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Pittsburgh synagogue alleged shooter says he wanted 'all Jews to die': Police identify sisters found dead, bound in river. Reward doubles for missing year-old Jayme Closs. Pittsburgh synagogue shooting suspect named. New storm on the way for Midwest, Northeast. Video shows bomb suspect at club before arrest. A mass murder in Mr. Possible bomb materials in suspect's van: The latest from a mourning Pittsburgh community.

Two winners in Saturday's giant Powerball lottery. Mass shooting comes as hate crimes in the country are on the rise. Pittsburgh community shattered by mass shooting at synagogue. Pittsburgh mayor reacts to deadly synagogue shooting. Latest details on suspected mail bomber. Trump reacts to deadly synagogue shooting.

Former Tree of Life Synagogue rabbi speaks out. The latest on Pittsburgh synagogue shooting suspect and the investigation. Pittsburgh residents react to shooting at synagogue. Mail bombing suspect seen on surveillance footage night before arrest. Same-sex couple carries same baby, calls experience 'priceless' Ashleigh and Bliss Coulter both carried their baby boy Stetson.

Here's the news you missed this weekend Before you begin your week have a look back at the top stories of the weekend. Surveillance video shows alleged mail bomber at club night before arrest Sayoc has been charged with sending suspected explosive devices to politicians. Officials The alleged gunman in the Pittsburgh synagogue massacre used four guns. Fire stations recruit burn survivor dogs to help advocate for fire safety Clover and Ruby were adopted by fire stations in Florida.

Officials Police responded to reports of an active shooter on Saturday morning. New storm to hit Midwest, Northeast with strong winds A fast-moving storm will deliver some rain on Sunday and Monday. What we know about alleged mass shooter Robert Bowers Police named Robert Bowers, 46, the suspect in the killing of 11 people. Mail bombing suspect seen on surveillance footage night before arrest Cesar Sayoc was seen looking at clippings on surveillance from a club in West Palm Beach, Fla.

Bomb suspect's van contained possible bomb-making materials: Sources Cesar Sayoc, 56, is the suspect in the suspected mail bombing spree this week.

Reward for missing year-old Jayme Closs doubles amid funeral for slain parents Jayme Closs, 13, went missing Oct. Trump calls Pittsburgh synagogue shooting 'wicked act of mass murder' Trump called for more armed guards at places of worship after the shooting. Pittsburgh synagogue shooting prompts wide outpouring of public support The shooting is believed to be the deadliest attack on Jewish people in America. At least 8 dead in Pittsburgh synagogue shooting.

Fast-moving nor'easter bringing heavy rain, gusty winds to Northeast The storm will be cleared out by Sunday. Rapper linked to shooting investigation hours after court appearance Daniel Hernandez, known as 6ix9ine, was sentenced to probation Friday. Florida man Cesar Sayoc arrested in 'insidious' mail bomb spree: Officials Cesar Sayoc, 56, faces 48 years in prison for the charges, officials said. A look at the evidence that helped convict the killer Amy, Savvas and Philip Savopoulos and Veralicia Figueroa were killed in Preview ahead of World Series Game 3 Warmer weather conditions could make a difference in game play.

Matthew Shepard's ashes interred at National Cathedral In October , Matthew Shepard, 21, was abducted, beaten, tied to a fence and left to die in Wyoming for being openly gay. How mail bombing suspect was tracked down Cesar Sayoc, 56, of Florida, was arrested on Friday. Mail bombing suspect Cesar Sayoc in handcuffs Sayoc is charged with five federal crimes, including interstate transportation of an explosive, illegal mailing of explosives and threats against a This day in history: Read the charges against the bomb suspect that could imprison him for up to 48 years Sayoc was charged with five federal crimes.

Nor'easter to bring rain, winds to East Coast: What you need to know about the timing Overnight the rain will continue to push north, pounding the I corridor. What we know about the mail bombs sent to former presidents and prominent Democrats Multiple packages were found over the course of five days.

Mail bombing suspect faces up to 48 years in prison: Man allegedly yelled racial slurs and flashed gun at voting site. Suspect who allegedly sent pipe bombs identified as Cesar Sayoc The Florida man was taken into custody for an apparent mail bombing campaign. Matthew Shepard's ashes interred at National Cathedral 20 years after brutal murder Matthew Shepard was abducted, beaten and killed 20 years ago for being gay.

Authorities arrest bomb suspect The FBI has seized a white van that could be connected to the explosive packages sent around the country. Nor'easter headed to East Coast: What to know about this type of storm Nor'easters usually develop between Georgia and New Jersey. The legacy of a gay college student 20 years after his brutal murder Matthew Shepard was abducted, beaten and killed 20 years ago because he was gay.

Drivers dodge giant industrial spool The slow-rolling danger unfolded on one of Houston's busy highways. Video shows person of interest in Georgia model's death: Official A man and a woman were found dead after apparently falling from Taft Point in Yosemite National Park, the park said in a statement Thursday.

Georgia race, Trump's phone. What you need to know to start your day. The hunt for who mailed suspected bombs shifts to South Florida. Video shows person of interest in model's death: Police The woman was unconscious when paramedics pulled her from her car. Former city commissioner who shot alleged shoplifter hires George Zimmerman's lawyer Michael Dunn is a former city commissioner in Lakeland, Florida. Timeline details student's relationship with killer Melvin Rowland ate dinner with another woman after shooting Lauren McCluskey.

Wildfires ravage Northern California Aug New eruptions from Hawaii volcano create more lava destruction President Trump hosts French President Emmanuel Macron for first state visit. Anheuser-Busch delivering drinking water to Florida, Georgia Oct

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That's not the conversation she wanted. You know you're not faring well when Donald Trump calls you an "obnoxious blowhard" whose "taunting" Mohammed-drawing event was "disgusting. By haplessly dying, Simpson and Soofi deprived Geller of what she most wants, which is for us to be afraid of Muslims, like she is. The murderous assault on French satirical weekly Charlie Hebdo sparked a heated discussion on the merits of free speech versus "hate speech," but not even Charlie Hebdo wants any part in Geller's "harsh" and "anti-Islamic movement," as Charlie Hebdo cartoonists Jean-Baptiste Thoret and Gerard Biard explained to Charlie Rose on Monday:.

What will the Garland attack change? Probably nothing — though if I were in charge of renting out space in convention centers, or sending police to guard events, I would probably be less inclined now to book any gathering sponsored by the American Freedom Defense Initiative.

Geller and her allies have the constitutional right to draw cartoons of whomever they want, or to pay other people to — just as the National Socialist Party of America had the right to march through the heavily Jewish Chicago suburb of Skokie in wearing swastika armbands. Or as artist Andres Serrano had the right to photograph a crucifix immersed in a jar of his urine and call it art though, it should be noted, hammer-wielding Christian protesters in France vandalized Serrano's "Piss Christ" in , rendering it " beyond repair ".

You famously don't have the right to shout "fire" in a crowded theater, and Geller didn't. She tried to light a fire, and instead it rained.

It would be nice if all Muslims ignored Geller and her ally Robert Spencer. Because melanocytes are present in approximately equal numbers and have the same distribution over the body in both sexes, it is difficult to invoke a biological explanation for these differences in the locations of occurrence of melanoma; instead, the differences are attributed to clothing styles. The startling increase in the incidence of melanoma over the past 70 years, from a 1 in 1, to a 1 in 75 lifetime risk for Americans Koh et al.

The possibility that hormones influence melanoma has long been a subject of debate. The darkness of skin pigmentation at some body sites is affected by estrogenic hormones Abdel-Malek, Several studies suggest an adverse effect of pregnancy on the prognosis of melanoma Piepkorn, , and melanoma cells have been reported to express estrogen receptors Piepkorn, Melanoma is also influenced by immune factors.

For example, melanoma is responsive to adjuvant immunotherapy Piepkorn, Altered immune status during pregnancy may contribute to the spread of melanoma. Men age 50 or older have a striking excess rate of mortality due to melanoma compared with that for women Tsao et al.

It is unclear whether this reflects biological or behavioral differences. It is known, however, that most melanomas are first suspected by women, whether the lesions are on themselves or on their spouses, and that women then arrange for physician examination Koh et al. Such observations suggest ways in which both sex and gender figure in the incidence and prognosis of melanoma.

Sun exposure histories between men and women differ because of occupational and recreational sun exposures, clothing styles, and willingness to apply sunscreens. These gender-specific issues may influence who develops melanoma and at what site. Gender -specific influences can then be compounded by sex-and gender-neutral biological factors. For example, midback lesions most common in men carry a worse prognosis than lesions on other body sites Piepkorn, Once a melanoma has developed, hormonal differences may influence the probability of disease spread; and differences in body awareness and social priorities may influence how quickly medical attention is sought, with a large consequent influence on the prognosis.

Thus, a better understanding of the contributions of sex and gender differences to melanoma may have an enormous effect on the incidence and prognosis of this devastating malignancy. Because certain rheumatic, hepatic, and thyroid autoimmune diseases are predominant in females but other autoimmune diseases are not, the fact of autoimmunity alone does not explain the sex differences in autoimmune disease incidence. In humans, exposure and other extrinsic factors explain most sex differences in the incidence of infectious diseases.

If infections induce autoimmune diseases, differences in exposure may likely explain the sex differences. Most mammals respond to infections with a combination of innate inflammatory and adaptive immune responses Medzhitov and Janeway, Infectious agents include viruses, prions, bacteria, mycobacteria, fungi, and parasites.

The innate response engulfs, walls off, and, when appropriate, kills the invader with toxic cell products. The innate immune response recruits and in part directs the cells of the adaptive immune response. Adaptive immunity recruits and engages memory cells and their products to assist inflammatory cells.

Autoimmunity occurs when the adaptive immune system attacks normal tissue. Autoimmunity may result from a normal immune response to an invading organism gone awry or from the loss of normal immune regulation.

The levels and types of models used to study infection and inflammation are listed in Box 5—2. Each can be tested by use of various challenges: Spontaneous illness constitutes another form of test.

Whole organism in its environment. This level describes the interaction of an animal or person with its society or with its environment, for instance, the response to a living or inanimate more Portals of entry into the intact body include the skin; eyes; mouth, gastrointestinal tract, and rectum; nasal passages and lungs; and, in females, the vagina.

The urethra is less commonly an entry point, but it may be important in venereal diseases. Exposure may occur through direct penetration, as from a knife wound or transmission of a parasite through an insect bite; indirect penetration, such as by radiation; inhalation of a gas, aerosol, or organism; percutaneous absorption through the skin ; ingestion; or absorption from a mucosal surface.

Sex differences in types of exposure and portals of entry are rarely studied. Hypothetically, for behavioral and social reasons, males may experience more penetrating trauma and may inhale higher levels of toxic industrial materials. In general, a male's skin may be exposed to more industrial toxins, and female's skin may be exposed to more toxins in detergents and cosmetics.

In the course of work or relaxation, males may be more likely to place more unusual materials building nails, tobacco pipes in their mouths. In addition, males and females may have different diets. Females have a mucosal surface vagina absent from males and encounter products and agents tampons, semen, medical instruments, douches through vaginal insertion that males do not.

Furthermore, in females the cervical barrier between the internal and the external environments is transiently broken during menstruation. Finally, sexual practices present different types of exposure for males and females.

This section reviews differences in innate and adaptive immunities between females and males. Gonadal hormones partly control these normal defense systems. The literature on the nonhormonal effects of sex on mechanisms of innate and adaptive immunities is sparse, however.

Adaptive immunity varies markedly by sex; innate immunity varies less. Mature young females mount more vigorous immune responses than others. Whole-organism elements of inflammation and immunity include cycling, hormones, growth and nutrition, life stages, and life events discussed below.

Of these, only hormones have been extensively studied. Chronobiological events occur over short intervals e. Male and female chronobiologies, that is, menstrual or estrous cycles, should thus be considered separately from the associated hormonal changes.

Both sleep deprivation and jet lag, examples of chronobiological events, are immunosuppressive Ishida et al. Hypothetically, a chronobiological effect on immunity may occur in menstruating females or may render a fertile female vulnerable at certain times of the month. Studies that have compared exogenously cycled and noncycled castrated animals have not been done. Leukocytes and their products constitute the innate immune system. Leukocyte function, which is assessed by cellular synthesis of degradative enzymes Kuslys et al.

Pierre Schneider et al. Some estrogen-induced changes increase the levels of functioning of leukocytes in females; others decrease their level of functioning.

Overall changes are small, and sex differences in levels of leukocyte functioning probably do not affect human illness. The adaptive immune response includes activation and suppression of T and B lymphocytes, macrophages, and dendritic cells; secretion of their cytokine products; production of immunoglobulin antibodies; and activation of the complement and coagulation systems.

The adaptive immune response of females, as measured by determination of the level of cell proliferation or immunoglobulin levels, is more vigorous than that of males. The sex differences are relatively small. Comparable differences are seen between Caucasians and African Americans and between young and old individuals.

Persons with chronic inflammatory illnesses have activated immune systems. The implication of the differences between males and females is unknown. As a rule, estrogenic hormones upregulate and androgenic hormones downregulate the cellular effectors of human adaptive immunity: The adaptive immune response varies during the menstrual cycle.

However, most experiments on immune cells examine specific questions e. Reviews are readily available Cannon and St. Pierre, ; Cutolo et al. Representative recent data are displayed in Table 5—5. The hypothalamic-pituitary-adrenal-gonadal axis, which exerts important control on the adaptive immune system, differs between males and females. Exercise, stress, and depression all downregulate immune function Irwin, ; Nehlsen-Cannarella et al.

Since each of these differs between the sexes, sex differences in the resultant illness may occur. Sex -specific studies of responses to immunizations with vaccines show intriguing serological differences differences in circulating antibody levels but few clinical differences between females and males Table 5—6. Sex differences in serological response are not generalizable among organisms. Adverse systemic reactions to immunization, particularly arthritis, are more common in females.

Estradiol levels increase fold and estriol levels increase 1,fold during human pregnancy. Within these ranges, estrogens upregulate immune functions, but clinically evident immunological changes during pregnancy are small. Pregnancy-specific proteins suppress lymphocyte function. Changes differ at different stages of pregnancy, with no apparent general pattern. Cutaneous and humoral immune responses to specific microbial antigens are selectively depressed, as are leukocyte chemotaxis and adhesion.

Overall, during pregnancy the immune system deviates markedly from that during the nonpregnant state; the long-term effects, if any, of this deviation on women's biology or health are unknown. Specific infections, such as those caused by the measles virus, appear to be particularly virulent in pregnant women. The striking sex difference in many autoimmune disorders is incompletely understood. A new aspect under study is the role of fetal cells transferred to the maternal blood microchimerism Bianchi, and their persistence postpartum, in some instances for decades, in the pathogenesis of scleroderma also called systemic sclerosis, a connective tissue disorder that leads to fibrosis of skin and internal organs.

In women with scleroderma who had given birth to at least one son before disease onset, male DNA was detected more often and in larger amounts in their blood than in their normal sisters who had given birth to one or more sons Artlett et al. Persistent microchimerism of maternal lymphocytes in the circulation of offspring occurs as well, but its relationship, if any, to autoimmune disorders, is not yet known.

The implications of the association between autoimmune disorders and fetal microchimerism are unknown. The findings, however, do indicate a profound biological difference between men and women that may be relevant to sex ratios of disease. General Principles Males do not differ from females in terms of their responses to infections, regardless of whether the invading organism is a virus, bacterium, mycobacterium, or parasite.

In experiments with animals in controlled settings, males are more susceptible to parasites, fungi, bacteria, and viruses Klein, , probably because of hormonal effects. Most sex differences in humans, however, are caused by differences in exposures a societal level effect instead of differences between males and females at the individual, organ, or cell level.

The following are examples of sex differences caused by different exposures:. Virus In humans, sex differences in viral illnesses are primarily due to differences in behavior, such as vaccination rates or exposure Table 5—7. The apparent higher rate of fatality from measles in girls is not explained, and the different effects of vitamin A on antibody titers in males and females are controversial.

In animals, sex differences of virus effects occur in both directions. Bacteria Bacterial diseases affect males and females approximately equally. Even in the conversion of acute to chronic Lyme disease an illness that closely resembles autoimmune disease , the incidence and severity in males and females are similar Pena and Strickland, Mycobacteria, Fungi, and Parasites Males animals are slightly more susceptible to infection with mycobacteria, fungi, and parasites Klein, In humans, sex-specific rates of infection with mycobacteria, fungi, and parasites are approximately equal; most differences can be explained by differences in exposures Table 5—8.

Leprosy and Chagas' disease induce lupus autoantibodies and tuberculosis induces rheumatoid factor, but these diseases do not induce clinical autoimmune disease in humans. Data are scant, but infected males and females do not differ in their autoimmune responses to these diseases. The host antigens are either localized, as in thyroid and skin diseases, or ubiquitous, as in lupus. Autoimmunity characterizes the prototypical diseases whose occurrences differ by sex.

Autoimmune diseases pose the central question for the study of such sex differences: Explaining sexual dimorphisms in autoimmune diseases will likely bring to light heretofore unknown important biological differences between females and males.

Autoimmunity is defined to occur when an antibody binds to or reacts with an autoantigen an extract of a normal tissue. Cell -mediated mechanisms may participate in autoimmunity Draca, ; Marchetti et al. Other causes of autoimmunity include immunization and passive transfer of antibodies in animal models or participation of the major histocompatibility complex MHC. There is no consensus definition, however. The different definitions and classifications partly explain why different diseases are named autoimmune diseases in standard medical texts.

Most authorities agree that thyroid and rheumatic diseases are autoimmune diseases; they differ about inflammatory bowel disease, multiple sclerosis, some skin diseases, and juvenileonset diabetes. Some autoimmune diseases are strikingly predominant in females, others are not predominant in either sex, and still others are predominant in males. Table 5—9 lists several such diseases.

Predominance in females applies to some, but not all, of these diseases. By contrast, in parallel diseases in experimental animals, the term often refers to differences in disease severity. In human autoimmune diseases, severity is similar in females and males.

Environmental Causes of Autoimmunity The likelihood that environmental factors toxins and infections induce autoimmune disease is supported by the diseases and circumstances listed in Table 5— In several exogenously induced mimics of autoimmune disease, sex differences in disease occurrence are caused by exposure differences. These diseases are described here. Drug-induced lupus Yung et al. More males than females take drugs that induce lupus male predominant , and more males are exposed to silica inducers of scleroderma-like disease male predominant.

In Spain it was found that more females were exposed to the contaminated cooking oil that causes a sclerodermalike illness female predominant. More females than males took contaminated L-tryptophan, a putatively natural antidepressant; the resulting epidemic of eosinophilia-myalgia syndrome was predominant in females. Chronic Lyme disease is a self-perpetuating autoimmune illness that is initiated by but that does not require the persistence of live Borrelia burgdorferi organisms Carlson et al.

Its incidence has no sex difference, yet it closely resembles rheumatoid arthritis, whose incidence does have a sex difference. Fogo selvagem, or Brazilian endemic pemphigus foliaceus, is transmitted by a black fly bite and is presumed to be caused by an infectious agent passed at the time of the bite. Fogo selvagem shows no sex preference Hans-Filho et al. Contact dermatitis may be predominant in females, but differential exposure to allergens is the likely cause Kwangsukstith and Maibach, The possibility that infection induces rheumatic autoimmune disease is widely Miller et al.

It is unknown how infections induce different diseases by sex other than by different exposure rates. Potential male-female differences in the processing of infecting organisms, differences in vulnerable periods, or differences in threshold immune responses still apply.

Hormonal Causes of Autoimmunity , Including Life Events Case reports of clinical exacerbation or remission of autoimmune diseases after castration or hormone treatment suggest that gonadal hormone modulation plays an important role in disease severity in individuals but constitutes weak evidence for sexual dimorphisms in disease incidences in populations Lahita, Studies of the effects of postmenopausal estrogen or oral contraceptive therapy on autoimmune disease incidence most often show that such therapy has little effect Petri and Robinson, Synoviocyte estrogen receptors may be target organs in rheumatoid arthritis Castagnetta et al.

However, chronic Lyme disease causes a similar joint inflammation but is not predominant in females, and ankylosing spondylitis also causes a similar joint inflammation, but it is predominant in males. Androgens have no apparent role in ankylosing spondylitis Giltay et al. Although experimental feminization worsens autoimmune diseases in animal models and experimental masculinization ameliorates autoimmune diseases in animal models, variations in both severity and incidence are found.

Rheumatoid arthritis goes into remission during pregnancy, contradicting the theory of estrogen-enhanced immunological activity. The remission of rheumatoid arthritis is likely due to a human leukocyte antigen HLA mismatch between mother and fetus rather than to pregnancy-associated hormones Nelson et al. Multiple sclerosis also goes into remission during pregnancy Confavreux et al. Although it is often cited that pregnancy induces the flare-up of lupus, lupus in fact does not worsen or worsens only slightly during pregnancy Lockshin, Estrogen replacement therapy, oral contraceptives, and ovulation induction do not worsen lupus Guballa et al.

Insight can be gained through the study of rheumatoid arthritis and multiple sclerosis through the study of pregnancy and events during gestation as well as during the postpartum period. In these two diseases, clinical symptoms frequently lessen substantially and can even abate during the third trimester of pregnancy, but the diseases flare soon after delivery. At the cell level gonadal hormones modulate the immune response.

Why and how if it influences disease incidence at all this effect influences disease incidence is unclear. Estrogen could play a permissive role, allowing survival of forbidden autoimmune clones.

A threshold mechanism, that is, a specific level of estrogen at a vulnerable time, could explain the increase in incidence, but no such threshold has been postulated, tested, or demonstrated in humans.

Hormones may also influence the frequency of autoimmune disease in males and females in ways that are independent of the immune system. It is possible that sex differences in the endothelium are critical for disease initiation.

A still undiscovered sex difference related to, for example, ovulation- or menstruation-related cytokines, apoptosis of nonimmunological cells, or the presence of vaginal flora or the immune response to vaginal flora may be responsible for the different disease experiences of the two sexes.

Genetic Causes of Autoimmunity Evidence supporting the concept of genetic control of autoimmunity consists of studies with families and twins, the HLA types associated with specific illnesses, the identification of genes that enhance disease susceptibility, and transgenic experiments in which illness is induced in experimental animals Seldin et al. Evidence of this type is particularly strong for spondyloarthropathy Taurog et al.

HLA types by themselves do not explain the sexual dimorphism of the genetic causes of autoimmunity Chen et al. For each haplotype associated with a sexually dimorphic autoimmune disease, there is another haplotype associated with an autoimmune disease that is not sexually dimorphic. With the exception of the CD40 ligand, few putative autoimmune markers identified to date are on the X or Y chromosome.

No conclusive evidence for imprinting or X-chromosome inactivation differences exists for autoimmune diseases. The X chromosome has no role in human ankylosing spondylitis Hoyle et al. Non-MHC genes may be relevant. In a mouse model of diabetes, mutation of a tissue or a developmental stage-specific proteasome product shows sex differences Hayashi and Faustman, The sexual dimorphism of T-cell trafficking may be due to sex-determined cell surface markers or might be secondary to genomic or nongenomic effects.

Life Stage Causes of Autoimmunity Most diseases that are predominant in females cluster in the young-adult years, whereas autoimmune diseases that affect younger or older patients are more evenly divided between the sexes Table 5— Characteristics of young adulthood that may explain the predominance of a disease in females include the chronobiological effects of menstrual cycles, gonadal hormones, threshold effects, vascular responses, immune responses, vaginal flora, and other as yet unknown variables.

Very little experimental work has considered these topics. Animal Models of Autoimmunity Animal models of autoimmune disease give mixed messages about the causes of sex differences in autoimmunity. Table 5—12 displays some relevant data for three animal models of human autoimmune diseases, two of which are predominant in females and one of which is dominant in males.

Some information is dated and can be challenged by new technology. Animal models of autoimmune disease use immunization, inbreeding, and transgenic and gene knockout methods. In the model of thyroiditis, different strains of mice and rats are variably susceptible, implying strong genetic control of this disease.

Only young adult mice and rats were studied, however. In one rat strain, susceptibility was predominant in females. On the basis of backeross experiments, the X chromosome determines susceptibility. In mice, estrogen enhanced the antithyroid antibody titer a marker of disease but not thyroiditis itself.

The severity of induced thyroiditis was also found to vary with diet. Thus, genetic, X-chromosome, hormonal, and extrinsic factors may influence the occurrence of thyroiditis. In animal models, spontaneous autoimmune lupus develops in young adulthood, implying that maturation or cumulative damage is required for disease expression.

At maturation, susceptible mouse strains have more numerous and more avid estrogen receptors on lymphoid and uterine tissues than nonsusceptible strains, an explanation of strain susceptibility differences by strain but not of susceptibility differences by sex. Castration and replacement experiments demonstrate estrogen enhancement and testosterone suppression of spontaneous disease.

When animals are raised in a germfree environment, however, neither the phenotype nor the disease incidence changes, except that females tend to have higher autoantibody levels than males. Raising animals in a germfree, antigenfree environment ameliorates disease. Males and females in germfree environments are affected equally. Gene knockout experiments give conflicting results.

Of the two studies listed, one shows a markedly worse occurrence of glomerulonephritis in females, whereas the other shows equal incidences of glomerulonephritis in both sexes. Thus, in experimental lupus, genetic, hormonal, life stage, and environmental factors all appear to be relevant and sex differences remain unexplained. The human HLA B27 gene transgenically expressed in rats induces a phenotype with features of psoriasis and ankylosing spondylitis. In a germfree environment, the spondylitis does not occur but the psoriasis does.

Introduction of specific gastrointestinal pathogens to the germfree animal induces the spondylitis. The predominance of psoriasis and spondylitis in males is true of this model, as it is of the disease in humans. Genitourinary anatomy, sex hormones, immune response, and unknown factors are possible explanations. In summary, animal models suggest that autoimmune diseases have specific genetic, hormonal, life stage, and environmental causes. The human sex differences are not reproduced in many of the animal models, but no attempt has been made to understand why.

Gonadal hormones can modulate the adaptive immune response, but hormone effects alone are unlikely to explain the excess incidence of autoimmune illness in females. If gonadal hormones play a role, they must do so through a threshold or permissive mechanism. Although susceptibility to autoimmune illness is regulated by genetic background, no genetic mechanism that would explain sexual dimorphism has yet been postulated. The epidemiological risk factors for the sex-discrepant autoimmune diseases—young age and female sex—are consistent with the differential exposures to causative agents between males and females, the existence of vulnerable periods in females, and threshold effects rather than cell- or organ-level differences in the biologies of females and males.

A long period of latency between exposure and clinical disease is possible, complicating the search for etiologies that differ by sex. Coronary heart disease begins in utero, evolves through childhood, and emerges in middle and old age as a devastating and crippling problem. Plaques of cholesterol and other cellular materials are deposited in the inner lining of the coronary arteries and over time compromise the flow of blood, causing cell and organ death—myocardial infarction.

View in own window. In general, women manifest symptoms 10 to 20 years later than men National Center for Health Statistics, and have a higher prevalence of primary risk factors Becker et al. Men, however, die at an earlier age. Advances in knowledge about heart disease have led to steady declines in the rates of mortality from heart disease.

Yet, many questions remain, and none is more compelling than the differences between the sexes. The etiologies of coronary heart disease encompass the environment, genetics, age, and lifestyle. The most important environmental agents influencing coronary heart disease are diet, drugs, airborne toxins, and, possibly, infectious agents; and the effects of these agents may be synergistic.

For example, overeating or obesity and a sedentary lifestyle promote high blood pressure, high cholesterol, and diabetes, which are major risk factors for coronary heart disease in both males and females. Yet, susceptibilities and responses vary by sex. Dyslipidemias are among the strongest genetic contributors to coronary heart disease Goldstein et al. It is autosomal dominant and is more severe in homozygotes because of a gene dosage effect Goldstein et al.

Homozygotes develop atherosclerosis, which leads to coronary heart disease and death usually before age Sex differences are undocumented in homozygotes but do occur among heterozygotes; heterozygous males die about 10 years earlier than heterozygous females Table 5— In the FH heterozygote population, the age differences in incidence between the sexes are comparable to those for the general population.

Sex differences in heart disease mortality occur over the life span between women and men Figure 5—3. The Barker hypothesis postulates that the genesis of coronary heart disease may begin in utero, perhaps in response to malnutrition and stress Barker, ; see also Chapter 3. The fetus may adapt to the lack of critical nutrients or an excess of maternal stress hormones by permanently altering metabolic, endocrine, and cardiovascular systems in such a manner as to promote atherosclerosis later in life Barker, Death rates for diseases of the heart by age and sex, — National Center for Health Statistics Several longitudinal studies have demonstrated sex differences in coronary heart disease.

The Framingham Heart Study, initiated in Dawber et al. For example, it established the classical risk factor concept for coronary heart disease. This landmark study showed that a raised serum total cholesterol level, high blood pressure systolic and diastolic , and smoking increase the risk of developing coronary heart disease in men and women in a graded fashion.

Women develop coronary heart disease about 10 years later than men and women's risk is smaller. The Bogalusa Heart Study followed African-American and Caucasian children over time, beginning in the s, demonstrating that sex differences in risks for coronary heart disease begin at an early age. Hypertension, total cholesterol levels, high-density lipoprotein HDL cholesterol levels, and body mass index independently predicted increased carotid intimal thickness in both women and men.

The publisher's final edited version of this article is available at J Neurosci Res. See other articles in PMC that cite the published article. Abstract There are increasing numbers of overweight and obese individuals in the US and globally, and correspondingly, the associated healthcare costs are rising dramatically. Sex-dependent differences in voluntary physical activity in rodent models In this section, we will consider how rodent models have helped elucidate sex-dependent differences in voluntary physical activity levels.

Open in a separate window. Sex-dependent differences in exercise or leisure-time physical activity in humans A sampling of the many retrospective and cohort studies examining for sex-differences in leisure time physical activity LTPA will be discussed in this section.

Hippocampus Cannabinoid receptor 1 CB1 receptors may modulate wheel-running behavior by stimulating hippocampal neurogenesis. Hypothalamus Voluntary wheel running activity of calorically restricted male Wistar rats compared to ad libitum fed rats suggests that a decrease in adiposity may increase PA by elevating hypothalamic Npy expression, as well as other potential candidate genes in this area, including Lepr , Insr , Ampk , and Sirt1 Ruegsegger et al.

Discussion The current rodent and human studies provide strong evidence that there are normal differences in PA between males and females.

Acknowledgments The author is grateful to Sarah A. Role of Author The author takes responsibility for researching, summarizing, and accuracy in reporting the previously published peer-reviewed data: Footnotes Conflict of Interest Statement The author declares no conflict of interest. Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Effects of nucleus basolateralis amygdalae neurotoxic lesions on some spontaneous activities in the rat.

Central amygdalar and dorsal striatal NMDA receptor involvement in instrumental learning and spontaneous behavior. Physical activity pattern in men and women at the ages of 16 and 34 and development of physical activity from adolescence to adulthood. Scand J Med Sci Sports. Developmental origins of non-communicable disease: The medial prefrontal cortex and nucleus accumbens mediate the motivation for voluntary wheel running in the rat. Prevention of chronic disease in the 21st century: Gender differences in dopaminergic function in striatum and nucleus accumbens.

Age and sex affect spatial and emotional behaviors in rats: Neonatal ventral hippocampal lesions in male and female rats: Neurobehavioral effects of lead and manganese individually and in combination in developmentally exposed rats. Gender differences in college leisure time physical activity: J Am Coll Health.

Sex differences in open-field behavior in the rat: Reduced physical activity and risk of chronic disease: Eur J Appl Physiol. Lack of exercise is a major cause of chronic diseases. Effect of neonatal handling and paternal care on offspring cognitive development in the monogamous California mouse Peromyscus californicus Hormones and Behavior.

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A community based prevention of weight gain intervention Mothers In Motion among young low-income overweight and obese mothers: The effect of estrogen on dopamine and serotonin receptor and transporter levels in the brain: Results from an artificial selection experiment. Choosing voluntary exercise over sucrose consumption depends upon dopamine transmission: Psychopharmacology Berl ; 3: Nature, nurture and epigenetics. Differential miRNA expression in inherently high- and low-active inbred mice.

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