A pro-convulsive carbamazepine metabolite: quinolinic acid in drug resistant epileptic human brain

Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood-brain barrier (BBB). Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood-brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography-mass spectroscopy. Accelerated mass spectroscopy was used to identify (14)C metabolites deriving from the parent (14)C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from (14)C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. (14)C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites.     

Complementary effect of surgical resection and responsive brain stimulation in the treatment of bitemporal lobe epilepsy: a case report

We report a 39-year-old man with bilateral mesial temporal lobe epilepsy. He was implanted with a responsive brain stimulator (RNS System) with two depth electrodes placed in the bimesial temporal structures. After the implantation, his seizure frequency decreased by up to 50%. Electrocorticogram recorded by the RNS device revealed the right-sided predominance of seizure onset. He underwent a right temporal lobectomy, and his seizure significantly improved. After the RNS System was restarted 107 days after the temporal lobectomy, he has been seizure free for more than 1.5 years. However, the implanted device continued to record residual ictal activities at the posterior aspect of the right hippocampus and delivered electrical stimuli to suppress the seizure activities. Our report indicates the importance of electrocorticographic recordings by the RNS System to modify the treatment strategy and the complementary effect of surgical resection and brain stimulation in the treatment of epilepsy.     

L一粘附素单抗在缺血再灌注损伤中的作用

目的：中性粒细胞粘附在缺血再灌注损伤中有非常重要的作用。本文用ＳＤ大鼠趾长屈肌缺血再灌注损伤模型,观察Ｌ一粘附素单抗ＬＡＭ１—１１６在缺血再灌注损伤中的作用。方法：３０只ＳＤ大鼠被均分为２组：ＬＡＭ１—１１６组和生理盐水对照组。每只大鼠的一侧趾长屈肌作为正常对照,另外一侧进行 ３ ｈ缺血 ４ ｈ再灌注。结果：ＬＡＭ１— １１６组实验侧的髓过氧化物酶为正常的２倍（２．３±２．２）,生理盐水对照组则为正常的２８倍（２７．５±１１．７）（Ｐ＜０．００１）;ＬＡＭ１—１１６组的湿重比（１．１０± ０．１０）、疲劳肌力（７７． １％±１２．１％）与对照组相比（分别为 １． ２３± ０． １０和 ４９． ７％± ９ ．３％）明显改善（Ｐ＜ ０．０５）;组织学上,ＬＡＭ１—１１６组的中性粒细胞局部浸润显著减少,水肿减轻。结论：通过 Ｌ－粘附素单克隆抗体 ＬＡＭ１— １１６阻断 Ｌ－粘附素的功能,可以有效地降低中性粒细胞在再灌注肌肉中的浸润,防止组织水肿,从而改善肌肉的功能。     

Coronary laser thermal angioplasty in the swine: reduced complications with shorter laser delivery time

Although laser thermal angioplasty (LTA) with a laser heated metal probe has been tolerated in diseased human coronary arteries, definition of a safety threshold is lacking. Determination of safer operation parameters for coronary LTA using a new "over the wire" 1.3-mm laser probe catheter was attempted in seven normal pigs in which platelets were labeled with indium-111. Argon laser power of 10 watts was used for 1, 2, 3, and 5 seconds. Macroscopic findings, platelet deposition and histologic changes were compared between the laser treated coronary segments and controls, the nonheated laser probe, and the wire alone segments. After 1-second LTA, there was no vessel perforation or occlusive thrombi and only infrequent nonocclusive thrombi; platelet deposition was minimal; and histologic alterations rare and superficial. These findings were comparable to controls, the nonheated laser probe, and the wire alone segments. In contrast, vessels treated for 2, 3, and 5 seconds had more frequent perforation, and occlusive and nonocclusive thrombi that was accompanied by platelet deposition significantly greater than vessels treated with LTA for 1 second. A deep histologic injury was present in most of these segments. Additionally, the safety of laser delivery of 1 second repeated for five times was tested in two additional pigs. On macroscopic and histologic analysis the incidence of vessel perforation, occlusive and nonocclusive thrombi appeared slightly less when compared to the 2-, 3-, and 5-second LTA groups, and more than the 1-second LTA group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Red blood cell and platelet microparticles in myocardial infarction patients treated with primary angioplasty

Background

Red blood cell and platelet microparticles (RBCm and PLTm, respectively) have drawn research attention as to their potential prothrombotic and vasoconstrictive effects in experimental settings. However, the relevance of circulating microparticles in clinical settings is largely undetermined.

Methods

Circulating microparticles were quantified with a flow cytometric method in blood samples from consecutive STEMI patients after primary PCI. A matched cohort of healthy volunteers was used to derive reference values for comparison. STEMI patients were followed for 6 months for a composite clinical endpoint.

Results

Fifty-one STEMI patients (age 59.8 ± 8.8 years) and 50 controls (age 56.2 ± 9.2 years; p = 0.155) were enrolled. RBCm concentration was 18,198 ± 6062/μl in the reference cohort versus 33,740 ± 21,169/μl in STEMI patients (p < 0.001). RBCm count was not correlated to total RBCs (standardized beta 0.018; p = 0.861). PLTm did not differ between groups (17,529 ± 16,292/μl in STEMI patients versus 14,372 ± 6211/μl in controls; p = 0.203). RBCm c-statistic was 0.832 (95% confidence interval 0.720 to 0.944), while PLTm prognostic value was not statistically significant (c-statistic 0.614, 95% confidence interval 0.444 to 0.784). In the multivariate analysis, RBCm concentration was independently associated with the occurrence of the clinical endpoint, after adjustment for age, ejection fraction, serum creatinine and presence of diabetes (adjusted p = 0.034).

Conclusions

The present study demonstrates for the first time that erythrocyte microparticles are elevated in patients with STEMI treated with primary PCI, with levels approximately double those measured in a reference population of healthy volunteers, and their concentrations appear to be positively associated with adverse clinical events.     

Angiographic success and procedural complications in patients undergoing retrograde percutaneous coronary chronic total occlusion interventions: A weighted meta-analysis of 3482 patients from 26 studies

Background

The efficacy and safety profile of retrograde chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study. We sought to perform a weighted meta-analysis of the success and complication rates of retrograde CTO PCI.

Methods

We conducted a meta-analysis of 26 studies published between 2006 and April 2013 reporting in-hospital outcomes of retrograde CTO PCI. Data on procedural success, frequency of death, emergent coronary artery bypass graft surgery (CABG), stroke, myocardial infarction (MI), perforation, tamponade, stent thrombosis, major vascular or bleeding events, contrast nephropathy, and radiation skin injury were collected.

Results

A total of 26 studies with 3482 patients and 3493 target CTO lesions were included. Primary retrograde CTO PCI was attempted in 52.4%. Pooled estimates of outcomes were as follows: procedural success 83.3% [95% confidence interval (CI): 79.0% to 87.7%]; death 0.7% (95% CI: 0.5% to 1.2%); urgent CABG 0.7% (95% CI: 0.4% to 1.2%); tamponade 1.4% (95% CI: 1.0% to 2.2%); collateral perforation 6.9% (95% CI: 4.6% to 10.4%); coronary perforation 4.3% (95% CI: 1.2% to 15.4%); donor vessel dissection 2% (95% CI: 0.9% to 4.5%); stroke 0.5% (95% CI: 0.2% to 1.0%); MI 3.1% (95% CI: 0.2% to 5.0%); Q wave MI 0.6% (95% CI: 0.4% to 1.1%); vascular access complications 2% (95% CI: 0.9% to 4.5%); contrast nephropathy 1.8% (95% CI: 0.8% to 3.7%); and wire fracture and equipment entrapment 1.2% (95% CI: 0.6% to 2.5%).

Conclusions

Retrograde CTO PCI is associated with high procedural success rate and acceptable risk for procedural complications.     

Molecular characterization of a high A2 beta thalassemia by direct sequencing of single strand enriched amplified genomic DNA

Two families, one of Anglo-Saxon-Dutch descent, and the other, West Indian black, have an atypical beta thalassemia characterized by an unusually high level of Hb A2 in the heterozygous state. Restriction endonuclease mapping showed a deletion of about 1.35 kilobase (kb) in the 5' region of the beta globin gene. Direct sequencing of a specific region of genomic DNA amplified by a new modification of the polymerase chain reaction defined the deletion to be 1,393 base pairs (bp) and to be the same in both families. The deletion extends from 485 bp 5' to the mRNA CAP site to the middle of the second intervening sequence. This deletion, together with three others previously described that remove the 5' end of the beta gene but leave the delta gene intact, are all associated with unusually high levels of Hb A2 in the heterozygous state.     

Headache in lacunar stroke

The presence of headache within a 72-h interval of stroke onset was investigated in a cohort of 145 lacunar infarcts. Fourteen (10%) experienced diffuse or bilateral headache. Hypertension was less frequent (43 vs 76%; 95% CI: 6 to 60%) and of shorter duration (2.4 vs 7.8 years; t = 2.29; p = 0.02) among patients with headache. Leukoaraiosis was less frequent (40% vs 71%; 95% CI: −57 to −7%) and severe (7 vs 24%; 95% CI: −33 to −2%) in patients with headache. Age, sex, stroke risk factors, type of lacunar stroke, mode of onset, stroke severity, ultrasound and other CT findings were similar in patients with and without headache. No differences in the sixth month neurological or functional outcome were detected between lacunar patients with and without headache. Headache in lacunar stroke cannot be predicted by the clinical characteristics of the stroke and is not due to coexisting cardiembolism, intra or extracranial disease. Hypertensive small-vessel disease is less common and severe in lacunar strokes with associated headache.     

The 24-hour heart rate behavior in long-term survivors of cardiac transplantation

A detailed computerized analysis of heart rate (HR) behavior during ambulatory monitoring was performed in 19 long-term survivors of cardiac transplantation (12 orthotopic, 7 heterotopic) and in 10 normal volunteers. Compared with normal hearts, the transplanted denervated and the recipient innervated hearts in the heterotopic group showed higher average HRs over the whole 24 hours, the waking and sleeping periods. The rates of the denervated and the recipient hearts did not differ significantly. The maximal HR was similar in all 3 groups, but the minimal HR was lower in the normal hearts than in denervated and recipient hearts. The 24-hour RR interval variability was greatly reduced in the denervated hearts (60 +/- 22 ms) compared with the recipient (89 +/- 26 ms) and normal (151 +/- 38 ms) hearts. During arousal from sleep, the magnitude, time and rate of the HR change were significantly reduced in the denervated hearts compared with the innervated hearts and in the recipient compared with the normal hearts. These findings demonstrate that denervated hearts can show significant variations in HR during the 24-hour period, but to a lesser extent than normal hearts. The widest deviation from normal occurs during sleep, when the denervated heart shows minimal slowing probably due to lack of parasympathetic innervation. In heterotopic transplant recipients, the patients' own HR responses also are significantly blunted.