Tehran University Medical Journal

TOX3 Gene polymorphisms and breast cancer; effects and implications of the variations: review article

Alireza Pasdar

Breast carcinoma is the most common cause of cancer mortality among women globally. Primary and secondary prevention through avoiding known risk factors, screening for early detection of tumors with different methods as well as timely treatment, can be effective in reduction of the burden of this devastating disease. This can in turn prevent death and also increase survival in patients with breast cancer. Both environmental and genetic factors are involved in the pathogenesis of breast cancer. Multiple genetic factors can influence the risk and development of breast cancer. Identification of genetic variants including single nucleotide polymorphisms (SNPs), which are associated with the risk of breast cancer development, are mostly done through genetic association studies. It is demonstrated that SNP allele frequencies vary amongst different populations. It has been shown that genetic risk factors like variations in TOX high mobility group box family member 3 (TOX3), which affect the liability for neoplasm, play an important role in the development of breast cancer. Although TOX3 is expressed mainly in the brain, its expression in other tissues especially breast has also been reported. TOX3 maps to chromosome 16q12 and encodes the nuclear high-mobility group (HMG)-box. It has calcium (Ca²⁺)-dependent transcriptional activities and is a co-factor of cAMP response element (CRE)-binding protein (CREB) and CREB-binding protein (CBP). TOX3, activated with Ca²⁺, is related with activation of the promoter of some other genes including BCL2 and C3 complement and also CITED1 gene expression. It also induces activation of the c-fos promoter and therefore its expression. Genome-wide association studies (GWAS) in different populations including European, Asian and African-American have demonstrated that a SNP near its 5ʹ end and the promoter of TOX3 gene appears to be significantly associated with breast cancer susceptibility. Furthermore, breast cancer–associated SNPs lead to enhanced FOXA1 bindings and in turn, a reduction in TOX3 gene expression. This review has highlighted the importance of TOX3 function, SNPs and its association with breast cancer risk and also its potential effects on breast cancer treatment; TOX3 plays dual and somehow conflicting roles in cancer initiation and progression which remains to be further investigated.

Extracorporeal shock wave therapy for the reduction of post stroke spasticity: review article and meta-analysis

Nahid Tahan

Background: Spasticity is a clinical deficit of upper motor neurons lesions that presented immediately or at delayed times after lesions and occurs in about 38% of stroke patients. Extracorporeal shock wave therapy (ESWT) has been recently reported as a safe and effective method for reducing spasticity in stroke patients. In the present study, we sought to investigate the impact of the ESWT on post stroke spasticity using a meta-analysis method.
Methods: All primary reports of spasticity indexed in PubMed, MEDLINE, Science Direct, Scopus and search engine of Google Scholar from January 2000 to December 2016 were searched. The following terms were used as keywords: Spasticity, muscle hypertonicity, ESWT, stroke and hemiplegia. Any report was included if it met the following criteria: involving clinical trials, full-version availability, and being written in english. Two reviewers selected articles independently and reviewed the studies considering quality and eligibility, and then they extracted general information on objectives, design, participants, and outcomes. The methodologic quality of each study was assessed using the Pedro Scale. In the statistical analyses, we considered two outcomes; Modified Ashworth scale (MAS) grade and passive rang of movement (PROM). The meta-analysis was done using random effect model in Stata, version 11 (Stata Corp., TX, USA).

Results: Eleven studies within a total of 261 patients were included in this review. In seven studies the shock waves were applied to the upper limb muscles, and in four other studies, the effects of ESWT on the spasticity of the lower limb muscles were assessed. Immediately after applying the ESW, MAS grade was significantly decreased in comparison to the baseline values. (Standardized mean difference [SMD], -1.62; 95% confidence interval [CI], -2.2 to -1.04). The PROM was significantly increased immediately after ESWT in comparison to the baseline values (SMD, 3.23; CI 95%, 1.35 to 5.12).
Conclusion: The results of this study showed that ESWT can immediately improve the spasticity and increased PROM, but it seems that the mechanism of action of shock waves on spasticity is still unclear. Further clinical trial studies with higher methodological quality should be recommended.

Phytochemical composition, antibacterial and anticancer activities of Trifolium cherleri extract on lung cancer cell line (A549) and analysis of caspase 3 and caspase 9 apoptosis genes expression

Amir Mirzaie

Background: Medicinal plants have been identified and used from prehistoric times and these plants make many chemical compounds for biological functions. Trifolium cherleri is an herbaceous species belonging to the family of the Fabaceae to Africa, Eurasia and Australia. T. cherleri is an important member of the Fabaceae family that is well-known herbal medicine in Iran. The aim of this study was to investigate the phytochemical composition, antibacterial and anti-cancer activities of T. cherleri extract.
Methods: This experimental study was performed in Islamic Azad University, from December 2016 to February 2017. At first, the phytochemical constituents of T. cherleri extract were determined using gas chromatography-mass spectrometry (GC-MS) method. Subsequently, the antibacterial activity of the extract was evaluated against some gram positive and negative pathogenic bacteria included Staphylococcus aureus ATCC 25923, Streptococcus pyogenes ATCC 19615, Salmonella enteritidis ATCC 13076 and Listeria monocytogenes ATCC 35152 via minimum inhibitory concentration (MIC) method. Moreover, anticancer potential of extract was examined by colorimetric MTT assay toward lung cancer (A549) cell line. Then, the evaluation of caspase 3 and 9 apoptosis gene expression was determined using Real-Time Polymerase Chain Reaction (Real-Time PCR) technique. Moreover, the Real-Time PCR was performed using relative quantitative method.

Results: The phytochemical analyses of T. cherleri extract showed the 20 major components and the most frequent component was belonged to hexadecanoic acid, ethyl ester (20.7%) and 2-Pentadecanone, 6,10,14-trimethyl (19.9%). The extract had maximum antibacterial effects against Staphylococcus aureus and Streptococcus pyogenes. There was a dose dependent increase in the cytotoxicity effect of extract against A549 cancer cell. Moreover, the Real-Time PCR results indicated that the caspase 3 and caspase 9 gene expression was significantly up-regulated 2.57±0.27 (P<0.05), and 3.3±0.46 (P<0.05), respectively.

Conclusion: The results of this study showed that the T. cherleri extract had significant anti-bacterial and anti-cancer effects and it appear that the extract has potential uses for pharmaceutical industries. Moreover, it could be considered as a promising source for novel drug compounds, but more studies are needed.

Comparison of sexual dysfunction in women with breast cancer: case control study

Malihe Hasanzadeh

Background: Breast cancer is the most common cancer in women and can have several profound effects on women’s life. Estrogen and androgens reduction cause sexual problems. Reduction of hormones produce problems such as vaginal dryness, vaginal and vulvar tissue thinning, loss of elasticity of the vagina, hot flashes and other problems. Depression in these patients is also a factor in reducing sexuality. Disruption at any sexual stage can cause sexual problems. In this article; we compare sexual dysfunction in patients with breast cancer and healthy people.
Methods: According to the women’s case-control study with simple un-randomized sampling method a total of 245 patients with breast cancer in Ghaem and Emam Reza and Omid hospital from july 2011 to july 2013 entered the study. All patients were on follow-up after therapy, and had a therapy portfolio. In order to achieve better results, questionnaires were distributed among 126 healthy subjects that matched our patient group in terms of age and other factors and were used as the control group. Female sexual function index (FSFI) questionnaire was filled out by an independent interviewer and all medical, personal and social ethics were applied. The data was then gathered and the score were analyzed with statistical tests.

Results: The study was performed on patients 20 to 50 years, mainly in patients aged 35 to 45 years (51.8%). The average age was 41.44±5.87 years. In our study, the most dysfunction was in sexual desire (57.6%), vaginal moisture (53.1%), sexual excitement (48.2%), orgasm (44.1%), and dyspareunia (52.2%) in breast cancer patients. There was significant difference between two group (P<0.001).There is no difference about sexual satisfaction between two groups (P=0.262).
Conclusion: Sexual dysfunction is common in breast cancer patients compared to healthy women. Dysfunction in orgasm, dyspareunia, reducing vaginal moisture and sexual desire were common in the breast cancer patient. The results of this study should be used to inform patients and physician about sexual problems.

Relative quantification of AXIN2 mRNA expression in different pathological types of colorectal polyps

Ehsan Nazemalhosseini Mojarad

Background: Most of colorectal cancers (CRC) have originated from intestinal polyps. Evaluating of the expression level of genes that are involved in tumors growth and development, may consider as diagnostic factor of malignancy in the polyps. AXIN2 regulates the level of nuclear β-catenin in a negative-feedback loop there by being a negative regulator and target gene at the same time. The aims of current study were to examine the expression level of the AXIN2 in the colonic polyps and its linkage with the pathological features of the polyps.
Methods: In the present analytical-descriptive study, the investigated population was chosen from the cases with colonic polyps that referred to the Gastroenterology and Liver Diseases Research Center, Taleghani Hospital, Tehran, Iran, from October 2014 to April 2015. Forty four biopsy polyp samples and 10 normal tissue samples were collected, as well as the demographic and clinical properties of the patients and the expression level of AXIN2 gene was quantified by Real-time PCR. The outcomes were analyzed by the ABI Prism 7500 Sequence Detection System (SDS) software, version 2.1.0 (Applied Biosystems Inc., Foster City, CA, USA) and GraphPad Prism, version 3 (GraphPad Software Inc., La Jolla, CA, USA) Also, the expression changes of the intended gene in target groups were compared with the normal tissues using the 2^-ΔΔCt equation.

Results: The data showed enhanced level of the expression of AXIN2 gene in the colonic polyps in comparison to the normal tissues (RQ>2), which was significantly upper in adenoma polyps compared to the hyperplastic group (P=0.015). Also, unlike the rectum, the AXIN2 gene activity in colon area was higher than normal tissue.

Conclusion: The results of the current study show that the expression pattern of AXIN2 gene, was markedly changed during the transformation of the normal tissue to polyp. The increased expression level of this gene could be applied as a diagnostic marker in dissociation of the adenoma polyps from hyperplastic ones. On the other hand, the location of the polyps modulates the AXIN2 gene function. Taking together, evaluating the changes of AXIN2, has a precise diagnostic value in the CRC related studies.

Comparison of gabapentin, pregabalin and placebo as premedication for attenuation of hemodynamic response to laryngoscopy and endotracheal intubation

Nazli Karami

Background: Tracheal intubation and direct laryngoscopy are powerful noxious stimuli that can elicit sever hemodynamic responses. These hemodynamic responses should be attenuated by appropriate use of premedication, smooth induction of anesthesia and rapid tracheal intubation. Gabapentin and pregabalin have been suggested in several studies to be efficient. Gabapentin is an antiepileptic drug and a structural analogue of gamma-Aminobutyric acid (GABA) but it does not act through GABA receptors and pregabalin, is also an antiepileptic agent. The aim of this study was to compare the effect of gabapentin and pregabalin as premedication for attenuation of hemodynamic response to laryngoscopy and endotracheal intubation.
Methods: In a prospective double blinded randomized clinical trial, during April 2015 to March 2016 in Urmia Imam Khomeini Hospital, a total of ninety normotensive adult consented patients, candidate to elective abdominal surgery aged 20-50 years, American Society of Anesthesiologist (ASA) class I, of both gender were randomized into three groups. Patients in group I received oral placebo, group II received oral gabapentin 900 mg and group III patients received oral pregabalin 150 mg two hours prior to induction of anesthesia. Anesthetic technique was same in three groups and all groups were assessed for hemodynamic changes such as heart rate, systolic blood pressure and diastolic blood pressure, after the premedication, before and after induction of anesthesia, and 1, 3 and 5 minutes. after laryngoscopy and tracheal intubation.
Results: Significant increase in heart rate and systolic blood pressure and diastolic arterial pressure was observed in placebo group after tracheal intubation, while statistically significant attenuation of hemodynamic changes was seen in gabapentin and pregabalin groups. (P=0.001) No adverse outcome was reported in the study groups.
Conclusion: Oral gabapentin premedication is effective for control of hemodynamic pressor response of laryngoscopy and tracheal intubation. The study data showed that the pregabalin have the same effect. Pregabalin and gabapentin are both useful and safe for control of hemodynamic pressor response as premedication.

Diagnosis of fungal keratitis in patients with corneal lesions at Amiralmomenin hospital in Rasht, Iran

Parivash Kordbacheh

Background: Keratomycosis is a fungal infection of the cornea which could be sight-threatening and even causes eye loss. Considering the high humidity and the dominance of agriculture as important predisposing factors of keratomycosis in north of Iran, this study was carried out for diagnosis of fungal keratitis in patients with corneal lesions in Rasht, Gilan province, Iran.
Methods: This descriptive cross-sectional study was conducted from July 2015 to November 2016 on 56 patients with corneal lesion suspected to keratomycosis and referred to eye emergency ward of Amiralmomenin hospital, Rasht, Iran. Corneal scraping was performed in all cases and specimens were subjected to direct examination and culture. Only colonies grown in sites of corneal scraping inoculation were considered significant. Fungal isolates were identified according to their macroscopic features of colonies and microscopic characteristics in slide cultures. Data were analyzed in SPSS software, version 21 (IBM SPSS, Armonk, NY, USA) and P<0.05 was considered significant.

Results: The patients included 42 (75%) men and 14 (25%) women with the mean age of 49.5 years (9 to 90 years). Positive culture was observed in 9 cases but, only in one of these patients direct examination was positive and fungal elements were seen in 10% KOH preparation. Though, fungal keratitis was confirmed in 9 (16%) patients including seven (77.8%) men and two (22.2%) women. The majority of cases (88.9%) had a history of corneal trauma with plants and they were mainly farmer. According to statistical analysis, there was a significant association between corneal trauma and keratomycosis (P=0.007). The most common etiologic agents were Fusarium spp. (n: 4, 44.4%), followed by Aspergillus flavus (n: 2, 22.2%), Penicillium sp. (n: 1, 11.1%), Acremonium sp. (n: 1, 11.1%), and Cladosporium sp. (n: 1, 11.1%) respectively.
Conclusion: In the presence of sufficient predisposing factors such as corneal injuries caused by plants, keratomycosis could be caused by a variety of fungi. Furthermore, low sensitivity of direct examination in this study, revealed the necessity of culture in diagnosis of keratomycosis.

Association of CFI p.Gly119Arg gene polymorphism with age-related macular degeneration (AMD) disease in the population living in Tehran

Mortaza Bonyadi

Background: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and is characterized by progressive degeneration of the retinal pigment epithelium and secondary photoreceptor loss, resulting in visual loss. Etiological research suggests that age related macular degeneration is a complex disease, caused by the interactions of several genetic and environmental factors. Polymorphisms in genes encoding the alternative complement pathway, complement factor I (CFI), are associated with the risk for age related macular degeneration. The purpose of this investigation was studying of complement factor I p.Gly119Arg (C.355G>A) polymorphism with age related macular degeneration in the population living in Tehran, Iran.
Methods: This case-control study was conducted at Tabriz University from June 2015 to June 2016. In this study the association of p.Gly119Arg polymorphism in complement factor I gene was investigated in 150 patients suffering from age-related macular degeneration and 150 healthy age, sex and ethnicity matched unrelated people as control group. Both of the case and control groups were originated from the population living in Tehran. Genotypes of both groups were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and data was analyzed the Chi-square test in 2x2.Contingency table.

Results: Investigation of the association of p.Gly119Arg polymorphism in complement factor I gene with age related macular degeneration showed that there are statistically significant differences between patients and controls in genotype and allele frequencies of this polymorphism (P=0.005 and OR=6.68 in TT, P=0.04 and OR=0.61 in CC, P=0.03 and OR=1.76 in T, P=0.04 and OR=0.56 in C). Therefore CC, TT genotypes and C, T alleles were significantly associated with age related macular degeneration.

Conclusion: This study showed a significant association between this polymorphism p.Gly119Arg (C.355G>A) complement factor I gene and age related macular degeneration disease in the population living in Tehran (P<0.05). Our data suggests that this locus polymorphism is not as rare in our studied population as previously reported from different population.

Measuring the amount of serum albumin in burn patients and the relationship between the burned area and length of hospital stay

Mohammad Javad Fatemi

Background: Albumin is one of the most important proteins in the body by several important functions, it is essential in the maintenance of normal plasma colloid oncotic pressure and is the primary serum binding protein responsible for the transport of various substances in the circulation including fatty acids, hormones, and drugs. Decrease in the amount of serum Albumin (Hypoalbuminemia) is a common finding in the burn patients, but its relationship with mortality is not accurately clear. Our purpose of this study was to measure the amount of Albumin serum in burn patients and find out its relationship between the burned area and length of hospital stay.
Methods: This cross-sectional study was conducted on patients aged over 16 years who referred to the Motahari Hospital of September 2014 to February 2015 in the first 24 hours of their referral. The amount of Albumin was measured in two groups of discharged patients and patients who died while hospitalized, one week after hospital stay and in the time of discharge and death; and its relationship in terms of each other was determined by statistical analysis. We also assessed the relationship between burn and duration of hospital stay with the amount of Albumin on the day of patient’s admission.

Results: This study showed that the average amount of albumin in the group of discharged patients in the time of admission, one week after and during admission was significantly higher than the group of expired patients (P<0.0001). Also there was a significant relation between the burned area and the amount of albumin (P<0.0001). The more the burned area, the less the amount of Albumin. But there was no significant relationship between the amount of albumin with age and length of hospital stay.

Conclusion: Measuring the level of Albumin is one of the yardsticks that can be used for prognosis of recovery or death of burn patients, and its assessment at regular intervals in burn patients is essential.

Huge mucinous cystadenoma of ovary, describing a young patient: case report

Saeedehsadat Batayee

Background: About 90% ovarian cancers are epithelial and 10-15% of this group are mucinous. The treatment is the hysterectomy with bilateral salpingo-oophorectomy. However, most of these tumors occur in young women that have not yet given birth in which preservation of fertility should be considered. We present a case of huge mucinous cystadenoma and massive ascites managed by preserving uterus and ovaries. Meigs’ syndrome is found in fibroma, and thecoma of ovary, however, in rare occasion this syndrome is occurred in mucinous cystadenoma.
Case presentation: A 21-year-old unmarried woman presented with the complaint about weight gains and irregular menstruation for four months to gynecology clinic of Firoozgar hospital in Tehran in October 2016. Preop lab data including tumor marker was gathered, and sonography with CT scanning of pelvic and chest was performed. The ascitic fluid was negative for malignancy. Also, laparotomy with staging the ovarian tumors was carried out including cytology of ascitic-fluid, cytology of diaphragm, ovarian cystectomy, biopsy of the paracolic gutter, exploring abdomen and pelvis. Histopathology report revealed mucinous cystadenoma. Moreover, according to the normal appearance of the appendix in this case, the appendectomy was not performed.
Conclusion: Ovarian cysts in young women who are associated with elevated levels of tumor markers and ascites require careful evaluation. Management of ovarian cysts depends on patient's age, size of the cyst, and its histopathological nature. Conservative surgery such as ovarian cystectomy or salpingo-oophorectomy is adequate in mucinous tumors of ovary. Multiple frozen sections are very important to know the malignant variation of this tumor and helps accurate patient management. Surgical expertise is required to prevent complications in huge tumors has distorted the anatomy, so gynecologic oncologist plays a prominent role in management. In this case, beside of the huge tumor and massive ascites uterine and ovaries were preserved by gynecologist oncologist and patient is well up to now.