Experimental Bilateral Deep Temporal Epilepsy. Effects of Ablation of One Focus and of Different Brain Lesions

In acute experiments in the rabbit, the amygdaloid nuclear complexes of the two sides were made epileptogenic through electrical stimulation or local injection of penicillin in gel. The effects on the epileptic pattern produced by surgical removal of one of the two epileptogenic amygdalae and the effects of sterotactic lesioning of the region of anterior commissure, head of caudate nucleus, and occipital cortex were analyzed. The occurrence of phenomena of both inhibitory and facilitatory interaction between the two epileptogenic amydalae was confirmed. In some experimental conditions, the restraining influence of an amygdaloid penicillin focus on the contralateral one was quite relevant, and its effect could persist even after surgical removal of the focus from which it originated. The mediation of the interamygdadoid epileptic interaction could not be ascribed to a single cerebral structure or anatomofunctionally homogenous group of structures. The phenomenon appears to involve several structures at different encephalic levels.     

Selective effect of conjugated linoleic acid isomers on atherosclerotic lesion development in apolipoprotein E knockout mice

Research suggests that conjugated linoleic acid (CLA) may inhibit atherosclerosis, but there are contradictory results in different animal models fed heterogeneous mixtures of CLA isomers. This study addressed the hypothesis that the individual CLA isomers may exert different atherogenic properties. ApoE(-/-) mice were fed isocaloric, isonitrogenous westernized diets containing 0.15% cholesterol and enriched with 1% (w/w) cis-9,trans-11-CLA (c9,t11-CLA), trans-10,cis-12-CLA (t10,c12-CLA) or linoleic acid (control diet) for 12 weeks. At the end of the dietary intervention, the effects of CLA isomers on the development of atherosclerotic vascular lesions, lipid metabolism, inflammation and oxidative stress were assessed. The t10,c12-CLA diet had a profound pro-atherogenic effect, whereas c9,t11-CLA impeded the development of atherosclerosis. En face aortic lesion assessment showed more dorsal and lumbar extensions presenting atherosclerotic foci after the t10,c12-CLA diet. Furthermore, animals fed t10,c12-CLA had pronounced hyperlipidemia, higher 8-iso-prostaglandin F(2alpha) levels, higher vulnerable atherosclerotic plaque with a lower smooth muscle and fibre contents and higher macrophage content and activation, assayed as plasma chitotriosidase compared to the control or c9,t11-CLA dietary groups. Plasma chitotriosidase activity was more closely associated with the extent of the plaque than with MOMA staining or than monocyte chemoattractant protein-1 levels. Our results demonstrate that CLA isomers differentially modulate the development of atherosclerosis, c9,t11-CLA impedes, whereas t10,c12-CLA promotes atherosclerosis. These opposing effects may be ascribed to divergent effects on lipid, oxidative, inflammatory and fibro muscular components of this pathology. Plasma chitotriosidase is a better indicator of dietary fat interventions that alter plaque monocyte activity in this murine model.     

The Effects of Chronic Ethanol Consumption on Carcinogen Metabolism and on O6-Methylguanine Transferase-Mediated Repair of Alkylated DNA

This article presents a review and update of recent experiments conducted in collaboration with Dr. C. S. Lieber on mechanisms underlying the increased cancer risk associated with alcohol abuse. Ethanol has been found to be a potent inducer of microsomal enzymes involved in carcinogen metabolism in a variety of rat tissues including liver, esophagus, lungs, and intestines. In some of these tissues, ethanol's inductive effect on microsomal cytochrome P-450 enzyme activity may result in enhanced levels of electrophilic metabolites of procarcinogens which are not readily detoxified. In addition, chronic ethanol feeding has been found to depress the activity of O⁶-methylguanine transferase, an enzyme involved in the repair of carcinogen-induced DNA alkylation. The effects of ethanol on carcinogen metabolism and on DNA repair would be expected to enhance the initiation phase of chemically induced cancers.     

缺血性与扩张性心肌病终末期心肌白细胞介素-6 mRNA表达与心功能参数间的关系

目的在检测晚期心力衰竭患者心肌组织中白细胞介素-6(IL-6)mRNA表达的基础上,探讨IL-6mRNA与心功能参数间的关系,为揭示IL-6参与心力衰竭发生发展提供依据.方法以Northern-blot法检测27例接受心脏移植患者(缺血性心肌病12例,扩张性心肌病15例)不同部位心肌组织中IL-6mRNA表达水平,并以线性回归比较IL-6mRNA与移植前血流动力学和超声心动参数间的关系.结果所有患者心肌组织中均有Ⅱ-6mRNA表达,扩张性心肌病左心室IL-6mRNA表达水平高于缺血性心肌病(P=0.006).IL-6mRNA在左心室的表达水平与左心室射血分数负相关(r=-O.62,P＜O.05),在左、右心房的表达水平与左心室舒张末内径正相关(r=0.70,P＜0.05;r=0.93,P＜O.001),在右心室的表达水平与心排指数负相关(r=-O.49,P＜0.05),在右心房的表达水平不但与肺血管阻力正相关(r=0.63,P＜O.05),也与左心室收缩末内径正相关(r=0.82,P＜0.001).结论晚期心力衰竭患者心肌组织中有IL-6mRNA表达,Ⅱ-6mmRNA水平与部分心功能参数相关,提示IL-6可能参与心力衰竭的发生发展.     

Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up from the RESPONSE trial

RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 [87.5%] crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944.     

Brugada-type patterns are easily observed in high precordial lead ECGs in collegiate athletes

Background

Displacement of ECG leads can result in unwarranted findings. We assessed the frequency of Brugada-type patterns in athletes when precordial leads were purposely placed upward.

Methods

Four hundred ninety-one collegiate athletes underwent two ECGs: one with standard leads, one with V1 and V2 along the 2nd intercostal space. A positive Brugada-type pattern was defined as ST elevation in V1 or V2 consistent with a Type 1, 2, or 3 pattern in the high-lead ECG. A control group was comprised of 181 outpatients.

Results

No Type 1 patterns were seen. In 58 athletes (11.8%), a Brugada-type 2 or 3 pattern was observed. Those with Brugada-type 2 or 3 patterns were more likely male, taller, and heavier. In the control group, 18 (9.9%) had Brugada-type 2 or 3 patterns and were more likely male.

Conclusions

Proper lead positioning is essential to avoid unwarranted diagnosis of a Brugada-type ECG, especially in taller, heavier male athletes.     

Bevacizumab plus XELOX as first-line treatment of metastatic colorectal cancer: The OBELIX study

AIM: To confirm the efficacy and safety of bevacizumab/XELOX combination for the treatment of locally advanced or metastatic colorectal cancer(CRC)in Italy.METHODS: This multicentric, prospective, open-label study included patients with CRC previously untreated with chemotherapy. Patients were administered bevacizumab in combination with XELOX. The primary efficacy end-point was progression-free survival(PFS). Secondary end-points included time to overall response(TOR), duration of response(DOR), time to treatment failure(TTF) and overall survival(OS).The incidence and type of adverse events AEs and severe AEs were evaluated. Also, the mutational status of BRAF and KRAS was assessed by high resolution melting and direct sequencing, and quality of life(QoL)was measured by the EuroQoL EQ-5D questionnaire at baseline and at the last visit.RESULTS: The intention-to-treat population included197 patients(mean age: 62.3 ± 9.9 years, 56.4%males). At baseline, 16/34 evaluable subjects(47.1%)harbored a KRAS and/or a BRAF mutation; the mean QoL index was 80.2 ± 14.3. First-line therapy was given for 223.7 ± 175.9 d, and after a mean followup of 387.7 ± 238.8 d all patients discontinued from the study mainly for disease progression(PD, 45.4%)and AEs(25.4%). Median PFS was 9.7 mo(95%CI:8.4-10.5) and the median values for secondary endpoints were: TOR = 3.9 mo(95%CI: 2.6-4.7), DOR= 8.5 mo(95%CI: 7.3-10.3), TTF = 6.7 mo(95%CI:6.0-7.7) and OS = 23.2 mo(95%CI: 20.1-27.2).Patients carrying at least one lesion had a lower overall response rate(66.7% vs 88.9%) and a lower probability of achieving complete or partial response than those without mutations, but the difference in relative risk was not statistically significant(P =0.2). Mean EQ-5D-3L raw index score significantly decreased to 74.9 ± 19.1 at the last visit(signed-rank test, P = 0.0076), but in general the evaluation on QoL perceived by patients was good.CONCLUSION: The efficacy of bevacizumab in combination with XELOX in terms of PFS in patients with aCRC or mCRC in Italy was confirmed, with acceptable toxicity.