[Age-related peculiarities of acute cholecystitis].

In the present study the analysis of dynamics of basic laboratory parameters of patients with acute cholecystitis (AC) in the four age groups subdivided according to the WHO classification into young, middle age, elderly and senile was carried out. The most pronounced changes were found in the senile age group in which the AC was accompanied by the decreased number of erythrocytes, low hemoglobin and total protein, leukocytosis, lower percentage of lymphocytes and the highest levels of ALT, AST, bilirubin and urea. Changes in the elderly and senile groups differed and in a number of cases were opposite. In the elderly and especially in the senile group the dynamics of the studied parameters related to surgery, was poorly expressed. These findings can be used in the preparation of the elderly and senile patients for AC surgery.

[NUCLEAR AND PERIKARYA SIZES OF THE NEURONS IN THE NUCLEUS BASALIS OF MEYNERT AND POSTERIOR HYPOTHALAMUS IN DIFFERENT AGE GROUPS].

Morphometric parameters of neuronal metabolic activity, such as the area of neuronal nuclei and perikarya and nuclear-cytoplasmic ratio, in the nucleus basalis of Meynert (NBM), tuberomamillary (TMN) and medial mammillary (MMN) hypothalamic nuclei of human subjects belonging to four age groups were studied. Statistically significant increase in the size of neuronal perikarya and their nuclei was found in elderly people aged 60-74 years. The surge in the metabolic activity of neurons in the NBM starts earlier than in the TMN and MMN, and becomes apparent morphologically in people of middle age (45-59 years). The age-related increase in the metabolic activity of neurons in the studied structures of the human brain participating in the regulation of memory and other cognitive functions, may represent protective, adaptive and/or compensatory mechanisms of the aging process that also prevents the development of Alzheimer's disease.

[Lamellar complex changes in the human basal forebrain and hypothalamic nuclei neurons in different age groups].

In the present study the lamellar complex (LC, Golgi complex) changes in the major cholinergic nuclei of the human basal forebrain - the nucleus basalis of Meynert (NBM), the vertical nucleus of the diagonal band of Broca (VDB) and hypothalamus--the tuberomamillary (TMN), the medial mammillary (MMN) and supraoptic (SON) nuclei were analyzed considering the WHO aging classification. The increase in the size of the LC was present in NBM, MMN and SON in the 3rd age group of elderly people (60-74 years of age), in the VDB--in the 4th group (75-89 years of age), whereas in the TMN LC changes were not apparent. In conclusion, the WHO aging classification reflects the LC values age ranges and can be used to estimate age-related alterations of this parameter. The increase in the size of the neuronal LC in elderly people may represent the compensatory reaction of neuroplasticity triggered by the aging process.

Transcriptional activity of human brain estrogen receptor-α splice variants: evidence for cell type-specific regulation.

Estrogen receptor α (ERα) isoforms with complex types of alternative splicing are naturally present in the human brain and may affect canonical receptor signaling. In the present study we investigated transcriptional activity of common ERα splice variants from this group with different molecular defects: MB1 (intron retention), TADDI (small deletion between exons 3 and 4 with an insert), the Δ (deletion) 3(⁎)-7(*)/819 (complete skipping of exons 4, 5 and 6 and partial deletion of exons 3 and 7) and the Δ3-6 (lacking exons 3, 4, 5 and 6) in HeLa and M17 cells upon stimulation with (17ß)estradiol or insulin-like growth factor 1 (IGF-1). In HeLa cells, all these splice variants showed the dominant negative function that was more pronounced for the TADDI. In M17 cells the dominant negative variants appeared to be the MB1 and the Δ3-6, whereas TADDI turned out to be a clearly dominant positive variant. In M17 cells mRNA levels of Δ3-6 and Δ3(*)-7(*)/819 variants increased following (17ß)estradiol administration. In Hela cells (17ß)estradiol up-regulated the IGF-1 receptor mRNA levels in cultures transfected with MB1, TADDI and Δ3(*)-7(*)/819. Our data demonstrate that ERα splice variants show differential levels of the transcriptional activity in a cell type-specific way and that IGF-1 signaling pathways are differentially employed in a cell-type specific manner depending on the level of the discrete ERα splice variants expressed. Functional properties of various ERα splice variants and their cell type-specificity should, thus, be considered as potential confounders of estrogen therapy effects on the brain.

Hippocampal estrogen receptor-alpha splice variant TADDI in the human brain in aging and Alzheimer's disease.

BACKGROUND/AIMS: Estrogen receptor-alpha (ER alpha) splice variants are important for understanding estrogen effects on the brain and estrogen therapy pitfalls. We addressed the question whether a novel ER alpha splice variant TADDI is expressed at the protein level in the human brain and whether it changes in relation to aging and Alzheimer's disease (AD). METHODS: Immunoreactivity (-ir) for TADDI was assessed on postmortem human brain material from a total of 116 cases. RESULTS: The highest levels of this splice form were found in the hypothalamic supraoptic nucleus (SON), pontine nuclei, medulla oblongata, gray matter of the spinal cord, the hippocampus, glomeruli of the cerebellum, the nucleus basalis of Meynert (NBM), and the tuberomamillary nucleus (TMN). TADDI-ir was mainly confined to the cytoplasm but was also determined in the nuclei of hippocampal neurons from young patients. In the hippocampus, the NBM, and the TMN, TADDI-ir was higher in postmenopausal women than in women

Alterations in the human brain in menopause.

In a series of studies we showed that menopause in women causes alterations not only in the neuronal expression of estrogen receptors (ER) alpha and beta, but also in local estrogen production in several brain areas and in the rate of neuronal metabolism. Although such changes are clearly brain region-specific, there seems to be no evidence at present for a decrease in neuronal metabolic rate. On the contrary, an increase in the neuronal metabolic activity and in the level of ERalpha in postmenopausal women was noted. In the supraoptic nucleus (SON) that is a major source of plasma arginine-vasopressin (AVP) we found that neuronal metabolic activity as judged from the Golgi apparatus and cell size was markedly enhanced in women after menopause accompanied by an increase in ERalpha and a decrease in ERbeta. Similar changes were noted in the medial mamillary nucleus and in the hippocampus that are involved in the regulation of learning and memory. Recently we aimed at determining whether in addition to the canonical ERalpha and ERbeta, estrogen receptor splice variants lacking entire exons may also be involved in the menopause-associated changes in the human brain. We detected del. 2 (missing exon 2), del. 4 (lacking exon 4), del. 7 (exon 7 absent) and MB1 (deletion of 168 nucleotides in the exon 1) in the frozen hippocampal tissue of 6 women (46, 52, 59, 64, 77 and 83 years of age). No age-related changes were observed for the mentioned splice forms in women of this group.

Structural and functional sex differences in the human hypothalamus.

Sex differences in the brain may be the basis not only for sex differences in reproduction, gender identity (the feeling of being male or female), and sexual orientation (heterosexuality vs homosexuality), but also for the sex difference in prevalence of psychiatric and neurological diseases ( Swaab and Hofman, 1995 ). In this brief article we discuss a few examples of structural and functional sex differences in the human brain.

Increased expression of estrogen receptor alpha and beta in the nucleus basalis of Meynert in Alzheimer's disease.

The human nucleus basalis of Meynert (NBM) is severely affected in Alzheimer's disease (AD). Since estrogens may reduce both the risk and severity of AD, possibly by an action on the cholinergic system, we determined whether estrogen receptors are present in the human NBM and what their changes are in normal aging and in AD. ERalpha was expressed to a higher degree than ERbeta and was localized mainly in the cell nucleus, while ERbeta was mainly confined to the cytoplasm. A significant positive correlation between the percentage of ERalpha nuclear positive neurons and age was found in men but not in women, whereas the proportion of ERbeta cytoplasm positive cells increased during aging in both sexes. In AD the proportion of neurons showing nuclear staining for both ERalpha and beta and cytoplasmic staining for ERbeta was markedly increased. The percentage of ERbeta nuclear positive neurons increased in AD only in women but not in men. The ApoE genotype had no effect on ER expression in the NBM in AD. In conclusion, whereas only minor sex- and age-related changes in both ERs were found in the human NBM, a clear upregulation of ERalpha and beta was observed in AD.

[Activity of vasopressin neurons in the human supraoptic nucleus: estrogen inhibitory effect]. / Aktivnost' vazopressinovykh neironov v supraopticheskom iadre gipotalamusa u cheloveka: ingibiruiushchii éffekt éstrogenov.

Activity of magnocellular vasopressin (VP) neurons in the human hypothalamus is sex- and age-dependent as judged from the size of the Golgi apparatus, neuronal size and VP mRNA levels. These parameters are significantly higher in young (< or = 50 years old) men than in young women and are markedly increased in postmenopausal women compared to premenopausal women. This data suggest an inhibitory effect of estrogens on metabolic activity of VP neurons in the human supraoptic nucleus (2SON), which is likely to be mediated via estrogen receptor (ER) beta. Estrogens were shown to mediate their inhibitory effect via ER beta. It is expressed to a much higher degree in the SON of young women than in other groups, whereas estrogen receptor alpha, that mediates stimulatory effects of estrogens, is present in a small proportion of SON neurons. In addition, estrogens inhibit p75 neurotrophin receptor expression in VP cells. In conclusion, we discuss the inhibitory role of estrogens in functional activity of human VP neurons, which is most probably mediated directly via ER beta and indirectly by p75 neurotrophin receptor.

Metabolic activity of the human ventromedial nucleus neurons in relation to sex and ageing.

The ventromedial nucleus (VMN) in animals is involved in a number of sexually dimorphic behaviors, including reproduction, and is a well-documented target for sex steroids. In rats and in lizards, it is also characterized by the presence of structural sexual dimorphisms. In the present study, we determined whether the metabolic activity of human ventromedial nucleus neurons was sex- or age-related. The size of the immunocytochemically defined Golgi apparatus (GA) and cell profiles were determined as measures for neuronal metabolic activity in 12 male and 16 female control brains sub-divided into four groups with the dividing line being the age of 50. It appeared that the size of the GA relative to cell size was 34% larger in young women (<50 years old) than in young men and was 25% larger in elderly men (> or = 50 years old) than in young men. In addition, the GA/cell size ratio correlated significantly with age in men and not in women. Our data suggest that androgens play an inhibitory role with respect to the metabolic activity of the human VMN neurons.

Multinucleated arginine-vasopressin neurons in the human supraoptic nucleus: a hallmark of pulmonary pathology.

The human supraoptic nucleus (SON) is the main production site of plasma arginine-vasopressin (AVP). The present study aimed to define the subpopulation of patients in which multinucleated SON neurons (MNN) are present. We determined the proportion of MNN in immunocytochemically defined SON AVP population and compared AVP mRNA levels in the SON of 29 patients with and without MNN. Interestingly, MNN appeared to be present in a high proportion in patients with pneumonia and other pulmonary pathologies (Pul P). The percentage of MNN in the SON of Pul P patients turned out to be age- and sex-dependent. In young women with Pul P their proportion was 10 times higher than in women without such a pathology and in young men with Pul P their frequency was 22 times higher than in other men. In those patients with the highest proportion of MNN, i.e. young females and males with Pul P, AVP mRNA expression in the SON was the lowest. In addition, young women (less than or = 50 years old) had lower AVP mRNA levels than young men and than elderly women (>50 years old). In conclusion, our study suggests that multinucleated neurons are a hallmark of Pul P in the human SON and that this phenomenon may be accompanied by lower AVP production in young subjects.

Differential expression of estrogen receptor alpha and beta immunoreactivity in the human supraoptic nucleus in relation to sex and aging.

The dorsolateral supraoptic nucleus (dl-SON) is the main production site of plasma arginine vasopressin (AVP). Plasma AVP levels and the activity of AVP neurons in humans are higher in males than in premenopausal females. On the other hand, an increased activity of AVP neurons becomes prominent in postmenopausal women who have strongly decreased estrogen levels. As estrogens are presumed to inhibit AVP production in a receptor-mediated way, we studied estrogen receptor (ER) alpha and beta immunoreactivity in the dl-SON. Hypothalami of 34 controls were subdivided into 4 groups within a 50-yr boundary (young men, young women, elderly men, and elderly women). The AVP part of the dl-SON of young women contained 50 times more neurons with ERbeta nuclear staining than that in young men and 250 times more than that in elderly women. In addition, young women also showed more ERbeta cytoplasmic staining than young men and elderly women. In contrast to the ERbeta immunoreactivity, no differences were found in the number of ERalpha-positive neurons in the 4 groups, but the age and sex pattern of ERalpha staining was basically opposite that of ERbeta. Significant correlations between the percentage of ERbeta- and ERalpha-positive and -negative AVP neurons and age were found in women, but not in men. Our data demonstrate for the first time a strong decrease of ERbeta and an increase of ERalpha immunoreactivity in AVP neurons of the dl-SON of postmenopausal women. Both receptor changes are proposed to participate in the activation of the AVP neurons in postmenopausal women.

Sex- and age-related P75 neurotrophin receptor expression in the human supraoptic nucleus.

The human supraoptic nucleus (SON) is the main production site of plasma vasopressin. Previously, using the Golgi apparatus and cell size as measures for neuronal metabolic activity, an activation of vasopressinergic neurons was found during ageing in the human SON in women but not in men. We hypothesized that the low-affinity neurotrophin receptor p75 (p75(NTR)) might be involved in the mechanism of activation of vasopressin neurons in postmenopausal women, since this receptor was found to be expressed in the SON neurons of aged individuals, and because p75(NTR) expression was shown to be suppressed by estrogens. Therefore, we investigated whether p75(NTR) immunoreactivity in the SON neurons was age- and sex-dependent. For this purpose, we studied paraffin sections of the SON in 32 postmortem brains of control patients ranging in age from 29 to 94 years with an anti-p75(NTR) antibody and determined the area of p75(NTR) immunoreactivity per neuron using an image analysis system. To study whether the p75(NTR) might also participate in the activation of SON neurons, we related Golgi apparatus size to the area of p75(NTR) immunoreactivity per cell in the same patients. We found that the area of p75(NTR) immunoreactivity per cell correlated indeed significantly with age and with Golgi apparatus size only in women but not in men. Therefore, our results suggest that p75(NTR) is involved in postmenopausal activation of vasopressinergic neurons in the human SON.

Vasopressin and oxytocin neurons of the human supraoptic and paraventricular nucleus: size changes in relation to age and sex.

The hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei consist of arginine vasopressin (AVP)- and oxytocin (OT)-synthesizing neurons that send projections to the neurohypophysis, whereas the PVN also projects to other brain areas. A growing body of evidence in animals suggests the presence of sex differences in the vasopressinergic and oxytocinergic systems. The present study was aimed at determining whether the sizes of AVP and OT neurons in the human SON and PVN show sex differences, as earlier studies demonstrated that a change in neuronal size is a sensitive parameter for activity. The minimal and maximal diameters were determined to estimate the volumes of cell somata and cell nuclei in AVP and OT neurons stained with an antibody against human glycoprotein-(22-39), a part of the AVP precursor, and a monoclonal anti-OT antibody in 15 men and 17 women ranging in age from 29-94 yr. The AVP neurons appeared to be larger in young men than in young women (< or =50 yr old). In elderly women (>50 yr old) AVP cell size considerably exceeded that in young women. In elderly men AVP neurons were larger than in young men and elderly women, although these differences were not significant. In addition, AVP cell size correlated positively with age in women but not in men. No significant differences were found in the AVP cell nucleus volumes among all four groups studied. Sex differences in the size of the PVN vasopressin neurons were pronounced at the left side (P = 0.048) and absent at the right side (P = 0.368), indicating the presence of functional lateralization in this nucleus. No difference was found in any morphometric parameter of OT neurons in the PVN among the 4 groups studied. Thus, our data demonstrate sex differences in the size of the AVP neurons, and thus in their function, that are age and probably also side dependent and the absence of such changes in OT neurons in the PVN. These data provide a basis for the reported higher AVP plasma levels in men compared to women.

Activity of vasopressinergic neurones of the human supraoptic nucleus is age- and sex-dependent.

In the human hypothalamus, arginine-vasopressin (AVP) is produced for a major part by the neurones of the supraoptic nucleus (SON). Since plasma AVP levels in men were reported to be higher than those of women and we did not find a sex difference in the neurone number, a higher vasopressinergic neurone activity was supposed to be present in the SON of men. Therefore we studied the size of the Golgi-apparatus (GA), which has been demonstrated previously to be a sensitive parameter for protein synthetic ability of neurones, in 15 men and 17 women ranging in age from 29 to 94 years. A polyclonal antibody against immunoaffinity purified MG-160, a sialoglycoprotein of the medial cisternae of the GA was applied on paraffin-embedded sections containing the dorsolateral SON (dl-SON) from which 90-95% of neurones are vasopressinergic. SON areas that contain oxytocin (OT) cells were excluded on the basis of adjacent sections stained with a monoclonal antibody against OT. By means of an image analysis system the size of the GA and the cellular profile area were determined in dl-SON neurones with a nucleolus. Our results showed indeed an age-dependent sex difference in the size of the GA that appeared to be twice as large in young men (< or = 50 years old) than in young women of the same age. The size of the GA increased with age in women but not in men. In addition, the mean cell profile area, another measure for neuronal activity, was significantly larger in young men than in young women and was in old women larger than in young women. In conclusion, these data show the presence of a sex-dependent age-difference in the activity of vasopressinergic neurones in dl-SON which may relate to differences in AVP and sex hormone levels and kidney AVP receptors.

[The role of oxytocin and vasopressin in the regulation of mammalian reproduction]. / Rol' oksitotsina i vazopressina v reguliatsii razmnozheniia mlekopitaiushchikh.

Nonapeptides, oxytocin and vasopressin are known to be involved in the realization of mammalian reproduction. Nonapeptides are synthetized in neuroendocrine and neuronal brain structures as well as in peripheral tissues, including gonads. The aim of the present review is the analysis of recent literary and authors own data on sexual dimorphism in the nonapeptidergic hypothalamo-hypophysial system, interaction between this system and hypothalamo-pituitary-gonadal axis, the role of nonapeptides in sexual behaviour as well as autocrine production of oxytocin and vasopressin in the testis. The special reference in the review is given to the nonapeptide gene expression in the brain and testis.