مجله دانشکده پزشکی دانشگاه علوم پزشکی تهران
سال شصت و نهم شماره 3 (پیاپی 123، خرداد 1390)

Despite advances in cancer diagnosis and treatment, survival rate of patients suffering from glioblastoma multiform (GBM) has not been significantly improved. Therefore, novel therapeutic adjuncts to routine therapies have been suggested over time. Inhibition of angiogenesis by antiangiogenic drugs is one of the new approaches to inhibit the growth of malignant cells. Microvessel density (MVD) assay is a technique performed by counting immunohistochemically-stained blood vessels. Nowadays, athymic nude mice are widely used for the establishment of xenograft tumor models in cancer research. The aim of this study was to evaluate the MVD of autochthonous xenograft models of GBM isolated from Iranian patients for use in pharmaceutical research on antiangiogenic drugs. Fresh tumor samples of GBM were obtained from three patients in Cancer Institute of Tehran University of Medical Sciences in Fall of 2010 and Winter of 2011. After preliminary processing, minced tumor samples were implanted heterotopically on flanks of athymic nude mice. Two months later, the animals were sacrificed and the xenograft tumor samples were sent to the pathology laboratory. After establishing the proof of the xenograft tumor type, MVD-CD34, an endothelial cell marker, was assessed by counting hot spot areas in 22 samples. The mean number of microvessels in these xenograft tumor models was 30±2.1. These autochthonous xenograft models of GBM can be used in preclinical settings for research on antiangiogenic drugs regarding a pharmacogenomics-based treatment regimen for the Iranian population. Moreover, such models can be used in future studies for determining the sensitivity or resistance to antiangiogenic drugs in individualized cancer therapy.

ATP-binding cassette transporter A1 (ABCA1) is a key mediator of cholesterol efflux to apoA-I in lipid-laden macrophages, the first step of reverse cholesterol transport (RCT) in vivo and a critical step in preventing atherosclerosis. Enhanced ABCA1 expression may inhibit foam cell formation and consequently reduce atherogenic risk. On the other hand, garlic, Allium sativum, and garlic extracts have been demonstrated to have potential cardiovascular benefits. Moreover, garlic has direct antiatherogenic and antiathersclerotic effects on artery walls. The aim of this study was to evaluate the effects of alcoholic garlic extract on the expression of ABCA1 in macrophages.

Cell viability assay was used in order to detect the cytotoxic dose of alcoholic garlic extract on macrophages. Real-time PCR and Western blotting were performed to study the effects of alcoholic garlic extract on the expression of ABCA1. Macrophage cells were treated by different concentrations of alcoholic garlic extract for 48 h. The total RNA of the treated macrophages were extracted and analyzed by real-time PCR. ABCA1 protein expression was also analyzed using the Western blotting technique.

Alcoholic garlic extract increased the ABCA1 mRNA (20-23%) and protein expression (18-37%) in THP-1 macrophage cells compared with the controls (untreated cells).

The results of this study are suggestive of the potential effects of alcoholic garlic extract in increasing ABCA1 expression in macrophages, the possibility of promoting reverse cholesterol efflux in macrophages and preventing atherosclerosis.

The innate and adaptive immune responses are dependent on the migration of leukocytes across endothelial cells. Dendritic cells (DCs) play an important role in the initiation of cellular immune responses during their migration from tissues into the lymph nodes where they interact with endothelial cells of lymphatic vessels. We investigated the effects of surface-adherent and non-activated endothelial cells on phenotypic and functional characteristics of dendritic cells. Immature dendritic cells were generated from the isolation of peripheral blood mononuclear cells and their subsequent culture in DC-RPMI 1640 medium containing 10% FCS, interleukin-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for five days. On day five, a maturation factor (composed of monocyte-conditioned medium, tumor necrosis factor-α (TNF-α) and poly I:C) was added to the RPMI medium where immature DCs were co-cultured with endothelial cell monolayer for 24 h. The maturation of harvested DCs on day seven was evaluated via flow cytometry, a beta-counter and an ELISA kit. This study showed that the endothelial cells interact with dendritic cells generated from peripheral blood monocytes via cell-to-cell interaction. This interaction inhibits the maturation of DCs via decrease in the expression of CD83, CD86, CD80, HLA-DR and up-regulation of CD14. The interaction also inhibits the stimulation of T-lymphocytes resulting in a decrease in their proliferation. According to the findings of this study, it could be concluded that the endothelial cells can act as a potent regulator for DCs differentiation and function at the encounter made between them during the migration of DCs from tissues to lymph nodes.

Ewing sarcoma family tumors (ESFTs) are among the most malignant tumors in children and young adults. ESFTs include Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumors (pPNETs). As there seemed to be few studies on the molecular biology of ESFTs, we investigated the frequency of CD99, Ki67, p53 and Fli-1 protein expression in 15 Iranian patients with ESFTs. In addition, the correlation between expression rate of these proteins and various clinical factors, including age, sex and survival was computed.

The expression of the aforesaid proteins was studied by immunohisto-chemistry in formalin-fixed and paraffin-embedded blocks of 15 ESFTs specimens. Stained sections were classified according to the percentage of stained tumor cells.

The results showed the membrane expression of CD99 protein in all of the specimens. The nuclear expression of Fli-1 protein was observed in 86.7% and the over-expression of p53 nuclear protein was seen in 53.3% of the specimens. The expression rate of Ki67 protein was 60%. Although a significant correlation was not shown between the expression levels of Ki67, p53 or Fli-1 proteins with age, sex or survival of the patients, there was a significant correlation between expression levels of p53 and Ki67 proteins (P=0.003).

The results underline the role of p53 and Ki67 proteins in the development and progression of ESFTs and suggest the simultaneous immunohistochemical staining of Fli-1 and CD99 proteins for the diagnosis of ESFTs.

Thymidine phosphorylase (TP) catalyses the conversion of thymidine into thymine. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease which is caused by mutations in the nuclear gene encoding TP, bringing about severe impairment of TP-enzyme specific activity and accumulation of thymidine in plasma. The clinical manifestations of MNGIE are recognizable and homogenous, but not in the early stages of the disease. In patients who are suspected of having MNGIE, determination of TP-specific activity in leukocytes and thymidine levels in plasma are diagnostic. The methods that are usually used for the measurement of TP activity and plasma thymidine are not rapid or accurate enough and lack sensitivity. The specific activity of TP was measured by RP-HPLC in leukocytes of both the controls and the patients exhibiting clinical features suggestive of MNGIE. Moreover, plasma thymidine was assessed by the same method. The patients had detectable plasma thymidine (>3 µmol/L) but it was undetectable in the healthy controls. The patient's TP-specific activity decreased to less than 5% relative to the controls (14±4 nmol/h/mg vs. 525±165 nmol/h/mg, P<0.05). A diagnostic algorithm for the definitive diagnosis of MNGIE is suggestible based on the results of this study which relies on the measurement of plasma thymidine, TP-specific activity in leukocytes, or both. In this study, we set up a sensitive and rapid assay for the evaluation of TP-specific activity by using RP-HPLC in Iran. In addition, we established reference values for TP-specific activity and plasma thymidine in the Iranian patients.

Rosa damascene has a special role in the Iranian traditional medicine due to its sedative, anticonvulsant and analgesic effects. Regarding its alkaloid, flavonoid and other organic compounds, this plant has always been used to reduce nervousness and treat depression and chronic insomnia. In the present time, synthetic drugs with sedative and anxiolytic properties are used for such problems but due to their side-effects and economic issues, the significance of natural medicines with fewer side-effects is of interest. Considering the importance of sedative and anxiolytic effects of Rosa damascene, we decided to compare this plant with synthetic drugs of the same properties. Two different groups of male Wistar rats received either Rosa damascene extract in doses of 150, 300, 450 mg/kg or Diazepam and dimethyl sulphoxide in doses of 1.2 mg/kg intraperitoneally 30 minutes before assessing the sleep duration, sedation and preanesthetic effects induced by intraperitoneal ketamine, 40 mg/kg. The anti-anxiety effect was evaluated by using an elevated plus maze and a rota rod. The results showed a meaningful increase in the period of sleep induced by Ketamine (P≤0.01) and also a meaningful increase in time spent at the open arms of the device in the group receiving Rosa damascene extract (P≤0.01). The results showed that the Rosa damascene extract dose 450mg/kg has sedative, preanesthetic and anxiolytic effects (P≤0.01).

Unlike quantified MRI, no correlation has been stated between radiologic findings and the clinical signs in patients with knee osteoarthritis. This study evaluates the relationship between quantified clinical signs including pain, restriction of movement, stiffness and structural changes with MRI and plain radiography findings. Eighty patients with knee osteoarthritis were successively recruited in the study in Rasole Akram Hospital from 2009 to 2010. Upon physical examination, quantified scales of pain and joint stiffness and limitation of movement were recorded and quantified findings of MRI and plain x-ray were reported during the paraclinical study. All the gathered data including the demographic characteristics of the participants were read to the statistical software. In MRI study, pain was significantly correlated with knee effusion (P=0.008), osteophytes (P=0.006), meniscal degeneration (P=0.036) and subchondral cysts (P=0.044) as was joint stiffness correlated with chondral lesions (P=0.020) and meniscal degeneration (P=0.026). On the other hand, there were no relationship between pain and joint stiffness or limitation of movement in radiologic studies but significant relationships existed between radiologic findings with bone marrow inflammation (P=0.015), chondral lesions (P=0.022) and subchondral cysts (P=0.014). As shown in this study, MRI findings including chondral lesions, subchondral cysts and bone marrow inflammation were correlated with radiologic findings and osteophytes, subchondral cysts, joint effusion and meniscal degeneration were correlated with pain as were meniscal degenerations and chondral lesions were with joint stiffness. On the other hand, clinical findings (pain, stiffness and limitation of movement) had no correlation with radiologic findings.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Metformin which is effectively used for the treatment of anovulatory PCOS improves pregnancy rate and endometrial receptivity and reduces the risk of miscarriage. The aim of this study was to evaluate the effects of metformin on the endometrium, the number of fetuses and hormonal levels of PCOS rats. Forty female adult Sprague-Dawley rats were assigned randomly into four equal groups. Group I: control rats, group II: rats receiving metformin (150 mg/kg/day), group III: Estradiol Valerate-induced PCOS rats (4 mg/rat) and group IV: induced PCOS rats receiving metformin. Body weight and serum levels of glucose, LH, FSH, testosterone, progesterone and estradiol were measured. Following mating, each group was divided into two subgroups and the rats were sacrificed on the 5th and 15th day of gestation to evaluate endometrial reaction to implantation and fetus count, respectively. Hormone assay showed a significant increase in testosterone, estradiol, LH, FSH and blood glucose levels in group III compared to the controls (P≤0.01) and a significant decrease in blood glucose in group IV versus group III (P≤0.01). Progesterone concentration had no significant differences between groups III and the controls. Weight was higher in group III than group I but it had no decrease after metformin administration. No significant differences were detected regarding implantation rate and number of fetuses in all rats. Metformin has significant effects on pregnancy rate and the hormonal and blood glucose levels of Estradiol Valerate-induced PCOS rats.

Non-steroidal anti-inflammatory drugs (NSADs) and opioids are frequently administered to relieve postoperative pain. Uncontrolled postoperative pain may produce a range of detrimental acute and chronic health consequences and increase mortality and morbidity. Practically, the analgesic efficacy of opioids is typically limited by the development of tolerance to them or by opioid-related side-effects such as nausea, vomiting, sedation or respiratory depression. This study aims to assess the effects of suppository diclofenac on post-herniorrhaphy pain management.

In this prospective double-blind clinical trial, 60 patients who were candidate for the surgical repair of inguinal hernia were divided into two groups. Patients in group A received 100 mg of suppository diclofenac and patients in group B 50 mg of pethidine after the induction of anesthesia and before surgical incision. Postoperative pain assessment was done by an unbiased observer on the arrival of patients in the recovery room, using a 10-cm visual analogue scale (VAS(at 2-hour intervals for 6 hours.

Pain relief was similar in the two groups (P=0.3). Patients in group B required more analgesia two hours post-operatively (P=0.03), while patients in group A had more favorable results regarding pain control (P<0.05). Statistically, there was no difference between the two groups at other intervals. The occurrence of nausea and vomiting was similar in both groups. No respiratory depression was observed in the patients.

Preventive analgesia with 100 mg of suppository diclofenac after anesthesia induction for herniorrhaphy produced effective postoperative analgesia with minimum side-effects.

Cardiovascular diseases, especially atherosclerosis, are the main causes of morbidity and mortality worldwide. The disease has had an increasing prevalence in Iran in recent years. Homocysteine and C-reactive protein (CRP) are two novel cardiovascular risk factors that independently predict risks of atherosclerosis. The purpose of this study was to investigate the effects of one session of circuit resistance training on the blood levels of the aforesaid inflammatory markers in inactive middle-aged men. The participants of this study included twenty-three healthy but inactive middle-aged men who were overweight and were randomly divided into two experimental (n=14) and control (n=9) groups. The activity included doing exercises with the subject's 35% one-repetition maximum (1-RM) intensity at ten different stations. Blood levels of homocysteine and hs-CRP were measured before and after the exercise. Analysis of data using independent samples t-test showed a significant increment in the serum levels of homocysteine and hs-CRP after training in the experimental (P<0.05) versus the control group. Elevation of homocysteine levels is due to the increase in protein metabolism and creatine synthesis for energy production and elevation of hs-CRP levels could be due to hepatic induction of interleukin-6 that acts as a signal for the stimulation of lipolysis and glycogenolysis. However, beneficial or adverse physiological effects of these changes are not thoroughly understood and more research is needed to conclude about the acute and chronic effects of different types of physical activity on the blood levels of these atherosclerosis risk factors.