Tehran University Medical Journal

The importance of fibronectin in development, regeneration and treatment: review article

Masoud Feridoni

Fibronectin (FN) is one of the essential component of the extra cellular matrix and their important role is as regulator of cellular activities and also fibronectin is an important scaffold for maintaining tissue. Fibronectin conformational changes expose additional binding sites that participate in fibril formation and in conversion of fibrils into a stabilized, insoluble form. In fact fibronectin is a connected glycoprotein disulfide dimer with sedimentation coefficient of approximately S 13 and 440 kDa molecular mass which is exist in many extracellular matrix and plasma with concentration of approximately 300 µg/ml that during the regeneration body tissues acts in severely regulated stages until regenerate the damaged tissue. Fibronectin has domains for interacting with other extra cellular matrix proteins, cell surface receptors, glycosaminoglycans (GAGs), and other FN molecules. This combination of domains allows FNs to bind simultaneously to cells and to molecules within the surrounding matrix. Also fibronectin have binding sites for collagen/ gelatin, heparin, fibrinogen, and other molecules. In the present study important roles of fibronectin in development, regeneration especially in nerves system and important role of it in treatment of some diseases have been reviewed. Present study has reviewed 77 publications by using of PubMed, NCBI, Elsevier, EBSCO and Nature databases for describing the important roles of fibronectin in biological systems. Studies have shown that fibronectin has diverse roles such as: cellular adhesion, embryonic differentiation, assembly of extra cellular matrix, connecting and cell growth, transformation as well as cell migration that each of this roles depends to fibronectins action site. Considering the important role of fibronectin in attachment of cancer cells to basal lamina, spread neoplasm, tissue regeneration and formation of extra cellular matrix better identification the properties as well as physiological applications of fibronectin in tissues and bodies of animals can provide the better understanding of physiological mechanisms and pathophysiological effects of cells on each other, and also provides the new ways for treatment a variety of diseases.

Hydro-alcoholic extract of Ziziphora tenuior L. on polycystic ovary syndrome in Wistar rats

Mohammad Nabiuni

Background: Polycystic ovary syndrome (PCOS) that occurs with chronic lack of ovulation, systemic inflammation and hyperandrogenism is manifested most common endocrine disorder in women of reproductive age. Ziziphora tenuior L. due to possess its Pulegone, flavenoid and anthocyanin has anti-inflammatory and anti-oxidant activity. This study investigates the modulating effects of Ziziphora tenuior L. extract by its anti-inflammatory properties on hormonal profile and the improvement of tissue symptoms of estradiol valerate- induced PCOS. Methods: In this experimental study that established in Laboratory,s Animal Center and Cellular And Molecular Research Laboratory, Kharazmi University, Karaj, from October 2012 to November 2013, 144 female adult Wistar rats divided into three groups of control (without injection), estradiol valerate- induced polycystic ovarian syndrome (2 mg/rat estradiol valerate, subcutaneously) and Ziziphora tenuior L. extract-treated groups. After induction of the syndrome within 60 days, experimental groups were injected 100, 150 and 200 mg/kg bw Ziziphora tenuior L. extract for 10 consecutive days intraperitoneally. The animals were anesthetized by chloroform. Their ovaries and blood serum was harvested to hormonal analysis and histomorphometric studies. Data using of one-way ANOVA test and P< 0.05 was considered significant level. Results: The ovarian sections in PCOS group exhibited a significant reduction in thickness granulosa layer (82%), number of corpus luteums (54%), appearance of some cysts (79%) and increased CRP serum level (68%) compared with the control group, while the histological changes in Ziziphora tenuior L. extract-treated ovaries did not have significant difference compared with control (P= 142). The decrease of LH, estradiol, and testosteron was significant in Ziziphora tenuior L. extract-treated groups compared with the estradiol valerate- induced PCOS. Conclusion: It seems that Ziziphora tenuior L. extract may improve functional and endocrine disturbances of estradiol valerate- induced PCOS and modulate the hormone level by anti-inflammatory effects. Ziziphora tenuior L. extract also starts the ovulation process again in polycystic ovary syndrome group.

Safety and effectiveness of everolimus compared with sirolimus and tacrolimus in preventing kidney transplantation rejection: a systematic review and meta-analysis

Ali Akbari Sari

Background: Everolimus is an immunosuppressive agent with a novel mode of action but has a different clinical role with calcineurin inhibitors (CNI). The aim of this study was to evaluate the safety and effectiveness of everolimus compared with sirolimus and tacrolimus in preventing kidney transplantation rejection. Methods: Search was conducted for finding randomized clinical trials (RCT) until the end of 2013 in main databases include Cochrane, Medline and other related databases in February 2014. To find the ongoing trials two databases were searched (Clinicaltrial.gov and irct.ir/fa/). Two independent reviewers checked studies for quality and eligibility and finally extracted the data. Data extraction was performed using Cochrane data extraction form for clinical trial. Discrepancies were resolved via consultation with third person. The studies examined in term of heterogeneity with I2 and Chi-square test. The mata-analysis was carried out using RevMan 5.2 (Wintertree Software Inc, Ontario, Canada) when there was homogeneity. Results: Finally, seven reports from six RCTs included in this study. All reports were in english language and total numbers of participant in these studies were 824. No studies were found in comparison of everolimus and sirolimus and all seven reports were combination of everolimus, tacrolimus and other relative drugs. Follow up time of studies were different from 6 to 36 months. Due to the heterogeneity of included studies, only two studies were entered into meta-analysis. The recorded mean values for glomerular filtration rate, serum creatinine and creatinine clearance were between 60-80 ml/min, 50 to 80 ml/min and 1.2 to 1.9 mg/dl respectively. The results of meta-analysis in three outcomes include serum creatinine, creatinine clearance and glomerular filtration rate were significantly in favor of low dose tacrolimus plus everolimus. Conclusion: In general, everolimus showed better results in combination with tacrolimus. Given the available evidence in this study, everolimus in combination with low dose tacrolimus showed better safety and effectiveness in preventing kidney transplantation rejection.

Effect of mesenchymal stem cells on allergic asthma in mouse model

Nowruz Delirezh

Background: Allergic Asthma is an inflammatory disease of the respiratory system that is well known by increased inflammatory cells in the airways and causes difficulty in respiration. The prevalence of allergic asthma is increasing worldwide, and it has become a significant cause of health challenge especially in developed countries. Inhaled β2-agonists and Inhaled or oral corticosteroids are common medications for treating the disease, but they cannot be used for long periods of time because of frequently occurring side effects and they can’t change the main pathogenesis of the problem. Deficiency in regulatory system against inflammation could be an important factor in allergic asthma. Mesenchymal stem cells (MSCs) have potential of cellular immunosuppressive therapy of inflammatory disorders. The aim of present study was to evaluate the effects of MSC therapy on mechanisms of allergic asthma in mice model. Methods: This experimental study was conducted from August 2014 to March 2015. The animals were housed and maintained in Biotechnology Center of Urmia University, Iran. Mice were sensitized by intra-peritoneal injection of ovalbumin (OVA) and aluminum hydroxide emulsion and then were challenged intra-nasally with OVA. Before allergen challenge on day 14, experimental mice received tail vein injection of MSCs in PBS. Regulatory T cells of spleen, cytokines and IgE analysis were carried out using lungs wash as well as serum samples. Results: Our results showed that MSCs significantly reduced total cells and eosinophilia, serum OVA-specific IgE concentration in OVA-sensitized and challenged mice. Also results showed that MSCs markedly inhibited expressions of Th2 cytokines and elevated levels of Treg cells and Treg cytokines. Conclusion: In the present study, we demonstrated the inhibitory effect of MSCs on airway inflammation using mice model of allergic asthma. The mice were sensitized with OVA and compared to the results of dexamethasone administration. Our results demonstrated that administration of MSCs could be used as a potential therapeutic approach for the allergic asthma.

Epidemiology of prothrombin G20210A polymorphism in the Southern Iran

Ahmad Ebrahimi

Background: There are many genetic and non-hereditary risk factors that are known to causes venous thromboembolic (VTE) disorders, Cardiovascular diseases and types of cancer. One of these is the Prothrombin G20210A mutation. Prothrombin mutation (guanine to adenine G→A) at nucleotide position 20210, which is present in the 3′ untranslated region of the prothrombin gene. Prothrombin G20210A mutation is present outside the coding region for prothrombin, and hence it does not affect the actual structure of the prothrombin molecule and it does not affect its function as a strong clotting factor when activated into thrombin. However, several studies have shown that, G20210A heterozygosity was associated with a threefold increased risk for VTE. Moreover, the association of PTH G20210A polymorphisms with cancer has been reported. The present study was designed to determine the frequency of PTH G20210A polymorphism in Southern Iran. Methods: In this cross-sectional study, 140 healthy women were from Southern Iran recruited among participants in Namazi Hospital, Shiraz, Iran, from March 2013 to February 2014. A total of 5 ml of peripheral blood was taken from individuals then Genomic DNA was extracted using blood DNA kit (Ron’s Blood and Cell DNA Mini Kit, BioRon, Germany). The amplification refractory mutation system- polymerase chain reaction (ARMS-PCR) method was used for the detection of PTH G20210A single nucleotide polymorphism in each subject. Results: The frequencies of the GG and GA genotypes were as 97.9%, 2.1% respectively. The frequency of G allele was and the frequency of A allele was 1.1%. Conclusion: Results of the present study might be important in understanding the distribution of PTH G20210A polymorphism in the Southern Iran. Minor allele frequency in this population is higher than in the Iranian and European population but similar to the prevalence in the Western Iran, Iranian Jews, American, Irish, Tunisian and Bahraini population.

Age-specific reference ranges of serum prostate-specific antigen in Iranian men

Gholamreza Pourmand

Background: Prostate-Specific Antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), is the best marker for early diagnosis of prostate cancer. Since age and race are affecting PSA levels, determining age-specific reference ranges of PSA in every community is necessary for increasing the efficiency rate of PSA. The aim of the present study was to evaluate the normal distribution of total prostate-specific antigen (TPSA) and free prostate-specific antigen (FPSA) and determine age-specific reference ranges of PSA in Iranian men. Methods: In this cross-sectional study, 1200 normal men with the age range of 50 to 79 referred to Shahid Rajaie Hospital, Qazvin Province in Iran, from 2011 to 2013. After excluding patients with prostate cancer and urinary tract infection, 1020 men were included in this study. Then, their blood samples were collected and after the extraction of serum from blood, serum levels of FPSA and TPSA were measured using commercial kits the reference range of PSA was specified for each age group and compared with reference ranges of other populations. Results: The mean age of the patients was 61.03±7.5 years and the mean values of FPSA and TPSA were 0.47±0.6 ng/ml and 1.56±2.05 ng/ml, respectively. PSA serum levels (95th percentile range) in 50 to 59, 60 to 69 and 70 to 79-year age groups were 0-3.6 ng/ml, 0-5.7 ng/ml and 0-6.8 ng/ml, respectively. TPSA (r= 0.2, P< 0.001) and FPSA (r= 0.22, P< 0.001) were significantly associated with age. In addition, a significant relationship was found between TPSA serum levels and alcohol consumption (P= 0.017), smoking (P< 0.001) and family history of prostate cancer (P= 0.014). Conclusion: Findings of the present study showed that PSA levels are correlated with age. It was also revealed that the PSA age-specific reference range obtained in this study is different from other races and is specific to Iranian men. Therefore, age-specific reference ranges of PSA obtained in the present study can increase PSA test sensitivity and specificity by reducing unnecessary diagnostic procedures and early detection of prostate cancer in Iranian men.

General inflammation and stress in patients with intestinal protozoan infections in two hospitals in Tehran

Shahnaz Shirbazou

Background: Protozoa are unicellular eukaryotes. A type of intestinal protozoan pathogens is the cause of infection and serious injuries in human with or without clinical symptoms. It seems that parasitic infections as a stressor factor can affect on stress system activity and immune system function and sensitivity. The major purpose of this paper was to evaluate serum cortisol level and the general inflammation by measuring neutrophil to lymphocyte ratio in patients with intestinal protozoa. Methods: A total of 40 men were entered in a case-control study in Besat and Baqyiatallah (a.s.) Hospitals in Tehran from April to September 2014. Men were equally divided into 2 groups based on infection with the intestinal protozoa (control and patient groups). This study was conducted on blood samples of these people. Serum cortisol level and neutrophil to lymphocyte ratio were determined in control and patient with the intestinal protozoa groups. Cortisol was measured using cortisol kit (Diagnostic Biochem, Canada) and by ELISA method. In addition, the samples were treated with Wright stain method, and neutrophil to lymphocyte ratio was calculated using WBC diffraction method. Results: According to the results of this study, mean age between control and patient groups was not statistically significant (P= 0.91). Serum cortisol concentration in patients with the intestinal protozoa was significantly higher than the control group (P= 0.043). In addition, a significant increase was observed in neutrophil to lymphocyte ratio in patients with parasitic infections compared to the control group (P= 0.026). Conclusion: Based on the results of this study, parasitic infection (intestinal protozoa) as a stressor factor can increase serum cortisol concentration. In addition, intestinal protozoa was reduced immune system sensitivity and function. It seems that the neutrophil to lymphocyte ratio can be a potential useful parameters for evaluating the stress system activity and function in patients infected with the intestinal protozoa.

The effects of nonlinear resistance and aerobic interval training on serum levels of apelin and insulin resistance in middle-aged obese men

Mahmoud Nikseresht

Background: Apelin is an adipokine which may contribute to the link between obesity and metabolic diseases. Regular exercise training has been proposed as a strategy for reducing the risk of these diseases by positive adaptations in adipokines, but there is limited research directly comparing different types of training. The purpose of this study was to determine and compare the effects of nonlinear resistance training (NRT) and aerobic interval training (AIT) on serum levels of apelin-13 and insulin resistance in middle-aged obese men. Methods: This quasi-experimental study was conducted from October to February 2012 in Ilam City, Iran. Eligible subjects (33 obese men) between aged 34-46 years participated in this study and were allocated to the following groups: NRT (n= 12), AIT (n= 10), and control (n= 11). The inclusion criteria were sedentary (less than 60 minutes physical activity per week), nonsmokers, no regular exercise for at least the past 6 months, no regular consumption of medication, no special diet, percentage body fat > 23% and no history of medical conditions that would prevent them from participating in the exercise intervention. Only the subjects who performed more than 90% of the training sessions were included in this study. The experimental groups performed 3 weekly sessions for 12 weeks, whereas the control group maintained a sedentary lifestyle. NRT consisted of 40-65 minutes of weight training at different intensities and with a flexible period. AIT consisted of running on a treadmill (4×4 min at 80-90% maximal heart rate, 3 min recovery intervals). Results: Analysis of variance showed that there were no significant differences betwee n the groups for apelin-13 and insulin resistance at baseline (P> 0.05). Compared to control group, two exercise programs were equally effective at reducing insulin resistance, but apelin-13 levels increased significantly only with the AIT (P= 0.04). After the training, maximal oxygen uptake increased significantly in AIT and NRT compared with control group (both P= 0.001) and in AIT more than NRT (P= 0.001). Conclusion: The practical applications indicate that obese men can use both AIT and NRT exercise programs to reduce insulin resistance. However, the AIT may have better beneficial effects (as indicated by apelin-13) compared to NRT.

Evaluation of noise level at intensive care units in selected hospitals of Sanandaj

Shahram Sadeghi

Background: One of the critical unit in each hospital is intensive care unit (ICU). The United States’ Environmental Protection Agency (EPA) recommends to control the noise level of this unit in order to not exceed 45 decibels (dBA) during the day and 35 dBA at night. In this study, our goal was to evaluate the noise level at adult and neonatal ICUs at some Sanandaj’s hospitals, Iran. Methods: This cross-sectional study was conducted from May 4th to June 4th 2012 in adult and neonatal intensive care units at three major hospitals in Sanandaj (Besat, Tohid and Tamin-Ejtemaei). In order to assess the noise level properly, measurements obtained during the days and nights. At a given day, a unit was selected randomly and measurement of sound levels obtained successively within two-hour periods. The noise levels were measured in decibels using a sound level meter (SLM). This process took four weeks to be completed (one week per unit). In the end of study, the total of 336 records of noise levels were obtained. Descriptive analysis as well as fitting a mixed effect models were used to interpret collected observations. All statistical analysis performed using R developed by R core team. Results: The preliminary analysis of observations showed that mean level of noise varied from 65 to 71 dBA among ICUs under study. Noise levels during the day were slightly higher than that of were observed during the night. Descriptive analysis of observations showed no major differences between the noise levels over the time and between the days/nights. Fitting a mixed-effects model showed significant differences of the noise levels between ICUs (P< 0.001). Conclusion: We found the noise levels were always above the EPA thresholds at all three hospitals both during the day and night. It is recommended to train hospital officials and staffs for keeping noise levels to an acceptable level.

Metastatic breast cancer to uterine leiomyoma: case report

Fatemeh Movarrei

Background: Breast cancer is not only considered as the most common cancer in women but also is known as the second cause of death among them. One of the main causes of death in breast cancer patients is metastasis to different organs such as lymph nodes, bones, lung, liver, brain or other parts of the body. Metastasis to genital organs especially uterus is rare and a few cases are reported. Case Presentation: In this report we present a case of invasive ductal breast carcinoma metastasizing to a uterine leiomyoma in a 52 year old woman who was admitted to Imam Khomeini Hospital, Tehran, in September 2013, diagnosed and treated by modified radical mastectomy of the right breast six years ago. Currently, she presented with complaint of persistent abnormal uterine bleeding for which hysterectomy was performed. The histopathologic examination of the uterine specimen revealed a focus in the myometrial wall composed of spindle cell proliferation without signs of atypia which was accompanied by epithelial glandular structures with cells containing hypochromatic nuclei embedded in a desmoplastic stroma. Considering the history of invasive ductal breast carcinoma in this patient, the diagnosis of stromal nodule or metastasis from a breast origin was suggested as the main differential diagnosis. The Immunohistochemical study performed with different markers showed positivity for GCDFP15 staining confirming metastasis from the breast carcinoma. Conclusion: Although metastasis of breast cancer to the genital organs is an uncommon event, breast carcinoma is still considered the second source of extragenital malignant metastasis to the uterus. Overall, the most popular sites for metastasis of breast carcinoma to the female reproductive system include the ovaries and the uterine cervix. The uterine corpus is the least common site involved. In this regard metastasis to a uterine leiomyoma is a rare event.