Behavioral characterization of co-exposure to cannabinoids and hormonal contraceptives in female rats.

Hormonal contraceptives are among the most widely used drugs by young healthy women to block ovulation and avoid pregnancy. They reduce the ovarian secretion of estradiol and progesterone, hormones that also modulate neuronal plasticity, cognitive functions, emotions and mood. Cannabis is the most commonly used illicit drug worldwide and its use is increasing among young women, many of which regularly take the "pill". Despite evidence of a bidirectional interaction between the endocannabinoid system and gonadal hormones, only very few studies have examined the consequences of cannabis consumption in young females under hormonal contraceptives treatment. To fill this gap, this study evaluated the behavioral effects of co-exposure to chronic 1) hormonal contraceptives, i.e., ethinyl estradiol (EE) plus levonorgestrel (LNG), one of the synthetic estrogen-progestin combinations of hormonal contraceptives, and 2) cannabinoid receptor agonist, i.e., WIN 55,212-2 (WIN), on motor activity, emotional state and cognitive functions in young adult female rats (8-11/experimental group). Hormonal and cannabinoid treatment started at post-natal day (PND) 52 and 56, respectively, while behavioral testing occurred between PND 84-95. The results show that chronic EE-LNG treatment, at doses (0.020 and 0.060 mg/rat, respectively) known to drastically reduce plasma progesterone levels, and the contextual exposure to WIN, at a dose (12.5 µg/kg/infusion) known to be rewarding in the rat, alters the hormonal milieu but does not cause further changes in locomotor activity compared to EE-LNG or WIN alone, and does not modify anxiety-like state (as measured by the elevated plus maze and the marble burying tests) and cognitive abilities (as measured by the novel object recognition and the prepulse inhibition tests) in young adult female rats. Although exposure to EE-LNG and WIN tends to increase the duration of immobility and to reduce the time spent swimming in the forced swimming test, there was not a significant additive effect suggestive of a depressive-like state. These findings allow deepening the current knowledge on the interaction between cannabinoid agonists and hormonal contraceptives and suggest that low, rewarding doses of cannabinoids do not significantly alter the motor and cognitive skills and do not induce anxiety or depressive-like states in females that use hormonal contraceptives.

Are preconceptional stressful experiences crucial elements for the aetiology of autism spectrum disorder? Insights from an animal model.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by changes in social interactions, impaired language and communication, fear responses and presence of repetitive behaviours. Although the genetic bases of ASD are well documented, the recent increase in clinical cases of idiopathic ASD indicates that several environmental risk factors could play a role in ASD aetiology. Among these, maternal exposure to psychosocial stressors during pregnancy has been hypothesized to affect the risk for ASD in offspring. Here, we tested the hypothesis that preconceptional stressful experiences might also represent crucial elements in the aetiology of ASD. We previously showed that social isolation stress during adolescence results in a marked decrease in the brain and plasma concentrations of progesterone and in the quality of maternal care that these female rats later provide to their young. Here we report that male offspring of socially isolated parents showed decreased agonistic behaviour and social transmission of flavour preference, impairment in reversal learning, increased seizure susceptibility, reduced plasma oxytocin levels, and increased plasma and brain levels of BDNF, all features resembling an ASD-like phenotype. These alterations came with no change in spatial learning, aggression, anxiety and testosterone plasma levels, and were sex-dependent. Altogether, the results suggest that preconceptional stressful experiences should be considered as crucial elements for the aetiology of ASD, and indicate that male offspring of socially isolated parents may be a useful animal model to further study the neurobiological bases of ASD, avoiding the adaptations that may occur in other genetic or pharmacologic experimental models of these disorders.

Management of patients presenting with haemoptysis to a Tertiary Care Italian Emergency Department: the Florence Haemoptysis Score (FLHASc).

We analysed the clinical features and diagnostic workup of patients presenting with haemoptysis to an Italian teaching hospital to derive an easy-to-use clinical score to guide risk stratification and initial management in the emergency department (ED). We retrospectively reviewed clinical records of consecutive patients with haemoptysis over 1 year. A pre-specified set of variables, including demographic data, vital signs, type of expectorate (pure blood vs. blood-streaked sputum), comorbidities, and diagnostic tests and treatments was originally registered. The primary outcome was a composite of any of the following: death from any cause, invasive or non-invasive ventilation, Intensive Care Unit admission, blood transfusions or invasive haemostatic procedures. We investigated associations between the pre-specified clinical variables and the primary outcome using a logistic regression analysis. Finally, we derived a score (the Florence Haemoptysis Score, FLHASc) giving a proportional weight to each variable according to the Odds Ratios (OR). We included 197 patients with a median age of 60 years. The first radiological study was a plain chest X-ray in 128 patients (65%). For 33 (17%) patients, a chest computer tomography (CT scan) was the first radiological study. The most common diagnosis was lung malignancy (19% of cases). The diagnosis remained undetermined in one-third of patients. The primary outcome was met by 11.2% of the study population. Systolic blood pressure <100 mmHg (OR 9.7), a history of malignancy (OR 3), the expectoration of pure blood (OR 2.8), and more than 2 episodes of haemoptysis in the prior 24 h (OR 2.5) are found as independent predictors of the primary outcome. The FLHASc ranges from 0 to 6 with a prognostic accuracy of 78% (IC 95%, 68-88%). The primary outcome incidence is 2.4% (IC 95%, 0.2-8.2%) in patients with a FLHASc equal to zero (n = 85, 43%) versus 13.4% (IC 95% 7.8-21.1%) in patients with a FLHASc > 0 (p < 0.01). Among patients with a FLHASc equal to zero, a negative chest X-ray study identifies patients who may be safely discharged. Patients who presented to the ED with haemoptysis experience a heterogeneous management. We derive a simple clinical prognostic score that may rationalize their diagnostic workup.

Differential Diagnosis of Vertigo in the Emergency Department: A Prospective Validation Study of the STANDING Algorithm.

OBJECTIVE: We investigated the reliability and accuracy of a bedside diagnostic algorithm for patients presenting with vertigo/unsteadiness to the emergency department. METHODS: We enrolled consecutive adult patients presenting with vertigo/unsteadiness at a tertiary hospital. STANDING, the acronym for the four-step algorithm we have previously described, based on nystagmus observation and well-known diagnostic maneuvers includes (1) the discrimination between SponTAneous and positional nystagmus, (2) the evaluation of the Nystagmus Direction, (3) the head Impulse test, and (4) the evaluation of equilibrium (staNdinG). Reliability of each step was analyzed by Fleiss' K calculation. The reference standard (central vertigo) was a composite of brain disease including stroke, demyelinating disease, neoplasm, or other brain disease diagnosed by initial imaging or during 3-month follow-up. RESULTS: Three hundred and fifty-two patients were included. The incidence of central vertigo was 11.4% [95% confidence interval (CI) 8.2-15.2%]. The leading cause was ischemic stroke (70%). The STANDING showed a good reliability (overall Fleiss K 0.83), the second step showing the highest (0.95), and the third step the lowest (0.74) agreement. The overall accuracy of the algorithm was 88% (95% CI 85-88%), showing high sensitivity (95%, 95% CI 83-99%) and specificity (87%, 95% CI 85-87%), very high-negative predictive value (99%, 95% CI 97-100%), and a positive predictive value of 48% (95% CI 41-50%) for central vertigo. CONCLUSION: Using the STANDING algorithm, non-sub-specialists achieved good reliability and high accuracy in excluding stroke and other threatening causes of vertigo/unsteadiness.

Diagnostic performance of focused cardiac ultrasound performed by emergency physicians for the assessment of ascending aorta dilation and aneurysm.

OBJECTIVES: The diagnostic performance of transthoracic focused cardiac ultrasound (FoCUS) performed by emergency physicians (EP) to estimate ascending aorta dimensions in the acute setting has not been prospectively studied. The diagnostic accuracy and the interobserver variability of EP-performed FoCUS were investigated to estimate thoracic aortic dilation and aneurysm compared with the results of computed tomography angiography (CTA). METHODS: This was a prospective single-center cohort study of a convenience sample of patients who underwent CTA in the emergency department for suspected aortic pathology. FoCUS was performed before CTA, and the maximum ascending aorta diameter evaluated in parasternal long-axis view. Aorta diameter < 40 mm by visual estimation or by diameter measurement was considered normal. Measurements were recorded in all patients with aorta diameter ≥ 40 mm. Diagnostic accuracy of FoCUS for detection of aortic dilation (diameter ≥ 40 mm) and aneurysm (diameter ≥ 45 mm) were calculated considering the CTA result as reference standard. In a subgroup of patients, a second EP-sonographer performed FoCUS to evaluate interobserver agreement for the diagnosis of ascending aorta dilation. RESULTS: A total of 140 patients were enrolled in the study. Ascending aorta dilation and aneurysm were detected with FoCUS in 50 (35.7%) and in 27 (17.8%) patients, respectively. Sensitivity and specificity of FoCUS were 78.6% (95% confidence interval [CI] = 65.6% to 88.4%) and 92.9% (95% CI = 85.1% to 97.3%), respectively, for ascending aorta dilation and 64.7% (95% CI = 46.5% to 80.2%) and 95.3% (95% CI = 89.3% to 98.4%), respectively, for ascending aorta aneurysm. Interobserver agreement of FoCUS was k = 0.82. CONCLUSIONS: FoCUS performed by EP is specific for ascending aorta dilation and aneurysm when compared to CTA and appears a reproducible technique.

High-frequency QRS analysis compared to conventional ST-segment analysis in patients with chest pain and normal ECG referred for exercise tolerance test.

BACKGROUND: The novel analysis of high-frequency QRS components (HFQRS-analysis) has been proposed in patients with chest pain (CP) and normal electrocardiography (ECG) referred for exercise tolerance test (ex-ECG). The aim of the study was to compare the diagnostic value of ex-ECG with ex-HFQRS-analysis. METHODS: Patients with CP and normal ECG, troponin, and echocardiography were considered. All patients underwent ex-ECG for conventional ST-segment-analysis and ex-HFQRS-analysis. A decrease ≥ 50% of the HFQRS signal intensity recorded in at least 2 contiguous leads was considered an index of ischemia, as ST-segment depression ≥ 2 mm or ≥ 1 mm and CP on ex-ECG. Exclusion criteria were: QRS duration ≥ 120 ms and inability to exercise. End-point: The composite of coronary stenosis ≥ 70% or acute coronary syndrome, revascularization, cardiovascular death at 3-month follow-up. RESULTS: Three-hundred thirty-seven patients were enrolled (age 60 ± 15 years). The percent-age of age-adjusted maximal predicted heart rate was 89 ± 10 beat per minute and the maximal systolic blood pressure was 169 ± 23 mm Hg. Nineteen patients achieved the end-point. In multivariate analysis, both ex-ECG and ex-HFQRS were predictors of the end-point. The ex-HFQRS-analysis showed higher sensitivity (63% vs. 26%; p < 0.05), lower specificity (68% vs. 95%; p < 0.001), and comparable negative predictive value (97% vs. 96%; p = 0.502) when compared to ex-ECG-analysis. Receiver operator characteristics analysis showed the incremental diagnostic value of HFQRS (area: 0.655, 95% CI 0.60-0.71) over conventional ex-ECG (0.608, CI 0.55-0.66) and CP score (0.530, CI 0.48-0.59), however without statistical significance in pairwise comparison by C-statistic. CONCLUSIONS: In patients with CP submitted to ex-ECG, the novel ex-HFQRS-analysis shows a valuable incremental diagnostic value over ST-segment-analysis.