Disruption of genomic neighbourhood at the imprinted IGF2-H19 locus in Beckwith-Wiedemann syndrome and Silver-Russell syndrome

Hyper- and hypomethylation at the IGF2-H19 imprinting control region (ICR) result in reciprocal changes in IGF2-H19 expression and the two contrasting growth disorders, Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). DNA methylation of the ICR controls the reciprocal imprinting of IGF2 and H19 by preventing the binding of the insulator protein, CTCF. We here show that local changes in histone modifications and CTCF--cohesin binding at the ICR in BWS and SRS together with DNA methylation correlate with the higher order chromatin structure at the locus. In lymphoblastoid cells from control individuals, we found the repressive histone H3K9me3 and H4K20me3 marks associated with the methylated paternal ICR allele and the bivalent H3K4me2/H3K27me3 mark together with H3K9ac and CTCF--cohesin associated with the non-methylated maternal allele. In patient-derived cell lines, the mat/pat asymmetric distribution of these epigenetic marks was lost with H3K9me3 and H4K20me3 becoming biallelic in the BWS and H3K4me2, H3K27me3 and H3K9ac together with CTCF-cohesin becoming biallelic in the SRS. We further show that in BWS and SRS cells, there is opposing chromatin looping conformation mediated by CTCF--cohesin binding sites surrounding the locus. In normal cells, lack of CTCF--cohesin binding at the paternal ICR is associated with monoallelic interaction between two CTCF sites flanking the locus. CTCF--cohesin binding at the maternal ICR blocks this interaction by associating with the CTCF site downstream of the enhancers. The two alternative chromatin conformations are differently favoured in BWS and SRS likely predisposing the locus to the activation of IGF2 or H19, respectively.     

PTOV-1, a novel protein overexpressed in prostate cancer,shuttles between the cytoplasm and the nucleus and promotes entry into the S phase of the cell division cycle

PTOV1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. The PTOV1 protein consists of two novel protein domains arranged in tandem, without significant similarities to known protein motifs. By immunohistochemical analysis, we have found that PTOV1 is overexpressed in 71% of 38 prostate carcinomas and in 80% of samples with prostate intraepithelial neoplasia. High levels of PTOV1 in tumors correlated significantly with proliferative index, as assessed by Ki67 immunoreactivity, and associated with a nuclear localization of the protein, suggesting a functional relationship between PTOV1 overexpression, proliferative status, and nuclear localization. In quiescent cultured prostate tumor cells, PTOV1 localized to the cytoplasm, being excluded from nuclei. After serum stimulation, PTOV1 partially translocated to the nucleus at the beginning of the S phase. At the end of mitosis, PTOV1 exited the nucleus. Transient transfection of chimeric green fluorescent protein-PTOV1 forced the entry of cells into the S phase of the cell cycle, as shown by double fluorescent imaging for green fluorescent protein and for Ki67, and also by flow cytometry. This was accompanied by greatly increased levels of cyclin D1 protein in the transfected cells. These observations suggest that overexpression of PTOV1 can contribute to the proliferative status of prostate tumor cells and thus to their biological behavior.     

Complement Fixation Test To Assess Humoral Immunity in Cattle and Sheep Vaccinated with Brucella abortus RB51

The live attenuated Brucella abortus strain RB51 is a rifampin-resistant, lipopolysaccharide (LPS) O-chain-deficient mutant of virulent B. abortus 2308. The reduced O-chain content in RB51 prevents this bacterium from inducing antibodies detectable by the conventional serologic tests for bovine brucellosis diagnosis that mainly identify antibodies to LPS. The absence of available serologic tests for RB51 also complicates the diagnosis of possible RB51 infections in humans exposed to this strain. The purpose of this study was to evaluate the suitability of a complement fixation (CF) test performed with the rough strain B. abortus RB51, previously deprived of anticomplementary activity, in detecting anti-B. abortus RB51 antibodies in cattle and sheep experimentally vaccinated with this strain. The results of this study showed that a CF test with RB51 as the antigen is able to specifically detect antibodies following RB51 vaccination in cattle and sheep. In addition, this method could be a useful tool for detecting B. abortus RB51 infection in humans.     

Amyotrophic lateral sclerosis: a new missense mutation in the SOD1 gene

Copper-zinc superoxide dismutase-1 (SOD1) is the second most common mutated gene in amyotrophic lateral sclerosis (ALS). To date more than 150 missense mutations of SOD1 have been reported. The objective of this study was to describe a novel SOD1 mutation and its phenotypic expression. We describe a 74-year-old Caucasian man who began to complain of progressive weakness and atrophy of the right hand and over 10 months developed a severe tetraparesis, with atrophies of upper and lower limbs and neck muscles, dysphagia, and dyspnea that led to percutaneous endoscopic gastrostomy and tracheotomy. A diagnosis of ALS was made. Genetic analysis identified a heterozygous mutation in exon 4 of SOD1 that results in the amino acid substitution from arginine to cysteine at position 115 (p.R115C). We identified a novel pathogenic SOD1 mutation in a patient with a very rapid disease progression and aggressive phenotype providing additional information on the wide range of SOD1 mutations in apparently sporadic ALS and confirming the possibility of a strong genotype-phenotype correlation for distinct SOD1 mutations.     

Confirmatory factor analysis and measurement invariance by gender,age and levels of psychological distress of the short TEMPS-A

Background

The Temperament Evaluation of Memphis, Pisa, Paris and San Diego – Autoquestionnaire (TEMPS-A) is a widely used self-reported tool aimed at measuring the affective temperaments that define the bipolar spectrum, with cyclothymic, depressive, irritable, hyperthymic, and anxious subscales. Confirmatory factor analysis (CFA) was rarely used to confirm the expected five-factor model. Measurement invariance was never tested.

Methods

Cross-sectional, survey design involving 649 Italian college students (males: 47%). The short 39-item TEMPS-A and the 12-item General Health Questionnaire (GHQ-12) were used as measures of the affective temperaments and of psychological distress, respectively. CFA was applied to the TEMPS-A. Measurement invariance by gender, age and levels of psychological distress on the GHQ-12 was calculated with the establishment of subsequent equivalence constraints in the model parameters across groups.

Results

The expected five-factor model had the best fit for all CFA indexes. Configural, metric and scalar invariance of the five-factor model of the TEMPS-A was proved across gender, age and levels of psychological distress of the participants. The hyperthymic temperament subscale has low or no links with the other affective temperament subscales, which were interrelated with medium to large effect sizes.

Limitations

College students might be not representative of the general population. No information on the clinical status of the students was available beyond self-report data.

Conclusion

The study proved the measurement invariance of the (short) TEMPS-A, which is a pre-requisite to compare groups or individuals in cross-sectional and longitudinal surveys. Generalizability cannot be assumed without replication of the findings in clinical samples.     

Prospective examination of adolescent sleep patterns and behaviors before and during COVID-19

Study ObjectivesTo prospectively examine changes in adolescent sleep before and during the COVID-19 pandemic in adolescents with and without ADHD.MethodsParticipants were 122 adolescents (ages 15–17; 61% male; 48% with ADHD). Parents reported on adolescents’ sleep duration and difficulties initiating and maintaining sleep (DIMS); adolescents reported on sleep patterns, sleep duration, delayed sleep/wake behaviors, and daytime sleepiness before (September 2019 to February 2020) and during (May–June 2020) COVID-19. Adolescents also reported on their health behaviors, COVID-19-related negative affect, and difficulties concentrating due to COVID-19.ResultsParents reported adolescents had more DIMS during COVID-19 than before COVID-19, with clinically elevated rates increasing from 24% to 36%. Both bedtimes and waketimes shifted later during COVID-19, and adolescents reported more delayed sleep/wake behaviors. Adolescents also reported less daytime sleepiness and longer school night sleep duration during COVID-19. In considering differences between adolescents with and without ADHD, adolescents with ADHD did not experience an increase in school night sleep duration and were less likely to obtain recommended sleep duration during COVID-19. In the full sample, controlling for ADHD status, COVID-19-related sadness/loneliness was associated with increases in DIMS, and spending less time outside and more COVID-19-related worries/fears were associated with increases in delayed sleep/wake behaviors during COVID-19.ConclusionsCOVID-19 had negative and positive impacts on adolescent sleep. Adolescents with ADHD did not experience the benefit of increased school night sleep duration during COVID-19 like adolescents without ADHD. Negative affect and health behaviors may be useful intervention targets for reducing negative impacts of COVID-19 for adolescent sleep.     

Withdrawal of synthetic hormones during the perimenopause: A case study

Objective. The purpose of this study was to investigate pregnant women's intentions for opting for caesarean section (CS), their experiences regarding previous births and their expectations for subsequent delivery. Our objectives were to identify medical and psychological predictors pertaining to the decision for CS on demand.

Design. The cross-sectional survey was conducted at two study centres over a three-month period including German speaking women at any time of pregnancy and consisted of an anonymous structured questionnaire. Logistic regression was computed to investigate the predictive value of medical variables, birth experience and birth anxiety on the demand for CS.

Results. Nineteen of 201 participants preferred to deliver by CS on demand and 15 felt uncertain about their decision. How the preceding delivery had been experienced was significantly better in the vaginal delivery (VD)-group (women not considering CS on demand) than in the CS-group (good experience in 81.7% and 52.0% respectively, p = 0.007). A negative previous birth experience and a preceding CS were predictors for the wish to deliver by CS.

Conclusions. As negative birth experience predicts the wish for a CS, specific supportive care during first pregnancy could play a pivotal role in making this decision.     

Long-Term Treatment of Severe SAPHO Syndrome with Adalimumab

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome defines an association of inflammatory cutaneous disorders with osteoarticular manifestations and represents a clinical and therapeutic challenge. We report a case of severe SAPHO syndrome with acne conglobata and a diffuse involvement of the anterior chest wall and sacroiliac joints that required treatment with isotretinoin and adalimumab, a new fully human anti-tumor necrosis factor (TNF)-α monoclonal antibody. Combination treatment determined a complete clinical remission of cutaneous and osteoarticular manifestations after 48 weeks. Despite maintenance of clinical remission, follow-up imaging studies after 24 months of adalimumab monotherapy revealed osteoarticular disease progression, with features of inflammatory osteitis. TNFα antagonists have been used as third-line therapy for SAPHO syndrome in single case reports or case series, but these lack consistent long-term follow-up. SAPHO syndrome can present an intermittent-favorable course in the majority of cases as well as a chronic-progressive course, the latter requiring aggressive combination treatment with TNFα antagonists and conventional systemic agents.