مجله دانشکده پزشکی دانشگاه علوم پزشکی تهران
سال هفتاد و دوم شماره 8 (پیاپی 164، آبان 1393)

Embryonic stem cells are pluripotent stem cells which have the ability to indefinitely self-renew and differentiate into all differentiated cells of the body. Regarding their two main properties (unlimited self-renewal and multi-lineage differentiation), these cells have various biomedical applications in basic research and cell based therapy. Because the transplantation of differentiated cells that are derived from embryonic stem cells is allogenic, they face the problem of immune rejection following the transplantation of embryonic stem cell-derived cells into patients. In 2006, researchers from Japan reported the derivation of a new type of pluripotent stem cells which could overcome the problem of immune rejection that is associated with the application of embryonic stem cells. They designated these cells as induced pluripotent stem (iPS) cells, because their production was ‘induced’ from differentiated somatic cells using a combination of four embryonic stem cell-associated transcription factors. Importantly, these pluripotent stem cells exhibit all the key features of embryonic stem cells including unlimited self-renewal and multi-lineage differentiation potential, and can pass the most stringent test of pluripotency which is known as the tetraploid (4n) complementation. Hence, in addition to bypassing the problem of immune rejection, iPS cells have all of the potential applications of embryonic stem cells, including in developmental studies, toxicology research, drug discovery and disease modeling. Also, considering that they could be generated from patient’s own cells, iPS cells hold great promise in the future of patient-specific cell replacement therapies using pluripotent stem cells. In this review article, we will present a comprehensive review on the how and why of the generation of iPS cell from somatic cells of the body and discuss how they should be characterized in terms of morphologically, pluripotent stem cell behavior, and the molecular signature. In addition, their medical applications as well as some of the considerations and future challenges in their use will be discussed.

Uterine leiomyoma is one of the most common benign smooth muscle tumors occurring in 20-40% of women worldwide in their reproductive years. Recent studies revealed that estrogen plays an important role in the pathogenesis of uterine leiomyoma. Since, Glutathione s-transferase (GST) gene families are involved in the biosynthesis of estrogen, the prior probability that variants at this locus are associated with uterine leiomyoma is likely to be above the null. Therefore, this study was carried out to examine whether GSTP1 Ile105Val polymorphism is associated with uterine leiomyoma in Iranian population. In this case-control study, 50 women affected with uterine leiomyoma and 50 healthy controls were recruited among participants at the Pasteur Institute of Iran from November 2012 to September 2013. The genomic DNA was extracted from peripheral blood leucocytes using the standard phenol-chloroform method and subsequently the GSTP1 polymorphism was genotyped using Amplification Refractory Mutation System (ARMS-PCR). Association of Ile105Val polymorphism with uterine leiomyoma was examined using the SPSS statistical software package, version 18.0 after age adjustment. The results showed significant differences between case and control groups in terms of genotype frequency (P<0.0001). In addition, the results indicated that the presence of the valine allele significantly increased risk of uterine leiomyoma approximately 3 times more in individuals carrying the mutant allele compared to control group (Odds Ratio: 3.34; 95%CI: 1.82-6.15; P<0.0001). To our knowledge, this is the first study performed in Iranian population assessing the association between GSTP1 Ile105Val polymorphism and risk of uterine leiomyoma. However, further extensive researches with a large number of samples from different populations and ethnicities are required to validate the results obtained in this study.

Red Blood Cell's (RBC)’s folate may be related to decreased risk of colorectal adenoma. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate metabolism. The MTHFR C677T polymorphism is located in the Exon 4 region and is associated with the change of folate level. This study evaluated the associations between RBC’s Folate levels and colorectal adenoma risk, taking into account whether this associations is modified by MTHFR Polymorphism. In a case-control study conducted from January to October 2007 in Endoscopy-Colonoscopy ward of Shahid Faghihi Hospital, Shiraz. Participants were 177 case of colorectal adenoma who had pathologic-confirmed adenomatous polyps in full colonoscopy examination and 366 controls without polyps in full colonoscopy. Fasting venous blood were drawn from patients in order to determine RBC’s folate and to identify the MTHFR polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Gender Distribution in the patient group were 57.6% male and 42.3% female and control group consisted of 55.1% male and 43.9% female. 50.2% of cases and 49.2% of controls were in the age group “45 years and above”. The T allele frequency was 56.6% in control group and 34.4% in colorectal adenoma patients. There was a significant association between T allele in -677 position of MTHFR gene and colorectal adenoma susceptibility (OR: 1.85, 95% CI: 0.76-4.24, P<0.001). Mean concentration of RBC’s folate was not statistically significant among three groups with TT genotype (mutation homozygote), CT genotype (heterozygote), and CC genotype (wild-type homozygote) (P>0.05) but mean concentration of RBC’s folate was the lowest in TT genotype compare with two other genotype. Odd's Ratio for low (<140ng/ml) versus high level of RBC’s folate in participants with TT genotype was (OR: 2.08, 95% CI: 0.10-2.19, P<0.05) as compare with the CC ones. The result of this study suggested an inverse association between RBC's folate concentration and colorectal adenomas risk, which may be more relevant for those with the MTHFR TT genotype.

Medullary thyroid carcinoma (MTC) occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of the rearranged during transfection (RET) proto-oncogene in MTC development have been well demonstrated. Several studies have been published that indicate the molecular analysis of RET gene may offer early identification of those patients at high risk to develop MTC and may provide the opportunity for early intervention. The aim of this study was to investigate frequency of G691S/S904S haplotype in MTC patients and their relatives. From 2004 to 2014, 358 participants were studied, including 213 patients (119 female, 94 male) and 145 their relatives (79 female, 66 male) in cellular and molecular research center of Shahid Beheshti Research Institute for Endocrine Sciences, Tehran, Iran. Genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection was performed using PCR and direct DNA sequencing methods. The RET mutations and SNPs, sequences were analyzed. According to DNA sequencing results, 189 individuals (119 patients, 70 relatives) had both G691S (rs1799939) missense mutation in exon11 and S904S (rs1800863) synonymous mutation in exon 15 of RET proto-oncogene. The allele frequency of G691S/S904S haplotype was 35.02% in patients and 29.92% in their relatives. The obtained data showed the frequency of G691S/S904S RET gene haplotype among Iranian MTC patients and their relatives. The G691S and S904S nucleotide changes were in complete linkage disequilibrium, so the results were grouped together and referred to as G691S/S904S haplotype. This haplotype are not considered as oncogenic mutations at this time, its functional role should be investigated. Further analysis is needed to demonstrate the association between this haplotype and MTC development.

Radiotherapy can cause DNA damage in normal cells, misrepaired or unrepaired double strand breaks in DNA lead to chromosomal breaks. As a result patient experience early and late effects in normal tissue during and after radiotherapy. Cytogenetic techniques can be used as a cancer predictive assay because there is an association between chromosome abnormalities and the risk of developing cancer. Also it can assess patient's complications during the therapy. The aim of the present study was evaluation of the cytogenetic alteration in peripheral blood lymphocytes of esophageal cancer patients treated with radiotherapy. The present study is an experimental and prospective research. It was done at radiotherapy department at Omid Center in Urmia from January to December 2012. Blood samples were obtained from 15 esophageal cancer patients, before (0 Gy), during (21.6 Gy), and after radiotherapy treatment (43.2 Gy). Blood samples were cultured in RPMI-1640 complete medium containing 1% phytohaemagglutinin and incubated in a CO2 incubator. Cytochalasin-B was added to the cultures at a final concentration of 5 µg/ml. Finally, harvesting, slide making, and analysis were performed according to standard procedures. This study consisted of 15 patients, including 7 men and 8 women from 55 to 84 years old (70.07±11.548). Results indicate that, in the middle of treatment the average frequency of micronuclei increased significantly compared with their concurrent pre-treatment samples (greater than four-fold). Also, an increase in chromosome damage (MN frequency) proportional increasing radiation doses at the end of treatment was observed (P=0.001). Increasing in the MN frequency in the second and third stages is due to radiation effects. Thus, the use of the MN technique for assessing of the side effects in patients during the therapy is very helpful. Moreover, MN assay can be used as a predictive assay for detecting individuals (patient or healthy) with intrinsic radiosensitivity.

Assessment of the serum lead’s concentration in the newborn immediately after birth can be effective for the detection of lead poisoning in the early stages and prevent of developmental disorders and neuropsychiatric behaviors. This study aimed to assess the serum lead levels of cord blood in some of the hospitalized newborns. This cross-sectional analytic study conducted in the newborns ward of two hospitals (Rasoul Akram and Akbar Abadi) From December 2011 to October 2012 in Tehran, Iran. After non-probability sampling, 60 newborns in the first days after birth, underwent the cord blood sampling and the cord blood lead levels were measured by atomic absorption spectrophotometer. Then all of data were collected and analyzed. The serum lead concentration greater than 5 μg/dl was considered valuable. In total, 61.4% of samples were boys. The mean (±SD) of gestational age was 37.4±2.64 weeks and mean (±SD) of birth weight was 2701±642.8g. The mean (±SD) of maternal age was 29.20±6.73 years. 70% of mothers were urban. 13% of mothers had a history of drug use, and 5% were current smokers. The mean (±SD) of the serum lead level of cord blood was 2.97±2.24 μg/dl. This level was not associated with fetal gender, place of residence, drug history and current smoking. This level in the 16.7% of samples was greater than 5 μg/dl (high risk cases). High risk level was associated with maternal age, weight and fetal age (P=0.02, P=0.004, P=0.03), but this level was not associated with fetal gender, place of residence, drug history and current smoking. Serum lead level of cord blood was relatively higher than other studies, although the prevalence of the high risk newborns (serum blood lead levels greater than 5 μg/dl) was low. Further research has recommended assessing the serum lead level in other newborns in the different areas to identify risk factors of neuromotor outcome in infants to prevent.

Hypernatremic dehydration in neonate is a serious potentially life treating can damage the central nervous system. The aim of this study was to determine the clinical and laboratory signs of hypernatremic dehydration in term infant. A cross sectional study was performed from April 2010 to March 2012 in 111 neonates with sodium>145 mmol/l who were admitted at the Mostafa Khomeini and Hazrat Zainab Hospitals in Tehran, Iran. The incidence of clinical and laboratory findings and relationship between some risk factors influencing the severity of hypernatremia were reviewed. The patients were subdivided in two groups: Na<150 mmol/l (group 1) and Na≥150 mmol/l (group 2). Premature infants less than 37 weeks, congenital malformations, formula fed, sepsis and organic disease were excluded. The Student’s t-test, Mann-Whitney U test and Chi-square test were used for statistical data analysis. P<0.05 were considered significant. One hundred and eleven of 2015 (5.2%) patients had hypernatremia. Fifty eight (52.25%) infants were male and sodium ranging was from 146 to 175 mmol/l with an average of 150.3 mg/dl. The most common clinical findings in both groups 1 and 2 were lethargy (81%, 84.5%), fever (74.1%, 73.6%), poor feeding (67.3%, 73.6%), weight loss (60.2%, 84.9%) and a decrease in urine volume (31%, 52.8%). Oliguria, restlessness, seizures, weight loss, orange urine, pathologic hyperbilirubinemia were significantly higher in group 2 than group 1 (P<0.05). There was correlation between severity of hyprnatremia and weight (P=0.022) and age of neonate (P=0.046), time of first feeding (P=0.016), serum creatinie>1.5 mg/dl (P=0.016) and bilirubin level (P=0.01). The relationship between type of nutrition, type of delivery, parity, maternal age, sex, gestational age, discharge, maternal education level were not significant. Sufficient attention to the warning signs of hypernatremia such as lethargy, weight loss, oliguria, poor feeding, fever, restlessness and determination of serum sodium levels in suspected cases can significantly reduce the potential complications of hypernatremic dehydration in neonate.

Gestational diabetes is associated with increased risk of congenital heart disease in neonates. The study was performed to evaluate the cardiac parameters in neonates of mothers with abnormal glucose tolerance test (GTT) and compare them with data of normal newborn. In a cross-sectional study in Amiralmomenin Hospital, Semnan City, Iran from April to October 2013, two groups of infants were eligible for the study. Sampling was performed in succession for the infants who were eligible. Echocardiography was performed for the babies on the second day, and cardiac parameters including interventricular septal diameter, left ventricular shortening fraction and mass, left ventricular posterior wall thickness, aortic and left atrial diameter were measured. Maternal glycemic control and HbA1c were measured indicators. Analysis with the SPSS software version 16, the Student’s t-test, Mann-Whitney and Chi-square test were performed. Thirty five newborn infants of mothers with impaired GTT and newborn of 33 healthy women were studied. Birth weight, maternal age and HbA1c among infants of mothers with impaired GTT were greater than the control group (P=0.003 and P=0.000 and P=0.000 respectively). Diastolic and systolic ventricular septal thickness, ratio of diastolic ventricular septal thickness to diastolic diameter of the left ventricular posterior wall, the aortic diameter and left ventricular outflow tract diameter in infants of mothers with impaired GTT were significantly increased in comparison to data of the normal group (P=0.008, P=0.034, P=0.016, P=0.017 and P=0.020 respectively). No significant difference was reported in other diameters. Gestational diabetes mellitus results in changes of echocardiographic findings particularly relevant in diastolic ventricular septal thickness. The increase in wall thickness especially during diastole, is associated with pathological cardiac hypertrophy. Based on the results of the present study, cardiac hypertrophy can be related to gestational diabetes. Poor control of disease may cause or aggravate the process.

Mycosis fungoides (MF) is the commonest T-Cell lymphoma (CTCL) involving skin and its appendages to variable degrees. Nail involvement is one of multiple dermatologic manifestation of this disorder and could have negative impact on psychological status of patients and producing therapeutic challenge to physician. We aimed to evaluate prevalence and subtypes of nail involvement in MF patients attending dermatology clinic, Razi Hospital in Tehran, Iran. All patients having MF confirmed via histopathology, visiting Razi Hospital Dermatology Clinic, Phototherapy and follow-up on inpatient wards from 2010 to 2011, were included. Patients examined by dermatologist researcher focusing on nail changes and all detected nail changes including onycholysis, longitudinal ridges and 11 more other changes, recorded in appropriated questionnaires. Treatment regimen prescribed to the patients also recorded as well as clinical CTCL staging. A total of 60 patients, including 28 (46.7%) males and 32 (53.3%) females entered the study. 18 patients (12 males and 6 females) had different nail changes including longitudinal ridging, leukonychia, pitting and nine more morphological changes in decrescendo order. Ten patients had smoking history including four patients with nail changes. The commonest used treatment was local bath Psoralen and UVA light therapy (PUVA). Overall nail involvement in our study was approximately 30%. There was no significant relationship between prevalence of nail changes, demographic and clinical specification of underlying CTCL disorder especially tumor stage. Also, no significant relationship between prevalence and type of nail involvement with prescribed therapeutic regimen was found. We found about 30% prevalence that is a little higher than previously shown. It seems that nail changes in CTCL have no relationship to CTCL staging or other specifications including demographic specifications.

Cardiovascular complications have very high incidence and are the main cause of mortality in human. Although the cardiovascular risk factors among apparently healthy subjects have been studied, these factors among patients who have undergone coronary artery bypass graft surgery have not evaluated clearly. The present study is a descriptive, cross-sectional survey on 1592 patients which suffered coronary artery bypass surgery (CABG) from May 2009 to May 2013 in Baqiyatallah Hospital, Tehran. Before surgery, all patients were carefully assessed and typical and atypical cardiovascular risk factors were determined and the desired data were collected. More than 70.8% of subjects were men and 29.2% were women. Average age of all patients was 60.39±7.5 years and the mean weight was 73.91±6.3 kg. Typical risk factors including: smoking, plasma cholesterol level, hypertension, diabetes mellitus and family history of cardiac problems, were common in these patients. Forty seven percent of patients had diabetes mellitus, 79.4% had hypercholesterolemia, 34.3% had a smoking history, 64.5% had hypertension and 44.2% of patients had a family history of cardiovascular disease. Among atypical risk factors, various types of angina (chest pain) had high prevalence (88.8% of all). Also, mean body mass index (BMI) were higher than normal (27.46±2.1) which showed the incidence of obesity among these patients. But, other atypical risk factors did not have high incidence. We demonstrated that typical and well known risk factors have also high prevalence in CABG patients. Our results indicates that we can recognize high risk persons with continuous and accurate screening as a safe and inexpensive preventive tool. This can be done in both apparently healthy subjects and in cardiovascular patients. We can prevent the occurrence of severe degrees of atherosclerosis and also CABG. So the cost and performing surgeries will be decreased.