BACKGROUND & AIMS: :Maternal diabetes can cause fetal macrosomia and increased risk of obesity, diabetes, and cardiovascular disease in adulthood of the offspring. Although increased transplacental lipid transport could be involved, the impact of maternal type 1 diabetes on molecular mechanisms for lipid transport in placenta is largely unknown. To examine whether maternal type 1 diabetes affects placental lipid metabolism, we measured lipids and mRNA expression of lipase-encoding genes in placentas from women with type 1 diabetes (n = 27) and a control group (n = 21). The placental triglyceride (TG) concentration and mRNA expression of endothelial lipase (EL) and hormone-sensitive lipase (HSL) were increased in placentas from women with diabetes. The differences were more pronounced in women with diabetes and suboptimal metabolic control than in women with diabetes and good metabolic control. Placental mRNA expression of lipoprotein lipase and lysosomal lipase were similar in women with diabetes and the control group. Immunohistochemistry showed EL protein in syncytiotrophoblasts facing the maternal blood and endothelial cells facing the fetal blood in placentas from both normal women and women with diabetes. These results suggest that maternal type 1 diabetes is associated with TG accumulation and increased EL and HSL gene expression in placenta and that optimal metabolic control reduces these effects.

背景与目标： 孕产妇糖尿病会导致胎儿巨大儿，并在后代成年后增加肥胖，糖尿病和心血管疾病的风险。尽管可能涉及胎盘脂质转运的增加，但母体1型糖尿病对胎盘脂质转运分子机制的影响尚不清楚。为了检查母体1型糖尿病是否影响胎盘脂质代谢，我们测量了1型糖尿病女性（n = 27）和对照组（n = 21）的胎盘中脂质和脂肪酶编码基因的mRNA表达。糖尿病妇女胎盘中胎盘甘油三酸酯（TG）浓度和内皮脂肪酶（EL）和激素敏感性脂肪酶（HSL）的mRNA表达增加。糖尿病和代谢控制欠佳的女性比糖尿病和代谢控制良好的女性更明显。糖尿病女性和对照组胎盘脂蛋白脂肪酶和溶酶体脂肪酶的mRNA表达相似。免疫组织化学显示，正常女性和糖尿病女性的胎盘中，面向孕妇血液的合体滋养层细胞和面向胎儿血液的内皮细胞中的EL蛋白。这些结果表明，孕妇1型糖尿病与TG蓄积和胎盘中EL和HSL基因表达的增加有关，最佳的代谢控制可降低这些影响。

BACKGROUND & AIMS: The Orphan Annie-eyed clear nucleus, defined as a large, optically clear nucleus, devoid of chromatin strands, with sharp chromatin rim, is a more specific feature than are nuclear grooves or intranuclear cytoplasmic inclusions in papillary thyroid carcinoma. In addition, this characteristic nuclear feature is detectable at low magnification. Although these clear nuclei are routinely seen in paraffin sections, they are inconspicuously seen in conventionally processed touch-imprints and fine-needle aspiration (FNA) smears. Among our two institutions, there have been 148 thyroid cases processed by Ultrafast Papanicolaou stain (UFP), including 43 papillary carcinomas, 38 cellular follicular lesions, and 67 cases of nodular hyperplasia. We observed clear nuclei in all of the cases of UFP-processed FNA and intraoperative smears of papillary carcinoma but not of other thyroid lesions. The clear nuclei are most evident in tumor cells with direct contact to the glass slide and are not seen in tumor cells soaked in cystic fluid. UFP is a valuable way to detect Orphan Annie-eyed clear nuclei of papillary thyroid carcinoma early in the diagnostic evaluation, either at immediate on-site evaluation of FNA or at intraoperative consultation and before the availability of permanent sections.

背景与目标： 孤儿安妮眼透明核，定义为一个大的，光学透明的核，没有染色质链，具有清晰的染色质边缘，比乳头状甲状腺癌的核槽或核内胞质内含物更具特异性。另外，该特征核特征在低放大倍率下是可检测的。尽管通常在石蜡切片中经常看到这些清晰的核，但在常规处理的接触烙印和细针抽吸（FNA）涂片中却看不见它们。在我们的两个机构中，有148例经超快巴氏染色（UFP）处理的甲状腺病例，包括43例乳头状癌，38例细胞滤泡性病变和67例结节性增生。我们在所有UFP处理的FNA病例和术中乳头状癌涂片中观察到清晰的细胞核，但其他甲状腺病变未见。透明核在直接接触载玻片的肿瘤细胞中最为明显，而在浸入囊性液体的肿瘤细胞中则未见。在诊断评估中，无论是立即进行现场FNA评估还是在术中会诊之前以及在获得永久性切片之前，UFP是一种在早期诊断评估中检测出孤儿安妮眼状乳头状甲状腺癌的宝贵方法。

BACKGROUND & AIMS: CONTEXT:Estrogen treatment of men with prostate cancer is associated with increased cardiovascular morbidity and mortality; however, the role of endogenous estrogen levels for atherosclerotic disease in men is unknown. OBJECTIVE:The objective of the study was to determine whether endogenous serum estradiol (E2) levels predict the progression of carotid artery intima-media thickness in men. DESIGN, SETTING AND PARTICIPANTS:This was a population-based, prospective cohort study (the Atherosclerosis and Insulin Resistance study) conducted in Göteborg, Sweden, among 313 Caucasian men without cardiovascular or other clinically overt diseases. Carotid artery intima-media thickness, an index of preclinical atherosclerosis, was measured by ultrasound at baseline (58 yr of age) and after 3 yr of follow-up. Serum sex hormone levels and cardiovascular risk factors (body mass index, waist to hip ratio, systolic blood pressure, serum triglycerides, plasma c-peptide, and smoking status) were assessed at study entry. INTERVENTION:There was no intervention. MAIN OUTCOME MEASURES:Association between baseline total and free E2 levels and progression of carotid intima-media thickness over 3 yr with adjustments for cardiovascular risk factors was measured. RESULTS:In univariate analyses, both total and free E2 levels at baseline were positively associated with the annual change in intima-media thickness. In linear regression models including E2 and cardiovascular risk factors, low-density lipoprotein and high-density lipoprotein cholesterol and E2 were identified as independent predictors of progression of carotid artery intima-media thickness (total E2 beta = 0.187, P = 0.001; and free E2 beta = 0.183, P = 0.003). CONCLUSIONS:Circulating E2 is a predictor of progression of carotid artery intima-media thickness in middle-aged men. Further studies are needed to investigate the role of endogenous E2 for incident cardiovascular disease events.

背景与目标： 背景：雌激素治疗前列腺癌的男性会增加心血管疾病的发病率和死亡率。然而，内源性雌激素水平在男性动脉粥样硬化疾病中的作用尚不清楚。
目的：研究的目的是确定内源性血清雌二醇（E2）水平是否能预测男性颈动脉内膜中层厚度的发展。
设计，地点和参与者：这是一项在瑞典哥德堡进行的基于人群的前瞻性队列研究（动脉粥样硬化和胰岛素抵抗研究），研究对象是313名无心血管疾病或其他临床明显疾病的白人。在基线（58岁）和随访3年后，通过超声测量颈动脉内膜中层厚度（临床前动脉粥样硬化的指标）。在研究开始时评估了血清性激素水平和心血管危险因素（体重指数，腰围与臀部的比率，收缩压，血清甘油三酸酯，血浆c肽和吸烟状况）。
干预：没有干预。
主要观察指标：测量基线总E2水平和游离E2水平与3年以上颈动脉内膜中膜厚度进展的相关性，并调整心血管危险因素。
结果：在单变量分析中，基线时的总E2水平和游离E2水平均与内膜中膜厚度的年度变化呈正相关。在包括E2和心血管危险因素的线性回归模型中，低密度脂蛋白和高密度脂蛋白胆固醇和E2被确定为颈动脉内膜-中膜厚度进展的独立预测因子（总E2 beta = 0.187，P = 0.001；免费） E2 beta = 0.183，P = 0.003）。
结论：循环E2是中年男性颈动脉内膜中层厚度发展的预测指标。需要进一步的研究来研究内源性E2在心血管事件中的作用。

BACKGROUND & AIMS: :Studies were performed to elucidate the possible relationship between microvessel density, proliferative activity and angiogenesis in eutopic endometrium from women with and without endometriosis and peritoneal endometriotic lesions. The question whether changes in these parameters in endometriotic lesions were reflected by the level of vascular endothelial growth factor-A (VEGF-A) in serum and peritoneal fluid was also studied. Biopsy specimens of both eutopic endometrium and peritoneal endometriotic lesions from women with endometriosis (n = 25) as well as eutopic endometrium from women without endometriosis (n = 14) were analysed immunohistochemically regarding microvessel density, proliferative activity, and expression of VEGF-A and its receptors vascular endothelial growth factor receptors 1 and 2 (VEGFR-1 and VEGFR-2) in stroma, glands and blood vessels. The VEGF-A concentration was measured in peritoneal fluid and serum. Secretory phase eutopic endometrium from women with endometriosis had significantly higher microvessel density, expression of VEGF-A in glandular epithelium and VEGFR-2 in endometrial blood vessels than those from women without endometriosis. Endometriotic lesions with high proliferative activity had a higher microvessel density and showed higher vascular expression of VEGFR-2 as well as being accompanied by higher levels of VEGF-A in peritoneal fluid and serum, compared with lesions with low proliferative activity. In conclusion, there seems to be a dysregulation of angiogenic activity in the eutopic endometrium of women with endometriosis and endometriotic lesions with high proliferative activity were accompanied by higher local angiogenic activity and higher levels of VEGF in serum and peritoneal fluid.

背景与目标： ：进行了研究以阐明患有和不患有子宫内膜异位和腹膜子宫内膜异位病变的女性在位子宫内膜的微血管密度，增殖活性和血管生成之间的可能关系。还研究了是否通过血清和腹膜液中血管内皮生长因子-A（VEGF-A）的水平反映子宫内膜异位病变中这些参数的变化的问题。对子宫内膜异位症妇女（n = 25）和非子宫内膜异位症妇女（n = 14）的对位子宫内膜和腹膜子宫内膜异位病变的活检标本进行了免疫组织化学分析，涉及微血管密度，增殖活性，VEGF-A和其受体位于基质，腺体和血管中的血管内皮生长因子受体1和2（VEGFR-1和VEGFR-2）。测定腹膜液和血清中的VEGF-A浓度。子宫内膜异位症女性的分泌期异位子宫内膜比无子宫内膜异位症女性的子宫内膜微血管密度，腺上皮中的VEGF-A表达和子宫内膜血管中的VEGFR-2显着更高。与具有低增殖活性的病变相比，具有高增殖活性的子宫内膜异位病变具有更高的微血管密度，并在腹膜液和血清中具有较高的VEGFR-2血管表达以及较高的VEGF-A水平。总之，子宫内膜异位症妇女的异位子宫内膜血管新生活性似乎异常，具有高增殖活性的子宫内膜异位病变伴有较高的局部血管新生活性和血清和腹膜液中较高的VEGF水平。

BACKGROUND & AIMS: Elderly patients with malignant glioma have a poor prognosis and the benefit of standard radical radiotherapy is equivocal. Twenty-two percent of the adult referral base with malignant glioma at our centre is of age 70 years or greater. A phase II study was undertaken to determine if a shorter course of therapy yields a comparable median survival to radical radiotherapy and thus constitutes an appropriate investigational palliative regimen. 25 patients were accrued between 1988-1995, all of whom had histologically proven malignant glioma, 23 glioblastoma multiforme and 2 anaplastic astrocytoma. The median age was 73 (range 70-78) and median Karnofsky Performance Status (KPS) was 70.40% had a stereotactic biopsy only for diagnosis. Radiotherapy was delivered to limited fields to a dose of 37.5 Gy in 15 daily fractions over 3 weeks. An intention-to-treat analysis was undertaken with survival determined from date of initial consultation. The median survival of the whole group was 8.0 months (95% CI 4.8-9.6). Patients with good performance status (KPS > 70) had a median survival of 10.4 months (95% CI 9.6-14.7). 37.5 Gy in 15 daily fractions appears to yield comparable median survival to that of other series of radical radiotherapy. A phase III study of this regimen is recommended in investigating optimal palliation of elderly malignant glioma patients.

背景与目标： 老年恶性神经胶质瘤患者预后较差，标准根治性放疗的益处是模棱两可的。我们中心的成人恶性神经胶质瘤转诊基数中有22％的年龄为70岁或更高。进行了II期研究，以确定较短的疗程是否可以产生与根治性放疗相当的中位生存期，从而构成一种适当的姑息治疗方案。 1988年至1995年期间，共有25例患者，均经组织学证实为恶性神经胶质瘤，23例多形性胶质母细胞瘤和2例间变性星形细胞瘤。中位年龄为73岁（范围为70-78岁），中位Karnofsky绩效状态（KPS）为70.40％，仅进行了立体定向活检以进行诊断。放射治疗在3周内分15天内分次以37.5 Gy的剂量传送到有限的领域。进行了意向性治疗分析，生存期从初次咨询之日起确定。整个组的中位生存期为8.0个月（95％CI 4.8-9.6）。表现良好状态（KPS> 70）的患者中位生存期为10.4个月（95％CI 9.6-14.7）。 15个每日剂量中的37.5 Gy似乎可以产生与其他系列放射疗法相当的中位生存期。建议对该方案进行III期研究，以调查老年恶性神经胶质瘤患者的最佳缓解情况。

BACKGROUND & AIMS: :The primary objectives of this study were to follow the temporal patterns of testicular LH and FSH receptor (LH-R and FSH-R) concentrations and affinity (Ka) during sexual maturation in bulls and to see if such patterns could help explain the control of rapid testicular growth that occurs after 25 weeks of age, when serum gonadotropin concentrations are low. Separate groups of Hereford x Charolais calves (n = 6) were castrated every 4 weeks from 5 to 33 weeks of age and at 56 weeks of age. A week prior to castrations, from 5 to 33 weeks of age, blood was collected every 15 min for 10 h. The transition from indifferent supporting cells to Sertoli cells in seminiferous tubules was rapid between 13 and 25 weeks and rapid testis growth occurred after 25 weeks of age. Serum LH and FSH concentrations were transiently elevated at 12 weeks of age (P < 0.05). LH-R concentrations decreased from 13 to 25 weeks of age and increased to 56 weeks of age (P < 0.05). LH-RKa decreased from 9 to 17 weeks of age, increased to 29 weeks of age and declined to 33 weeks of age (P < 0.05). FSH-R concentrations declined from 17 to 25 weeks of age then increased to 56 weeks of age (P < 0.05). FSH-RKa increased from 17 to 25 weeks of age (P < 0.05). High concentrations of gonadotropins and their receptors may be critical to initiate testis growth postnatally and support it after 25 weeks of age in the face of low serum gonadotropin concentrations.

背景与目标： ：本研究的主要目的是追踪公牛性成熟过程中睾丸LH和FSH受体（LH-R和FSH-R）浓度和亲和力（Ka）的时间模式，并观察这种模式是否有助于解释控制因素血清促性腺激素浓度低时，在25周龄后出现睾丸快速生长的情况。从5到33周龄和56周龄每4周cast割一次赫瑞福德x夏洛来牛犊（n = 6）组。 5至33周龄weeks割前一周，每15分钟收集一次血液，持续10 h。在13至25周之间，从生精小管中的冷漠支持细胞向Sertoli细胞的过渡迅速，并且25周龄后睾丸迅速生长。血清LH和FSH浓度在12周龄时短暂升高（P <0.05）。 LH-R浓度从13周龄降低到25周龄，增加到56周龄（P <0.05）。 LH-RKa从9周龄降低到17周龄，增加到29周龄，下降到33周龄（P <0.05）。 FSH-R浓度从17周下降到25周，然后上升到56周（P <0.05）。 FSH-RKa从17周龄增加到25周龄（P <0.05）。高浓度的促性腺激素及其受体对于出生后开始睾丸生长并在25周龄后面对低血清促性腺激素浓度的情况下支持睾丸生长可能至关重要。

BACKGROUND & AIMS: The effect of nutritional status on IGF-I mRNA expression in the liver and brain of juvenile barramundi (Lates calcarifer) was investigated. Fish were either fed a satiety ration (SAT) or starved (STV) for 6 weeks. Starved fish demonstrated significantly lower condition factor and hepatic IGF-I mRNA expression at 3 and 6 weeks, when compared with the SAT group. IGF-I mRNA expression in the brain was 10 fold lower than the liver and was not affected by ration size. These results suggest the liver is the major site of IGF-I mRNA synthesis and hepatic but not brain IGF-I mRNA expression is regulated by food availability in juvenile barramundi.

背景与目标： 研究了营养状况对少年肺鱼（Lates calcarifer）肝脏和脑中IGF-I mRNA表达的影响。给鱼喂饱口粮（SAT）或饿死（STV）6周。与SAT组相比，在3周和6周时，饥饿的鱼表现出明显较低的条件因子和肝脏IGF-I mRNA表达。脑中IGF-I mRNA表达比肝脏低10倍，并且不受口粮大小的影响。这些结果表明，肝脏是IGF-I mRNA合成的主要部位，肝而不是脑IGF-I mRNA的表达受幼鱼的食物供应量的调节。

BACKGROUND & AIMS: :The objective of this study was to confirm whether hemoglobin (Hb) levels during chemoradiotherapy are associated with survival in patients with locally advanced cervical carcinoma and to assess impact of the Hb level on survival according to lymph node (LN) metastasis. A retrospective review of 85 cervical carcinoma patients treated with concurrent chemoradiotherapy was conducted. The stage of disease ranged between FIGO stage IB and stage IVA. Disease-free and overall survivals were evaluated by univariate and multivariate analyses. After median follow-up of 35.7 months, 24 patients developed recurrence of disease and 14 patients died from their disease. Stage, LN metastasis, and squamous cell carcinoma antigen and Hb levels during chemoradiation were correlated significantly with survival (P < 0.05). Maintenance of Hb above 10.0 g/dL was associated with better survival (P < 0.05). However, no such benefits were observed in patients with LN metastasis by magnetic resonance imaging (MRI). Multivariate Cox regression hazard model showed that Hb levels during chemoradiation were an independent prognostic factor in patients without LN metastasis by MRI. Maintenance of Hb during chemoradiation is of benefit in cervical carcinoma patients without LN metastasis but not with LN metastasis by MRI.

背景与目标： ：本研究的目的是确定化学放疗期间血红蛋白（Hb）水平是否与局部晚期宫颈癌患者的生存相关，并根据淋巴结（LN）转移评估Hb水平对生存的影响。回顾性回顾了85例同时放化疗的宫颈癌患者。疾病的阶段在FIGO的IB阶段和IVA阶段之间。通过单因素和多因素分析评估无病生存期和总生存期。在中位随访35.7个月后，有24例患者复发疾病，有14例患者死于疾病。化学放疗期间的分期，LN转移，鳞状细胞癌抗原和血红蛋白水平与生存率显着相关（P <0.05）。维持Hb高于10.0 g / dL与更好的生存率相关（P <0.05）。但是，通过磁共振成像（MRI）在LN转移患者中未观察到此类益处。多元Cox回归风险模型显示，放化疗期间Hb水平是无LN转移的患者（通过MRI）的独立预后因素。对于没有LN转移但没有MRI的LN转移的宫颈癌患者，放化疗期间维持Hb有益。

BACKGROUND & AIMS: OBJECTIVE:In the absence of immunodeficiency, only microchimerism (<0.1%) has been achieved in human fetal recipients or nonhuman primates following in utero hematopoietic cell transplantation (IUHCT). We hypothesized that enhanced long-term engraftment might be more reliably achieved in microchimeric systems if higher levels of chimerism existed during development of adaptive immunity. To evaluate this hypothesis, we stimulated the donor cells with vascular endothelial growth factor (VEGF) and stem cell factor (SCF) prior to IUHCT in a chimerism-resistant murine strain combination. METHODS:Donor Balb/c marrow was cultured in media with or without VEGF and SCF supplementation for 12 hours prior to IUHCT into B6 fetuses at 14 days postcoitum (dpc). Donor cell phenotype, homing, and chimerism were assessed at short and long-term time points and transplanted animals received skin allografts at 8 weeks. RESULTS:In pretreated allogeneic recipients, early chimerism rates were more than double that of controls (71% vs 33%, p = 0.01). These differences were associated with higher numbers of pretransplant donor cell colony-forming cells without change in donor cell homing. Despite prolonged skin allograft survival for pretreated recipients compared with controls (mean survival = 20.8 vs 8.2 days, p < 0.001), long-term engraftment was unchanged. CONCLUSIONS:These findings demonstrate that higher levels of early chimerism in recipients of cytokine-stimulated marrow result in improved short-term chimerism and tolerance. Future studies are needed to confirm the existence of a "threshold" level of chimerism necessary to sustain long-term engraftment.

背景与目标： 目的：在缺乏免疫缺陷的情况下，子宫内造血细胞移植（IUHCT）后，人类胎儿接受者或非人类灵长类仅获得微嵌合体（<0.1％）。我们假设，如果在适应性免疫发展过程中存在较高水平的嵌合体，则在微嵌合系统中可以更可靠地实现增强的长期植入。为了评估该假设，我们在抗嵌合体的鼠类菌株组合中，在IUHCT之前用血管内皮生长因子（VEGF）和干细胞因子（SCF）刺激了供体细胞。
方法：在IUHCT植入后的第14天（dpc）将IUBCT注入B6胎儿之前，在添加或不添加VEGF和SCF的培养基中培养供体Balb / c骨髓12小时。在短期和长期的时间点评估供体细胞的表型，归巢和嵌合，移植的动物在第8周接受皮肤同种异体移植。
结果：在经过预处理的同种异体受体中，早期嵌合率是对照的两倍以上（71％vs 33％，p = 0.01）。这些差异与更高数量的移植前供体细胞集落形成细胞相关，而未改变供体细胞归巢。尽管与对照组相比，经过预处理的接受者的皮肤同种异体移植存活时间延长（平均存活率= 20.8 vs 8.2天，p <0.001），但长期移植并未改变。
结论：这些发现表明，受细胞因子刺激的骨髓受体的早期嵌合水平较高，可改善短期嵌合和耐受性。需要进行进一步的研究，以确认是否存在维持长期植入所必需的“阈值”水平的嵌合体。

BACKGROUND & AIMS: :The objective of this study was to determine whether paclitaxel and a strong antioxidant, pyrrolidinedithiocarbamate (PDTC), can affect the activation of nuclear factor-kappa B (NF-kappaB) in SKOV-3 human ovarian cancer cell line and the effect of these two agents on the growth and apoptosis of the cancer cells. The cells were treated with various concentrations of paclitaxel and/or PDTC at various time intervals. Following treatments, cell growth and apoptosis were determined by 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulphonyl)-2H-tetrazolium (WST-8) (WST) assay and flow cytometry, respectively. Western blot assay was used to determine the nuclear p65 protein and cytoplasmic IkappaB-alpha protein. High doses of PDTC significantly inhibited the growth of SKOV-3 cells and caused apoptosis. Paclitaxel and lower doses of PDTC combined demonstrated additive inhibition of cell growth and increased levels of apoptosis. Treatment of paclitaxel alone showed increased nuclear p65 protein and decreased cytoplasmic IkappaB-alpha protein expression, while pretreatment of PDTC reversed this function. PDTC blocks the paclitaxel-induced activation of NF-kappaB leading to increased chemosensitivity to paclitaxel and enhanced apoptosis. Combining antioxidants and paclitaxel has significant potential to overcome the risk of paclitaxel resistance.

背景与目标： ：这项研究的目的是确定紫杉醇和强抗氧化剂吡咯烷二硫代氨基甲酸酯（PDTC）是否会影响SKOV-3人卵巢癌细胞系中核因子-κB（NF-kappaB）的活化及其作用两种药剂对癌细胞的生长和凋亡都有影响。在不同的时间间隔用不同浓度的紫杉醇和/或PDTC处理细胞。处理后，通过2-（2-甲氧基-4-硝基苯基）-3-（4-硝基苯基）-5-（2,4-二磺酰基）-2H-四唑鎓（WST-8）（WST）测定细胞生长和凋亡）分析和流式细胞术。蛋白质印迹法用于确定核p65蛋白和细胞质IkappaB-alpha蛋白。高剂量的PDTC显着抑制SKOV-3细胞的生长并引起细胞凋亡。紫杉醇和较低剂量的PDTC联合显示可抑制细胞生长和增加细胞凋亡水平。单独使用紫杉醇的治疗显示核p65蛋白增加，而细胞质IkappaB-α蛋白表达降低，而PDTC的预处理逆转了该功能。 PDTC阻止紫杉醇诱导的NF-κB活化，从而导致对紫杉醇的化学敏感性增加和细胞凋亡增强。抗氧化剂和紫杉醇的组合具有克服紫杉醇耐药性的巨大潜力。

BACKGROUND & AIMS: :Several mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been identified both in familial and sporadic cases of Parkinson's disease (PD). G2019S, located at a kinase (MAPKKK) domain, is the most common mutation in the LRRK2 gene in PD, Two adjacent mutations (I2012T and I2020T) were mapped to the same domain suggesting shared pathogenic mechanism of these mutations. Since phenotypes of PD overlap with essential tremor (ET), we investigated LRRK2 G2019S, I2012T, and I2020T mutations in a cohort of 272 patients with ET. No mutations were found in our ET cohort and, therefore, we conclude that LRKK2 I2012T, G2019S and I2020T variants are rare causes of Caucasian ET.

背景与目标： ：在家族性和散发性帕金森氏病（PD）病例中，均已鉴定出富含亮氨酸的重复激酶2基因（LRRK2）的多个突变。位于激酶（MAPKKK）结构域的G2019S是PD中LRRK2基因中最常见的突变，两个相邻的突变（I2012T和I2020T）被定位到同一结构域，表明这些突变具有共同的致病机制。由于PD的表型与原发性震颤（ET）重叠，因此我们在272例ET患者中研究了LRRK2 G2019S，I2012T和I2020T突变。在我们的ET队列中未发现突变，因此，我们得出结论，LRKK2 I2012T，G2019S和I2020T变体是白种人ET的罕见原因。

BACKGROUND & AIMS: :Gonorrhea is essentially out of control in many settings and high disease rates are coupled with the spread of multiresistant gonococci. Increases in quinolone resistance have followed loss of the penicillins and tetracyclines as useful treatments. Decreasing susceptibility to third-generation cephalosporins is also reported. Over-reliance on antibiotic treatment as a disease control measure in settings with high disease rates and poor control of antibiotic usage is a significant contributor to the antimicrobial resistance reported. Conversely, containment of resistance is more likely to be achieved when combined with disease control principles shown to be effective. However, until a higher priority is given to funding for sexually transmitted diseases, this prospect is unlikely to eventuate and the possibility of untreatable gonorrhea becomes more real.

背景与目标： 淋病在许多情况下基本上是无法控制的，高发病率与多耐药性淋球菌的传播有关。青霉素和四环素类药物丧失后，喹诺酮类药物耐药性增加，这是有用的治疗方法。还报道了对第三代头孢菌素的敏感性降低。在疾病发生率高且抗生素使用控制不佳的环境中，过度依赖抗生素治疗是一种疾病控制措施，是导致抗生素耐药性的重要原因。相反，当与已证明有效的疾病控制原则相结合时，更可能实现抗药性。但是，除非将更高的优先权用于性传播疾病的资助，否则这种前景不太可能实现，无法挽回的淋病的可能性变得更加现实。

BACKGROUND & AIMS: :Oral tolerance, an important feature of the mucosal immune system, appears to protect against immune-mediated disease by blunting production of systemic IgG and IgM antibody directed toward immunogens chronically present at mucosal surfaces. In this study, we explored the role of oral tolerance and mucosal immunoregulation in an experimental model of IgA nephropathy (IgAN), an important form of nephritis in humans. Cyclophosphamide and estradiol were used to inhibit the expression of oral tolerance, which otherwise develops after chronic oral presentation of Ag. BALB/c mice given drinking water containing 0.1% bovine gamma globulin (BGG) continuously for 14 wk were randomly assigned to groups given either 2 mg of cyclophosphamide i.p., 2 mg of estradiol s.c. or both drugs. Groups of control mice received neither BGG nor drugs. In three separate experiments, a low percentage of saline-treated orally immunized mice had microscopic hematuria (0 to 20%), as did nonimmunized controls (0 to 20%). However, 58 to 83% of mice given estradiol and/or cyclophosphamide at appropriate times developed significant hematuria. If drugs were given at suboptimal times, only 25 to 56% of mice developed hematuria. Drug-treated immunized mice also had more serum IgG and IgM anti-BGG antibodies than control and saline groups. Immunofluorescence showed significantly more glomerular deposits of IgG, IgM, and C3 in drug-treated immunized mice compared to saline-treated immunized and normal untreated control mice. Hematuria and glomerular deposits of IgG, IgM, and C3 paralleled serum IgG and IgM antibody. All immunized mice showed significant mesangial IgA and BGG deposits and there were no differences in such deposits between saline- and drug-treated immunized mice. We suggest that blunting of oral tolerance with promotion of systemic IgG and IgM antibody production leads to nephritis in chronically orally immunized mice and that glomerular immune complexes containing IgG and/or IgM promote complement deposition and hematuria in IgAN. Analogous defects in oral (or more generally mucosal) tolerance could play a role in the genesis of symptomatic human IgAN.

背景与目标： ：口腔耐受是粘膜免疫系统的一个重要特征，它似乎通过减弱针对长期存在于粘膜表面的免疫原的全身性IgG和IgM抗体的产生，来保护自身免受免疫介导的疾病的侵害。在这项研究中，我们探讨了口服耐受性和粘膜免疫调节在IgA肾病（IgAN）（一种人类肾炎的重要形式）实验模型中的作用。环磷酰胺和雌二醇被用来抑制口腔耐受的表达，否则这种耐受会在长期口服银后产生。连续14周连续喝含0.1％牛γ-球蛋白（BGG）的饮用水的BALB / c小鼠被随机分为两组，分别给予2 mg环磷酰胺i.p.，2 mg雌二醇s.c.或同时使用这两种药物。对照组小鼠既不接受BGG也不接受药物。在三个独立的实验中，经盐水处理的经口免疫小鼠中有低百分比的患者出现镜下血尿（0％至20％），而未免疫的对照小鼠则为0％至20％。但是，在适当的时间接受雌二醇和/或环磷酰胺的小鼠中有58％至83％出现了明显的血尿。如果在次佳的时间服用药物，则只有25％到56％的小鼠会出现血尿。药物治疗的免疫小鼠也比对照组和生理盐水组具有更多的血清IgG和IgM抗BGG抗体。免疫荧光显示与盐水处理的免疫小鼠和正常未处理的对照小鼠相比，在药物处理的免疫小鼠中IgG，IgM和C3的肾小球沉积明显更多。血尿和IgG，IgM和C3的肾小球沉积物与血清IgG和IgM抗体平行。所有免疫的小鼠均显示出明显的肾小球系膜IgA和BGG沉积物，盐水和药物处理的免疫小鼠之间的沉积物无差异。我们建议通过口服全身免疫的小鼠促进全身性IgG和IgM抗体产生的口服耐受性减退会导致肾炎，而含有IgG和/或IgM的肾小球免疫复合物会促进IgAN中的补体沉积和血尿。口腔（或更常见的粘膜）耐受性的类似缺陷可能在有症状的人类IgAN的发生中起作用。

BACKGROUND & AIMS: :A mouse perfusion model using fluorescently labeled dextran has been developed to investigate the functionality of blood vessels during cutaneous wound healing. By immunostaining cryostat sections of perfused wounds with antibodies that identify vessels, we were able to assess their functionality. There was an increase in the proportion of CD31(+)-perfused vessels in all wound regions with time, although the vessels of the wound margins and superficial granulation tissue (GT) took the longest to become perfused. More than 50% of the latter vessels were not perfused at 10 days postwounding. This is consistent with the growth of functional vessels from the wound base proceeding to the more superficial GT. The CD34 marker was expressed by a subpopulation of CD31(+) vessels. However, in contrast to CD31(+) vessels, the functionality of CD34(+) vessels did not change significantly with time and 50-75% of CD34(+) vessels in the GT and wound margins were nonfunctional. This might be explained either by apoptosis of the CD34(+) vessels or the loss of the marker with time. This study has important implications for assays of wound-healing angiogenesis based on histology and immunohistochemical markers for vessels, because vessel functionality differs both spatially and temporally during wound healing.

背景与目标： ：已经开发了使用荧光标记的葡聚糖的小鼠灌注模型，以研究皮肤伤口愈合过程中血管的功能。通过用识别血管的抗体免疫染色灌注伤口的低温恒温器切片，我们能够评估其功能。尽管伤口边缘和浅表肉芽组织（GT）的灌注时间最长，但所有伤口区域的CD31（）灌注血管比例均随时间增加。受伤后10天，没有再灌注50％以上的血管。这与功能性血管从伤口基部到更浅层的GT的生长是一致的。 CD34标记由CD31（）血管的亚群表达。然而，与CD31（）血管相反，CD34（）血管的功能并未随时间而显着变化，GT中50-75％的CD34（）血管和伤口边缘均无功能。这可能是由于CD34（）血管凋亡或标记随时间流逝而造成的。这项研究对基于组织学和血管免疫组织化学标记的伤口愈合血管生成的测定具有重要意义，因为在伤口愈合过程中血管功能在空间和时间上都不同。

BACKGROUND & AIMS: Controversy exists on the merits of the various approaches to inguinal repair. Evolution of the classic open repair has culminated in the Shouldice repair. Challenges from newcomers, namely, tension-free repair and laparoscopy, are being examined. These two techniques have a number of disadvantagesthe presence of foreign bodies (prostheses) and their implication in cases of infection; the cost of prosthetic material, which is no longer negligible (particularly with expanded polytetrafluoroethylene); and problems of safety in that the laparoscopic approach is no longer a dependable asset except in the hands of a highly specialized and dextrous operator. Still, complications occur with laparoscopic repair that should not be associated with a surgical procedure that is considered benign, safe and cost-effective. Surgeons must recognize the pertinent facts and decide according to their conscience which method of repair to use.

背景与目标： 关于腹股沟修补的各种方法的优缺点存在争议。经典的开放式维修的演变最终达到了Shouldice维修的最高水平。正在研究来自新移民的挑战，即无张力修复和腹腔镜检查。这两种技术有许多缺点，即异物（假体）的存在及其在感染病例中的影响。修复材料的成本不再可忽略不计（尤其是使用膨胀的聚四氟乙烯）；以及安全性问题，因为只有在高度专业化和灵巧的操作员手中，腹腔镜检查方法才不再是可靠的资产。尽管如此，腹腔镜修复仍会发生并发症，这种并发症不应与被认为是良性，安全且具有成本效益的外科手术相关联。外科医生必须认识到相关事实，并根据自己的良心决定使用哪种修复方法。