measures should be maintained in hematological patients, especially those with B-cell lymphoproliferative diseases treated with anti-CD20 monoclonal antibodies, because these subjects could have a reduced neutralizing antibody production. [ABSTRACT FROM AUTHOR]

Daratumumab, an anti-CD38 monoclonal antibody, is worldwide approved for treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM) patients and is available as intravenous or subcutaneous formulations. Intravenous daratumumab is associated with frequent infusion-related reactions, while eye complications, especially refractive shifts, are very rare, with only previously reported cases. Here, we described a rare case of multi-refractory MM who developed transient myopic shift during intravenous daratumumab infusion successfully treated only with cycloplegic collyrium not requiring infusion rate lowering or drug discontinuation. This conservative therapeutic approach allowed termination of induction therapy and autologous hematopoietic stem-cell transplantation resulting in durable complete remission. [ABSTRACT FROM AUTHOR]