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2.
Stem Cell Res Ther ; 13(1): 408, 2022 08 12.
Article in English | MEDLINE | ID: covidwho-2002225

ABSTRACT

BACKGROUND: The increasing number of clinical trials for induced pluripotent stem cell (iPSC)-derived cell therapy products makes the production on clinical grade iPSC more and more relevant and necessary. Cord blood banks are an ideal source of young, HLA-typed and virus screened starting material to produce HLA-homozygous iPSC lines for wide immune-compatibility allogenic cell therapy approaches. The production of such clinical grade iPSC lines (haplolines) involves particular attention to all steps since donor informed consent, cell procurement and a GMP-compliant cell isolation process. METHODS: Homozygous cord blood units were identified and quality verified before recontacting donors for informed consent. CD34+ cells were purified from the mononuclear fraction isolated in a cell processor, by magnetic microbeads labelling and separation columns. RESULTS: We obtained a median recovery of 20.0% of the collected pre-freezing CD34+, with a final product median viability of 99.1% and median purity of 83.5% of the post-thawed purified CD34+ population. CONCLUSIONS: Here we describe our own experience, from unit selection and donor reconsenting, in generating a CD34+ cell product as a starting material to produce HLA-homozygous iPSC following a cost-effective and clinical grade-compliant procedure. These CD34+ cells are the basis for the Spanish bank of haplolines envisioned to serve as a source of cell products for clinical research and therapy.


Subject(s)
Induced Pluripotent Stem Cells , Antigens, CD34/genetics , Antigens, CD34/metabolism , Blood Banks , Fetal Blood , Homozygote , Induced Pluripotent Stem Cells/metabolism
3.
J Clin Lab Anal ; 36(5): e24343, 2022 May.
Article in English | MEDLINE | ID: covidwho-1844030

ABSTRACT

Etiologies of acute liver failure in children can be multiple factors including virus infection, drug-induced damage, and different pathogens. Next-generation sequencing (NGS) is an emerging method for pan-pathogen screening. Here we reported a case of acute liver failure in a 15-month-old male, using NGS and gene sequencing to determine the cause of acute liver failure may be caused by pathogens, drug-induction and pathogenic variant gene.


Subject(s)
Liver Failure, Acute , Neoplasm Proteins , Child , High-Throughput Nucleotide Sequencing , Homozygote , Humans , Infant , Liver Failure, Acute/diagnosis , Liver Failure, Acute/genetics , Liver Failure, Acute/pathology , Male , Mutation/genetics , Neoplasm Proteins/genetics
4.
Muscle Nerve ; 65(5): 498-507, 2022 05.
Article in English | MEDLINE | ID: covidwho-1813581

ABSTRACT

Spinal muscular atrophy (SMA) is a group of neurodegenerative disorders resulting from the loss of spinal motor neurons. 95% of patients share a pathogenic mechanism of loss of survival motor neuron (SMN) 1 protein expression due to homozygous deletions or other mutations of the SMN1 gene, with the different phenotypes influenced by variable copy numbers of the SMN2 gene. Advances in supportive care, disease modifying treatment and novel gene therapies have led to an increase in the prevalence of SMA, with a third of SMA patients now represented by adults. Despite the growing number of adult patients, consensus on the management of SMA has focused primarily on the pediatric population. As the disease burden is vastly different in adult SMA, an approach to treatment must be tailored to their unique needs. This review will focus on the management of the adult SMA patient as they age and will discuss proper transition of care from a pediatric to adult center, including the need for continued monitoring for osteoporosis, scoliosis, malnutrition, and declining mobility and functioning. As in the pediatric population, multidisciplinary care remains the best approach to the management of adult SMA. Novel and emerging therapies such as nusinersen and risdiplam provide hope for these patients, though these medications are of uncertain efficacy in this population and require additional study.


Subject(s)
Muscular Atrophy, Spinal , Adult , Genetic Therapy , Homozygote , Humans , Motor Neurons/pathology , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/therapy , Phenotype , Survival of Motor Neuron 1 Protein/genetics
5.
BMJ Case Rep ; 15(3)2022 Mar 16.
Article in English | MEDLINE | ID: covidwho-1745767

ABSTRACT

A man in his early 30s, presented with multiple soft tissue swellings over the buttocks, around the knees, ankles and dorsum of both the hands since childhood. His father and paternal uncle had similar lesions, and his father had coronary artery disease. One of his sisters had a history of sudden death due to an unknown cause at 14 years. The patient and his parents had very high serum levels of total cholesterol and low-density lipoprotein. Based on the above findings, a clinical diagnosis of familial hyperlipidaemia type II was made. Larger lesions were excised in stages, and histopathological evaluation revealed the lesions to be eruptive xanthoma. A cardiac assessment revealed no significant abnormality. Lipid-lowering agents and low-dose aspirin were started, and the patient was advised for regular cardiology and endocrine evaluation. This case emphasises its rare presentation and the importance of early diagnosis and management to prevent any untoward future incidence.


Subject(s)
Coronary Artery Disease , Hyperlipidemias , Hyperlipoproteinemia Type II , Xanthomatosis , Child , Coronary Artery Disease/complications , Homozygote , Humans , Hyperlipidemias/complications , Hyperlipoproteinemia Type II/complications , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/genetics , Male , Xanthomatosis/pathology
6.
Nephron ; 146(2): 185-189, 2022.
Article in English | MEDLINE | ID: covidwho-1495753

ABSTRACT

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) affecting the kidneys. Compared with typical HUS due to an infection from shiga toxin-producing Escherichia coli, atypical HUS involves a genetic or acquired dysregulation of the complement alternative pathway. In the presence of a mutation in a complement gene, a second trigger is often necessary for the development of the disease. We report a case of a 54-year-old female, with a past medical history of pulmonary tuberculosis, who was admitted to the emergency service with general malaise and reduction in urine output, 5 days after vaccination with ChAdOx1 nCoV-19. Laboratory results revealed microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Given the clinical picture of TMA, plasma exchange (PEX) was immediately started, along with hemodialysis. Complementary laboratory workup for TMA excluded thrombotic thrombocytopenic purpura and secondary causes. Complement study revealed normal levels of factors H, B, and I, normal activity of the alternate pathway, and absence of anti-factor H antibodies. Genetic study of complement did not show pathogenic variants in the 12 genes analyzed, but revealed a deletion in gene CFHR3/CFHR1 in homozygosity. Our patient completed 10 sessions of PEX, followed by eculizumab, with both clinical and laboratorial improvement. Actually, given the short time lapse between vaccination with ChAdOx1 nCoV-19 and the clinical manifestations, we believe that vaccine was the trigger for the presentation of aHUS in this particular case.


Subject(s)
Atypical Hemolytic Uremic Syndrome/etiology , Blood Proteins/genetics , Complement C3b Inactivator Proteins/genetics , Gene Deletion , Homozygote , Female , Humans , Middle Aged
7.
Mol Genet Genomic Med ; 9(8): e1740, 2021 08.
Article in English | MEDLINE | ID: covidwho-1375613

ABSTRACT

BACKGROUND: Diarrhea is a common occurrence in children below the age of 5 years. In chronic cases, it induces malnutrition that severely stunts growth. Bile acid diarrhea (BAD), caused by malabsorption of bile acid (BA), is a rare form of chronic diarrhea seldom observed in pediatric patients. Here, we present a clinical report on a novel case of chronic BAD, with severe stunting in an infant, induced by a homozygous mutation of SLC10A2. METHODS: We performed DNA extraction, whole-exome sequencing analysis, and mutation analysis of SLC10A2 to obtain genetic data on the patient. We subsequently analyzed the patient's clinical and genetic data. RESULTS: The patient's clinical manifestations were chronic diarrhea with increased BAs in the feces and extreme stunting, which was diagnosed as BAD. A homozygous mutation of SLC10A2 at the c.313T>C (rs201206937) site was detected. CONCLUSION: Our report reveals the youngest case illustrating the characteristics of BAD induced by genetic variant at 313T>C, and the second case entailing a clear association between a SLC10A2 genetic mutation and the onset of BAD. Our findings expand the mutant spectrum of the SLC10A2 gene and contribute to the refinement of the genotype-phenotype mapping of severe stunting induced by pediatric BAD. Moreover, they highlight the value of molecular genetic screening for diagnosing BAD in young patients.


Subject(s)
Diarrhea/genetics , Growth Disorders/genetics , Organic Anion Transporters, Sodium-Dependent/genetics , Symporters/genetics , Bile Acids and Salts/metabolism , Diarrhea/pathology , Female , Growth Disorders/pathology , Homozygote , Humans , Infant , Mutation , Organic Anion Transporters, Sodium-Dependent/chemistry , Organic Anion Transporters, Sodium-Dependent/metabolism , Protein Stability , Symporters/chemistry , Symporters/metabolism
10.
Front Immunol ; 12: 641900, 2021.
Article in English | MEDLINE | ID: covidwho-1140646

ABSTRACT

Human leukocyte antigen (HLA) class I molecules play a crucial role in the development of a specific immune response to viral infections by presenting viral peptides at the cell surface where they will be further recognized by T cells. In the present manuscript, we explored whether HLA class I genotypes can be associated with the critical course of Coronavirus Disease-19 by searching possible connections between genotypes of deceased patients and their age at death. HLA-A, HLA-B, and HLA-C genotypes of n = 111 deceased patients with COVID-19 (Moscow, Russia) and n = 428 volunteers were identified with next-generation sequencing. Deceased patients were split into two groups according to age at the time of death: n = 26 adult patients aged below 60 and n = 85 elderly patients over 60. With the use of HLA class I genotypes, we developed a risk score (RS) which was associated with the ability to present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides by the HLA class I molecule set of an individual. The resulting RS was significantly higher in the group of deceased adults compared to elderly adults [p = 0.00348, area under the receiver operating characteristic curve (AUC ROC = 0.68)]. In particular, presence of HLA-A*01:01 allele was associated with high risk, while HLA-A*02:01 and HLA-A*03:01 mainly contributed to low risk. The analysis of patients with homozygosity strongly highlighted these results: homozygosity by HLA-A*01:01 accompanied early deaths, while only one HLA-A*02:01 homozygote died before 60 years of age. Application of the constructed RS model to an independent Spanish patients cohort (n = 45) revealed that the score was also associated with the severity of the disease. The obtained results suggest the important role of HLA class I peptide presentation in the development of a specific immune response to COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Genotype , HLA-A Antigens/genetics , SARS-CoV-2/genetics , Severity of Illness Index , Age Factors , Aged , Aged, 80 and over , Alleles , COVID-19/pathology , COVID-19/virology , Cohort Studies , Female , Gene Frequency , Genetic Testing/methods , High-Throughput Nucleotide Sequencing/methods , Homozygote , Humans , Male , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction
11.
Cochrane Database Syst Rev ; 3: CD003427, 2021 03 08.
Article in English | MEDLINE | ID: covidwho-1135064

ABSTRACT

BACKGROUND: Sickle cell disease (SCD) is a group of inherited disorders that result in haemoglobin abnormalities and other complications. Injury to the spleen, among other factors, contribute to persons with SCD being particularly susceptible to infection. Infants and very young children are especially vulnerable. The 'Co-operative Study of Sickle Cell Disease' observed an incidence rate for pneumococcal septicaemia of 10 per 100 person-years in children under the age of three years. Vaccines, including customary pneumococcal vaccines, may be of limited use in this age group. Therefore, prophylactic penicillin regimens may be advisable for this population. This is an update of a Cochrane Review which was first published in 2002, and previously updated, most recently in 2017.  OBJECTIVES: To compare the effects of antibiotic prophylaxis against pneumococcus in children with SCD receiving antibiotic prophylaxis compared to those without in relation to: 1. incidence of Streptococcus pneumoniae infection; 2. mortality (as reported in the included studies); 3. drug-related adverse events (as reported in the included studies) to the individual and the community; 4. the impact of discontinuing at various ages on incidence of infection and mortality. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which is comprised of references identified from comprehensive electronic database searches and also two clinical trials registries: ClinicalTrials.gov and the WHO International Registry Platform (not in 2020 given access issues relating to Covid-19 pandemic). Additionally, we carried out hand searching of relevant journals and abstract books of conference proceedings. Date of the most recent search: 25 January 2021. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing prophylactic antibiotics to prevent pneumococcal infection in children with SCD with placebo, no treatment or a comparator drug. DATA COLLECTION AND ANALYSIS: The standard methodological procedures expected by Cochrane were used. Both authors independently extracted data and assessed trial quality. The authors used the GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: Six trials were identified by the searches, of which three trials were eligible for inclusion. A total of 880 children, who were between three months to five years of age at randomization were included. The included studies were conducted in centres in the USA and in Kingston, Jamaica. In trials that investigated initiation of penicillin on risk of pneumococcal infection, the odds ratio was 0.37 (95% confidence interval 0.16 to 0.86) (two trials, 457 children) (low-certainty evidence), while for withdrawal the odds ratio was 0.49 (95% confidence interval 0.09 to 2.71) (one trial, 400 children) (low-certainty evidence). Adverse drug effects were rare and minor. Rates of pneumococcal infection were found to be relatively low in children over the age of five years. Overall, the certainty of the evidence for all outcomes was judged to be low. The results from the risk of bias assessment undertaken identified two domains in which the risk of bias was considered to be high, these were incomplete outcome data (attrition bias) (two trials) and allocation concealment (selection bias) (one trial). Domains considered to have a low risk of bias for all three trials were selective reporting (reporting bias) and blinding (performance and detection bias). AUTHORS' CONCLUSIONS: The evidence examined was determined to be of low certainty and suggests that prophylactic penicillin significantly reduces risk of pneumococcal infection in children with homozygous SCD, and is associated with minimal adverse reactions. Further research may help to determine the ideal age to safely withdraw penicillin.


Subject(s)
Anemia, Sickle Cell/complications , Antibiotic Prophylaxis , Penicillins/therapeutic use , Pneumococcal Infections/prevention & control , Age Factors , Anemia, Sickle Cell/genetics , Antibiotic Prophylaxis/adverse effects , Bias , Child, Preschool , Hemoglobin SC Disease/complications , Homozygote , Humans , Incidence , Infant , Medication Adherence , Penicillins/adverse effects , Pneumococcal Infections/epidemiology , Pneumococcal Infections/mortality , Randomized Controlled Trials as Topic , Streptococcus pneumoniae , beta-Thalassemia/complications
12.
J Lipid Res ; 62: 100061, 2021.
Article in English | MEDLINE | ID: covidwho-1117120

ABSTRACT

Individuals with features of metabolic syndrome are particularly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus associated with the severe respiratory disease, coronavirus disease 2019 (COVID-19). Despite considerable attention dedicated to COVID-19, the link between metabolic syndrome and SARS-CoV-2 infection remains unclear. Using data from the UK Biobank, we investigated the relationship between severity of COVID-19 and metabolic syndrome-related serum biomarkers measured prior to SARS-CoV-2 infection. Logistic regression analyses were used to test biomarker levels and biomarker-associated genetic variants with SARS-CoV-2-related outcomes. Among SARS-CoV-2-positive cases and negative controls, a 10 mg/dl increase in serum HDL-cholesterol or apolipoprotein A1 levels was associated with ∼10% reduced risk of SARS-CoV-2 infection, after adjustment for age, sex, obesity, hypertension, type 2 diabetes, and coronary artery disease. Evaluation of known genetic variants for HDL-cholesterol revealed that individuals homozygous for apolipoprotein E4 alleles had ∼2- to 3-fold higher risk of SARS-CoV-2 infection or mortality from COVID-19 compared with apolipoprotein E3 homozygotes, even after adjustment for HDL-cholesterol levels. However, cumulative effects of all evaluated HDL-cholesterol-raising alleles and Mendelian randomization analyses did not reveal association of genetically higher HDL-cholesterol levels with decreased risk of SARS-CoV-2 infection. These results implicate serum HDL-cholesterol and apolipoprotein A1 levels measured prior to SAR-CoV-2 exposure as clinical risk factors for severe COVID-19 infection but do not provide evidence that genetically elevated HDL-cholesterol levels are associated with SAR-CoV-2 infection.


Subject(s)
Apolipoprotein A-I , COVID-19 , Cholesterol, HDL , Homozygote , Metabolic Syndrome , SARS-CoV-2/metabolism , Adult , Aged , Apolipoprotein A-I/blood , Apolipoprotein A-I/genetics , Biomarkers/blood , COVID-19/blood , COVID-19/genetics , COVID-19/mortality , Cholesterol, HDL/blood , Cholesterol, HDL/genetics , Female , Humans , Male , Metabolic Syndrome/blood , Metabolic Syndrome/genetics , Metabolic Syndrome/mortality , Middle Aged , Patient Acuity , United Kingdom/epidemiology
13.
In Vivo ; 35(2): 965-968, 2021.
Article in English | MEDLINE | ID: covidwho-1100485

ABSTRACT

BACKGROUND/AIM: Adult outpatients with symptomatic COVID-19 treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. Fluvoxamine strongly binds to the sigma-1 receptor (S1R) that regulates inflammation by inhibiting the production of cytokines, believed to be responsible for severe COVID-19. We evaluated the S1R locus on chr 9p13.3 in subjects tested positive for SARS-CoV-2. We focused on SNP rs17775810 that has been previously identified by examining loss-of-function mutations in the S1R gene associated with distal hereditary motor neuropathy. PATIENTS AND METHODS: We utilized UK Biobank (UKB) data. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. RESULTS: The effect of rs17775810 genotype on survival was significant (p=0.036, 2 tailed Fisher exact test). The minor allele homozygotes (TT) had the lowest death rate (0%), whereas the non-TT genotypes (i.e. CT and CC) had the highest death rate (16.2%). CONCLUSION: The rs17775810 analysis corroborates the favorable effect of fluvoxamine on COVID-19 survival.


Subject(s)
Biological Specimen Banks/statistics & numerical data , COVID-19/genetics , Polymorphism, Single Nucleotide , Receptors, sigma/genetics , Alleles , Anti-Anxiety Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Cohort Studies , Female , Fluvoxamine/therapeutic use , Genotype , Homozygote , Humans , Male , Middle Aged , Receptors, sigma/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Survival Analysis , United Kingdom
17.
J Infect Dis ; 222(1): 34-37, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-599711

ABSTRACT

A major unanswered question in the current global coronavirus disease 2019 (COVID-19) outbreak is why severe disease develops in a small minority of infected individuals. In the current article, we report that homozygosity for the C allele of rs12252 in the interferon-induced transmembrane protein 3 (IFITM3) gene is associated with more severe disease in an age-dependent manner. This supports a role for IFITM3 in disease pathogenesis and the opportunity for early targeted intervention in at-risk individuals.


Subject(s)
Alleles , Betacoronavirus/genetics , Coronavirus Infections/genetics , Membrane Proteins/genetics , Pneumonia, Viral/genetics , Polymorphism, Single Nucleotide , RNA-Binding Proteins/genetics , Severity of Illness Index , Adult , Aged , Aged, 80 and over , COVID-19 , Cohort Studies , Coronavirus Infections/virology , Female , Genotype , High-Throughput Nucleotide Sequencing , Homozygote , Hospitalization , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/virology , Real-Time Polymerase Chain Reaction , SARS-CoV-2
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