Therapy Insight: fibromyalgia--a different type of pain needing a different type of treatment

In the past decade, we have made tremendous progress in our understanding of fibromyalgia, which is now recognized as one of many 'central' pain syndromes that are common in the general population. Specific genes that might confer an increased risk of developing fibromyalgia syndrome are beginning to be identified and the environment (in this case exposure to stressors) might also have a significant effect on triggering the expression of symptoms. After developing the syndrome, the hallmark aberration noted in individuals with fibromyalgia is augmented central pain processing. Insights from research suggest that fibromyalgia and related syndromes require a multimodal management program that is different from the standard used to treat peripheral pain (i.e. acute or inflammatory pain). Instead of the nonsteroidal anti-inflammatory drugs and opioids commonly used in the treatment of peripheral pain, the recommended drugs for central pain conditions are neuroactive compounds that downregulate sensory processing. The most efficacious compounds that are currently available include the tricyclic drugs and mixed reuptake inhibitors that simultaneously increase serotonin and norepinephrine concentrations in the central nervous system. Other compounds that increase levels of single monoamines (serotonin, norepinephrine or dopamine), and anticonvulsants also show efficacy in this condition. In addition to these pharmacologic therapies, which are useful in improving symptoms, nonpharmacologic therapies such as exercise and cognitive behavioral therapy are useful treatments for restoring function to an individual with fibromyalgia.     

不同基因型地中海贫血患儿伴铁缺乏的研究

目的 :了解不同基因型地中海贫血 (地贫 )患儿并发铁缺乏的发生率。方法 :对 2 33例临床诊断为地中海贫血的患儿进行点阵列杂交技术基因分析和铁指标检测。结果 :2 33例患儿中并发缺铁的有 5 9例(2 5 .3% ) ;30例α 地贫并发缺铁 9例 (30 % ) ,2 0 3例 β 地贫并发缺铁 5 0例 (2 4 .6 % ) ,差异无统计学意义 (P >0 .2 5 )。HbH病患儿中 ,基因缺失型的缺铁发生率为 33.3% (5 / 15 ) ,非缺失型的缺铁发生率为 12 .5 % (1/ 8) ,前者高于后者 ,但差异无统计学意义 (P >0 .10 )。双重杂合子 β 地贫无缺铁病例 ,而杂合子 β 地贫铁缺乏率为2 6 .7% (5 0 / 16 5 ) ,两者差异有统计学意义 (P <0 .0 1)。结论 :本文发现地贫患儿可并发铁缺乏 ,尤其是杂合子 β 地贫及除非缺失型HbH病外的α 地贫患儿的铁缺乏发生率较高。因此有必要对其进行适当治疗。     

Electrocardiographic morphology changes with different type of repolarization dispersions

Background

T-wave morphology changes have been linked to heterogeneity of ventricular repolarization and increase of arrhythmia vulnerability. Therefore, century-long debates around the genesis of T wave become even more relevant. Here are some interesting questions for the debates: (1) why T waves are usually concordant with QRS complex? (2) Is there a significant and consistent transmural dispersion of repolarization across heart wall? (3) What kind of T-wave morphology changes can be induced by either transmural or apical-basal dispersion of repolarization?

Method

The previously developed GE's cell-to-electrocardiogram (ECG) model (GE Healthcare, Milwaukee, WI) was used to study the relation between cellular behavior and the T-wave morphology. The study focused on 2 types of repolarization dispersions: (1) Transmural (from endocardium to epicardium) and (2) Apical-basal (from apex to base of ventricles). More specifically, the transmural dispersions were created by adjusting the slow and fast delayed potassium rectifier current (Iks, Ikr) and transient outward current (Ito), on endocardial, midmyocardial (M cell) and epicardial cells separately. The apical-basal dispersion was adjusted according to the coordinates along the axis from the base to the apex of the ventricle. The contribution of M cell toward T-wave morphology were studied by adjusting the M cell's repolarization time in the range of shorter to longer than those of endocardial repolarization time.

Results

In the global transmural dispersion cases, QT interval is prolonged from 350 to 450 milliseconds, T-peak to T-end interval (TpTe) is prolonged from 50 to 130 milliseconds, and T-wave notches appeared when the heterogeneity is increased. In the localized transmural dispersion cases, significant T-wave morphology features such as TpTe, T-wave notches appeared in very limited precordial leads. In the global apical-basal dispersion cases, main T-wave change is on the amplitude, and T waves in several precordial leads and lead II turn to positive from negative. And the localized apical-basal dispersion does not generate significant T-wave morphology changes.

Conclusions

The cell-to-ECG model provides a unique way to study electrophysiology and to link physiologic factors to ECG morphology changes. The simulation results suggest that the apical-basal dispersion of repolarization contributes to positive T wave more than the transmural dispersion. The contribution of localized transmural dispersion to surface ECG is very much localized to certain precordial leads.     

Treatment of type III hyperlipoproteinemia with four different treatment regimens

The efficacy of clofibrate (CPIB) and nicotinic acid (NA) in the treatment of type III hyperlipoproteinemia was evaluated in 5 male subjects in a randomized cross-over study with clofibrate 1 g b.i.d. and NA 3 g/day (given either b.i.d. or t.i.d.). Following a baseline period of 6 weeks, each drug was given for 12 weeks with samples for lipid and lipoprotein determinations obtained at 6, 9, and 12 weeks. Both clofibrate and NA resulted in a significant reduction from baseline of total cholesterol (23% and 28%), VLDL cholesterol (49% and 56%), total triglycerides (40% and 43%), and VLDL triglycerides (46% and 48%), as well as a significant increase in HDL cholesterol (22% and 28%) and HDL/LDL ratio (31% and 62%). The HDL/LDL ratio was higher on NA than clofibrate (0.47 +/- 0.19 vs. 0.38 +/- 0.09, P less than 0.05). Four subjects were continued in the study and treated sequentially with NA 3.0 g/day (alternate to the previous schedule) and gemfibrozil 1.2 g/d in divided doses. Each of the 4 regimens resulted in a significant change from baseline of each of the measured lipid and lipoprotein determinations except LDL cholesterol. Comparison among the treatment regimens revealed no differences except for significantly higher HDL cholesterol and HDL/LDL ratio with NA given t.i.d.     

Challenges in diagnosing type 1 diabetes in different populations

Diabetes affects today an estimated 366 million people world-wide, including 20 million to 40 million of patients with type 1 diabetes (T1D). While T1D accounts for 5% to 20% of those with diabetes, it is associated with higher morbidity, mortality and health care cost than the more prevalent type 2 diabetes. Patients with T1D require exogenous insulin for survival and should be identified as soon as possible after diagnosis to avoid high morbidity due to a delay in insulin treatment. It is also important to present to the patient correct prognosis that differs by the type of diabetes. From the research point of view, correct classification should help to identify the etiologies and to develop specific prevention for T1D. This review summarizes evidence that may be helpful in diagnosing T1D in various ethnic groups. Challenges in interpretation of results commonly used to determine the type of diabetes are highlighted.     

Angiotensin II type 1 and type 2 receptors bind angiotensin II through different types of epitope recognition

OBJECTIVE: This study was designed to demonstrate that the principle of molecular recognition underlying high-affinity binding of angiotensin II to the type 2 (AT2) receptor is distinct from that of the type 1 (AT1) receptor. In general, the same functional pharmacophores in hormones are used to bind and activate different subtypes of cell surface receptors. However, the binding of angiotensin II to the AT2 receptor is distinct from that of the AT1 receptor. DESIGN AND METHODS: To systematically evaluate the effect of modification of angiotensin II side chains on binding to both the receptors, several analogs of angiotensin II were synthesized. Rat AT1 or AT2 receptors expressed in COS1 cell membranes were used to determine the affinity of analogs using radioligand competition binding experiments under equilibrium conditions. RESULTS: Modifications of all angiotensin II side chains affected binding to the AT2 receptor to nearly similar extents. In contrast, binding to the AT1 receptor was significantly affected by modifications at side chain positions 2, 4, 6 and 7. In accordance with previous observations that Tyr4- or Phe8-modified angiotensin II analogs antagonized vasoconstriction mediated exclusively by the AT1 receptor, binding to the AT1 receptor was significantly dependent on Tyr4 or Phe8 of angiotensin II whereas binding to the AT2 receptor was not. Rather surprisingly, the affinity profile of several angiotensin II analogs towards the AT2 receptor was similar to the measured affinity of the constitutively active N111G mutant AT1 receptor. CONCLUSIONS: These results suggest that the AT2-receptor pharmacophore is very distinct from that of the AT1 receptor. The AT1 receptor is in a constrained conformation and is activated only when bound to angiotensin II. In contrast, the AT2 receptor is 'relaxed' in that no single interaction is critical for binding, like the N111G mutant AT1 receptor, which is constitutively active.     

Independent evolution of HIV type 1 in different brain regions.

HIV-1-associated brain pathology exhibits regional variability and we therefore studied the genetic differences in the V1-V5 domains of the HIV env gene in up to four regions of brain (frontal lobe, basal ganglia, medial temporal lobe, and nonmedial temporal lobe) from three patients. We found that in each separate brain region HIV-1 forms different quasispecies and that there is little gene flow among these regions. In further support of brain region-specific evolution of HIV-1, we analyzed amino acid signatures in these clones. In addition to known amino acid signatures associated with macrophage tropism and the lack of syncytium formation, we found 15 majority amino acid signature patterns from the V1-V5 env sequences associated with the neuroanatomical regions analyzed from the three individuals. Furthermore, on average, intrabrain genetic distances for the HIV-1 env were estimated to be much smaller than genetic distances between brain regions. Specific strains of HIV-1 may be neurotropic or neuroinvasive (replication preference in brain tissue) and may contribute to pathology, cognitive loss, and neuropsychiatric disease.     

Calcium channel activation: a different type of drug action.

Depolarization of NG108-15 (neuroblastoma-glioma) cells causes an increase in 45Ca2+ influx. This effect is blocked by low concentrations of dihydropyridines such as nitrendipine and by other blockers of voltage-sensitive calcium channels such as D-600, diltiazem, and Cd2+. Two other dihydropyridines, BAY K8644 and CGP 28392, have the opposite effect. Low concentrations of these compounds enhance depolarization-induced 45Ca2+ influxes. BAY K8644 is more effective than CGP 28392. Both agents have no effect on fluxes measured under nondepolarizing conditions. The effects of BAY K8644 and CGP 28392 can be inhibited by nitrendipine, D-600, diltiazem, or Cd2+. Whereas the interaction between nitrendipine and BAY K8644 is shown to be competitive in nature, that between BAY K8644 and D-600 is shown to be noncompetitive. These results indicate that dihydropyridines show a variety of effects on calcium channels, ranging from agonistic through partially agonistic to antagonistic. Moreover, the results also indicate that dihydropyridines and D-600 exert their effects on calcium channels at different sites.     

药桑不同提取物对2型糖尿病大鼠的治疗作用

目的 探讨药桑醇提物与水提物对2型糖尿病(T2DM)大鼠的治疗作用.方法 采用高脂高糖饮食同时腹腔注射链脲佐菌素复制T2DM大鼠模型.将动物随机分为模型组、拜糖平阳性对照、药桑醇提物组(20 mg/kg)和水提物组(20 mg/kg),并设置正常对照组.4 w后处死大鼠取血清测定血糖、果糖胺、血脂生化指标[总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)];取新鲜肝脏测定肝糖原、超氧化物歧化酶(SOD)、丙二醛(MDA).结果 与正常对照组比较,模型组血糖、果糖胺、MDA、TC、TG、LDL-C水平明显升高(P＜0.01),肝糖窄、HDL-C含量、SOD活性明显降低(P＜0.05).与模型组比较,药桑组各项指标有明显改善(P＜0.05).结论 药桑不同提取物可降低血糖、提高机体抗氧化能力,对T2DM大鼠具有一定的治疗作用.     

Weight gain in type 2 diabetics with different treatment modalities

Background: The aim of this study was to study (1) weight gain in type 2 diabetics with different treatment modalities and (2) relationship of weight gain with stable adult weight. Methods: A study of 469 type 2 diabetics on regular follow-up was undertaken to determine the effect of modality of therapy on patient's weight. Stable weight maintained by the patient in good health was ascertained. Weight at visit 1 and subsequently at every follow-up was noted. Patients were grouped as per treatment modality. Weight gain was correlated with pretreatment weight loss, stable weight, and degree of metabolic control. Results: All treatment subgroups showed a steady upward trend of weight gain at 1-year follow-up. Maximum weight gain was seen in the sulphonylurea and insulin (SU + I) group (mean +/- SD, kg; 2.9 +/- 3.8, p < 0.05) followed by the insulin group (1.8 +/- 4.9), SU group (1.2 +/- 2.9), and SU + metformin (MF) + I group (0.6 +/- 2.8), and was the least in the SU + MF group (0.6 +/- 2.9). Weight gain was not significant, except in SU + I group. Addition of metformin prevented weight gain until 9 months follow-up, but the trend reversed on prolonged follow-up. Most patients tended to move towards their stable body weight. Patients with weight loss in the pre-treatment period (n = 253; weight loss 4.1 +/- 1.6 kg) gained significant weight (4.5 +/- 1.9 kg), while those without significant weight loss in the pre-treatment period (n = 216) did not. Weight gain was significant in the good and fair glycemic control groups, but not so in the poor glycemic control group. Conclusions: Only the SU + I group gained significant weight. The weight gain on treatment was significantly related to pre-treatment weight loss. Most patients moved towards their stable body weight with improved metabolic control.     

Real-world outcomes with different technology modalities in type 1 diabetes

Background and aimsSeveral treatment modalities are available for type 1 diabetes (T1D), including continuous glucose monitoring (CGM) and flash glucose monitoring (FGM) with MDI, sensor-augmented pumps with predictive low-glucose suspend function (SAP-PLGS) and hybrid closed-loop systems (HCL). The aim of the study was to evaluate the real-world benefits obtained with these treatment modalities.Methods and resultsA cross-sectional study was performed, selecting 4 groups of T1D subjects, regarding their treatment modalities, paired by age, sex and diabetes duration. A comparison was performed, concerning time in different glucose ranges in 2-week sensor downloads. Estimated HbA1c, glycaemic variability measures and sensor use were also compared.302 T1D people were included (age: 39 ± 12 years, 47% male, diabetes duration: 21 ± 10 years, estimated HbA1c: 7.28 ± 0.84% (56 ± 9 mmol/mol), baseline HbA1c: 7.4 ± 1.0% (57 ± 11 mmol/mol), length of use of the device 8 [3?21] months). Group 1 (CGM + MDI) and 2 (FGM + MDI) showed no differences in time in different glucose ranges. Group 4 (HCL) showed a higher time 70–180 mg/dl and a lower time in hypoglycaemia than group 3 (SAP-PLGS). Group 1 and 2 showed lower time 70–180 mg/dl, higher time in hyperglycaemia and higher glycaemic variability measures than group 3. Group 4 was superior to groups 1 and 2 in all the outcomes.ConclusionReal-life achievements in glycaemic control and glycaemic variability are described. HCL offer the maximum benefit in terms of time in range and hypoglycaemia protection, compared to CGM + MDI, FGM + MDI and SAP-PLGS.     

慢性肝病患者血浆内皮素水平变化的研究

探讨内皮素(ET)在慢性肝病患者中的变化规律.采用非平衡竞争性放射免疫法测定血浆中ET水平.128例慢性肝病患者中的ET水平分别为慢性轻度肝炎(50.46±32.74)pg/ml;慢性中度肝炎(51.16±30.69)pg/ml;慢性重度肝炎(63.61±24.86)pg/ml;肝硬化代偿期(43.78±18.97)pg/ml;肝硬化失代偿期(79.29±14.02)pg/ml;肝癌(77.00±59.20)pg/ml.各型慢性肝病的El水平与正常(32.33±3.70)pg/nl比较有显著性升高(P＜0.01).各型之间有显著性差异(P＜0.01).结论 ET随着肝脏损害程度加重而升高,与肝病的慢性化程度相关,ET越高,预后越差.     

Pathogenesis and classification of intrahepatic cholangiocarcinoma: different characters of perihilar large duct type versus peripheral small duct type

Intrahepatic cholangiocarcinomas (ICCs) are made up of heterogenous carcinomas arising from different anatomical sites of the liver. Two types of candidate stem/progenitor cells of the biliary tree are postulated to exist at the peribiliary glands for large bile ducts and at the canals of Hering for small ducts and hepatocytes. According to the recent observations, ICCs can be subclassified into two types: tumors involving the large bile ducts comparable in size to the intrahepatic second branches and composed of a tubular or papillary component with tall columnar epithelium, and tumors involving the smaller duct than segmental branches and composed of small tubules with cuboidal epithelium. Perihilar large duct type ICCs can be interpreted as arising from large bile duct type ICCs, and peripheral small duct type ICCs may arise from small bile duct type or ductular type ICCs. Chronic biliary inflammation induces neoplastic change of the large bile ducts and thereby progression to the perihilar large duct type ICC, which can be grossly classified into periductal filtrating type ICC and intraductal growth type ICC, while chronic hepatitis or cirrhosis induces mass‐forming peripheral small duct type ICC. The different morphological and molecular features, including stromal components and tumor vasculature, support the hypothesis that perihilar large duct type ICCs and peripheral small duct type ICCs arise from different backgrounds, have different carcinogenetic pathways, and exhibit different biologic behaviors.     

不同膳食替代对超重2型糖尿病患者的影响

目的 探讨部分膳食替代(PMR)和完全膳食替代(CMR)对超重2型糖尿病患者血糖控制及生活质量的影响.方法 以在天津市大港油田总医院糖尿病科门诊就诊的超重2型糖尿病患者60例作为研究对象,按照随机数字法分为对照组、CMR组和PMR组,干预3个月.CMR组每天采用特殊膳食完全替代早餐,PMR组每天3餐前服用少量特殊膳食,并适当减少正餐量.采用酶比色法检测HbAl c,计算稳态模型评估-胰岛素抵抗指数(HOMA-IR)、体重指数,通过问卷调查了解糖尿病痛苦情况及生活质量.结果 研究结束后,与对照组相比,CMR组和PMR组HbA1c[(7.6±0.7)％比(8.2±0.8)％,(7.7±0.4)％比(8.2±0.8)％]、HOMA-IR[(4.3±1.2)比(6.0±2.0),(4.7±1.4)比(6.0±0.2)]均明显降低(P均＜0.05).PMR组与CMR组相比,在改善糖尿病痛苦[(25.9±2.8)比(27.7±2.4)]及生活质量[(73.8±4.1)比(70.2±4.2)]方面具有明显的优势(P均＜ 0.05).结论 PMR在改善糖、脂代谢的效果与CMR相当,但PMR更有利于减轻尿病患者的心理压力,提高其生活质量.     

八家不同类型结核病定点医院肺结核网络报告情况分析

目的 评价专科医院和综合医院两种不同类型的结核病定点医院肺结核网络报告情况。方法 选择镇江、宜昌和汉中3个地市级定点医院，并采用分层随机抽样方法分别在每个地市按人均GDP水平分别各抽取3个县（区）级定点医院，排除被确定为结核病定点医院时间少于1年的医院，最终确定3家专科医院和5家综合医院作为调查点，通过核查定点医院门诊科室和住院部在2012年第4季度的工作日志，统计发现所有肺结核患者共659例，并与传染病网络直报系统进行比较分析网络报告情况；以Excel 2007软件建立数据库和进行数据整理和数据统计，不同结果之间的比较采用卡方检验，P〈0.05为差异有统计学意义。结果 被调查医院肺结核网络报告率为89.4%（589/659），其中专科医院和综合医院网络报告率分别为91.4%（374/409）和86.0%（215/250），差异有统计学意义（χ^2=4.84，P〈0.05）；专科医院结核病门诊、非结核门诊和住院部报告肺结核者分别占45.5%（170/374）、19.3%（72/374）和35.3%（132/374），综合医院结核病门诊、非结核门诊和住院部报告肺结核者分别占50.7%（109/215）、29.8%（64/215）和19.5%（42/215），专科医院和综合医院不同科室报告肺结核的比例差异有统计学意义（χ^2=18.81，P〈0.01），未进行网络报告的科室主要为门诊科室，占61.4%（43/70）。结论 两种类型的定点医院肺结核网络报告总体情况较好；专科医院报告水平高于综合医院。