Brighton合作组关于Guillain-Barré综合征的诊断定义和资料收集规范

Guillain-Barr啨综合征(GBS)和Miller Fisher综合征(MFS)的诊断标准随着临床研究的深入在不断演变。2011年1月,《疫苗》杂志发表了国际疫苗安全性监测Brighton合作组关于GBS/MFS的诊断定义和研究资料收集规范。此文献中未采用"诊断标准"而采用"诊断定义"是因为其主要目的为评价疫苗安全性而制定,而非用于神经科的GBS/     

Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis

Lymphoblasts in bone marrow samples, obtained from 43 children with acute lymphoblastic leukemia at diagnosis, were incubated with 1.0 mumols/L [3H] methotrexate for 24 hours in vitro. Nonexchangeable methotrexate and methotrexate polyglutamates were separated and quantitated. Event-free survival at 5 years was 38% +/- 9% for all 43 patients (27 failures), and 44% +/- 10% for the 35 with non-T, non-B- cell acute lymphoblastic leukemia (20 failures). Of these 35 children, those whose lymphoblasts accumulated more than 100 pmol methotrexate and 500 pmol methotrexate polyglutamates per billion cells experienced better 5-year event-free survival than those whose lymphoblasts did not (65% +/- 12% v 22% +/- 9%, P = .010). This difference characterized "good-risk" patients who were female (P = .014), less than age 7 at diagnosis (P = .005), or had low initial white blood cell counts (less than 20 X 10(9)/L, P = .018). Findings were similar for the 43 children with acute lymphoblastic leukemia and for the "good-risk" children in this total group. Thus, the ability of lymphoblasts to accumulate methotrexate and form methotrexate polyglutamates may be important to the curative properties of current therapy of acute lymphoblastic leukemia in children, particularly for "good-risk" patients. In such patients, inherent rather than acquired drug resistance may be the initial event leading to treatment failure.     

Commentary on “A novel treatment strategy for newly diagnosed high-grade T1 bladder cancer: Gemcitabine and cisplatin adjuvant chemotherapy—A single-institution experience.”

Background

Management of high-grade T1 (formerly T1G3) bladder cancer continues to be controversial. Should patients with T1G3 bladder cancer have an immediate radical cystectomy or should they receive intravesical bacillus Calmette-Guérin preserving bladder? Gemcitabine and cisplatin (GC) adjuvant chemotherapy may help to strike a balance between intravesical and early cystectomy. For purposes of this study, we continue to refer high-grade T1 lesion as “T1G3.”

Adjuvant continuous metronomic adriamycin + cyclophosphamide followed by weekly nab‐paclitaxel for high‐risk early‐stage breast cancer

Many studies have sought to optimize the dosing schedule of adjuvant chemotherapy in early‐stage breast cancer. Here, we assessed the use of continuous metronomic weekly doxorubicin plus daily oral cyclophosphamide (AC) with continuous G‐CSF growth factor support for 12 weeks followed by weekly nab‐paclitaxel (nP) for 12 weeks. A nonrandomized phase II clinical trial was designed to assess (1) DFS at 2 years, (2) dose delivered, (3) use of nP in the adjuvant setting, and (4) toxicities. The dosing of A was 24 mg/m2 IV weekly and C was 60 mg/m2 oral daily (with scheduled filgrastim 5mcg/kg 6 days/week); nP, 100 mg/m2 IV weekly. For patients with HER2 + disease, trastuzumab was started during the nP portion of therapy and continued for 12 months. Sixty patients enrolled with a median follow‐up of 6 years. Node‐positive disease was present in 58% of patients. Receptor categories included hormone receptor positive/HER2 negative (n = 25; 42%); triple negative (n = 19; 32%); or HER2 positive (n = 16; 27%). DFS at 2 years was 93%. Mean dose delivered was greater than 90% for metronomic AC and 88% for nP. Treatment was well tolerated with a 2% incidence of febrile neutropenia. Continuous metronomic AC followed by nP was well tolerated in our patients with comparable DFS to historical controls.     

Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium

Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator- inhibitor. High concentrations of thrombin-but not of factor Xa or IXa-- had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.     

The final destiny of acantholytic cells in pemphigus is Fas mediated

Background  Pemphigus is an autoimmune disease characterized by the formation of intra-epidermal blisters. Patients develop auto-antibodies against desmoglein 1 and 3 proteins and induce acantholysis.
Objective  This work addresses the issue of whether the Fas pathway mediates acantholysis. Furthermore, the possible suppliers of the Fas pathway were investigated.
Methods  Seventeen biopsies of pemphigus patients were studied by haematoxylin and eosin staining, and apoptosis was defined by TUNEL. The expression of Fas, FasL and caspase 3 was studied by in situ hybridization and immunohistochemistry. Cell infiltrates were studied by immunofluorescence with monoclonal anti-CD3, CD4, CD8, CD19 and CD69.
Results  All of the biopsies showed intra-epidermal blisters, acantholytic cells and inflammatory infiltrates. The blisters expressed Fas, FasL and caspase 3. Cell infiltrates were composed of CD8 and a few CD4⁺CD69⁺ cells. Additionally, CD19⁺ cells were detected. Interestingly, the Fas expression was increased in acantholytic cells and perilesional keratinocytes. Incidentally, these cells exhibited apoptotic features. Interestingly, the CD8 cells expressed FasL.
Conclusion  This paper presents the morphological evidence that apoptosis and acantholysis are linked. Therefore, the Fas pathway is associated with CD8 cells in pemphigus lesions.

Conflicts of interest

None declared.     

Elevated serotonin is involved in hyperactivity but not in the paradoxical effect of amphetamine in mice neonatally lesioned with 6-hydroxydopamine

The neonatal lesion with 6-hydroxydopamine (6-OHDA) in rodents induces juvenile hyperactivity and paradoxical hypolocomotor response to psychostimulants, in striking contrast to what is observed when similar lesions are carried out in adults. The early disruption of central dopaminergic pathways is followed by increased striatal serotonin (5-HT) contents although the functional role of this neurodevelopmental adaptation remains unclear. The aim of the present study is to investigate the participation of this neurochemical imbalance in the main behavioral phenotypes of this model. To this end, mice received a neonatal administration of 6-OHDA that induced an 80% striatal dopamine depletion together with 70% increase in 5-HT. Serotoninergic hyperinnervation was evidenced further by increased [(3)H] citalopram autoradiographic binding and 5-HT transporter immunohistochemistry in striatal sections. To investigate whether elevated 5-HT was implicated in hyperactivity, we treated control and 6-OHDA neonatally lesioned mice with the selective irreversible tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) to induce 5-HT depletion. Normalization of striatal 5-HT in 6-OHDA neonatally lesioned mice to control levels reversed hyperactivity to normal locomotor scores, whereas the same extent of 5-HT depletion did not affect spontaneous locomotor activity of control mice. In turn, the paradoxical response to amphetamine in neonatal DA-depleted mice was not prevented by PCPA treatment. Taken together, our results suggest that the increased striatal 5-HT that follows neonatal DA depletion is involved in hyperlocomotor behavior but not in the paradoxical calming response to amphetamine observed in this mouse model.