Synergistic effect of TRAIL and irradiation in elimination of glioblastoma stem-like cells

Glioblastoma multiforme (GBM) is the most common malignancy in central nervous system. A small subpopulation of GBM cells known as GBM stem-like cells (GSLCs) were supposed to be the most malignant cells among GBM cells as they are resistant to multiple therapies including radiotherapy. In this study, we set up two GSLCs cell lines from the two parental U87 and U251 glioma cell lines, and studied the expression of apoptosis-related genes alteration in GSLCs before and after irradiation. We found that one of the receptors of TNF-related apoptosis-inducing ligand (TRAIL), DR5, was dramatically up-regulated in GSLCs after irradiation (IR). Although GSLCs are resistant to both TRAIL and radiation treatment alone, the combined treatment with TRAIL and irradiation achieved maximum killing effect of GSLCs due to inducing the expression of DR5 and inhibiting the expression of cFLIP. Therefore, TRAIL and IR combined treatment would be a simple but practical therapeutic strategy for clinical application.     

Beyond somatisation: a review of the understanding and treatment of medically unexplained physical symptoms (MUPS).

Patients commonly present in primary care with symptoms for which no physical pathology can be found. This study is a review of published research on medically unexplained symptoms (MUPS) in primary care. A literature review and qualitative comparison of information was carried out. Four questions were addressed: what is the prevalence of MUPS; to what extent do MUPS overlap with psychiatric disorder; which psychological processes are important in patients with MUPS; and what interventions are beneficial? Neither somatised mental distress nor somatisation disorders, based on symptom counts, adequately account for most patients seen with MUPS. There is substantial overlap between different symptoms and syndromes, suggesting they have much in common. Patients with MUPS may best be viewed as having complex adaptive systems in which cognitive and physiological processes interact with each other and with their environment. Cognitive behavioural therapy and antidepressant drugs are both effective treatments, but their effects may be greatest when the patient feels empowered by their doctor to tackle their problem.     

Synergistic combination of azithromycin and sulfadiazine for treatment of toxoplasmosis in mice

Experiments were performed in vivo in a mouse model of acute toxoplasmosis to evaluate the effectiveness of the combination azithromycin/sulfadiazine. Azithromycin alone or sulfadiazine alone, at doses that did not provide any protection against death due to toxoplasmosis, were remarkably and significantly synergistic against murine toxoplasmosis when administered in combination.     

Synergistic antiviral effect of a combination of mouse interferon-alpha and interferon-gamma on mouse hepatitis virus

Although interferon (IFN)-alpha and IFN-gamma have been reported to exhibit a synergistic antiviral effect through the different signaling pathways in vitro, their therapeutic efficacy is not well defined in vivo. The current study was carried out to investigate the combined antiviral effect in a model of mouse hepatitis virus Type 2 (MHV-2) infection, in which fulminant hepatitis is developed. MHV-2 was injected intraperitoneally into 4-week-old ICR mice, IFN or the vehicle was administered intramuscularly for 5 days, and the antiviral effect was evaluated based on survival periods, liver histology, serum alanine transaminase (ALT) levels, and MHV-2 virus titers in the liver tissues. The animals in the group treated with a combination of IFN-alpha and IFN-gamma survived for longer periods than the groups treated with IFN-alpha alone and IFN-gamma alone (IFN-alpha 10(3) (IU/mouse)/-gamma 10(3) vs. IFN-alpha 10(3), P < 0.005; IFN-alpha 10(3)/-gamma 10(3) vs. IFN-gamma 10(3), P < 0.001). This is consistent with the lower levels of hepatocellular necrosis and serum ALT and the decreased titers of MHV-2 virus in the liver tissues (48 hr, P < 0.001; 72 hr, P < 0.001). These findings indicate that a combination of IFN-alpha and IFN-gamma exhibits a synergistic antiviral effect on MHV-2 infection. The biology of MHV-2 is quite different from that of human hepatitis viruses; however, these results suggest the beneficial combined therapy of IFN-alpha and IFN-gamma for the treatment of human viral hepatitis.     

Synergistic effect of a combination of nicarbazin and monensin against coccidiosis in the chicken caused by Eimeria spp.

ABSTRACT

A clinical study was made into the abilities of nicarbazin and monensin and a nicarbazin?+?monensin combination to control Eimeria acervulina, E. maxima, and E. tenella in chickens. When included in the feed, at concentrations of 40?ppm nicarbazin or 40?ppm monensin, these products showed partial efficacy evaluated by daily weight gain (DWG) but no activity judged by daily feed intake (DFI) or feed conversion ratio (FCR). By contrast, the combination of 40?ppm nicarbazin?+?40?ppm monensin provided complete control of infection judged by greater DWG and DFI, and lower FCR. Monensin at a concentration of 40?ppm was ineffective in preventing lesions caused by all three species. Nicarbazin at a concentration of 40?ppm was unable to suppress lesions of E. acervulina and E. maxima but was able to suppress lesions caused by E. tenella. Nicarbazin 40?ppm?+?monensin 40?ppm suppressed lesions of all three species.

RESEARCH HIGHLIGHTS

• Nicarbazin or monensin at 40 ppm gave only partial control of Eimeria spp.

• A combination of 40 ppm nicarbazin + 40 ppm monensin controlled DWG, DFI and FCR.

• Nicarbazin or monensin at 40 ppm did not suppress all Eimeria spp. lesions.

• Nicarbazin 40 ppm + monensin 40 ppm suppressed lesions of all three species.

     

Responsiveness of vascular endothelium to shear stress: potential role of ion channels and cellular cytoskeleton (review).

The frictional forces associated with blood flow expose vascular endothelium in arteries to a complex and highly dynamic shear stress distribution. The ability of endothelial cells to respond to shear stress is essential for arterial vasoregulation in response to acute hemodynamic changes and for vascular wall remodeling following chronic changes in blood flow. Furthermore, endothelial responsiveness to shear stress may play a role in the localization of early atherosclerotic lesions. Shear stress elicits a wide range of humoral, metabolic, and structural responses in endothelial cells. These include activation of ion channels and of G proteins, induction of oscillations in intracellular calcium concentration, alterations in the expression of various important genes, and extensive cytoskeletal reorganization. Mechanisms of shear stress sensing and transmission in endothelium are discussed in light of the complex shear stress distribution to which endothelial cells are exposed in vivo and with particular emphasis on the potentially central role of flow-sensitive ion channels and the cellular cytoskeleton. Finally, the ability of endothelial cells to distinguish among and to respond differentially to different types of shear stress is highlighted.     

Risk factors and treatment of refractory anaphylaxis - a review of case reports

Introduction: Patients experiencing anaphylaxis who do not recover after treatment with intramuscular adrenaline are regarded as suffering from refractory anaphylaxis. The incidence of refractory anaphylaxis is estimated to range between 3–5% of anaphylaxis cases. The risk factors for refractory anaphylaxis are unknown.

Areas covered: In the present analysis, we aimed to evaluate the management and risk factors of refractory anaphylaxis to highlight possible clinical implications for updating current management algorithms.

Expert commentary: According to international guidelines, adrenaline given through the intramuscular (i.m.) route is a rapid and safe treatment but may be insufficient. Therefore, defined standardized treatment protocols for such cases of refractory anaphylaxis are needed to optimize the treatment. Point-of-care diagnostics may enable doctors to identify patients experiencing severe, refractory anaphylaxis early in order to initiate intensified critical care treatment.     

The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil

Evidence from behavioral and self-reported data suggests that the patients' beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual's expectation of a drug's effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients' beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.     

Synergistic effect of IL-4 and TNF-alpha in the induction of monocytic differentiation of a mouse myeloid leukaemic cell line (WEHI-3B JCS).

We have previously shown that non-cytotoxic concentrations (600-1200 U/ml) of recombinant mouse tumour necrosis factor-alpha (TNF-alpha) can induce differentiation of a subclone (JCS) of the WEHI-3B myelomonocytic leukaemia cell line into mature cells with the characteristics of macrophages. In the present study, the effects of recombinant mouse interleukin-4 (IL-4), either alone or in combination with mouse TNF-alpha, on the growth and differentiation of JCS cells were examined. IL-4 alone (20-5000 U/ml) inhibited the growth of JCS cells in a dose-dependent manner but did not induce cell differentiation. However, combinations of IL-4 and TNF-alpha acted in synergy to inhibit cell proliferation and induce monocytic differentiation of JCS cells, as shown by increased expression of the macrophage differentiation antigens (F4/80, Mac-1), stimulation of phagocytic activity, induction of non-specific esterase and NBT-reducing activities, increased plastic adherence and morphological criteria. Similar synergistic interactions were also shown by human TNF-alpha and mouse IL-4, indicating that TNF-alpha might exert its effects through the low-affinity (p55) TNF receptors. Moreover, the clonogenicity of JCS cells in vitro and their tumorigenicity in vivo were significantly reduced by combined TNF-alpha and IL-4 treatment. Our results indicate that TNF-alpha can act as a differential signal for JCS cells and that its effects are modulated by IL-4. Therefore, the combination of TNF-alpha and IL-4 may be useful in the treatment of some forms of myelomonocytic leukaemia.     

The effect of combination of different inducers on the refractory state in interferon production.

A second injection of 100 mug poly (rI) poly (rC) per mouse at 6 and 24 hours after the first injection stimulated additional peaks of interferon production. The dynamics of the process of accumulation and disappearance of interferon was similar to that after a single injection of poly (rI). poly (rC). Injection of the above dose 12 hours after the first injection induced no interferon production as it apparently coincided with the refractory state in interferon production. After pretreatment of poly (rI) poly (rC) with DEAE-dextran, the refractory phase occurred in 6 hours. Inoculation of Venezuelan equine encephalomyelitis virus as a second interferon inducer resulted in a repeated stimulation of interferon production both in animals and in tissue culture; however, interferon titres in this case were low. The use of an inactivated virus as a second interferon inducer stimulated interferon production to higher titres (5120 IU/ml) than a single injection of DEAE-dextran-treated poly (rI). poly (rC). It is possible that a combined use of poly (rI). poly (rC) and noninfectious virus as a second interferon inducer eliminates the development of the refractory state.     

The effect of colchicine treatment on sperm production and function: a review

Colchicine is used for the treatment of various diseases including gouty arthritis, familial Mediterranean fever (FMF) and Behcet's disease. As a modulator of the microtubules at the cytoskeleton level, it arrests cell division at metaphase and inhibits microtubular- dependent cell motility. Controversy exists as to the adverse effect of colchicine on sperm production and function in healthy subjects as well as in gout, FMF and Behcet's patients. Sperm analysis shows a spectrum of pathology, from oligo- and azoospermia to normospermia with disturbances in sperm motility. These inconsistent sperm pathologies can be explained in part by the variability of the pathophysiology of the underlying disease. Thus, it seems that colchicine by itself may not have a significant direct adverse effect on sperm production and function.      

胰岛素联合硒协同抗糖尿病心肌细胞凋亡的作用

目的:观察胰岛素联合硒对糖尿病心肌病(diabetic cardiomyopathy,DCM)大鼠心肌细胞凋亡、Ku70、乙酰化Ku70、Bax和细胞色素C(cytochrome C)蛋白水平的影响,初步探讨胰岛素和硒协同抗DCM的机制。方法:将SD大鼠50只随机分为空白对照组(control组)、糖尿病心肌病模型组(DCM组)、糖尿病心肌病+胰岛素(DCM+In)组、糖尿病心肌病+硒(DCM+Se)组和糖尿病心肌病+胰岛素+硒(DCM+In+Se)组。流式细胞术检测心肌细胞线粒体膜电位;末端脱氧核糖核苷酸转移酶介导的缺口末端标记(terminal deoxynucleotidyl transferasemediated nick end labeling,TUNEL)法观察心肌细胞凋亡;Western blot法观察Ku70、Bax和cytochrome C蛋白水平的变化;免疫共沉淀法检测Ku70乙酰化。结果:与对照组比较,DCM组大鼠心肌细胞发生明显凋亡(P0.01),Ku70和乙酰化Ku70表达明显增加(P0.01),Bax由胞浆向线粒体转位同时cytochrome C由线粒体向胞浆转位(P0.01);与DCM+In组或DCM+Se组比较,胰岛素联合硒明显抑制心肌细胞凋亡(P0.05),下调Ku70以及乙酰化Ku70的表达(P0.05)并阻止Bax和cytochrome C转位(P0.05)。结论:胰岛素和硒可能通过调控Ku70乙酰化和抑制Bax转位而协同抗糖尿病心肌细胞凋亡。     

Higher incidence of aggressive breast cancers in African-American women: a review

Despite a lower incidence of breast cancers in African Americans than in Caucasians, mortality rates from breast cancer are higher in African Americans. This review summarizes disparate characteristics of breast cancer diagnosed in African Americans as compared with Caucasians, such as more advanced stage at diagnosis and less estrogen-receptor positivity of disease, in an effort to explain differences in their survival outcomes. Multifactorial explanations are offered, including differences in access to care, disparate utilization of mammography screening and often differences in treatment course-as well as biologic factors, such as higher incidence of aggressive breast cancer phenotypes, higher grade of tumor and higher growth index of tumors in African Americans as compared with Caucasians. Multiple population-based studies have been reviewed and screening and treatment interventions proposed in order to heighten awareness of these differences and to improve disease outcomes among this high-risk population.     

经巩膜睫状体光凝术治疗难治性青光眼的疗效观察

目的 探讨810nm激光经巩膜睫状体光凝术（TSCPC）治疗难治性青光眼的效果。方法 前瞻性研究2011年11月—2013年1月在第三军医大学大坪医院野战外科研究所眼科进行TSCPC治疗的117例患者（118眼）,男59例（60眼）,女58例（58眼）,年龄31—79岁。按视力损害程度分为3组：视力≤数指为A组、数指〈视力〈0．1为B组、视力≥0．1为C组,对3组患者分阶段实施TSCPC。观察3组患者术前及术后1d、3d、1个月、3个月、1年的眼压和1年时视力,C组观察术前和术后1年时视野情况。术后失访者退出统计,不纳入疗效评定。结果 A、B、C组TSCPC术后分别成功随访44例（44眼）、32例（32眼）、28例（28眼）。3组患者术后1d、3d、1个月、3个月、1年时的眼压分别与术前比较,差异均有统计学意义（P值均〈0．05）。3组患者术后1年视力分别与术前比较,差异无统计学意义（Hc=0．64,P〉0．05）。C组术后1年视野MD值（-16．02±d．72）与术前（-17．36±4．42）比较,差异无统计学意义（Z=-1．68,P〉0．05）。术后并发球结膜水肿7例,虹膜睫状体炎59例,前房积血5例,经对症治疗后消失。随访1年时,眼球萎缩5例。结论 TSCPC是治疗难治性青光眼的有效措施,能有效挽救不同视力的难治性青光眼的残存视功能,安全性高,是降低眼压、保护视神经的有效治疗措施。     

The grieving adult and the general practitioner: a literature review in two parts (Part 1).

This article is the first of a two-part literature review on bereavement. In part 1, those psychological theories that have improved the understanding of the bereavement process are summarized. In addition, the research examining the mortality and morbidity following a bereavement is critically analysed.     

The grieving adult and the general practitioner: a literature review in two parts (Part 2).

In part 1 of this review, published last month, literature exploring the psychological bereavement theories and the health consequences of bereavement are summarized. The second part builds on this to outline the debate surrounding the characteristics of abnormal bereavement, while also focusing on risk factors for this morbidity. This leads on to a summary of the literature on bereavement care, particularly from a general practice point of view. Finally, areas for further research are highlighted.     

Eculizumab in refractory catastrophic antiphospholipid syndrome: a case report and systematic review of the literature

Clinical and Experimental Medicine - Catastrophic antiphospholipid syndrome (CAPS) is a rare disorder, characterized by the development of multiple vascular thrombosis over a short period of time,...