APOE and LRPAP1 gene polymorphism and risk of Parkinson’s disease

Epidemiologic findings suggest that lipids and alteration in lipid metabolizing protein/gene may contribute to the development of neurodegenerative disorders. The aim of the current study was to determine the serum lipid levels and genetic variation in two lipid metabolizing genes, low-density lipoprotein receptor-related protein-associated protein (LRPAP1) and apolipoprotein E (APOE) gene in Parkinson’s disease (PD). Based on well-defined inclusion and exclusion criteria, this study included 70 patients with PD and 100 age-matched controls. LRPAP1 and APOE gene polymorphism were analyzed by polymerase chain reaction and restriction fragment length polymorphism, respectively. Fasting serum lipid levels were determined using an autoanalyser. The logistic regression analysis showed that high levels of serum cholesterol [odds ratio (OR) = 1.101, 95 % confidence interval (CI_95%) = 1.067–1.135], LRPAP1 I allelic variant alone (OR = 2.766, CI_95% = 1.137–6.752) and in combination with APOE ε4 allelic variant (OR = 4.187, CI_95% = 1.621–10.82) were significantly associated with increase in PD risk. Apart from that, the high levels of LDL cholesterol appears to have a protective role (OR = 0.931, CI_95% = 0.897–0.966) against PD. The LRPAP1 I allelic variant may be considered a candidate gene for PD, predominantly in patients having the APOE ε4 allelic variant.     

The fludarabine,cytarabine, and granulocyte colony‐stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline‐based therapy for the treatment of acute myeloid leukemia for patients with pre‐existing cardiac disease

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony‐stimulating factor) as first‐line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline‐based treatment due to advanced age, significant comorbidities, or pre‐existing cardiac disease. The median age was 69 (21–80); 46% received FLAG for pre‐existing cardiac disease and others due to age (32%), non‐cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre‐existing cardiac disease. Among non‐transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse‐free survival was 14.7 months. The median overall survival was 9.3 months with 1‐ and 2‐yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline‐based induction for Acute myeloid leukemia in those with significant comorbidities including pre‐existing cardiac disease.     

Medical Research Misconduct Need Regulatory Reforms

The medical research misconduct has become a global problem. Except from countries like the USA, China, and Germany the exact figures of misconduct are not available. The research misconduct include fabricating the data, falsifying data, and plagiarism. The irresponsible research practices are publishing research data more than once, conflicts of interest is not declared, selective reporting of data and including an author who has not contributed at all and many more. About 2% of scientists have been found to admit the fabricating the data and 33% researchers were involved in irresponsible research practices. There is no formal regulatory programs available to monitor the research projects. Few developed countries like the USA, Germany, and China tried to develop programs which can monitor the medical research misconduct. There is a need to develop a regulatory system at national and institutional level to regulate the research activity to ensure that good ethical and scientific standards are practiced by medical researchers.     

Magnetocardiography for the Diagnosis of Coronary Artery Disease—A Systematic Review and Meta‐Analysis

Background: Coronary artery disease (CAD) has a significant disease burden making early diagnosis and management imperative. Magnetocardiography (MCG) is a relatively new noninvasive technique that allows diagnosis of CAD by recording the magnetic fields generated by the electrical activity of the heart. Methods: We searched MEDLINE and the Cochrane Central Register of Controlled Trials for prospective studies that evaluated the test characteristics (e.g., sensitivity, specificity, likelihood ratios) of MCG for detection of CAD. Studies were included if they evaluated either patients with stable CAD documented by angiogram or patients presenting initially with acute coronary syndrome and subsequently diagnosed with CAD. The quality of included studies was assessed using an adaptation of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. We performed meta‐analyses of sensitivity, specificity and positive and negative likelihood ratios using Meta‐DiSc software. Results: Screening of titles and abstracts followed by full‐text review yielded seven studies that met our inclusion criteria. Meta‐analyses yielded a pooled sensitivity of 83% (95% confidence interval [CI] 80% to 86%) and a specificity of 77% (95% CI 73% to 81%). The pooled positive likelihood ratio was 3.92 (95% CI 2.30 to 6.66) and negative likelihood ratio was 0.20 (95% CI 0.12 to 0.35). Significant heterogeneity was present in all meta‐analyses. Conclusions: The pooled test characteristics for MCG are similar to those of existing noninvasive modalities for diagnosing CAD. Our results suggest that MCG is a potential complementary or alternative tool for noninvasive detection of CAD.     

Granulomatous and lymphocytic hypophysitis – are they immunologically distinct?

Hypophysitis includes three histopathologically distinct entities – granulomatous, lymphocytic and xanthomatous forms. Etiopathogenesis and the immunological differences among these is not well characterized. This study aims to explore the immunopathogenesis of granulomatous and lymphocytic forms of hypophysitis. Demographic, clinical, endocrine function and radiological features of 33 histologically confirmed cases of hypophysitis were reviewed. Immunophenotyping of inflammatory component was performed in 13/33 cases. Visual disturbances (46%), headache (36%), polyuria/polydipsia (6%), menstrual disturbance (6%) and galactorrhoea (6%) were the frequent presenting symptoms. Endocrine abnormalities were noted in 11/18 cases evaluated (61%). Hypothyroidism was the most common endocrine abnormality (33.33%) followed by hyperprolactinaemia (22%) and hypocortisolism (16.66%). On neuroimaging, sellar mass with variable contrast enhancement was observed. On histology, granulomatous hypophysitis (GH) was more common (84.84%) than lymphocytic hypophysitis (LH) (15.15%). In GH, the infiltrate had almost equal proportions of CD3+ T cells and CD68+ histiocytes. Cytotoxic T cells (CD8+) predominated [CD4:CD8 < 1]. CD20+ B cell component ranged from <5% to 50%. Fibrosis, necrosis and giant cells accompanied GH. LH in contrast, had CD4+ T‐helper cell predominance [CD4: CD8 > 1]. CD68+ histiocytes constituted <20% and CD20+ B cells, 5–40% of the infiltrates. In conclusion, GH revealed cytotoxic T cell and histiocyte rich infiltrate in contrast to CD4+ T‐cell predominance in LH suggesting that the two forms have distinct immunological mechanisms in evolution, an autoimmune process in LH and type IV hypersensitivity response in GH.     

The Impact of Comprehensive Care for Joint Replacement Bundled Payment Program on Care Delivery

Background

Comprehensive Care for Joint Replacement (CJR) is a Medicare initiative to test the impact of holding a hospital accountable for services provided during an episode of care for a lower extremity joint arthroplasty on costs and quality. This study examines whether hospital participation in CJR is associated with having programs focused on improving posthospitalization care or reducing costs using a survey of orthopedic surgeons.

Methylmalonic acidemia mimicking diabetic ketoacidosis and septic shock in infants

Methylmalonic acidemia (MMA) is most common inherited type of organic acidemia. It has diverse presentation in older infants without any initial apparent symptoms. MMA sometimes present with sudden metabolic decompensation, which may mimics common emergencies like septic shock and diabetic ketoacidosis (DKA) without early recognition can be fatal. In born error of metabolism especially organic acidemia should be suspected in any infant presented with severe high anion gap metabolic acidosis. We report two cases of MMA in infants presented acutely mimicking DKA and septic shock.     

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.     

Conserved residues in yeast initiator tRNA calibrate initiation accuracy by regulating preinitiation complex stability at the start codon

Eukaryotic initiator tRNA (tRNA_i) contains several highly conserved unique sequence features, but their importance in accurate start codon selection was unknown. Here we show that conserved bases throughout tRNA_i, from the anticodon stem to acceptor stem, play key roles in ensuring the fidelity of start codon recognition in yeast cells. Substituting the conserved G31:C39 base pair in the anticodon stem with different pairs reduces accuracy (the Sui⁻ [suppressor of initiation codon] phenotype), whereas eliminating base pairing increases accuracy (the Ssu⁻ [suppressor of Sui⁻] phenotype). The latter defect is fully suppressed by a Sui⁻ substitution of T-loop residue A54. These genetic data are paralleled by opposing effects of Sui⁻ and Ssu⁻ substitutions on the stability of methionylated tRNA_i (Met-tRNA_i) binding (in the ternary complex [TC] with eIF2-GTP) to reconstituted preinitiation complexes (PICs). Disrupting the C3:G70 base pair in the acceptor stem produces a Sui⁻ phenotype and also reduces the rate of TC binding to 40S subunits in vitro and in vivo. Both defects are suppressed by an Ssu⁻ substitution in eIF1A that stabilizes the open/P_OUT conformation of the PIC that exists prior to start codon recognition. Our data indicate that these signature sequences of tRNA_i regulate accuracy by distinct mechanisms, promoting the open/P_OUT conformation of the PIC (for C3:G70) or destabilizing the closed/P_IN state (for G31:C39 and A54) that is critical for start codon recognition.