Revealing the Influences of Sex Hormones and Sex Differences in Atrial Fibrillation and Vascular Cognitive Impairment

The impacts of sex differences on the biology of various organ systems and the influences of sex hormones on modulating health and disease have become increasingly relevant in clinical and biomedical research. A growing body of evidence has recently suggested fundamental sex differences in cardiovascular and cognitive function, including anatomy, pathophysiology, incidence and age of disease onset, symptoms affecting disease diagnosis, disease severity, progression, and treatment responses and outcomes. Atrial fibrillation (AF) is currently recognized as the most prevalent sustained arrhythmia and might contribute to the pathogenesis and progression of vascular cognitive impairment (VCI), including a range of cognitive deficits, from mild cognitive impairment to dementia. In this review, we describe sex-based differences and sex hormone functions in the physiology of the brain and vasculature and the pathophysiology of disorders therein, with special emphasis on AF and VCI. Deciphering how sex hormones and their receptor signaling (estrogen and androgen receptors) potentially impact on sex differences could help to reveal disease links between AF and VCI and identify therapeutic targets that may lead to potentially novel therapeutic interventions early in the disease course of AF and VCI.     

Fetal Zone Steroids and Estrogen Show Sex Specific Effects on Oligodendrocyte Precursor Cells in Response to Oxidative Damage

Oxygen causes white matter damage in preterm infants and male sex is a major risk factor for poor neurological outcome, which speculates the role of steroid hormones in sex-based differences. Preterm birth is accompanied by a drop in 17β-estradiol (E2) and progesterone along with increased levels of fetal zone steroids (FZS). We performed a sex-based analysis on the FZS concentration differences in urine samples collected from preterm and term infants. We show that, in preterm urine samples, the total concentration of FZS, and in particular the 16α-OH-DHEA concentration, is significantly higher in ill female infants as compared to males. Since we previously identified Nup133 as a novel target protein affected by hyperoxia, here we studied the effect of FZS, allopregnanolone (Allo) and E2 on differentiation and Nup133 signaling using mouse-derived primary oligodendrocyte progenitor cells (OPCs). We show that the steroids could reverse the effect of hyperoxia-mediated downregulation of Nup133 in cultured male OPCs. The addition of FZS and E2 protected cells from oxidative stress. However, E2, in presence of 16α-OH-DHEA, showed a negative effect on male cells. These results assert the importance of sex-based differences and their potential implications in preterm stress response.     

Gender Differences in Diabetic Kidney Disease: Focus on Hormonal,Genetic and Clinical Factors

Diabetic kidney disease (DKD) is one of the most serious complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- differences in medicine is considered one of the first steps toward personalized medicine, but the gender issue in DM has been scarcely explored so far. Gender differences have been reported in the incidence and the prevalence of DKD, in its phenotypes and clinical manifestations, as well as in several risk factors, with a different impact in the two genders. Hormonal factors, especially estrogen loss, play a significant role in explaining these differences. Additionally, the impact of sex chromosomes as well as the influence of gene–sex interactions with several susceptibility genes for DKD have been investigated. In spite of the increasing evidence that sex and gender should be included in the evaluation of DKD, several open issues remain uncovered, including the potentially different effects of newly recommended drugs, such as SGLT2i and GLP1Ras. This narrative review explored current evidence on sex/gender differences in DKD, taking into account hormonal, genetic and clinical factors.     

Osteoarthritis in the XXIst Century: Risk Factors and Behaviours that Influence Disease Onset and Progression

Osteoarthritis (OA) is a growing public health problem across the globe, affecting more than half of the over 65 population. In the past, OA was considered a wear and tear disease, leading to the loss of articular cartilage and joint disability. Nowadays, thanks to advancements in molecular biology, OA is believed to be a very complex multifactorial disease. OA is a degenerative disease characterized by “low-grade inflammation” in cartilage and synovium, resulting in the loss of joint structure and progressive deterioration of cartilage. Although the disease can be dependent on genetic and epigenetic factors, sex, ethnicity, and age (cellular senescence, apoptosis and lubricin), it is also associated with obesity and overweight, dietary factors, sedentary lifestyle and sport injuries. The aim of this review is to highlight how certain behaviors, habits and lifestyles may be involved in the onset and progression of OA and to summarize the principal risk factors involved in the development of this complicated joint disorder.     

The Impact of Angiogenesis in the Most Common Salivary Gland Malignant Tumors

Salivary gland carcinomas (SGCs) represent a group of rare tumors, with complete surgical resection being the main treatment option. Therapeutic armory for cases of locally aggressive, recurrent, and/or metastatic SGCs, though, remains poor since they exhibit high rates of resistance to systematic therapy. Angiogenesis is considered one of the contemporary hallmarks of cancer and anti-angiogenic factors have already been approved for the treatment of several cancer types. This review aims to summarize, in a histotype-specific manner, the most current available data on the angiogenic factors implicated in SGC angiogenesis, in order to highlight the differences between the most common SGC histotypes and the factors that may have a potential role as therapeutic targets.     

Regulatory Role of Sex Hormones in Cardiovascular Calcification

Sex differences in cardiovascular disease (CVD), including aortic stenosis, atherosclerosis and cardiovascular calcification, are well documented. High levels of testosterone, the primary male sex hormone, are associated with increased risk of cardiovascular calcification, whilst estrogen, the primary female sex hormone, is considered cardioprotective. Current understanding of sexual dimorphism in cardiovascular calcification is still very limited. This review assesses the evidence that the actions of sex hormones influence the development of cardiovascular calcification. We address the current question of whether sex hormones could play a role in the sexual dimorphism seen in cardiovascular calcification, by discussing potential mechanisms of actions of sex hormones and evidence in pre-clinical research. More advanced investigations and understanding of sex hormones in calcification could provide a better translational outcome for those suffering with cardiovascular calcification.     

Spectral‐reflectance‐factor deconvolution and colorimetric calculations by local‐power expansion

The experimental data of the spectral‐reflectance factor are considered as dependent on the instrument‐spectral‐bandwidth function in order to perform their deconvolution and to compute the tristimulus values. The deconvolution is performed by local‐power expansion. In the case that the spectral‐bandpass dependence regards only the spectral transmittance of the monochromator, the goodness of this technique is evaluated by simulation (1325 reflectance factors of the Munsell samples are considered as trial functions) and compared with other usual techniques: Stearns and Stearns method for bandpass error, ASTM‐weighting function interpolation, and Venable‐ASTM weighting function. The zero order of the deconvoluted spectral‐reflectance factor can be related to the Stearns and Stearns method for bandpass error. With respect to any other technique, the second‐order deconvolution, for the CIE standard illuminants, gives color differences lower by a factor 0.1 or more for a bandpass Δλ = 10 nm, color differences lower by a factor 0.3 or more for a bandpass Δλ = 20 nm and, for the CIE fluorescent illuminants, color differences generally lower. © 2000 John Wiley & Sons, Inc. Col Res Appl, 25, 176–185, 2000     

Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking

Alcohol use disorder remains a substantial social, health, and economic problem and problem drinking levels in women have been increasing in recent years. Understanding whether and how the underlying mechanisms that drive drinking vary by sex is critical and could provide novel, more targeted therapeutic treatments. Here, we examine recent results from our laboratories and others which we believe provide useful insights into similarities and differences in alcohol drinking patterns across the sexes. Findings for binge intake and aversion-resistant, compulsion-like alcohol drinking are considered, since both are likely significant contributors to alcohol problems in humans. We also describe studies regarding mechanisms that may underlie sex differences in maladaptive alcohol drinking, with some focus on the importance of nucleus accumbens (NAcb) core and shell regions, several receptor types (dopamine, orexin, AMPA-type glutamate), and possible contributions of sex hormones. Finally, we discuss how stressors such as early life stress and anxiety-like states may interact with sex differences to contribute to alcohol drinking. Together, these findings underscore the importance and critical relevance of studying female and male mechanisms for alcohol and co-morbid conditions to gain a true and clinically useful understanding of addiction and neuropsychiatric mechanisms and treatment.     

Cholesteryl Ester Transfer Protein Impairs Triglyceride Clearance via Androgen Receptor in Male Mice

Elevated postprandial triacylglycerols (TAG) are an important risk factor for cardiovascular disease. Men have higher plasma TAG and impaired TAG clearance compared to women, which may contribute to sex differences in risk of cardiovascular disease. Understanding mechanisms of sex differences in TAG metabolism may yield novel therapeutic targets to prevent cardiovascular disease. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high-density lipoprotein (HDL) cholesterol levels. Although mice lack CETP, we previously demonstrated that transgenic CETP expression in female mice alters TAG metabolism. The impact of CETP on TAG metabolism in males, however, is not well understood. Here, we demonstrate that CETP expression increases plasma TAG in males, especially in very-low density lipoprotein (VLDL), by impairing postprandial plasma TAG clearance compared to wild-type (WT) males. Gonadal hormones were required for CETP to impair TAG clearance, suggesting a role for sex hormones for this effect. Testosterone replacement in the setting of gonadectomy was sufficient to restore the effect of CETP on TAG. Lastly, liver androgen receptor (AR) was required for CETP to increase plasma TAG. Thus, expression of CETP in males raises plasma TAG by impairing TAG clearance via testosterone signaling to AR. Further understanding of how CETP and androgen signaling impair TAG clearance may lead to novel approaches to reduce TAG and mitigate risk of cardiovascular disease.     

A Sex Perspective in Neurodegenerative Diseases: microRNAs as Possible Peripheral Biomarkers

Sex is a significant variable in the prevalence and incidence of neurological disorders. Sex differences exist in neurodegenerative disorders (NDs), where sex dimorphisms play important roles in the development and progression of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the last few years, some sex specific biomarkers for the identification of NDs have been described and recent studies have suggested that microRNA (miRNA) could be included among these, as influenced by the hormonal and genetic background. Failing to consider the possible differences between males and females in miRNA evaluation could introduce a sex bias in studies by not considering some of these sex-related biomarkers. In this review, we recapitulate what is known about the sex-specific differences in peripheral miRNA levels in neurodegenerative diseases. Several studies have reported sex-linked disparities, and from the literature analysis miR-206 particularly has been shown to have a sex-specific involvement. Hopefully, in the near future, patient stratification will provide important additional clues in diagnosis, prognosis, and tailoring of the best therapeutic approaches for each patient. Sex-specific biomarkers, such as miRNAs, could represent a useful tool for characterizing subgroups of patients.     

The Chemical Basis of Species,Sex, and Individual Recognition Using Feces in the Domestic Cat

Scents emitted from excretions provide important information about the owner. Volatile compounds with higher levels in a species and/or sex, or that vary among individuals could be odor cues for species and/or sex, or individual recognition. However, such compounds have been identified in only a few vertebrate species. In domestic cats (Felis silvestris catus), it is known that unburied cat feces are territorial markers asserting the border of their home range, but little was known which fecal compounds are scent cues for species, sex, and individual recognition in cats. In the present study, we demonstrated the chemical basis for species, sex, and individual recognition using feces of cats. For males, major contents were fatty acids and 3-mercapto-3-methyl-1-butanol (MMB), a derivative of the unusual amino acid, felinine. MMB emission levels from feces had sex-based differences (male > female) and dynamic temporal changes during aging. Cats distinguished fecal odors with and without MMB, and different fatty acid compositions among individuals. No cat-specific compound, such as MMB, was detectable from their anal odor emitting fatty acids. We concluded that fecal MMB is a male sex recognition pheromone in cats and also provides a temporal trace of the owner. After sensing MMB, they may distinguish individual differences of conspecific feces with variable subsets of fatty acids. In contrast to scent marks, since cats can obtain species information from visual cues before sniffing conspecific anal odors, they may use their efforts to distinguish individual differences of anal odors during sniffing.     

Dietary fat in the prevention of cardiovascular disease — a review

In developed countries atherosclerotic cardiovascular disease is the reason for about 50% of all deaths. With growing prosperity coronary heart disease (CHD) is becoming the major cause of premature death. Most complications of atherosclerosis occur unexpectedly and more than 50% of the patients developing a myocardial infarction do not survive more than one year. Because of the severe morbidity and high mortality primary prevention is likely to be the only solution. Epidemiological studies show a strong, positive relationship between plasma cholesterol concentrations and the incidence of CHD. People who immigrate from low‐risk to high‐risk areas usually acquire similar plasma cholesterol levels as the native population and a similar CHD risk. This demonstrates that environmental rather than genetic factors lead to the differences in cardiovascular risk and supports the notion that nutrition and lifestyle play a major role. The association between dietary intake of fat and cholesterol and the extent of atherosclerosis and CHD has been recognized in previous studies. The amount of saturated fat in the diet correlates stronger with the incidence of CHD than with total fat intake. The consumption of unsaturated fatty acids, however, appears to be beneficial, since it is inversely correlated with the plasma cholesterol concentration and risk of myocardial infarction. Lately additional nutritional factors like trans fatty acids with a negative influence on risk as well as positive factors like linolenic acid have attracted much attention. In conclusion, as a challenge to public health, preventive medicine needs to focus on changes in dietary habits with priority, particularly fat modification. A nutrition low in total fat primarily avoiding saturated and trans fatty acids, but rich in fruit and vegetables should be recommended.     

Sex-and age-related differences in ceramide dihexosides of primary human brain tumors

Neutral glycolipids (NGL) are promising diagnostic markers of human gliomas, but differences in NGL with age and sex have not been examined. Previous work demonstrated that ceramide dihexosides (CDH) levels in mouse kidney are age- and sex-dependent, probably due to levels of sex hormones. We quantitated CDH in 181 human gliomas and found significant differences with sex and age, particularly menopause and male puberty. This emphasizes the importance of assessing results of studies on glycolipids in disease states with respect to age and sex in order to avoid erroneous conclusions concerning the relationship of glycolipid composition with diagnosis and pathogenesis.     

Risk based decision‐making in plant design

Accidental events that have occurred in chemical and nuclear plants show that the application of technical regulations on its own, even when extremely detailed, does not assure that adequate safety levels are reached and, above all, maintained in time. The paper illustrates, with a simple example, how a risk analysis can be considered as an essential tool for a correct plant design, above all when dealing with major risk installations. In particular the use of the Recursive Operability Analysis is shown, in the phase of accident identification, since it allows to directly draw the logic trees, both Fault and Event Trees for the quantification phase, thus assuring the congruence of the whole analysis.     

Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development

Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease.     

Diabetes and Hypertension Consistently Predict the Presence and Extent of Coronary Artery Calcification in Symptomatic Patients: A Systematic Review and Meta-Analysis

Background: The relationship of conventional cardiovascular risk factors (age, gender, ethnicity, diabetes, dyslipidaemia, hypertension, obesity, exercise, and the number of risk factors) to coronary artery calcification (CAC) presence and extent has never before been assessed in a systematic review and meta-analysis. Methods: We included only English language studies that assessed at least three conventional risk factors apart from age, gender, and ethnicity, but excluded studies in which all patients had another confirmed condition such as renal disease. Results: In total, 10 studies, comprising 15,769 patients, were investigated in the systematic review and seven studies, comprising 12,682 patients, were included in the meta-analysis, which demonstrated the importance of diabetes and hypertension as predictors of CAC presence and extent, with age also predicting CAC presence. Male gender, dyslipidaemia, family history of coronary artery disease, obesity, and smoking were overall not predictive of either CAC presence or extent, despite dyslipidaemia being a key risk factor for coronary artery disease (CAD). Conclusion: Diabetes and hypertension consistently predict the presence and extent of CAC in symptomatic patients.     

Sources of nutrition information of Chilean schoolers, metropolitan region, Chile, survey 1986-1987.

The purpose of the present study was to determine the relative importance of different sources of nutrition information used by Chilean schoolers to learn the basics of nutrition. In this respect, a representative sample of 4,509 elementary and high-school children was randomly selected and stratified according to grade, sex, type of school and geographic area. Schoolers were individually interviewed in order to collect data related with socioeconomic status (SES) and sociocultural conditions, as well as to learn as to what they considered to be the most important sources of nutrition information influencing their nutritional learning, gathering the necessary data through a questionnaire especially designed for this purpose. Results indicated that 87.8% schoolers mentioned their family (mainly the mother), as the most important source of nutrition information; 10.7% said the school teacher, and 1.5%, mass media (0.8% television, 0.5% books, 0.1% magazines and 0.1% radio) without significant differences by sex, age and geographic area. The role attributed to the family (mother) was important in all SES categories, but proved to be significantly higher in the high SES group (91.9%) than in the low SES group (84.6%). The role attributed to the school teacher, in contrast, was lower (6.7%) in the high SES group than in the low SES group (13.8%) (p less than 0.001). In relation to mass media, the influence attributed to books and magazines was high in the high SES group, but television and radio were more important in the low SES group. On the other hand, significant differences found by type of school were related to SES. These findings could be useful in the establishment of food and nutrition policies, as well as in educational planning focused on the Chilean school population, considering that few studies have been carried out along these lines.     

Current Understanding of the Involvement of the Insular Cortex in Neuropathic Pain: A Narrative Review

Neuropathic pain is difficult to cure and is often accompanied by emotional and psychological changes. Exploring the mechanisms underlying neuropathic pain will help to identify a better treatment for this condition. The insular cortex is an important information integration center. Numerous imaging studies have documented increased activity of the insular cortex in the presence of neuropathic pain; however, the specific role of this region remains controversial. Early studies suggested that the insular lobe is mainly involved in the processing of the emotional motivation dimension of pain. However, increasing evidence suggests that the role of the insular cortex is more complex and may even be related to the neural plasticity, cognitive evaluation, and psychosocial aspects of neuropathic pain. These effects contribute not only to the development of neuropathic pain, but also to its comorbidity with neuropsychiatric diseases. In this review, we summarize the changes that occur in the insular cortex in the presence of neuropathic pain and analgesia, as well as the molecular mechanisms that may underlie these conditions. We also discuss potential sex-based differences in these processes. Further exploration of the involvement of the insular lobe will contribute to the development of new pharmacotherapy and psychotherapy treatments for neuropathic pain.     

Autophagy—A Hidden but Important Actor on Oral Cancer Scene

The duration of denture use, oral hygiene, smoking and male sex were identified as risk factors for oral mucosal lesions. As it is well known, all the oral mucosal lesions associated with risk factors have an important degree of malignity. Chronic mechanical irritation can be another cause of oral cancer and it is produced by the constant action of a deleterious agent from the oral cavity. Autophagy represents a complex evolutionary conserved catabolic process in which cells self-digest intracellular organelles in order to regulate their normal turnover and remove the damaged ones with compromised function to further maintain homeostasis. Autophagy is modulated by mTOR kinase and indirectly by PI3K/AKT survival pathway. Due to its dual capacity to either induce cell death or promote cell survival, important evidence pointed that autophagy has a two-faced role in response to chemotherapy in cancer. In conclusion, understanding how to overcome cytoprotective autophagy and how to take advantage of autophagic cell death is critical in order to enhance the cancer cells sensitivity to particular therapeutic agents.     

The rs2516839 Polymorphism of the USF1 Gene May Modulate Serum Triglyceride Levels in Response to Cigarette Smoking

Single nucleotide polymorphisms (SNPs) of the USF1 gene (upstream stimulatory factor 1) influence plasma lipid levels. This study aims to determine whether USF1 SNPs interact with traditional risk factors of atherosclerosis to increase coronary artery disease (CAD) risk. In the present study serum lipid levels and USF1 gene polymorphisms (rs2516839 and rs3737787) were determined in 470 subjects: 235 patients with premature CAD and 235 controls. A trend of increasing triglycerides (TG) levels in relation to the C allele dose of rs2516839 SNP was observed. The synergistic effect of cigarette smoking and C allele carrier state on CAD risk was also found (SIM = 2.69, p = 0.015). TG levels differentiated significantly particular genotypes in smokers (1.53 mmol/L for TT, 1.80 mmol/L for CT and 2.27 mmol/L for CC subjects). In contrast, these differences were not observed in the non-smokers subgroup (1.57 mmol/L for TT, 1.46 mmol/L for CT and 1.49 mmol/L for CC subjects). In conclusion, the rs2516839 polymorphism may modulate serum triglyceride levels in response to cigarette smoking. Carriers of the C allele seem to be particularly at risk of CAD, when exposed to cigarette smoking.