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Biomedical subjects

S Palacios

Publications and source records attributed to S Palacios.

At least 19 recordsLinked to original sources
PubMed2004

Pulsed estrogen exposure selectively modulates tissue response: a hypothesis.

All postmenopausal hormone replacement therapies (HTs) aim to provide a steady mid-follicular serum concentration of estrogen, with the exception of pulsed estrogen therapy, which concentrates hormone exposure in the few hours following administration. This alteration in the kinetics of estradiol exposure does not change the beneficial effect of HT on climacteric symptoms or bone loss, but does reduce the stimulation of the breast and uterus leading to less mastalgia and bleeding. The following hypothesis provides a plausible pharmacological explanation as to how estradiol kinetics can selectively modify tissue response. Pulsed estradiol exposure influences the relative abundance of estrogen receptors (ERs) alpha and beta, via a tissue-dependent non-genomic signaling pathway, resulting in selective upregulation and activation of ERbeta in breast and endometrium, but not in bone. In addition, pulsed estrogen exposure also increases local concentration of 2-methoxyestradiol, a specific estradiol metabolite with proven anti-tumor properties.

2-Methoxyestradiol↗
PubMed2003

The new terminology.

Explore the source record for details and available documents.

Estrogen Replacement Therapy↗
PubMed2002

Sexuality in the climacteric years.

Menopause is a time of anatomic, physiological and psychological changes that often influence in the sexuality of aging female. Being sexual functioning an important aspect of health and well-being, doctors should have an holistic approach reassuring about the possibility of treating the various symptoms. The central nervous system is an important target for sex steroid hormone; estrogen, progestagens and androgens are able to modulate several brain functions, and receptors for gonadal steroids have been identified in several brain areas. Because there is no test that physicians can make to assess sexual function, taking a sexual history is probably the most important aspect in the diagnostic and treatment of sexual problems. Hormonal transition with decreasing levels of estrogen and testosterone produces clinical effects, so women need to make adjustments for this period of life. Testosterone is an important component of female sexuality, and alterations in its circulating levels play an important role in psychological and sexual changes that occur after menopause. This is the reason why the research in identifying women who have a decrease androgen active should be aimed. Treatment may include education about sexuality and medical management of symptoms or problems interfering with sexual activity. Also treatment implications and the diverse aspects that may influence on sexuality in the climacteric years are discussed.

Aging↗
PubMed2002

Effects of tibolone and continuous combined hormone replacement therapy on bleeding rates, quality of life and tolerability in postmenopausal women.

OBJECTIVE: To compare the effects of tibolone and conjugated equine oestrogens continuously combined with medroxyprogesterone acetate on bleeding rates, quality of life (QoL) and tolerability. DESIGN: A double-blind, randomised comparative trial. SETTING: Thirty-seven centres in six European countries. POPULATION: Five hundred and one postmenopausal women, under 65 years of age with an intact uterus. INTERVENTIONS: For 12 months, women received daily treatment with tibolone 2.5 mg (n = 250), or conjugated equine oestrogens 0.625 mg continuously combined with medroxyprogesterone acetate 5 mg (CEE-MPA, n = 251). MAIN OUTCOME MEASURES: The primary outcome was vaginal bleeding rate during cycles 4-6. The secondary outcomes were vaginal bleeding rate during cycles 1-3, 7-9 and 10-13, cumulative bleeding rate, QoL, wellbeing, climacteric symptoms, urogenital complaints and tolerability. RESULTS: Treatment with tibolone led to a significantly lower bleeding rate during cycles 4-6 compared with CEE-MPA (15.0% vs 26.9%; P = 0.004); there was a similar difference during cycles 1-3. Both treatments improved QoL, wellbeing, climacteric symptoms and urogenital complaints. By intent-to-treat analysis, tibolone significantly improved sexual drive, interest and/or performance, compared with CEE-MPA at 12 months (P = 0.017). Although both treatments were well tolerated, there was a significantly lower incidence of breast tenderness with tibolone than CEE-MPA (2.4% vs 17.1%; P < 0.001). CONCLUSION: The vaginal bleeding rate during cycles 4-6 was significantly lower in women using tibolone. Both treatments improved QoL, wellbeing, climacteric symptoms and urogenital symptoms. Breast tenderness was significantly less frequent with tibolone.

Drug Combinations↗
PubMed2002

Pulsed estrogen therapy: relieving climacteric symptoms, preventing postmenopausal bone loss.

Aerodiol with its new mode of action--pulsed estrogen therapy made possible by a unique pharmacokinetic profile and an innovative route of administration--acts on the full range of climacteric symptoms and on the long-term consequences of estrogen deprivation. Four well-designed, international studies investigating the efficacy of pulsed estrogen therapy on both the short- and long-term consequences of estrogen deprivation were conducted. Climacteric symptoms and their reduction were assessed individually and also using the Kupperman index, which is a weighted score. Aerodiol produced a significant reduction in the Kupperman index and in the occurrence of menopausal symptoms, such as hot flushes and night sweats. This reduction appeared to be significant as early as the second week of treatment. Moreover, Aerodiol remained effective even among highly symptomatic women with more than seven hot flushes per day, and also among smokers. Since it avoids hepatic first-pass metabolism, pulsed estrogen therapy also has a favorable action on the lipid profile, decreasing lipoprotein(a), apolipoprotein B, total cholesterol, and low-density lipoprotein cholesterol. Furthermore, Aerodiol is neutral with regard to clotting factors, angiotensinogen and insulin levels. The effect of pulsed estrogen therapy on bone has been assessed in both the short and the long term. Bone turnover, as measured by markers of resorption and formation, was normalized to premenopausal levels after 3 months of treatment at a dose of 300 microg/day. Aerodiol, again at the dose of 300 microg/day, is as effective as a 50-microg/day transdermal patch in increasing bone mineral density (p < 0.001 versus baseline) at the spine and hip after 56 weeks. Finally, data collected during the development of Aerodiol have shown that pulsed estrogen therapy is at least as effective as 2 mg of oral estrogen or 50 microg of transdermal estrogen in relieving climacteric symptoms and preventing postmenopausal bone loss.

Administration, Cutaneous↗
PubMed2001

BDNF mediates the neuroprotective effect of PACAP-38 on rat cortical neurons.

In primary cultures from rat cerebral cortex, pituitary adenylate cyclase-activating polypeptide (PACAP-38) exerted a protective effect on cell death induced by the excitotoxin NMDA in neuron-enriched cultures and also on apoptotic cell death induced by serum deprivation in mixed neuronal-glial cultures. The neuroprotective effect was already observed at subnanomolar concentrations of PACAP and was slightly more pronounced against excitotoxic cell death. BDNF protein expression was reduced by NMDA and much more markedly by serum deprivation (approximately 28 and 93% reduction respectively). In both cellular injury conditions, the diminished BDNF expression was significantly prevented by PACAP. When purified neuronal cultures were preincubated with an antiserum anti-BDNF, at a concentration without any intrinsic effect on cell viability, the neuprotective effect of PACAP was no longer observed. The results suggest that the neuroprotective effect of PACAP-38 is mediated, at least in part, by preventing the suppressed expression of a neurotrophin essential for cortical neuron survival.

Animals↗
PubMed2001

Tibolone: what does tissue specific activity mean?

Preclinical studies has found that tibolone can display a weak estrogenic, progestational and androgenic activity. The effect produced depends mainly on the target tissue involved. Clinical data indicate that tibolone produces the hormonal effects needed to treat climacteric symptoms and to prevent long-term effects of the menopause without stimulating breast and endometrial tissues. This clinical profile would be produced by the tissue specific activity of tibolone and its main metabolites. Tibolone's tissue specific activity may be explained by the interplay of several mechanisms, such as the metabolic conversion of tibolone to compounds with different biological activity, the classical interaction with the steroid receptor and the specific local metabolism, within the target tissue. Therefore, the tissue response and thus the clinical effect produced by tibolone in a given tissue seem to depend on the predominating mechanisms and interactions present in that tissue.

Anabolic Agents↗
PubMed2001

Ras/MEK but not p38 signaling mediates NT-3-induced neurite extension from spiral ganglion neurons.

Neurotrophin (NT)-3 is expressed in the neuronal target tissue of the developing rat cochlea and has been shown to promote the survival and neurite outgrowth of spiral ganglion (SG) neurons, suggesting a role for this protein during the innervation of the organ of Corti. In other neurons, NT-3 can mediate neuritogenesis and survival via a number of intracellular signal pathways. To date, the intracellular transduction pathways involved in the mediation of NT-3 effects have not been investigated in SG neurons. To determine whether the activities of NT-3 on SG neurons are dependent on the activation of mitogen-activated protein kinase kinases (MEK)/extracellular-signal-regulated kinases (ERK), Ras, and/or p38, SG explants from postnatal-day 4 rats were cultured with NT-3 and increasing concentrations of the MEK inhibitor U0126, the Ras farnesyl-transferase inhibitor (FTI)-277, and the p38 inhibitor SB203580. After fixation and immunocytochemical labeling, neurite growth was evaluated. A dose-dependent decrease of the effects of NT-3 on length and number of processes was observed in the U0126- and FTI-277-treated SG neurons. In contrast, SB203580 had no significant effect on NT-3-mediated stimulation of neurite growth, in terms of either number or length. The results suggest that NT-3 effects on SG neurons are mediated primarily by the Ras/MEK/ERK signaling pathway.

Animals↗
PubMed2000

Distinct reading of different structural determinants modulates the dileucine-mediated transport steps of the lysosomal membrane protein LIMPII and the insulin-sensitive glucose transporter GLUT4.

Leucine-based motifs mediate the sorting of membrane proteins at such cellular sites as the trans-Golgi network, endosomes, and plasma membrane. A Leu paired with a second Leu, Ile, or Met, while itself lacking the ability to mediate transport, is the key structural feature in these motifs. Here we have studied the structural differences between the leucine-based motifs contained in the COOH tails of LIMPII and GLUT4, two membrane proteins that are transported through the secretory pathway and are targeted to lysosomes () and to a perinuclear compartment adjacent to the Golgi complex (), respectively. LIMPII and GLUT4 display negatively (Asp(470)/Glu(471)) and positively (Arg(484)/Arg(485)) charged residues, respectively, at positions -4 and -5 upstream from the critical Leu residue. The change in the charge sign of residues -4 and -5 results in missorting of LIMPII and GLUT4. We note that the acidic Glu residue at position -4 is critical for efficient intracellular sorting of LIMPII to lysosomes, but is dispensable for its surface internalization by endocytosis. Efficient intracellular sorting and endocytosis of GLUT4 require an Arg pair between positions -4 and -7. These results are consistent with the existence of distinct leucine-based motifs and provide evidence of their different readings at different cellular sites.

3T3 Cells↗
PubMed2000

Recycling of the insulin-sensitive glucose transporter GLUT4. Access of surface internalized GLUT4 molecules to the perinuclear storage compartment is mediated by the Phe5-Gln6-Gln7-Ile8 motif.

The insulin-sensitive glucose transporter GLUT4 is translocated to the plasma membrane in response to insulin and recycled back to the intracellular store(s) after removal of the hormone. We have used clonal 3T3-L1 fibroblasts and adipocyte-like cells stably expressing wild-type GLUT4 to characterize (a) the intracellular compartment where the bulk of GLUT4 is intracellularly stored and (b) the mechanisms involved in the recycling of endocytosed GLUT4 to the store compartment. Surface internalized GLUT4 is targeted to a large, flat, fenestrated saccular structure resistant to brefeldin A that localized to the vicinity of the Golgi complex is sealed to endocytosed transferrin (GLUT4 storage compartment). Recycling of endocytosed GLUT4 was studied by comparing the cellular distributions of antibody/biotin tagged GLUT4 and GLUT4(Ser(5)), a mutant with the Phe(5)-Gln(6)-Gln(7)-Ile(8) inactivated by the substitution of Ser for Phe(5). Ablation of the Phe(5)-Gln(6)-Gln(7)-Ile(8) inhibits the recycling of endocytosed GLUT4 to the GLUT4 store compartment and results in its transport to late endosomes/lysosomes where it is rapidly degraded.

3T3 Cells↗
PubMed2000

Clinical equivalence of intranasal and oral 17beta-estradiol for postmenopausal symptoms.

OBJECTIVE: The aim of this study was to demonstrate clinical equivalence between a novel intranasal estradiol formulation and a reference oral drug. STUDY DESIGN: In this multinational, double-blind, parallel-group study 659 postmenopausal women with moderate to severe postmenopausal symptoms were randomly assigned to receive either 300 microg/d intranasal 17beta-estradiol (S21400) or 2 mg/d oral micronized estradiol, plus the appropriate placebo, for 24 weeks. All patients also received 10 mg/d dydrogesterone for 14 days per 28-day cycle. Adjustment of intranasal dosage was permitted from week 14 on. The primary efficacy criterion was the Kupperman index at week 14, with a predefined limit of equivalence of 4. RESULTS: Kupperman index scores improved similarly in the 2 groups, from 28.4 +/- 6.2 to 10.0 +/- 8.6 (mean +/- SD) for S21400 and from 28.1 +/- 6.0 to 8.9 +/- 8.0 for oral therapy, with a difference between groups at week 14 of 1.1 +/- 0.6 (90% confidence interval, 0. 0 to 2.2). This was below the predefined equivalence limit of +4 for statistical noninferiority (P <.001). The daily number and intensity of hot flushes decreased similarly in the two treatment groups. Withdrawal bleeding was 20% less frequent with intranasal therapy (90% confidence interval, 12.5 to 27.6). Severe mastalgia was less frequent in the S21400 group (1.0%) than in the group with oral therapy (5.2%; P <.01). Triglyceride and angiotensinogen levels increased significantly with oral therapy but not with S21400. The same number of patients required dose adaptation in the 2 groups (approximately 20%). CONCLUSION: Intranasal administration of 300 microg/d estradiol was at least as effective as oral administration of 2 mg/d estradiol in alleviating postmenopausal symptoms, with less frequent mastalgia and uterine bleeding and without the metabolic consequences of the first-pass effect.

Administration, Intranasal↗
PubMed2000

prpR, ntrA, and ihf functions are required for expression of the prpBCDE operon, encoding enzymes that catabolize propionate in Salmonella enterica serovar typhimurium LT2.

The genes required for the catabolism of propionate in Salmonella enterica serovar Typhimurium are organized as two transcriptional units (prpR and prpBCDE) that are divergently transcribed from one another. Sequence homology to genes encoding members of the sigma-54 family of transcriptional activators and the identification of a consensus sigma-54 promoter 5' to the prpBCDE operon suggested that PrpR was required to activate expression of this operon. We isolated insertions in prpR and showed that prpR function was needed for growth on propionate as a carbon and energy source. A medium-copy-number plasmid carrying the lacZ gene under the control of the native sigma-54 promoter of prpBCDE was used to study prpBCDE operon expression. Transcription of the lacZ reporter in prpR, ntrA, and ihfB mutants was 85-, 83-, and 15-fold lower than the level of transcription measured in strains carrying the wild-type allele of the gene tested. These data indicated that PrpR, IHF, and transcription sigma factor RpoN were required for the expression of the prpBCDE operon. Further analysis of the involvement of the integration host factor (IHF) protein in the expression of this operon is required due to the well-documented pleiotropic effect the lack of this global regulator has on gene expression. Deletion of the 5' 615-bp portion of the prpR gene resulted in a PrpR(c) mutant protein that activated prpBCDE transcription regardless of the ability of the strain to synthesize 2-methylcitrate, the putative coactivator of PrpR. These results indicate that the N terminus of PrpR is the coactivator-sensing domain of the protein. When placed under the control of the arabinose-inducible promoter P(araBAD), expression of prpR(c) allele by arabinose had a strong negative effect on growth of the cell. It is proposed that this deleterious effect of PrpR(c) may be due to an uncontrolled ATPase activity of PrpR or to cross-activation of genes whose functions negatively affect cell growth under the conditions tested.

Adenosine Triphosphatases↗
PubMed2000

[Improvement in inspiratory muscle function in patients with mitral stenosis after percutaneous mitral valvuloplasty. Preliminary communication].

BACKGROUND: It has been proved that there is an inspiratory muscle dysfunction in mitral stenosis; Although its causes still remain unknown. AIM: To evaluate the effect of percutaneous balloon mitral valvuloplasty (PMV) on inspiratory muscle performance (IMP) in patients with mitral stenosis (mitral area < 1.5 cm2). PATIENTS AND METHODS: We studied IMP in 8 patients (35 +/- 10 years) before and 3 months after successful PMV. Inspiratory muscle strength was studied by measuring maximal statistical inspiratory mouth pressure (MIP). Endurance was evaluated using a two minute incremental threshold loading test in order to obtain the maximal sustainable inspiratory pressure (SIP), with the maximal sustainable load (MSL) the patients could sustain for 2 minutes. RESULTS: Mitral valvuloplasty increased mean cardiac index from 3.1 +/- 0.3 to 4.15 +/- 0.3 l/min/m2 (p < 0.01), and significantly decreased mean pulmonary and capillary pressures. The MIP value(118 +/- 6 cmH2O), similar to that of normal group, increased to 137 +/- 7 cmH2O (p < 0.01). SIP and maximal sustainable load were 52 +/- 3 cmH2O and 294 +/- 29 g respectively, lower than normal subjects (p < 0.05). They increased after PMV to 80 +/- 3 cmH2O and 463 +/- 26 g respectively (p < 0.001). CONCLUSIONS: PMV improved inspiratory muscle function in patients with severe mitral stenosis, probably secondary to a decrease work of breath and improvement of ventricular function.

Case-Control Studies↗
PubMed1999

Current perspectives on the benefits of HRT in menopausal women.

AIMS: Women in the West can now expect to live one third of their life in a postmenopausal state, and consequently in a state of estrogen deficiency. This can have a number of consequences, and many women suffer vasomotor symptoms during the climacteric. Estrogen deficiency can also result in changes to the skin, hair, urogenital, cardiovascular and skeletal systems. This article reviews some of the main actions of replacement estrogen in postmenopausal women, and discusses the major benefits of estrogen replacement therapy (ERT) and hormone replacement therapy (HRT). REVIEW: HRT is well documented to reduce vasomotor symptoms in women suffering from estrogen deficiency, and can have beneficial effects on the skin and the prevention of skin aging. HRT has beneficial effects on urogenitary function including reductions in urinary incontinence and vaginal atrophy. HRT is used as a first-line treatment to prevent or reverse the development of postmenopausal osteoporosis and can reduce the risk of fractures if taken for 5-10 years from the menopause. In epidemiological studies, ERT was associated with a reduction in the risk of coronary heart disease. Estrogens seem to affect the cardiovascular system directly and indirectly such as reducing some of the coronary risk factors. In recent years, estrogen has been linked to beneficial effects in the CNS including an association with a reduction in the risk of developing Alzheimer's Disease. Despite these benefits, HRT compliance remains low, and physicians need to address this if patients are to gain the benefits.

Estrogen Replacement Therapy↗
PubMed1998

The deduced primary structure of a ribosomal protein S4 from Trypanosoma cruzi.

Two cDNA clones encoding a protein homologous to ribosomal protein S4 from the protozoan parasite Trypanosoma cruzi were isolated and characterized. Both clones potentially encode for an identical basic protein of 273 amino acids. Sequence comparisons with other species indicate that this protein is highly conserved. Hybridization studies are consistent with the occurrence of two genes in T. cruzi encoding this ribosomal protein. An RNA of approximately 1 kb was present in both exponentially growing and stationary phase derived epimastigotes, and no significant differences were detected in its steady state concentration.

Amino Acid Sequence↗