木通马兜铃化学成分研究

从木通马兜铃(Aristolochia manshuriensis Kom)茎皮中分得一个新化合物(5),经光谱(IR,UV,HRMS,^{1HNMR,NOEDS)鉴定为3,4-二甲氧基-10-硝基菲-1-羧酸甲酯,命名为马兜铃酸BII甲酯。另11个已知化合物是马兜铃酸Ⅰ,Ⅱ,Ⅲa,Ⅳ,Ⅳa,对羟基桂皮酸,β-谷甾醇,豆甾烷-3,6-二酮,6-羟基-豆甾-4-烯-3-酮,胡萝卜甙,二十八酸甘油单酯;其中二十八酸甘油单酯为首次从该属植物中分得。}     

A tissue reconstitution model to study cancer cell‐intrinsic and ‐extrinsic factors in mammary tumourigenesis

The contribution of cancer cell‐intrinsic and ‐extrinsic factors to metastatic breast cancer is still poorly understood, hampering development of novel therapeutic strategies that decrease breast cancer mortality. Cre/loxP‐based conditional mouse models of breast cancer present unique opportunities to study sporadic tumour formation and progression in a controlled setting. Unfortunately, the generation of mouse strains carrying multiple mutant alleles needed for such studies is very time‐consuming. Moreover, conditional mouse tumour models do not permit independent manipulation of tumour cell‐intrinsic and ‐extrinsic factors. Although the latter can be achieved by cleared fat‐pad transplantation of mouse mammary epithelial cells (MMECs) from tumour suppressor gene (TSG) knockouts into wild‐type or mutant recipients, this procedure is not possible for mutations that cause embryonic lethality or preclude mammary gland development. Here we show that cleared fat‐pad transplantations with MMECs isolated from K14cre;Cdh1^F/F; Trp53^F/F mice expressing Cre recombinase under control of the cytokeratin‐14 promoter and carrying conditional null alleles for p53 and E‐cadherin (Cdh1) first resulted in the formation of phenotypically normal mammary glands, followed by the development of invasive metastatic mammary tumours. Tumour formation in the recipients mimicked tumour latency, spectrum, morphology, immunophenotype, and metastatic characteristics of the original mammary tumour model. This transplantation system, which can be expanded to other conditional TSG knockouts, permits independent genetic analysis of stromal factors and testing of additional cancer cell‐intrinsic mutations that would otherwise be embryonic lethal or require intensive breeding. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Plasma adipokine and inflammatory marker concentrations are altered in obese, as opposed to non-obese, type 2 diabetes patients

Elevated plasma free fatty acid (FFA), inflammatory marker, and altered adipokine concentrations have been observed in obese type 2 diabetes patients. It remains unclear whether these altered plasma concentrations are related to the diabetic state or presence of obesity. In this cross-sectional observational study, we compare basal plasma FFA, inflammatory marker, and adipokine concentrations between obese and non-obese type 2 diabetes patients and healthy, non-obese controls. A total of 20 healthy, normoglycemic males (BMI <30 kg/m²), 20 non-obese (BMI <30 kg/m²) and 20 obese (BMI >35 kg/m²) type 2 diabetes patients were selected to participate in this study. Groups were matched for age and habitual physical activity level. Body composition, glycemic control, and exercise performance capacity were assessed. Basal blood samples were collected to determine plasma leptin, adiponectin, resistin, tumor necrosis factor α (TNFα), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP) and FFA concentrations. Plasma FFA, inflammatory marker (hsCRP, IL-6, TNFα), adipokine (adiponectin, resistin, leptin), and triglyceride concentrations did not differ between non-obese diabetes patients and healthy, normoglycemic controls. Plasma FFA, IL-6, hsCRP, leptin, and triglyceride levels were significantly higher in the obese diabetes patients when compared with the healthy normoglycemic controls (P < 0.05). Furthermore, plasma hsCRP and leptin levels were significantly higher in the obese versus non-obese diabetes patients (P < 0.05). Significant correlations between plasma parameters and glycemic control were observed, but disappeared after adjusting for trunk adipose tissue mass. Elevated plasma leptin, hsCRP, IL-6, and FFA concentrations are associated with obesity and not necessarily with the type 2 diabetic state.     

Intramyocellular lipid and glycogen content are reduced following resistance exercise in untrained healthy males

Resistance exercise has recently been shown to improve whole-body insulin sensitivity in healthy males. Whether this is accompanied by an exercise-induced decline in skeletal muscle glycogen and/or lipid content remains to be established. In the present study, we determined fibre-type-specific changes in skeletal muscle substrate content following a single resistance exercise session. After an overnight fast, eight untrained healthy lean males participated in a ~45 min resistance exercise session. Muscle biopsies were collected before, following cessation of exercise, and after 30 and 120 min of post-exercise recovery. Subjects remained fasted throughout the test. Conventional light and (immuno)fluorescence microscopy were applied to assess fibre-type-specific changes in intramyocellular triacylglycerol (IMTG) and glycogen content. A significant 27±7% net decline in IMTG content was observed in the type I muscle fibres (P<0.05), with no net changes in the type IIa and IIx fibres. Muscle glycogen content decreased with 23±6, 40±7 and 44±7% in the type I, IIa and IIx muscle fibres, respectively (P<0.05). Fibre-type-specific changes in intramyocellular lipid and/or glycogen content correlated well with muscle fibre-type oxidative capacity. During post-exercise recovery, type I muscle fibre lipid content returned to pre-exercise levels within 120 min. No changes in muscle glycogen content were observed during recovery. We conclude that intramyocellular lipid and glycogen stores are readily used during resistance exercise and this is likely associated with the reported increase in whole-body insulin sensitivity following resistance exercise.     

The gene responsible for Clouston hidrotic ectodermal dysplasia maps to the pericentromeric region of chromosome 13q

Hidrotic ectodermal dysplasia (HED), Clouston type, is an autosomal dominant skin disorder which is most common in the French-Canadian population and is characterized by hair defects, nail dystrophy and palmoplantar hyperkeratosis. Biophysical and biochemical studies conducted in HED suggested a molecular abnormality of keratins. We tested eight French-Canadian families segregating HED for linkage to microsatellite markers flanking the known keratin genes and were able to exclude linkage to these loci. Therefore, a genome-wide search for the HED gene was initiated. The first lod score above 3.00 was obtained with the marker D13S175 located in the pericentromeric region of chromosome 13q (Zmax = 8.12 at zero recombination). The cumulative lod scores were above 3.00 for six other markers in the region. A multipoint linkage analysis using the markers D13S175, D13S141 and D13S143 gave a maximum lod score of 11.12 at D13S141 with the one-lod- unit support interval spanning a 12.7 cM region which includes D13S175 and D13S141. Haplotype analysis allowed us to establish D13S143 as the telomeric flanking marker for the HED candidate region.      

Severe maternal morbidity among immigrant women in the Netherlands: patients' perspectives

This 2006 study investigated ethnicity-related factors contributing to sub-standard maternity care and the effects on severe maternal morbidity among immigrant women in the Netherlands. In-depth interviews were carried out with 40 immigrant and 10 native Dutch women. The immigrant women reported that health care providers often paid insufficient attention to their pregnancy-related complaints, especially in cases of pre-eclampsia. They also reported delays in receiving information about diagnosis and treatment. Obstetricians who reviewed 20 of these cases judged sub-standard care to have played a role in the development of complications in 16 of them. The women themselves had problems identifying medically significant complications, presenting their complaints to health care providers effectively, and taking an active role as patients. Even highly educated migrant women showed low health literacy skills in their interaction with doctors. Patients' perspectives are valuable as one of the tools to evaluate the quality of maternity care. Communication by maternal health professionals can be improved through more sensitivity to social factors that affect immigrant women's health problems. Women with limited health literacy should be empowered through education about danger signs in pregnancy and information about preferences and policies in obstetrics in the Netherlands. They should also be invited to participate in medical decision-making.     

Deletions of 11q22.3-q25 Are Associated with Atypical Lung Carcinoids and Poor Clinical Outcome

Carcinoids are slow-growing neuroendocrine tumors that, in the lung, can be subclassified as typical (TC) or atypical (AC). To identify genetic alterations that improve the prediction of prognosis, we investigated 34 carcinoid tumors of the lung (18 TCs, 15 ACs, and 1 unclassified) by using array comparative genomic hybridization (array CGH) on 3700 genomic bacterial artificial chromosome arrays (resolution ≤1 Mb). When comparing ACs with TCs, the data revealed: i) a significant difference in the average number of chromosome arms altered (9.6 versus 4.2, respectively; P = 0.036), with one subgroup of five ACs having more than 15 chromosome arms altered; ii) chromosomal changes in 30% of ACs or more with additions at 9q (≥1 Mb) and losses at 1p, 2q, 10q, and 11q; and iii) 11q deletions in 8 of 15 ACs versus 1 of 18 TCs (P = 0.004), which was confirmed via fluorescence in situ hybridization. The four critical regions of interest in 45% ACs or more comprised 11q14.1, 11q22.1-q22.3, 11q22.3-q23.2, and 11q24.2-q25, all telomeric of MEN1 at 11q13. Results were correlated with patient clinical data and long-term follow-up. Thus, there is a strong association of 11q22.3-q25 loss with poorer prognosis, alone or in combination with absence of 9q34.11 alterations (P = 0.0022 and P = 0.00026, respectively).Pulmonary carcinoids comprise a group of usually smoking-unrelated neuroendocrine tumors. Compared with poorly differentiated neuroendocrine tumors of the lung, ie, large-cell neuroendocrine carcinoma and small-cell lung cancer, carcinoids are well-differentiated and characterized by a low metastatic rate and a relatively favorable prognosis. On the basis of histopathologic features (number of mitoses and presence of necrosis), lung carcinoid tumors are classified as typical carcinoids (TCs) or atypical carcinoids (ACs), although classification is sometimes difficult and its reliability to predict disease outcome is variable.¹ Compared with TCs, in general, ACs more often exhibit malignant behavior and are associated with a lower 5-year survival rate (61% to 88% and 92% to 100%, respectively).² Metastases will develop in 4% to 64% of patients with carcinoids (TCs, 4% to 14%, and ACs, 35% to 64%), usually in regional lymph nodes but also at distant sites including liver, bone, brain, subcutaneous tissue, and breast.^2,3 Although most patients remain cancer-free within 5 years after surgery, there is no curative treatment available for metastatic disease.A few studies have reported clinical and molecular factors associated with higher risk of developing metastases or with poor disease outcome. Clinical factors with prognostic value include size 3.5 cm or larger, mitotic index, degree of differentiation, presence of necrosis, co-secretion of peptides, and metastasis.^4,5 Immunohistochemistry on TC samples revealed that a high Ki-67 labeling index or up-regulation of the anti-apoptotic proteins Bcl-2 and p53 were associated with metastatic disease and shorter survival time, whereas immunostaining for the adhesion molecule CD44 was associated with localized disease and lower mortality.⁶ An additional study of 121 pulmonary neuroendocrine tumors including 21 carcinoids demonstrated a shift to low Bax and high Bcl-2 expression in association with ACs, resulting in an unfavorable prognosis.⁷ The Rb pathway is more often modified in ACs than in TCs. P16 negativity was observed in 23% of ACs, compared with 9% of TCs, and absent staining for pRb in 21% of ACs and no TCs.⁸Genomic alterations contribute to carcinogenesis by changing the expression levels of critical oncogenes and tumor-suppressor genes. In lung carcinoid tumorigenesis, few p53 and no EGFR or KRAS gene mutations have been detected, although the percentage of lung carcinoids expressing EGFR is higher in TCs than in ACs.^9,10 Previous studies have primarily demonstrated multiple endocrine neoplasia type 1 (MEN1) gene mutations and/or chromosome 11q deletions.^11–17 MEN1 is a syndrome in which an inherited mutation in the MEN1 gene, located at 11q13, predisposes to formation of multiple neuroendocrine tumors. Although formation of bronchial carcinoid tumors has been observed in only 2% of patients with MEN1,¹⁸ functional inactivation of menin, the MEN1 gene product, has been implicated in the tumorigenesis of sporadic lung carcinoids. In these bronchial carcinoids not associated with MEN1 syndrome, the frequency of loss of heterozygosity at 11q (36%) is higher than the somatic MEN1 mutation rate (18%), pointing to the presence of other tumor-suppressor genes at this chromosome arm and/or involvement of epigenetic silencing mechanisms.¹²To improve the discrimination between pulmonary carcinoid tumors with a favorable or poor prognosis and to identify critical genetic events in lung carcinoid tumorigenesis, we investigated 34 reclassified bronchial carcinoids by using array-based comparative genomic hybridization (array CGH) with a resolution of ≤1 Mb (megabase). Fluorescence in situ hybridization (FISH) was used to determine chromosome copy numbers and to validate array CGH data. Furthermore, the array CGH data were correlated with available histopathologic data and long-term clinical follow-up.     

注射用右兰索拉唑治疗急性胃和/或十二指肠溃疡引起的上消化道出血的有效性及安全性

目的：以注射用兰索拉唑为对照,评价注射用右兰索拉唑15 mg q12 h治疗急性胃和/或十二指肠溃疡引起的上消化道出血的有效性及安全性。方法：选取全国31家研究中心的急性胃和/或十二指肠溃疡引起的上消化道出血患者共202例,按照1∶1随机分配至试验组（注射用右兰索拉唑组）和对照组（注射用兰索拉唑组）。主要疗效终点为72 h有效止血率。对主要疗效终点采用非劣效评价,非劣效性界值δ是10%。结果：有效性方面,全分析数据集分析结果显示：用药72 h后,注射用右兰索拉唑组有效止血率为96.08%(98/102);注射用兰索拉唑组有效止血率为98.00%(98/100),两组率差为-1.92%(95%CI-6.58,2.74)。两组72 h有效止血率差异无统计学意义（P=0.682 9）。两组率差的双侧界值均低于δ(10%),注射用右兰索拉唑非劣于注射用兰索拉唑。安全性方面,试验组的不良事件及不良反应发生率与对照组差异无统计学意义,无非预期不良反应和严重不良反应。主要的不良反应为白细胞计数降低、中性粒细胞计数降低等。结论：注射用右兰索拉唑15 mg q12 h在治疗急性胃和/或十二指肠溃疡引起的...