Nonlinear Analysis of Fibrillatory Electrogram Similarity to Optimize the Detection of Complex Fractionated Electrograms During Persistent Atrial Fibrillation

Nonlinear Analysis of Atrial Fibrillation . Introduction: Currently, the identification of complex fractionated atrial electrograms (CFEs) in the substrate modification is mostly based on cycle length‐derived algorithms. The characteristics of the fibrillation electrogram morphology and their consistency over time are not clear. The aim of this study was to optimize the detection algorithm of crucial CFEs by using nonlinear measure electrogram similarity. Methods and Results: One hundred persistent atrial fibrillation patients that underwent catheter ablation were included. In patients who required CFE ablation (79%), the time‐domain fibrillation signals (6 seconds) were acquired for a linear analysis (mean fractionation interval and dominant frequency [DF]) and nonlinear‐based waveform similarity analysis of the local electrograms, termed the similarity index (SI). Continuous CFEs were targeted with an endpoint of termination. Predictors of the various signal characteristics on the termination and clinical outcome were investigated. Procedural termination was observed in 39% and long‐term sinus rhythm maintenance in 67% of the patients. The targeted CFEs didn't differ based on the linear analysis modalities between the patients who responded and did not respond to CFE ablation. In contrast, the average SI of the targeted CFEs was higher in termination patients, and they had a better outcome. Multivariate regression analysis showed that a higher SI independently predicted sites of termination (≥0.57; OR = 4.9; 95% CI = 1.33–18.0; P = 0.017). Conclusions: In persistent AF patients, a cycle length‐based linear analysis could not differentiate culprit CFEs from bystanders. This study suggested that sites with a high level of fibrillation electrogram similarity at the CFE sites were important for AF maintenance. (J Cardiovasc Electrophysiol, Vol. 24, pp. 280‐289, March 2013)     

A high performance liquid chromatographic assay of cis- and trans- isomers of tricyclic neuroleptic drugs

Tricyclic neuroleptics based upon the thioxanthene nucleus exhibit geometrical isomerism and the major pharmacological activity resides in the Z-component. An h.p.l.c. procedure which enables the separation detection and quantification of these isomers is described. The method is applicable to the analysis of flupenthixol, clopenthixol, chlorprothixene, doxepin and dothiepin. Measurement of the isomer-ratios in various samples of flupenthixol has shown that small batch to batch variations are apparent. The determination of the isomer-ratio in formulations has been shown to rely upon the complete extraction of the medicament. This is due to the differential release of the components from the tablet matrix with the cis-isomer being favoured. There is little difference observed between the adsorption isotherms of the two components (onto charcoal) but in competition experiments differential adsorption may be demonstrated. This has clear implications for the pharmacokinetics of these drugs.     

Child health statistical review, 1996

There is much evidence that the children born in the last decade of the 20th century are healthier and living longer than children born earlier this century, and that children born too small or too soon are now more likely to reach adulthood than similar children born 10 or 20 years ago. Yet measures of social disadvantage (poverty, underachievement in education, lone parenthood) are increasing, putting this generation of children at higher risk of morbidity later in life.     

原发性胆囊癌的临床诊治分析

目的　总结原发性胆囊癌的诊治经验 ,探讨其诊断与治疗的有效途径。方法　回顾性分析 1981年 1月～ 2 0 0 2年 8月间收治的 3 6例原发性胆囊癌病例的临床病理资料。结果　 3 6例原发性胆囊癌患者中 ,有胆道病史者 2 5例 ( 69.44 % ) ;术前B超诊断符合率为 65 .3 8% ,CT诊断符合率为 85 .0 0 % ;全部病例均经手术治疗 ,肿瘤切除率为 5 8.3 3 % ;随访率 83 .3 3 % ,NevinⅠ期 2例均生存 5年以上 ,Ⅱ～Ⅳ期患者平均生存 2 2个月 ,Ⅴ期患者平均生存 13个月 ,仅行剖腹探查者平均生存期仅 3个月。结论　提高原发性胆囊癌疗效的关键在于早期诊断 ,手术是治疗胆囊癌的首选方法 ,对有癌变倾向的胆囊病变行预防性切除 ,是预防胆囊癌的有效措施     

减重步行训练对缺血性脑卒中后抑郁患者疗效及生活质量的影响

目的 观察减重步行训练对缺血性脑卒中后抑郁障碍患者疗效及生活质量的影响。方法 共选取60例缺血性脑卒中后抑郁患者，将其随机分为训练组和对照组（每组30例）。对照组每天给予神经内科药物治疗及常规康复锻炼，训练组在此基础上辅以减重步行训练。2组患者治疗前、后分别采用改良爱丁堡-斯堪的那维亚评分标准（MESSS）评定其神经功能缺损程度，采用汉密尔顿抑郁量表（HAMD）进行抑郁程度评分，采用Fugl-Meyer评分（FMA）及Barthel指数（BI）评定其步行、平衡能力及ADL水平。结果 2组患者分别经4周治疗后，其MESSS、HAMD、FMA及BI评分等均较治疗前有明显改善；治疗后2组间比较，训练组各项指标改善程度均明显优于对照组，差异均有统计学意义（P〈0．05）。结论 对缺血性脑卒中后抑郁症患者尽早实施减重步行训练，町以显著改善患者的抑郁症状、步行、平衡及ADL功能，使其生活质量进一步提高。     

Idiopathic recurrent calcium urolithiasis (IRCU): pathophysiology evaluated in light of oxidative metabolism,without and with variation of several biomarkers in fasting urine and plasma - a comparison of stone-free and -bearing male patients,emphasizing mineral,acid-base,blood pressure and protein status

Background

IRCU is traditionally considered as lifestyle disease (associations with, among others, overweight, obesity, hypertension, type-2 diabetes), arising from excess, in 24 h urine, of calcium (Ca) salts (calcium oxalate (CaOx), calcium phosphate (CaPi)), supersaturation of, and crystallization in, tubular fluid and urine, causing crystal-induced epithelial cell damage, proteinuria, crystal aggregation and uroliths.

Methods

Another picture emerges from the present uncontrolled study of 154 male adult IRCU patients (75 stone-bearing (SB) and 79 age-matched stone-free (SF)), in whom stone-forming and other parameters in fasting urine and plasma were contrasted with five biomarkers (see footnote) of oxidative metabolism (OM), without and with variation of markers.

Results

1) In SB vs. SF unstratified OM biomarkers were statistically unchanged, but the majority of patients was overweight; despite, in SB vs. SF urine pH, total and non-albumin protein concentration were elevated, fractional urinary uric acid excretion and blood bicarbonate decreased, whereas urine volume, sodium, supersaturation with CaOx and CaPi (as hydroxyapatite) were unchanged; 2) upon variation of OM markers (strata below and above median) numerous stone parameters differed significant!)'', among others urine volume, total protein, Ca/Pi ratio, pH, sodium, potassium, plasma Ca/Pi ratio and parathyroid hormone, blood pressure, renal excretion of non-albumin protein and other substances; 3) a significant shift from SF to SB patients occurred with increase of urine pH, decrease of blood bicarbonate, and increase of diastolic blood pressure, whereas increase of plasma uric acid impacted only marginally; 4) in both SF and SB patients a strong curvilinear relationship links a rise of urine Ca/Pi to urine Ca/Pi divided by plasma Ca/Pi, but in SB urine Ca/Pi failed to correlate significantly with urine hydroxyapatite supersaturation; 5) also in SB, plasma Ca/Pi and urinary nitrate were negatively correlated, whereas in SF plasma Ca/Pi ratio, PTH and body mass index correlated positively; 6) multivariate regression analysis revealed that PTH, body mass index and nitrate together could explain 22 (p = 0.002) and only 7 (p = 0.06) per cent of variation of plasma Ca/Pi in SF and SB, respectively

Conclusions

In IRCU a) numerous constituents of fasting urine, plasma, blood and blood pressure change in response to variation of OM biomarkers, suggesting involvement of OM imbalance as factor in functional deterioration of tissue; b) in the majority of patients a positive exponential relationship links urine Ca/Pi to urine Ca/Pi divided by plasma Ca/Pi, presumably to accumulate Ca outside tubular lumen, thereby minimizing intratubular and urinary Ca salt crystallization; c) alteration of interactions of low urine nitrate, PTH and Ca/Pi in plasma may be of importance in formation of new Ca stone and co-regulation of dynamics of blood vasculature; d) overweight, combined with OM-modified renal interstitial environment appears to facilitate these processes, carrying the risk that CaPi mineral develops within or/and close to blood vessel tissue, and spreads towards urothelium.For future research focussing on IRCU pathogenesis studies are recommended on the role of affluent lifestyle mediated renal ischemia, mild hypertensive nephropathy, rise of uric acid precursor oxypurines and uricemia, clarifying also why loss of significance of interrelationships of OM biomarkers with traditional Ca stone risk factors is characteristic for SB patients.

OM biomarkers

Plasma uric acid - Discussed as scavenger of reactive oxygen species, but also as donator (via the xanthine oxido-reductase reaction)Urinary malonedialdehydc - Accepted as indicator of peroxidation of lipids within biological cell membranesUrinaiy nitrate - Accepted as indicator of vasodilation-mediating nitric oxide production by blood vessel endotheliumUrinary malonedialdehyde/Plasma uric acid - Tentative markers of oxidant/antioxidant imbalanceUrinary nitrate/Plasma uric acid - Tentative markers of oxidant/antioxidant imbalance     

The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases in vitro drug delivery across blood–brain barrier cells

BACKGROUND AND PURPOSE

The passage of drugs across the blood–brain barrier (BBB) limits the efficacy of chemotherapy in brain tumours. For instance, the anticancer drug doxorubicin, which is effective against glioblastoma in vitro, has poor efficacy in vivo, because it is extruded by P-glycoprotein (Pgp/ABCB1), multidrug resistance-related proteins and breast cancer resistance protein (BCRP/ABCG2) in BBB cells. The aim of this study was to convert poorly permeant drugs like doxorubicin into drugs able to cross the BBB.

EXPERIMENTAL APPROACH

Experiments were performed on primary human cerebral microvascular endothelial hCMEC/D3 cells, alone and co-cultured with human brain and epithelial tumour cells.

KEY RESULTS

Statins reduced the efflux activity of Pgp/ABCB1 and BCRP/ABCG2 in hCMEC/D3 cells by increasing the synthesis of NO, which elicits the nitration of critical tyrosine residues on these transporters. Statins also increased the number of low-density lipoprotein (LDL) receptors exposed on the surface of BBB cells, as well as on tumour cells like human glioblastoma. We showed that the association of statins plus drug-loaded nanoparticles engineered as LDLs was effective as a vehicle for non-permeant drugs like doxorubicin to cross the BBB, allowing its delivery into primary and metastatic brain tumour cells and to achieve significant anti-tumour cytotoxicity.

CONCLUSIONS AND IMPLICATIONS

We suggest that our ‘Trojan horse’ approach, based on the administration of statins plus a LDL receptor-targeted liposomal drug, might have potential applications in the pharmacological therapy of different brain diseases for which the BBB represents an obstacle.