Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

The sex steroid hormone estrogen is a key modulator of numerous physiological processes and adaptive behaviors, but it may also be co-opted to drive maladaptive behaviors. While many behavioral roles for estrogen signaling have been shown to occur through canonical genomic signaling mechanisms via nuclear receptors, estrogen can also act in a neurotransmitter-like fashion at membrane-associated estrogen receptors to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen but a causal role for estrogen in alcohol drinking has not been established. Here, we demonstrate that gonadally intact female mice consume more alcohol and display an anxiolytic phenotype when they have elevated levels of ovarian-derived estrogen across the estrous cycle. We found that rapid, nongenomic estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis (BNST) is necessary and sufficient for the pro-alcohol drinking effects of ovarian estrogen signaling, regardless of the transcriptional program of a high ovarian estrogen state. We further show that a population of corticotropin-releasing factor (CRF) BNST neurons (BNSTCRF) is a critical mediator of these effects, as high estrogen rapidly enhances synaptic excitation of BNSTCRF neurons and promotes their role in driving binge alcohol drinking. These findings show a causal role for endogenous, ovarian-derived estrogen in hormonal modulation of risky alcohol consumption and provide the first demonstration of a purely rapid, nongenomic signaling mechanism of ovarian estrogen in the brain controlling behavior in gonadally intact females.

Phenyl bioisosteres in medicinal chemistry: discovery of novel γ-secretase modulators as a potential treatment for Alzheimer's disease.

Phenyl rings are one of the most prevalent structural moieties in active pharmaceutical ingredients, even if they often contribute to poor physico-chemical properties. Herein, we propose the use of a bridged piperidine (BP) moiety as a phenyl bioisostere, which could also be seen as a superior phenyl alternative as it led to strongly improved drug like properties, in terms of solubility and lipophilicity. Additionally, this BP moiety compares favorably to the recently reported saturated phenyl bioisosteres. We applied this concept to our γ-secretase modulator (GSM) project for the potential treatment of Alzheimer's disease delivering clinical candidates.

Assessment of Salmonella survival in dry-cured Italian salami.

The inactivation of Salmonella during curing of Italian traditional pork salami was investigated. A total of 150 batches of ground raw meat (GRM) used for salami manufacturing by four producers were tested for Salmonella by real-time PCR followed by ISO 6579 cultural confirmation and MPN enumeration. Salami produced with Salmonella positive GRMs were re-tested at the end of their curing period. Aw, pH and NaCl content were also measured. Detection of Salmonella was performed testing both 25 and 50g of the samples. By Real-Time PCR 37% of the GRMs resulted positive, but cultural detection of Salmonella was obtained in 14% of the samples only. Salmonella enumeration ranged from 31 MPN/g to <1.3 MPN/g. The difference between testing 50g and 25g of the samples was statistically significant (p value≤0.01). In particular, ISO-50g detected Salmonella in 100% of all positive samples, vs. 62% of ISO-25g. Salami made of the contaminated GRMs were 29% Salmonella-positive, as most batches of salami produced with Salmonella-positive GRMs resulted negative after regular curing (20-48days). Overall, 13% of salami produced with Salmonella-contaminated GRMs were positive. They belonged to six batches, which turned out negative after prolonged curing ranging between 49 and 86days. Salmonella enumeration in salami ranged from 8.7 MPN/g to <1.3 MPN/g. Unlike GRMs, no significant difference was observed between the ISO-50g and the ISO-25g in detecting Salmonella in cured salami (p value: >0.05). The most common Salmonella serovars in GRMs were Derby (52%), Typhimurium monophasic variant 4, (Barbuti et al., 1993), 12:i:- (19%) and Stanley (10%). Salmonella Derby (56%), London, Branderup, Panama (13%, respectively) and Goldcoast (6%) were most frequent in cured salami. The study showed negative correlation between real-time CT values and cultural confirmation of Salmonella, as well as the importance of sample size for Salmonella detection. Among considered factors with possible effect on the occurrence of Salmonella in salami, statistical analysis revealed a role for aw in salami and for Salmonella load in GRMs, while pH and NaCl content did not significantly affect the probability of finding Salmonella in dry-cured salami in the context of this study. In particular the lower aw values due to longer curing were associated with lower Salmonella presence in traditional dry-cured salami.

Value of pharmacologic stress echocardiography in risk stratification of patients with single-vessel disease: a report from the Echo-Persantine and Echo-Dobutamine International Cooperative Studies.

OBJECTIVES: This study sought to verify the effectiveness of pharmacologic stress echocardiography in risk stratification of patients with single-vessel disease. BACKGROUND: Noninvasive prognostic assessment of single-vessel disease is an unresolved issue to date. METHODS: The study evaluated prospectively collected data from 754 patients with angiographic single-vessel disease who underwent either dipyridamole (n = 576) or dobutamine (n = 178) stress echocardiography. Invasive treatment (coronary revascularization within 3 months of stress testing) was performed in 260 patients and medical treatment in 494. RESULTS: Echocardiographic positivity was observed in 421 patients (56%). Patients treated invasively had a higher incidence of stress test positivity (69% vs. 49%, p < 0.001) and left anterior descending coronary artery involvement (60% vs. 46%, p < 0.001) than patients maintained with medical therapy. During a mean follow-up of 37 months, 54 hard cardiac events occurred (14 deaths, 40 nonfatal infarctions): 37 in medically and 17 in invasively treated patients (7.5% vs. 6.5%, p = NS). On Cox analysis, a positive result on stress testing was the only independent prognostic predictor in medically treated patients (relative risk 2.92, 95% confidence interval 1.29 to 6.59). The 4-year infarction-free survival rate was higher for a negative than a positive stress test result in medically (93.9% vs. 87.3%, p = 0.009) but not invasively treated patients (92.7% vs. 97.1%, p = 0.545). Moreover, a significantly higher 4-year infarction-free survival rate was found in invasively versus medically treated patients with a positive (p = 0.012), but not in those with a negative, stress test result (p = 0.853). CONCLUSIONS: Pharmacologic stress echocardiography is effective in risk stratification of single-vessel disease and can accurately discriminate patients in whom coronary revascularization can have the maximal beneficial effect. These findings have a potential favorable impact on the cost-effectiveness of invasive procedures.

Left atrial appendage function assessed by transesophageal echocardiography before and on the day after elective cardioversion for nonvalvular atrial fibrillation.

We investigated left atrial appendage function by transesophageal echocardiography, on the day after external electrical cardioversion to sinus rhythm, in 41 patients with nonvalvular atrial fibrillation. After cardioversion, appendage contraction synchronized with the electrical and mechanical activity of the atrium, which was restored in about 70% of the patients.

Noninvasive assessment of left ventricular diastolic function: comparative analysis of pulsed Doppler ultrasound and digitized M-mode echocardiography.

The relation between Doppler and digitized M-mode echocardiographic indexes of left ventricular (LV) diastolic function was analyzed. Diastolic variables obtained with these 2 techniques were compared in 19 normal volunteers and in 25 patients with a variety of cardiac diseases. The 2 techniques were in agreement in distinguishing normal from abnormal diastolic function in 20 of the 25 patients (80%) with cardiac disease. Furthermore, a close linear relation with a high correlation coefficient and a small standard error of the estimate was identified between measurements of isovolumic relaxation determined by Doppler and by M-mode echocardiography (r = 0.82, standard error of the estimate = 18 ms). Doppler indexes of diastolic filling such as the slope (descent) and the duration of the early diastolic flow-velocity peak did not show a close correlation with the peak rate and the time to peak rate of increase in LV internal dimension determined by digitized echocardiography. Thus, Doppler and digitized echocardiography were consistent in distinguishing normal from abnormal diastolic function in most of the study patients, although specific variables of LV ventricular filling determined by the 2 techniques were not closely related. In addition, Doppler and M-mode echocardiographic measurements of isovolumic relaxation showed an excellent correlation.

Influence of thrombolytic treatment followed by full dose anticoagulation on the frequency of left ventricular thrombi in acute myocardial infarction.

This study evaluated the influence of thrombolysis followed by full anticoagulation on the frequency of left ventricular (LV) thrombi after acute myocardial infarction (AMI). Nineteen consecutive patients with a first anterior wall AMI who received 1,500,000 IU of streptokinase within 3 hours of symptom onset, followed by full anticoagulation, underwent echocardiographic studies within 24 hours of symptoms, and then on days 2, 3, 5, 7, 12, 30 and 90. Forty-four patients, with comparable clinical features and echocardiographic protocol but without antithrombotic therapy, served as the control group. LV thrombi developed in 4 of 19 (21%) treated patients and in 23 of 44 (52%) control subjects (p = 0.02). LV aneurysm or major wall motion abnormalities were noted in 8 of 19 (42%) treated patients and in 30 of 44 (68%) control subjects (p less than 0.05). No significant difference was found between treated and untreated patients when comparing the incidence of thrombi in the subgroups of patients with aneurysm or major wall motion abnormalities (3 of 8 vs 21 of 30) and in the subgroups with less extensive LV dysfunction. Thrombi disappeared during hospitalization in 3 of 4 treated patients, but in none of the controls. Fewer patients treated with intravenous streptokinase followed by full anticoagulation developed LV thrombi compared to patients treated with conventional therapy. This difference may be related to a reduced occurrence of major LV wall motion abnormalities. Resolution of thrombi frequently occurs in the hospital phase of AMI; therefore, only frequent echocardiographic examinations can assess the true frequency of LV thrombi.

Long-term prospective assessment of left ventricular thrombus in anterior wall acute myocardial infarction and implications for a rational approach to embolic risk.

To prospectively assess the predictive value of left ventricular (LV) thrombus anatomy for defining the embolic risk after acute myocardial infarction (AMI), 2 comparable groups of patients with a first anterior AMI (group A, 97 thrombolysed patients; group B, 125 patients untreated with antithrombotic drugs [total 222]) underwent prospective serial echocardiography (follow-up 39 +/- 13 months) at different time periods. LV thrombi were detected in 26 patients in group A (27%) and in 71 in group B (57%; p <0.005). Embolism occurred in 12 patients (5.4%; 1 in group A [1%] vs 11% in group B [9%], p < 0.04). At multivariate analysis, thrombus morphologic changes were the most powerful predictor of embolism (p <0.001), followed by protruding shape (p <0.01) and mobility (p <0.02). In patients untreated with thrombolysis, a higher occurrence of thrombus morphologic changes (48% vs 8%, p <0.002) and protruding shape (69% vs 31%, p <0.002) were observed, whereas thrombus mobility was similar in the 2 groups (18% vs 8%, p = NS). Thrombus resolution occurred more frequently in thrombolysed patients (85% vs 56%, p <0.002). Thus, after anterior AMI, changes in LV thrombus anatomy frequently occur and appear the most powerful predictor of embolization. A minor prevalence of thrombus, a more favorable thrombus anatomy, and a higher resolution rate may contribute to reduce embolic risk after thrombolysis.

Methotrexate, mitoxantrone, 5-fluorouracil and leucovorin in metastatic breast cancer patients.

We have evaluated the efficacy and toxicity of a chemotherapy consisting of methotrexate, mitoxantrone, 5-Fluorouracil and leucovorin in 21 advanced breast cancer patients. Among 20 evaluable patients, objective response was obtained in 6 patients (30%) with two complete responses, stable disease in 4 patients (20%), while 10 patients (50%) progressed. Median progression-free survival and survival were 10 and 15 months, respectively. The most frequently observed side-effects were myelosuppression and emesis; one patient, who had previously received doxorubicin at the maximum dose-limiting cardiac toxicity, died of congestive heart failure after the third cycle. This treatment is moderately effective for advanced breast cancer patients.

Chronic aneurysmatic dilatation: a possible source of lethal embolization in patients with acute myocardial infarction undergoing thrombolysis.

Left ventricular thrombosis is relatively common after acute myocardial infarction, especially in the anterior site, and represents a possible cause of potentially lethal peripheral embolization 1. Therefore, several studies have been performed in order to assess the efficacy of different antithrombotic drugs in resolving the detected thrombi or reducing their embolic potential. Fibrinolytic agents appear effective in this regard: in the majority of cases, they produce complete lysis and resolution of the thrombi. However, this treatment may itself cause embolic complications by producing a rapid fragmentation of thrombus and the subsequent emission of disrupted portions of the intracardiac mass into the systemic vascular bed [2]. This dramatic effect of thrombolysis has suggested the possibility that even the standard treatment of acute myocardial infarction with fibrinolysis implies a danger of embolization in those patients in whom a left ventricular thrombus may be present either from a previous myocardial infarction or from a very early thrombus development. However, this hypothesis has not yet been confirmed by direct observation. We report the case of a patient with a first acute anterior myocardial infarction, in whom the thrombolytic treatment induced lysis and embolization from a left ventricular thrombus present in an aneurysmatic dilatation of the infero-posterior wall due to a previous inferior myocardial infarction.

Protein S deficiency. Description of a case associated with chronic inflammatory bowel disease.

Thrombotic disease is one of the most relevant clinical problems for morbility and mortality. We can differentiate congenital and acquired forms. In this short communication we describe 1 case observed by us that seems interesting for the association of a congenital and acquired form [Protein S deficiency and inflammatory bowel disease (IBD)] and for the dramatic events suffered before receiving a complete diagnosis and therapy, indicating the importance of recollection of information from the patients, starting from anamnestic data.

Two-dimensional and Doppler echocardiographic diagnosis of left ventricular pseudoaneurysm.

In an oligosymptomatic patient with recent acute anterior myocardial infarction, two-dimensional and Doppler echocardiography allowed us to detect, unmistakably, the presence of an apical pseudoaneurysm. Prompt and successful repair was made without performing left ventriculography. To our knowledge, this is the first case of pseudoaneurysm referred for surgery on the basis of echocardiographic findings.

Dipyridamole echocardiographic test performed 3 days after an acute myocardial infarction: feasibility, tolerability, safety and in-hospital prognostic value.

In recent years, increasing evidence has pointed to the potential of dipyridamole stress echocardiography as a fast, effective, inexpensive method of risk stratification after an acute myocardial infarction. A very early stratification by this test could improve the patient's management and reduce the duration of in-hospital stay, and, thus, the costs. Two-hundred and fifty-one consecutive patients (208 male, age 58 +/- 11) with a two-dimensional echocardiogram of good technical quality underwent a dipyridamole echocardiographic test (DET) 70 +/- 6 h after an acute myocardial infarction. Criterion for positivity was the identification of a transient regional asynergy that was absent or of a lower degree in the baseline examination. Positivity was defined as 'at low-dose' or 'at high-dose' if the asynergy was detected before or after the 8th min of a drug infusion. All tests were performed without any major side effects. DET was positive in 149 (59%) and negative in 102 (41%) patients. During the hospital stay, cardiac events (death, reinfarction, angina) occurred in 52/251 patients: in 49/149 with a positive and in 3/102 with a negative test (sensitivity 94%, negative predictive value 97%, P < 0.00001). Severe events (death and reinfarction) occurred in 14/251: in 12/149 with a positive DET and in 2/102 with a negative DET (sensitivity 86%; negative predictive value: 98%; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular thrombus in anterior acute myocardial infarction after thrombolysis. A GISSI-2 connected study.

BACKGROUND: Streptokinase reduces the incidence of left ventricular thrombosis after acute myocardial infarction. However, it is unknown whether a similar effect can be obtained with different thrombolytic agents and whether subcutaneous calcium heparin can have an additional efficacy. METHODS AND RESULTS: To compare the effects of two different thrombolytic agents combined or not with heparin on the incidence and features of left ventricular thrombi and their related embolic events, we performed a GISSI-2 ancillary echocardiographic study (the first echocardiogram obtained within 48 hours of symptoms onset and the second before hospital discharge) that enrolled 180 consecutive patients (mean age, 63 +/- 11 years, 142 men) with a first anterior acute myocardial infarction. Patients were randomized into four groups of treatment: recombinant tissue-type plasminogen activator (rt-PA) (n = 47), rt-PA plus heparin (n = 45), streptokinase (n = 39), and streptokinase plus heparin (n = 49). Left ventricular thrombosis was observed in 51 of 180 patients (28%). No significant differences were found concerning the incidence of thrombi in the four treatment groups. Mural shape of left ventricular thrombi was found more frequently than the protruding shape (71% versus 29% at the first examination, 64% versus 36% at the second), particularly in heparin-treated patients (93% versus 7% at first examination, 70% versus 30% at the second). Only one embolic event (0.5%) occurred during the hospitalization. CONCLUSIONS: We conclude that 1) the rate of left ventricular thrombi does not differ in patients with acute myocardial infarction treated either with streptokinase or rt-PA, 2) subcutaneous heparin, when begun 12 hours after intravenous thrombolysis, does not appear to further reduce the occurrence of thrombi but seems to influence the shape of left ventricular thrombi, and 3) during the predischarge period, embolic events are rare in patients treated by thrombolysis.