A novel homozygous RAG1 mutation is associated with severe combined immunodeficiency and neurological presentations.

INTRODUCTION AND OBJECTIVES: Severe combined immunodeficiency (SCID) is a subset of primary immunodeficiency diseases caused by a hereditary deficiency of the adaptive immune system. Mutation in recombination activating gene (RAG) is known as the underlying genetic cause of SCID. RAG protein plays a pivotal role in V(D)J recombination which is the main process to assemble lymphocyte antigen receptors during T- and B-cell development. The patients are characterized by recurrent infections, failure to thrive, chronic diarrhea, and fever, in early infancy. Herein, we present a case of SCID with rare neurological manifestations affected by a mutation in RAG1. PATIENTS AND METHODS: The patient was a 15-month-old infant born to a consanguineous family. She was presented with neurological abnormalities including facial nerve palsy, seizure, and decreased consciousness. Next-generation sequencing (NGS)-based primary immunodeficiency disease (PID)-gene panel screen and Sanger sequencing were performed to identify the genetic mutation. RESULTS: We found a novel homozygous missense mutation in RAG1, c.1210C>T,p.Arg404Trp, which was predicted to be deleterious (combined annotation dependent depletion, CADD score of 27.4). Both parents were heterozygous carriers for this mutation. According to her laboratory data, both T cell and B cell numbers were decreased and the patient was diagnosed as RAG1- SCID. CONCLUSIONS: SCID is a pediatric emergency with a variety of manifestations in infants. Therefore, accurate diagnosis importantly in the case of rare manifestations must be considered in these patients. Our findings point toward the importance of genetic assessment for early diagnosis and timely treatment of this disorder.

Evaluation of Antibody Response to Polysaccharide Vaccine and Switched Memory B Cells in Pediatric Patients with Inflammatory Bowel Disease

BACKGROUND/AIMS: Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract, whose etiologies are still unknown. This study was performed to evaluate the humoral immune response in terms of B cell functions in selected IBD patients. METHODS: Eighteen pediatric patients with IBD, including 12 cases of ulcerative colitis (UC) and six with Crohn disease (CD), were enrolled in this study. The pneumococcal vaccine was injected in all patients, and the IgG antibody level to the polysaccharide antigen was measured before and 4 weeks after injection. The B cell switch-recombination process was evaluated. RESULTS: Five patients with IBD (three CD and two UC) had defects in B cell switching, which was significantly higher than in controls (p=0.05). Ten patients had a specific antibody deficiency and exhibited a higher frequency of bacterial infection than the healthy group. The mean increased level of IgG after vaccination was lower in IBD patients (82.9+/-32.5 microg/mL vs 219.8+/-59.0 microg/mL; p=0.001). Among the patients who had an insufficient response, no significant difference in the number of switched memory B-cell was observed. CONCLUSIONS: A defect in B lymphocyte switching was observed in pediatric IBD patients, and especially in those patients with CD. Owing to an increased risk of bacterial infections in those patients with antibody production defects, pneumococcal vaccination could be recommended. However, not all patients can benefit from the vaccination, and several may require other prophylactic methods.

Bloody Diarrhea as a Presentation Manifestation of Familial Mediterranean Fever in a Patient with Compound Heterozygote Mutations of the MEFV Gene

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by episodic fever and inflammatory polyserositis, which could lead to a variety of manifestations, including recurrent abdominal pain. Herein, a 12-year-old boy who has suffered from fever and bloody diarrhea since early childhood is described. All structural and underlying disorders leading to bleeding were excluded. Genetic studies indicated compound heterozygote mutations of M680I/R761H in the MEFV gene, which confirmed the diagnosis of FMF. Therefore, treatment with colchicine was started, which led to symptom relief. As gastrointestinal manifestations appear to be the main features of FMF, bloody diarrhea could also be considered an initial symptom of FMF.

Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons.

Local protein synthesis in neuronal dendrites is critical for synaptic plasticity. However, the signaling cascades that couple synaptic activation to dendritic protein synthesis remain elusive. The purpose of this study is to determine the role of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling in regulating dendritic protein synthesis in live neurons. We first characterized the involvement of various subtypes of glutamate receptors and the mTOR kinase in regulating dendritic synthesis of a green fluorescent protein (GFP) reporter controlled by alphaCaMKII 5' and 3' untranslated regions in cultured hippocampal neurons. Specific antagonists of N-methyl-d-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and metabotropic glutamate receptors abolished glutamate-induced dendritic GFP synthesis, whereas agonists of NMDA and metabotropic but not AMPA glutamate receptors activated GFP synthesis in dendrites. Inhibitions of the mTOR signaling, as well as its upstream activators, phosphatidylinositol 3-kinase and AKT, blocked NMDA receptor-dependent dendritic GFP synthesis. Conversely, activation of mTOR signaling stimulated dendritic GFP synthesis. In addition, we also found that inhibition of the mTOR kinase blocked dendritic synthesis of the endogenous alphaCaMKII and MAP2 proteins induced by tetanic stimulations in hippocampal slices. These results identify critical roles of NMDA receptors and the mTOR signaling pathway for control of synaptic activity-induced dendritic protein synthesis in hippocampal neurons.

Cow's Milk Allergy among Children with Gastroesophageal Reflux Disease

BACKGROUND/AIMS: Gastroesophageal reflux disease (GERD) and cow's milk allergy (CMA) are two common conditions that occur in infancy. This study was performed to investigate the frequency of CMA in a group of patients with GERD. METHODS: Eighty-one children with signs and symptoms of GERD were enrolled in this study. All subjects received omeprazole for 4 weeks after the initial evaluation. Empirical elimination of cow's milk from the diet was started for the patients who did not respond to the omeprazole treatment. RESULTS: Seventy-two cases presented with gastrointestinal signs and symptoms, whereas the remaining nine cases presented with respiratory complaints. After the initial treatment with omeprazole, two thirds of the cases (54 patients, 66.7%) responded well, and all of their symptoms were resolved. Cow's milk was eliminated from the diets of the remaining 27 patients. All signs and symptoms of GERD were resolved in this group after a 4 week elimination of cow's milk from the diet. CONCLUSIONS: A diagnosis of CMA was considered in one third of the pediatric cases with signs and symptoms of GERD. This finding shows that CMA can mimic or aggravate all signs and symptoms of severe GERD during infancy.

Coronavirus(COVID-19)Outbreak Prediction Using Epidemiological Models of Richards Gompertz Logistic Ratkowsky and SIRD

On 30 July 2020, a total number of 301,530 diagnosed COVID-19 cases were reported in Iran, with 261,200 recovered and 16,569 dead. The COVID-19 pandemic started with 2 patients in Qom city in Iran on 20 February 2020. Accurate prediction of the end of the COVID-19 pandemic and the total number of populations affected is challenging. In this study, several widely used models, including Richards, Gompertz, Logistic, Ratkowsky, and SIRD models, are used to project dynamics of the COVID-19 pandemic in the future of Iran by fitting the present and the past clinical data. Iran is the only country facing a second wave of COVID-19 infections, which makes its data difficult to analyze. The present studys main contribution is to forecast the near-future of COVID-19 trends to allow non-pharmacological interventions (NPI) by public health authorities and/or government policymakers. We have divided the COVID-19 pandemic in Iran into two waves, Wave I, from February 20, 2020 to May 4, 2020, and Wave II from May 5, 2020, to the present. Two statistical methods, i.e., Pearson correlation coefficient (R) and the coefficient of determination (R2), are used to assess the accuracy of studied models. Results for Wave I Logistic, Ratkowsky, and SIRD models have correctly fitted COVID-19 data in Iran. SIRD model has fitted the first peak of infection very closely on April 6, 2020, with 34,447 cases (The actual peak day was April 7, 2020, with 30,387 active infected patients) with the re-production number R0=3.95. Results of Wave II indicate that the SIRD model has precisely fitted with the second peak of infection, which was on June 20, 2020, with 19,088 active infected cases compared with the actual peak day on June 21, 2020, with 17,644 cases. In Wave II, the re-production number R0=1.45 is reduced, indicating a lower transmission rate. We aimed to provide even a rough project future trends of COVID-19 in Iran for NPI decisions. Between 180,000 to 250,000 infected cases and a death toll of between 6,000 to 65,000 cases are expected in Wave II of COVID-19 in Iran. There is currently no analytical method to project more waves of COVID-19 beyond Wave II.

COVID-19 in Iran: A Deeper Look Into The Future

The novel corona-virus (COVID-19) has led to a pandemic, affecting almost all countries and regions in a few weeks, and therefore a global plan is needed to overcome this battle. Iran has been among the first few countries that has been affected severely, after China, which forced the government to put some restriction and enforce social distancing in majority of the country. In less than 2 months, Iran has more than 80,000 confirmed cases, and more than 5,000 death. Based on the official statistics from Irans government, the number of daily cases has started to go down recently, but many people believe if the lockdown is lifted without proper social distancing enforcement, there is a possibility for a second wave of COVID-19 cases. In this work, we analyze at the data for the number cases in Iran in the past few weeks, and train a predictive model to estimate the possible future trends for the number of cases in Iran, depending on the government policy in the coming weeks and months. Our analysis may help political leaders and health officials to take proper action toward handling COVID-19 in the coming months.

Cardiovascular Diseases and COVID-19 Mortality and Intensive Care Unit Admission: A Systematic Review and Meta-analysis

BackgroundHigh rate of cardiovascular disease (CVD) have been reported among patients with novel coronavirus disease (COVID-19). Meanwhile there were controversies among different studies about CVD burden in COVID-19 patients. Hence, we aimed to study CVD burden among COVID-19 patients, using a systematic review and meta-analysis. MethodsWe have systematically searched databases including PubMed, Embase, Cochrane Library, Scopus, Web of Science as well as medRxiv pre-print database. Hand searched was also conducted in journal websites and Google Scholar. Meta-analyses were carried out for Odds Ratio (OR) of mortality and Intensive Care Unit (ICU) admission for different CVDs. We have also performed a descriptive meta-analysis on different CVDs. ResultsFifty-six studies entered into meta-analysis for ICU admission and mortality outcome and 198 papers for descriptive outcomes, including 159,698 COVID-19 patients. Results of meta-analysis indicated that acute cardiac injury, (OR: 13.29, 95% CI 7.35-24.03), hypertension (OR: 2.60, 95% CI 2.11-3.19), heart Failure (OR: 6.72, 95% CI 3.34-13.52), arrhythmia (OR: 2.75, 95% CI 1.43-5.25), coronary artery disease (OR: 3.78, 95% CI 2.42-5.90), and cardiovascular disease (OR: 2.61, 95% CI 1.89-3.62) were significantly associated with mortality. Arrhythmia (OR: 7.03, 95% CI 2.79-17.69), acute cardiac injury (OR: 15.58, 95% CI 5.15-47.12), coronary heart disease (OR: 2.61, 95% CI 1.09-6.26), cardiovascular disease (OR: 3.11, 95% CI 1.59-6.09), and hypertension (OR: 1.95, 95% CI 1.41-2.68) were also significantly associated with ICU admission in COVID-19 patients. ConclusionFindings of this study revealed a high burden of CVDs among COVID-19 patients, which was significantly associated with mortality and ICU admission. Proper management of CVD patients with COVID-19 and monitoring COVID-19 patients for acute cardiac conditions is highly recommended to prevent mortality and critical situations. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/20062869v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@21e53corg.highwire.dtl.DTLVardef@150dcc6org.highwire.dtl.DTLVardef@1ce7f21org.highwire.dtl.DTLVardef@1fc5fd7_HPS_FORMAT_FIGEXP M_FIG C_FIG

Implications Derived from S-Protein Variants of SARS-CoV-2 from Six Continents

Spike (S) proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are critical determinants of the infectivity and antigenicity of the virus. Several mutations in the spike protein of SARS-CoV-2 have already been detected, and their effect in immune system evasion and enhanced transmission as a cause of increased morbidity and mortality are being investigated. From pathogenic and epidemiological perspectives, spike proteins are of prime interest to researchers. This study focused on the unique variants of S proteins from six continents Asia, Africa, Europe, Oceania, South America, and North America. In comparison to the other five continents, Africa (29.065%) had the highest percentage of unique S proteins. Notably, only North America had 87% (14046) of the total (16143) specific S proteins available in the NCBI database(across all continents). Based on the amino acid frequency distributions in the S protein variants from all the continents, the phylogenetic relationship implies that unique S proteins from North America were significantly different from those of the other five continents. Overtime, the unique variants originating from North America are most likely to spread to the other geographic locations through international travel or naturally by emerging mutations. Hence it is suggested that restriction of international travel should be considered, and massive vaccination as an utmost measure to combat the spread of COVID-19 pandemic. It is also further suggested that the efficacy of existing vaccines and future vaccine development must be reviewed with careful scrutiny, and if needed, further re-engineered based on requirements dictated by new emerging S protein variants.

Heterologous vaccination with inactivated and mRNA vaccines increases B and T cell responses to SARS-CoV-2

BackgroundThere has been an unprecedented global effort to produce safe and effective vaccines against SARS-CoV-2. However, production challenges, supply shortages and unequal global reach, together with an increased number of breakthrough infections due to waning of immunity and the emergence of new variants of concern (VOC), have prolonged the pandemic. To boost the immune response, several heterologous vaccination regimes have been tested and have shown increased antibody responses compared to homologous vaccination. Here we evaluated the effect of mRNA vaccine booster on immunogenicity in individuals who had been vaccinated with two doses of inactivated vaccines. MethodsThe levels of specific antibodies against the receptor-binding domain (RBD) of the spike protein from wild-type virus and the Beta, Delta and Omicron variants were measured in healthy individuals who had received two doses of homologous inactivated (BBIBP-CorV or CoronoVac) or mRNA (BNT162b2 or mRNA-1273) vaccines, and in donors who were given an mRNA vaccine boost after two doses of either vaccine. Pre-vaccinated healthy donors, or individuals who had been infected and subsequently received the mRNA vaccine were also included as controls. In addition, specific memory B and T cell responses were measured in a subset of samples. ResultsA booster dose of an mRNA vaccine significantly increased the level of specific antibodies that bind to the RBD domain of the wild-type (6-fold) and VOCs including Delta (8-fold) and Omicron (14-fold), in individuals who had previously received two doses of inactivated vaccines. The level of specific antibodies in the heterologous vaccination group was furthermore similar to that in individuals receiving a third dose of homologous mRNA vaccines or boosted with mRNA vaccine after natural infection. Moreover, this heterologous vaccination regime significantly enhanced the specific memory B and T cell responses. ConclusionsHeterologous prime-boost immunization with inactivated vaccine followed by an mRNA vaccine boost markedly increased the levels of specific antibodies and B and T cell responses and may thus increase protection against emerging SARS-CoV-2 variants including Omicron.