CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic ...variants inactivating CDKL5 or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion. The use of recently developed genomic techniques (optical genome mapping and whole-genome sequencing) allowed us to finely characterize the breakpoints, with one of them interrupting CDKL5 at intron 1. This is the fifth case of CDD reported in the scientific literature harboring a structural rearrangement on the X chromosome, providing evidence for the hypothesis that this type of anomaly can represent a recurrent pathogenic mechanism, whose frequency is likely underestimated, with it being overlooked by standard techniques. The identification of the molecular etiology of the disorder is extremely important in evaluating the pathological outcome and to better investigate the mechanisms associated with drug resistance, paving the way for the development of specific therapies. Karyotype and genomic techniques should be considered in all cases presenting with CDD without molecular confirmation.
To evaluate the effects of qualitative dietary changes and the interaction with aerobic exercise training on liver fat content independent of weight loss in patients with type 2 diabetes.
With use of ...a factorial 2 × 2 randomized parallel-group design, 37 men and 8 women, aged 35-70 years, with type 2 diabetes in satisfactory blood glucose control on diet or diet plus metformin treatment were assigned to one of the following groups for an 8-week period: 1) high-carbohydrate/high-fiber/low-glycemic index diet (CHO/fiber group), 2) high-MUFA diet (MUFA group), 3) high-carbohydrate/high-fiber/low-glycemic index diet plus physical activity program (CHO/fiber+Ex group), and 4) high-MUFA diet plus physical activity program (MUFA+Ex group). Before and after intervention, hepatic fat content was measured by (1)H NMR.
Dietary compliance was optimal and body weight remained stable in all groups. Liver fat content decreased more in MUFA (-29%) and MUFA+Ex (-25%) groups than in CHO/fiber (-4%) and CHO/fiber+Ex groups (-6%). Two-way repeated-measures ANOVA, including baseline values as covariate, showed a significant effect on liver fat content for diet (P = 0.006), with no effects for exercise training (P = 0.789) or diet-exercise interaction (P = 0.712).
An isocaloric diet enriched in MUFA compared with a diet higher in carbohydrate and fiber was associated with a clinically relevant reduction of hepatic fat content in type 2 diabetic patients independent of an aerobic training program and should be considered for the nutritional management of hepatic steatosis in people with type 2 diabetes.
Multiple sclerosis (MS) is an autoimmune, neurological disease. We investigated genome-wide DNA methylation profiles of CD4+ and CD8+ T cells from MS patients and healthy controls at baseline and a ...follow-up visit. Patients were all treatment-naïve at baseline, and either on treatment or remained untreated at the follow-up visit. MS patients show more changes in their T cell DNA methylation profiles as compared to healthy controls over time, with the most pronounced differences observed in the untreated MS patients. These findings underline the potential of DNA methylation as biomarkers in MS.
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•Genome-wide DNA methylation profiles were obtained from MS patients and healthy controls at baseline and one follow-up visit.•MS patients were treatment-naïve at baseline, and untreated or on treatment with immunomodulatory drugs at follow-up.•MS patients show more changes in their DNA methylation profiles compared to healthy controls over time.•Untreated MS patients show more differential DNA methylation at follow-up as compared to treated MS patients .•There is an abundance of hypermethylated DMPs in CD8+ T cells from treated and untreated MS patients at the follow-up visit.
The current study investigated attachment representations and complex trauma in a sample of gender dysphoric adults. Although it has been proven that the psychological wellbeing of gender diverse ...persons is largely mediated by family acceptance and support, research on their relationships with parental figures is scarce. A total of 95 adults took part in the study. The attachment distribution was as follows: 27% secure, 27% insecure and 46% disorganized. Regarding early traumas, 56% experienced four or more traumatic forms. Further, gender dysphoric adults showed significantly higher levels of attachment disorganization and polyvictimisation, relative to controls. Comparisons of subgroups, defined by natal gender, showed that
women, compared to control males, had more involving and physically and psychologically abusive fathers, and were more often separated from their mothers;
men, relative to female controls, had more involving mothers and were more frequently separated from and neglected by their fathers. The research has several implications for treatment, clinical health psychology, family support and education.
Transgender and gender nonconforming (TGNC) people are a highly-stigmatized population. For this reason, they might internalize society's normative gender attitudes and develop negative mental health ...outcomes. As an extension of the minority stress model, the psychological mediation framework sheds light on psychological processes through which anti-transgender discrimination might affect mental health. Within this framework, the current study aimed at assessing in 149 TGNC Italian individuals the role of internalized transphobia as a mediator between anti-transgender discrimination and mental health, considering resilience as the individual-level coping mechanism buffering this relationship. The results suggest that both indicators of internalized transphobia (i.e., shame and alienation) mediate the relationship between anti-transgender discrimination and depression, while only alienation mediates the relationship between anti-transgender discrimination and anxiety. Furthermore, the results suggest that the indirect relation between anti-transgender discrimination and anxiety through alienation is conditional on low and moderate levels of resilience. Findings have important implications for clinical practice and psycho-social interventions to reduce stigma and stress caused by interpersonal and individual stigma.
Sediment toxicity plays a fundamental role in the health of inland fish communities; however, the assessment of the hazard potential of contaminated sediments is not a common objective in ...environmental diagnostics or remediation. This study examined the potential of transcriptional endpoints investigated in zebrafish (
Danio rerio
) exposed to riverbed sediments in ecotoxicity testing. Embryo-larval 10-day tests were conducted on sediment samples collected from five sites (one upstream and four downstream of the city of Milan) along a polluted tributary of the Po River, the Lambro River. Sediment chemistry showed a progressive downstream deterioration in river quality, so that the final sampling site showed up to eight times higher concentrations of, for example, triclosan, galaxolide, PAH, PCB, BPA, Ni, and Pb, compared with the uppermost site. The embryo/larval tests showed widespread toxicity although the middle river sections evidenced worse effects, as evidenced by delayed embryo development, hatching rate, larval survival, and growth. At the mRNA transcript level, the genes encoding biotransformation enzymes (
cyp1a
,
gst
,
ugt
) showed increasing upregulations after exposure to sediment from further downstream sites. The genes involved in antioxidant responses (
sod
,
gpx
) suggested that more critical conditions may be present at downstream sites, but even upstream of Milan there seemed to be some level of oxidative stress. Indirect evidences of potential apoptotic activity (
bcl2/bax
< 1) in turn suggested the possibility of genotoxic effects. The genes encoding for estrogen receptors (
erα
,
erβ1
,
erβ2
) showed exposure to (xeno)estrogens with a progressive increase after exposure to sediments from downstream sites, paralleled by a corresponding downregulation of the
ar
gene, likely related to antiandrogenic compounds. Multiple levels of thyroid disruption were also evident particularly in downstream zebrafish, as for thyroid growth (
nkx2.1
), hormone synthesis and transport (
tg
,
ttr
,
d2
), and signal transduction (
trα
,
trβ
). The inhibition of the
igf2
gene reasonably reflected larval growth inhibitions. Although none of the sediment chemicals could singly explain fish responses, principal component analysis suggested a good correlation between gene transcripts and the overall trend of contamination. Thus, the combined impacts from known and unknown covarying chemicals were proposed as the most probable explanation of fish responses. In summary, transcriptional endpoints applied to zebrafish embryo/larval test can provide sensitive, comprehensive, and timeliness information which may greatly enable the assessment of the hazard potential of sediments to fish, complementing morphological endpoints and being potentially predictive of longer studies.
Cardiovascular ischaemic diseases are one of the main causes of death all over the world. In this class of pathologies, a quick diagnosis is essential for a good prognosis in reperfusive treatment. ...In particular, an automatic classification procedure based on statistical analysis of teletransmitted electrocardiograph ('ECG') traces would be very helpful for an early diagnosis. This work presents an analysis of ECG traces, either physiological or pathological, of patients whose 12-lead prehospital ECG has been sent to the 118 Dispatch Center in Milan by life-support personnel. The statistical analysis starts with a preprocessing step, where functional data are reconstructed from noisy observations and biological variability is removed by a non-linear registration procedure. Then, a multivariate functional k-means clustering procedure is carried out on reconstructed and registered ECGs and their first derivatives. Hence, a new semi-automatic diagnostic procedure, based solely on the ECG morphology, is proposed to classify ECG traces; finally, the performance of this classification method is evaluated.
To assess the accuracy of electroencephalogram (EEG) and somatosensory evoked potentials (SEPs) recorded at 12 and 72 h from resuscitation for predicting six-months neurological outcome in patients ...who are comatose after cardiac arrest.
Prospective multicentre prognostication study. EEG was classified according to the American Clinical Neurophysiology Society terminology. SEPs were graded according to the presence and amplitude of their cortical responses. Neurological outcome was defined as good (cerebral performance categories CPC 1–3) vs. poor (CPC 4–5). None of the patients underwent withdrawal of life-sustaining treatment.
A total of 351 patients were included, of whom 134 (38%) had good neurological outcome. At 12 h, a continuous, nearly continuous and low-voltage EEG pattern predicted good neurological outcome with 7161–80% sensitivity, while an isoelectric EEG and a bilaterally absent/absent-pathological amplitude (AA/AP) cortical SEP pattern predicted poor neurological outcome with 148–21% and 5950–68% sensitivity, respectively. Specificity was 10097–100% for all predictors. At 72 h, both an isoelectric, suppression or burst-suppression pattern on EEG and an AA/AP SEP pattern predicted poor outcome with 10097–100% specificity. Their sensitivities were 6355–70% and 6658–74%, respectively. When EEG and SEPs were combined, sensitivity for poor outcome prediction increased to 79%.
In comatose resuscitated patients, EEG and SEPs predicted good and poor neurological outcome respectively, with 100% specificity as early as 12 h after cardiac arrest. At 72 h after arrest, unfavourable EEG and SEP patterns predicted poor neurological outcome with 100% specificity and high sensitivity, which further increased after their combination.
Differential serological diagnosis of Chagas disease and leishmaniasis is difficult owing to cross-reactivity resulting from the fact that the parasites that cause these pathologies share antigenic ...epitopes. Even with optimized serological assays that use parasite-specific recombinant antigens, inconclusive test results continue to be a problem. Therefore, new serological tests with high sensitivity and specificity are needed. In the present work, we developed and evaluated the performance of a new flow cytometric serological method, referred to as FC-TRIPLEX Chagas/Leish IgG1, for the all-in-one classification of inconclusive tests. The method uses antigens for the detection of visceral leishmaniasis, localized cutaneous leishmaniasis, and Chagas disease and is based on an inverted detuned algorithm for analysis of anti-Trypanosomatidae IgG1 reactivity. First, parasites were label with fluorescein isothiocyanate or Alexa Fluor 647 at various concentrations. Then serum samples were serially diluted, the dilutions were incubated with suspensions of mixed labeled parasites, and flow cytometric measurements were performed to determine percentages of positive fluorescent parasites. Using the new method, we obtained correct results for 76 of 80 analyzed serum samples (95% overall performance), underscoring the outstanding performance of the method. Moreover, we found that the fluorescently labeled parasite suspensions were stable during storage at room temperature, 4 °C, and -20 °C for 1 year. In addition, two different lots of parasite suspensions showed equivalent antigen recognition; that is, the two lots showed equivalent categorical segregation of anti-Trypanosomatidae IgG1 reactivity at selected serum dilutions. In conclusion, we have developed a sensitive and selective method for differential diagnosis of Chagas disease, visceral leishmaniasis, and localized cutaneous leishmaniasis.
Despite the rapid increase in lesbian and gay (LG) people who desire and decide to become parents, LG childless individuals may encounter serious obstacles in the parenthood process, such as minority ...stress. Notwithstanding, the psychological processes by which prejudice events might affect the desire to become parents are still understudied. As an extension of the minority stress theory, the psychological mediation framework sheds light on these psychological processes, as it encompasses a more clinical view of stress. Within this framework, the current study aimed at assessing the role of prejudice events in affecting parenting desire in 290 childless Italian LG individuals (120 lesbians and 170 gay men), as well as the role of internalized heterosexism and sexual orientation concealment in mediating the relationship between prejudice events and parenting desire. The results suggest that only in lesbians prejudice events were negatively associated with parenting desire, and that sexual orientation concealment and internalized heterosexism were also negatively associated with parenting desire. Furthermore, sexual orientation concealment, and not internalized heterosexism, mediated the relationship between prejudice events and parenting desire in lesbians, but not gay men. The findings have important implications for clinical practice.
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