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Our single-center case-control study aimed to evaluate the unclear glymphatic system alteration in autism spectrum disorder (ASD) through an innovative neuroimaging tool which allows to segment and quantify perivascular spaces in the white matter (WM-PVS) with filtering of non-structured noise and increase of the contrast-ratio between perivascular spaces and the surrounding parenchyma. Briefly, files of 65 ASD and 71 control patients were studied. We considered: ASD type, diagnosis and severity level and comorbidities (i.e., intellectual disability, attention-deficit hyperactivity disorder, epilepsy, sleep disturbances). We also examined diagnoses other than ASD and their associated comorbidities in the control group. When males and females with ASD are included together, WM-PVS grade and WM-PVS volume do not significantly differ between the ASD group and the control group overall. We found, instead, that WM-PVS volume is significantly associated with male sex: males had higher WM-PVS volume compared to females (p = 0.01). WM-PVS dilation is also non-significantly associated with ASD severity and younger age (< 4 years). In ASD patients, higher WM-PVS volume was related with insomnia whereas no relation was found with epilepsy or IQ. We concluded that WM-PVS dilation can be a neuroimaging feature of male ASD patients, particularly the youngest and most severe ones, which may rely on male-specific risk factors acting early during neurodevelopment, such as a transient excess of extra-axial CSF volume. Our findings can corroborate the well-known strong male epidemiological preponderance of autism worldwide.

Biological differences between sexes should be considered in all stages of research, as sexual dimorphism starts in utero leading to sex-specific fetal programming. In numerous biomedical fields, there is still a lack of stratification by sex despite primary cultured cells retaining memory of the sex and of the donor. The sex of donors in biological research must be known because variations in cells and cellular components can be used as endpoints, biomarkers and/or targets of pharmacological studies. This selective review focuses on the current findings regarding sex differences observed in the umbilical cord, a widely used source of research samples, both in the blood and in the circulating cells, as well as in the different cellular models obtainable from it. Moreover, an overview on sex differences in fetal programming is reported. As it emerges that the sex variable is still often forgotten in experimental models, we suggest that it should be mandatory to adopt sex-oriented research, because only awareness of these issues can lead to innovative research.

Ionizing radiation (IR) can induce some associated pathological conditions due to numerous cell damages. The influence of sex is scarcely known, and even less known is whether the effect of antioxidants is sex-dependent. Given the increased use of IR, we investigated whether male human umbilical vein endothelial cells (MHUVECs) and female human umbilical vein endothelial cells (FHUVECs) respond differently to IR exposure and whether the antioxidants 10 mM taurine (TAU) and 5 mM N-acetylcysteine (NAC) can prevent IR-induced damage in a sex-dependent way. In untreated cells, sex differences were observed only during autophagy, which was higher in FHUVECs. In non-irradiated cells, preincubation with TAU and NAC did not modify viability, lactate dehydrogenase (LDH) release, migration, or autophagy, whereas only NAC increased malondialdehyde (MDA) levels in FHUVECs. X-ray irradiation increased LDH release and reduced viability and migration in a sex-independent manner. TAU and NAC did not affect viability while reduced LDH release in irradiated cells: they have the same protective effect in FHUVECs, while, TAU was more protective than NAC in male cells.. Moreover, TAU and NAC significantly promoted the closure of wounds in both sexes in irradiated cells, but NAC was more effective at doing this in FHUVECs. In irradiated cells, TAU did not change autophagy, while NAC attenuated the differences between the sexes. Finally, NAC significantly decreased MDA in MHUVECs and increased MDA in FHUVECs. In conclusion, FHUVECs appear to be more susceptible to IR damage, and the effects of the two antioxidants present some sex differences, suggesting the need to study the influence of sex in radiation mitigators.

Prematurity is the leading cause of neonatal deaths and high economic costs; it depends on numerous biological and social factors, and is highly prevalent in males. Several factors can affect the metabolome of premature infants. Accordingly, the aim of the present study was to analyze the role played by gestational age (GA), parenteral nutrition (PN), and caffeine treatment in sex-related differences of blood metabolome of premature neonates through a MS/MS-based targeted metabolomic approach for the detection of amino acids and acylcarnitines in dried blood spots. GA affected the blood metabolome of premature neonates: male and female very premature infants (VPI) diverged in amino acids but not in acylcarnitines, whereas the opposite was observed in moderate or late preterm infants (MLPI). Moreover, an important reduction of metabolites was observed in female VPI fed with PN, suggesting that PN might not satisfy an infant’s nutritional needs. Caffeine showed the highest significant impact on metabolite levels of male MLPI. This study proves the presence of a sex-dependent metabolome in premature infants, which is affected by GA and pharmacological treatment (e.g., caffeine). Furthermore, it describes an integrated relationship among several features of physiology and health.

Amniotic fluid is essential for fetus wellbeing and is used to monitor pregnancy and predict fetal outcomes. Sex affects health and medicine from the beginning of life, but knowledge of its influence on cell-depleted amniotic fluid (AF) and amniotic fluid cells (AFCs) is still neglected. We evaluated sex-related differences in AF and in AFCs to extend personalized medicine to prenatal life. AFCs and AF were obtained from healthy Caucasian pregnant women who underwent amniocentesis at the 16th–18th week of gestation for advanced maternal age. In the AF, inflammation biomarkers (TNFα, IL6, IL8, and IL4), malondialdehyde, nitrites, amino acids, and acylcarnitines were measured. Estrogen receptors and cell fate (autophagy, apoptosis, senescence) were measured in AFCs. TNFα, IL8, and IL4 were higher in female AF, whereas IL6, nitrites, and MDA were similar. Valine was higher in male AF, whereas several acylcarnitines were sexually different, suggesting a mitochondrial involvement in establishing sex differences. Female AFCs displayed higher expression of ERα protein and a higher ERα/ERβ ratio. The ratio of LC3II/I, an index of autophagy, was higher in female AFCs, while LC3 gene was similar in both sexes. No significant sex differences were found in the expression of the lysosomal protein LAMP1, while p62 was higher in male AFCs. LAMP1 gene was upregulated in male AFCs, while p62 gene was upregulated in female ones. Finally, caspase 9 activity and senescence linked to telomeres were higher in female AFCs, while caspase 3 and β-galactosidase activities were similar. This study supports the idea that sex differences start very early in prenatal life and influence specific parameters, suggesting that it may be relevant to appreciate sex differences to cover knowledge gaps. This might lead to improving the diagnosis of risk prediction for pregnancy complications and achieving a more satisfactory monitoring of fetus health, even preventing future diseases in adulthood.

Several dermal substitutes are available on the market, but there is no precise indication that helps surgeons choose the proper one. Few studies have tried to compare different xenogeneic bioengineered products, but no objective bio-parametric comparison has been made yet. Fifteen patients who underwent skin reconstruction with Integra® or Pelnac® were retrospectively evaluated. After at least 12 months of follow-up, an objective and quantitative assessment of several skin biophysical properties, such as color, texture, elasticity, hydration, glossiness and trans-epidermal water loss, were measured with non-invasive skin measurement devices. The grafted skin showed a reduction of the superficial hydration level and a tendency to lower values of trans-epidermal water loss with both dermal substitutes. Melanic and hemoglobin pigmentation were higher in comparison to the donor site in both groups, while a melanic pigmentation increase versus the surrounding skin was seen just with Integra®. Finally, the skin was found to be more elastic when reconstructed with Integra®. The skin barrier appeared to be intact in both groups. Hence, these substitutes are valuable means of skin regeneration. Integra® seems to be more advantageous for reconstructing areas that need more skin flexibility.

Near peer teaching (NPT) is becoming recognized as a valuable instrument with advantages for both students and teachers. Despite the recognized benefits, NPT programmes are not usually embedded within university healthcare curricula and, to our knowledge, there have been few studies assessing medical students’ attitudes towards NPT for histology courses. Our study is the first that assess medical students’ perceptions concerning the value of NPT for a course in the human organ histology component of anatomy. A NPT programme was provided for second-year medical students and delivered during laboratory sessions for microscopic anatomy. The NPT tutors were recruited from third-, fourth- or fifth-year medical students. The medical tutees completed a questionnaire to assess their attitudes towards NPT. The initial hypothesis tested was that students preferred to be taught by their professional teachers and not by NPT tutors. A total of 113 students completed the questionnaire (46% response rate). Of these, 70% of respondents rated the support of the NPT tutors as being excellent or good. Furthermore, 60% of respondents agreed that the NPT programme should be introduced officially into the medical curriculum. The findings are not consistent with our initial hypothesis, and suggest that NPT could be a valuable instrument for the understanding of histological concepts.

Development of molecules chemically modifying the expression of crucial orchestrator(s) of stem cell commitment may have significant biomedical impact. We have recently developed hyaluronan mixed esters of butyric and retinoic acids (HBR), turning cardiovascular stem cell fate into a high-yield process. The HBR mechanism(s) remain still largely undefined. We show that in both mouse embryonic stem (ES) cells and human mesenchymal stem cells from fetal membranes of term placenta (FMhMSCs), HBR differentially affected the patterning of Smad proteins, one of the major conductors of stem cell cardiogenesis. Real-time RT-PCR and Western blot analyses revealed that in both cell types HBR enhanced gene and protein expression of Smad1,3, and 4, while down-regulating Smad7. HBR acted at the transcriptional level, as shown by nuclear run-off experiments in isolated nuclei. Immunofluorescence analysis indicated that HBR increased the fluorescent staining for Smad1,3, and 4, confirming that the transcriptional action of HBR encompassed the upregulation of the encoded Smad proteins. Chromatin immune precipitation and transcriptional analyses showed that HBR increased the transcription of the cardiogenic gene Nkx-2.5 through Smad4 binding to its own consensus Smad site. Treatment of mouse ES cells and FMhMSCs with HBR led to the concomitant overexpression of both Smad4 and α-sarcomeric actinin. Smad4 silencing by the aid of lentiviral-mediated Smad4 shRNA confirmed a dominant role of Smad4 in HBR-induced cardiogenesis. The use of HBR may pave the way to novel combinatorial strategies of molecular and stem cell therapy based on fine tuning of targeted Smad transciption and signaling leading to a high-throughput of cardiogenesis without the needs of gene transfer technologies.

Cardiovascular diseases (CVD) display many sex and gender differences, and endothelial dysfunction, angiotensin II (Ang II), and autophagy represent key factors in the autophagic process Therefore, we studied whether Ang II modulates the mentioned processes in a sex-specific way in HUVECs obtained from healthy male and female newborns. In basal HUVECs, the Parkin gene and protein were higher in FHUVECs than in MHUVECs, while the Beclin-1 protein was more expressed in MHUVECs, and no other significant differences were detected. Ang II significantly increases LAMP-1 and p62 protein expression and decreases the expression of Parkin protein in comparison to basal in MHUVECs. In FHUVECs, Ang II significantly increases the expression of Beclin-1 gene and protein, and Parkin gene. The LC3 II/I ratio and LAMP-1 protein were significantly higher in MHUVECs than in FHUVECs, while Parkin protein was significantly more expressed in Ang II-treated FHUVECs than in male cells. Ang II affects the single miRNA levels: miR-126-3p and miR-133a-3p are downregulated and upregulated in MHUVECs and FHUVECs, respectively. MiR-223 is downregulated in MHUVEC and FHUVECs. Finally, miR-29b-3p and miR-133b are not affected by Ang II. Ang II effects and the relationship between miRNAs and organelles-specific autophagy is sex-dependent in HUVECs. This could lead to a better understanding of the mechanisms underlying sex differences in endothelial dysfunction, providing useful indications for innovative biomarkers and personalized therapeutic approaches.

There is an urgent need to optimize pharmacology therapy with a consideration of high interindividual variability and economic costs. A sex–gender approach (which considers men, women, and people of diverse gender identities) and the assessment of differences in sex and gender promote global health, avoiding systematic errors that generate results with low validity. Care for people should consider the single individual and his or her past and present life experiences, as well as his or her relationship with care providers. Therefore, intersectoral and interdisciplinary studies are urgently required. It is desirable to create teams made up of men and women to meet the needs of both. Finally, it is also necessary to build an alliance among regulatory and ethic authorities, statistics, informatics, the healthcare system and providers, researchers, the pharmaceutical and diagnostic industries, decision makers, and patients to overcome the gender gap in medicine and to take real care of a person in an appropriate manner.