Marine records reveal multiple phases of Toba's last volcanic activity.

The Indonesian Young Toba Tuff (YTT), classically dated around 74 ka BP, is considered as a short-lived explosive cataclysmic super-eruption. The huge amounts of ash and SO2 emitted are likely to have triggered a volcanic winter which accelerated the transition to the last glaciation, and may have induced a human genetic bottleneck. However, the global climatic impact of the YTT or its duration are hotly debated. The present work offers a new interpretation of the Toba volcanic complex eruptive history. Analysing the BAR94-25 marine core proximal to the Toba volcanic center and combining it with high-resolution tephrostratigraphy and δ18O stratigraphy, we show that the Toba complex produced a volcanic succession that consists of at least 17 distinct layers of tephra and cryptotephra. Textural and geochemical analyses show that the tephra layers can be divided in 3 main successive volcanic activity phases (VAP1 to VAP3) over a period of ~ 50 kyr. The main volcanic activity phase, VAP2, including the YTT, is likely composed of 6 eruptive events in an interval whose total duration is ~ 10 ka. Thus, we suggest that the eruptive model of the Toba volcano must be revised as the duration of the Toba volcanic activity was much longer than suggested by previous studies. The implications of re-estimating the emission rate and the dispersion of ashes and SO2 include global environmental reconstitutions, climate change modelling and possibly human migration and evolution.

Two peaks of interleukin 1 expression in human leukocytes cultured with tobacco glycoprotein.

We have previously shown that tobacco glycoprotein (TGP), a polyphenol-rich glycoprotein isolated from tobacco or from cigarette smoke, affects the immune system. In this study we show that TGP induces human PBL and adherent cells to produce IL-1 alpha and IL-1 beta. Two peaks of IL-1 activity were observed; one at 18-24 h, the second at 4-6 d after initiation of culture. A similar pattern was observed for the steady state level of IL-1 mRNA. These data suggest that the production of IL-1 by cells stimulated with TGP might be a factor in cardiovascular disease associated with cigarette smoking.

[Morpho-functional iterative surgery in a patient with von Recklinghausen disease]. / Chirurgia reiterativa morfofunzionale in paziente con malattia di von Recklinghausen. Case report.

Neurofibromatosis 1 is an autosomal dominant disease with an estimated incidence 1:2500 to 1:3000 live newborns. The disease presents with multiple cutaneous and non cutaneous lesions. NF1 occurs with equal frequency in males and females and has been identified in all ethnic group. The morbidity and the mortality caused by NF1 are the result of complications that may involve any of the body systems. This disease has been linked with mutations of the NF1 gene which encodes tumor suppressor neurofibromin. At least half of patients with NF1 will have only cutaneous involvement that is not considered to be a major medical problem, even though it can be a source of psychologic burden as a result of cosmetic disfigurement. The cardinal features of the disorder are cafè-au-lait spots, axillary freckling, cutaneous neurofibromas and Lisch nodules, but there are a lot of wide variety of complications affecting almost every system of the body, including the eyes (optic glioma), the nervous system (intracranial tumors), the skeleton (short stature, scoliosis), the endocrine and cardiovascular system (hypertension). Manifestations of NF1 vary at different times in an individual's life. Substantial variability exists among affected members of a single family. This variability confounds clinical management and the severity of the disease cannot be predicted. We present a case in young woman 24 years-old treated by reiterative plastic surgery.

Astronomy and Solar Physics: X-ray Gas Scintillation Spectrometer Experiment.

The payload complement on Spacelab 1 included a spectrometer for observations of the brighter cosmic x-ray sources. The primary scientific objective was to study the detailed spectral features of cosmic x-ray sources and their associated temporal variations over a wide energy range from about 2 to 80 kiloelectron volts. The instrument, based on the gas scintillation proportional counter, had a geometrical area of some 180 square centimeters with an energy resolution of about 9 percent at 7 kiloelectron volts. The results presented here show new results from two galactic binary x-ray sources, Cygnus X-3 and Centaurus X-3, and from the Perseus cluster of galaxies. The excellent energy resolution of the instrument permits line features to be identified in these sources with unprecedented quality.

Ejaculatory training lengthens the ejaculation latency and facilitates the functioning of the spinal generator for ejaculation of rats with rapid ejaculation.

A spinal pattern generator controls the ejaculatory response. Central pattern generators (CPGs) may be entrained to improve the motor patterns under their control. In the present study we tested the hypothesis that training of the spinal generator for ejaculation (SGE) by daily copulation until ejaculation, could promote substantive changes in its functioning permitting a better SGE control of the genital motor pattern of ejaculation (GMPE) and, as a consequence, a normalization of the ejaculation latency of rats with rapid ejaculation. To that aim, we evaluated in sexually experienced male rats with rapid ejaculation (1) the effects of daily copulation to ejaculation, following different entrainment schedules, on their ejaculation latencies, (2) the impact of these different ejaculatory entrainment schedules upon the parameters of the GMPE and (3) the possible emergence of persistent changes in the functioning of the SGE associated to the daily ejaculation entrainment schedules. The data obtained show that intense ejaculatory training of rats with rapid ejaculation lengthens the ejaculation latency during copulation and augments the ejaculatory capacity of the SGE in this population when spinalized. Thus, present data reveal that like other CPGs, the SGE can be trained and put forward that training of the SGE by daily copulation to ejaculation might be a promising alternative that should be taken into consideration for the treatment of premature ejaculation.

Evidence for the presence of the spinal pattern generator involved in the control of the genital ejaculatory pattern in the female rat.

Substantial progress has been made during recent years in elucidating the control of male ejaculatory function by the central nervous system. These efforts have revealed the participation of a central pattern generator in the control of ejaculation. There is a strong similarity in the neural organization of male and female sexual functions. In the present study, the hypothesis that the spinal generator for ejaculation was present and functional in the female rat was evaluated. To this purpose, the expression of the ejaculatory motor pattern and its pharmacological activation in spinally transected female rats were investigated. Results revealed the presence in females of the already described rhythmic ejaculatory motor pattern of male rats. This ejaculatory motor pattern could be registered in the urethralis muscle of the female rat after mechanical stimulation of the urethra, vagina and clitoris and consisted, as in the male rat, of a first ejaculatory motor train followed by an after-discharge component. Besides, the female genital ejaculatory motor pattern could be pharmacologically induced by the systemic injection of sodium nitroprusside with similar motor characteristics. No significant differences between the sensorial and pharmacologically induced female genital motor patterns were found. Present findings provide evidence for the presence of the genital motor pattern of ejaculation in female rats and suggest that the spinal generator for ejaculation is also present and functional in this gender.

alpha-Adrenergic agents modulate the activity of the spinal pattern generator for ejaculation.

Spinal cord transection at a thoracic level activates fictive ejaculation (FE) in the male rat. It has earlier been demonstrated that fictive motor patterns may be activated by pharmacological means and that the noradrenergic system seems to be particularly efficient in triggering locomotor fictive patterns in spinal animals. In the present study, the hypothesis was tested that the spinal noradrenergic system participates in the activation of the spinal generator for ejaculation (SGE). To this aim, the effect of the adrenergic agents, methoxamine, prazosin, clonidine, and yohimbine, upon FE was evaluated in spinal male rats using electromyographic techniques. The results obtained show that ejaculatory rhythmic patterns, accompanied by the expulsion of urethral contents and phasic penile movements, can be elicited by the intravenous (i.v.) injection of methoxamine or yohimbine. These drug-induced motor sequences appear superimposed to the intrinsic ejaculatory spinal rhythm. By contrast, i.v. injection of prazosin or clonidine blocked the expression of the spontaneous ejaculatory rhythmic pattern without inducing any other genital response. These data suggest that an increased noradrenergic tone, either by blockade of presynaptic alpha2-adrenoceptors or by stimulation of postsynaptic alpha1-adrenoceptors, results in the activation of the SGE. Present findings provide the evidence that the SGE might be importantly influenced by the noradrenergic system, which exerts a facilitatory control on the expression of the genital motor pattern of ejaculation.

Production of transgenic mice expressing the Ki-ras oncogene under the control of a thyroglobulin promoter.

Transgenic mice have been generated bearing three fusion genes consisting of: (a) a 900-base pair rat thyroglobulin promoter followed by a gene coding for a chloramphenicol acetyl transferase activity; (b) the same promoter followed by the complementary DNA of the human activated Ki-ras oncogene; (c) a 2000-base pair rat thyroglobulin promoter followed by the complementary DNA of the human activated Ki-ras. We have shown that the 900-base pair rat thyroglobulin promoter is able to direct the expression of the reporter gene specifically in the thyroid gland of transgenic mice. The mice bearing the two Ki-ras constructs, which express the transgene in thyroid glands, show thyroid abnormalities, although at very low incidence. These lesions appear after a long latency and with a benign aspect, thus suggest that, in agreement with literature data on naturally occurring human thyroid tumors, the action of an activated ras gene is not sufficient to attain a complete malignant conversion of thyroid glands in vivo. However, ras expression in thyroid follicular cells represents a favorable ground for tumor development, as shown by the fact that goitrogen stimulation experiments increase the occurrence of tumors.

Current practice in Latin America of flexible ureterorenoscopy with laser for treating kidney stones. / Práctica actual de la ureteronefroscopia flexible con láser en América Latina para el tratamiento de la litiasis renal.

INTRODUCTION: The use of flexible ureterorenoscopy for treating kidney stones has increased in recent years, with considerable worldwide variation in the surgical technique and indications. OBJECTIVES: To determine the current practice, technique variations, use and indications of flexible ureterorenoscopy for treating kidney stones in Latin American. METHODS: We sent (by email and web link) an anonymous questionnaire with 30 questions on flexible ureterorenoscopy for treating kidney stones to Latin American urologists from January 2015 to July 2015. We collected the responses through the Survey Monkey system. RESULTS: A total of 283 urologists in 15 Latin American countries participated (response rate, 10.8%); 254 answered the questionnaire completely; 52.8% were urologists from Mexico and 11% were from Argentina; 11.8% of the responders stated that they performed >100 cases per year; 15.2% considered ureterorenoscopy as the treatment of choice for stones >2cm, and 19.6% performed ureterorenoscopy in single stages for calculi measuring >2.5cm. Some 78.4% use fluoroscopy, 69.1% use a ureteral sheath in all cases, 55.8% place double-J catheters at the end of surgery, 37.3% considered a stone-free state to be 0 fragments, and 41.2% use plain radiography to assess the stone-free condition. CONCLUSIONS: Most participating urologists consider flexible ureterorenoscopy as the first-choice treatment for stones <2cm; a small percentage of these urologists perform >100 ureterorenoscopies per year. More than half of the urologists routinely used fluoroscopy and ureteral access sheath; the most common method for determining the stone-free state is plain abdominal radiography.

Upregulation of the angiogenic factors PlGF, VEGF and their receptors (Flt-1, Flk-1/KDR) by TSH in cultured thyrocytes and in the thyroid gland of thiouracil-fed rats suggest a TSH-dependent paracrine mechanism for goiter hypervascularization.

Placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) represent two closely related angiogenic growth factors active as homodimers or heterodimers. Since goiters of the thyroid gland are extremely hypervascular, we investigated the expression of PlGF, VEGF and their receptors, Flt-1 and Flk-1/KDR, in a small panel of human goiters from patients with Graves's disease, in an animal model of thyroid goitrogenesis and in in vitro cultured thyroid cells. Here we report that the mRNA expression of PlGF, VEGF and their receptors is markedly enhanced in biopsies of goiters resected from Graves's patients. In vivo studies demonstrated that in the thyroid gland of thiouracil-fed rats, increased mRNA and protein expression of PIGF, VEGF, Flt-1 and Flk-1/KDR occurred subsequent to the rise in the serum thyroid stimulating hormone (TSH) levels and in parallel with thyroid capillary proliferation. In vitro studies confirmed the existence of such TSH-dependent paracrine communication between thyroid epithelial cells and endothelium since the conditioned medium collected from TSH-stimulated thyrocytes acquired mitogenic activity for human umbilical vein endothelial (HUVE) cells. Altogether, these data suggest that PlGF and VEGF, released by thyrocytes in response to the chronic activation of the TSH receptor pathway, may act through a paracrine mechanism on thyroid endothelium.

Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice.

Gene rearrangements activating the RET proto-oncogene are frequently associated with human thyroid carcinomas belonging to the papillary subtype. These arrangements cause the fusion of the tyrosine-kinase domain of RET to the 5'-terminal region of different genes creating the RET/PTC chimeric oncogenes. Here we report the generation of transgenic mice lines expressing the RET/PTC1 oncogene under the control of the thyroid-specific rat thyroglobulin promoter. RET/PTC1-transgenic mice developed thyroid tumors displaying the histological aspect of papillary carcinomas. These tumors were slowly progressive and did not cause premature death of the animals. Two additional mice developed areas of thyroid hyperplasia. Immunohistochemical and reverse-transcriptase polymerase chain reaction analyses confirmed the thyroid-specific expression of the transgene. Given the frequency of activating rearrangements of RET in human papillary thyroid carcinomas we conclude that this animal system could be a good model for studying the neoplastic progression of thyroid carcinomas.

Neovascularization in human germ cell tumors correlates with a marked increase in the expression of the vascular endothelial growth factor but not the placenta-derived growth factor.

Neoangiogenesis is a prerequisite for tumor growth and metastasis. In germ cell cancer patients with the disease limited to the testicle (stage A), tumor-associated neovascularization is predictive of metastatic disease (stage B). To investigate the molecular mechanisms underlying neovascularization in human germ cell tumors (GCTs), we analysed the expression of two angiogenic growth factors, vascular endothelial growth factor (VEGF) and placenta growth factor (P1GF), and of their receptors (FLT-1) and Flk-1/KDR) in a panel of testicular tumors. In this study we show a marked increase in VEGF expression in 36/44 (81.8%) primary testicular-derived GCTs, as compared to normal testis, that significantly correlates with a high density of intratumor microvessels (r = 0.72461, P < 0.001; n = 24). As determined by RT - PCR and/or Western blot, the predominant VEGF isoforms expressed in GCTs are the VEGF121 and VEGF165, which are more efficiently secreted by the cells, and thus more active in eliciting angiogenesis. Conversely, in the case of PIGF, only a weak correlation with the vascular density of tumors is observed (r = 0.26599, P < 0.05; n = 24). Northern blot analysis also revealed significant up-regulation of VEGF/ PIGF receptors in highly vascularized germ cell tumors, compared to normal testes. These findings suggest that VEGF may act in a paracrine manner to induce neovascularization, oedema extravasation and cyst formation in human germ cell tumors. The correlation between VEGF expression and the vascular density of tumors, suggest that the evaluation of VEGF expression may be of help in predicting patients at risk for metastatic diseases. Finally, we demonstrate that VEGF up-regulation may occur at the RNA level since no gene amplification is observed; conversely, in in vitro models such as the embryonal stem cell line NTERA-2 and the choricarcinoma JEG-3 cell line, VEGF (but not PIGF) mRNA expression is regulated by hypoxic stress.

Evidence for the presence and functioning of the spinal generator for ejaculation in the neonatal male rat.

A spinal pattern generator controls ejaculation in the male rat. In the present study, the hypothesis that the spinal generator for ejaculation was functional at early postnatal stages was evaluated. To this purpose, the expression of the ejaculatory motor pattern and its pharmacological activation in spinally transected neonatal rats from postnatal day 2 to weaning were investigated. Results revealed the presence of the rhythmic ejaculatory motor pattern in neonatal male rats. As in adult sexually experienced animals, the neonatal ejaculatory motor pattern could be elicited after the application of an ejaculation-like-releasing stimulus. The rhythmic genital motor response of neonates exhibited a gradual maturation that was reflected in its motor parameters until showing the features of the adult response at postnatal day 28. Besides, the ejaculatory motor pattern could be induced by the systemic injection of oxytocin in 7-day-old neonates as well as in adult animals. Present findings provide evidence for the presence of the spinal generator for ejaculation early during postnatal development, suggesting that its organisation is innate.

Role of genital sensory information in the control of the functioning of the spinal generator for ejaculation.

An intrinsic spinal rhythm mediates fictive ejaculation (FE). In this study, the effect of genital sensory stimulation on the functioning of the spinal generator of ejaculation was investigated. To this aim, the effect of (a) stimulation of internal and external genital structures; (b) repeated elicitation of FE and (c) genital stimulation during in progress expression of FE on the rhythmic genital motor pattern of ejaculation (GMPE) was analysed in sexually experienced, spinal male rats. Results showed that the spinal intrinsic ejaculatory rhythm can be modulated by genital inputs, and that repeated stimulation modifies this rhythm, progressively inhibiting its expression. Finally, in progress GMPEs could be reset by overlapping genital stimulation, supporting the notion of the spinal cord mediating the inhibition of FE following repeated genital inflow. Results reveal the nature of the modulatory role that genital afferent information exerts on the expression of FE.

Unraveling the modulatory actions of serotonin on male rat sexual responses.

Animal studies and clinical investigations reveal that serotonin plays a central role in the control of the ejaculatory threshold. The chronic use of selective serotonin reuptake inhibitors (SSRIs) frequently results in sexual dysfunction, inviting to analyze the modulatory actions of serotonin on male sexual function in depth. Even though the main effect of serotonin on male sexual responses is inhibitory, this neuromodulator also mediates brief important stimulatory actions. Serotonin (5-HT) can activate two intracellular signaling pathways: a lower-threshold facilitatory pathway, and a higher-threshold inhibitory pathway, leading to biphasic effects. We propose that these divergent actions are related to the stimulation or inhibition of glutamatergic and GABAergic interneurons. Experimental evidence suggests that low 5-HT concentrations produce stimulatory actions on male ejaculatory aspects that might be mediated by the blockade of the GABAergic neurotransmission in the MPOA and spinal cord, which in turn releases a tonic inhibition that allows other neurotransmitters such as glutamate, noradrenaline, oxytocin and dopamine to initiate a sequence of molecular events resulting in the expression of ejaculation. Similar serotonin actions, mediated via interneurons, have been proposed for the regulation of other processes and occur in many central nervous system areas, indicating that it is not an isolated phenomenon.

Regulation of thymosin beta10 expression by TSH and other mitogenic signals in the thyroid gland and in cultured thyrocytes.

OBJECTIVE: To investigate the expression of thymosin beta10 - a small conserved acidic protein involved in the inhibition of actin polymerization - in human and experimental thyroid goiters as well as the regulation exerted by TSH on thymosin beta10 expression in thyroid follicular cells both in vivo and in vitro. DESIGN: To this aim, we have used 5 bioptic specimens from patients affected by thyroid goiter, a well known experimental model of thyroid goitrogenesis (rat fed with the drug propylthiouracil) and a cultured rat thyroid cell line (PC Cl 3 cells) as a model system. RESULTS: We report that the mRNA expression of thymosin beta10 is markedly enhanced in human goiters compared with normal thyroid. In vivo results showed that the steady-state level of thymosin beta10 mRNA is up-regulated in the thyroid gland of propylthiouracil-fed rats in parallel with follicular cell proliferation: iodide administration to goitrous rats, which induced a marked involution of thyroid hyperplasia, reduced the mRNA level of thymosin beta10. Finally, in vitro studies showed that in cultured rat thyrocytes, the expression of thymosin beta10 mRNA is induced in a time- and dose-dependent manner by the activation of pathways which are mitogenic for thyroid cells (i.e. the protein kinase (PK) A and PKC pathways). CONCLUSION: Taken together, the findings reported here demonstrate that thymosin beta10 expression is regulated by extracellular signals that stimulate growth of thyroid cells both in vitro and in vivo, and suggest a role for this protein in thyroid diseases characterized by proliferation of follicular cells.

Comparison of losartan and hydrochlorothiazide on cognitive function and quality of life in hypertensive patients.

We examined long-term changes in cognitive function and quality of life (QL) in hypertensive patients by comparing the antihypertensive effect of hydrochlorothiazide (HCTZ) and losartan. We studied 69 patients (age range, 30 to 73 years) with mild-to-moderate hypertension. All patients, in a double-blind study, were randomly allocated to either treatment with 50 mg losartan once daily or 25 mg HCTZ once daily. The sample in each treatment group was divided by age (younger than 60 years or 60 years or older). At baseline and after 26 months, a QL questionnaire appropriate for the hypertensive patients was given. Cognitive function was evaluated, at baseline and after 26 months, by psychometric tests consisting of items from the Mini-Mental State Examination (MMSE) and the Sandoz Clinical Assessment Geriatric (SCAG). A score of less than 24 on the MMSE and more than 40 on the SCAG was predictive of cognitive impairment. The losartan group had a significant improvement in SCAG (P<.001) and MMSE (P<.001). No significant changes were observed in the HCTZ group (SCAG, P = .1; MMSE, P = .2). Sixty-five percent of the elderly had a MMSE score less than 24 and 70% had a SCAG score greater than 40, v. 35% and 48%, respectively, in younger patients. The health state index of QL improved significantly in both groups (losartan group, P<.01; HCTZ group, P<.02); the improvement in QL scores in patients using HCTZ was significant only in subjects aged 60 years and older (P<.04). These results suggest that losartan can have a positive effect not only on blood pressure but also on impaired cognitive function, reversing even minimal cognitive deficits induced by hypertension. The elderly patients in our sample had worse scores and cognitive performance was lower than in younger patients, even if in the losartan group the score improvement was the same at all ages. The same could not be said for HCTZ.

Stimulation of the medical preoptic area facilitates sexual behavior but does not reverse sexual satiation.

The aim of the present study was to establish whether electrical and/or drug stimulation of the medial preoptic area/anterior hypothalamus (mPOA/AH) surmounts the sexual behavior inhibition that results from copulation to exhaustion. Thus, intermittent electrical stimulation of the mPOA/AH (alone or combined with the systemic injection of yohimbine or apomorphine, at doses that were subthreshold for reversing sexual exhaustion) or intrapreoptic treatments to block GABAergic transmission were applied to sexually satiated rats. The results suggest that the mPOA/AH is not responsible for male sexual behavior inhibition or for the pharmacologically induced sexual behavior expression in satiated rats. Data are discussed in terms of the roles ascribed to the mPOA/AH, both in the control of sexual behavior expression and in the regulation of the postejaculatory interval.

Opioid antagonists and the sexual satiation phenomenon.

This study evaluates the effects of the IP injection of naloxone (0.3, 3 and 30 mg/kg) and naltrexone (0.2, 2 and 20 mg/kg) on the sexual satiation phenomenon. It was found that both antagonists exert a dose-based biphasic effect on the proportion of sexually exhausted rats displaying copulation. The intermediate doses of both opioid antagonists were more effective than the low and high doses in increasing the percentage of animals engaged in copulation. The analysis of the specific sexual behaviour parameters revealed that naloxone produces a slight inhibitory effect at the lowest dose, evidenced as an increase in the intromission number. The higher doses of this compound facilitated copulation reflected as a shortening of the ejaculation latency and the interintromission interval (III) and an increase in the copulatory rate. Naltrexone treatment had only facilitatory effects at the lower doses by reducing the III. The higher doses of naloxone (3 and 30 mg/kg) and the intermediate dose of naltrexone (2 mg/kg) decreased the spontaneous ambulatory behaviour of sexually satiated rats without impairing sexual behaviour execution. Data suggest a participation of the endogenous opioid systems in the sexual inhibition resulting from sexual exhaustion.