Decreased prefrontal 5-HT2A receptor binding in subjects at enhanced risk for schizophrenia

The brain serotonin-2A receptor (5-HT_2AR) has been implicated in both the pathology of schizophrenia and the therapeutic action of atypical antipsychotics. However, little is known about the 5-HT_2AR status before the onset of schizophrenia and before the exposure to antipsychotics. We used [¹⁸F] altanserin and positron emission tomography (PET) in a pilot study of 6 individuals suspected to be at elevated risk for schizophrenia and seven age-matched controls to test the hypothesis that regional 5-HT_2AR binding is altered in the prodromal stages of schizophrenia. Distribution volume ratios (DVRs) as a proxy for 5-HT_2AR availability were significantly reduced in prefrontal cortex regions of at-risk subjects, implicating early abnormalities of serotonergic neurotransmission that antecede the onset of schizophrenia.     

Digoxin dosing in the aged: new pharmacokinetic system versus Jellife and Koup methods

To evaluate three methods for digoxin dose adjustment in aged patients, we determined the plasma digoxin levels that would be attained in 87 aged patients with doses adjusted to the kidney function by means of three separate procedures. Mean patient age was: 79.0 +/- 6.3 years; creatinine clearance (Clc): 0.70 +/- 0.23 mL/Kg of lean body weight and minute; digoxinemia/dose ratio (RCpD): 0.421 +/- 0.237 Kg/L. The dose that would attain a digoxinemia of 1.2 ng/mL, calculating the elimination constant (K) and the volume of distribution (V) as linear functions of the Clc, so that K ranges between 0.173 and 0.462 days-1 and V between 4 and 10 L/Kg of lean body weight when the Clc varies from 0 to 110 mL/minute, was 2947 ng/Kg of lean body weight, coefficient of variation (CV): 25.2%. The digoxinemia that patients would have with this D, taking into account the individual RCpD, was 1.1 ng/mL, CV: 38.0%; with figures between 0.8 y 2.0 ng/mL and above 2.0 ng/mL in the 81.6% and the 0.0% of the patients (95% confidence intervals (95% CI): 72.2% to 88.4 and 0.0% to 4.6%), respectively. The precision and the bias were 0.43 and -0.06 ng/mL (95% CI: 0.38 to 0.48 and -0.16 to 0.03 ng/mL), respectively, and with this method the digoxinemia was not associated with the Clc. We concluded that the described method would lead to good results if digoxin has not been prescribed in order to control the cardiac frequency in the setting of auricular fibrilation.     

Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor-related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells.

PURPOSE: Bcl-2 overexpression is frequently detected in lymphoid malignancies, being associated with poor prognosis and reduced response to therapy. Here, we evaluated whether Bcl-2 overexpression affects the cytotoxic activity of proteasome inhibitors taken alone or in association with conventional anticancer drugs or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). EXPERIMENTAL DESIGN: Jurkat cells engineered to overexpress Bcl-2 were treated with proteasome inhibitors (MG132, epoxomicin, and bortezomib), anticancer drugs (etoposide and doxorubicin), TRAIL, or combinations of these compounds. Cell death and loss of mitochondrial transmembrane potential were detected by flow cytometry. Cytosolic relocalization of cytochrome c and SMAC/Diablo, caspase cleavage, and Bcl-2 and Mcl-1 levels were determined by immunoblotting. Nuclear factor-kappaB inhibition was done by retroviral transduction with a dominant-negative mutant of IkappaBalpha. RESULTS: Bcl-2 overexpression results in significant inhibition of apoptosis in response to proteasome inhibitors, antiblastics, and TRAIL. Addition of TRAIL to proteasome inhibitors results in a synergistic cytotoxic effect in Bcl-2-overexpressing cells, whereas this result is not reproduced by the combination of proteasome inhibitors with antiblastic drugs. Importantly, proteasome inhibitors plus TRAIL induce mitochondrial dysfunction irrespective of up-regulated Bcl-2. Bcl-2 cleavage to a fragment with putative proapoptotic activity and elimination of antiapoptotic Mcl-1 may both play a role in proteasome inhibitors-TRAIL cooperation. Conversely, nuclear factor-kappaB inhibition by proteasome inhibitors is per se insufficient to explain the observed synergy. CONCLUSIONS: Combined proteasome inhibitors and TRAIL overcome the apoptotic threshold raised by Bcl-2 and may prove useful in the treatment of chemoresistant malignancies with up-regulated Bcl-2.     

Plasmablastic lymphomas with light chain restriction – plasmablastic extramedullary plasmacytomas?

J Oral Pathol Med (2010) 39 : 435–439 Background: It is diagnostically difficult to differentiate plasmablastic lymphomas (PBLs) from plasma cell neoplasms with plasmablastic differentiation. Plasmablastic lymphomas are currently classified as ‘PBL of the oral mucosa’ and ‘PBL with plasmacytic differentiation’. Methods: Forty‐five cases of PBL were retrieved from the Departments of Oral Pathology of the Universities of Pretoria and Limpopo, South Africa. Clinical features and HIV status were recorded and each case was classified as ‘PBL of the oral mucosa type’ or as ‘PBL with plasmacytic differentiation’. Immunohistochemistry included: CD45, CD3, CD20, CD79a, CD38, CD138, MUM1, Ki‐67 and kappa and lambda light chains. Positivity was recorded based on the percentage of positive staining cells as focal (5–20%); intermediate (20–70%) or diffuse (>70%). In situ hybridization was performed for Epstein–Barr virus (EBV) and HHV‐8. Results were recorded as positive or negative. Results: All cases showed some degree of plasmacytic differentiation. All were negative for CD20 with reactive T cells detected with CD3. Diffuse and strong positive staining was found with Ki‐67 and MUM1, but variable immunoreactivity was found with CD79a, CD45, CD38 and CD138. Twenty cases (47%) showed light chain restriction. Epstein–Barr virus was detected in 44/45 cases and HHV‐8 in none. Conclusions: The morphological classification of PBLs is not valid as all cases showed some degree of plasmacytic differentiation. We propose that PBLs with light chain restriction be reclassified as ‘plasmablastic extramedullary plasmacytomas’ and managed accordingly. The rest represents true PBLs. The true nature of these neoplasms as an entity should be further investigated with molecular and genetic studies.     

The use of dendritic cells in cancer immunotherapy

Cancer immunotherapy aims at eliciting an immune response directed against tumor antigens to help fight off residual tumor cells and thereby improve survival and quality of life of cancer patients. Different immunotherapeutic approaches share the use of dendritic cells (DCs) to present tumor-associated antigens to T-lymphocytes. Ex vivo generated DCs can be loaded with antigens and re-infused to the patients, or they can be used for ex vivo expansion of antitumor lymphocytes. Alternatively, methods exist to target antigens to DCs in vivo without need for ex vivo cell manipulations. The clinical studies have shown that DC administration to patients is safe and induces antigen-specific immunity. However, it seldom elicits objective clinical responses in patients with advanced-stage malignancies. Novel insights into DC and lymphocyte regulation are expected to lead to more effective vaccines in the near future. Meanwhile, efforts are directed at identifying the most appropriate clinical targets for active specific immunotherapies. Data suggests that vaccinations may indeed be beneficial when given in the adjuvant setting rather than to treat metastatic cancers. These issues are discussed here together with an overview of the DC-based antitumor immunotherapy studies.     

Pegfilgrastim compared with filgrastim after autologous peripheral blood stem cell transplantation in patients with solid tumours and lymphomas

To evaluate the safety and efficacy of pegfilgrastim administered as haematological support after autologous peripheral blood stem cell transplantation, we compared 44 patients with solid tumours and lymphomas receiving a 6-mg single dose of pegfilgrastim on day +5 after transplantation to a historical control group of 25 patients receiving filgrastim 5 μg kg⁻¹ day⁻¹ starting on day +5. There were no significant differences in haematological recovery nor in the incidence and duration of neutropenic fever. Median duration of grade 4 neutropenia in the pegfilgrastim and filgrastim group was similar. The incidence of grade III–IV mucositis was lower in pegfilgrastim than in filgrastim group due to the significant difference observed among the patients with solid tumours (p = 0.00). The only adverse event considered to be cytokine related was mild to moderate bone pain occurring during haematological recovery. According to the present study design and taking into account the current prices in our institution, the cost of the two drugs was similar in both treatment groups. In conclusion, a single injection of pegfilgrastim administered at day +5 post-transplantation shows comparable safety and efficacy profiles to daily injections of filgrastim and may be cost effective. Alberto Ballestrero and Davide Boy contributed equally to this article.     

The adulterated XANAX pill: a fatal intoxication with etizolam and caffeine

International Journal of Legal Medicine - A 49-year old man was found dead at home next to a glass containing a dried, white, crystalline substance and near a bag containing pills with the imprint...     

翁维良温阳活血法治疗缓慢性心律失常合并阵发性房颤验案及分析

缓慢性心律失常合并阵发性房颤,目前在口服西药的选择上存在一定的困难,翁维良教授认为阳虚血瘀为主要病机关键,治疗以温阳补气、活血化瘀为基本治法。文章中患者经中医治疗后头晕、乏力等症状明显改善,最小心率从36次/min提升至43次/min,房颤心搏次数减少,生命质量提高。笔者通过验案分析总结翁维良教授在治疗本病方面的遣方用药特点,为中医治疗本病提供一种可供参考的治疗方案,此外,通过图文结合的个案分析阐述法对名医经验总结方法进行了一种新的尝试与探索。     

智谋在进展期胃癌患者癌因性疲乏和失志间的中介效应

目的 了解进展期胃癌患者失志综合征的现状,探讨智谋在进展期胃癌患者癌因性疲乏和失志间的作用机制。方法 选取2019年5月至2020年10月在郑州大学第二附属医院接受术后化疗的145例进展期胃癌患者作为研究对象。采用一般资料调查表、智谋量表(RS)、中文版失志量表(DS-MV)、癌因性疲乏量表(CFS)进行调查。结果 最终回收有效问卷132份。132例进展期胃癌患者失志综合征得分为(33.46±13.02)分。不同受教育程度、付费方式、家庭人均月收入和疾病分期的患者的失志综合征得分比较,差异有统计学意义(P<0.05)。智谋与癌因性疲乏、失志水平均呈负相关(r=-0.491、-0.577,P<0.05),癌因性疲乏与失志水平呈正相关(r=0.617,P<0.05)。中介效应分析结果显示,智谋在癌因性疲乏与失志综合征间起中介效应,其中介效应占比为26.58%。结论 进展期胃癌患者失志综合征处于中等水平,智谋在患者癌因性疲乏与失志综合征间起中介作用。这提示临床工作者及时识别并采取多种措施进行癌因性疲乏的干预,提升患者个人、社会智谋水平,以达到降低失志水平的目的。     

骨关节炎疾病改善型药物研究进展

骨关节炎(OA)是一种常见的慢性关节疾病,主要的病理改变为关节软骨的退化和继发性骨质增生.现有的药物治疗方式存在明显的局限性,仅从镇痛角度治疗或行关节置换术,二者均不能从根本上改善关节软骨的病变.因此,抑制OA疾病进展的药物(DMOAD)应运而生.DMOAD通过参与调节软骨代谢平衡、参与软骨下骨重塑和控制局部炎症等机制...