Prenatal paracetamol exposure and risk of asthma and elevated immunoglobulin E in childhood

BACKGROUND: We recently found that paracetamol (acetaminophen) use in late pregnancy was associated with an increased risk of early wheezing in the offspring. OBJECTIVE: To see whether use of paracetamol in late pregnancy is associated with an increased risk of asthma, wheezing and other atopic outcomes in the child at school age. METHODS: In the population-based Avon Longitudinal Study of Parents and Children, we measured associations of paracetamol and aspirin use in late pregnancy (20-32 weeks) with asthma, hayfever, eczema (n = 8511) and wheezing (8381) in the offspring at 69-81 months, and with atopy (positive skin prick test to Dermatophagoides pteronyssinus, cat or grass, n = 6527) and blood total IgE (n = 5148) at 7 years. We used logistic and linear regression to analyse binary outcomes and log-transformed IgE, respectively, controlling for potential confounders. RESULTS: Use of paracetamol, but not aspirin, in late pregnancy was positively associated with asthma (odds ratios (ORs), comparing children whose mothers took paracetamol 'sometimes' and 'most days/daily' with those whose mothers never took it, 1.22 (95% confidence interval (CI): 1.06-1.41) and 1.62 (95% CI: 0.86-3.04), respectively; P trend = 0.0037), wheezing (ORs 1.20 (95% CI: 1.02-1.40) and 1.86 (95% CI: 0.98-3.55), respectively; P trend = 0.011), and total IgE (geometric mean ratios 1.14 (95% CI: 1.03-1.26) and 1.52 (95% CI: 0.98-2.38), respectively; P trend = 0.0034), but not hayfever, eczema or skin test positivity. The proportion of asthma attributable to paracetamol use in late pregnancy, assuming a causal relation, was 7%. CONCLUSION: Paracetamol exposure in late gestation may cause asthma, wheezing and elevated IgE in children of school age.     

Infective endocarditis due to Salmonella typhi--a case report

Endocarditis is a rare complication of typhoid fever. We report a case in which Salmonella enterica serotype typhi was isolated from a case of endocarditis. The isolate was resistant to ampicillin, chloramphenicol and ciprofloxacin but sensitive to ceftriaxone, amikacin and gentamicin.     

The clinical significance of methylenetetrahydrofolate reductase (MTHFR) polymorphisms in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Genetic polymorphisms in the folate metabolic pathway may contribute to the susceptibility to childhood ALL because they affect the DNA synthesis, methylation, and repair. The most common polymorphisms are methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C. The current study aimed at detecting the frequency of these two genetic polymorphisms in de novo ALL patients, and to clarify their impact on the response to induction chemotherapy, as well as treatment toxicity. MTHFR C677T and A1298C polymorphisms were tested in 30 de novo ALL patients by restriction fragment length polymerase chain reaction technique. Thirty normal age- and sex-matched subjects were subjected to the same analysis as a control group. The frequency of MTHFR A1298C gene polymorphism was significantly lower in ALL patients than the controls thus showing a protective effect. The two polymorphisms had no effect on the response to induction chemotherapy. As regards the treatment toxicity, MTHFR C677T polymorphism was associated with marked thrombocytopenia, while A1298C polymorphism was associated with hepatic toxicity. Identifying predictors of methotrexate sensitivity may lead to the development of individualized treatment strategies with improved efficacy and reduced toxicity as well as adjusting the initial methotrexate dose.     

The osteogenic differentiation potentials of umbilical cord blood hematopoietic stem cells

Under specific culture conditions, umbilical cord blood derived mesenchymal stem cells (MSCs) can differentiate into osteogenic, adipogenic, and chondrogenic lineages. The purpose of the current study was to assess the differentiation potential of osteogenic umbilical cord blood derived hematopoietic stem cells (HSCs) and to develop an appropriate osteogenic differentiation medium for in vitro differentiation of umbilical cord blood derived HSCs. The study was conducted on 20 cord blood samples. The cells were cultured in osteogenic differentiating medium for 3?weeks. The HSCs differentiated into osteoblasts, which expressed osteoblast-associated genes (osteocalcin and bone sialoprotein), which were detected by RT-PCR. They showed alkaline phosphatase activity and a positive Alizarin red-S (AR-S) stain (calcium phosphate deposition). Umbilical cord blood is a rich source of hematopoietic stem cells that can be differentiated into osteoblasts; thus, it can be used for therapeutic strategies in the context of regenerative therapy.     

Erratum to: Engineering cotton (Gossypium hirsutum L.) for resistance to cotton leaf curl disease using viral truncated AC1 DNA sequences

Virus Genes - An error notified in the labelling of Fig.&;nbsp;1b, 3′tAC1 has been erroneously published as 5′tAC1.     

Second-degree Heart Block Caused by Itolizumab-induced Infusion Reaction in COVID-19

How to cite this article: Kumar A, Kumar N, Lenin D, Kumar A, Ahmad S. Second-degree Heart Block Caused by Itolizumab-induced Infusion Reaction in COVID-19. Indian J Crit Care Med 2021;25(4):474–475.

Sir,Itolizumab, an anti-CD6 humanized IgG1 monoclonal antibody, binds to domain-1 of CD-6 that is responsible for priming, activation, and differentiation of T-cells.^[1] It significantly reduces T-cell proliferation along with substantial downregulation of the production of cytokines/chemokines.¹ It was approved for moderate to severe chronic plaque psoriasis in 2013. However, it has recently been approved by the Drug Controller General of India for emergency use in India for the treatment of cytokine release syndrome in moderate to severe acute respiratory distress syndrome patients due to COVID-19.² Here, we report a case of life-threatening infusion-related hypersensitivity reaction of itolizumab.A 65-year-old male COVID-19 patient got admitted to the intensive care unit (ICU) with complaints of shortness of breath and cough without any history of known disease. However, the baseline electrocardiogram (ECG) done in the ICU was suggestive of left bundle branch block (LBBB) (Fig. 1A). The patient was supported through noninvasive ventilation (NIV) and was started on remdesivir, dexamethasone, low-molecular-weight heparin, antibiotics, and other supportive treatment as per our institutional standard protocol. The patient was maintaining on continuous positive airway pressure mode of NIV with a fraction of inspired oxygen (FiO₂) of 0.5 on the third day of ICU admission. Among the laboratory markers, the total leucocyte counts were raised (12,000/μL) with decreased lymphocytes (3.2%) and increased inflammatory markers (CRP, 320 mg/L; D dimer >20 μg/mL; LDH, 1694 U/L; IL6, 329 pg/mL). Serum electrolytes, renal function tests, liver function tests, and arterial blood gases were within acceptable limits. The patient was hemodynamically stable with a respiratory rate of 30 to 35/minute and a PO₂/FiO₂ ratio of 140. After taking informed written consent, inj. itolizumab was planned in this patient because of the increasing severity of the disease along with increased inflammatory markers. Inj. hydrocortisone 100 mg IV and inj. pheniramine 30 mg IV were given 30 minutes before itolizumab infusion. And 100 mg of itolizumab (Alzumab-L, Biocon Biologics) was diluted to 250 mL with normal saline and was started at 25 mL/hour. After about 20 minutes of infusion, the patient started complaining of shivering, sweating, and impending doom. The patient had sudden bronchospasm, and oxygen saturation dropped to 90%. ECG showed second-degree AV nodal block with an increased blood pressure of 180/110 mm Hg (Fig. 1B). The drug was immediately withdrawn and the patient was given a repeat dose of hydrocortisone and pheniramine along with other supportive measures. After sometime patients became alert and their respiratory symptoms were relieved. However, the second-degree heart block in ECG was persistent. ECHO was normal and troponin I was within normal limits while there was a slight increase in CPK-MB. The patient was observed closely and the ECG reverted to its previous state only after 24 hours. The patient was weaned from the ventilator in due course of time and put on face mask on the eighth day of stay.Open in a separate windowFigs 1A and B(A) Baseline ECG showing LBBB; (B) ECG showing second-degree AV nodal block after infusion reactionMost infusion reactions related to monoclonal antibodies are IgE mediated and are mild (grade 1 or 2) in nature.³ The incidence of severe (grade 3 or 4) reactions is generally low. The reported infusion-related reactions to itolizumab are chills/rigors (common), nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, wheezing, dyspnea, oxygen desaturation, dizziness, headache, and hypertension. In our case, itolizumab infusion leads to a grade 4 reaction causing a persistent second-degree heart block for about 24 hours. Among the monoclonal antibodies, rituximab is most notorious for causing infusion reactions.⁴ There are only a few reports of cardiac arrhythmias (monomorphic VT, supraventricular tachycardia, trigeminy, and irregular pulse) during therapeutic infusion of rituximab,⁵ and there is no reported case of cardiac arrhythmia during itolizumab infusion. In our case, the patient was having LBBB and was on a QT prolonging drug (remdesivir), which might be a predisposing factor for the occurrence of second-degree heart block during infusion reaction. Premedications (e.g., antipyretics, antihistamines, and steroids) are recommended before the administration of some chemotherapeutic agents and monoclonal antibodies. These drugs should never be given as IV bolus and should always be given slowly in an infusion. Baseline assessments including vital signs and cognition should be documented carefully before the start of treatment and all the emergency equipment and drugs should be kept ready. Grade 3 and 4 reactions should be managed promptly with epinephrine, antihistaminics, and steroids along with other symptomatic supportive measures. As itolizumab is approved for emergency use in COVID-19, risk-benefit ratio should be assessed before prescribing this and should be explained before taking consent for infusion.The patient provided written informed consent for the publication.     

A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1^CP) in two siblings with CP. POT1^CP induced a proliferative arrest that could be bypassed by telomerase. POT1^CP was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1^CP was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1^CP was also defective in the maintenance of the telomeric C strand, causing extended 3′ overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).     

Genetic investigation of 93 families with microphthalmia or posterior microphthalmos

Microphthalmia is a developmental eye defect that is highly variable in severity and in its potential for systemic association. Despite the discovery of many disease genes in microphthalmia, at least 50% of patients remain undiagnosed genetically. Here, we describe a cohort of 147 patients (93 families) from our highly consanguineous population with various forms of microphthalmia (including the distinct entity of posterior microphthalmos) that were investigated using a next‐generation sequencing multi‐gene panel (i‐panel) as well as whole exome sequencing and molecular karyotyping. A potentially causal mutation was identified in the majority of the cohort with microphthalmia (61%) and posterior microphthalmos (82%). The identified mutations (55 point mutations, 15 of which are novel) spanned 24 known disease genes, some of which have not or only very rarely been linked to microphthalmia (PAX6, SLC18A2, DSC3 and CNKSR1). Our study has also identified interesting candidate variants in 2 genes that have not been linked to human diseases (MYO10 and ZNF219), which we present here as novel candidates for microphthalmia. In addition to revealing novel phenotypic aspects of microphthalmia, this study expands its allelic and locus heterogeneity and highlights the need for expanded testing of patients with this condition.