小鼠皮肤超氧化物歧化酶活性与枸杞多糖的干预

目的:观察枸杞多糖对皮肤胶原代谢和自由基产生的影响,探讨其抗皮肤衰老的作用。方法:实验于2005-06/2006-05在广东医学院整形外科研究所完成。①实验材料:清洁级昆明小鼠60只,月龄2个月,体质量16～24g,雌雄各半。②实验分组:将小鼠随机分为正常对照组、衰老模型组和抗衰老模型组,每组20只。③实验干预:模型组每日用D-半乳糖溶液皮下注射制造衰老模型,用量和时间为80mg/(kg·d)7d,120mg/(kg·d)14d,140mg/(kg·d)14d,180mg/(kg·d)7d。正常对照组每日注射同体积的生理盐水。抗衰老模型组在注射D-半乳糖期间以枸杞多糖灌胃,剂量为20mg/(kg·d),正常对照组和衰老组则以同体积的生理盐水代之灌胃。④实验评估:42d后切取小鼠颈背部皮肤,测定超氧化物歧化酶活力、羟脯氨酸和丙二醛含量。结果:56只小鼠进入结果分析(4只死亡)。①小鼠皮肤超氧化物歧化酶活力:与正常对照组相比,衰老组和抗衰老组小鼠皮肤超氧化物歧化酶活力降低,差异有显著性意义(P<0.01);抗衰老组与衰老模型组比较,超氧化物歧化酶活力增加,差异有显著性意义(P<0.01)。②与正常对照组相比,衰老组和抗衰老组小鼠皮肤羟脯氨酸和丙二醛含量增加,差异有显著性意义(P<0.01);抗衰老组与衰老组比较,羟脯氨酸和丙二醛含量均降低,差异有显著性意义(P<0.01)。结论:枸杞多糖改善皮肤老化的作用与提高小鼠皮肤超氧化物歧化酶活力,降低羟脯氨酸、丙二醛含量,影响胶原代谢有关。     

PIK3CA‐related overgrowth spectrum (PROS): Diagnostic and testing eligibility criteria,differential diagnosis,and evaluation

Somatic activating mutations in the phosphatidylinositol‐3‐kinase/AKT/mTOR pathway underlie heterogeneous segmental overgrowth phenotypes. Because of the extreme differences among patients, we sought to characterize the phenotypic spectrum associated with different genotypes and mutation burdens, including a better understanding of associated complications and natural history. Historically, the clinical diagnoses in patients with PIK3CA activating mutations have included Fibroadipose hyperplasia or Overgrowth (FAO), Hemihyperplasia Multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, macrodactyly, Fibroadipose Infiltrating Lipomatosis, and the related megalencephaly syndromes, Megalencephaly‐Capillary Malformation (MCAP or M‐CM) and Dysplastic Megalencephaly (DMEG). A workshop was convened at the National Institutes of Health (NIH) to discuss and develop a consensus document regarding diagnosis and treatment of patients with PIK3CA‐associated somatic overgrowth disorders. Participants in the workshop included a group of researchers from several institutions who have been studying these disorders and have published their findings, as well as representatives from patient‐advocacy and support groups. The umbrella term of “PIK3CA‐Related Overgrowth Spectrum (PROS)” was agreed upon to encompass both the known and emerging clinical entities associated with somatic PIK3CA mutations including, macrodactyly, FAO, HHML, CLOVES, and related megalencephaly conditions. Key clinical diagnostic features and criteria for testing were proposed, and testing approaches summarized. Preliminary recommendations for a uniform approach to assessment of overgrowth and molecular diagnostic testing were determined. Future areas to address include the surgical management of overgrowth tissue and vascular anomalies, the optimal approach to thrombosis risk, and the testing of potential pharmacologic therapies. © 2014 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.     

Aven‐mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma

Conventional high‐grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis‐free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti‐apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G₂ cell‐cycle arrest; Chk1 protein levels were attenuated and ATR–Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven‐depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven‐controlled ATR–Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix‐embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR–Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Utilization of Behavioral Therapy Services Long-Term After Traumatic Brain Injury in Young Children

Objective

To examine associations of clinical need, defined by elevated parent ratings of child behavior problems and utilization of behavioral health services in young children with traumatic brain injury (TBI) and an orthopedic injury (OI) comparison group.

Design

Parents completed outcome measures 18 months after injury and at an extended follow-up conducted an average of 38 months postinjury.

Setting

Children's hospitals and a general hospital.

Participants

Participants included parents of 3 groups of children injured between 3 and 7 years of age (N=139): 47 children with complicated mild to moderate TBI, 18 with severe TBI, and 74 with OI.

Interventions

Not applicable.

Main Outcome Measures

Parents completed ratings of child behavior, mental health symptomology, and family functioning at both visits; at the extended follow-up, they reported utilization of behavior therapy or counseling services since the 18-month follow-up visit.

Results

Children with TBI had more behavior problems than those with OI. Although clinical need at both follow-ups was associated with greater service utilization at the extended follow-up, all groups had unmet needs as defined by a clinical need in the absence of services. Lower socioeconomic status was associated with higher rates of unmet need across groups.

Conclusions

The results document unmet long-term behavioral health needs after both TBI and OI in children and underscore the importance of monitoring and treatment of postinjury behavior problems.     

Pituitary apoplexy: correlation between magnetic resonance imaging and histopathological results

OBJECT: The aim of this study was to correlate the magnetic resonance (MR) imaging findings in pituitary apoplexy with histopathological results and determine whether the histopathology influences clinical presentation and outcome. METHODS: The records of 36 patients with histologically confirmed pituitary apoplexy, who were treated surgically at the University of Virginia Health System between 1996 and 2006, were retrospectively reviewed. The MR images were divided into 3 groups: 1) infarction alone; 2) hemorrhage with or without infarction; and 3) tumor only with no evidence of apoplexy. The histological examination was divided into infarction alone or hemorrhagic infarction/hemorrhage. The MR imaging findings were then correlated with the histopathological results to assess how accurately the histopathology was predicted by the MR imaging. The clinical features and outcomes of the two histopathological groups were also compared. RESULTS: The MR imaging findings were able to predict the histopathology accurately in the majority of cases. The group of patients with infarction had less severe clinical features and a better outcome than those with hemorrhagic infarction/hemorrhage. CONCLUSIONS: Magnetic resonance imaging findings in the setting of pituitary apoplexy accurately predict the nature of the apoplectic process and help to guide the type and timing of therapy.     

Methamphetamine use and depressive symptoms among heterosexual men and women

This study investigated the relationship between intensity of methamphetamine use and depressive symptoms in a sample of 182 heterosexually identified methamphetamine users. Perceived stigma and social and health problems were hypothesized as potential mediators of the relationship between methamphetamine use and depressive symptoms. Forty per cent of the sample met criteria for moderate to severe depression. As hypothesized, the greater the intensity of methamphetamine use, the higher the levels of depressive symptoms. Results of the mediation analyses failed to identify mediating effects for stigma, social problems or health problems. However, perceived stigma had a significant positive direct effect on depressive symptoms. Gender, age and marital status also predicted higher levels of depression. This research suggests the need for drug treatment programmes to: (1) identify and treat depressive symptoms among methamphetamine users; and (2) address social and psychological issues, such as perceived stigma, in an effort to decrease depressive symptomatology and ultimately enhance programme effectiveness.     

Use of E mu-PIM-1 transgenic mice short-term in vivo carcinogenicity testing: lymphoma induction by benzo[a]pyrene, but not by TPA

E mu-pim-1 transgenic mice are predisposed to develop lymphomas. Due to their low spontaneous tumour incidence and their increased sensitivity towards the lymphomagen ethylnitrosourea these mice may present an interesting model for short-term carcinogenicity testing. Here, we report on the further exploration of this transgenic mouse model with two additional carcinogens known to have, among others, the lymphohaematopoietic system as target, i.e. benzo[a]pyrene (B[a]P) and 12-O-tetradecanoylphorbol-13-acetate (TPA). B[a]P, given three times a week (by gavage) for 13 weeks at 4.3, 13 or 39 mg/kg body weight, resulted in a dose-related increase in lymphomas up to a 90% incidence in E(mu)-pim-1 mice during the observation period of 40 weeks. B[a]P also induced tumours of the forestomach within this observation period, though at a lower incidence and apparently equally effective in wildtype and transgenic mice. TPA, on the other hand, was unable to induce lymphomas (or tumours in any other organ) in either transgenic or wildtype animals within the observation period of 44 weeks, when applied dermally at the maximum tolerated dose of 3 microg/mouse, twice a week for 35 weeks. Molecular analysis showed that B[a]P-induced lymphomas in transgenic mice were of T-cell origin, 80% of which had elevated levels of c-myc expression. None of the lymphomas had increased N-myc expression and mutation analysis of the ras-gene family revealed a K-ras mutation in only one out of eight tumours investigated. Also, none of the lymphomas showed aberrant expression of p53 as determined by immunohistochemistry. It is concluded that the E mu-pim-1 mouse model will not be very suitable for short-term carcinogenicity testing in general: only genotoxic chemicals that have the lymphohaematopoietic system as target for carcinogenesis in wild- type mice, appear to be efficiently identified.