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The Perichromatin Region (PR) is the 200-nm-thick rim surrounding the condensed chromatin areas in the interphase cell nucleus. First described by Bernhard (1969), PR has been studied for years and several fundamental processes have been shown to take place there: DNA replication, repair, transcription, co-transcriptional splicing. Recently we have pointed out that possibly other mechanisms occur in that region (Masiello et al. 2018). We have studied the PR in several cell and tissue models, both in physiological conditions and after drug treatment. We can confirm that not only methylation on cytosine in DNA and RNA occurs there (Masiello and Biggiogera, 2017) but also demethylation of 5mC leading to 5hmC formation. We have detected by EM immunocytochemistry the presence of DNMT3 as well as TET enzymes within this area. Our data strengthens the hypothesis that PR represents one of the most active nuclear areas, where the active focus is mobile. Since only particular conditions allow its study, it will be challenging to work on PR in vivo via super resolution. References: Bernhard W (1969) A new staining procedure for electron microscopical cytology. J Ultrastruct Res 27(3):250–265 Masiello I, Biggiogera M (2017) Ultrastructural localization of 5-methylcytosine on DNA and RNA. Cell Mol Life Sci 74:3057–3064 Masiello I, Siciliani S, Biggiogera MHistochem Cell Biol (2018) 150:227–233

The nucleolus is a nuclear body where different important molecular processes occurs. Beyond ribosomal biogenesis, other relevant functions were recently assigned to this nuclear region, which are related to cell proliferation control and apoptosis, involvement in telomere formation, transfer RNA modifications and stress sensing. Morphologically it is organized in three main areas: roundish electron-light regions, known as Fibrillar Centers (FCs), surrounded by the Dense Fibrillar Component (DFC). These fibrillary structures lie inside the Granular Component (GC), which constitutes most of the nucleolus. Moreover patches of heterochromatin delimitate the nucleolar periphery, interspaced by euchromatin, with thin strands of condensed chromatin enter the nucleolar body. Some aspects of nucleolar morphology have been correlated to their corresponding molecular activity. It is established that rDNA is present within the FC, DFC, in the perinucleolar heterochromatin and in its intranucleolar strands, whereas ribosomal RNA was localized to DFC and GC. rRNA transcription occurs in the FC/DFC complex, while outside the nucleolus reside transcriptionally inactive rDNA repeats. However we still have little knowledge about the condensed regions of perinucleolar heterochromatin. In order to characterize the molecular activity of this area, we decided to investigate its epigenetics status. We hypothesized that, being a condensed region, it would show the classical markers of repression find in the other nuclear regions characterized by compact chromatin. Indeed we analysed at ultrastructural level the distribution of the histone markers H3K27me3 and H3K9me3, which are known to be involved in chromatin condensation and gene silencing. This study was carried out by immunocytochemistry of these histone marker distributions at electron microscopy. Moreover quantifications and statistics of the marker distributions using bioinformatics tools were carried out. We were able to highlight that not only in all compact regions of the nuclear and nucleolar heterochromatin these two repressive histone markers were present, but also that they were specifically confined to the heterochromatin. From our analysis no significant difference in their density or distributions were found between the nucleolar associated and nuclear heterochromatin. Considering these results, we hypothesize that the general mechanisms of chromatin condensation which involve H3K27me3 and H3K9me3 could be similar in different nuclear domains.

This article reviews research on the role of psychological stress, personality, social support and other psychosocial factors in bacterial, viral and parasitic infections. After 100 years of research on man and animals, psychological stress is considered as a potential cofactor in the pathogenesis of infectious disease. Psychological stress seems able to alter the susceptibility of animals and man to infectious agents, influencing the onset, course and outcome of certain infectious pathologies. Many experiments have identified in neuroimmunomodulation the principal mediator of the alterations associated with conditions of stress. The development of psychoneuroimmunology has fostered in-depth study of the complex relationship between psychosocial factors, the central nervous system, the immune system and infectious disease. Although antimicrobial drugs have certainly remained the basis of all anti-infective therapy, this type of study has already led some authors to propose and experiment protocols of psychological intervention or psychoimmunotherapy in pathologies such as tuberculosis, or herpes simplex virus or human immunodeficiency virus infections. The psychoneuroimmunological approach to infectious diseases will probably grow in importance in the future not only in the setting of research in psychosomatic medicine but also in that of clinical microbiology.

Methylation and demethylation are two epigenetic processes of a big relevance for different biological pathways. The two events happen on the carbon in position five of the cytosine belonging to the so called CpG island. The methylation implies the addition of a methyl group on the cytosine, forming the 5-methylcytosine (5mC) thanks to enzymes called DNMT (Dna-Methyltransferase). After, when required, the methyl group is oxidized or demethylated by a family of enzyme called TET, forming the 5-hydroxymethylcytosine (5hmC). The role of the 5mC is generally correlated with gene expression repression, while the 5hmC function must be clarified. In this context, in order to elucidate the hypothetic role of these markers we decide to investigate at ultrastructural level, by looking at the distribution of two epigenetic modifications putting our attention on different areas of the cell nucleus. Our study where carried out by using transmission electron microscope, light microscope and molecular biology techniques. We observed that in condensed regions of the nucleus the DNA is always highly methylated rather than hydroxymethylated, but in the so called perichromatin region the pattern changes. Indeed, in this region it was possible to notice an abundancy of demethylation underlined both by the presence of the 5hmC and of the enzymes involved in the processes: TET2. This result could allow to hypothesize a sort of activating role for the oxidized modification respect to its reduced form and underline how the perichromatin region is a dynamic region where DNA status changes.

In order to evaluate the role of Mycoplasma pneumoniae and Chlamydia pneumoniae, we studied 613 children aged 2–14 years who were hospitalized for community-acquired lower respiratory tract infections (LRTIs). The patients were enrolled in the study by 21 centers in different regions of Italy from May 1998 through April 1999. Paired serum samples were obtained on admission and after 4–6 weeks to assay the titers of M. pneumoniae and C. pneumoniae antibodies. Nasopharyngeal aspirates for the detection of M. pneumoniae and C. pneumoniae were obtained on admission. Acute M. pneumoniae infections in 210 patients (34.3%) and acute C. pneumoniae infections in 87 (14.1%) were diagnosed. Fifteen of the 18 children with M. pneumoniae and/or C. pneumoniae infections whose treatments were considered clinical failures 4–6 weeks after enrollment had not been treated with macrolides. Our study confirms that M. pneumoniae and/or C. pneumoniae plays a significant role in community-acquired LRTIs in children of all ages and that such infections have a more complicated course when not treated with adequate antimicrobial agents.

Aims/hypothesis We investigated effects of renal function and albuminuria on cardiovascular outcomes in 9,795 low-risk patients with diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Methods Baseline and year 2 renal status were examined in relation to clinical and biochemical characteristics. Outcomes included total cardiovascular disease (CVD), cardiac and non-cardiac death over 5 years. Results Lower estimated GFR (eGFR) vs eGFR ≥90 ml min⁻¹ 1.73 m⁻² was a risk factor for total CVD events: (HR [95% CI] 1.14 [1.01-1.29] for eGFR 60-89 ml min⁻¹ 1.73 m⁻²; 1.59 [1.28-1.98] for eGFR 30-59 ml min⁻¹ 1.73 m⁻²; p < 0.001; adjusted for other characteristics). Albuminuria increased CVD risk, with microalbuminuria and macroalbuminuria increasing total CVD (HR 1.25 [1.01-1.54] and 1.19 [0.76-1.85], respectively; p = 0.001 for trend) when eGFR ≥90 ml min⁻¹ 1.73 m⁻². CVD risk was further modified by renal status changes over the first 2 years. In multivariable analysis, 77% of the effect of eGFR and 81% of the effect of albumin:creatinine ratio were accounted for by other variables, principally low HDL-cholesterol and elevated blood pressure. Conclusions/interpretation Reduced eGFR and albuminuria are independent risk factors for cardiovascular events and mortality rates in a low-risk population of mainly European ancestry. While their independent contributions to CVD risk appear small when other risk factors are considered, they remain excellent surrogate markers in clinical practice because they capture risk related to a number of other characteristics. Therefore, both should be considered when assessing prognosis and treatment strategies in patients with diabetes, and both should be included in risk models.

Preterm birth is associated with altered brain development, with younger gestational age (GA) at birth often associated with greater brain volume reduction. Such volume alterations at term equivalent age (TEA) have been found with differing magnitude across different brain regions, although this has mostly been investigated with regards to whole tissue volumes and large-scale subdivisions. In addition to degree of prematurity, many other perinatal factors have been found to influence brain structure and development in infants born preterm. We aimed to clarify the relationships between degree of prematurity and regional brain volumes at TEA, and between perinatal factors and regional brain volumes at TEA, in finer spatial detail. 285 preterm and term-born infants (GA at birth 24.6–42.1 weeks; 145 female; 59 born at term) were scanned at TEA. Data on perinatal factors were obtained by chart review, including sex, multiple birth, birthweight standard deviation (SD) score, postnatal growth and social risk. The Melbourne Children's Regional Infant Brain (M-CRIB) atlas was registered to the current sample, then 100 brain regions were labelled for volumetric analyses. Linear regressions with generalised estimating equations and likelihood ratio tests were performed to investigate whether GA at birth or perinatal factors were associated with regional volumes at TEA. Younger GA at birth was associated with smaller volumes at TEA in some regions including bilateral cerebral white matter, middle temporal gyri, amygdalae, pallidum and brainstem. In other regions, younger GA at birth was associated with larger volumes, including in primary visual, motor and somatosensory cortices. Positive associations between perinatal factors and regional volumes at TEA were found in many brain regions for birthweight SD score, and male sex, independent of GA at birth. These associations were seen on both univariable analyses, and multivariable analyses controlling for other perinatal factors. Social risk and multiple birth were generally not associated with regional brain volumes, and postnatal growth was associated with volume in many regions only after adjusting for other perinatal factors. These results elucidate regional brain volume differences associated with preterm birth and perinatal factors at a more detailed parcellated level than previously reported, and contribute to understanding of the complex array of correlates of preterm birth. •Preterm birth was associated with regional volume changes at term equivalent age.•Of 100 regions measured, many were smaller with younger gestational age at birth.•Unexpectedly, some regions were larger in infants born more preterm.•Birthweight and male sex were strongly associated with larger regional volumes.

Aims/hypothesis In the double-blind placebo-controlled Fenofibrate Intervention and Event Lowering in Diabetes trial ( n  = 9,795), fenofibrate reduced major cardiovascular events in type 2 diabetes. Sex-related differences in fenofibrate response could be clinically relevant and were pre-specified analyses. Methods Women ( n  = 3,657) and men ( n  = 6,138) with type 2 diabetes not using statins were assigned fenofibrate (200 mg/day) or placebo for 5 years. Effects on lipoproteins and total cardiovascular events were evaluated by sex. Results Baseline total, LDL-, HDL- and non-HDL cholesterol and apolipoproteins A-I and B differed between sexes, and these and triacylglycerol levels improved with fenofibrate in both sexes (all p  < 0.001). Fenofibrate reduced total, LDL- and non-HDL cholesterol and apolipoprotein B more in women (all p  < 0.001), independent of menopausal status and statin uptake. Adjusted for covariates, fenofibrate reduced total cardiovascular outcomes (cardiovascular death, fatal and non-fatal stroke and carotid and coronary revascularisation) by 30% in women (95% CI 8%, 46%; p  = 0.008) and 13% in men (95% CI −1%, 24%; p  = 0.07) with no treatment-by-sex interaction ( p >  0.1). In patients with high triacylglycerol levels and low HDL-cholesterol, fenofibrate reduced total cardiovascular outcomes by 30% (95% CI −7%, 54%) in women and 24% (95% CI 2%, 42%) in men, with no treatment-by-sex interaction ( p >  0.1). Conclusions/interpretation Fenofibrate improved the lipoprotein profile more in women than men. Cardiovascular event reductions with fenofibrate were consistently similar in women and men, both overall and among those with low HDL-cholesterol and high triacylglycerol levels. These data provide reassurance about fenofibrate efficacy in women and men. Both sexes with type 2 diabetes should be considered for fenofibrate therapy for cardioprotection.

BackgroundFor infants born in the contemporary era of neonatal care, little is known about adult mental health outcomes of extremely preterm birth (EP; <28 weeks' gestation) or extremely low birthweight (ELBW; <1000 g). This study aimed to compare attention deficit hyperactivity disorder (ADHD), anxiety, mood, and substance use disorder prevalence in young adults born EP/ELBW and normal birthweight (NBW; >2499 g) controls, and to compare change in prevalence of mental health symptoms and disorders from 18 to 25 years.MethodsParticipants were a prospective geographical cohort of 297 consecutive survivors born EP/ELBW during 1991–1992 and 260 NBW controls. At age 25 years, 174 EP/ELBW and 139 NBW participants completed the Adult ADHD Rating Scale, Structured Clinical Interview for DSM-IV Disorders, Beck Anxiety Inventory, and Center for Epidemiologic Studies Depression Scale-Revised. Data from follow-up at 18 years were also utilized. Multiple imputation was used to account for attrition.ResultsMental health outcomes at 25 years were similar between groups: prevalence rates were ADHD 7% v. 5%; anxiety 32% v. 27%; mood 38% v. 35%; substance use 12% v. 14% in the EP/ELBW and NBW groups, respectively. In both groups, ADHD declined between 18 and 25 years [odds ratio (OR) per year = 0.87, 95% confidence interval (CI) 0.79–0.95], and generalized anxiety disorder and major depressive episode became more common (OR 1.22, 95% CI 1.10–1.35 per year; OR 1.20, 95% CI 1.10–1.30 respectively).ConclusionsThis contemporary EP/ELBW cohort has comparable young adult mental health outcomes to controls, and similar patterns of change in mental health from late adolescence.

Children born very preterm (VP) display altered growth in corticolimbic structures compared with full-term peers. Given the association between the cortiocolimbic system and anxiety, this study aimed to compare developmental trajectories of corticolimbic regions in VP children with and without anxiety diagnosis at 13 years. MRI data from 124 VP children were used to calculate whole brain and corticolimbic region volumes at term-equivalent age (TEA), 7 and 13 years. The presence of an anxiety disorder was assessed at 13 years using a structured clinical interview. VP children who met criteria for an anxiety disorder at 13 years ( = 16) displayed altered trajectories for intracranial volume (ICV, < 0.0001), total brain volume (TBV, = 0.029), the right amygdala ( = 0.0009) and left hippocampus ( = 0.029) compared with VP children without anxiety ( = 108), with trends in the right hippocampus ( = 0.062) and left medial orbitofrontal cortex ( = 0.079). Altered trajectories predominantly reflected slower growth in early childhood (0-7 years) for ICV ( = -0.461, = 0.020), TBV ( = -0.503, = 0.021), left ( = -0.518, = 0.020) and right hippocampi ( = -0.469, = 0.020) and left medial orbitofrontal cortex ( = -0.761, = 0.020) and did not persist after adjusting for TBV and social risk. Region- and time-specific alterations in the development of the corticolimbic system in children born VP may help to explain an increase in anxiety disorders observed in this population.