Sleep‐wake abnormalities in patients with cirrhosis

A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep‐wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24‐hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24‐hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep‐wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed. (H epatology 2014;59:705–712)

Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) may increase the risk for cardiac dysfunction. The present study aimed to determine whether, in children, NAFLD is associated with subclinical left ventricular (LV) structural and functional abnormalities independently of metabolic risk factors. We performed a complete echocardiographic study including tissue Doppler imaging, magnetic resonance imaging (MRI) for measurement of hepatic fat fraction (HFF) and abdominal fat mass distribution, along with lipid profile, insulin sensitivity, and high‐sensitivity C‐reactive protein in 108 obese children, 54 with (HFF ≥5%) and 54 without NAFLD, and 18 lean healthy subjects. The three groups were matched for age, gender, and pubertal status, and obese children with NAFLD were matched for body mass index/standard deviation score with those without NAFLD. Forty‐one of the children with NAFLD underwent liver biopsy. Compared to controls and children without liver involvement, those with NAFLD had features of LV diastolic dysfunction, including higher E‐to‐e' ratio and lower e' tissue velocity. The Tei index (reflecting the combined systolic and diastolic LV function) was also significantly higher in NAFLD children. Among children with biopsy‐proven NAFLD, 26 had definite nonalcoholic steatohepatitis (NASH) and 15 were not‐NASH. Patients with definite‐NASH had significantly lower e' velocity and significantly higher E‐to‐e' and Tei index ( P  < 0.001, respectively) than those without NASH. In multiple logistic regression analysis, NAFLD was the only statistically significant variable associated with increased E‐to‐e' ratio, whereas NAFLD and systolic blood pressure were significantly associated with increased Tei index. Conclusion : Asymptomatic obese children with NAFLD exhibit features of early LV diastolic and systolic dysfunction, and these abnormalities are more severe in those with NASH. (H epatology 2014;59:461–470)

Effects of increasing CREB‐dependent transcription on the storage and recall processes in a hippocampal CA1 microcircuit

The involvement of the hippocampus in learning processes and major brain diseases makes it an ideal candidate to investigate possible ways to devise effective therapies for memory‐related pathologies like Alzheimer's Disease (AD). It has been previously reported that augmenting CREB activity increases the synaptic Long‐Term Potentiation (LTP) magnitude in CA1 pyramidal neurons and their intrinsic excitability in healthy rodents. It has also been suggested that hippocampal CREB signaling is likely to be down‐regulated during AD, possibly degrading memory functions. Therefore, the concept of CREB‐based memory enhancers, i.e. drugs that would boost memory by activation of CREB, has emerged. Here, using a model of a CA1 microcircuit, we investigate whether hippocampal CA1 pyramidal neuron properties altered by increasing CREB activity may contribute to improve memory storage and recall. With a set of patterns presented to a network, we find that the pattern recall quality under AD‐like conditions is significantly better when boosting CREB function with respect to control. The results are robust and consistent upon increasing the synaptic damage expected by AD progression, supporting the idea that the use of CREB‐based therapies could provide a new approach to treat AD. © 2013 Wiley Periodicals, Inc.

Hippocampal slow EEG frequencies during NREM sleep are involved in spatial memory consolidation in humans

The hypothesis that sleep is instrumental in the process of memory consolidation is currently largely accepted. Hippocampal formation is involved in the acquisition of declarative memories and particularly of spatial memories. Nevertheless, although largely investigated in rodents, the relations between spatial memory and hippocampal EEG activity have been scarcely studied in humans. Aimed to evaluate the effects of spatial learning on human hippocampal sleep EEG activity, we recorded hippocampal Stereo‐EEG (SEEG) in a group of refractory epilepsy patients undergoing presurgical clinical evaluation, after a training on a spatial navigation task. We observed that hippocampal high‐delta (2–4 Hz range) activity increases during the first NREM episode after learning compared to the baseline night. Moreover, the amount of hippocampal NREM high‐delta power was correlated with task performance at retest. The effect involved only the hippocampal EEG frequencies inasmuch no differences were observed at the neocortical electrodes and in the traditional polysomnographic measures. The present findings support the crucial role of hippocampal slow EEG frequencies during sleep in the memory consolidation processes. More generally, together with previous results, they suggest that slow frequency rhythms are a fundamental characteristic of human hippocampal EEG during both sleep and wakefulness, and are related to the consolidation of different types of memories. © 2014 Wiley Periodicals, Inc.

Sex‐specific disruptions in spatial memory and anhedonia in a “two hit” rat model correspond with alterations in hippocampal brain‐derived neurotrophic factor expression and signaling

Post‐mortem studies have demonstrated reduced expression of brain‐derived neurotrophic factor (BDNF) in the hippocampus of schizophrenia and major depression patients. The “two hit” hypothesis proposes that two or more major disruptions at specific time points during development are involved in the pathophysiology of these mental illnesses. However, the role of BDNF in these “two hit” effects is unclear. Our aim was to behaviorally characterize a “two hit” rat model of developmental stress accompanied by an in‐depth assessment of BDNF expression and signalling. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young‐adult corticosterone (CORT) treatment. In adulthood, models of cognitive and negative symptoms of mental illness were analyzed. The hippocampus was then dissected into dorsal (DHP) and ventral (VHP) regions and analyzed by qPCR for exon‐specific BDNF gene expression or by Western blot for BDNF protein expression and downstream signaling. Male “two hit” rats showed marked disruptions in short‐term spatial memory (Y‐maze) which were absent in females. However, female “two hit” rats showed signs of anhedonia (sucrose preference test), which were absent in males. Novel object recognition and anxiety (elevated plus maze) were unchanged by either of the two “hits”. In the DHP, MS caused a male‐specific increase in BDNF Exons I, II, IV, VII, and IX mRNA but a decrease in mature BDNF and phosphorylated TrkB (pTrkB) protein expression in adulthood. In the VHP, BDNF transcript expression was unchanged; however, in female rats only, MS significantly decreased mature BDNF and pTrkB protein expression in adulthood. These data demonstrate that MS causes region‐specific and sex‐specific long‐term effects on BDNF expression and signaling and, importantly, mRNA expression does not always infer protein expression. Alterations to BDNF signaling may mediate the sex‐specific effects of developmental stress on anhedonic behaviors. © 2014 Wiley Periodicals, Inc.

A Novel in‐Frame 18‐bp Microdeletion in MT ‐ CYB Causes a Multisystem Disorder with Prominent Exercise Intolerance

A novel heteroplasmic mitochondrial DNA (mt DNA ) microdeletion affecting the cytochrome b gene ( MT ‐ CYB ) was identified in an Italian female patient with a multisystem disease characterized by sensorineural deafness, cataracts, retinal pigmentary dystrophy, dysphagia, postural and gait instability, and myopathy with prominent exercise intolerance. The deletion is 18‐base pair long and encompasses nucleotide positions 15,649–15,666, causing the loss of six amino acids (Ile‐Leu‐Ala‐Met‐Ile‐Pro) in the protein, but leaving the remaining of the MT ‐ CYB sequence in frame. The defective complex III function was cotransferred with mutant mt DNA in cybrids, thus unequivocally establishing its pathogenic role. Maternal relatives failed to show detectable levels of the deletion in blood and urinary epithelium, suggesting a de novo mutational event. This is the second report of an in‐frame intragenic deletion in MT ‐ CYB , which most likely occurred in early stages of embryonic development, associated with a severe multisystem disorder with prominent exercise intolerance.

Exposure to secondhand tobacco smoke and lung cancer by histological type: A pooled analysis of the International Lung Cancer Consortium (ILCCO)

While the association between exposure to secondhand smoke and lung cancer risk is well established, few studies with sufficient power have examined the association by histological type. In this study, we evaluated the secondhand smoke‐lung cancer relationship by histological type based on pooled data from 18 case–control studies in the International Lung Cancer Consortium (ILCCO), including 2,504 cases and 7,276 control who were never smokers and 10,184 cases and 7,176 controls who were ever smokers. We used multivariable logistic regression, adjusting for age, sex, race/ethnicity, smoking status, pack‐years of smoking, and study. Among never smokers, the odds ratios (OR) comparing those ever exposed to secondhand smoke with those never exposed were 1.31 (95% CI: 1.17–1.45) for all histological types combined, 1.26 (95% CI: 1.10–1.44) for adenocarcinoma, 1.41 (95% CI: 0.99–1.99) for squamous cell carcinoma, 1.48 (95% CI: 0.89–2.45) for large cell lung cancer, and 3.09 (95% CI: 1.62–5.89) for small cell lung cancer. The estimated association with secondhand smoke exposure was greater for small cell lung cancer than for nonsmall cell lung cancers (OR=2.11, 95% CI: 1.11–4.04). This analysis is the largest to date investigating the relation between exposure to secondhand smoke and lung cancer. Our study provides more precise estimates of the impact of secondhand smoke on the major histological types of lung cancer, indicates the association with secondhand smoke is stronger for small cell lung cancer than for the other histological types, and suggests the importance of intervention against exposure to secondhand smoke in lung cancer prevention.

Pleiotropic antitumor effects of the pan‐HDAC inhibitor ITF2357 against c‐Myc‐overexpressing human B‐cell non‐Hodgkin lymphomas

Histone deacetylases (HDAC) extensively contribute to the c‐Myc oncogenic program, pointing to their inhibition as an effective strategy against c‐Myc‐overexpressing cancers. We, thus, studied the therapeutic activity of the new‐generation pan‐HDAC inhibitor ITF2357 (Givinostat®) against c‐Myc‐overexpressing human B‐cell non‐Hodgkin lymphomas (B‐NHLs). ITF2357 anti‐proliferative and pro‐apoptotic effects were analyzed in B‐NHL cell lines with c‐Myc translocations (Namalwa, Raji and DOHH‐2), stabilizing mutations (Raji) or post‐transcriptional alterations (SU‐DHL‐4) in relationship to c‐Myc modulation. ITF2357 significantly delayed the in vitro growth of all B‐NHL cell lines by inducing G1 cell‐cycle arrest, eventually followed by cell death. These events correlated with the extent of c‐Myc protein, but not mRNA, downregulation, indicating the involvement of post‐transcriptional mechanisms. Accordingly, c‐Myc‐targeting microRNAs let‐7a and miR‐26a were induced in all treated lymphomas and the cap‐dependent translation machinery components 4E‐BP1, eIF4E and eIF4G, as well as their upstream regulators, Akt and PIM kinases, were inhibited in function of the cell sensitivity to ITF2357, and, in turn, c‐Myc downregulation. In vivo , ITF2357 significantly hampered the growth of Namalwa and Raji xenografts in immunodeficient mice. Noteworthy, its combination with suboptimal cyclophosphamide, achieved complete remissions in most animals and equaled or even exceeded the activity of optimal cyclophosphamide. Collectively, our findings provide the rationale for testing the clinical advantages of adding ITF2357 to current therapies for the still very ominous c‐Myc‐overexpressing lymphomas. They equally provide the proof‐of‐concept for its clinical evaluation in rational combination with the promising inhibitors of B‐cell receptor and PI3K/Akt/mTOR axis currently in the process of development.

ANTECEDENTS AND CONSEQUENCES OF FEAR OF CHILDBIRTH IN NULLIPAROUS AND PAROUS WOMEN

The study aimed to explore the differences in the role of specific personal and interpersonal risk factors in predicting fear of childbirth (FOC) and to examine whether FOC predicts postnatal maternal adaptation in nulliparous and parous women. A prospective correlational design with two time periods (pre‐ and postnatal) was carried out with 158 women, 85 nulliparous and 73 parous. Women at Week 32 of gestation completed a demographic questionnaire, the Wijma Delivery Expectancy Questionnaire (K.Wijma, B. Wijma, & M. Zar, 1998), the State‐Trait Anxiety Inventory (C.D. Spielberger, R.L. Gorsuch, & R.E. Lushene, 1970), the Symptom Checklist‐90‐Revised (L.R. Derogatis, 1983), the Dyadic Adjustment Scale (G.B. Spanier, 1976), and the Reciprocal Attachment Questionnaire (M. West, A. Sheldon, & L. Reiffer, 1987). Three months after delivery, the women completed the Edinburgh Postnatal Depression Scale (J.L. Cox, J.M. Holden, & R. Sagovsky, 1987) and the Parenting Stress Index‐Short Form (R. Abidin, 1986). Pearson's correlations and a series of multiple regressions were conducted. The results indicated that in the prenatal period, higher state anxiety, β = .35, p < .001, lower dyadic adjustment, β = −.26, p  = .03, and higher insecurity in attachment relationships, β = .39, p < .001, predicted FOC in first‐time mothers only. In the postnatal period, FOC predicted postnatal maternal risk for depression, β = .39, p  = .02, and parenting stress, β = .42, p  = .02, for nulliparous women only. The specific antecedents and consequences of FOC in nulliparous and parous women should be taken into consideration when developing specific interventions.

Problem Framing: How Can Model‐Based Methods Help Systems Engineers Solve The Right Problem?