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On the theory of subdifferentials

Testosterone influences the brain via organizational and activational effects. Numerous relevant studies on rodents and a few on humans focusing on specific behavioral and cognitive parameters have been published. The results are, unfortunately, controversial and puzzling. Dosing, timing, even the application route seem to considerably affect the outcomes. In addition, the methods used for the assessment of psychometric parameters are a bit less than ideal regarding their validity and reproducibility.

Metabolism of testosterone contributes to the complexity of its actions. Reduction to dihydrotestosterone by 5-alpha reductase increases the androgen activity; conversion to estradiol by aromatase converts the androgen to estrogen activity. Recently, the non-genomic effects of testosterone on behavior bypassing the nuclear receptors have attracted the interest of researchers.

This review tries to summarize the current understanding of the complexity of the effects of testosterone on brain with special focus on their role in the known sex differences. Despite current efforts of the European commission to combat gender issues with respect to gender equality, men and women are different in several important aspects Cahill, These aspects include cognitive functioning and behavioral traits. Some of these may be socially induced, but scientists have showed on intact animals that other factors such as genetics and gender itself are mostly responsible forthe sex differences in behavior and cognition.

Therefore, the current research strategies are calling for including both males and females in the research in order to report the possible gender differences Ruigrok et al. Indeed, the exact mechanisms and reasons of sex differences in brain structures that mediate some of these functional dissimilarities are unknown.

Genetics and endocrine factors are the most prominent biological explanations and are interconnected. Testosterone is the major male sex hormone. It is present in women, although in much lower concentrations. Testosterone has also been intensively studied in relation to sex differences and behavioral functions.

This review focuses on physiology of testosterone to give the reader understanding of the mechanisms and complexity of testosterone action and then tries to summarize the studies and experiments focusing on the functional changes in anxiety, depression, spatial abilities and memory. Readers interested in sex differences and brain structures might find the needed information in the recently published focused review Filova et al.

Testosterone is produced mainly in Leydig cells of testes in males, and in ovaries in females. In both, testosterone can be synthetized in the adrenal gland cortex Burger, ; Dohle et al. However, in addition to the classic steroidogenic organs such as gonads, adrenals and even placenta, the active biosynthesis of steroids also occurs in the brain Mellon et al.

This synthesis can be either de novo from the cholesterol, or testosterone is derived from classical steroids as is deoxycorticosterone or progesterone, which enter through blood stream into nervous system. The latter one depends on the enzymatic ability of the neural region or cell.

This phosphoprotein mediates the transfer of cholesterol from the outer to the inner mitochondrial membrane, from where cholesterol can be further processed by corresponding enzymes. The StAR gene is expressed solely in the steroidogenic tissues.

The complexity of testosterone mechanism of action is underlined by its metabolism and steroid nature. The classical view suggests genomic mechanism, i. During recent years, a new pathway for non-genomic mechanism was shown. This can include activating the membrane receptors and thus activating the second messengers, or after translocation to the cell, testosterone can either directly activate second messenger intracellular cascade, or can bind to its respective receptor and as a complex of hormone-receptor it can activate the second messenger cascade Michels and Hoppe, Additionally, testosterone can be changed into either estradiol by aromatase or into dihydrotestosterone by reductase.

The pathway depends on the enzymatic equipment of the cells. The synthesis of sex hormones is ultimately controlled by gonadotropin-releasing hormone GnRH , which is produced by the hypothalamus and which stimulates the pituitary gland to release luteinizing hormone and follicle stimulating hormone, where LH increases the expression of StaR protein in target cells Ubuka et al.

GnRH secretion in adulthood is pulsatile and highest during sleep with subsequent highest peaks of testosterone to be during the early morning hours Lord et al. Nevertheless, the testosterone levels decline gradually with aging, mainly due to the attrition of Leydig cells and hypothalamic GnRH pulse generation slow down.

Rapid drop can be observed in the 6th decade of life in males. Basaria, However, not all studies agree with this simple explanation. Sartorius et al. Similarly, Camacho et al. In any respect, the causal role of testosterone deficiency and behavioral disorders including effect on cognitive abilities is still debated. Therefore, in the next chapters we will try to summarize the main experimental studies on individual behavioral traits.

Our daily decision-making as well as response to stress is our everyday experience. Indeed, many factors contribute and even more factors modify the decision-making and stress reaction, with anxiety level to be one of them. Nevertheless, it has clearly been shown, and recently reviewed that women show higher anxiety in comparison to men Mchenry et al. From all behavioral parameters, the anxiety seems to be most sensitive to testosterone. The most cited paper analyzing the effects of testosterone on anxiety in mice has shown in several experiments that testosterone—either endogenous or exogenous decreased anxiety in elevated plus maze Aikey et al.

In addition, the same study showed that this anxiolytic effect of testosterone is dose-dependent and very likely mediated by 5-alpha reductase that reduces testosterone to dihydrotestosterone.

The study was conducted in male mice, but similar anxiolytic effects of single testosterone administration resulted in reduced fear of healthy women Van Honk et al. In rats, a single testosterone injection did not reduce anxiety, however, a repeated administration had anxiolytic effects tested by the burying behavior test Fernandez-Guasti and Martinez-Mota, A possible mechanism can include the androgen receptor, as its blockade has been shown to prevent the testosterone-induced anxiolysis.

Similar results were obtained in our experiment. However, the anxiolytic effect was observed only in the light-dark box. We were not able to reproduce the anxiolytic effects of testosterone in the elevated plus maze and in the open field Hodosy et al. On the other hand, flutamide alone had anxiolytic effects in the open field.

This suggests that the association between testosterone and anxiety might not be linear. A number of experiments on gonadectomized rats from the lab of professor Frye further showed that dihydrotestosterone 3-alpha metabolites can be the mediators of testosterone anxiolytic effects Edinger and Frye, , In addition, blockade of the dihydrotestosterone transformation to 3-alpha androstanediol by a 3-alpha hydroxysteroid dehydrogenase inhibitor prevented the anxiolysis Frye and Edinger, Age-related decline in cognitive and affective functions was associated with lower concentrations of testosterone metabolites in the hippocampus.

Again, this effect blocked by administration of 3-alpha metabolites administration Frye et al. Another mechanism of anxiolytic effect of testosterone was explained in recently published experiment, where exogenous or endogenous opioids could modulate anxiolysis Khakpai, In this study, the gama aminobutyric acid systemthat has been proposed in the past, on the other hand, did not alleviate the anxiety level Roohbakhsh et al.

An important determinant of the postnatal association between anxiety and testosterone or its metabolites might be prenatal stress. Stress induced during gestation resulted in both, reduced testosterone and increased anxiety of the adult offspring Walf and Frye, Taken together, the results are consistent and despite differences in the methodology it seems clear that testosterone reduces anxiety in both genders.

Its higher concentrations in men might be the reason for the sex differences in anxiety. However, a very important study in rhesus monkeys showed that pharmacological castration reduced and testosterone supplementation normalized anxiety levels Suarez-Jimenez et al.

A result that is in contrast to the majority of literature of experiments in rodents. Of course, this discrepancy might be discussed with major differences in the methodology—other behavioral tests, and in the intervention—surgical vs. But in general, experiments on monkeys are more relevant to human behavior and, thus, this study must not be overseen. Some of the animal experiments on testosterone and anxiety are summarized in Table 1. Table 1. Selected animal studies analyzing the relationship between testosterone and anxiety.

Although the depressive disorder is more prevalent in females Bebbington, when compared to males, the prevalence of depression in males increases with age Khera, as plasma testosterone drops. Consequently, many experiments and studies were performed to confirm the causative role of testosterone decline in depression pathogenesis. Indeed, these studies were not triggered by the lone fact of testosterone decline and sex difference in prevalence of depressive disorders.

In depressive disorders with decreased libido and low testosterone, the androgen hormone replacement therapy was at least as effective as serotonin reuptake transporters Kranz et al.

Further it was investigated that testosterone can modulate serotonergic transmission, where serotonin plays a crucial role in depression development Jovanovic et al. But it is not only the prevalence of depression that differ between sexes. In a study on opposite sex twins, it has been demonstrated that also the etiology of depression is different in men and women Kendler and Gardner, Whether testosterone plays a major role in the sex differences in depression is unclear, but a number of studies indicate that it can affect the mood of depressive patients as well as healthy probands Mchenry et al.

Nevertheless, it is only one of many biological factors potentially responsible for the sex differences in depression. These were reviewed recently Altemus et al. Observational studies on older men revealed that their depressive symptoms are associated with low plasma testosterone Joshi et al. Low testosterone and depressive symptoms are both associated with the risk of falls, which are important for life expectancy in the elderly Kurita et al.

Similarly, in women testosterone concentrations are lower in depressive patients when compared to healthy controls Kumsar et al. However, standard antidepressant treatment leads to normalization of testosterone. This suggests that the causality could be different than predicted—depression lowers testosterone. On the other hand, in both men and women, testosterone supplementation leads to improvement of depressive symptoms Pope et al.

However, not all interventional studies confirmed the anti-depressant effect of testosterone. At least in one published randomized controlled trial, the effects of testosterone were comparable to placebo effects Seidman et al. Similarly, not all observational studies show a consistent picture. At least in one small study, depressive women had higher testosterone Weber et al. When publication bias and the high intra- and inter-individual variability of testosterone are taken into account, these small negative or contradictory studies could be even more important.

The meta-analyses of the published studies are also to be taken into account. In a meta-analysis of the effects of testosterone on depression, the anti-depressant effect was positive, at least in patients suffering from hypogonadism Zarrour et al.

The biology of the association between testosterone and depression has been reviewed recently Mchenry et al. In an animal model of aging the associated depressive-like behavior correlated with lower testosterone Egashira et al.

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Testosterone influences the brain via organizational and activational effects. Numerous relevant studies on rodents and a few on humans focusing on specific behavioral and cognitive parameters have been published. The results are, unfortunately, controversial and puzzling.

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The theory presented in the paper consists of two parts. The first is devoted to basic concepts and principles such as the very concept of a subdifferential, trustworthiness and its characterizations, geometric consistence, fuzzy principles and calculus rules, methods of creation of new subdifferentials etc. In the second part we study certain specific subdifferentials, namely, subdifferentials associated with bornologies, their limiting versions and metric modifications. For each subdifferential we verify that the basic properties discussed in the first part are satisfied and prove calculus rules for two main operations: summation and partial minimization.

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From the Department of Medicine, University of Wisconsin. Since the isolation of pure ephedrine by Nagai in , 1 several clinical observations have been made with regard to its mydriatic action. Thus Miura 2 in the same year reported that a 6 to 7 per cent solution of ephedrine hydrochloride produces mydriasis in most people in from forty to sixty minutes. He observed that the use of a 10 per cent solution in eighteen patients did not cause a maximal dilatation of the pupils but produced sufficient dilatation for the visualization of the retina. During dilatation, the light reflex is retained, and the accommodation is not paralyzed. There is no increase in intra-ocular pressure, no irritation or inflammation after its instillation and no ill effects after prolonged use. One patient receiving three treatments daily for fifteen days showed no pathologic changes. The duration of mydriasis varies from five to twenty hours. Children and aged people are more susceptible than young. Arch Intern Med Chic.

Short Dick Man

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This guide is based on the principles behind the success of Carnegie, Ford, Edison, and other 20th-century tycoons.

It also appears on 20 Fingers' second self-titled studio album and on Gillette's debut solo album, On the Attack. The tune was a global success, particularly in France and Italy, where it was a number-one hit. It also reached number three in Germany, number four in Australia, number six in Austria and the Wallonia region of Belgium, and number seven in the Netherlands and New Zealand. This single, which involves a woman mocking the size of a man's penis, was also released in a toned down version replacing the word "dick" with "short" the song was also released under the censored title "Short Short Man".

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Но ведь для обычных пользователей они все не поддаются взлому. - Верно… - Стратмор задумался.  - На какое-то время.

Черт возьми! - снова мысленно выругался.  - Никакая это не паранойя. Этот чертов компьютер бьется над чем-то уже восемнадцать часов. Конечно же, все дело в вирусе. Чатрукьян это чувствовал.

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Пока не везет.  - Она вздохнула.  - Быть может, придется ждать, пока Дэвид не найдет копию Танкадо. Стратмор посмотрел на нее неодобрительно. - Если Дэвид не добьется успеха, а ключ Танкадо попадет в чьи-то руки… Коммандеру не нужно было договаривать.

concepts like solving equations, but most units you'll have room to do the In short we see that 3 Note that the pre-image, the original picture, is labeled as е The fourth transformation does not preserve the size of the pre-image, only the Use the following graph showing a function modeling a man's stock market.

Простите. - Проваливай и умри, - повторил немец, приложив левую ладонь к жирному правому локтю, имитируя итальянский жест, символизирующий грязное ругательство.

Но Беккер слишком устал, чтобы обращать внимание на оскорбления. Проваливай и умри. Он повернулся к Росио и заговорил с ней по-испански: - Похоже, я злоупотребил вашим гостеприимством.

On the effects of testosterone on brain behavioral functions

Сьюзан вздохнула. Она чувствовала себя виноватой из-за того, что так резко говорила с коммандером. Ведь если кто и может справиться с возникшей опасностью, да еще без посторонней помощи, так это Тревор Стратмор.

Возле фреоновых помп. Сьюзан повернулась и направилась к двери, но на полпути оглянулась. - Коммандер, - сказала.  - Это еще не конец.

- Еще не было случая, чтобы в моих данных появлялись ошибки.

Его копчик больно вдавливался в низ ее живота через тонкую ткань юбки. Кровь из ноздрей капала прямо на нее, и она вся была перепачкана. Она чувствовала, как к ее горлу подступает тошнота. Его руки двигались по ее груди.

Сьюзан отказывалась его понимать. - Это долгая история. Она повернулась к монитору и показала на работающего Следопыта. - Я никуда не спешу. Стратмор сокрушенно вздохнул и начал мерить шагами комнату. - Очевидно, когда Танкадо умер, рядом находились свидетели.

Согласно словам офицера, который отвел Дэвида в морг, некий канадский турист сегодня утром в панике позвонил в полицию и сказал, что у одного японца в парке случился сердечный приступ.

PGP, Lucifer, DSA - не важно. Алгоритм создает шифр, который кажется абсолютно стойким, а ТРАНСТЕКСТ перебирает все варианты, пока не находит ключ.

Стратмор ответил ей тоном учителя, терпеливого и умеющего держать себя в руках: - Да, Сьюзан, ТРАНСТЕКСТ всегда найдет шифр, каким бы длинным он ни.  - Он выдержал длинную паузу.

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