Preclinical and clinical evidence on the approach-avoidance conflict evaluation as an integrative tool for psychopathology.

The approach-avoidance conflict (AAC), i.e. the competing tendencies to undertake goal-directed actions or to withdraw from everyday life challenges, stands at the basis of humans' existence defining behavioural and personality domains. Gray's Reinforcement Sensitivity Theory posits that a stable bias toward approach or avoidance represents a psychopathological trait associated with excessive sensitivity to reward or punishment. Optogenetic studies in rodents and imaging studies in humans associated with cross-species AAC paradigms granted new emphasis to the hippocampus as a hub of behavioural inhibition. For instance, recent functional neuroimaging studies show that functional brain activity in the human hippocampus correlates with threat perception and seems to underlie passive avoidance. Therefore, our commentary aims to (i) discuss the inhibitory role of the hippocampus in approach-related behaviours and (ii) promote the integration of functional neuroimaging with cross-species AAC paradigms as a means of diagnostic, therapeutic, follow up and prognosis refinement in psychiatric populations.

LSD1 is an environmental stress-sensitive negative modulator of the glutamatergic synapse.

Along with neuronal mechanisms devoted to memory consolidation -including long term potentiation of synaptic strength as prominent electrophysiological correlate, and inherent dendritic spines stabilization as structural counterpart- negative control of memory formation and synaptic plasticity has been described at the molecular and behavioral level. Within this work, we report a role for the epigenetic corepressor Lysine Specific Demethylase 1 (LSD1) as a negative neuroplastic factor whose stress-enhanced activity may participate in coping with adverse experiences. Constitutively increasing LSD1 activity via knocking out its dominant negative splicing isoform neuroLSD1 (neuroLSD1KO mice), we observed extensive structural, functional and behavioral signs of excitatory decay, including disrupted memory consolidation. A similar LSD1 increase, obtained with acute antisense oligonucleotide-mediated neuroLSD1 splicing knock down in primary neuronal cultures, dampens spontaneous glutamatergic transmission, reducing mEPSCs. Remarkably, LSD1 physiological increase occurs in response to psychosocial stress-induced glutamatergic signaling. Since this mechanism entails neuroLSD1 splicing downregulation, we conclude that LSD1/neuroLSD1 ratio modulation in the hippocampus is instrumental to a negative homeostatic feedback, restraining glutamatergic neuroplasticity in response to glutamate. The active process of forgetting provides memories with salience. With our work, we propose that softening memory traces of adversities could further represent a stress-coping process in which LSD1/neuroLSD1 ratio modulation may help preserving healthy emotional references.

Maternal anxiety, depression and sleep disorders before and during pregnancy, and preschool ADHD symptoms in the NINFEA birth cohort study.

AIMS.: Maternal mental disorders have been associated with the risk of attention-deficit/hyperactivity disorder (ADHD) in children. Within the context of a mother-child cohort, we examined whether maternal anxiety, depression and sleep disorders are associated with pre-school ADHD symptoms. METHODS.: The study included 3634 singletons from the Italian NINFEA (Nascita e INFanzia: gli Effetti dell'Ambiente') cohort. Maternal doctor-diagnosed anxiety, depression and sleep disorders before and during pregnancy were assessed from the questionnaires completed during pregnancy and 6 months after delivery. Mothers rated child ADHD symptoms at 4 years of age, according to the Diagnostic and Statistical Manual of Mental Disorders. Hyperactive-impulsive (ADHD-H), inattentive (ADHD-I) and total ADHD scores were analysed in the models adjusted for child's gender, first-born status, maternal age, education, alcohol consumption and smoking during pregnancy. RESULTS.: The total ADHD score at age 4 was associated with maternal lifetime anxiety (17.1% percentage difference in score compared with never; 95% CI 7.3-27.9%), sleep disorders (35.7%; 95% CI 10.7-66.5%) and depression (17.5%; 95% CI 3.2-33.8%). Similar positive associations were observed also for ADHD-H and ADHD-I traits, with slightly attenuated associations between maternal sleep disorders and child ADHD-I score, and maternal depression and both ADHD scores. All the estimates were enhanced when the disorders were active during pregnancy and attenuated for disorders active only during the pre-pregnancy period. CONCLUSIONS.: Maternal anxiety, depression and sleep disorders are associated with a relative increase in the number of ADHD-H, ADHD-I and total ADHD symptoms in preschoolers.

Three-dimensional longitudinal evaluation of facial mimicry in orthognathic class III surgery.

The effect of bimaxillary orthognathic surgery on facial mimicry was assessed longitudinally in 15 patients with dentoskeletal class III facial dysmorphism (seven men, eight women, mean age 28 years). The patients were analysed pre-surgery and at 6, 12, and 24 months post-surgery while performing verbal (five vowels) and non-verbal (open and closed mouth smile, lip purse) soft tissue facial movements. The three-dimensional motions of right and left nasogenian, crista philtri, cheilion, and lower lip landmarks were detected by an optoelectronic instrument, and a total mobility index was obtained. Differences between the sides were quantified by the symmetry index. Patient values were compared to those collected previously from healthy volunteers by computing z-scores. On average, no significant differences were found in the mobility of the buccal soft tissues at 24 months after surgery (ANOVA P-value, range 0.075-0.808), with positive median z-scores (pooled mean value close to 0.6). Symmetry indices ranged around the control reference values, showing no stage-related differences (Friedman test P-value, range 0.252-0.937), and exceeding 90% for all movements at 24 months after surgery. Bimaxillary osteotomy does not compromise facial mimicry in either verbal or non-verbal facial movements.

Lipid-lowering therapy of everolimus-related severe hypertriglyceridaemia in a pancreatic neuroendocrine tumour (pNET).

WHAT IS KNOWN AND OBJECTIVE: Hypertriglyceridaemia (HTG) is a potentially serious side effect of everolimus therapy. We here report a case of severe HTG in an everolimus-treated patient and provide recommendations for its management. CASE SUMMARY: The patient was a 70-year-old woman, being treated with everolimus for a pancreatic neuroendocrine tumour (pNET). She developed severe HTG to a maximum of 969 mg/dL after 22 months of therapy. Treatment with fenofibrate rapidly normalized triglyceride (TG) levels. WHAT IS NEW AND CONCLUSION: Severe HTG may occur in everolimus-treated patients. Prescription of the appropriate therapy can allow patients to continue this medication.

Perinatal health services organization for preterm births: a multinational comparison.

OBJECTIVE: To explore population characteristics, organization of health services and comparability of available information for very low birth weight or very preterm neonates born before 32 weeks' gestation in 11 high-income countries contributing data to the International Network for Evaluating Outcomes of Neonates (iNeo). STUDY DESIGN: We obtained population characteristics from public domain sources, conducted a survey of organization of maternal and neonatal health services and evaluated the comparability of data contributed to the iNeo collaboration from Australia, Canada, Finland, Israel, Italy, Japan, New Zealand, Spain, Sweden, Switzerland and UK. RESULTS: All countries have nationally funded maternal/neonatal health care with >90% of women receiving prenatal care. Preterm birth rate, maternal age, and neonatal and infant mortality rates were relatively similar across countries. Most (50 to >95%) between-hospital transports of neonates born at non-tertiary units were conducted by designated transport teams; 72% (8/11 countries) had designated transfer and 63% (7/11 countries) mandate the presence of a physician. The capacity of 'step-down' units varied between countries, with capacity for respiratory care available in <10% to >75% of units. Heterogeneity in data collection processes for benchmarking and quality improvement activities were identified. CONCLUSIONS: Comparability of healthcare outcomes for very preterm low birth weight neonates between countries requires an evaluation of differences in population coverage, healthcare services and meta-data.

DOT1L-mediated H3K79me2 modification critically regulates gene expression during cardiomyocyte differentiation.

Epigenetic changes on DNA and chromatin are implicated in cell differentiation and organogenesis. For the heart, distinct histone methylation profiles were recently linked to stage-specific gene expression programs during cardiac differentiation in vitro. However, the enzymes catalyzing these modifications and the genes regulated by them remain poorly defined. We therefore decided to identify the epigenetic enzymes that are potentially involved in cardiomyogenesis by analyzing the expression profile of the 85 genes encoding the epigenetic-related proteins in mouse cardiomyocytes (CMs), and then study how they affect gene expression during differentiation and maturation of this cell type. We show here with gene expression screening of epigenetic enzymes that the highly expressed H3 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) drives a transitional pattern of di-methylation on H3 lysine 79 (H3K79) in CMs at different stages of differentiation in vitro and in vivo. Through a genome-wide chromatin-immunoprecipitation DNA-sequencing approach, we found H3K79me2 enriched at genes expressed during cardiac differentiation. Moreover, knockdown of Dot1L affected the expression of H3K79me2-enriched genes. Our results demonstrate that histone methylation, and in particular DOT1L-mediated H3K79me2 modification, drives cardiomyogenesis through the definition of a specific transcriptional landscape.

Mould/dampness exposure at home is associated with respiratory disorders in Italian children and adolescents: the SIDRIA-2 Study.

AIMS: To report on the relation between home mould and/or dampness exposure and respiratory disorders in a large sample of children and adolescents in Italy, accounting for age at time of exposure. METHODS: 20,016 children (mean age 7 years) and 13,266 adolescents (mean age 13 years) completed questionnaires on indoor exposures and respiratory symptoms/diseases. Statistical analyses were adjusted for sex, age, questionnaire's compiler, area of residence, season of interview, parental educational status, family history of asthma, rhinitis, eczema, chronic obstructive pulmonary disease, presence of gas water heaters, passive smoking, pets, and active smoking (only for adolescents). Population attributable risk % (PAR) was also computed. RESULTS: Asthma was more strongly related to only early than to only current exposure, both in children (OR 1.80, 95% CI 1.41 to 2.30) and adolescents (OR 1.89, 95% CI 1.38 to 2.59). The same result was found for rhino-conjunctivitis (OR 1.46, 95% CI 1.17 to 1.82), in children, and for wheeze among adolescents (OR 1.56, 95% CI 1.15 to 2.11). In children, wheeze (OR 1.98, 95% CI 1.47 to 2.66) and eczema (OR 1.44, 95% CI 1.09 to 1.91) were more strongly related to mould/dampness when exposed both early and currently; the same occurred in adolescents for rhino-conjunctivitis (1.78, 95% CI 1.30 to 2.45). Although persistent cough/phlegm was significantly related to mould/dampness exposure in children, regardless of exposure timing, no significant association between mould/dampness exposure and eczema or cough/phlegm was found among adolescents. PAR estimates were higher for only early than only current exposures. Avoiding early only exposure would abate wheeze by 6%, asthma or cough/phlegm by 7%, rhino-conjunctivitis in children by 4%, and in adolescents, asthma by 6%, and wheeze by 4%. CONCLUSIONS: Respiratory disorders such as wheeze and asthma can often be explained by exposure to home mould/dampness, especially early in life. The association seems more evident in children than in adolescents. These findings may suggest the need for environmental prevention strategies.

Pulmonary and sinus diseases in primary humoral immunodeficiencies with chronic productive cough.

AIMS: To prospectively evaluate sinopulmonary disease in 24 patients with primary humoral immunodeficiency (11 with agammaglobulinaemia, nine with isolated IgA deficiency, and two with common variable immunodeficiency) and chronic productive cough, ascertain the usefulness of chest high resolution computed tomography (HRCT) in evaluating the progression of lung disease, and test a therapeutic approach to chronic sinusitis. METHODS: Pulmonary abnormalities were evaluated using lung function tests and HRCT (Bhalla score); chronic sinusitis was diagnosed clinically and confirmed by flexible fibreoptic endoscopy. Sixteen patients entered the three year follow up. RESULTS: Lung function testing revealed an obstruction in four patients; chest HRCT was abnormal in 16. There was a linear relation between the Bhalla score > or =4 and the number of months with cough/year over the previous two years (clinical score), and between the difference in clinical scores during follow up and in the previous two years and the difference in Bhalla score. The pulmonary lesions did not significantly progress over a three year period. Thirteen patients had chronic sinusitis; 6/10 patients followed up were successfully treated with antibiotics plus topical therapy and two with nasal polypoid disease with endoscopic sinus surgery. CONCLUSIONS: In patients with primary humoral immunodeficiency and chronic productive cough, HRCT is very useful in delineating the extent of lung damage. The correlation between Bhalla score and clinical findings and the favourable outcome of the disease suggests that in most patients chest HRCT should not be repeated annually as previously suggested. Medical therapy seems to be effective in many cases of chronic sinusitis.

Quantification of sodium dodecyl sulfate in microliter-volume biochemical samples by visible light spectroscopy.

A method for sodium dodecyl sulfate (SDS) quantitation in microliter-volume complex biochemical samples is described. The quantitation is based on the use of a dye, stains-all, the color of which changes from intense fuchsia to yellow upon addition of SDS. We show that this color change is gradual and proportional to the amount of SDS added to the stains-all solution, thus allowing its use to reliably quantitate SDS in biochemical samples by means of a visible light spectrophotometer. A large number of compounds widely used in biochemistry are herein shown not to interfere with the SDS measurement when they are present in the sample at usual biochemical concentrations. Furthermore, linearity between the color change and the amount of SDS present in the sample is never impaired when huge amounts of these compounds are also present, thus making this quantitation method highly reliable with use of a calibration curve. The method allows easy and reliable quantitation of microgram amounts of SDS in microliter-volume biochemical samples.

Total serum IgE and outcome in infants with recurrent wheezing.

OBJECTIVE: To investigate the relation between total serum IgE at 0.5-3 and 3-6 years, and the risk of allergic sensitisation and persistent wheezing up to 8 years of age. METHODS: Prospective follow up study of 45 infants with highly recurrent wheezing, no allergic symptoms, and negative skin tests. RESULTS: In the last follow up year, 15 children still suffered from wheezing. Five wheeze-free and four episodically wheezing children had become sensitised. No association was found between early (0.5-3 years) IgE z scores and the recurrence of wheezing during follow up, or atopic sensitisation. IgE z scores at 3-6 years were significantly higher in children with positive skin tests (p = 0.013), but were still not associated with recurrence of wheezing. CONCLUSIONS: In subjects with frequent early wheezing and no signs of atopy, early total serum IgE measurements are not predictive of outcome.

Consumption of fresh fruit rich in vitamin C and wheezing symptoms in children. SIDRIA Collaborative Group, Italy (Italian Studies on Respiratory Disorders in Children and the Environment).

BACKGROUND: A beneficial effect of fresh fruit consumption on lung function has been observed in several studies. The epidemiological evidence of the effect on respiratory symptoms and asthma is limited. The consumption of fruit rich in vitamin C was examined in relation to wheezing and other respiratory symptoms in cross sectional and follow up studies of Italian children. METHODS: Standardised respiratory questionnaires were filled in by parents of 18 737 children aged 6-7 years living in eight areas of Northern and Central Italy. The winter intake of citrus fruit and kiwi fruit by the children was categorised as less than once per week, 1-2 per week, 3-4 per week, and 5-7 per week. A subset of 4104 children from two areas was reinvestigated after one year using a second parental questionnaire to record the occurrence of wheezing symptoms over the intervening period. RESULTS: In the cross sectional analysis, after controlling for several confounders (sex, study area, paternal education, household density, maternal smoking, paternal smoking, dampness or mould in the child's bedroom, parental asthma), intake of citrus fruit or kiwi fruit was a highly significant protective factor for wheeze in the last 12 months (odds ratio (OR) = 0.66, 95% confidence intervals (CI) 0.55 to 0.78, for those eating fruit 5-7 times per week compared with less than once per week), shortness of breath with wheeze (OR = 0.68, 95% CI 0.56 to 0.84), severe wheeze (OR = 0.59, 95% CI 0.40 to 0.85), nocturnal cough (OR = 0.73, 95% CI 0.65 to 0.83), chronic cough (OR = 0.75, 95% CI 0.65 to 0.88), and non-coryzal rhinitis (OR = 0.72, 95% CI 0.63 to 0.83). In the follow up study fruit intake recorded at baseline was a strong and independent predictor of all symptoms investigated except non-coryzal rhinitis. In most cases the protective effect was evident even among children whose intake of fruit was only 1-2 times per week and no clear dose-response relationship was found. The effect was stronger (although not significantly so (p = 0.13)) in subjects with a history of asthma; those eating fresh fruit at least once a week experienced a lower one year occurrence of wheeze (29. 3%) than those eating fruit less than once per week (47.1%) (OR = 0. 46, 95% CI 0.27 to 0.81). CONCLUSIONS: Although the effect of other dietary components cannot be excluded, it is concluded that the consumption of fruit rich in vitamin C, even at a low level of intake, may reduce wheezing symptoms in childhood, especially among already susceptible individuals.

Purification of the c-erbB2/neu membrane-spanning segment: a hydrophobic challenge.

High quality purification of membrane-spanning peptides and proteins remains a challenging problem. In this work we describe a tailored chromatographic purification of a synthetic 35-residue peptide corresponding to the transmembrane region of the tyrosine kinase receptor c-erb2/neu. Composed to over 70% by the amino acids alanine, isoleucine, leucine, phenylalanine and valine, this peptide presents a very hydrophobic character. Product isolation from the complex peptide mixture, obtained after acid cleavage of the resin matrix used during the solid-phase synthesis, represents a difficult task. We propose a three step strategy based on gel permeation and reversed-phase high-performance liquid chromatography, using aprotic polar solvent mixtures. The challenge consisted in obtaining a sufficient amount of an extremely pure sample, in order to allow structural analysis by NMR spectroscopy. Keeping trace of the synthetic peptide throughout the different purification steps was assured by MALDI TOF mass spectrometry, and the final product purity was checked by coupled liquid chromatography-ESI TOF mass spectrometry.

The second stalk of the yeast ATP synthase complex: identification of subunits showing cross-links with known positions of subunit 4 (subunit b).

A component of the stator of the yeast ATP synthase (subunit 4 or b) showed many cross-linked products with the homobifunctional reagent dithiobis[succinimidyl propionate], which reacts with the amino group of lysine residues. The positions in subunit 4 that were involved in the cross-linkings were determined by using cysteine-generated mutants constructed by site-directed mutagenesis of ATP4. Cross-linking experiments with the heterobifunctional reagent p-azidophenacyl bromide, which has a spacer arm of 9 A, were performed with mitochondria and crude Triton X-100 extracts containing the solubilized enzyme. Substitution of lysine residues by cysteine residues in the hydrophilic C-terminal part of subunit 4 allowed cross-links with subunit h from C98 and with subunit d from C141, C143, and C151. OSCP was cross-linked from C174 and C209. A cross-linked product, 4+beta, was also obtained from C174. It is concluded that the C-terminus of subunit 4 is distant from the membrane surface and close to F(1) and OSCP. The N-terminal part of subunit 4 is close to subunit g, as demonstrated by the identification of a cross-linked product involving subunit g and the cysteine residues 7 or 14 of subunit 4.

Risk factors for early, persistent, and late-onset wheezing in young children. SIDRIA Collaborative Group.

Wheezing in childhood is not a single disorder and different wheezing-associated respiratory illnesses have been recently described. We investigated the association between wheezing conditions and familial, pre-, peri-, and postnatal risk factors. We studied 16,333 children, 6 to 7 yr old, enrolled in a population-based study. Standardized questionnaires were filled in by parents. A total of 1,221 children had transient early wheezing, 671 had persistent wheezing, 918 had late-onset wheezing, and 13,523 never had wheezing or asthma (control group). Maternal asthma or chronic obstructive airway disease were significantly (p < 0.0001) more associated with persistent wheezing than with transient early and late-onset wheezing. The same pattern was observed for exposure to maternal smoke during pregnancy. Having a mother > 35 yr old was protective against transient early wheezing (odds ratio [OR]: 0.68, 95% confidence intervals [95% CI]: 0.53 to 0.86). Breast feeding >/= 6 mo was slightly protective against transient early wheezing (OR: 0.82, 95% CI: 0.68 to 0.97), whereas it was a moderate risk factor for late-onset wheezing (OR: 1.22, 95% CI: 0.99 to 1.50). On the contrary, having siblings and attending a day care center were both risk factors for transient early wheezing (OR: 1.41 [95% CI: 1.21 to 1.64] and 1.70 [95% CI: 1.48 to 1.96], respectively) and protective factors against wheezing of late onset (OR: 0.83 [95% CI: 0.70 to 0.97] and 0.72 [95% CI: 0.59 to 0.88]). There was a stronger (p < 0.0001) positive association between personal history of eczema or allergic rhinitis and persistent and late-onset wheezing than transient early wheezing. Our findings suggest a different contribution of risk factors to wheezing conditions in childhood.

The impact of parental smoking on asthma and wheezing. SIDRIA Collaborative Group. Studi Italiani sui Disturbi Respiratori nell'Infanzia e l'Ambiente.

To evaluate the impact of parental smoking on childhood asthma and wheezing, we studied two random samples of subjects ages 6-7 and 13-14 years in ten areas of northern and central Italy. Standardized questionnaires were completed by parents of 18,737 children and 21,068 adolescents (response rates, 92.8% and 96.3%, respectively) about their smoking habits and the respiratory health of their children. Adolescents were asked about their respiratory health and personal smoking. We compared two groups of cases with healthy subjects: (1) "current asthma" (children, 5.2%; adolescents, 6.2%) and (2) "current wheezing" not labeled as asthma (children = 4.5%, adolescents = 8.5%). Exposure to smoke of at least one parent increased the relative risk of current asthma among children [odds ratio (OR) = 1.34; 95% confidence interval (CI) = 1.11-1.62] and of current wheezing among adolescents (OR = 1.24; 95% CI = 1.07-1.44). Maternal smoking had a stronger effect than paternal smoking. Maternal smoking during pregnancy was associated with current asthma (OR = 1.62; 95% CI = 1.34-1.96) and current wheezing in children (OR = 1.31; 95% CI = 1.06-1.62); the effects were lower among adolescents. Among subjects with a negative history of parental asthma, maternal smoking was associated with current wheezing in both age groups, whereas among those with a positive history of parental asthma it was associated with current asthma in children, but not in adolescents. We estimated that 15% (95% CI = 12-19) of the current asthma cases among children and 11% (95% CI = 8.3-14) of the current wheezing cases among adolescents are attributable to parental smoking in Italy.