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Chronic migraine is a disabling neurovascular disorder that ranks amongst the top causes of years lived with disability worldwide. The duration and the frequency of migraine affect cognitive and affective domains, inducing worsening of memory, executive functions, orientation and causing anxiety. Population-based studies report a worrying level of resistance to treatments. Therefore, this study aims: 1) to assess efficacy of monoclonal antibodies (mAbs) directed towards the calcitonin gene-related peptide (CGRP) or its receptor (CGRP-R) for chronic migraine resistant to current preventatives; 2) to design a clinical trial protocol to evaluate the efficacy and safety of combination therapy utilizing anti-CGRP/CGRP-R together with onabotulinumtoxin A in patients suffering from resistant chronic migraine; 3) to provide a molecular rationale for combination therapy. A controlled trial is warranted as pooled analysis of real-world data from our group highlighted that combined treatment provides ≥50% reduction vs. baseline (onabotulinumtoxin A) of monthly headache days (MHDs) in up to 58.8% of patients, but there has been only sparse application of this combined therapy to date. The mAbs chosen are: erenumab, because its combination effect with onabotulinumtoxin A improved symptoms in 65% of patients; eptinezumab, due to its faster action. The results highlight that early diagnosis of migraine improves therapeutic outcomes with mAbs alone, confirming their effectiveness and the need for an adequately powered clinical trial evaluating the safety and potential superior effectiveness of eptinezumab/erenumab and onabotulinumtoxin A together.
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OBJECTIVE: Despite widespread abuse of anabolic-androgenic steroids (AAS), the endocrine effects of supraphysiologic doses of these compounds remain unclear. We administered the AAS methyltestosterone (MT) to 20 normal volunteers in an in-patient setting, examined its effects on levels of pituitary-gonadal, -thyroid, and -adrenal hormones, and examined potential relationships between endocrine changes and MT-induced psychological symptoms. METHOD: Subjects received MT (three days of 40 mg/day, then three days of 240 mg/day) or placebo in a fixed sequence with neither subjects nor raters aware of order. Samples were obtained at the ends of the baseline, high-dose MT and withdrawal phases. Potential relationships between hormonal changes and visual analog scale measured mood changes were examined. RESULTS: Significant decreases in plasma levels of gonadotropins, gonadal steroids, sex hormone binding globulin, free T3 and T4, and thyroid binding globulin (Bonferroni t, p<0.01 for each) were seen during high-dose MT; free thyroxine and TSH increased during high-dose MT, with TSH increases reaching significance during withdrawal. No significant changes in pituitary-adrenal hormones were observed. Changes in free thyroxine significantly correlated with changes in aggressiveness (anger, violent feelings, irritability) (r=0.5,p=0.02) and changes in total testosterone correlated significantly with changes in cognitive cluster symptoms (forgetfulness, distractibility) (r=0.52,p=0.02). Hormonal changes did not correlate with plasma MT levels. CONCLUSIONS: Acute high-dose MT administration acutely suppresses the reproductive axis and significantly impacts thyroid axis balance without a consistent effect on pituitary-adrenal hormones. Mood and behavioral effects observed during AAS use may in part reflect secondary hormonal changes.
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Afecto/efectos de los fármacos , Anabolizantes/farmacología , Metiltestosterona/farmacología , Sistemas Neurosecretores/efectos de los fármacos , Adolescente , Adulto , Agresión/efectos de los fármacos , Análisis de Varianza , Andrógenos/metabolismo , Relación Dosis-Respuesta a Droga , Estrógenos/metabolismo , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Valores de Referencia , Globulina de Unión a Hormona Sexual/efectos de los fármacos , Pruebas de Función de la Tiroides , Hormonas Tiroideas/metabolismoRESUMEN
BACKGROUND: Balloon expandable metal stents (BEMS) are used to treat restenosis following percutaneous transluminal angioplasty (PTA) and as primary treatment. Intimal proliferation (IP) and resultant restenosis occurs in 25-50% of patients despite all preventive measures. OBJECTIVE: to test the intra-arterial response to the insertion of a fibrin sealant (FS) coated BEMS vs an uncoated BEMS by measuring endothelization and IP. HYPOTHESIS: that a BEMS coated with FS will lead to rapid endothelization and prevent or reduce IP. RATIONALE: FS consists of fibrinogen and thrombin. Thrombin affects endothelial cell proliferation and reduces smooth muscle proliferation, the forerunner of IP and restenosis. Normal endothelium also releases substances that promote vascular relaxation and normal smooth muscle tone regulation. METHODS: Thirty-40 kg pigs (EA), Palmaz-Shatz BEMS (Cordis), FS Tissucol (Baxter Immuno). Stents were uniformly coated with FS in a special mold. Both coated and uncoated stents were mounted on balloon catheters and deployed caudad in the carotid arteries via an arteriotomy. Angiograms were obtained postdeployment. All specimens were examined grossly, photographed then fixed for histology and in some cases, scanning electron microscopy (SEM). RESULTS: Fifteen animals form this preliminary report. Sacrifice at five days as per original protocol showed insufficient stent incorporation. Thereafter 1/2 of the animals were sacrificed at 15 days and 1/2 at 30 days. PATENCY: coated stents: 6 patent, 9 thrombosed. UNCOATED: 7 patent, 8 thrombosed. Of five EA given postoperatively low molecular weight heparin (LMWH) 4 animals had patent stents 80%. HISTOLOGY: varying degrees of IP were seen in all specimens. In general the coated stents showed a greater degree than the uncoated. STENOSIS: presacrifice angiography revealed that where the stents were patent no stenosis was present, in fact, some demonstrated mild dilatation. This was particularly the case with the coated stents. CONCLUSIONS: Coating stents with FS is not detrimental. IP in these EA at 30 days did not produce stenosis. Postoperative LMWH appears helpful in maintaining patency in a thrombogenic experimental animal. Further study maintaining EA for 6-12 months should resolve whether the IP seen had achieved its maximum expression or would progress and produce stenosis.
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Arterias Carótidas/crecimiento & desarrollo , Endotelio Vascular/crecimiento & desarrollo , Adhesivo de Tejido de Fibrina , Stents , Angioplastia de Balón , Animales , Constricción Patológica/etiología , Constricción Patológica/prevención & control , Porcinos , Túnica Íntima/crecimiento & desarrollo , Grado de Desobstrucción VascularRESUMEN
OBJECTIVE: To determine independent predictors of neurologic outcome and hospital mortality after surgery of the thoracic aorta using moderate hypothermic circulatory arrest and antegrade selective cerebral perfusion. METHODS: Between November 1996 and June 2000, 96 consecutive patients (69 men, 27 women; mean age 63+/-10 years) underwent operations on the thoracic aorta with the aid of moderate hypothermic circulatory arrest and antegrade selective cerebral perfusion. Sixty-four patients were operated on electively (66.7%), 32 emergently (33.3%). Indications for surgery were: type A acute dissection in 30 patients (31.3%), chronic aneurysm in 66 (68.8%). Seventeen patients (17.7%) had undergone previous aortic/cardiac surgical procedures. The mean selective cerebral perfusion time was 52.2+/-31.9 min (range, 18-220 min). Preoperative, intraoperative, and postoperative factors were analyzed by univariate and multivariate analysis to identify predictors of hospital mortality and neurologic outcome. RESULTS: There were no operative deaths; the hospital mortality rate was 11.5% (11/96). Stepwise logistic regression revealed preoperative renal dysfunction (P=0.021), type A acute dissection (P=0.053), coronary artery bypass grafting (P=0.058), post-operative pulmonary complications (P=0.000) and repeat thoracotomy for bleeding (P=0.027) as independent predictors of hospital mortality. One patient sustained a permanent neurologic deficit (1%). Transient neurologic deficit occurred in eight patients (8.3%). Coronary artery bypass grafting (P=0.013), and postoperative cardiac complications (P=0.049) were statistically associated with an increased risk of any (transient and permanent) neurologic dysfunction on univariate analysis. Stepwise logistic regression indicated coronary artery bypass grafting as independent factor for any neurologic dysfunction. CONCLUSION: This study confirmed that selective cerebral perfusion is an effective method of cerebral protection allowing complex thoracic aorta operations to be performed with low risk of hospital mortality and adverse neurologic outcome. We didn't find that the duration of selective cerebral perfusion time influence hospital mortality and any neurologic deficit.
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Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/cirugía , Disección Aórtica/cirugía , Circulación Cerebrovascular/fisiología , Adulto , Anciano , Puente Cardiopulmonar , Puente de Arteria Coronaria , Femenino , Paro Cardíaco Inducido , Humanos , Enfermedades Pulmonares/complicaciones , Masculino , Persona de Mediana Edad , Insuficiencia Renal/complicaciones , Factores de RiesgoRESUMEN
OBJECTIVE: To evaluate the acute effects of anabolic steroids on mood and behavior in male normal volunteers. DESIGN: A 2-week, double-blind (subject and rater), fixed-order, placebo-controlled crossover trial of methyltestosterone. SETTING: An inpatient research unit at the National Institutes of Health. SUBJECTS: A volunteer sample of 20 men who were medication free, free of medical and psychiatric illness, not involved in athletic training, and had no prior history of anabolic steroid use. INTERVENTION: A sequential trial for 3 days each of the following four drug conditions: placebo baseline, low-dose methyltestosterone (40 mg/d), high-dose methyltestosterone (240 mg/d), and placebo withdrawal. MAIN OUTCOME MEASURES: Mood and behavioral ratings were completed during each drug condition and included both subjective and objective measures. RESULTS: Significant (P < .05) albeit subtle increases in symptom scores were observed during high-dose methyltestosterone administration compared with baseline in positive mood (euphoria, energy, and sexual arousal), negative mood (irritability, mood swings, violent feelings, and hostility), and cognitive impairment (distractibility, forgetfulness, and confusion). An acute manic episode was observed in one of the 20 subjects, representing a 5% incidence, even under these conservative conditions. An additional subject became hypomanic. Baseline characteristics including family psychiatric history or previous drug abuse did not predict symptom changes. CONCLUSION: This is the first placebo-controlled prospective study demonstrating the adverse and activating mood and behavioral effects of anabolic steroids.