A systematic review on thyroid organoid models: time-trend and its achievements.

Current in vitro models have played important roles in improving knowledge and understanding of cellular and molecular biology, but cannot exactly recapitulate the physiology of human tissues such as thyroid. In this article, we conducted a systematic review to present scientific and methodological time-trends of the reconstruction and generation of 3 D functional thyroid follicles and organoids for thyroid research in health and disease. "Web of Science (ISI)", "Scopus", "Embase", "Cochrane Library", and "PubMed" were systematically searched for papers published since 1950 to May 2020 in English language, using the predefined keywords. 212 articles were reviewed and finally 28 papers that met the inclusion and exclusion criteria were selected. Among the evidence for the examination of 3 D cell culture methods in thyroid research, there were only a few studies related to the organoid technology and its potential applications in understanding morphological, histological, and physiological characteristics of the thyroid gland and reconstructing this tissue. Besides, there was no study using organoids to investigate the tumorigenesis process of thyroid. Based on the results of this study, despite all the limitations and controversies, the exciting and promising organoid technology offers researchers a wide range of potential applications for more accurate modeling of thyroid in health and diseases and provides an excellent preclinical in vitro platform. In future, organoid technology can provide a better understanding of the molecular mechanisms of pathogenesis and tumorigenesis of thyroid tissue and more effective treatment for related disorders due to more accurate simulation of the thyroid physiology.

Molecular mechanisms of long non-coding RNAs in anaplastic thyroid cancer: a systematic review.

BACKGROUND: anaplastic thyroid cancer (ATC) is one of the most lethal and aggressive cancers. Evidence has shown that the tumorigenesis of ATC is a multistep process involving the accumulation of genetic and epigenetic changes. Several studies have suggested that long non-coding RNAs (lncRNAs) may play an important role in the development and progression of ATC. In this article, we have collected the published reports about the role of lncRNAs in ATC. METHODS: "Scopus", "Web of Science", "PubMed", "Embase", etc. were systematically searched for articles published since 1990 to 2020 in English language, using the predefined keywords. RESULTS: 961 papers were reviewed and finally 33 papers which fulfilled the inclusion and exclusion criteria were selected. Based on this systematic review, among a lot of evidences on examining the function of lncRNAs in thyroid cancer, there are only a small number of studies about the role of lncRNAs and their molecular mechanisms in the pathogenesis of ATC. CONCLUSIONS: lncRNAs play a crucial role in regulation of different processes involved in the development and progression of ATC. Currently, just a few lncRNAs have been identified in ATC that may serve as prognosis markers such as GAS5, MIR22HG, and CASC2. Also, because of the dysregulation of Klhl14-AS, HOTAIRM1, and PCA3 during ATC development and progression, they may act as therapeutic targets. However, for most lncRNAs, only a single experiment has evaluated the expression profile in ATC tissues/cells. Therefore, further functional studies and expression profiling is needed to resolve this limitation and identify novel and valid biomarkers.

Sildenafil and ventriculo-arterial coupling in Fontan-palliated patients: a noninvasive echocardiographic assessment.

The fundamental role of pulmonary vascular resistance in the Fontan circulation is obvious. Medications decreasing this resistance may have an impact on the fate of this population. Hence, we assessed noninvasively the effect of oral sildenafil on the ventriculo-arterial coupling in patients with Fontan circulation. In a single-center, prospective case series study, 23 patients with fenestrated extracardiac total cavopulmonary connection age 12-31 years were enrolled in this study. Clinical characteristics and echocardiographic examination were performed before and after a 1 week course of sildenafil at 0.5 mg/kg every 8 h. Sildenafil had no effect on heart rate and blood pressure. However, oxygen saturation was significantly increased with sildenafil (87.6 ± 4.3 vs. 90.1 ± 3.6; P < 0.0001). The calculated noninvasive ventricular end-systolic elastance (Ees) was greater after sildenafil compared with the pre-sildenafil values (1.59 ± 0.17 vs. 1.72 ± 0.27 mm Hg/ml; P = 0.001). Moreover, significant decreases in arterial elastance (Ea) (1.62 ± 0.53 vs. 1.36 ± 0.43 mm Hg/ml; P < 0.0001), ventricular end-diastolic elastance (Eed) (0.05 ± 0.021 vs. 0.04 ± 0.013; P = 0.002), and, finally, ventriculo-arterial coupling index (0.99 ± 0.26 vs. 0.76 ± 0.15; P < 0.0001) were found after sildenafil administration. The intolerable side effects that led to stopping the sildenafil occurred only in one (4 %) patient. Sildenafil has increased ventricular systolic elastance and improved ventriculo-arterial coupling in patients palliated with Fontan circulation. Short-term sildenafil was well tolerated in most of the patients with only minor side effects.

The impact of preload alteration on the myocardial performance index through implementing positive end expiratory pressure.

Load independent methods should be used for the assessment of ventricular function. Debate still exists regarding whether tissue Doppler imaging (TDI) indices are influenced by preload. Here, we evaluated the effect of positive end expiratory pressure (PEEP) related preload reduction on both conventional pulsed Doppler (PD) and TDI myocardial performance index (MPI). Thirty-eight mechanically ventilated patients of 3 months to 12 years old (mean ± SD age of 30 ± 11 months) without overt heart disease were enrolled. Doppler mitral inflow velocities, isovolumetric contraction and relaxation times and aortic ejection time in addition to TDI peak systolic, early and late diastolic velocities from the basal segment of left ventricular lateral wall were determined for each patient before and after applying high PEEP (10 cmH(2) O).PD-MPI was load dependent (0.61 ± 0.22 vs. 0.78 ± 0.25, P = 0.002). However, TDI-MPI did not significantly change after the use of high PEEP declining the left ventricular volume loading (0.78 ± 0.21 vs. 0.84 ± 0.22, P = 0.23). Hence, regarding various interfering pathophysiologic factors particularly preload reduction, it seems that TDI-MPI would be a more reliable index for the assessment of ventricular function.

Myocardial performance index and atrial ejection force in patients with Duchenne's muscular dystrophy.

BACKGROUND: Progressive movement limitation in patients with Duchenne's muscular dystrophy (DMD) may mask the onset of cardiac involvement. We aimed to determine whether myocardial performance index (MPI), either by conventional Doppler (CD) or tissue Doppler imaging (TDI), could detect subclinical myocardial dysfunction in DMD patients. Furthermore, we assessed the atrial ejection force (AEF) to evaluate possible existence of latent diastolic dysfunction. METHOD: Twenty DMD patients without signs and symptoms of cardiac impairment and 20 age matched control group enrolled into the study. MPI for right ventricle and left ventricle (LV) was assessed with CD and TDI for comparison. RESULTS: No significant difference was detected in ejection fraction, fractional shortening, and AEF between two groups. CD derived MPI was higher for both ventricles in the patients (P < 0.0001). Moreover, the TDI derived MPI were significantly higher in the patients in mitral, tricuspid, and septal views (P < 0.0001). A significant decrease of mitral myocardial systolic wave velocity was detected in the patients, in favor of early involvement of the posterobasal LV myocardium. All acceleration and deceleration times' values for the late mitral inflow were higher whereas the rates were significantly lower in the patients. There was no significant difference between AEF of both groups. CONCLUSION: MPI might be a useful parameter for early detection of occult cardiac dysfunction in DMD patients when other simple and standard echocardiographic parameters are within the normal limits. Lack of atrial contribution in LV filling due to atrial contractile dysfunction may play a role in DMD cardiac dysfunction.

The bigger, the better? When multicenter clinical trials and meta-analyses do not work.

Courtesy of the development of the Internet, bursts of information technology, and globalization, huge multicenter studies along with meta-analyses have been introduced to the medical sciences society. Meta-analyses and multicenter studies revolutionized modern medicine and drug development, and empowered evidence based medicine by providing extremely high levels of evidence. Nevertheless, there are occasions that while results of local multi/single center studies showed efficacy of a new treatment, larger multicenter studies or meta-analyses failed to show efficacy, and vice versa. Generally, bigger studies are more powerful and we rely on their results in clinical decision making. Nevertheless, we should keep in mind that in certain circumstances, single center studies are of great importance, and are preferred to multicenter studies and meta-analyses. In order to have a better understanding of why and when multicenter studies along with meta-analyses might not be the best options, we have discussed three different scenarios.

Pirfenidone: A novel hypothetical treatment for COVID-19.

Cytokine storm, multiorgan failure, and particularly acute respiratory distress syndrome (ARDS) is the leading cause of mortality and morbidity in patients with COVID-19. A fulminant ARDS kills the majority of COVID-19 victims. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), is a novel anti-fibrotic agent with trivial adverse effects. Pirfenidone is approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF) for patients with mild to moderate disease. Pirfenidone could inhibit apoptosis, downregulate ACE receptors expression, decrease inflammation by several mechanisms and ameliorate oxidative stress and hence protect pneumocytes and other cells from COVID-19 invasion and cytokine storm simultaneously. Based on the pirfenidone mechanism of action and the known pathophysiology of COVID-19, I believe that pirfenidone has the potential for the treatment of COVID-19 patients.

Coronary artery tortuosity: a narrative review.

Coronary artery tortuosity (CAT) is a prevalent angiographic finding commonly associated with aging, hypertension, atherosclerosis and other conditions. Preliminary evidence suggests that degradation of elastin, a key component of extracellular matrix in the vascular wall, may be responsible for the development of CAT. The clinical significance of CAT should be considered in several aspects. First, coronary flow alteration associated with CAT may result in myocardial ischemia owing to reduced perfusion pressure distal to the tortuous segment. Second, increased and oscillatory shear stress in the tortuous vessel may promote atherosclerotic plaque formation and acute coronary syndrome. Third, as one of the criteria for coronary lesion complexity, the presence of severe tortuosity proximal to the culprit lesion may pose a challenge to wiring and stent or balloon delivery, thereby increasing the risk of periprocedural complications. Last, the presence of CAT may serve as a diagnostic clue of concurrent vasculopathy such as fibromuscular dysplasia or spontaneous coronary artery dissection. In general, CAT represents a benign entity that does not require specific treatment or intervention. Further research is warranted to elucidate the pathogenesis and prognostic effect of coronary tortuosity.

Inappropriate modeling of chronic and complex disorders: How to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine.

Preclinical investigations such as animal modeling make the basis of clinical investigations and subsequently patient care. Predictive, preventive, and personalized medicine (PPPM) not only highlights a patient-tailored approach by choosing the right medication, the right dose at the right time point but it as well essentially requires early identification, by the means of complex and state-of-the-art technologies of unmanifested pathological processes in an individual, in order to deliver targeted prevention early enough to reverse manifestation of a pathology. Such an approach can be achieved by taking into account clinical, pathological, environmental, and psychosocial characteristics of the patients or an individual who has a suboptimal health condition. Inappropriate modeling of chronic and complex disorders, in this context, may diminish the predictive potential and slow down the development of PPPM and consequently modern healthcare. Therefore, it is the common goal of PPPM and translational medicine to find the solution for the problem we present in our review. Both, translational medicine and PPPM in parallel, essentially need accurate surrogates for misleading animal models. This study was therefore undertaken to provide shreds of evidence against the validity of animal models. Limitations of current animal models and drug development strategies based on animal modeling have been systematically discussed. Finally, a variety of potential surrogates have been suggested to change the unfavorable situation in medical research and consequently in healthcare.

Comparison of Conventional Versus Spiral Computed Tomography with Three Dimensional Reconstruction in Chronic Otitis Media with Ossicular Chain Destruction.

BACKGROUND: Chronic otitis media (COM) can be treated with tympanoplasty with or without mastoidectomy. In patients who have undergone middle ear surgery, three-dimensional spiral computed tomography (CT) scan plays an important role in optimizing surgical planning. OBJECTIVES: This study was performed to compare the findings of three-dimensional reconstructed spiral and conventional CT scan of ossicular chain study in patients with COM. PATIENTS AND METHODS: Fifty patients enrolled in the study underwent plane and three dimensional CT scan (PHILIPS-MX 8000). Ossicles changes, mastoid cavity, tympanic cavity, and presence of cholesteatoma were evaluated. Results of the two methods were then compared and interpreted by a radiologist, recorded in questionnaires, and analyzed. Logistic regression test and Kappa coefficient of agreement were used for statistical analyses. RESULTS: Sixty two ears with COM were found in physical examination. A significant difference was observed between the findings of the two methods in ossicle erosion (11.3% in conventional CT vs. 37.1% in spiral CT, P = 0.0001), decrease of mastoid air cells (82.3% in conventional CT vs. 93.5% in spiral CT, P = 0.001), and tympanic cavity opacity (12.9% in conventional CT vs. 40.3% in spiral CT, P=0.0001). No significant difference was observed between the findings of the two methods in ossicle destruction (6.5% conventional CT vs. 56.4% in spiral CT, P = 0.125), and presence of cholesteatoma (3.2% in conventional CT vs. 42% in spiral CT, P = 0.172). In this study, spiral CT scan demonstrated ossicle dislocation in 9.6%, decrease of mastoid air cells in 4.8%, and decrease of volume in the tympanic cavity in 1.6%; whereas, none of these findings were reported in the patients' conventional CT scans. CONCLUSION: Spiral-CT scan is superior to conventional CT in the diagnosis of lesions in COM before operation. It can be used for detailed evaluation of ossicular chain in such patients.

Effects of Normobaric Hyperoxia in Severe Acute Stroke: a Randomized Controlled Clinical Trial Study.

Oxygen therapy might increase damaged tissue oxygenation, turn on the aerobic pathway, and save neurons from death and could improve clinical outcome of the patients with stroke and head trauma. Hyperbaric oxygen therapy is accompanied by some unfavorable effects. Results of normobaric oxygen therapy on clinical outcomes of patients with stroke were controversial up till now.  This study was therefore designed to evaluate effects of normobaric hyperoxia on clinical outcomes of patients with severe acute stroke. A total of 52 consecutive patients with stroke who meet the inclusion criteria of the study were entered into this randomized controlled clinical trial. The patients in the case group underwent oxygen therapy with Venturi mask for first 12 hours of admission. The patients were examined for neurologic defects at the time of discharge and after six months using both Barthel and modified Rankin Scale (mRS) neurologic disability scoring systems. There was no significant sex difference between the two groups (P=0.5). There was no statistically significant difference between ischemic-hemorrhagic stroke constitutions of two groups (P=0.2). There were no significant difference in Barthel index scores of both groups at the time of discharge as well as the follow-up examination (P=0.7) According to the mRS scoring system, there was no difference between the patients of both groups at the time of admission (P= 0.8), however after treatment there was a significant difference between mRS scores of the treated group compared to the controls (P=0.04). According to the results of this study, normobaric oxygen therapy in the first 12 hours of accident could improve long time outcome of the patients with either ischemic or hemorrhagic stroke.

Interleukin-1 beta, interferon-gamma, and tumor necrosis factor-alpha gene expression in peripheral blood mononuclear cells of patients with coronary artery disease.

BACKGROUND: Several inflammatory mediators have been proposed to contribute to the pathogenesis of atherosclerosis. The aim of this study was to evaluate the quantitative expression of pro-inflammatory cytokines in un-stimulated peripheral blood mononuclear cell of patients with coronary artery disease (CAD). METHODS: Interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha, and interferon-gamma (IFN-γ) gene expression were evaluated in angiography confirmed patients with and without CAD in a case-control study using quantitative real-time polymerase chain reaction. RESULTS: A significant increase (P = 0.030) in IL-1ß gene expression was found in patients with CAD [median interquartile range (IQR) = 4.890 (6.084)] compared to patients without CAD [median (IQR) = 1.792 (3.172)]. Despite the increase in IFN-γ gene expression in patients with CAD [median (IQR) = 1.298 (3.896)] versus patients without CAD [median (IQR) = 0.841 (2.79)], there was not statistically significant difference (P = 0.990). CONCLUSION: Our results provide evidence for possible association between IL-1ß and development of atherosclerosis as a crucial cytokine that induce a network of signaling pathways. This finding if proved in future would suggest IL-1ß as a potent therapeutic target in CAD.

Effect of Sample Storage Temperature and Time Delay on Blood Gases, Bicarbonate and pH in Human Arterial Blood Samples.

BACKGROUND: Results of arterial blood gas analysis can be biased by pre-analytical factors, such as time interval before analysis, temperature during storage and syringe type. OBJECTIVES: To investigate the effects of samples storage temperature and time delay on blood gases, bicarbonate and PH results in human arterial blood samples. PATIENTS AND METHODS: 2.5 mL arterial blood samples were drawn from 45 patients via an indwelling Intraarterial catheter. Each sample was divided into five equal samples and stored in multipurpose tuberculin plastic syringes. Blood gas analysis was performed on one of five samples as soon as possible. Four other samples were divided into two groups stored at 22°C and 0°C. Blood gas analyses were repeated at 30 and 60 minutes after sampling. RESULTS: PaO2 of the samples stored at 0°C was increased significantly after 60 minutes (P = 0.007). The PaCO2 of the samples kept for 30 and 60 minutes at 22°C was significantly higher than primary result (P = 0.04, P < 0.001). In samples stored at 22°C, pH decreased significantly after 30 and 60 minutes (P = 0.017, P = 0.001). There were no significant differences in other results of samples stored at 0°C or 22°C after 30 or 60 minutes. CONCLUSIONS: In samples stored in plastic syringes, overestimation of PaO2 levels should be noted if samples cooled before analysis. In samples stored in plastic syringes, it is not necessary to store samples in iced water when analysis delayed up to one hour.

Uterine primitive neuroectodermal tumor.

Primitive neuroectodermal tumors are fairly rare in uterus. A case of uterine body primitive neuroectodermal tumor in a 32-year-old Iranian woman is presented. The patient was admitted with abdominal pain and fever and underwent emergency exploratory surgery with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node dissection. Posterior wall of the uterus was necrotic and ruptured and a huge tumor disrupted the uterine body. The tumor was strongly positive for CD99, NSE, and chromogranin; No reaction was seen for CD10, CD45 and myogenin. To the best of our knowledge, this is the first report of an uterine body primitive neuroectodermal tumor and the second report of uterine primitive neuroectodermal tumor from Iran.

Effects of CoQ10 Supplementation on Lipid Profiles and Glycemic Control in Patients with Type 2 Diabetes: a randomized, double blind, placebo-controlled trial.

BACKGROUND: Low grade inflammation and oxidative stress are the key factors in the pathogenesis and development of diabetes and its complications. Coenzyme Q10 (CoQ10) is known as an antioxidant and has a vital role in generation of cellular energy providing. This study was undertaken to evaluate the effects of CoQ10 supplementation on lipid profiles and glycemic controls in patients with diabetes. METHODS: Fifty patients with diabetes were randomly allocated into two groups to receive either 150 mg CoQ10 or placebo daily for 12 weeks. Before and after supplementation, fasting venous blood samples were collected and lipid profiles containing triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and glycemic indices comprising of fasting plasma glucose (FPG), insulin and hemoglobin A1C (HbA1C) were measured. Insulin resistance was calculated using HOMA-IR index. RESULTS: Forty patients completed the study. After intervention FPG and HbA1C were significantly lower in the CoQ10 group compared to the placebo group, but there were no significant differences in serum insulin and HOMA-IR between the two groups. Although total cholesterol did not change in the Q10 group after supplementation, triglyceride and HDL-C significantly decreased and LDL-C significantly increased in the CoQ10 group. CONCLUSION: The present study showed that treatment with Q10 may improve glycemic control with no favorable effects on lipid profiles in type 2 patients with diabetes. TRIAL REGISTRATION: IRCT registry number: IRCT138806102394N1.

Effects of extremely low frequency electromagnetic fields on paraoxonase serum activity and lipid peroxidation metabolites in rat.

BACKGROUND: Atherogenic effects of ELF-MF exposure have not been studied well so far. Therefore we have hypothesized that ELF-MF exposure might have atherogenic effect by impairing antioxidant function and increasing lipid peroxidation. This study was therefore undertaken to examine the effects of ELF-MF on paraoxonase (PON) activity, antioxidant capacity and lipid peroxidation metabolites. Effects of time on remodeling of antioxidant system were also investigated in this study. METHODS: Seventy five Wistar rats were randomly allocated into five groups as follows: 1) Sham exposure, 2) Single exposure to 60 Hz, sacrificed immediately after exposure, 3) Single exposure to 60 Hz, sacrificed 72 hours after exposure, 4) Fourteen days of exposure to 60 Hz, sacrificed immediately after exposure, and 5) Fourteen days of exposure to 60 Hz, sacrificed 72 hours after exposure. Blood samples were collected and analyzed. The results were compared using ANOVA and post hoc Tukey HSD for multiple caparisons. RESULTS: Single ELF-MF exposure significantly increased lipid peroxidation (CD and MDA) and increased antioxidant serum activity (HDL, paraoxonase activity, and serum total antioxidant capacity). Chronic ELF-MF exposure increased lipid peroxidation and affected antioxidant system. Free fatty acids levels were significantly increased after both single and two weeks exposure. Chronic exposure led to irreversible changes while acute exposure tended to reversible alterations on above mentioned parameters. CONCLUSIONS: According to the results of this study, ELF-MF exposure could impair oxidant-antioxidant function and might increase oxidative stress and lipid peroxidation. Antioxidant capability was dependent on the duration and continuity of ELF-MF exposure.