Sex differences in angiotensin II- induced hypertension

Sex differences in the development of hypertension and cardiovascular disease have been described in humans and in animal models. In this paper we will review some of our studies which have as their emphasis the examination of the role of sex differences and sex steroids in modulating the central actions of angiotensin II (ANG II) via interactions with free radicals and nitric oxide, generating pathways within brain circumventricular organs and in central sympathomodulatory systems. Our studies indicate that low-dose infusions of ANG II result in hypertension in wild-type male mice but not in intact wild-type females. Furthermore, we have demonstrated that ANG II-induced hypertension in males is blocked by central infusions of the androgen receptor antagonist, flutamide, and by central infusions of the superoxide dismutase mimetic, tempol. We have also found that, in comparison to females, males show greater levels of intracellular reactive oxygen species in circumventricular organ neurons following long-term ANG II infusions. In female mice, ovariectomy, central blockade of estrogen receptors or total knockout of estrogen a receptors augments the pressor effects of ANG II. Finally, in females but not in males, central blockade of nitric oxide synthase increases the pressor effects of ANG II. Taken together, these results suggest that sex differences and estrogen and testosterone play important roles in the development of ANG II-induced hypertension.

Animal model for age- and sex-related genotoxicity of diethylstilbestrol

Environmental xenoestrogens pose a significant health risk for all living organisms. There is growing evidence concerning the different susceptibility to xenoestrogens of developing and adult organisms, but little is known about their genotoxicity in pre-pubertal mammals. In the present study, we developed an animal model to test the sex- and age-specific genotoxicity of the synthetic estrogen diethylstilbestrol (DES) on the reticulocytes of 3-week-old pre-pubertal and 12-week-old adult BALB/CJ mice using the in vivo micronucleus (MN) assay. DES was administered intraperitoneally at doses of 0.05, 0.5, and 5 µg/kg for 3 days and animals were sampled 48, 72 and 96 h, and 2 weeks after exposure. Five animals were analyzed for each dose, sex, and age group. After the DES dose of 0.05 µg/kg, pre-pubertal mice showed a significant increase in MN frequency (P < 0.001), while adults continued to show reference values (5.3 vs 1.0 MN/1000 reticulocytes). At doses of 0.5 and 5 µg/kg, MN frequency significantly increased in both age groups. In pre-pubertal male animals, MN frequency remained above reference values for 2 weeks after exposure. Our animal model for pre-pubertal genotoxicity assessment using the in vivo MN assay proved to be sensitive enough to distinguish age and sex differences in genome damage caused by DES. This synthetic estrogen was found to be more genotoxic in pre-pubertal mice, males in particular. Our results are relevant for future investigations and the preparation of legislation for drugs and environmentally emitted agents, which should incorporate specific age and gender susceptibility.

The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development

Male sex determination in humans is controlled by the SRY gene, which encodes a transcriptional regulator containing a conserved high mobility group box domain (HMG-box) required for DNA binding. Mutations in the SRY HMG-box affect protein function, causing sex reversal phenotypes. In the present study, we describe a 19-year-old female presenting 46,XY karyotype with hypogonadism and primary amenorrhea that led to the diagnosis of 46,XY complete gonadal dysgenesis. The novel p.E89K missense mutation in the SRY HMG-box was identified as a de novo mutation. Electrophoretic mobility shift assays showed that p.E89K almost completely abolished SRY DNA-binding activity, suggesting that it is the cause of SRY function impairment. In addition, we report the occurrence of the p.G95R mutation in a 46,XY female with complete gonadal dysgenesis. According to the three-dimensional structure of the human SRY HMG-box, the substitution of the conserved glutamic acid residue by the basic lysine at position 89 introduces an extra positive charge adjacent to and between the positively charged residues R86 and K92, important for stabilizing the HMG-box helix 2 with DNA. Thus, we propose that an electrostatic repulsion caused by the proximity of these positive charges could destabilize the tip of helix 2, abrogating DNA interaction.

De sale

Variantti B.

The chronic blockade of angiotensin I-converting enzyme eliminates the sex differences of serum cytokine levels of spontaneously hypertensive rats

Sex hormones modulate the action of both cytokines and the renin-angiotensin system. However, the effects of angiotensin I-converting enzyme (ACE) on the proinflammatory and anti-inflammatory cytokine levels in male and female spontaneously hypertensive rats (SHR) are unclear. We determined the relationship between ACE activity, cytokine levels and sex differences in SHR. Female (F) and male (M) SHR were divided into 4 experimental groups each (n = 7): sham + vehicle (SV), sham + enalapril (10 mg/kg body weight by gavage), castrated + vehicle, and castrated + enalapril. Treatment began 21 days after castration and continued for 30 days. Serum cytokine levels (ELISA) and ACE activity (fluorimetry) were measured. Male rats exhibited a higher serum ACE activity than female rats. Castration reduced serum ACE in males but did not affect it in females. Enalapril reduced serum ACE in all groups. IL-10 (FSV = 16.4 ± 1.1 pg/mL; MSV = 12.8 ± 1.2 pg/mL), TNF-α (FSV = 16.6 ± 1.2 pg/mL; MSV = 12.8 ± 1 pg/mL) and IL-6 (FSV = 10.3 ± 0.2 pg/mL; MSV = 7.2 ± 0.2 pg/mL) levels were higher in females than in males. Ovariectomy reduced all cytokine levels and orchiectomy reduced IL-6 but increased IL-10 concentrations in males. Castration eliminated the differences in all inflammatory cytokine levels (IL-6 and TNF-α) between males and females. Enalapril increased IL-10 in all groups and reduced IL-6 in SV rats. In conclusion, serum ACE inhibition by enalapril eliminated the sexual dimorphisms of cytokine levels in SV animals, which suggests that enalapril exerts systemic anti-inflammatory and anti-hypertensive effects.

Deficiency of sex hormones does not affect 17-ß-estradiol-induced coronary vasodilation in the isolated rat heart

The relaxation of coronary arteries by estrogens in the coronary vascular beds of naive and hypertensive rats has been well described. However, little is known about this action in gonadectomized rats. We investigated the effect of 17-ß-estradiol (E2) in coronary arteries from gonadectomized rats, as well as the contributions of endothelium-derived factors and potassium channels. Eight-week-old female and male Wistar rats weighing 220-300 g were divided into sham-operated and gonadectomized groups (n=9−12 animals per group). The baseline coronary perfusion pressure (CPP) was determined, and the vasoactive effects of 10 μM E2 were assessed by bolus administration before and after endothelium denudation or by perfusion with NG-nitro-L-arginine methyl ester (L-NAME), indomethacin, clotrimazole, L-NAME plus indomethacin, L-NAME plus clotrimazole or tetraethylammonium (TEA). The CPP differed significantly between the female and sham-operated male animals. Gonadectomy reduced the CPP only in female rats. Differences in E2-induced relaxation were observed between the female and male animals, but male castration did not alter this response. For both sexes, the relaxation response to E2 was, at least partly, endothelium-dependent. The response to E2 was reduced only in the sham-operated female rats treated with L-NAME. However, in the presence of indomethacin, clotrimazole, L-NAME plus indomethacin or L-NAME plus clotrimazole, or TEA, the E2 response was significantly reduced in all groups. These results highlight the importance of prostacyclin, endothelium-derived hyperpolarizing factor, and potassium channels in the relaxation response of coronary arteries to E2 in all groups, whereas nitric oxide may have had an important role only in the sham-operated female group.

Effect of genotype, finishing system, and sex on physiochemical characteristics of goat meat

Seventy-eight kids of both sexes and five genotypes were used: Alpine, ½ Boer + ½ Alpine (½ BA), ¾ Boer + ¼ Alpine, ½ Anglo-nubian + ½ Alpine and "tricross" (½ Anglo-nubian + ¼ Boer + ¼ Alpine) with initial average weight of 14.1 ± 2.5. The objective was to evaluate the effect of genotype, finishing system, and sex on the physiochemical characteristics of goat meat. Finishing systems were: ST1 - kid + dam in pasture and ST2 - weaned kid and feedlot. Kids in ST1 were kept in an area with Panicum maximum cv. Tanzania, and after grazing, water and mineral salt/mix were fed ad libitum to the animals. The animals in ST2 were confined in collective pens distributed according to genotypes and received diet with 16% CP and 73% TDN. The values of pH, a* (red content), Cooking Loss (CL), and Ether Extract (EE) percentage were influenced by genotype. Values for red content (a*) and L* (brightness), CL and percentages of moisture, protein, EE, and ash were influenced by the finishing system. Longissimus dorsi muscle from animals ½ BA exhibited better physiochemical characteristics. For greater tenderness and higher percentages of fat, consumers should choose female kid goat meat.

Sex Quartetter för 2 Violiner, Alt och Violoncello. Op. 1.

Erik Tulindberg (1761–1814) on maamme ensimmäisiä nimeltä tunnettuja taidesäveltäjiä. Hänen sävellyskäsikirjoituksensa hautautuivat sukuarkistojen kätköihin yli sadaksi vuodeksi, eikä tänä aikana tiedetty säveltäjästä mitään. Vuonna 1925 kirjastonhoitaja Arne Jörgensen löysi Kansalliskirjaston yksityisestä vanhojen nuottien kokoelmasta kolme käsin kirjoitettua nuottivihkoa, joiden todettiin sisältävän Tulindbergin ensiviulun, alttoviulun ja sellon äänet kuuteen jousikvartettoon. Toisen viulun stemmat puuttuvat. Tarkkaa sävellysvuotta kvartetoissa ei ole merkittynä, mutta on arveltu että ne sijoittuisivat 1780-luvulle.

Tavanomaisen irtaimen esineen sale and lease back -järjestely. Tarkastelussa erityisesti vuokralleottajan sivullissuoja.

Tutkielman aiheena on tavanomaisen irtaimen esineen sale and lease back -järjestely. Järjestelyyn kuuluu nimensä mukaisesti luovutus ja takaisinvuokraus. Kokonaisjärjestelyn avulla rahoittaja ja luotonsaaja pyrkivät luomaan luotonmaksun vakuudeksi omistusoikeuteen perustuvan esinevakuuden. Järjestelyn tavoitteena on, että luotonsaajan asemassa oleva myyjä pystyisi käyttämään samaa esinettä samanaikaisesti sekä va-kuusobjektina että elinkeinotoimintansa tuotantovälineenä. Juuri siitä syystä, että luo-tonsaaja tarvitsee esinettä koko ajan elinkeinotoiminnassaan, ei panttausta voida käyttää. Tutkielma on oikeusdogmaattinen ja sen pyrkimyksenä on antaa selkeä kokonaiskäsitys irtaimen esineen sale and lease back -järjestelystä ja sen käytettävyydestä vakuusjärjestelynä. Oikeusdogmaattiselle tutkimukselle tyypillisesti tutkielmassa tarkastellaan olemassa olevaa tietomateriaalia. Keskeisimmät tutkielmassa käytetyt kirjallisuuslähteet ovat Jarno Teporan useat sale and lease back -järjestelyyn keskittyvät artikkelit, Jarmo Tuomiston omistusvakuuksia koskeva kirjallisuus sekä Erkki Havansin esineoikeudellinen perusteos Esinevakuudet. Virallislähteistä selvästi merkittävimmät ovat vuonna 1997 voimaantullut maakaari ja sen esityöt. Tutkimuksessa keskitytään erityisesti vuokralleottajan sivullissuojaan. Näin ollen tärkeimmäksi tutkimuskysymykseksi jäsentyy se, voiko sale and lease back -järjestelyssä ostajan roolissa oleva sijoittaja tai rahoittaja saavuttaa järjestelyn avulla kollisiotilanteiden varalta turvaavan vakuusaseman. Tutkimuksen kannalta keskeinen omistusvakuus-järjestely on vakuusluovutus, jollaiseksi vakuustarkoituksessa tehty sale and lease back -järjestely melko vakiintuneesti tulkitaan. Tutkimuksessa tarkastellaan mahdollisuutta hyväksyä sale and lease back -järjestely rahoittajalle dynaamista kollisiosuojaa tarjoavaksi vakuusjärjestelyksi ilman julkivarmistusta. Toisaalta selvitetään julkivarmistuksen toteuttamisen mahdollisuutta ilman hallinnansiirtoa muun muassa maakaaren 14:4.1:n 1 kohdan mukaisen kirjaamisen avulla. Nykylainsäädännön puitteissa järjestelyn hyväksyminen itsenäiseksi omistusvakuudeksi näyttää olevan epätodennäköistä ja ilman julkivarmistusta dynaaminen sivullissuoja jää saavuttamatta, vaikka järjestely on sitova inter partes. Tutkimuksen loppupäätelmissä pohditaan, voisiko sale and lease back -järjestelyyn liittyviä ongelmia ratkaista muuttamalla voimassa olevaa lainsäädäntöä tai antamalla täysin uutta lainsäädäntöä. Asiaa pohditaan myös oikeusvertailun keinoin selvittäen muiden Pohjoismaiden sekä Saksan oikeusjärjestelmien kantaa järjestelyyn.

Sueciae magnae, totius orbis regni antiquissimi, hodierna in sex principales suas partes, Gothiam nempe, Sueciam propriam sive stricté sumptam, Nordlandiam, Finniam, Ingriam, Livoniam, earundemque subdivisionum, ac adiacentium insularum geographica distinctio

Nimeke ylämarginaalissa.

historiae ecclesiasticae gentis Anglorum libri quinque : authore Beda, Presbytero ; praemittitur epitaphium discipulorum sex sancti Gregorii, Papae.

Colbertinus

historiae Longobardorum libri sex : initio et ad calcem occurrunt folia aliquot loco suo mota ; authoris nomen non comparet, is autem est Paulus Diaconus.

Faurianus

1.° Petri Pauli Vergerii, Justinopolitani, liber de politia Venetorum, eorumque legibus ac moribus, urbis situ, naturaque regionis. — 2.° Ejusdem liber de situ veteris Romae. — 3.° Anonymi chronica Italica. — 4.° Historiae ecclesiasticae omnium temporum libri sex : authore anonymo. — 5.° Sexti Rufi, viri Consularis, historiae Romanae breviarium. — 6.° Benevenuti de Rambaldis, Imolensis, liber augustalis de vitis Caesarum.

Faurianus

sancti Gregorii Turonensis historiae Francorum libri novem : primus liber integer, secundi sex priora capitula et alia passim desiderantur : ad calcem libri noni subjicitur Fredegarii chronicon ab anno quo desierat Gregorius, deductum ad annum 656. quod quidem à variis authoribus productum fuit ad annum 741. porrò chronicon Fredegarii cum additamentis, decimus Gregorii Turonensis liber in hoc codice inscribitur.

Colbertinus

rerum Sicanicarum libri sex : authore Francisco Maurolyco, Abbate Messanensi ; exemplar autographum.

Colbertinus