异常心电图的自动分析与诊断

目的当前自动诊断系统中,专家系统不具备学习功能,神经网络系统由于"黑箱"特性缺乏可解释性,因此提出一种结合专家系统和神经网络优势的心电图自动诊断算法。方法本系统包含有特征提取模块、诊断矩阵模块和诊断推理模块等主要模块。在诊断系统的实现过程中,首先从心电信号中提取语义特征,然后结合描述语义特征与病类关系的诊断矩阵计算出该患者患每种疾病的可能性概率,最后根据阈值判断患者所患的疾病。在实验验证部分,利用系统以前没有诊断过的数据进行了测验,通过分析诊断的准确率对系统进行了验证。结果从Physio Bank数据库提取了1200条数据进行预测和结果分析,平均准确率为95.2%。结论本文提出的心电图自动诊断算法,以语义特征作为诊断依据,结合了神经网络和专家系统二者的优势,在各种病类的诊断上准确率都较高。     

Postoperative atrial fibrillation and mortality after coronary artery bypass surgery

OBJECTIVES: We sought to determine if the occurrence of postoperative atrial fibrillation (AF) affects early or late mortality following coronary artery bypass surgery (CABG). BACKGROUND: Atrial fibrillation is the most common arrhythmia seen following CABG. METHODS: The Texas Heart Institute Cardiovascular Research Database was used to identify all patients that developed AF after isolated initial CABG from January 1993 to December 1999 (n = 994). This population was compared with patients who underwent CABG during the same period but did not develop AF (n = 5,481). In-hospital end points were adjusted using logistic regression models to account for baseline differences. Long-term survival was evaluated using a retrospective cohort design, where Cox proportional hazards methods were used to adjust for baseline differences, and with case-matched populations (n = 390, 195 per arm). RESULTS: Atrial fibrillation was diagnosed in 16% of the population. Postoperative AF was associated with greater in-hospital mortality (odds ratio [OR] 1.7, p = 0.0001), more strokes (OR 2.02, p = 0.001), prolonged hospital stays (14 vs. 10 days, p < 0.0001), and a reduced incidence of myocardial infarction (OR 0.62, p = 0.01). At four to five years, survival was worse in patients who developed postoperative AF (74% vs. 87%, p < 0.0001 in the retrospective cohort; 80% vs. 93%, p = 0.003 in the case-matched population). On multivariate analysis, postoperative AF was an independent predictor of long-term mortality (adjusted OR 1.5, p < 0.001 in the retrospective cohort; OR 3.4, p = 0.0018 in the case-matched population). CONCLUSIONS: The occurrence of AF following CABG identifies a subset of patients who have a reduced survival probability following CABG. The impact of various strategies, such as antiarrhythmics and warfarin, aimed at reducing AF and its complications deserves further study.     

低度屈光不正对中年干眼患者的影响

目的 探讨低度屈光不正对中年干眼患者眼部症状的影响,为干眼患者选择安全合理的治疗措施.方法 选取在我院眼科门诊就诊的年龄为40 ～ 60岁,屈光度为-3.00～ +3.00D的干眼患者191例(373眼),对所有入选病例进行干眼常规检查和干眼症状评分,同时对所有患者进行医学验光并按照初诊时屈光度分成3组:正视组:-0.50～ +0.25 D,不伴散光,64例125眼;近视组:-0.75～-3.00 D,68例131眼;远视组:+0.50～ +3.00 D,59例117眼.结合分组情况对患者进行相应的屈光矫正,并给予人工泪液及糖皮质激素眼液滴眼.治疗1个月后随访,对结果进行统计学分析.结果 3组患眼初诊时客观体征间差异均无统计学意义(均为P ＞0.05),但远视组患者的症状评分为(25.61±8.07)分,明显高于正视组的(15.43±5.27)分和近视组的(17.19±6.34)分(均为P＜0.05),而正视组和近视组之间差异无统计学意义(P＞0.05).远视组117眼中,戴镜矫正合并干眼治疗者63眼,仅接受干眼治疗者54眼,治疗1个月后戴镜矫正组症状评分与治疗前的差值为(8.89±1.74)分,明显高于未矫正组的(4.73±3.57)分,差异有统计学意义(P＜0.05).近视组是否戴镜矫正联合干眼治疗并未表现出统计学上的疗效差异.结论 对合并屈光不正的中年干眼患者,尤其是低度远视患者,给予恰当的屈光矫正可以明显改善干眼症状.     

Role of Components in the Formation of Self-microemulsifying Drug Delivery Systems

Components:In order to formulate a successful SMEDDS for maximum therapeutic effect, due consideration must be given to various factors such as physicochemical properties of the active moiety as well as excipients, potential for drug excipient interaction (in vitro and in vivo) and physiological factors that promote or inhibit the bioavailability. Further, other important factors such as regulatory status, solubilization capacity, miscibility, physical state of the excipients at room temperature, digestibility and compatibility with capsule shell, chemical stability and cost of the materials should also be considered during the formulation[15]. Such a rationale approach not only helps in reducing the time involved in the formulation development but also reduces the cost of its development[11].

Oil/lipid phase:

The function of oil phase in self-microemulsifying system is to solubilize the hydrophobic/lipophilic active moiety in order to improve both drug loading and bioavailability of the hydrophobic active moiety. Selection of oil plays a vital role in the formulation as it determines the amount of drug that can be solubilized in the system[16]. A lipid molecule with a large hydrophobic portion compared to hydrophilic portion is desirable as it maximizes the amount of drug that can be solubilized. Open in a separate windowLIST OF OILS USED IN FORMULATION OF SMEDDS

Long chain triglycerides:

Lipids that have fatty acid chains of 14-20 carbons are categorized as LCTs[17]. Fixed oils i.e., vegetable oils contain a mixture of glyceride esters of unsaturated long chain fatty acids. These are considered safe as they are commonly present in daily food and are easily digestible[15]. Large hydrophobic portion of triglycerides is responsible for their high solvent capacity for lipophilic moieties. Though it is difficult to microemulsify, some marketed formulations such as Neoral^® (composed of olive oil which, has shown superior oral bioavailability) and Topicaine^® gel (composed of Jojoba oil for transdermal application) have been successfully practicing the microemulsification of LCTs[18].

Medium chain triglycerides and related esters:

Lipids that have fatty acid chains of 6-12 carbons are categorized as MCTs[17]. MCTs are the most common choice of oil for SMEDDS as they are resistant to oxidation and possess high solvent capacity compared to LCT because of their high effective concentration of ester group. MCTs produced from the distillation of coconut oil are known as glyceryl tricaprylate and comprises of saturated C8 and C10 fatty acids in the liquid state[15]. Labrafac CM 10, a MCT, has shown superior solubility for fenofibrate and produced wider microemulsion region at all surfactant/co-surfactant combinations than Maisine 35, which, is a LCT[19]. Drug substance should possess minimum solubility of 50 mg/ml in LCTs for lymphatic absorption[20]. Upon digestion, products of short and medium chain triglycerides are directed towards portal vein whereas chylomicrons formed from LCTs triggers the lymphatic transport. Further, highly hydrophobic drug substances are easily soluble in vegetable oils and can easily be formulated as simple oil solutions which are readily emulsified in the gut. However, most conventional hydrophobic drug substances do not exhibit superior solubility in LCT such as vegetable oil[21,22].Moderately hydrophobic drug substances, on the other hand, cannot be formulated into simple oil solutions as their solubility is limited. In such cases, SMEDDS are promising alternative where the drug solubility in the oil will be enhanced due to microemulsification of oil by surfactants. It is well accepted that oils with long hydrocarbon chains (high molecular volume) such as soybean oil, castor oil are difficult to microemulsify compared to MCT (low molecular volume) such as capmul MCM and Miglyol. However, solubilizing capacity of oil for lipophilic moiety increases with chain length (hydrophobic portion) of the oil. Hence the selection of oil is a compromise between the solubilizing potential and ability to facilitate the formation of microemulsion[23]. Malcolmson et al. studied the solubility of testosterone propionate in various oils for the formulation of O/W microemulsion and concluded that oils with larger molecular volume such as triglycerides show superior solubility than the corresponding micellar solution containing only surfactants without oil[24,25]. Enhancement of drug solubility in SMEDDS not only relies on the solubility of the drug in the oil but also on the surfactant(s). For instance, ethyl butyrate, small molecular volume oil, has shown higher solubility for testosterone propionate but its ME formulation has only improved the solubility slightly than the corresponding micellar solution. On the contrary, Miglyol 812 which is a larger molecular volume oil has shown improved solubilization in the ME formulation though the solubility of testosterone propionate is less in the individual components compared to ethyl butyrate[24].

Drug solubility in lipid:

Oil component alters the solubility of the drug in SMEDDS by penetrating into the hydrophobic portion of the surfactant monolayer. Extent of oil penetration varies and depends on the molecular volume, polarity, size and shape of the oil molecule. Overall drug solubility in SMEDDS is always higher than the solubility of drug in individual excipients that combine to form SMEDDS. However, such higher solubility considerably depends on the solubility of drug in oil phase, interfacial locus of the drug and drug-surfactant interactions at the interface[26]. In light scattering experiments, it was observed that oils with small molecular volume act like co-surfactants and penetrate into the surfactant monolayer. This forms thinner polyoxyethylene chains near the hydrophobic core of the micelle disrupting the main locus of the drug solubilization due to which, a higher solubility of drug is not observed. Large molecular volume oils, however, forms a distinct core and do not penetrate effectively into the surfactant monolayer. The locus of drug solubilization was found to be effected by the microstructure and solubility of the drug in the excipients. The locus of drug solubilization was found to be at the interface of micelle for phytosterols whereas the same for cholesterol was found to be between the hydrophobic head groups of surfactant molecules. This is attributed to altered side chain flexibility of phytosterol due to the additional substitution of alkyl side chain compared to cholesterol[27].In addition to molecular volume and polarity of the oil, drug solubility in oil is affected by physicochemical properties of drug molecule itself. Consideration of BCS classification and Lipinski''s rule of 5 for the selection of drug is only useful during initial screening stages. As per BCS classification, some of the acidic drugs are listed in Class II despite having good absorption and disposition as they do not satisfy the requirement of higher solubility at low pH values. Lipinski''s rule of 5, on the other hand, holds good only when the drug is not a substrate for the active transporter[4]. This suggests that aqueous solubility and log P alone are not sufficient to predict the solubility of drug in the oil. This further indicates that the solubility of any two drugs with similar log P would not be the same due to their different physicochemical properties.To demonstrate this, a study was conducted in our laboratory with two antihypertensive drugs having close partition coefficient (log P) values, different aqueous solubility and varying physicochemical properties. Candesartan cilexetil is hydrophobic and has log P value of 7.3, molecular weight 610.66 g/mol with a polar surface area 135.77 whereas, valsartan is slightly soluble in aqueous phase with log P value of 5.3, molecular weight 434.53 g/mol with a polar surface area 103.48 (clogP and polar surface area were calculated using chembiodraw ultra 11.0). Unlike candesartan cilexetil, valsartan exhibits pH dependent solubility[28].If only log P and aqueous solubility of these two drugs are considered, it is only natural to assume that candesartan cilexetil would be highly soluble in lipid phase whereas valsartan would be less soluble. A specific and sensitive HPLC-UV method was developed and validated to measure the super saturation solubility of these two drugs in various oils and the results showed a completely different solubility profiles. Solubility profile of these two drugs in different oil phase is given in fig. 2.Open in a separate windowFig. 2Solubility of active ingredients in various oils. Valsartan, candesartan cilexetil.Although log P and polar surface area of valsartan and candesartan cilexetil are closer, their solubility with triacetin, castor oil and capmul MCM C8 differs significantly. This may be attributed to the hydrogen bonding capacity and electrostatic interaction of both the scaffold with the oils. Nevertheless, valsartan is having aliphatic carboxylic group which is expected to be involved in hydrogen bond interaction with the hydrogen acceptor functionality of the triacetin as well as castor oil. We assume that the branched chain aliphatic ester moiety of triacetin, capmul MCM C8 and castor oil gets involved in the electrostatic repulsion with cilexetil part of candesartan. In case of valsartan, such electrostatic interactions are not possible. Furthermore, aliphatic ester chain of triacetin and castor oil may solvate the lipophilic chain of valsartan more favorably than candesartan in the absence of any electrostatic repulsion (proposed interaction is shown in fig. 3). However, significant difference was not observed with other oils such as olive oil, peanut oil, corn oil, miglyol 810, sunflower oil and soybean oil (data not shown).Open in a separate windowFig. 3Proposed interactions of valsartan and candesartan cilexetil with triacetin.     

Insulin-like growth factors-I and -II differentially regulate endogenous acetylcholine release from the rat hippocampal formation

Insulin-like growth factors-I and -II (IGF-I and -II) are structurally related mitogenic polypeptides with potent growth promoting effects. These peptides and their corresponding IGF-I and -II receptors are selectively localized in the brain. To date, most of the effects of IGFs are believed to be mediated by IGF-I receptors whereas the significance of IGF-II receptor in mediating biological responses remains unclear. In the present study, we characterized the distribution of IGF-I and IGF-II receptor sites and investigated the effects of both factors on endogenous acetylcholine (ACh) release in adult rat hippocampus. [¹²⁵I]IGF-I receptor binding sites are recognized by IGF-I> IGF-II> insulin, whereas [¹²⁵I]IGF-II binding was competed potently by IGF-II> IGF-I but not by insulin. At the cellular level, IGF-I receptor sites were primarily noted in the molecular layer of the dentate gyrus and the CA2-CA3 subfields of the Ammon’s horn whereas IGF-II sites were localized predominantly in the pyramidal cell layer of the CA1-CA3 subfields and in the granular cell layer of the dentate gyrus. IGF-I (10⁻¹⁴–10⁻⁸ M) and des(1–3) IGF-I (10⁻¹⁰–10⁻⁸ M) were found to inhibit whereas IGF-II (10⁻¹⁴–10⁻⁸ M) potentiated K⁺-evoked ACh release from hippocampal slices. Tetrodotoxin altered the effects of IGF-I but not those of IGF-II suggesting that IGF-I acts indirectly via the release of other modulators whereas IGF-II acts directly on or in close proximity to the cholinergic terminals. The inhibitory effects of IGF-I were also observed in the frontal cortex but not in the striatum. In contrast, the stimulatory effects of IGF-II were evident both in the frontal cortex and striatum. Taken together, these results reveal the differential localization of IGF-I and IGF-II receptor sites in the hippocampal formation and the opposite role for these growth factors in the acute regulation of ACh release likely via two distinct mechanisms. Additionally, these data provide the first evidence for a direct role for IGF-II and its receptors in the regulation of transmitter release in the central nervous system.     

Anti-cholesterol antibodies (ACHA) in patients with different atherosclerotic vascular diseases and healthy individuals. Characterization of human ACHA

In animal experiments the protective role of anti-cholesterol antibodies (ACHA) in the development of atherosclerosis has been demonstrated. Despite the fact that ACHA are present in the serum of healthy humans, no data on the occurrence of these antibodies in human diseases are available. We determined serum concentrations of IgG type ACHA by an enzyme immunosorbent assay in 600 patients with atherosclerotic vascular diseases (86 patients with peripheral occlusive atherosclerosis, 146 patients with cerebrovascular diseases, 341 patients with severe coronary heart disease (CHD) who received aorto-coronary by-pass, 27 patients with myocardial infarction who did not undergo by-pass operation), in 57 patient controls (complaints of CHD, without coronarographic alterations) and in 218 healthy individuals. ACHA were present in the sera of all persons tested. No serum cofactor is needed for the binding of human ACHA to solid phase cholesterol, binding can be inhibited dose-dependently by LDL and even more strongly with LDL/VLDL preparations purified from human serum. ACHA levels were found to be considerably lower in patients with peripheral occlusive atherosclerosis and cerebrovascular diseases compared with the levels in healthy individuals. By contrast, the ACHA levels of patients with CHD were considerably higher. No differences in the IgG subclass distribution and binding efficiency of ACHA in the sera of CHD patients and controls were found. Thus, our present findings indicate that both low and high ACHA production may be associated with different atherosclerotic vascular diseases.     

Influence of quasispecies on virological responses and disease severity in patients with chronic hepatitis C

AIM： To elucidate the influence of quasispecies on virological response and disease severity in patients with chronic hepatitis C.
METHODS： Forty seven patients with hepatitis C [32 with chronic active hepatitis （CAH）, 9 with cirrhosis, and 6 with hepatocellular carcinoma （HCC）] were screened for the presence of quasispecies by single stranded conformational polymorphism （SSCP） analysis in the hypervariable region （HVR） and non-structural 5B （NS5B） viral genes of hepatitis C virus. The 41 patients excluding those with HCC were on therapy and followed up for a year with the determination of virological response and disease severity. Virus isolated from twenty three randomly selected patients （11 non-responders and 12 showing a sustained virological response） was sequenced for the assessment of mutations.
RESULTS： The occurrence of quasispecies was proportionately higher in patients with HCC and cirrhosis than in those with CAH, revealing a significant correlation between the molecular evolution of quasispecies and the severity of disease in patients with hepatitis C. The occurrence of complex quasispecies has a significant association （P 〈 0.05） with the non-responders, and leads to persistence of infection. Significant differences （P 〈 0.05） in viral load （log10 IU/mL） were observed among patients infected with complex quasispecies （CQS）, those infected with simple quasispecies （SQS） and those with no quasispecies （NQS）, after 12 wk （CQS-5.2 ± 2.3, SQS-3.2 ± 1.9, NQS-2.8 ± 2.4） and 24 wk （CQS-3.9 ± 2.2, SQS-3.0 ± 2.2, NQS-2.1 ± 2.3） in the HVR region. However, a statistically significant difference （P 〈 0.05） was observed between the viral loads of patients infected with CQS and those infected with NQS in NS5B viral gene after 24 wk （CQS-3.9 ± 2.2, SQS-3.0 ± 2.2, and NQS-2.1 ± 2.3） and 48 wk （CQS-3.1 ± 2.7, SQS-2.3 ± 2.4, NQS-2.0 ± 2.3） of therapy. Disease severity was significantly associated with viral load during th     

Investigation of malaria prevalence at National Thermal Power Corporation, Shaktinagar, Sonbhadra District (Uttar Pradesh), India.

Malaria in industrial complexes is promoted by extensive mosquitogenic potential generated by excavations and importation of parasite through migratory labor. The National Thermal Power Corporation (NTPC), Shaktinagar, Sonbhadra district was surveyed for malariogenic conditions from 1994 to 1996. The major mosquito breeding sites were drains, storm-water drains, lakes, outside tanks, overhead tanks, sluice-valve chambers, ornamental tanks, wells, pit wells and water reservoirs, etc. Anopheles culicifacies was the major vector of malaria in this area. Sibling species identification of An. culicifacies revealed that species C predominated during the transmission season and responsible to transmit malaria. Insecticide susceptibility tests against An. culicifacies sl showed that An.culicifacies population was 100% susceptible to malathion, fenitrothorn and deltamethrin while it was found 44% resistant to DDT. The malaria cases recorded in 1994, 1995 and 1996 were 847, 590 and 409 respectively. In vitro study on P. falciparum cases showed that 41, 70, 50% of the isolates tested were resistant to chloroquine in 1994, 1995 and 1996 respectively while an in vivo follow-up study showed 20-30% P. falciparum cases resistant to chloroquine. An integrated approach involving alternate vector control measures along with judicious use of insecticides has been suggested to bring down malaria in industrial complexes.