Uma Kumar

Magnetic Resonance Features of Cerebral Malaria

Background: Cerebral malaria is a major health hazard, with a high incidence of mortality. The disease is endemic in many developing countries, but with a greater increase in tourism, occasional cases may be detected in countries where the disease in not prevalent. Early diagnosis and evaluation of cerebral involvement in malaria utilizing modern imaging modalities have an impact on the treatment and clinical outcome. Purpose: To evaluate the magnetic resonance (MR) features of patients with cerebral malaria presenting with altered sensorium. Material and Methods: We present the findings in three patients with cerebral malaria presenting with altered sensorium. MR imaging using a 1.5-Tesla unit was carried out. The sequences performed were 5-mm-thick T1-weighted, T2-weighted, fluid-attenuated inversion-recovery (FLAIR), and T2-weighted gradient-echo axial sequences, and sagittal and coronal FLAIR. Diffusion-weighted imaging was performed with b values of 0 and 1000 s/mm2, and apparent diffusion coefficient (ADC) maps were obtained. Results: Focal hyperintensities in the bilateral periventricular white matter, corpus callosum, occipital subcortex, and bilateral thalami were noticed on T2-weighted and FLAIR sequences. The lesions were more marked in the splenium of the corpus callosum. No enhancement on postcontrast T1-weighted MR images was observed. There was no evidence of restricted diffusion on the diffusion-weighted sequence and ADC map. Conclusion: MR is a sensitive imaging modality, with a role in the assessment of cerebral lesions in malaria. Focal white matter and corpus callosal lesions without any restricted diffusion were the key findings in our patients.

Genome-wide analysis of methotrexate pharmacogenomics in rheumatoid arthritis shows multiple novel risk variants and leads for TYMS regulation.

Objective Methotrexate (MTX) is the drug of first choice for the treatment of rheumatoid arthritis (RA), but is effective only in around 60% of the patients. Identification of genetic markers to predict response is essential for effective treatment within a critical window period of 6 months after diagnosis, but have been hitherto elusive. In this study, we used genome-wide genotype data to identify the potential risk variants associated with MTX (poor)response in a north Indian RA cohort. Materials and methods Genome-wide genotyping data for a total of 457 RA patients [297 good (DAS28-3⩽3.2) and 160 poor (DAS28-3≥5.1) responders] on MTX monotherapy were tested for association using an additive model. Support vector machine and genome-wide pathway analysis were used to identify additional risk variants and pathways. All risk loci were imputed to fine-map the association signals and identify causal variant(s) of therapeutic/diagnostic relevance. Results Seven novel suggestive loci from genome-wide (P⩽5×10−5) and three from support vector machine analysis were associated with MTX (poor)response. The associations of published candidate genes namely DHFR (P=0.014), FPGS (P=0.035), and TYMS (P=0.005) and purine and nucleotide metabolism pathways were reconfirmed. Imputation, followed by bioinformatic analysis indicated possible interaction between two reversely oriented overlapping genes namely ENOSF1 and TYMS at the post-transcriptional level. Conclusion In this first ever genome-wide analysis on MTX treatment response in RA patients, 10 new risk loci were identified. These preliminary findings warrant replication in independent studies. Further, TYMS expression at the post-transcriptional level seems to be probably regulated through an antisense-RNA involving the 6-bp ins/del marker in the overlapping segment at 3′UTR of TYMS-ENOSF1, a finding with impending pharmacogenetic applications.

A Genome‐Wide Association Study Reveals ARL15, a Novel Non‐HLA Susceptibility Gene for Rheumatoid Arthritis in North Indians

OBJECTIVE Genome-wide association studies (GWAS) and their subsequent meta-analyses have changed the landscape of genetics in rheumatoid arthritis (RA) by uncovering several novel genes. Such studies are heavily weighted by samples from Caucasian populations, but they explain only a small proportion of total heritability. Our previous studies in genetically distinct North Indian RA cohorts have demonstrated apparent allelic/genetic heterogeneity between North Indian and Western populations, warranting GWAS in non-European populations. We undertook this study to detect additional disease-associated loci that may be collectively important in the presence or absence of genes with a major effect. METHODS High-quality genotypes for >600,000 single-nucleotide polymorphisms (SNPs) in 706 RA patients and 761 controls from North India were generated in the discovery stage. Twelve SNPs showing suggestive association (P < 5 × 10(-5)) were then tested in an independent cohort of 927 RA patients and 1,148 controls. Additional disease-associated loci were determined using support vector machine (SVM) analyses. Fine-mapping of novel loci was performed by using imputation. RESULTS In addition to the expected association of the HLA locus with RA, we identified association with a novel intronic SNP of ARL15 (rs255758) on chromosome 5 (Pcombined = 6.57 × 10(-6); odds ratio 1.42). Genotype-phenotype correlation by assaying adiponectin levels demonstrated the functional significance of this novel gene in disease pathogenesis. SVM analysis confirmed this association along with that of a few more replication stage genes. CONCLUSION In this first GWAS of RA among North Indians, ARL15 emerged as a novel genetic risk factor in addition to the classic HLA locus, which suggests that population-specific genetic loci as well as those shared between Asian and European populations contribute to RA etiology. Furthermore, our study reveals the potential of machine learning methods in unraveling gene-gene interactions using GWAS data.

Disease activity and lipids in rheumatoid arthritis: a prospective study

Abstract Background Atherosclerotic cardiovascular disease (CVD) is the major cause for mortality in rheumatoid arthritis (RA). Dyslipidemia is an important risk factor for CVD and is influenced by the disease activity of RA. There is paucity of data on this subject in Indian patients with RA. Objectives To study the lipid levels in patients with RA and their relation with disease activity. Method The prospective study was carried out at a tertiary care centre in northern India. Results The study population included 96 patients with RA. Using the “high” cut-off values of National Cholesterol Education Programme–Adult Treatment Panel (NCEP-ATP III) as many as 38.5% (37/96) of patients exhibited dyslipidemia. Low high-density lipoprotein cholesterol (HDL-C) was the commonest abnormality seen in 34.3% of (33/96) patients. Disease activity scores (DAS-28) were at baseline and on a follow-up visit after 3 months they were 4.9 (1.02) and 4.4 (0.9), respectively (P = 0.003). With a decline in disease activity, a rising trend was observed for all lipids, statistically significant only for HDL. DAS-28 showed significant negative correlation with TC, r = 0.302 (0.003) and LDL-C, r = 0.274 (0.007). For HDL and TG, the correlation was not significant. Conclusion Lipid abnormalities are common in Indian patients with RA. Low HDL is the commonest abnormality. Disease activity is negatively related with lipids.

Unusual associations of pachydermoperiostosis: a case report.

Primary hypertrophic osteoarthropathy (HOA), or pachydermoperiostosis, is a rare benign disorder of unknown etiology. It is characterized by clubbing, periosteal reaction, and thickening of the skin. Disease usually progresses slowly, and natural arrest may occur. Reported herein is the case of a 28-year-old male patient with progressively increasing swelling of large joints of lower limbs with severe anemia. He was diagnosed as a case of pachydermoperiostosis with myelofibrosis, which is a rare association. The development of myelofibrosis makes primary HOA a disease with unfavorable outcome.

Rheumatoid Arthritis Revisited - Advanced Imaging Review.

Summary Rheumatoid Arthritis (RA) is a multisystem disorder, which causes significant morbidity. An early diagnosis of RA is essential to prevent the development of irreversible bone and joint changes. The disease has characteristic clinical features, but an early evaluation of the quantum of disease may be difficult with plain radiography alone. Recent developments in the imaging of RA have contributed significantly to an early diagnosis of the disease. In this article, we review the role and current status of various imaging modalities including recent advances in the evaluation and follow-up of early RA.

Dual energy computed tomography: a novel technique for diagnosis of gout

To evaluate the sensitivity and specificity of dual energy computed tomography (DECT) for diagnosing gout compared with a composite gold standard (CGS) comprising joint aspiration and/or American College of Rheumatology clinico‐radiographic criteria.

Tuberculous mycotic aneurysm of aortic root: an unusual cause of cardiac tamponade.

We describe a young male who presented to the emergency room with sudden onset dyspnea, and was found to have aortic root aneurysm with aortic regurgitation and cardiac tamponade. He underwent a Bentall procedure, and excised aortic root tissue showed epithelioid cell granulomas with panaortitis. He was started on anti-tubercular therapy, with which he improved. Although tubercular aortitis is fairly common, tuberculous mycotic aneurysm of the aorta is rare, with involvement of the aortic root being exceedingly uncommon. We report only the fifth case in English literature of tuberculous mycotic aneurysm of the aortic root.

Diagnostic utility of fluorodeoxyglucose positron emission tomography/computed tomography in pyrexia of unknown origin

Purpose of the Study: The present study was undertaken to evaluate the diagnostic utility of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) in patients presenting as pyrexia of unknown origin (PUO). Materials and Methods: Forty-seven patients (31 males and 16 females; mean age of 42.7 ± 19.96 years) presenting as PUO to the Department of Medicine at the All India Institute of Medical Sciences, New Delhi over a period of 2 years underwent F-18 FDG PET/CT. PET ⁄ CT was considered supportive when its results correlated with the final definitive diagnosis. Final diagnosis was made on the basis of combined evaluation of history, clinical findings, investigations, and response to treatment. Results: Thirty-five PET/CT studies (74.5%) were positive. However, only 18 (38.3%) were supportive of the final diagnosis. In three patients (6.4%), PET/CT was considered diagnostic as none of the other investigations including contrast-enhanced computed tomography of chest and abdomen, and directed tissue sampling could lead to the final diagnosis. All these three patients were diagnosed as aortoarteritis. Conclusion: Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography is an important emerging modality in the workup of PUO. It supported the final diagnosis in 38% of our patients and was diagnostic in 6.4% of patients. Thus, PET/CT should only be considered as second-line investigation for the diagnostic evaluation of PUO; especially in suspected noninfectious inflammatory disorders.

Leucocyte complement receptor 1 (CR1/CD35) transcript and its correlation with the clinical disease activity in rheumatoid arthritis patients

In view of the exaggerated complement activation in rheumatoid arthritis (RA) and significance of complement receptor 1 (CR1/CD35) as a complement regulatory protein (CRP), we aimed to determine the leucocyte‐complement receptor 1 (L‐CR1) transcript levels and the relationship of this protein with the clinical disease activity of RA patients. Sixty‐six controls and 45 RA patients were enrolled. L‐CR1 transcript levels were correlated with the levels of circulating immune complexes (CIC), C3, C4 and C3d in controls and patients and with disease activity score 28 (DAS28) in patients only. CIC levels were determined by polyethylene glycol (PEG) precipitation, C3 and C4 levels by nephlometry and C3d levels by enzyme‐linked immunosorbent assay (ELISA). Eleven patients were recruited for follow‐up of L‐CR1 and DAS28 levels at weeks 0, 12 and 24. Appropriate statistical methods were used for the data analysis. L‐CR1 (P < 0·01) transcript levels were decreased in patients compared to controls. L‐CR1 levels correlated negatively with DAS28, CIC and C3d. DAS28 correlated positively with levels of CIC, C3 and C3d. Levels of CIC correlated positively with C3 and C3d. Levels of C3 correlated positively with C3d in patients and with C4 in both controls and patients. Levels of L‐CR1 increased with decline in DAS28 scores in follow‐up patients. Observations were statistically significant. Lower levels of L‐CR1 transcript in patients compared to controls, their correlations with the levels of CIC, C3d and DAS28 at different time‐points in RA patients suggest CR1 as a potential disease marker for RA.