Sydenham's Chorea in Children with Acute Rheumatic Fever: An Echocardiographic Survey of Pediatric Patients in Northwestern Iran.

Background: Although infrequent, Sydenham's chorea (SC) may occur as a result of injury to the basal ganglia in children with acute rheumatic fever (ARF) secondary to group A Streptococcal infection. Certain hallmarks of SC, such as movement disorders, could be utilized as a predictive marker for carditis. The present study aimed to investigate neurologic and cardiologic symptoms in children with suspected SC after ARF. Methods: All children aged 5-16 who were admitted at Shahid Madani Pediatric Hospital (Tabriz, Iran), with an initial diagnosis of ARF and SC between 2009 and 2022 were included for echocardiographic assessment and prospective follow-up within 6 and 12 months after the start point. The pattern and severity of valvulopathy, as well as the prevalence of Jones criteria for rheumatic fever, were used to assess the effect. The collected data were analyzed using SPSS Statistics software (version 22.0) using Chi square and Fisher's exact tests. P<0.05 was considered statistically significant. Results: The study enrolled 85 children, 36 girls and 49 boys, with a mean age of 9.7±2.7. On the first echocardiography, 42.4% of patients had mitral valve regurgitation (MR), with a predominance of female patients (P=0.04). Of those diagnosed with SC (12 girls and 6 boys), 66.7% showed cardiac involvement, with a higher prevalence of MR in both sexes (P=0.04). The pattern of cardiac involvement after 6 months was significantly different between the groups (P=0.04). However, no such difference was observed during the one-year follow-up (P=0.07). Female sex was found to have a significant relationship with SC localization (P=0.01). Conclusion: In addition to its neurological manifestations, SC can be associated with clinical or subclinical cardiac valve dysfunction that might last for more than a year. In addition to attempting early detection and appropriate management, a precise cardiac and neurologic assessment during admission and follow-up is recommended.A preprint version of this manuscript is available at DOI: 10.21203/rs.3.rs-772662/v1 (https://www.researchsquare.com/article/rs-772662/v1).

Detailed role of mesenchymal stem cell (MSC)-derived exosome therapy in cardiac diseases.

Coronary heart disease (CHD) continues to be the leading cause of morbidity and mortality. There are numerous therapeutic reperfusion methods, including thrombolytic therapy, primary percutaneous coronary intervention, and anti-remodeling drugs like angiotensin-converting enzyme inhibitors and beta-blockers. Despite this, there is no pharmacological treatment that can effectively stop cardiomyocyte death brought on by myocardial ischemia/reperfusion (I/R) injury. For the purpose of regenerating cardiac tissue, mesenchymal stem cell (MSC) therapy has recently gained more attention. The pleiotropic effects of MSCs are instead arbitrated by the secretion of soluble paracrine factors and are unrelated to their capacity for differentiation. One of these paracrine mediators is the extracellular vesicle known as an exosome. Exosomes deliver useful cargo to recipient cells from MSCs, including peptides, proteins, cytokines, lipids, miRNA, and mRNA molecules. Exosomes take part in intercellular communication processes and help tissues and organs that have been injured or are ill heal. Exosomes alone were found to be the cause of MSCs' therapeutic effects in a variety of animal models, according to studies. Here, we have focused on the recent development in the therapeutic capabilities of exosomal MSCs in cardiac diseases.

New immunotherapy approaches for colorectal cancer: focusing on CAR-T cell, BiTE, and oncolytic viruses.

Colorectal cancer is one of the most common causes of mortality worldwide. There are several potential risk factors responsible for the initiation and progression of colorectal cancer, including age, family history, a history of inflammatory bowel disease, and lifestyle factors such as physical activity and diet. For decades, there has been a vast amount of study on treatment approaches for colorectal cancer, which has led to conventional therapies such as chemotherapy, surgery, etc. Considering the high prevalence and incidence rate, scholars believe there is an urgent need for an alternative, more efficacious treatment with fewer adverse effects than the abovementioned treatments. Immunotherapy has emerged as a potential treatment alternative in a few years and has become one of the fastest-evolving therapeutic methods. Immunotherapy works by activating or enhancing the immune system's power to identify and attack cancerous cells. This review summarizes the most crucial new immunotherapy methods under investigation for colorectal cancer treatment, including Immune checkpoint inhibitors, CAR-T cell therapy, BiTEs, Tumor-infiltrating lymphocytes, and Oncolytic virus therapy. Furthermore, this study discusses the application of combination therapy, precision medicine, biomarker discovery, overcoming resistance, and immune-related adverse effects. Video Abstract.

The Effects of Vitamin B-Complex Supplementation on Serum Homocysteine Levels and Migraine Severity in Children A Randomized Controlled Trial.

Objectives: Given that deficiency in B vitamins can lead to the accumulation of homocysteine (Hcy), and hyperhomocysteinemia may have a role in migraine pathogenesis, the present prospective randomized double-blinded placebo-controlled trial aimed to evaluate the effect of vitamin B-complex supplementation on the alleviation of migraine in children through a possible reduction in Hcy levels. Materials & Methods: Ninety children under 15 years of age suffering from typical migraine were included in the present trial. They were randomly assigned into two groups (forty-five patients in each group) to receive either vitamin B-complex or a matching placebo for six months. Serum Hcy levels and headache characteristics were evaluated and compared before and after administering vitamin B-complex or placebo. Results: Unlike the placebo group, the monthly headache frequency, severity of headache, headache disability, and serum Hcy levels were significantly decreased after the vitamin administration. The headache duration was not significantly different before and after the treatment. In the vitamin group, there were significant positive correlations between the frequency and severity, frequency and disability, and severity and disability of headaches. Hcy also had significant positive correlations with the frequency and disability of headaches. In the placebo group, the only found significant correlation was between headache frequency and disability. Conclusion: The administration of vitamin B-complex might effectively relieve migraine severity in children by reducing serum Hcy. However, further studies are needed to confirm the results.

The possible anti-seizure properties of Klotho.

Recurrent seizures in epilepsy may lead to progressive neuronal damage, which can diminish health-related quality of life. Evaluation and control of pathological processes in the brain is valuable. It seems imperative that new markers and approaches for seizure alleviation be discovered. Klotho (Kl), an antiaging protein, has protective effects in the brain against neurological disorders. It may also have antiseizure effects by improving creatine transfer to the brain, upregulating excitatory amino acid transporters, and inhibiting insulin/insulin-like growth factor-1 (IGF-1), Wingless (Wnt), transforming growth factor-beta (TGF-ß), and retinoic-acid-inducible gene-I (RIG-I)/nuclear translocation of nuclear factor-κB (NF-κB) pathways. Stimulation and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and apoptosis signal-regulating kinase 1 (ASK1)/p38 mitogen­activated protein kinase (MAPK) signaling pathways could also be considered other possible antiseizure mechanisms of Kl. In the present review, the roles of Kl in the central nervous system as well as its possible anti-seizure properties are discussed for the first time.

Cancer immunotherapy focusing on the role of interleukins: A comprehensive and updated study.

Cytokines bind to specific receptors on target cells to activate intracellular signaling pathways that control diverse cellular functions, such as proliferation, differentiation, migration, and death. They are essential for the growth, activation, and operation of immune cells and the control of immunological reactions to pathogens, cancer cells, and other dangers. Based on their structural and functional properties, cytokines can be roughly categorized into different families, such as the tumor necrosis factor (TNF) family, interleukins, interferons, and chemokines. Leukocytes produce interleukins, a class of cytokines that have essential functions in coordinating and communicating with immune cells. Cancer, inflammation, and autoimmunity are immune-related disorders brought on by dysregulation of cytokine production or signaling. Understanding cytokines' biology to create novel diagnostic, prognostic, and therapeutic methods for various immune-related illnesses is crucial. Different immune cells, including T cells, B cells, macrophages, and dendritic cells, and other cells in the body, including epithelial cells and fibroblasts, generate and secrete interleukins. The present study's main aim is to fully understand interleukins' roles in cancer development and identify new therapeutic targets and strategies for cancer treatment.

New immunotherapeutic approaches for cancer treatment.

Neoplasms are a worldwide recognized non-contagious disease which has the most mortality rate after cardiovascular diseases. For decades, there has been a vast amount of study on treatment methods of cancer which has led to conventional therapies such as chemotherapy, radiation therapy, surgery and so on. Clinicians and researchers believed that there is an urgent need, considering the high rate of incidence and prevalence, for an alternative treatment option which is more efficacious and has less adverse effects than the above-mentioned treatments. Immunotherapy has emerged as a potential treatment alternative in a few years and became one of the fastest developing therapeutic approaches. Different kinds of immunotherapies are FDA approved and available for treatment of various cancer types. In this review, we have summarized the major immunotherapy methods including checkpoint inhibitors, CAR T cell therapies and cancer vaccines. Furthermore, application of combination therapy, precision medicine, biomarker discovery, overcoming resistance and reduction of adverse effects are discussed in this study.

Pattern-recognition receptors (PRRs) in SARS-CoV-2.

Pattern recognition receptors (PRRs) are specific sensors that directly recognize various molecules derived from viral or bacterial pathogens, senescent cells, damaged cells, and apoptotic cells. These sensors act as a bridge between nonspecific and specific immunity in humans. PRRs in human innate immunity were classified into six types: toll-like receptors (TLR), C-type lectin receptors (CLRs), nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and cyclic GMP-AMP (cGAMP) synthase (cGAS). Numerous types of PRRs are responsible for recognizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is immensely effective in prompting interferon responses. Detection of SARS-CoV-2 infection by PRRs causes the initiation of an intracellular signaling cascade and subsequently the activation of various transcription factors that stimulate the production of cytokines, chemokines, and other immune-related factors. Therefore, it seems that PRRs are a promising potential therapeutic approach for combating SARS-CoV-2 infection and other microbial infections. In this review, we have introduced the current knowledge of various PRRs and related signaling pathways in response to SARS-CoV-2.

An updated review of a novel method for examining P53 mutations in different forms of cancer.

In the past fifteen years, it has been clear that tumor-associated p53 mutations can cause behaviors distinct from those brought on by a simple loss of p53's tumor-suppressive function in its wild-type form. Many of these mutant p53 proteins develop oncogenic characteristics that allow them to encourage cell survival, invasion, and metastasis. But it is now understood that the immune response is also significantly influenced by the cancer cell's p53 status. The recruitment and activity of myeloid and T cells can be impacted by p53 loss or mutation in malignancies, allowing immune evasion and accelerating cancer growth. Additionally, p53 can work in immune cells, which can have various effects that either hinder or assist the growth of tumors. In this review article, we examined different mutations of P53 in some significant cancers, such as liver, colorectal, and prostate, and reviewed some new therapeutic approaches.

Dysregulation of P53 in breast cancer: Causative factors and treatment strategies.

One of the most prevalent cancers impacting women worldwide is breast cancer. Although there are several risk factors for breast cancer, the p53 gene's function has recently received much attention. The "gatekeeper" gene, or p53, is sometimes referred to as such since it is crucial in controlling cell proliferation and preventing the development of malignant cells. By identifying DNA damage and initiating cellular repair processes, p53 usually functions as a tumor-suppressor. But p53 gene alterations can result in a lack of function, allowing cells to divide out of control and perhaps triggering the onset of cancer. Various factors, such as mutation genes, signaling pathways, and hormones, can dysregulate P53 proteins and cause breast cancer. A promising strategy for individualized cancer treatment involves focusing on p53 mutations in breast cancer. While numerous techniques, including gene therapy and small compounds, have shown promise, further study is required to create safe and efficient treatments to target p53 mutations in breast cancer successfully.

Prevalence of positive findings of brain computed tomography scans in pediatric population.

Objectives: Computed tomography (CT) scans are used more frequently in medical centers, increasing unnecessary requests for it as a first-line evaluation. This study aimed to investigate the rate and prevalence of abnormal findings in a brain CT scan in children at the Children's Hospital of Tabriz, Iran. Materials &Methods: This study was a cross-sectional descriptive-analytical study that included all children under 15 years old undergoing a brain CT scan at the Children's Hospital of Tabriz, Iran. All patients who fulfilled the inclusion criteria and were referred to the Children's Hospital of Tabriz during the spring of 2018 entered the study. Age, gender, patient history, and clinical findings were examined. In the next step, the results of each patient's CT scan were evaluated. Results: In this study, 108 patients were studied with a median age of 18.0 months. CT scan results were normal in seventy-four cases (68.5%), hydrocephalus was seen in 15 (13.9%), and benign infantile hydrocephalus was seen in eight (7.4%). The study revealed a statistically significant relationship between patient history and CT scan results (p=0.017). A statistically significant relationship was observed between the clinical findings and CT scan results (p=0.042). Conclusion: Brain CT scans have more abnormal findings in patients with positive clinical findings. Although a CT scan is a highly sensitive and specificmodality in diagnosing central nervous system (CNS) abnormalities, its value depends on the underlying medical history and physical exam.

Brain CT Scan, Sonography and EEG Findings in Neonates with Seizure.

Objectives: This study aimed to determine the frequency of different types, causes, and abnormal findings of brain computed tomography scan (CT scan) and ultrasonography (US) and multichannel- electroencephalography (EEG) in neonates with seizure. The ability of brain CT scan was also compared with US in terms of detecting the underlying causes of neonatal seizures. Materials & Methods: In this cross-sectional retrospective study, the medical records of 90 neonates younger than 28 days with the definite diagnosis of seizure were reviewed. The data were analyzed using SPSS 22 through descriptive and Exact fisher tests. Results: Totally, 90 newborns (M: F = 1.5:1) with mean age of 63.11 ± 32.8 days were enrolled. 35.5% of newborns were born before the 37th week of pregnancy. In this study, 45.6% of EEG findings, 22% of brain CT scan findings, and 12.5% of US findings were abnormal. The automatisms (38.9%) and benign idiopathic neonatal seizure (70.7%) were the most common seizure type and cause respectively. The hypoxic Ischemic encephalopathy was the most common abnormal finding (30%) in brain CT scan. Conclusions: Given the accuracy of EEG in detection of brain pathologies, where available, all neonatal seizures should be initially confirmed using EEG. Radiologic investigations (CT scan, US) off the head/ cranium should be done to detect the cause of neonatal seizure. The capacity of brain CT scan to detect underlying causes of neonatal seizures is more than US.

Neutrophil to Lymphocyte Ratio as a Biomarker for Predicting the Coronary Artery Abnormality in Kawasaki Disease: A Meta-Analysis.

We conducted a systematic review and meta-analysis on the relationship between the neutrophil to lymphocyte ratio (NLR) and coronary artery abnormalities (CAA) in patients with Kawasaki disease (KD), according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements. We searched PubMed, Scopus, Web of Science, Embase, TRIP, Google Scholar, and ProQuest up to the 8th of August 2022. This was done to retrieve eligible studies. No date or language limitations were considered in this study. Methodology quality assessment was conducted according to the Newcastle-Ottawa scale (NOS). Standard mean difference (SMD) and its 95% confidence interval (CI) were used to depict the pooled continuous variables. Finally, 17 articles with 6334 KD patients, of whom 1328 developed CAA, were enrolled in this meta-analysis. NLR level was significantly higher in KD patients with CAA compared to those without CAA (SMD =0.81; 95% CI =0.05-1.57, P = 0.03). In addition, NLR level was significantly higher in patients with coronary artery aneurysms than those without coronary artery aneurysms (SMD =2.29; 95% CI =0.18-4.41, P = 0.03). However, no significant association between NLR and coronary artery dilation was observed in this meta-analysis (SMD =0.56; 95% CI = -0.86-1.99). There was no publication bias for the pooled SMD of NLR for coronary artery abnormality in KD (Egger's test P = 0.82; Begg's test P = 0.32). The NLR may be useful in monitoring CAA development in these patients and may further imply a mechanistic role in potential inflammation that mediates this process.

The Impact of Neutrophil-Lymphocyte Ratio in Febrile Seizures: A Systematic Review and Meta-Analysis.

This meta-analysis was conducted to determine the relationship between neutrophil to lymphocyte ratio (NLR) and febrile seizure (FS). Our study was registered with the PROSPERO (ID: CRD42021259944). Web of Science, Embase, PubMed, Scopus, and ProQuest Central were searched, and finally, 17 studies were included. Standardized mean difference (SMD) was reported with a 95% confidence interval (CI) for the NLR levels. Compared with the febrile control group, the FS patients' NLR levels were significantly higher (SMD = 0.49; 95%CI = 0.26 to 0.72, P < 0.001). Furthermore, we conducted a comparison of NLR levels between febrile controls against simple and complex FS cases separately and found that NLR levels of children with either simple or complex FS were higher compared with those of febrile controls (SMD = 0.42, 95%CI = 0.14 to 0.69, P = 0.003 and SMD = 0.90, 95%CI = 0.71 to 1.09, P < 0.001, respectively). Also, in comparison with the NLR levels of the simple FS group, the complex FS patients' NLR levels were significantly higher (SMD = 0.59, 95%CI = 0.34 to 0.85, P < 0.001). Our study indicated that NLR could be recommended as an inexpensive diagnostic biomarker for FS. In addition, it can be useful when distinguishing between simple FS and complex FS.

Role of the Neutrophil to Lymphocyte Ratio in Guillain Barré Syndrome: A Systematic Review and Meta-Analysis.

In this study, we conducted a systematic review and meta-analysis regarding the role of the neutrophil to lymphocyte ratio (NLR) in Guillain Barré syndrome (GBS). The most recent update to the search was on July 18, 2022, through the databases of Web of Science, PubMed, Embase, and Scopus. The Newcastle-Ottawa scale was used for quality assessment of included studies. Finally, 14 studies were included in the review, and among them, ten studies were included in the meta-analysis. Our results showed that NLR levels were significantly increased in the patients with GBS compared with healthy controls (SMD = 1.05; 95%CI = 0.59 to 1.50, P < 0.001). After treatment, NLR levels were decreased to the extent that they became similar to healthy controls (SMD = -0.03, 95%CI = -0.29 to 0.22, P = 0.204). Moreover, NLR was a stable predictor of outcome or response to treatment in such patients (SMD = 1.01, 95%CI = 0.65 to 1.37, P < 0.001); the higher the NLR, the worse the outcome. In addition, patients who underwent mechanical ventilation had higher levels of NLR compared to those who did not (SMD = 0.93, 95%CI = 0.05 to 1.82, P = 0.03). However, NLR levels were not different among distinct GBS subtypes, so it could not distinguish among them. In conclusion, our analysis indicates that the NLR levels are highly elevated in patients with GBS. Therefore, the NLR has the potential to be used as a biomarker to inform diagnosis, prognosis, or treatment responses in GBS, and future studies are warranted.

Neutrophil-to-Lymphocyte Ratio and Early Neurological Deterioration in Stroke Patients: A Systematic Review and Meta-Analysis.

In light of the growing emphasis on classifying stroke patients for different levels of monitoring intensity and emergency treatments, we conducted a systematic review of a wide range of clinical studies, according to the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, with no restrictions on the language or publication date, to analyze the potential of the neutrophil-to-lymphocyte ratio (NLR) as an early neurological deterioration (END) risk predictor. A comprehensive search was carried out in PubMed, Scopus, and Web of Science databases from the inception to March 13, 2022. Nine articles were included in our study. Stroke patients with END had significantly higher NLR levels than the those without END (SMD = 0.73; CI 95% = 0.42-1.05, P value < 0.001). In the subgroup analysis, according to ethnicity, East Asian patients with END had elevated levels of NLR compared to those without END (SMD = 0.79; CI 95% = 0.52-1.06, P value < 0.001). However, the difference in the Caucasian group was not significant (SMD = 0.60; CI 95% = -0.50-1.70, P value = 0.28). In the subgroup analysis according to the type of stroke, the NLR levels in patients with hemorrhagic stroke who developed END were similar to those without END (SMD = 0.84, CI 95% = -0.10-1.77, P value = 0.07). Vice versa, in the ischemic stroke group, patients with END had elevated levels of NLR compared to those without END (SMD = 0.67, CI 95% = 0.38-0.96, P value < 0.001). NLR is a unique inflammatory biomarker whose increase in END suggests an immune system dysfunction in the pathogenesis of the disease.

GAA gene mutation detection following clinical evaluation and enzyme activity analysis in Azeri Turkish patients with Pompe disease.

Pompe disease (PD) is a rare autosomal recessive multi-systemic lysosomal storage disorder, caused by mutations in the acid alpha-glucosidase (GAA) gene located on 17q25.2-q25.3. It is one of about 50 rare genetic diseases categorized as lysosomal storage disorders. This disease is characterized by a range of different symptoms related to acid alpha-glucosidase deficiency. Mutation recognition in the GAA gene can be very significant for purposes such as therapeutic interference, early diagnosis and genotype-phenotype relationship. In the current study, peripheral blood samples were gathered from patients with PD and healthy members of three families. Enzymatic activity of GAA was checked. Then, mutation detection was performed by polymerase chain reaction followed by direct sequencing of all exons in samples with decreased enzyme activity. The identified mutations were investigated using bioinformatics tools to predict possible effects on the protein product and also to compare the mutated sequence with near species. Three novel mutations (c.1966-1968delGAG, c.2011-2012delAT and c.1475-1481dupACCCCAC) were identified in the GAA gene. Assessment of the effects of these mutations on protein structure and function showed the possibility of harmful effects and their significant alterations in the protein structure. The three novel GAA gene mutations detected in this study expand the information about the molecular genetics of PD and can be used to helpdiagnosis and genetic counseling of affected families.

Determination of valproic acid and 3-heptanone in plasma using air-assisted liquid-liquid microextraction with the assistance of vortex: Application in the real samples.

Introduction: Valproic acid (VPA) is an antiepileptic drug used to treat epilepsy and bipolar disorder. Adverse effects of VPA were studied in many reports, however, a dose-response relationship between VPA and its metabolites in epilepsy patients are extremely limited. In this paper, a high efficient method was developed for the preconcentration and determination of VPA and its main metabolite in plasma. Methods: For the extraction and preconcentration of the selected analytes, a volume of an extractant was placed at the bottom of the microtube containing pretreated plasma. The mixture was repeatedly withdrawn from the microtube and pushed-out into it using a 1.0-mL glass syringe and resulted in a cloudy mixture. For further turbidity, the mixture was shaken on a vortex agitator. This procedure was used to analyze the plasma samples of patients with epilepsy (n = 70). Results: The results revealed that in most patients with a low level of VPA relative to its expected level, 3-heptanone concentrations were high. The limits of quantification of 3-heptanone and VPA were 0.04 mg L-1 and 0.2 mg L-1, respectively. A suitable precision at a concentration of 2 mg L-1 for each analyte was obtained (relative standard deviation ≤ 9%). Conclusion: The obtained results indicated that this procedure is easy, sensitive, and reliable, and can be used for the analysis of the selected analytes in the plasma samples of patients with epilepsy.