RESUMEN
Neutral atoms are a promising platform for scalable quantum computing, however, prior demonstration of high fidelity gates or low-loss readout methods have employed restricted numbers of qubits. Using randomized benchmarking of microwave-driven single-qubit gates, we demonstrate average gate errors of 7(2)×10^{-5} on a 225 site atom array using conventional, destructive readout. We further demonstrate a factor of 1.7 suppression of the primary measurement errors via low-loss, nondestructive, and state-selective readout on 49 sites while achieving gate errors of 2(9)×10^{-4}.
RESUMEN
BACKGROUND: The most common dementia worldwide, Alzheimer's disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aß1-42, and increases in total tau and phosphorylated tau-181. Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer's disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer's disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aß42's toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aß-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A's linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aß42's activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer's disease brain. OBJECTIVES: Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A's altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aß42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4. DESIGN: This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study. SETTING: Five clinical trial sites in the U.S. under an Investigational New Drug application. PARTICIPANTS: This study included 13 mild-to-moderate Alzheimer's disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aß42 ratio ≥0.30. INTERVENTION: PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days. MEASUREMENTS: Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer's disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aß42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1ß and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aß42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition. RESULTS: Consistent with the drug's mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer's disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125. Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aß42's signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aß42 increased slightly - a desirable result because low Aß42 indicates Alzheimer's disease. This increase is consistent with PTI-125's 1,000-fold reduction of Aß42's femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A's conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aß42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1. CONCLUSIONS: PTI-125 significantly reduced biomarkers of Alzheimer's disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Filaminas/metabolismo , Nootrópicos/farmacología , Nootrópicos/uso terapéutico , Compuestos de Espiro/farmacología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Femenino , Humanos , Inflamación/sangre , Inflamación/líquido cefalorraquídeo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/metabolismo , Conformación Proteica/efectos de los fármacos , Compuestos de Espiro/uso terapéutico , Receptor Toll-Like 4/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Proteínas tau/metabolismoRESUMEN
The study objective was to get more information on C. burnetii prevalence in wild birds and ticks feeding on them, and the potentialities of the pathogen dissemination over Europe by both. MATERIALS: Blood, blood sera, feces of wild birds and ticks removed from those birds or from vegetation were studied at two sites in Russia: the Curonian Spit (site KK), and the vicinity of St. Petersburg (site SPb), and at two sites in Bulgaria: the Atanasovsko Lake (site AL), and the vicinity of Sofia (site SR). METHODS: C. burnetii DNA was detected in blood, feces, and ticks by PCR (polymerase chain reaction). All positive results were confirmed by Sanger's sequencing of 16SrRNA gene target fragments. The antibodies to C. burnetii in sera were detected by CFR (complement fixation reaction). RESULTS: Eleven of 55 bird species captured at KK site hosted Ixodes ricinus. C. burnetii DNA was detected in three I. ricinus nymphs removed from one bird (Erithacus rubecula), and in adult ticks flagged from vegetation: 0.7% I. persulcatus (site SPb), 0.9% I. ricinus (site KK), 1.0% D. reticulatus (AL site). C. burnetii DNA was also detected in 1.4% of bird blood samples at SPb site, and in 0.5% of those at AL site. Antibodies to C. burnetii were found in 8.1% of bird sera (site SPb). C. burnetii DNA was revealed in feces of birds: 0.6% at AL site, and 13.7% at SR site. CONCLUSIONS: Both molecular-genetic and immunological methods were applied to confirm the role of birds as a natural reservoir of C. burnetii. The places of wild bird stopover in Russia (Baltic region) and in Bulgaria (Atanasovsko Lake and Sofia region) proved to be natural foci of C. burnetii infection. Migratory birds are likely to act as efficient "vehicles" in dispersal of C. burnetii -infested ixodid ticks.
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Animales Salvajes/microbiología , Enfermedades de las Aves/epidemiología , Aves/microbiología , Coxiella burnetii/aislamiento & purificación , Ixodes/microbiología , Fiebre Q/veterinaria , Migración Animal , Animales , Anticuerpos Antibacterianos/sangre , Países Bálticos/epidemiología , Enfermedades de las Aves/microbiología , Bulgaria/epidemiología , Coxiella burnetii/genética , ADN Bacteriano/aislamiento & purificación , Reservorios de Enfermedades/microbiología , Reservorios de Enfermedades/veterinaria , Europa (Continente)/epidemiología , Heces/microbiología , Secuenciación de Nucleótidos de Alto Rendimiento , Ninfa/microbiología , Reacción en Cadena de la Polimerasa , Prevalencia , Fiebre Q/epidemiología , ARN Ribosómico 16S/aislamiento & purificación , Federación de Rusia/epidemiología , Infestaciones por Garrapatas/epidemiología , Infestaciones por Garrapatas/microbiologíaRESUMEN
BACKGROUND: Most of the current scores and outcome prediction calculations in traumatology are based on the Abbreviated Injury Scale (AIS). However, this is not routinely used for documentation and coding of injuries in many countries, including Germany. Instead of the AIS, the International Classification of Diseases (ICD) is used. While the ICD functions as the basis for automated calculating of the diagnosis-related groups (DRG), no possibility of simple conversion of the 10th version of the ICD into AIS is available so far. OBJECTIVES: The aim of this work is to develop and apply a methodology for simple conversion from ICD 10 to current AIS. MATERIALS AND METHODS: The developed mapping procedure was based on a 1â:ân relationship between trauma codes of ICD-10-GM and the codes of the AIS2005. Calculated ISS from the conversion codes were then compared with the actual ISS coding available from the clinical trauma documentation. RESULTS: It can be shown that, despite the considerable differences in the structure and systematic of both classification systems, an automated translation is technically possible. CONCLUSIONS: The preliminary result of the mapping suggests, however, that despite the technical feasibility of a reliable conversion and comparability of ICD 10 and AIS in the required quality is still questionable. An automated conversion is still possible and quality would possibly improve by inclusion of additional information.
Asunto(s)
Control de Formularios y Registros/métodos , Almacenamiento y Recuperación de la Información/métodos , Clasificación Internacional de Enfermedades , Procesamiento de Lenguaje Natural , Reconocimiento de Normas Patrones Automatizadas/métodos , Índices de Gravedad del Trauma , AlgoritmosRESUMEN
OBJECTIVE: To clarify the relationship between fractures and antiepileptic drug (AED) use. METHODS: Menopausal women with epilepsy were interviewed at two clinics regarding site, year and circumstances of any fracture, duration of AED use and menopause. Fracture sites were analyzed according to AED use. RESULTS: Twenty-nine fractures occurred in 20 of the 50 interviewed subjects (mean age 54). Nine occurred prior to AEDs; seven attributed to accident and two to clumsiness. Twenty occurred on AEDs; 10 attributed to clumsiness (most in the leg and foot), eight to seizure (most in the arm or hand) and two to accident. Duration of AED exposure was similar in both groups and in osteoporotic vs non-osteoporotic sites. CONCLUSIONS: Epilepsy therapy may contribute more to the lifetime occurrence of fracture than seizures themselves. More screening for osteoporosis is required. While adjusting doses to prevent seizures, ongoing screening for neurotoxicity must be maintained in order to avoid fractures.
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Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Fracturas Óseas/epidemiología , Fracturas Óseas/etiología , Adulto , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Osteoporosis/inducido químicamente , Osteoporosis/complicaciones , Estudios Prospectivos , Factores de Riesgo , Convulsiones/complicacionesRESUMEN
OBJECTIVE: To clarify the in vitro effects of inhibin A (I) on apoptotic cell death and its mechanisms in ovarian granulosa cells the immunoexpression patterns of the apoptosis markers caspase-3 and pro- and anti-apoptotic proteins (Bcl-2, Bcl-xl, Bak) were evaluated in ovarian granulosa cells collected from women with different hormonal status. MATERIALS AND METHODS: Granulosa cells were isolated from follicles of women participating in an in vitro fertilization (IVF) program, normally cyclic (NC) and premenopausal women (PrM). The obtained cells were cultured for 72 h with inhibin A (Sigma, USA)--10 ng/ml. The concentration of estradiol in the culture medium was determined by radioimmunoassay using the Coat-A-Count kit (Nippon, Japan), whose intra- and interassay coefficients of variations were 6,8% and 6,2% respectively. The expression of caspase-3, Bak, Bcl-2, Bcl-xl was investigated immunohistochemically. The percentages of immunopositive cells were calculated and Student's t-test was used for statistical analysis. RESULTS: Addition of inhibin A (10 ng/ml) to granulosa cells cultures resulted in increased estradiol production. Maximal stimulation was observed in granulosa cells collected from women participating in IVF whereas minimal effect of inhibin treatment on estradiol production was demonstrated in premenopausal women. Inhibin A exposition enhanced the immunoexpression of prooncogenes (Bcl-2, Bcl-xl) and reduced the expression of caspase-3 and pro-apoptotic protein Bak in ovarian granulosa cells from the three experimental groups. CONCLUSIONS: Our findings suggest that inhibin A in vitro stimulates the estradiol secretion by granulosa cells dependently of the woman hormonal status, while it inhibits apoptotic process in granulosa cells independently of the hormonal status.
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Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Células de la Granulosa/efectos de los fármacos , Inhibinas/farmacología , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Adulto , Caspasa 3 , Células Cultivadas , Estradiol/metabolismo , Femenino , Células de la Granulosa/metabolismo , Humanos , Inmunohistoquímica , Radioinmunoensayo , Proteína Destructora del Antagonista Homólogo bcl-2 , Proteína bcl-XAsunto(s)
Endometriosis/cirugía , Terapia de Reemplazo de Estrógeno , Enfermedades del Ovario/cirugía , Enfermedades Peritoneales/cirugía , Enfermedades Uterinas/cirugía , Endometriosis/metabolismo , Endometriosis/prevención & control , Femenino , Estudios de Seguimiento , Humanos , Histerectomía , Laparoscopía , Enfermedades del Ovario/metabolismo , Enfermedades del Ovario/prevención & control , Enfermedades Peritoneales/metabolismo , Enfermedades Peritoneales/prevención & control , Recurrencia , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/prevención & controlRESUMEN
The present study was undertaken to investigate the possible involvement of prostanoids in the inhibitory effect of endothelin-1 (ET-1) on progesterone production of ovarian granulosa cells. ET-1 (1 x 10(-7) M) decreased the basal and follicle-stimulating hormone- (FSH) stimulated progesterone production from both human and porcine granulosa cells. Indomethacin dose-dependently inhibited progesterone release, but did not alter the inhibitory effect of ET-1 (1 x 10(-7) M) on progesterone production of cultured ovarian granulosa cells. This study shows that ET-1 suppresses basal and FSH-stimulated progesterone production by ovarian granulosa cells, but this effect is not mediated by prostanoids.
Asunto(s)
Endotelina-1/metabolismo , Células de la Granulosa/metabolismo , Progesterona/biosíntesis , Prostaglandinas/metabolismo , Animales , Células Cultivadas , Endotelina-1/farmacología , Femenino , Células de la Granulosa/efectos de los fármacos , Humanos , Prostaglandinas/farmacología , PorcinosRESUMEN
OBJECTIVE: To determine whether the age at menopause in women with epilepsy is associated with seizure frequency. METHODS: Women with epilepsy ages 45 and older from urban epilepsy centers were surveyed by interview and chart review for reproductive and general health characteristics, as well as seizure history, including frequency and treatment. Women who were not menopausal (> or = 1 year since last menses) were excluded. Subjects were divided into low, high, and intermediate seizure frequency groups. Statistical analyses included a one-way analysis of variance along with post hoc analysis (Bonferroni approach) to calculate pairwise comparisons. RESULTS: Sixty-eight subjects had a mean age at last menses (menopause) of 47.8 years (SD +/- 4.1, range 37 to 59 years). The age at menopause was 49.9 years in the low seizure frequency group (n = 15), 47.7 years in the intermediate seizure frequency group (n = 25), and 46.7 in the high seizure frequency group (n = 28). The difference in age at menopause in the three groups spanned approximately 3 years (p = 0.042). There was a negative correlation between the age at menopause and seizure group based on estimated lifetime seizures (p = 0.014, r = -0.310). No confounding influences such as history of cigarette smoking, number of pregnancies, or use of enzyme-inducing antiepileptic drugs were present. CONCLUSIONS: Seizure frequency or lifetime number of seizures is associated with the timing of cessation of reproductive cycling. Seizures may disrupt hypothalamic and pituitary function or alter neurally mediated trophic effects on the ovary.
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Epilepsia/epidemiología , Menopausia , Adulto , Factores de Edad , Edad de Inicio , Anciano , Epilepsia/fisiopatología , Femenino , Gonadotropinas Hipofisarias/metabolismo , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Persona de Mediana Edad , Ovario/fisiopatología , Historia ReproductivaRESUMEN
EDS alkylating agent has been shown to selectively and temporarily kill LCs in adult rats. The first newly formed single LCs appeared at 14th day post ESD and showed detectable activity for 3beta-HSD and NADH2-diaphorase, which became progressively stronger with time after treatment The ultrastructural study revealed that the progenitor LCs differentiated into immature LCs within a week, and two weeks later they were transformed into mature LCs. Therefore, the restoration of new LC population after EDS treatment repeated the dynamics of normal LC development within a similar time range. The dynamics of enzyme activity correlated with structural differentiation of the new LC population.
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Diferenciación Celular/efectos de los fármacos , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/enzimología , Mesilatos/farmacología , 3-Hidroxiesteroide Deshidrogenasas/efectos de los fármacos , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Dihidrolipoamida Deshidrogenasa/efectos de los fármacos , Dihidrolipoamida Deshidrogenasa/metabolismo , Células Intersticiales del Testículo/patología , Masculino , Ratas , Ratas Wistar , Esteroides/biosíntesisRESUMEN
OBJECTIVE: Nitric oxide (NO) is involved in different cell functions including ovarian steroid production. Endothelin-1 (ET-1) was found to regulate the steroidogenesis in ovarian granulosa cells (GC). The present study was designed to receive more information about the mechanism of action of NO in the process of ET-1 induced progesterone (P) inhibition, using nicotine amide dinucleotide phosphate-diaphorase (NADPH-d) histochemistry as a cofactor of oxidoreductase enzymes (e. g. nitric oxide). METHODS: Granulosa cells were isolated from ovaries of: 1. young women with natural cycle or after in vitro fertilization (IVF), 2. premenopausal women. The obtained cells were cultured with endothelin-1 and the concentration of progesterone in conditioned media was determined by RIA. For the estimation of NADPH-d the histochemical reaction was used. RESULTS: The suppressive effect of ET-1 on P production in granulosa cells was more pronounced in young women with natural cycles, slightly weaker after IVF and the most ineffective in premenopausal patients. The number of NADPH-d positive GCs was higher in young non-hormonally stimulated women, slightly lower after IVF and small in premenopausal ones. CONCLUSIONS: The results indicate the possible role of NADPH-d or NOS in the mechanism of ET-1 provoked P suppression.
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Endotelina-1/farmacología , Células de la Granulosa/fisiología , Óxido Nítrico/fisiología , Progesterona/metabolismo , Adulto , Células Cultivadas , Medios de Cultivo Condicionados , Femenino , Fertilización In Vitro , Células de la Granulosa/enzimología , Histocitoquímica , Humanos , NADPH Deshidrogenasa/análisis , PremenopausiaRESUMEN
Cell type of mammalian testis which is involved in the synthesis and secretion of testosterone and the maintenance of spermatogenesis are the fully differentiated interstitial Leydig cells (LC). Their ultrastructure possesses the typical characteristics of steroid-producing cells. It has been generally accepted that two waves of proliferation and differentiation can be discerned during the development of the Leydig cell population in the rodent and human testis. Treatment with ethane dimethane sulphonate (EDS) destroys selectively LC. A new LC population develops in the following weeks and this model has been used by us to study the proliferation and differentiation of new LC. Our results support the suggestion that the regeneration of a new LC population following EDS administration shows many similarities with the formation of the adult type LC in the prepubertal mammalian testis.
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Antineoplásicos Alquilantes , Células Intersticiales del Testículo/citología , Mesilatos , Regeneración , Testículo/citología , Animales , Diferenciación Celular , División Celular , Células Intersticiales del Testículo/fisiología , Células Intersticiales del Testículo/ultraestructura , Masculino , Microscopía Electrónica , Ratas , Ratas Wistar , Testículo/ultraestructuraRESUMEN
OBJECTIVE: To investigate degeneration and restoration patterns of spermatogenesis in relation to the changes in Leydig cells (LCs) after treatment with ethane dimethanesulfonate (EDS). MATERIALS AND METHODS: Adult Wistar male rats were treated with EDS at a dose 75 mg/kg body weight and the testes were sampled at 7, 14, 21, 35 and 49 days after treatment for histological and ultrastructural studies. RESULTS: During the first two weeks after treatment stage dependent loss of germ cells was found within seminiferous tubules that led to a profound disturbance of spermatogenesis. The restoration of seminiferous epithelium followed also in stage specific manner and in relation to development of a new LC population (third week). The development of new LCs after EDS treatment repeats the normal dynamics of postnatal LC development within a similar time range. CONCLUSION: EDS treatment of rats causes a temporary germ cell degeneration in the testis. The kinetics of disappearance of germ cells and their regeneration broadly follows the changes in LC population.
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Células Intersticiales del Testículo/efectos de los fármacos , Mesilatos/farmacología , Espermatogénesis/efectos de los fármacos , Animales , Recuento de Células , Hormona Folículo Estimulante/metabolismo , Cinética , Hormona Luteinizante/metabolismo , Masculino , Microscopía Electrónica , Hipófisis/metabolismo , Ratas , Ratas Wistar , Epitelio Seminífero/citología , Epitelio Seminífero/efectos de los fármacos , Testículo/metabolismo , Testosterona/sangre , Testosterona/metabolismoRESUMEN
OBJECTIVE: To investigate the in vitro effect of endothelin-1 (ET-1) on the steroid production (progesterone [P] and estradiol [E2]) by cultured human granulosa cells (GCs) during aging. MATERIAL AND METHODS: Human ovarian GCs and granulosa-luteal cells (GLCs) were isolated from ovaries of female patients (young and premenopausal) undergoing surgery for non-ovarian benign gynecological conditions. Cells were cultured with ET-1 in the presence or in the absence of FSH. The concentrations of P and E2 in conditioned media were determined by means of RIA. RESULTS: In human GCs and GLCs obtained from young and premenopausal women, ET-1 in vitro can significantly reduce the FSH stimulated biosynthesis of P, whereas the basal P biosynthesis is only insignificantly diminished. The in vitro application of ET-1 have only a sparse inhibitory effect on both the basal and FSH stimulated biosynthesis of E2 in GCs from the two patient groups. CONCLUSIONS: Our findings support the opinion that ET-1 is a local regulator of ovarian steroidogenesis which might modulate the steroid production and the stimulatory effect of FSH in cultured GCs and GLCs obtained from women at various ages.
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Envejecimiento/fisiología , Endotelina-1/farmacología , Estradiol/biosíntesis , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Progesterona/biosíntesis , Adulto , Femenino , Hormona Folículo Estimulante/farmacología , Humanos , Células Lúteas/metabolismo , Persona de Mediana Edad , PremenopausiaRESUMEN
PURPOSE: Antiepileptic drugs (AEDs) are frequently used for their beneficial psychoactive effects on affective disorders. We sought to demonstrate a psychoactive effect of gabapentin (GBP) when used as add-on AED therapy. METHODS: Forty adult patients with partial epilepsy were studied in a prospective, non-randomized fashion with interviewer-rated and self-rated scales of mood and anxiety: the Cornell Dysthymia Rating Scale (CDRS), Beck Depression Inventory (BDI), and Hamilton Depression (Ham-D) and Anxiety (Ham-A) Scales. After completion of baseline mood and anxiety scales (time 1), 20 of the 40 patients were prescribed add-on GBP (treated group). The remaining 20 patients served as a control group. Both groups were similar in age and sex distribution. Follow-up mood and anxiety scales were performed in all patients approximately 3 months later (time 2). The average GBP dose at time 2 was 1,615 mg/day. All patients were taking stable doses of one to four AEDs at baseline and throughout the study. Seizure frequency was monitored throughout. Statistical significance was assessed by analysis of variance (ANOVA) by using a two-factor repeated-measures model. RESULTS: The GBP-treated group had a significant decrease in CDRS score over time compared with the control group (p = 0.04). No significant differences between the control and the treated groups were found for any of the remaining mood scales (BDI, p = 0.58; Ham-D, p = 0.59; Ham-A, p = 0.93). There was no significant difference or change in seizure frequency between groups. CONCLUSIONS: GBP treatment is associated with mood improvement as measured by the CDRS. This improvement was not accounted for by seizure improvement.
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Acetatos/uso terapéutico , Afecto/efectos de los fármacos , Aminas , Anticonvulsivantes/uso terapéutico , Ácidos Ciclohexanocarboxílicos , Trastorno Depresivo/psicología , Epilepsias Parciales/tratamiento farmacológico , Ácido gamma-Aminobutírico , Acetatos/farmacología , Adulto , Anciano , Anticonvulsivantes/farmacología , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/psicología , Comorbilidad , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/epidemiología , Quimioterapia Combinada , Epilepsias Parciales/epidemiología , Epilepsias Parciales/psicología , Femenino , Gabapentina , Humanos , Masculino , Persona de Mediana Edad , Inventario de Personalidad/estadística & datos numéricos , Estudios Prospectivos , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Resultado del TratamientoRESUMEN
OBJECTIVE: To extend our previous observations of granulosa cell conditioned medium inhibition on basal and FSH-stimulated progesterone secretion by granulosa cells from large porcine antral follicles. METHODS: Granulosa cell conditioned media (SGCCM) were obtained from cultures of granulosa cells which were harvested from small porcine antral follicles. SGCCM were fractionated by filtration through an Amicon XM-50 and an PM-10 membrane. RESULTS: Two fractions - XM-50 filtrate (<50 kDa) and PM-10 retentate (10-50 kDa) - exhibited well expressed inhibitory effect on the progesterone secretion from large follicle granulosa cells in vitro. Such inhibitory effect was fully prevented by heat treatment, partially inactivated by trypsin digestion (P<0.05), but was resistant to several freeze-thaw cycles and storage at -20 or -70 degrees C for up to one year. CONCLUSIONS: It is suggested that SGCCM contains some regulatory substance(s) capable of inhibiting progesterone secretion by cultured granulosa cells and that the molecular weight of such substance is presumably between 10-50 kDa.
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Células de la Granulosa/metabolismo , Progesterona/metabolismo , Animales , Células Cultivadas , Medios de Cultivo Condicionados , Femenino , Tasa de Secreción , PorcinosRESUMEN
OBJECTIVE: To localize (by the light and electron microscopy) and partially characterize the antigen recognized by the Mab4E6 in rat ovaries. METHODS: Monoclonal antibody (4E6) against a rat ovarian granulosa cell antigen was prepared and identified the 40kDa protein specific for rat steroid producing cells. The localization of this antigen was studied by light and electron microscopic immunocytochemistry. RESULTS: The immunocytochemical observation suggested that the recognized antigen was localized in granulosa and thecal cells in all stages of follicular development. The intensity of immunostaining was found to depend on the developmental stage. In granulosa and thecal stage (health follicle) Mab 4E6 binding molecule was localized on the membranes of rough endoplasmic reticulum (RER) and on the surface of lipid droplets in close association with the RER. In atretic follicles we established that the final destination of the visualized antigen is in structures which we refer as the autophagic vacuoles in close contact with the steroidogenic organelles. In addition, we observed Mab 4E6 binding molecule in the cytoplasm of luteal cells. Leydig cells and adrenocortical cells. CONCLUSIONS: The results indicate that the 40kDa antigen may be common to all of rat steroidogenic organs. Our results suggest that the 40kDa protein may be associated with the processes governing steroidogenesis and/or follicular development.
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Anticuerpos Monoclonales , Células de la Granulosa/inmunología , Proteínas/análisis , Esteroides/biosíntesis , Corteza Suprarrenal/química , Animales , Antígenos/inmunología , Células Cultivadas , Citoplasma/química , Retículo Endoplásmico Rugoso/química , Femenino , Células de la Granulosa/química , Células de la Granulosa/ultraestructura , Células Intersticiales del Testículo/química , Células Lúteas/ultraestructura , Masculino , Ratones , Ratones Endogámicos BALB C , Peso Molecular , Folículo Ovárico/fisiología , Proteínas/química , Ratas , Células Tecales/química , Células Tecales/ultraestructuraRESUMEN
PURPOSE: Patients with symptomatic generalized epilepsy (SGE) may have antiepileptic drug (AED)-resistant mixed generalized seizures. Vagus nerve stimulation (VNS) reduces partial seizures and may help SGE. METHODS: We added VNS to stable AED therapy in five SGE patients. Nine-month postoperative VNS treatment seizure rates were compared to a 1-month preoperative baseline. RESULTS: All patients had mixed generalized seizures, EEG generalized slow spike-and-wave and behavioral abnormalities. Median number of previous AEDs taken was 6 (range 5-12). Median baseline seizure rate was 75/month (range 29-110). VNS produced a median seizure rate production of -41% (range -40% - -85%). Adverse events reported in one patient each were: incisional infection, choking sensation and voice change; and coughing (noted by two patients). One patient discontinued VNS due to coughing. CONCLUSIONS: We conclude that VNS may be useful add-on therapy for SGE. A larger, controlled, and blinded trial may be warranted.
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Terapia por Estimulación Eléctrica/métodos , Epilepsia Generalizada/terapia , Nervio Vago/fisiología , Adulto , Anticonvulsivantes/uso terapéutico , Terapia Combinada , Estimulación Eléctrica , Terapia por Estimulación Eléctrica/efectos adversos , Electroencefalografía , Epilepsia Generalizada/tratamiento farmacológico , Femenino , Humanos , Masculino , Proyectos Piloto , Resultado del TratamientoRESUMEN
Morphometrical and cytochemical techniques have been applied to characterize the islets of Langerhans tissue in lean and obese Zucker fa/fa and Wistar rats. The changes in cytologic composition correlated with levels of serum glucose and lipids in obese rats and progressed significantly with increasing body weight. Histochemical and enzyme abnormalities observed in Zucker fa/fa and Wistar rats reflect the degenerative and reactive processes in the pancreas: a decrease in Krebs cycle and pentose pathway and increased lysosomal acid phosphatase reflect the degeneration of the islets. Changes consisted of pronounced insulin cell hyperplasia and disruption of islet architecture. The raised functional activity in the islet B-cells of the Zucker fa/fa and Wistar rats was reflected in enlargement and fragmentation of the Golgi apparatus. An increased proportion of light granules is associated with increased insulin secretion, which reinforces the idea that light granules are responsible for immediate insulin secretion, whereas the dark granules represent the insulin stored in the cell for a longer period The islets of Langerhans of the Zucker fa/fa and Wistar rats show marked differences in morphological, histochemical and morphometrical characteristics when compared with littermates. There is a marked difference in insulin secretion between the obese Zucker fa/fa and Wistar rats and its non-obese littermate. These differences may be related to the development with obesity of aging and genetically-conditioned animals.