BACKGROUND & AIMS: :A 43-year-old man developed a skin eruption characterized by 'macules with blisters' typical to Stevens-Johnson syndrome, as well as erosions of the lips and buccal mucosa, 2 weeks after he had started treatment with lamotrigine. He had a fever (39.6 degrees C), elevated liver enzymes and atypical lymphocytes in the peripheral blood. This undoubtedly reflects a case of Stevens-Johnson syndrome induced by lamotrigine, but it can also fulfill the criteria of anticonvulsant hypersensitivity syndrome or drug rash with eosinophilia and systemic signs. A case that precisely fits the definition of two syndromes that have different characteristics, different treatments and different prognoses indicates that there is a flaw in the classification.

背景与目标： : 一名43岁的男子在开始使用拉莫三嗪治疗2周后，出现了以史蒂文斯-约翰逊综合征典型的 “带水疱的斑疹” 以及嘴唇和颊粘膜糜烂为特征的皮肤喷发。发热 (39.6 ℃)，肝酶升高，外周血淋巴细胞不典型。这无疑反映了拉莫三嗪诱发的史蒂文斯-约翰逊综合征，但它也可以满足抗惊厥超敏反应综合征或伴有嗜酸性粒细胞增多和全身体征的药疹的标准。一个精确地符合具有不同特征，不同治疗方法和不同预后的两种综合征的定义的案例表明，分类存在缺陷。

BACKGROUND & AIMS: In parkinsonism, glutamate pathways within the basal ganglia become overactive, leading to the suggestion that glutamate antagonists might possess antiparkinsonian qualities. This report examines the motor properties of antagonists of NMDA and AMPA-type glutamate receptors, as well as some inhibitors of glutamate release, in animal models of idiopathic Parkinson's disease. High affinity NMDA open-channel blockers (e.g. MK 801, phencyclidine), are highly potent antagonists with inconsistent antiakinetic and strong myorelaxant activity. Other compounds are better tolerated and are capable of relieving immobility and muscular rigidity by themselves (e.g. 1-aminoadamantanes, polyamine site antagonists, kappa agonists, riluzole). Yet others do not restore movements alone (e.g. dextromethorphan, ketamine), but may interact with and strengthen the antiparkinsonian action of L-DOPA (e.g. competitive NMDA and AMPA antagonists, lamotrigine). They may do this by potentiating dopaminergic behaviours mediated by D1 or D2 receptors, or by some other mechanism.

背景与目标： 在帕金森氏症中，基底神经节内的谷氨酸途径变得过度活跃，导致暗示谷氨酸拮抗剂可能具有抗帕金森氏症的特性。本报告研究了特发性帕金森氏病动物模型中NMDA和AMPA型谷氨酸受体拮抗剂以及谷氨酸释放抑制剂的运动特性。高亲和力的NMDA开放通道阻滞剂 (例如MK 801，苯环利定) 是具有不一致的抗肌毒性和强的肌松弛活性的高效拮抗剂。其他化合物具有更好的耐受性，并且能够自行缓解不动和肌肉僵硬 (例如1-氨基金刚烷，多胺位点拮抗剂，κ 激动剂，利鲁唑)。还有其他人不能单独恢复运动 (例如右美沙芬，氯胺酮)，但可能与L-DOPA的抗帕金森病作用相互作用并加强 (例如竞争性NMDA和AMPA拮抗剂，拉莫三嗪)。他们可以通过增强D1或D2受体或其他机制介导的多巴胺能行为来做到这一点。

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： : 母体糖尿病会导致胎儿巨大儿，并增加后代成年后肥胖，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) 胎盘中脂质和脂肪酶编码基因的mRNA表达。糖尿病女性胎盘中胎盘甘油三酯 (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。与糖尿病和代谢控制良好的女性相比，糖尿病和代谢控制不佳的女性的差异更为明显。糖尿病妇女和对照组的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，正常妇女和糖尿病妇女胎盘中面向母体血液的合体滋养层细胞中的EL蛋白和面向胎儿血液的内皮细胞。这些结果表明，母体1型糖尿病与胎盘中TG积累以及EL和HSL基因表达增加有关，而最佳的代谢控制会降低这些影响。

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，光学上透明的核，没有染色质链，具有尖锐的染色质边缘，是比甲状腺乳头状癌中核沟或核内细胞质包涵体更特异的特征。此外，这种特征性核特征在低放大倍率下是可检测到的。尽管这些清晰的核通常在石蜡切片中可见，但在常规处理的触摸印记和细针抽吸 (FNA) 涂片中却不明显。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例细胞滤泡病变和67例结节性增生。我们在所有经UFP处理的FNA病例和乳头状癌的术中涂片中都观察到了清晰的核，但没有观察到其他甲状腺病变。透明的核在与载玻片直接接触的肿瘤细胞中最为明显，在浸泡在囊性液中的肿瘤细胞中未见。UFP是一种有价值的方法，可以在诊断评估的早期，无论是在FNA的现场评估还是在术中咨询以及在永久性切片之前，检测甲状腺乳头状癌的孤儿安妮眼透明核。

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：

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症和腹膜子宫内膜异位病变的妇女的在位子宫内膜中微血管密度，增殖活性和血管生成之间的可能关系。还研究了血清和腹膜液中血管内皮生长因子-A (vegf-a) 的水平是否反映了子宫内膜异位病变中这些参数的变化的问题。免疫组织化学分析了子宫内膜异位症妇女 (n = 25) 的在位子宫内膜和腹膜子宫内膜异位病变的活检标本以及无子宫内膜异位症妇女 (n = 14) 的在位子宫内膜的活检标本，其微血管密度，增殖活性，并在间质、腺体和血管中表达vegf-a及其受体血管内皮生长因子受体1和2 (VEGFR-1和VEGFR-2)。在腹膜液和血清中测量vegf-a浓度。子宫内膜异位症妇女的分泌期在位子宫内膜的微血管密度，腺上皮和内膜血管VEGFR-2中vegf-a的表达明显高于无子宫内膜异位症妇女。与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，并且显示出更高的VEGFR-2血管表达，并且在腹膜液和血清中伴有较高的vegf-a水平。总之，子宫内膜异位症妇女的在位子宫内膜中似乎存在血管生成活性失调，而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生成活性以及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的预后较差，标准的根治性放疗的益处是模棱两可的。在我们中心，患有恶性神经胶质瘤的成人转诊基地中有22% 的年龄在70岁或以上。进行了一项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，从而构成适当的研究性姑息治疗方案。在1988-1995之间累积了25例患者，所有这些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70-78)，中位Karnofsky表现状态 (KPS) 70.40% 仅用于诊断的立体定向活检。在3周内，将放射疗法递送到有限的区域，剂量为37.5 Gy，每天15次。进行了意向性治疗分析，从初次咨询之日起确定生存率。全组的中位生存期为8.0个月 (95% CI 4.8-9.6)。表现良好的患者 (KPS > 70) 的中位生存期为10.4个月 (95% CI 9.6-14.7)。在15个每日分数中37.5 Gy似乎产生与其他系列的根治性放疗相当的中位生存期。建议对该方案进行III期研究，以研究老年恶性神经胶质瘤患者的最佳姑息治疗。

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： : 这项研究的主要目的是跟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25周龄后睾丸快速生长的控制,当血清促性腺激素浓度较低时。从5到33周龄和56周龄，每4周对不同的Hereford x Charolais小牛 (n = 6) 进行cast割。阉割前一周，从5到33周龄，每15分钟收集一次血液，持续10小时。在13至25周之间，生精小管中从冷漠的支持细胞向Sertoli细胞的过渡迅速，并且在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至25周龄降低，并增加至56周龄 (P <0.05)。Lh-rka从9周龄下降到17周龄，增加到29周龄，下降到33周龄 (P <0.05)。Fsh-r浓度从17至25周龄下降，然后增加至56周龄 (P <0.05)。Fsh-rka从17周增加到25周龄 (P <0.05)。面对低血清促性腺激素浓度，高浓度的促性腺激素及其受体对于启动出生后睾丸生长并在25周龄后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： 研究了营养状况对幼年barramundi (Lates calcarifer) 肝脏和大脑中igf-i mRNA表达的影响。对鱼喂食饱腹感 (SAT) 或饥饿 (STV) 6周。与SAT组相比，饥饿的鱼在3周和6周时表现出明显较低的条件因子和肝igf-i mRNA表达。大脑中igf-i mRNA的表达比肝脏低10倍，不受日粮大小的影响。这些结果表明，肝脏是igf-i mRNA合成的主要部位，而肝脏而不是大脑igf-i mRNA的表达受幼年barramundi食物的调节。

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：

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-κ B (NF-κ B) 的活化以及这两种药物对癌细胞生长和凋亡的影响。在不同的时间间隔用各种浓度的紫杉醇和/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-(2,4-二硫酰基)-2h-四唑 (WST-8) (WST) 测定和流式细胞仪测定细胞生长和凋亡。Western blot测定法用于测定核p65蛋白和细胞质IkappaB-α 蛋白。高剂量的PDTC显著抑制SKOV-3细胞的生长并引起细胞凋亡。紫杉醇和较低剂量的PDTC组合显示出对细胞生长的加性抑制和凋亡水平的增加。单独治疗紫杉醇显示核p65蛋白增加，胞质IkappaB-α 蛋白表达降低，而PDTC的预处理逆转了这一功能。PDTC阻断紫杉醇诱导的NF-κ b激活，从而增加对紫杉醇的化学敏感性并增强细胞凋亡。结合抗氧化剂和紫杉醇具有克服紫杉醇耐药性风险的巨大潜力。

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： : 在帕金森氏病 (PD) 的家族性和散发性病例中，已经发现了富含亮氨酸的重复激酶2基因 (LRRK2) 的几个突变。G2019S位于激酶 (MAPKKK) 结构域，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，表明这些突变的共同致病机制。由于PD的表型与原发性震颤 (ET) 重叠，我们在272例ET患者队列中研究了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变体是高加索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失控的，高发病率与多重耐药淋球菌的传播相结合。作为有用的治疗方法，青霉素和四环素类药物的丧失导致喹诺酮类药物耐药性增加。还报道了对第三代头孢菌素的敏感性降低。在疾病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作为疾病控制措施，是导致报告的抗菌素耐药性的重要因素。相反，当结合显示出有效的疾病控制原则时，更有可能实现对抵抗力的控制。然而，在对性传播疾病的资金给予更高的优先考虑之前，这种前景不太可能实现，无法治愈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： : 口服耐受性是粘膜免疫系统的重要特征，似乎可以通过钝化针对慢性存在于粘膜表面的免疫原的全身性IgG和IgM抗体的产生来预防免疫介导的疾病。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) 实验模型中的作用，IgA肾病是人类肾炎的重要形式。环磷酰胺和雌二醇用于抑制口服耐受性的表达，否则口服耐受性会在Ag的慢性口服表现后发展。连续14周饮用含有0.1% 牛丙种球蛋白 (BGG) 的BALB/c小鼠被随机分配到给予2 mg环磷酰胺i.p.，2 mg雌二醇的组。或者两种药物。对照组小鼠既未接受BGG也未接受药物。在三个单独的实验中，低百分比的经生理盐水处理的经口服免疫的小鼠具有显微镜下血尿 (0至20%)，与未免疫的对照 (0至20%) 一样。然而，在适当的时间给予雌二醇和/或环磷酰胺的小鼠中有58至83% 出现明显的血尿。如果在次优时间给予药物，只有25至56% 的小鼠出现血尿。药物处理的免疫小鼠的血清IgG和IgM抗BGG抗体也比对照组和盐水组多。免疫荧光显示，与盐水处理的免疫小鼠和正常未经处理的对照小鼠相比，药物处理的免疫小鼠中IgG，IgM和C3的肾小球沉积明显更多。IgG，IgM和C3的血尿和肾小球沉积物与血清IgG和IgM抗体平行。所有免疫小鼠均显示出明显的系膜IgA和BGG沉积物，并且在盐水和药物处理的免疫小鼠之间此类沉积物没有差异。我们建议，通过促进全身IgG和IgM抗体产生而使口服耐受性减弱会导致慢性口服免疫小鼠的肾炎，而含有IgG和/或IgM的肾小球免疫复合物会促进IgAN的补体沉积和血尿。口腔 (或更一般的粘膜) 耐受性的类似缺陷可能在有症状的人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对灌注伤口的低温恒温器切片进行免疫染色，我们能够评估其功能。尽管伤口边缘和浅表肉芽组织 (GT) 的血管灌注时间最长，但所有伤口区域中CD31 () 灌注血管的比例随时间增加。超过50% 的后一种血管在伤后10天没有灌注。这与从伤口基部到更浅表的GT的功能性血管的生长是一致的。CD34标记由CD31 () 血管的亚群表达。然而，与CD31(+) 血管相反，CD34(+) 血管的功能没有随时间显着变化，并且GT和伤口边缘中的50-75% CD34(+) 血管无功能。这可以通过CD34 () 血管的凋亡或标记物随时间的丢失来解释。这项研究对基于血管的组织学和免疫组织化学标记的伤口愈合血管生成测定具有重要意义，因为在伤口愈合过程中，血管功能在空间和时间上均不同。