RESUMEN
Cancer stem cells (CSCs) are a subpopulation of cancer cells within tumors that exhibit stem-like properties and represent a potentially effective therapeutic target toward long-term remission by means of differentiation induction. By leveraging an artificial intelligence approach solely based on transcriptomics data, this study scored a large library of small molecules based on their predicted ability to induce differentiation in stem-like cells. In particular, a deep neural network model was trained using publicly available single-cell RNA-Seq data obtained from untreated human-induced pluripotent stem cells at various differentiation stages and subsequently utilized to screen drug-induced gene expression profiles from the Library of Integrated Network-based Cellular Signatures (LINCS) database. The challenge of adapting such different data domains was tackled by devising an adversarial learning approach that was able to effectively identify and remove domain-specific bias during the training phase. Experimental validation in MDA-MB-231 and MCF7 cells demonstrated the efficacy of five out of six tested molecules among those scored highest by the model. In particular, the efficacy of triptolide, OTS-167, quinacrine, granisetron and A-443654 offer a potential avenue for targeted therapies against breast CSCs.
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Neoplasias de la Mama , Diferenciación Celular , Células Madre Neoplásicas , Humanos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Femenino , Inteligencia Artificial , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células MCF-7 , Línea Celular Tumoral , Redes Neurales de la Computación , Perfilación de la Expresión GénicaRESUMEN
AIMS/HYPOTHESIS: Numerous clinical studies have investigated the anti-CD3É monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose-response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes. METHODS: In this randomised, single-blind, placebo-controlled, 24 month study, conducted in five centres in Belgium via the Belgian Diabetes Registry, participants (16-27 years old, <32 days from diagnosis of type 1 diabetes) were scheduled to receive placebo or otelixizumab in one of four dose cohorts (cumulative i.v. dose 9, 18, 27 or 36 mg over 6 days; planned n = 40). Randomisation to treatment was by a central computer system; only participants and bedside study personnel were blinded to study treatment. The co-primary endpoints were the incidence of adverse events, the rate of Epstein-Barr virus (EBV) reactivation, and laboratory measures and vital signs. A mixed-meal tolerance test was used to assess beta cell function; exploratory biomarkers were used to measure T cell responses. RESULTS: Thirty participants were randomised/28 were analysed (placebo, n = 6/5; otelixizumab 9 mg, n = 9/8; otelixizumab 18 mg, n = 8/8; otelixizumab 27 mg, n = 7/7; otelixizumab 36 mg, n = 0). Dosing was stopped at otelixizumab 27 mg as the predefined EBV reactivation stopping criteria were met. Adverse event frequency and severity were dose dependent; all participants on otelixizumab experienced at least one adverse event related to cytokine release syndrome during the dosing period. EBV reactivation (otelixizumab 9 mg, n = 2/9; 18 mg, n = 4/8: 27 mg, n = 5/7) and clinical manifestations (otelixizumab 9 mg, n = 0/9; 18 mg, n = 1/8; 27 mg, n = 3/7) were rapid, dose dependent and transient, and were associated with increased productive T cell clonality that diminished over time. Change from baseline mixed-meal tolerance test C-peptide weighted mean AUC0-120 min following otelixizumab 9 mg was above baseline for up to 18 months (difference from placebo 0.39 [95% CI 0.06, 0.72]; p = 0.023); no beta cell function preservation was observed at otelixizumab 18 and 27 mg. CONCLUSIONS/INTERPRETATION: A metabolic response was observed with otelixizumab 9 mg, while doses higher than 18 mg increased the risk of unwanted clinical EBV reactivation. Although otelixizumab can temporarily compromise immunocompetence, allowing EBV to reactivate, the effect is dose dependent and transient, as evidenced by a rapid emergence of EBV-specific T cells preceding long-term control over EBV reactivation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02000817. FUNDING: The study was funded by GlaxoSmithKline. Graphical abstract.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Adolescente , Adulto , Péptido C/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Infecciones por Virus de Epstein-Barr/inducido químicamente , Femenino , Humanos , Infección Latente/inducido químicamente , Masculino , Método Simple Ciego , Adulto JovenRESUMEN
AIMS: This paper describes the pharmacological findings from a study where otelixizumab, an anti-CD3É mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3É mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3É target engagement and downmodulation. METHODS: Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of otelixizumab PK, CD3É target engagement and its pharmacodynamic effect (CD3ε/TCR modulation on circulating T lymphocytes). RESULTS: Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3É target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3É/TCR downmodulation by Day 6. CONCLUSIONS: Data from this study revealed maximum target engagement and CD3É/TCR modulation is achieved at doses of 18, 27 mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3É mAbs.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Complejo CD3/antagonistas & inhibidores , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/efectos de los fármacos , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/farmacocinética , Complejo CD3/inmunología , Complejo CD3/metabolismo , Diabetes Mellitus Tipo 1/inmunología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Masculino , Terapia Molecular Dirigida/métodos , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
Polycystic ovary syndrome is characterized by several endocrine impairments, insulin resistance and hyperinsulinemia. We aimed to evaluate the effects of myo-inositol (MYO), alpha-lipoic acid (ALA) and a combination of both. Setting: retrospective study. Ninety overweight/obese patients were considered. Presence or absence of first grade diabetic relatives was checked. Patients were administered MYO (1 g/die per os), ALA (400 mg/die per os), MYO (1 gr/die) + ALA (400 mg/die) per os. Only 76 out of 90 patients completed the 12 weeks of treatment. Patients were evaluated before and after the treatment interval for LH, FSH, E2 (estradiol), A (androstenedione), T (testosterone) plasma levels, oral glucose tolerance test (OGTT). All treatments demonstrated specific positive effects: MYO modulated more hormonal profiles and OGTT in polycystic ovary syndrome (PCOS) with no familial diabetes, ALA improved insulin response to OGTT and metabolic parameters in all patients with no effects on reproductive hormones, MYO + ALA improved hormonal and metabolic aspects and insulin response to OGTT in all patients. Presence of familial diabetes is a relevant clinical aspect. MYO is less effective when familial diabetes is present, ALA improved only metabolic aspects while MYO + ALA was effective on all PCOS patients independently from familial diabetes.
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Inositol/uso terapéutico , Insulina/metabolismo , Obesidad/metabolismo , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Ácido Tióctico/uso terapéutico , Complejo Vitamínico B/uso terapéutico , Adulto , Androstenodiona/metabolismo , Quimioterapia Combinada , Estradiol/metabolismo , Femenino , Hormona Folículo Estimulante/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Hormona Luteinizante/metabolismo , Obesidad/complicaciones , Sobrepeso/metabolismo , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/metabolismo , Estudios Retrospectivos , Testosterona/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: A systematic review was carried out of studies of women with endometriosis, to examine the evidence for efficacy of the use of hormonal contraception to improve disease-related pain and decrease postoperative risk of disease recurrence. METHODS: A search of the Medline/PubMed and Embase databases was performed to identify all published English language studies on hormonal contraceptive therapies (combined hormonal contraceptives [CHCs], combined oral contraceptives [COCs], progestin-only pills [POPs] and progestin-only contraceptives [POCs]) in women with a validated endometriosis diagnosis, in comparison with placebo, comparator therapies or other hormonal therapies. Main outcome measures were endometriosis-related pain (dysmenorrhoea, pelvic pain and dyspareunia), quality of life (QoL) and postoperative rate of disease recurrence during treatment. RESULTS: CHC and POC treatments were associated with clinically significant reductions in dysmenorrhoea, often accompanied by reductions in non-cyclical pelvic pain and dyspareunia and an improvement in QoL. Only two COC preparations (ethinylestradiol [EE]/norethisterone acetate [NETA] and a flexible EE/drospirenone regimen) demonstrated significantly increased efficacy compared with placebo. Only three studies found that the postoperative use of COCs (EE/NETA, EE/desogestrel and EE/gestodene) reduced the risk of disease recurrence. There was no evidence that POCs reduced the risk of disease recurrence. CONCLUSIONS: CHCs and POCs are effective for the relief of endometriosis-related dysmenorrhoea, pelvic pain and dyspareunia, and improve QoL. Some COCs decreased the risk of disease recurrence after conservative surgery, but POCs did not. There is insufficient evidence, however, to reach definitive conclusions about the overall superiority of any particular hormonal contraceptive.
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Anticoncepción/métodos , Anticonceptivos Orales Combinados/uso terapéutico , Anticonceptivos Hormonales Orales/uso terapéutico , Endometriosis/tratamiento farmacológico , Dolor Pélvico/tratamiento farmacológico , Adulto , Androstenos/uso terapéutico , Desogestrel/uso terapéutico , Combinación de Medicamentos , Endometriosis/complicaciones , Etinilestradiol/uso terapéutico , Femenino , Humanos , Noretindrona/uso terapéutico , Dolor Pélvico/etiología , Progestinas/uso terapéutico , Resultado del TratamientoRESUMEN
Acylcarnitines, fatty acid oxidation (FAO) intermediates, have been implicated in diet-induced insulin resistance and type 2 diabetes mellitus, as increased levels are found in obese insulin resistant humans. Moreover plasma acylcarnitines have been associated with clinical parameters related to glucose metabolism, such as fasting glucose levels and HbA1c. We hypothesized that plasma acylcarnitines would correlate with energy expenditure, insulin sensitivity and other clinical parameters before and during a weight loss intervention. We measured plasma acylcarnitines in 60 obese subjects before and after a 12 week weight loss intervention. These samples originated from three different interventions (diet alone (n = 20); diet and exercise (n = 21); diet and drug treatment (n = 19)). Acylcarnitine profiles were analysed in relation to clinical parameters of glucose metabolism, insulin sensitivity and energy expenditure. Conclusions were drawn from all 60 subjects together. Despite amelioration of HOMA-IR, plasma acylcarnitines levels increased during weight loss. HOMA-IR, energy expenditure and respiratory exchange ratio were not related to plasma acylcarnitines. However non-esterified fatty acids correlated strongly with several acylcarnitines at baseline and during the weight loss intervention (p < 0.001). Acylcarnitines did not correlate with clinical parameters of glucose metabolism during weight loss, questioning their role in insulin resistance and type 2 diabetes mellitus.
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Carnitina/análogos & derivados , Diabetes Mellitus Tipo 2/sangre , Obesidad/sangre , Pérdida de Peso , Adulto , Antropometría , Composición Corporal , Carnitina/sangre , Ácidos Grasos/química , Ácidos Grasos no Esterificados/sangre , Femenino , Glucosa/química , Humanos , Resistencia a la Insulina , Lipólisis , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Oxígeno/química , Respiración , Adulto JovenRESUMEN
OBJECTIVE: The effect on body composition and in particular on fat mass (FM) of 12 months' use of a desogestrel (DSG)-only contraceptive pill or the levonorgestrel-releasing intrauterine system (LNG-IUS) was evaluated in women in the perimenopause. METHODS: An observational study comprised 102 perimenopausal women: 42 received a 75 µg DSG pill, 34 received the 52 mg LNG-IUS, and 26 received no treatment. Body composition, body weight and resting metabolic rate (RMR) were evaluated at baseline and again after 12 months. RESULTS: FM did not change in the control group (- 0.5 ± 1.6%) but significantly increased in the LNG-IUS group (+ 1.1 ± 2.9%; p = 0.02 vs. controls) and in the DSG group (+ 2.8 ± 3.5%; p = 0.0001 vs. controls; p = 0.02 vs. LNG-IUS). Women treated with DSG or the LNG-IUS showed a non-significant increase in body weight, body mass index and waist circumference. RMR did not significantly vary in the control group (- 3.8 ± 292.9 kJ/ 24 h) and tended to decrease but not significantly in the LNG-IUS (115.5 ± 531.8 kJ/ 24 h) and DSG groups (305.9 ± 556.9 kJ/24 h). CONCLUSIONS: The results of this preliminary study seem to indicate that in perimenopausal women continuous use of the DSG-only pill and to a lesser extent the LNG-IUS may favour FM accumulation.
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Tejido Adiposo/efectos de los fármacos , Metabolismo Basal/efectos de los fármacos , Composición Corporal/efectos de los fármacos , Anticonceptivos Femeninos/farmacología , Desogestrel/farmacología , Dispositivos Intrauterinos , Levonorgestrel/farmacología , Perimenopausia , Progestinas/farmacología , Calorimetría Indirecta , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana EdadRESUMEN
OBJECTIVE: To study the three cycles effect on primary dysmenorrhea of the monophasic 24/4 estradiol/nomegestrol acetate (E2/NOMAC) and of the 21/7 ethinyl-estradiol/chlormadinone acetate (EE/CMA) oral contraceptive. The tolerability and the effect of both preparations on metabolism and health-related quality of life were also evaluated. DESIGN: Prospective observational cohort study. SETTING: Tertiary gynecologic center for pelvic pain. PATIENTS: Subjects with primary dysmenorrhea requiring an oral contraceptive, who spontaneously selected either E2/NOMAC (n = 20) or EE/CMA (n = 20). MAIN OUTCOME MEASURES: Visual Analogue Scale (VAS) score for dysmenorrhea, Short Form-36 questionnaire for health-related quality of life, lipoproteins and days of menstrual bleeding (withdrawal bleeding during oral contraceptive). RESULTS: Mean age and body mass index (BMI) were similar between the two groups. The final analysis was performed on 34 women, 15 in E2/NOMAC and 19 in EE/CMA group. Compliance with treatment was significantly higher with EE/CMA (100%) than E2/NOMAC (75%) (p = 0.02). Both treatments significantly (p < 0.0001) reduced VAS of primary dysmenorrhea, similarly (E2/NOMAC by a mean of 74.7%, EE/CMA by a mean of 78.4%; p = 0.973). Only E2/NOMAC significantly increased SF-36 score (p = 0.001), both in physical (p = 0.001) and mental domains (p = 0.004). The mean number of days of menstrual bleeding was significantly reduced in E2/NOMAC group (from 4.86 ± 1.20 d to 2.64 ± 1.59 d, p = 0.0005 versus baseline, p = 0.007 versus EE/CMA group). BMI did not vary in either group. E2/NOMAC did not change lipoproteins and apoproteins while EE/CMA increased total cholesterol (p = 0.0114), HDL-cholesterol (p = 0.0008), triglycerides (p = 0.002), apoprotein-A1 (Apo-A1; p = 0.0006) and apopoprotein-B (Apo-B; p = 0.008), decreasing LDL/HDL ratio (p = 0.024). CONCLUSIONS: Both oral contraceptives reduced similarly primary dysmenorrhea, with E2/NOMAC also reducing withdrawal bleedings and being neutral on lipid metabolism.
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Acetato de Clormadinona/uso terapéutico , Anticonceptivos Hormonales Orales/uso terapéutico , Dismenorrea/tratamiento farmacológico , Estradiol/uso terapéutico , Etinilestradiol/uso terapéutico , Megestrol/uso terapéutico , Norpregnadienos/uso terapéutico , Adulto , Combinación de Medicamentos , Femenino , Humanos , Estudios Prospectivos , Calidad de Vida , Resultado del Tratamiento , Adulto JovenRESUMEN
The authors describe a case of undifferentiated pleomorphic sarcoma of the breast occurring in a 50-year-old woman who presented with a palpable mass in her right breast. She first noticed the mass one month previously. Core needle biopsy showed connective tissue including epithelioid and spindle cells. The patient underwent total mastectomy without axillary lymph node dissection. Based on examination of the excised tumor, the initial pathologic diagnosis was atypical spindle-shaped and ovoid cells with uncertain malignant potential. Histological findings with immunomarkers led to the final diagnosis of undifferentiated pleomorphic sarcoma.This case highlights a rare and interesting variant of primary breast sarcoma and the important role of immunohistochemistry in defining histological type and differential diagnosis. Hence, undifferentiated pleomorphic sarcoma has been a diagnosis of exclusion performed through sampling and critical use of ancillary diagnostic techniques.
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Neoplasias de la Mama/patología , Células Gigantes/patología , Osteoclastos/patología , Sarcoma/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana EdadRESUMEN
Non-small cell lung cancer (NSCLC), the leading cause of cancer death worldwide, is still an unmet medical problem due to the lack of both effective therapies against advanced stages and markers to allow a diagnosis of the disease at early stages before its progression. Immunotherapy targeting the PD-1/PD-L1 checkpoint is promising for many cancers, including NSCLC, but its success depends on the tumor expression of PD-L1. PATZ1 is an emerging cancer-related transcriptional regulator and diagnostic/prognostic biomarker in different malignant tumors, but its role in lung cancer is still obscure. Here we investigated expression and role of PATZ1 in NSCLC, in correlation with NSCLC subtypes and PD-L1 expression. A cohort of 104 NSCLCs, including lung squamous cell carcinomas (LUSCs) and adenocarcinomas (LUADs), was retrospectively analyzed by immunohistochemistry for the expression of PATZ1 and PD-L1. The results were correlated with each other and with the clinical characteristics, showing on the one hand a positive correlation between the high expression of PATZ1 and the LUSC subtype and, on the other hand, a negative correlation between PATZ1 and PD-L1, validated at the mRNA level in independent NSCLC datasets. Consistently, two NSCLC cell lines transfected with a PATZ1-overexpressing plasmid showed PD-L1 downregulation, suggesting a role for PATZ1 in the negative regulation of PD-L1. We also showed that PATZ1 overexpression inhibits NSCLC cell proliferation, migration, and invasion, and that Patz1-knockout mice develop LUAD. Overall, this suggests that PATZ1 may act as a tumor suppressor in NSCLC.
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Behavioural and psychological factors related to eating have been associated with obesity, although their relationship to anthropometric measures, more specifically fat mass, has not been fully examined. This study examined the relationship between fat mass (n=98; 75M, 23 F) and behavioural measures of eating and obesity related psychological traits (n=337; 226M, 111 F) in overweight and obese individuals (Mean BMI 30.5±4.0; BMI range 25-46kg/m(2)). Two sets of principal component analyses (PCA) were performed: one on validated questionnaires of eating behaviour and psychological traits and a second on fat mass and body weight related anthropometric measures (BMI, weight) and the aforementioned questionnaire measures. From the initial PCA (n=337), the primary principal component, P1 (R(2) value of 0.33), represented a latent variable associated with overeating or binge eating behaviour. In a second PCA (questionnaire measures augmented by anthropometric variables, n=98), a single component was identified, P1(+) (R(2) of 0.28), similar to that identified as P1 in the previous analysis and this component was highly correlated with fat mass (ρ=0.68). These findings suggest that levels of body fat and eating behaviour (namely, binging or overeating) are strongly related and, at least in a subgroup of individuals, obesity may be driven by behavioural factors associated with eating in combination with pre-existing environmental and genetic factors.
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Tejido Adiposo , Bulimia/complicaciones , Conducta Alimentaria , Obesidad/etiología , Personalidad , Adulto , Índice de Masa Corporal , Peso Corporal , Bulimia/psicología , Conducta Alimentaria/psicología , Femenino , Humanos , Hiperfagia/complicaciones , Hiperfagia/psicología , Masculino , Persona de Mediana Edad , Obesidad/psicología , Sobrepeso/etiología , Sobrepeso/psicología , Análisis de Componente Principal , Encuestas y CuestionariosRESUMEN
We used functional magnetic resonance imaging to explore brain responses to food images in overweight humans, examining independently the impact of a prescan meal ("satiety") and the anti-obesity drug sibutramine, a serotonin and noradrenaline reuptake inhibitor. We identified significantly different responses to these manipulations in amygdala, hypothalamus, and ventral striatum. Each region was specifically responsive to high-calorie compared to low-calorie food images. However, the ventral striatal response was attenuated by satiety (but unaffected by sibutramine), while the hypothalamic and amygdala responses were attenuated by drug but unaffected by satiety. Direct assessment of regional interactions confirmed the significance of this double dissociation. We explored the regional responses in greater detail by determining whether they were predictive of eating behavior and weight change. We observed that across the different regions, the individual-specific magnitude of drug- and satiety-induced modulation was associated with both variables: the sibutramine-induced modulation of the hypothalamic response was correlated with the drug's impact on both weight and subsequently measured ad libitum eating. The satiety-induced modulation of striatal response also correlated with subsequent ad libitum eating. These results suggest that hypothalamus and amygdala have roles in the control of food intake that are distinct from those of ventral striatum. Furthermore, they support a regionally specific effect on brain function through which sibutramine exerts its clinical effect.
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Depresores del Apetito/farmacología , Encéfalo/fisiología , Ciclobutanos/farmacología , Alimentos , Respuesta de Saciedad/fisiología , Adiposidad/efectos de los fármacos , Adulto , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiología , Ganglios Basales/efectos de los fármacos , Ganglios Basales/fisiología , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Método Doble Ciego , Ingestión de Energía/fisiología , Conducta Alimentaria/efectos de los fármacos , Femenino , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiología , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Sobrepeso/psicología , Estimulación Luminosa , Adulto JovenRESUMEN
Endocrine and metabolic disorders are a common condition in Europe and worldwide, and, among these, thyroid dysfunction still remains a problem. The measurement of thyroid stimulating hormone (TSH) levels represents the first-line assay for the assessment of thyroid function. In the present study, we compared serum concentrations of TSH, measured using a commercially available point-of-care test (POCT) method (FastPack® IP) and an established "conventional" laboratory-based method (Beckmann Access 2) in a cohort of patients from Foggia in Southern Italy. A strong correlation (r = 0.994) was found between both methods and was also confirmed by receiver operating characteristic (ROC) curve analysis (0.82). The within-run coefficient of variation (CV) using FastPack® ranged from 4.03% and 8.57% at the TSH concentrations of 39.49 and 0.70 mIU/L, respectively. The between-run CV was 10.34% and 6.33% at the TSH concentrations of 0.87 and 26.55 mIU/L, respectively. The ratios of within- to between-assay CV were 0.83 and 1.06 at the TSH levels of 0.70 and 52.59 mIU/mL, respectively. In this study, we showed that serum TSH levels can be measured in a few minutes and at low-cost in terms of materials and equipment required. We observed that this approach is user-friendly, accurate, reproducible, and suitable for use in the clinic, while also meeting the criteria for effectiveness, impact, efficiency, and sustainability.
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BACKGROUND: Repeated computed tomography (CT) assessment of the adrenal glands is associated with a significant radiation burden. The increasing capabilities of magnetic resonance (MR) volumetric analysis of the adrenals make this a potentially alternative technique in man. PURPOSE: To determine whether MR imaging could be used to measure adrenal volume, and to determine the intra- and interobserver variation and repeatability of MR volume imaging of adrenals in healthy human subjects. MATERIAL AND METHODS: This was a single-cohort, sequential design, three-part study involving four MRI examinations per subject following ethical approval and informed consent. Information was collected on four healthy subjects (three male and one female). Two different investigators estimated the area of the adrenal gland for each of the 3-mm contiguous slices (and consequently adrenal volume). In order to estimate inter- and intrareader variability, a repeated-measures mixed model was fitted with adrenal volume as the dependent variable. In order to estimate any bias between readers, Bland-Altman methodology was applied. RESULTS: Intraobserver variation for adrenal gland volume is approximately 5% of a 3-cm(3 )adrenal gland. Interobserver variation is approximately 9% of a 3-cm(3) adrenal gland. Potential variation in measurement for adrenal volume from all sources equates to approximately 14% of a 3-cm(3) adrenal gland. Verification of image reading by a second investigator (consensus reading) reduces variability. CONCLUSION: Analysis of adrenal gland volume using MRI is a potentially reliable technique that could be used to assess a pathological change in adrenal size.
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Glándulas Suprarrenales/anatomía & histología , Imagen por Resonancia Magnética/métodos , Adolescente , Adulto , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Proyectos Piloto , Estudios ProspectivosRESUMEN
OBJECTIVE: To evaluate whether climacteric symptoms are related to pelvic organ prolapse (POP) in postmenopausal women. STUDY DESIGN: A cross-sectional investigation was performed on 1382 postmenopausal women attending an outpatient service for menopause at a university hospital. MAIN OUTCOME MEASURES: Data regarding climacteric symptoms, as captured by the Greene Climacteric Scale, and objective POP were retrieved from an electronic database. Additional data retrieved were age, anthropometric measures, personal and reproductive history, use of medication or drugs, coffee, smoking, state of anxiety (STAI scale score) and depression (Zung scale score). RESULTS: The score of Greene Climacteric Scale was higher (p=0.02) in women with (n=538) than in those without (n=844) POP (29.6±13.6 vs. 27.8±13.; p=0.02). In multiple logistic regression models, the score was independently related to POP as a whole (OR 1.012; 95%CI 1.003,1.022; p=0.009), and to bladder prolapse (OR 1.011; 95%CI 1.007,1.07; p=0.02) or to uterus prolapse (OR 1.003; 95%CI 0.99,1.016; p=0.63) or rectum prolapse (rectocele) (OR 1.004; 95%CI 0.988,1.02; p=0.62). CONCLUSIONS: In postmenopausal women, a higher burden of climacteric symptoms, is associated with POP. Underlying mechanisms were not assessed and deserve further investigation.
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Ansiedad/epidemiología , Depresión/epidemiología , Sofocos/epidemiología , Menopausia , Prolapso de Órgano Pélvico/epidemiología , Salud Reproductiva , Ansiedad/psicología , Café , Estudios Transversales , Cistocele/epidemiología , Depresión/psicología , Escolaridad , Femenino , Sofocos/psicología , Humanos , Histerectomía , Modelos Logísticos , Persona de Mediana Edad , Análisis Multivariante , Posmenopausia , Rectocele/epidemiología , Factores de Riesgo , Fumar/epidemiología , Prolapso Uterino/epidemiologíaRESUMEN
INTRODUCTION: Is the replacement of ethinyl-estradiol (EE) with estradiol (E2) in combined hormonal contraceptives (CHCs) associated with fewer metabolic effects, leading to a further improvement on safety of hormonal contraceptives? AREAS COVERED: This is a narrative review paper including all available data on the metabolic impact of CHCs containing E2 published in English up to December 2015. Modification of a metabolic variable of interest during the first months of treatment was considered as an outcome. EXPERT OPINION: E2 was extensively used in oral contraceptives associated to nomegestrol acetate (NOMAc) in a monophasic 24 + 4 or its ester E2 valerate to dienogest (DNG) in a quadriphasic 26 + 2 regimen. The impact on the lipid metabolism and the hemostatic system of these preparations seems milder than that caused by EE-based ones, associated with no change of blood pressure. The impact on bone metabolism was instead similar to EE. Data available in the literature are mainly derived from studies having secondary minor metabolic outcomes as the primary end-point, and so currently not completely applicable on the real variables of interest (arterial or venous cardiovascular events, bone fractures). The preliminar parenteral use of E2 seems promising, both transdermal and vaginal, in particular after the introduction of a specific progestin with a high anti-ovulatory activity, like nestorone.
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Anticonceptivos Orales Combinados/administración & dosificación , Anticonceptivos Hormonales Orales/administración & dosificación , Estradiol/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Anticonceptivos Orales Combinados/efectos adversos , Anticonceptivos Hormonales Orales/efectos adversos , Estradiol/efectos adversos , Etinilestradiol/administración & dosificación , Etinilestradiol/efectos adversos , Hemostasis/efectos de los fármacos , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Megestrol/administración & dosificación , Nandrolona/administración & dosificación , Nandrolona/análogos & derivados , Norpregnadienos/administración & dosificaciónRESUMEN
OBJECTIVE: The progestin dienogest (DNG) given alone effectively reduces pelvic pain of women with endometriosis. It is not clear whether the same occurs when DNG is associated with estradiol (E2). DESIGN: Patient preference prospective observational study. SETTING: Outpatient centre of university hospital. PATIENTS: 40 patients with endometriosis and menstrual pain. INTERVENTIONS: 24-week treatment with a quadriphasic association of E2 valerate (E2V) and DNG or a nonsteroidal anti-inflammatory drug (NSAID) to be used only in case of pain (ketoprofene 200-mg tablets). MAIN OUTCOME MEASURES: Menstrual pain and, when present, intermenstrual pain, and dyspareunia were investigated by means of a 10-cm visual analogue scale (VAS). Quality of life was investigated by the short form 36 (SF-36) of the health-related quality of life questionnaire. RESULTS: Final study group consists of 34 patients, 19 in the E2V/DNG group and 15 in the NSAID group. After 24 weeks, no significant modification of menstrual pain, intermenstrual pain, dyspareunia, or SF-36 score was observed in the NSAID group. Treatment with E2V/DNG reduced the VAS score of menstrual pain by 61% (P < .0001). In the subgroups of women with intermenstrual pain or dyspareunia, E2V/DNG reduced these complaints by 65% (P = .013) and 52% (P = .016), respectively. The reduction in menstrual (P = .0001) and intermenstrual pain (p = 0.03) was significantly greater during E2V/DNG than NSAID. Quality of life improved during E2V/DNG (P = .0002), both in physical (P = .0003) and mental domains (P = .0065). Only a few minor adverse effects were described during E2V/DNG, and none caused withdrawal from treatment. CONCLUSION: In patients with endometriosis and pelvic pain, the 24-week administration of the quadriphasic association of E2V/DNG decreases pelvic pain and improves quality of life.
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Anticonceptivos Hormonales Orales/administración & dosificación , Dismenorrea/tratamiento farmacológico , Endometriosis/tratamiento farmacológico , Estradiol/análogos & derivados , Nandrolona/análogos & derivados , Prioridad del Paciente , Dolor Pélvico/tratamiento farmacológico , Calidad de Vida , Adulto , Anticonceptivos Hormonales Orales/efectos adversos , Combinación de Medicamentos , Dismenorrea/diagnóstico , Dismenorrea/psicología , Endometriosis/diagnóstico , Endometriosis/psicología , Estradiol/administración & dosificación , Estradiol/efectos adversos , Femenino , Hospitales Universitarios , Humanos , Italia , Nandrolona/administración & dosificación , Nandrolona/efectos adversos , Dimensión del Dolor , Dolor Pélvico/diagnóstico , Dolor Pélvico/psicología , Proyectos Piloto , Estudios Prospectivos , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del TratamientoRESUMEN
This study investigated safety and efficacy of GSK256073, an in vitro potent, selective GPR109A agonist, for treatment of subjects with type 2 diabetes mellitus (Type 2 DM) poorly controlled with metformin alone. Patients with Type 2 DM (n=94) were enroled into this randomised, double-blind (sponsor unblinded), placebo-controlled, parallel group trial. Participants received placebo for two weeks before being randomised (2:2:2:2:1:1) to receive doses of GSK256073 5mg twice-daily (BID), 10mg once-daily (QD), 25mg BID, 50mg QD or placebo BID or QD in addition to their current metformin treatment. The primary efficacy endpoint was change from baseline in glycosylated haemoglobin (HbA1c) at week 12. The safety profile of GSK256073 did not significantly differ from that of placebo. Decreases from baseline in HbA1c were observed in all treatment groups but were not statistically significant compared to placebo; at week 12 a maximum decrease of 0.30% from placebo was reached in the GSK256073 50mg QD group. On day 2, GSK256073 significantly decreased non-esterified fatty acid (NEFA) (0-12h) concentrations but pharmacological activity was lost (5mg BID, 10mg QD, 25mg BID) or reduced (50mg QD) at week 6. Drug exposure demonstrated 2-fold accumulation over 6 weeks. The primary efficacy objective of the study was not met. GSK256073 did not improve HbA1c concentrations at week 12. Despite sustained drug exposure, the ability of the HCA2 agonist to suppress plasma NEFA concentrations waned over time and targeted effects on glucose oxidation and insulin sensitivity subsided.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptores Acoplados a Proteínas G/agonistas , Xantinas/uso terapéutico , Anciano , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Ácidos Grasos no Esterificados/sangre , Femenino , Fructosamina/sangre , Hemoglobina Glucada/análisis , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Receptores Nicotínicos , Resultado del Tratamiento , Xantinas/administración & dosificación , Xantinas/farmacocinética , Xantinas/farmacologíaRESUMEN
OBJECTIVE: Combined oral contraceptives (COCs) containing ethinyl-estradiol are known to increase blood pressure (BP). We evaluated whether COCs containing estradiol (E2) influence 24-h ambulatory BP and heart rate (HR) in normotensive and normal-weight women. STUDY DESIGN: Twenty-four-hour BP and HR were measured every 30 min with an ambulatory BP device in 18 normotensive healthy non-smoking women prior to (Days 3-6 of menstrual cycle) and after 6 months of use (Days 20-24 of cycle 6) of a COC containing either a quadriphasic combination of E2 valerate plus dienogest (n=11) or a monophasic association of micronized E2 plus nomegestrol acetate (n=7). RESULTS: Mean age and body mass index of the final sample were 32.50±7.49 years and 22.87±4.08, respectively. E2-based COCs induced no modification of 24-h systolic BP (+1.65±8.34 mmHg; p=.41), diastolic BP (+0.04±7.36 mmHg; p=.98), mean BP (+0.64±6.42 mmHg; p=.68) or HR (-0.72±5.86 beats/min; p=.61). Differences were not observed even when daytime or nighttime values were separately considered. Though this was not a comparative study, we did not find differences between the effects of the two formulations (24-h mean BP; p=.699). CONCLUSIONS: These data suggest a neutral effect of estradiol-based COCs on independent risk factors for cardiovascular diseases such as BP or HR. IMPLICATIONS: BP and HR of normotensive women are not increased by E2-based COCs.
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Presión Sanguínea/efectos de los fármacos , Anticonceptivos Orales Combinados/efectos adversos , Estradiol/efectos adversos , Frecuencia Cardíaca/efectos de los fármacos , Adulto , Ritmo Circadiano , Femenino , Humanos , Estudios ProspectivosRESUMEN
RATIONALE: The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding, motivation and arousal, to sleep and wakefulness. Orexin signaling is thus an exciting potential therapeutic target for disorders of sleep, feeding, addiction, and stress. OBJECTIVES/METHODS: Here, we investigated the low dose pharmacology of orexin receptor antagonist, SB-649868, on neuroendocrine, sympathetic nervous system, and behavioral responses to insulin-induced hypoglycemic stress, in 24 healthy male subjects (aged 18-45 years; BMI 19.0-25.9 kg/m(2)), using a randomized, double-blind, placebo-controlled, within-subject crossover design. Alprazolam, a licensed benzodiazepine anxiolytic, was used as a positive comparator, as it has previously been validated using the insulin tolerance test (ITT) model in humans. RESULTS: Of the primary endpoints, ITT induced defined increases in pulse rate, plasma cortisol, and adrenocorticotropic hormone in the placebo condition, but these responses were not significantly impacted by alprazolam or SB-649868 pre-treatment. Of the secondary endpoints, ITT induced a defined increase in plasma concentrations of adrenaline, noradrenaline, growth hormone (GH), and prolactin in the placebo condition. Alprazolam pre-treatment significantly reduced the GH response to ITT (p < 0.003), the peak electromyography (p < 0.0001) and galvanic skin response (GSR, p = 0.04) to acoustic startle, the resting GSR (p = 0.01), and increased appetite following ITT (p < 0.0005). SB-649868 pre-treatment produced no significant results. CONCLUSION: We concluded that the ITT model may be informative for assessing the effects of drugs directly acting on the neuroendocrine or sympathetic nervous systems, but could not be validated for studying low dose orexin antagonist activity.