Sexual dimorphism in autoimmunity: a focus on Th1/Th2 cytokines and multiple sclerosis

Many autoimmune diseases preferentially affect women. The underlying reasons for this gender bias are not clear, but are thought to relate to the effects of sex hormones on the immune system. Here we define many of the immune response differences between the genders that may contribute to the increased incidence of MS in females. There is extensive evidence that women respond more vigorously to immune stimuli than men. Increased inflammatory or Th1 cytokine secretion vs. regulatory or Th2 cytokine secretion in females could cause women with MS to have exaggerated immune reactions compared to men. Our previous studies and our preliminary data show that MS patients have a higher number of IFNγ secreting T cells in response to proteolipid protein (PLP) and that this appears to be strongly skewed toward MS females. We hypothesize that this elevated IFNγ response is due to increased IL-12 secretion in females, which has been suggested in animal models of MS. Since induction of IL-12 by antigen is costimulation dependent, we also propose that expression of costimulatory molecules has a strong likelihood of showing gender-specific upregulation. Here we review some of the controversy surrounding the role of sex hormones in regulating the immune response. One of our goals is to help define the role of sex hormones in promoting or suppressing autoimmune responses in MS. Ultimately, understanding the effect that gender plays in the Th1/Th2 cytokine balance in MS patients may allow development of new therapies that capitalize on the different immunological responses in women versus men.     

Impact of intracellular innate immune receptors on immunometabolism

Immunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K–AKT–mTOR and LKB1–AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.     

Sexual dimorphism in dentition mineralization.

This study determined for 121 boys and 111 girls of the serial experimental group of the Burlington Growth Centre the age, time interval and age sequence of 14 stages of mineralization of all tooth types. The two sexes differed significantly in the age at which the stages of tooth mineralization appeared, and in the length of the interstage intervals. In the canines, there was maximum sex difference in mineralization, which was almost 20 per cent and resulted from a delay in the boys. Changes in sequence of mineralization were due to delay rather than to acceleration. Sex differences in tooth mineralization manifested themselves before puberty, and mineralization was not accelerated at puberty. In contrast, post-pubertal mineralization of third molars appeared to be accelerated in both sexes and occurred earlier in the boys.     

Sexual dimorphism in modern Japanese crania

The Japanese population has gone through significant micro-evolutionary changes during the last half century. One approach to quantify these changes is an osteometric analysis of sexual variation in the skeleton. The present study evaluates sexual dimorphism in modern Japanese cranial dimensions. Comprehensive osteometric data were obtained from 84 modern Japanese skeletons of known sex and age at death from the dissecting room collection at Jikei Medical University, Tokyo. The remains were macerated between 1960 and 1970 and thus are from individuals who lived through World War II. A total of 16 cranial dimensions were subjected to SPSS-X discriminant function analysis. Using 11 measurements of the cranium, five dimensions were selected by the stepwise discriminant methods, including bigonial breadth. In a second stepwise function using 11 cranial measurements, seven contributed to the function. In both functions, mastoid height was selected first and prediction accuracy averaged 84%. Because of its significant contribution, a function was calculated from mastoid height alone. This produced an average of 74% prediction accuracy. In general, width dimensions better reflected differences between the sexes. The accuracy of correct classification from the Jikei sample was slightly lower than those of earlier Japanese populations. The results of this study also suggested that sexual dimorphism in Japanese crania may have decreased as a result of an increase in size of females. © 1995 Wiley-Liss, Inc.     

Flype: Software for enabling personalized medicine

The advent of next generation DNA sequencing (NGS) has revolutionized clinical medicine by enabling wide‐spread testing for genomic anomalies and polymorphisms. With that explosion in testing, however, come several informatics challenges including managing large amounts of data, interpreting the results and providing clinical decision support. We present Flype, a web‐based bioinformatics platform built by a small group of bioinformaticians working in a community hospital setting, to address these challenges by allowing us to: (a) securely accept data from a variety of sources, (b) send orders to a variety of destinations, (c) perform secondary analysis and annotation of NGS data, (d) provide a central repository for all genomic variants, (e) assist with tertiary analysis and clinical interpretation, (f) send signed out data to our EHR as both PDF and discrete data elements, (g) allow population frequency analysis and (h) update variant annotation when literature knowledge evolves. We discuss the multiple use cases Flype supports such as (a) in‐house NGS tests, (b) in‐house pharmacogenomics (PGX) tests, (c) dramatic scale‐up of genomic testing using an external lab, (d) consumer genomics using two external partners, and (e) a variety of reporting tools. The source code for Flype is available upon request to the authors.     

Nutrigenetics and nutraceuticals: the next wave riding on personalized medicine

The Human Genome Project and subsequent identification of single nucleotide polymorphisms (SNPs) within populations has played a major role in predicting individual response to drugs (pharmacogenetics) leading to the concept of "personalized medicine." Nutritional genomics is a recent off-shoot of this genetic revolution that includes (1) nutrigenomics: the study of interaction of dietary components with the genome and the resulting proteonomic and metabolomic changes; and (2) nutrigenetics: understanding the gene-based differences in response to dietary components and developing nutraceuticals that are most compatible with health based on individual genetic makeup. Despite the extensive data on genetic polymorphisms in humans, its translation into medical practice has been slow because of the time required to accumulate population data on SNP incidence, understand the significance of a given SNP in disease, and develop suitable diagnostic tests. Nutrigenomics revitalized the field by showing that nutrients and botanicals can interact with the genome and modify subsequent gene expression, which has provided a great impetus for nutrigenetic research and nutraceutical development based on nutrigenetics. Polymorphisms in methlyene tetrahydrofolate reductase (MTHFR) (involved in folate metabolism), apolipoprotein E (Apo E) and ApoA1 (in cardiovascular disease), and leptin/leptin receptor (obesity) genes are some good examples for understanding basic nutrigenetics. Developing nutraceuticals to prevent and manage thrombosis risk in women with thrombophilic gene mutations are discussed in the context of the opportunities that exist at the nutrigenetic/pharmacogenetic interphase leading to "personalized nutrition." Further research on individual differences in genetic profiles and nutrient requirements will help establish nutrigenetics as an essential discipline for nutrition and dietetics practice.     

Sexual dimorphism in foot length proportionate to stature

Background: The preponderance of existing results suggests that, relative to stature, women have smaller feet than men. However, several investigations indicate that the relationship between foot length and stature may be curvilinear, a pattern that, due to the dimorphic nature of stature, would mask the true direction of pedal sexual dimorphism in published results. Aim: The study aimed to determine whether proportionate foot length is sexually dimorphic and, if so, the nature of that dimorphism. Materials and methods: Surveying genetically disparate populations (USA, Turkey, and Native North and Central American), we examined data from three previous anthropometric studies (Davis 1990, Parham et al. 1992, Özaslan et al. 2003) and foot tracings from the Steggerda Collection at the US National Museum of Health and Medicine. Analyses explored sex differences in the ratio between foot length and stature, and tested for nonlinearity. Results: Although varying in degree across populations, proportionate to stature, female foot length is consistently smaller than male foot length. Conclusion: Given the biomechanical challenges posed by pregnancy, smaller female proportionate foot length is somewhat surprising, as foot length affects dorsoventral stability. It is possible that the observed pattern reflects intersexual selection for small female foot size, a cue of youth and nulliparity.     

Sexual dimorphism in foot length proportionate to stature

BACKGROUND: The preponderance of existing results suggests that, relative to stature, women have smaller feet than men. However, several investigations indicate that the relationship between foot length and stature may be curvilinear, a pattern that, due to the dimorphic nature of stature, would mask the true direction of pedal sexual dimorphism in published results. AIM: The study aimed to determine whether proportionate foot length is sexually dimorphic and, if so, the nature of that dimorphism. MATERIALS AND METHODS: Surveying genetically disparate populations (USA, Turkey, and Native North and Central American), we examined data from three previous anthropometric studies (Davis 1990, Parham et al. 1992, Ozaslan et al. 2003) and foot tracings from the Steggerda Collection at the US National Museum of Health and Medicine. Analyses explored sex differences in the ratio between foot length and stature, and tested for nonlinearity. RESULTS: Although varying in degree across populations, proportionate to stature, female foot length is consistently smaller than male foot length. CONCLUSION: Given the biomechanical challenges posed by pregnancy, smaller female proportionate foot length is somewhat surprising, as foot length affects dorsoventral stability. It is possible that the observed pattern reflects intersexual selection for small female foot size, a cue of youth and nulliparity.     

Sexual dimorphism in digit-length ratios of laboratory mice

The lengths of the index finger (2D) and ring finger (4D) are sexually dimorphic in humans, and men have a smaller 2D:4D ratio compared to women. Prenatal androgens appear to be important in the development of the 2D:4D sex difference, since it has been reported in children as young as 2 years old, and since humans exposed to supernormal prenatal androgen levels display a smaller 2D:4D ratio. We tested whether another mammalian species in which the process of peripheral sexual differentiation is androgen-dependent might also show a sex difference in digit ratios. The 2D:4D ratio of adult outbred mice was calculated for both the left and right rear paws. A sex difference was observed in the right rear paw: female mice had a larger 2D:4D ratio than did males. We also found this difference in prepubescent weanling mice. This sex difference is in the same direction as that observed in humans, and suggests that sexual dimorphism in digit length ratios is a feature common to many, if not all, mammals. The mouse may therefore be a useful animal model for studying the factors that influence finger length patterns, which have recently been correlated with several specific behaviors and disease predispositions in humans.     

Sexual dimorphism and species differences in HVC volumes of cowbirds

Cowbirds exhibit extensive variation in their social, territorial, and reproductive behaviors. Nissl-stained brain sections of specimens from a previous study (J. C. Reboreda, N. S. Clayton, & A. Kacelnik, 1996) were used to study the gross anatomy of a song control nucleus in 3 South American cowbirds (bay-winged, Molothrus badius; shiny, M. bonariensis; and screaming, M. rufoaxillaris). Cowbird high vocal center (HVC) volumes were consistently higher in males than in females in all 3 species. The largest HVC size of females found in bay-winged cowbirds is consistent with observations that females of this species, but not of the other 2 species, occasionally sing. The extent of the sexual dimorphism of relative HVC size was highest for the sexually dichromatic and promiscuous shiny cowbirds and smaller for the monochromatic and monogamous bay-winged and screaming cowbirds, suggesting that selection pressures associated with morphological traits and social systems are reflected in brain architecture.     

Tackling nasal symptoms in athletes: Moving towards personalized medicine

Adequate nasal breathing is indispensable for athletes, and nasal symptoms have been shown to interfere with their subjective feeling of comfortable breathing and quality of life. Nasal symptoms are caused by either structural abnormalities or mucosal pathology. Structural pathologies are managed differently from mucosal disease, and therefore, adequate diagnosis is of utmost importance in athletes in order to choose the correct treatment option for the individual. Literature suggests that nasal symptoms are more prevalent in athletes compared to the general population and certain sports environments might even trigger the development of symptoms. Given the high demands of respiratory function in athletes, insight into triggering factors is of high importance for disease prevention. Also, it has been suggested that athletes are more neglectful to their symptoms and hence remain undertreated, meaning that special attention should be paid to education of athletes and their caregivers. This review aims at giving an overview of nasal physiology in exercise as well as the possible types of nasal pathology. Additionally, diagnostic and treatment options are discussed and we focus on unmet needs for the management and prevention of these symptoms in athletes within the concept of precision medicine.     

Catalytic autoantibodies in clinical autoimmunity and modern medicine

Abzymes (catalytic autoantibodies) belong to an absolutely new group of physiologically active substances with dual characteristics: they represent a pool of canonical autoantibodies and possess catalytic activity. Among them, proteolytic and DNA-hydrolyzing autoantibodies are of special value. Abzymes are an important pathogenic factor in the progression of clinical autoimmunity syndrome. The presence of autoantibodies against various autoantigens is accompanied by their high catalytic potential. The increase in this activity correlates with serum levels of the autoantibodies, clinical manifestations of autoimmune disorders, disease severity and the rate of progressing disability. Abzymes are crucial for immune homeostasis regulation. They can be of practical value in the development of modern immunodiagnostic tools and schedules of immunotherapy.     

Sexual dimorphism in innate immune responses to infectious organisms

Gender has long been known to be a contributory factor in the incidence and progression of disorders associated with immune system dysregulation. More recently, evidence has accumulated that gender may also play an important role in infectious disease susceptibility. In general, females generate more robust and potentially protective humoral and cell-medated immune responses following antigenic challenge than their male counterparts. In contrast, males have frequently been observed to mount more aggressive and damaging inflammatory immune responses to microbial stimuli. In this article we review the evidence for sexual dimorphism in innate immune responses to infectious organisms and describe our recent studies that may provide a mechanism underlying gender-based differences in conditions such as bacterial sepsis.     

Targeted therapy in melanoma: the era of personalized medicine

Malignant melanoma is the most aggressive of all cutaneous tumours, with over 76, 000 new cases and 9700 deaths estimated for 2014 in the United States.¹ In Canada, both the incidence and mortality of melanoma are increasing, with a risk of developing melanoma being 1 in 59 for men and 1 in 73 for women.² The incidence of melanoma is higher in Australia, with a risk of 1 in 14 for males and 1 in 23 for females to age 85 reported for 2009.³ Although early melanoma can be managed surgically, until recently there have been few advances in the treatment of advanced melanoma. However, with the introduction of molecular targeted therapies, the landscape of melanoma treatment has changed dramatically in the past five years, resulting in improved survival rates for patients with metastatic disease. In this review, we will discuss the molecular basis and implementation for some of these novel treatments with particular emphasis on BRAF and BRAF inhibitors.