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Background: The post‐operative course after Liver Transplantation (LT) can be complicated by early allograft dysfunction (EAD), primary nonfunction (PNF) and death. A lactate concentration at the end of transplant of ≥5 mmol/L was recently proposed as a predictive marker of PNF, EAD, and mortality; this study aimed to validate these previous reports in a large single center cohort. Methods: This retrospective cohort study included adult liver transplant recipients who received grafts from deceased donors at our center between June 2012 and May 2021. Receiver operating characteristic (ROC) curves for the lactate concentration at the end of transplantation were computed to determine the AUC for PNF, EAD and mortality at 90 days. Results: In our cohort of 1137 cases, the AUCs for lactate to predict EAD, PNF and mortality were respectively.56 (95% confidence interval [CI]:.53–.60),.69 (95% CI:.52–.85), and.74 (95% CI:.63–.84). Conclusion: The clinical value of lactate concentration at the end of transplantation to predict PNF, EAD and mortality at 90 days was, at best, modest, as shown by the relatively low AUCs. Our findings cannot validate previous reports that the lactate level alone is a good predictor of poor outcomes after liver transplantation. [ABSTRACT FROM AUTHOR]

Background and Aims: Metabolic dysfunction (MD)‐associated fatty liver disease has been proposed to identify individuals at risk of liver events irrespectively of the contemporary presence of other liver diseases. The aim of this study was to examine the impact of MD in patients cured of chronic hepatis C (CHC). Patients and Methods: We analysed data from a real‐life cohort of 2611 Italian patients cured of CHC with direct antiviral agents and advanced liver fibrosis, without HBV/HIV, transplantation and negative for hepatocellular carcinoma (HCC) history (age 61.4 ± 11.8 years, 63.9% males, median follow‐up 34, 24–40 months). Information about ultrasonographic steatosis (US) after sustained virological response was available in 1978. Results: MD affected 58% of patients, diagnosed due to the presence of diabetes (MD‐diabetes, 19%), overweight without diabetes (MD‐overweight, 37%) or multiple metabolic abnormalities without overweight and diabetes (MD‐metabolic, 2%). MD was more frequent than and not coincident with US (32% MD‐only, 23% MD‐US and 13% US‐only). MD was associated with higher liver stiffness (p < 0.05), particularly in patients with MD‐diabetes and MD‐only subgroups, comprising older individuals with more advanced metabolic and liver disease (p < 0.05). At Cox proportional hazard multivariable analysis, MD was associated with increased risk of HCC (HR 1.97, 95% CI 1.27–3.04; p = 0.0023). Further classification according to diagnostic criteria improved risk stratification (p < 0.0001), with the highest risk observed in patients with MD‐diabetes. Patients with MD‐only appeared at highest risk since the sustained virological response achievement (p = 0.008), with a later catch‐up of those with combined MD‐US, whereas US‐only was not associated with HCC. Conclusions: MD is more prevalent than US in patients cured of CHC with advanced fibrosis and identifies more accurately individuals at risk of developing HCC. [ABSTRACT FROM AUTHOR]

Introduction: Molecular responses in the brains of persons with mild cognitive impairment (MCI), the earliest transitional state between normal aging and early Alzheimer's disease (AD), are poorly understood. Methods: We examined AD‐related neuropathology and transcriptome changes in the neocortex of individuals with MCI relative to controls and temporal responses to the mild hypoxia in mouse brains. Results: Subsets of vascular early response to hypoxia genes were upregulated in MCI prior to the buildup of AD neuropathology. Early activation of pro‐angiogenic hypoxia‐inducible factor signaling in response to mild hypoxia was detected in mouse brains similar to those that were altered in MCI. Protracted responses to hypoxia were characterized by activation of phosphoinositide 3‐kinase (PI3K)‐protein kinase B (Akt)‐the mammalian target of rapamycin (mTOR) pathways in brain microvessel isolates. Discussion: These findings suggest that cerebrovascular remodeling is an important antecedent to the development of dementia and a component of the homeostatic response to reduced oxygen tension in aging prior to the onset of AD. [ABSTRACT FROM AUTHOR]

Vascular structures in the developing brain are thought to form via angiogenesis from preformed blood vessels in the cephalic mesenchyme. Immunohistochemical studies of developing mouse brain from E10.5 to E13.5 revealed the presence of avascular blood islands of primitive erythroid cells expressing hemangioblast markers (Flk1, Tal1/Scl1, platelet endothelial cell adhesion molecule 1, vascular endothelial‐cadherin, and CD34) and an endothelial marker recognized by Griffonia simplicifolia isolectin B4 (IB4) in the cephalic mesenchyme. These cells formed a perineural vascular plexus from which angiogenic sprouts originated and penetrated the neuroepithelium. In addition, avascular isolated cells expressing primitive erythroid, hemangioblast and endothelial makers were visible in the neuroepithelium where they generated vasculogenic and hemogenic foci. From E10.5 to E13.5, these vasculogenic foci were a source of new blood vessel formation in the developing brain. In vitro, cultured E13.5 brain endothelial cells contained hemogenic endothelial cells capable of generating erythroid cells. Similar cells were present in primary cultures of dissociated cells from E10.5 embryonic head. Our results provide new evidence that the brain vasculature, like that of the yolk sac and the eye choriocapillaris and hyaloid vascular systems, develops at least in part via hemovasculogenesis, a process in which vasculogenesis and hematopoiesis occur simultaneously. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Rapid and reliable exclusion of invasive fungal infections (IFI) by markers able to avoid unnecessary empirical antifungal treatment is still a critical unmet clinical need. We investigated the diagnostic performance of a newly available β‐d‐Glucan (BDG) quantification assay, focusing on the optimisation of the BDG cut‐off values for IFI exclusion. Methods: BDG results by Wako β‐glucan assay (lower limit of detection [LLOD] = 2.16 pg/mL, positivity ≥ 11 pg/mL) on two consecutive serum samples were retrospectively analysed in 170 patients, admitted to haematological wards (N = 42), intensive care units (ICUs; N = 80), or other wards (N = 48), exhibiting clinical signs and/or symptoms suspected for IFI. Only patients with proven IFI (EORTC/MSG criteria) were considered as true positives in the assessment of BDG sensitivity, specificity and predictive values. Results: Patients were diagnosed with no IFI (69.4%), proven IFI (25.3%) or probable IFI (5.3%). Two consecutive BDG values < LLOD performed within a median of 1 (interquartile range: 1‐3) day were able to exclude a proven IFI with 100% sensitivity and negative predictive value (primary study goal). Test's specificity improved by using two distinct positivity and negativity cut‐offs (7.7 pg/mL and LLOD, respectively), but remained suboptimal in ICU patients (50%), as compared to haematological or other patients (93% and 90%, respectively). Conclusions: The classification of Wako's results as negative when < LLOD, and positive when > 7.7 pg/mL, could be a promising diagnostic approach to confidently rule out an IFI in both ICU and non‐ICU patients. The poor specificity in the ICU setting remains a concern, due to the difficulty to interpret positive results in this fragile population. [ABSTRACT FROM AUTHOR]

Abstract: Signaling via the androgen receptor (AR) stimulates myogenic progenitor differentiation. In addition, myogenic differentiation factor D (MyoD) and Numb, a Notch inhibitor, play key roles in regulating myogenic differentiation. Nandrolone, an anabolic steroid, upregulates both MyoD and Numb expression in myogenic cells. However, the molecular mechanisms by which MyoD is upregulated by nandrolone are unclear. Moreover, the potential crosstalk between nandrolone, MyoD, and Numb is not well understood. With these considerations in mind, we examined the effects of nandrolone on the expression of MyoD mRNA and protein, and determined the interactions of MyoD and Numb in the presence or absence of nandrolone in differentiating C2C12 myoblasts. Nandrolone increased MyoD mRNA and protein expression and significantly enhanced nuclear translocation of MyoD protein. The later effect of nandrolone was blunted by siRNA against Numb. Immunoprecipitation (IP) studies confirmed that Numb forms complexes with MyoD. Chromatin IP revealed that in the presence of nandrolone, Numb is recruited to a region of the MyH7 promotor containing the E‐box to which MyoD binds. These data indicate that nandrolone‐regulated MyoD activation occurs mainly through a posttranslational mechanism which promotes MyoD nuclear accumulation, and suggest that this effect of nandrolone is, at least in part, mediated by Numb. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the reliability of ultrasound-trained obstetricians performing a first-trimester fetal cardiac scan with high-frequency transabdominal probes in fetuses with increased nuchal translucency thickness (NT) in Italy. A total of 133 fetuses with increased NT at 11-14 weeks of gestation were examined. Findings of the study demonstrate the reliability of early fetal heart assessment in cases with increased NT, performed by trained operators using such probes.

Alzheimer's disease is the most common cause of senile dementia in the United States and Europe. At present, there is no effective treatment. Given the disease's prevalence and poor prognosis, the development of animal models has been a high research priority. Transgenic modeling has been pursued on the basis of the amyloid hypothesis and has taken advantage of mutations in the amyloid precursor protein and the presenilins that cause familial forms of Alzheimer's disease. Modeling has been most aggressively pursued in mice, for which the techniques of genetic modification are well developed. Transgenic mouse models now exist that mimic a range of Alzheimer's disease–related pathologies. Although none of the models fully replicates the human disease, the models have contributed significant insights into the pathophysiology of β-amyloid toxicity, particularly with respect to the effects of different β-amyloid species and the possible pathogenic role of β-amyloid oligomers. They have also been widely used in the preclinical testing of potential therapeutic modalities and have played a pivotal role in the development of immunotherapies for Alzheimer's disease that are currently in clinical trials. These models will, without a doubt, continue to play central roles in preclinical testing and be used as tools for developing insights into the biological basis of Alzheimer's disease. Mt Sinai J Med 77:69&–81, 2010. © 2010 Mount Sinai School of Medicine [ABSTRACT FROM AUTHOR]

Cortical development is disrupted in presenilin-1 null mutant ( Psen1−/−) mice. Prior studies have commented on similarities between Psen1−/− and reeler mice. Reelin induces phosphorylation of Dab1 and activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Psen1 is known to modulate PI3K/Akt signaling and both known reelin receptors (apoER2 and VLDLR) are substrates for Psen1 associated γ-secretase activity. The purpose of this study was to determine whether reelin signaling is disrupted in Psen1−/− mice. We show that, while Dab1 is hypophosphorylated late in cortical development in Psen1−/− mice, it is normally phosphorylated at earlier ages and reelin signaling is intact in Psen1−/− primary neuronal cultures. γ-secretase activity was also not required for reelin-induced phosphorylation of Dab1. Unlike reeler mice the preplate splits in Psen1−/− brain. Thus cortical development in Psen1−/− mice fails only after splitting of the preplate and is not due to an intrinsic failure of reelin signaling. Developmental Dynamics 237:2405-2414, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Until recently neurogenesis in mammals was considered to occur only during the embryonic and early post-natal periods and to have no significant role in the adult nervous system. However, it is now accepted that neurogenesis occurs in two brain regions in adult mammals, namely, the hippocampus and olfactory bulb. In both regions new neurons arise from a resident population of neural progenitor cells that are maintained throughout adult life. Hippocampal neurogenesis is required for some types of hippocampal-dependent learning. Many factors enhance hippocampal neurogenesis including hormones, growth factors, drugs, neurotransmitters, and physical exercise as well as learning a hippocampal-dependent task. Other factors suppress hippocampal neurogenesis; these include aging, stress, glucocorticoids and stimuli that activate the pituitary/adrenal axis. Recently much attention has focused on the relevance of hippocampal neurogenesis to the pathophysiology and treatment of mood disorders. Indeed all major pharmacological and non-pharmacological treatments for depression enhance hippocampal neurogenesis and suppressing hippocampal neurogenesis in mice blocks behavioral responses in some antidepressant-sensitive tests. Altered hippocampal neurogenesis may also play a pathophysiological role in neurodegenerative disorders such as Alzheimer's disease. How much neurogenesis occurs normally in other brain regions is unclear. Neural progenitors are found throughout the neuraxis including both neurogenic and non-neurogenic regions. When cultured in vitro or isolated and transplanted back into neurogenic brain regions, these cells can differentiate into neurons, although in their in situ location they seem to behave as lineage-restricted glial progenitors. The environmental cues that limit the potential of progenitor cells in non-neurogenic brain regions are unknown. However, an emerging view is that astrocytes, a subset of which also functions as neural progenitor cells, are critical in regulating the local environment. After transplantation into adult brain, neural stem cells are capable of surviving and differentiating into both neurons and glial cells, offering hope that stem cell therapy may be utilized to treat a variety of neurological and perhaps psychiatric disorders. The widespread existence of endogenous neural progenitors even in non-neurogenic brain regions also offers hope that the potential of these cells may be harnessed to repair cellular injuries caused by injuries such as stroke, trauma or neurodegenerative diseases. While obstacles remain to both approaches, stem-cell-based therapies remain an area of intense research interest. [ABSTRACT FROM AUTHOR]

Objective Several studies have assumed a parabolic velocity profile through the umbilical vein (UV) to derive the mean spatial velocity that is indispensable for flow rate calculations. However, the structure and arrangement of the umbilical cord suggest that velocity profiles may vary. The aim of this study was to evaluate UV spatial flow velocity profiles at different sites along the umbilical cord. Methods Ten singleton pregnancies with a gestational age between 26 and 34 weeks were included in the study. Ultrasound equipment with an inbuilt function for analysis of the spatial velocity profile along a line located in a fixed plane was used to obtain UV velocity profiles. Velocity profiles were obtained at the placental insertion and in a free intra-amniotic loop of the cord. Two-dimensional (2D) velocity distribution coefficients were evaluated as ratios between mean and maximum velocities along the investigated lines. Results 2D velocity distribution coefficients at the placental insertion (0.85 ± 0.03) were significantly higher (P < 0.00001) than those obtained from a free loop of cord (0.76 ± 0.03). Values indicated that velocity profiles are approximately flat at the placental insertion and become more parabolic moving downstream. Moreover, profiles become skewed in association with cord curvature and show peculiar biphasic shapes immediately downstream from the placenta. Conclusions Flow velocity profiles in the UV are not perfectly parabolic and modify along the cord. These characteristics may affect the evaluation of UV blood flow rate. [ABSTRACT FROM AUTHOR]

Canavan disease, an inherited leukodystrophy, is caused by mutationsin the aspartoacylase (ASPA) gene. It is most common among children of Ashkenazi Jewish descent but has been diagnosed in many diverse ethnic groups.Two mutations comprise the majority of mutant alleles in Jewish patients, while mutations in the ASPA gene among non-Jewish patients are different and more diverse. In the present study, the ASPA gene was analysed in 22 unrelated non-Jewish patients with Canavan disease, and 24 different mutations were found. Of these, 14 are novel, including five missense mutations (E24G, D68A, D249V, C152W, H244R), two nonsense mutations (Q184X, E214X), three deletions (923delT, 33del13, 244delA), one insertion mutation (698insC), two sequence variations in one allele ([10T > G; 11insG]), an elimination of the stop codon (941A > G, TAG → TGG, X314W), and one splice acceptor site mutation (IVS1 − 2A > T). The E24G mutation resulted in substitution of an invariable amino acid residue (Glu) in the first esterase catalytic domain consensus sequence. The IVS1 − 2A > T mutation caused the retention of 40 nucleotides of intron 1 upstream of exon 2. The results of transient expression of the mutant ASPA cDNA containing these mutations in COS-7 cells and assays for ASPA activity of patient fibroblasts indicated that these mutations were responsible for the enzyme deficiency. In addition, patients with the novel D249V mutation manifested clinically at birth and died early. Also, patients with certain other novel mutations, including C152W, E214X, X314W, and frameshift mutations in both alleles, developed clinical manifestations at an earlier age than in classical Canavan disease. [ABSTRACT FROM AUTHOR]

The aim of the study is to evaluate the prevalence of hepatitis B virus (HBV) markers in a population of non-institutionalized handicapped 1-19-year-old patients. Thirty-six out of 70 patients lived in southern Italy and 19 were affected by Down's syndrome. Only three (4.2%) were positive for anti-HBc (one of these also for anti-HBs) and none for HBsAg. Low prevalence seems to indicate that no particular anti-HBV vaccination strategy is to be considered on this subset of population and on their contacts. Serrum prevalence of HBV among nurses and other members of personnel was 11.3%. [ABSTRACT FROM AUTHOR]

ABSTRACTObjectiveTo investigate the feasibility of withdrawal of blood from the recipient twin as a new method for the treatment of severe twin–twin transfusion syndrome. MethodsSeven consecutive monozygotic monochorionic twin pregnancies affected by severe twin–twin transfusion syndrome were treated. Fetal blood was withdrawn from the recipient twin using cordocentesis. The volume of blood to be removed was determined using the formula for intrauterine blood transfusion of anemic fetuses. Fetal outcome was evaluated in relation to changes in the amniotic fluid and in growth curves (comparing the differences between the centiles of the estimated fetal weight before the procedure and the centiles of weight at birth), fetal mortality, gestational age at delivery, neonatal weight and neurological damage. ResultsOverall, seven of the 14 (50%) fetuses survived; at least one fetus survived in five (71%) pregnancies, both fetuses survived in two (29%) pregnancies, while in two (29%) pregnancies there were no survivors. No maternal complications were observed. At follow-up, one (14%) baby had minor neurological damage. ConclusionsWithdrawal of blood from the recipient twin in the treatment of severe twin–twin transfusion syndrome was associated with survival similar to that of the alternative techniques of serial amniodrainage and fetoscopic laser surgery, with some possible advantages such as reduced neurological damage compared with serial amniodrainage. It is also less invasive compared with fetoscopic laser surgery. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Doppler evaluation in fetuses with right ventricular prevalence: A contribution to the diagnosis of coarctation of aorta," by M. Bellotti and colleagues is presented.

An abstract of the conference paper "Role of cardiac output redistribution in maintaining cardiac function in fetuses with isolated congenital heart diseases (CHD)," by M. Bellotti and colleagues is presented.