Does telomere length mediate associations between inbreeding and increased risk for bipolar I disorder and schizophrenia?

We have recently found that consanguinity is a risk factor for bipolar I disorder (BP1) and schizophrenia (SZ) in Egypt. Inbreeding has been associated with increased cellular stress and impaired physiological function in plants and animals. Previous studies have reported that telomere length (TL), an index of oxidative stress and cellular senescence is significantly reduced among patients with SZ or mood disorders compared with control individuals. Hence we evaluated TL as a possible mediator of the observed association between consanguinity and BP1/SZ risk. Patients with BP1 (n = 108), or SZ (n = 60) were compared with screened adult controls in separate experiments. TL was estimated using a quantitative PCR (qPCR) based assay. The inbreeding coefficient/consanguinity rate was estimated in two ways: using 64 DNA polymorphisms (‘DNA-based’ rate); and from family history data (‘self report’). Significant correlation between TL and DNA based inbreeding was not observed overall, though suggestive trends were present among the SZ cases. No significant case-control differences in TL were found after controlling for demographic variables. In conclusion, reduced TL may not explain a significant proportion of observed associations between consanguinity and risk for BP1/SZ.     

A network of dopaminergic gene variations implicated as risk factors for schizophrenia

We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia (SZ). In stage I, we screened 18 dopamine-related genes in two independent US Caucasian samples: 150 trios and 328 cases/501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT and SLC18A2 (alias VMAT2). In stage II, we comprehensively evaluated these four genes by genotyping 68 SNPs in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < or = 0.05). We sought epistasis between pairs of SNPs providing evidence of a main effect and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. In stage III, we confirmed our findings by genotyping 65 SNPs among 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were overtransmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (p(joint) < 0.05). We tested 29 putative interactions from stage II and detected replication between seven locus pairs (p < or = 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). In stage IV we evaluated rs464049 and rs3756450 for functional effects and found significant allele-specific differences at rs3756450 using electrophoretic mobility shift assays and dual-luciferase promoter assays. Our data suggest that a network of dopaminergic polymorphisms increase risk for SZ.     

Strains of Mycobacterium tuberculosis from Western Maharashtra,India, Exhibit a High Degree of Diversity and Strain-Specific Associations with Drug Resistance,Cavitary Disease,and Treatment Failure

We performed spoligotyping of Mycobacterium tuberculosis isolates from 833 systematically sampled pulmonary tuberculosis (TB) patients in urban Mumbai, India (723 patients), and adjacent rural areas in western India (110 patients). The urban cohort consisted of two groups of patients, new cases (646 patients) and first-time treatment failures (77 patients), while only new cases were recruited in the rural areas. The isolates from urban new cases showed 71% clustering, with 168 Manu1, 62 CAS, 22 Beijing, and 30 EAI-5 isolates. The isolates from first-time treatment failures were 69% clustered, with 14 Manu1, 8 CAS, 8 Beijing, and 6 EAI-5 isolates. The proportion of Beijing strains was higher in this group than in urban new cases (odds ratio [OR], 3.29; 95% confidence limit [95% CL], 1.29 to 8.14; P = 0.003). The isolates from rural new cases showed 69% clustering, with 38 Manu1, 7 CAS, and 1 EAI-5 isolate. Beijing was absent in the rural cohort. Manu1 was found to be more common in the rural cohort (OR, 0.67; 95% CL, 0.42 to 1.05; P = 0.06). In total, 71% of isolates were clustered into 58 spoligotypes with 4 predominant strains, Manu1 (26%), CAS (9%), EAI-5 (4%), and Beijing (4%), along with 246 unique spoligotypes. In the isolates from urban new cases, we found Beijing to be associated with multidrug resistance (MDR) (OR, 3.40; 95% CL, 1.20 to 9.62; P = 0.02). CAS was found to be associated with pansensitivity (OR, 1.83; 95% CL, 1.03 to 3.24; P = 0.03) and cavities as seen on chest radiographs (OR, 2.72; 95% CL, 1.34 to 5.53; P = 0.006). We recorded 239 new spoligotypes yet unreported in the global databases, suggesting that the local TB strains exhibit a high degree of diversity.The resurgence of tuberculosis (TB) fuelled by multidrug resistance (MDR) and extensive drug resistance has caused significant concern among health care practitioners (36, 37). There have been renewed efforts to understand the biology of the pathogen alongside its epidemiology. Such data have come mostly from regions of sporadic incidence or from populations where the disease is driven by high HIV prevalence (8). Data from some of the highest-disease-burden regions, where tuberculosis has remained endemic, are scarce.India is one such region where Mycobacterium tuberculosis has remained in equilibrium with the population, resulting in an area of tuberculosis endemicity (6, 27). Under such conditions, the strain diversity is expected to be different compared to that for epidemic or sporadic incidents, where a few specific strain types dominate (8, 23); in a setting where tuberculosis is endemic, the pathogen and the host are expected to evolve simultaneously for long durations, resulting in a set of varied strain types (6, 20, 21).Studies from India show differential strain predominance between the southern and northern regions of the country. While the central Asian strain (CAS) is dominant in the north, East African Indian strains (EAI) are observed more frequently in the southern regions (29). Most studies from India as well as specifically from Mumbai, India, showed CAS and Manu1 as the predominant spoligotypes along with EAI as a third large strain lineage (3, 16, 18, 22, 28, 29, 30). Another study from a tertiary care center in Mumbai reported a high proportion of Beijing strains (23%) in a cohort associated with a high proportion of MDR (1). Interestingly, TbD1-positive strains of tuberculosis (such as EAI) predominate in India, whereas TbD1-negative strains of M. tuberculosis are more common in the rest of the world (11).Although previous studies provided preliminary data from various sites in India, they did not reflect strain variability from a single cosmopolitan region. Additionally, studies from Mumbai were biased toward MDR cases (1), had small sample sizes (16), or were derived from a cohort of chronic (re-treated) TB cases accessing tertiary care hospitals (22).Epidemiological studies of M. tuberculosis have been facilitated by a variety of genotyping tools. IS6110 restriction fragment length polymorphism (RFLP) remains the gold standard due to its high level of discrimination (15) but is time-consuming and less suitable in populations with low copy numbers (7). Mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing (10, 19, 31) is a high-throughput and discriminatory method, but the best combination of MIRU loci is yet to be achieved, and combinations may differ between populations (33). We used spoligotyping as a primary fingerprint method, due to its relatively high throughput nature. Spoligotyping has a lower discriminatory power than MIRU-VNTR typing, making it less suitable for determining strain transmission. However, spoligotyping served as a useful primary fingerprinting tool allowing comparisons of strain types from strains around the world through updated global databases (5, 17, 35).In this study, we describe the distribution of strain genotypes from a systematic collection of strains from urban Mumbai and two neighboring rural areas. Mumbai is a location where a confluence of people from all parts of the country live in poor, congested neighborhoods with high population densities, up to 64,168 people per square kilometer in one of the city wards as per the 2001 census (26). These conditions, coupled with a high proportion of MDR cases in the region (2, 9), were cause for concern and underlined the need for more information on local circulating strains. We wished to determine the distribution of strains among newly diagnosed TB patients in the region to extend previous observations (16, 22).This study describes the spoligotypes present in the cohort and the extent of their clustering. We further analyzed the association of spoligotypes with other parameters, namely, age, gender, geographical origin of the host, radiology, and multidrug resistance, to obtain deeper insights into strain behavior.     

Compass in COVID-19 Illness: Disseminated Intravascular Coagulation/Sepsis-induced Coagulopathy Scoring in Predicting Severity

How to cite this article: Zirpe KG, Bamne SN. Compass in COVID-19 Illness: Disseminated Intravascular Coagulation/Sepsis-induced Coagulopathy Scoring in Predicting Severity. Indian J Crit Care Med 2021;25(12):1333–1334.     

Evaluation of HLA Polymorphisms in Relation to Schizophrenia Risk and Infectious Exposure

Background:

Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ). Other studies implicate viral and protozoan exposure. Our study tests chromosome 6p SNPs for effects on SZ risk with and without exposure. Method: GWAS-significant SNPs and ancestry-informative marker SNPs were analyzed among African American patients with SZ (n = 604) and controls (n = 404). Exposure to herpes simplex virus, type 1 (HSV-1), cytomegalovirus (CMV), and Toxoplasma gondii (TOX) was assayed using specific antibody assays. Results: Five SNPs were nominally associated with SZ, adjusted for population admixture (P < .05, uncorrected for multiple comparisons). These SNPs were next analyzed in relation to infectious exposure. Multivariate analysis indicated significant association between rs3130297 genotype and HSV-1 exposure; the associated allele was different from the SZ risk allele. Conclusions: We propose a model for the genesis of SZ incorporating genomic variation in the HLA region and neurotropic viral exposure for testing in additional, independent African American samples.Key words: HLA, gene, HSV-1, cytomegalovirus, schizophrenia, African American, kwd>     

Do Glycemic Markers Predict Occurrence of Complications After Total Knee Arthroplasty in Patients With Diabetes?

Background

Patients with diabetes have increased risk of infections and wound complications after total knee arthroplasty (TKA). Glycemic markers identifying patients at risk for complications after TKA have not yet been elucidated.

Questions/purposes

We aimed to determine the correlations among four commonly used glycemic markers and to identify the glycemic markers most strongly associated with the occurrence of surgical site infections and postoperative wound complications in patients with diabetes mellitus after undergoing TKA.

Methods

Our retrospective study included 462 patients with diabetes, who underwent a total of 714 TKAs. Blood levels of glycemic markers, including preoperative fasting blood glucose (FBG), postprandial glucose (PPG2), glycated hemoglobin (HbA_1c), and levels obtained from random glucose testing on postoperative days 2, 5, and 14, were collected on all patients as part of a medical clearance program and an established clinical pathway for patients with diabetes at our center. Complete followup was available on 93% (462 of 495) of the patients. Correlations among markers were assessed. Associations between the markers and patient development of complications were analyzed using multivariate regression analyses of relevant cutoff values. We considered any of the following as complications potentially related to diabetes, and these were considered study endpoints: surgical site infection (superficial and deep) and wound complications (drainage, hemarthrosis, skin necrosis, and dehiscence). During the period of study, there were no fixed criteria applied to what levels of glycemic control patients with diabetes needed to achieve before undergoing arthroplasty, and there were wide ranges in the levels of all glycemic markers; for example, whereas the mean HbA_1c level was 7%, the range was 5% to 11.3%.

Results

There were positive correlations among the levels of the four glycemic markers; the strongest correlation was found between the preoperative HbA_1c and PPG2 levels (R = 0.502, p < 0.001). After controlling for potential confounding variables using multivariate analysis, the HbA_1c cutoff level of 8 (odds ratio [OR], 6.1; 95% confidence interval [CI], 1.6–23.4; p = 0.008) and FBG 200 mg/dL or higher (OR, 9.2; 95% CI, 2.2–38.2; p = 0.038) were associated with superficial surgical site infection after TKA.

Conclusions

In general, there is a positive correlation among the various available glycemic markers among patients with diabetes undergoing TKA, and patients undergoing surgery with HbA_1c ≥ 8 and/or FBG ≥ 200 mg/dL were associated with superficial surgical site infection. These findings should be considered in patient selection and preoperative counseling for patients with diabetes undergoing TKA.

Level of Evidence

Level III, prognostic study.

Electronic supplementary material

The online version of this article (doi:10.1007/s11999-014-4056-1) contains supplementary material, which is available to authorized users.     

A cross-sectional study to compare the normal corneal epithelial thickness in various age groups of Indian population using 9 mm wide optical coherence tomography scans

Purpose:To compare the corneal epithelial thickness among various age groups of normal Indians with 9-mm-wide optical coherence tomography scans.Methods:This cross sectional, observational study recruited patients in the age groups of 5–20 years (group 1), 21–35 years (group 2), 36–50 years (group 3), and more than 51 years (group 4). They underwent a detailed ophthalmic examination and were excluded if found to have any ocular surface or intraocular disease (except cataract and refractive error), undergone any ophthalmic surgery, corneal topography changes suggestive of corneal ectasias, or been continuously using any topical medication in either eye for a period of 3 months or more with the last instillation being within 1 month of inclusion in the study. Corneal epithelial thickness (CET) was measured using anterior segment optical coherence tomography (AS-OCT). The CET data from 25 sectors in each eye were analyzed for each age group.Results:There were 71 subjects in group 1, 76 subjects in group 2, 59 subjects in group 3, and 57 subjects in group 4. The mean (± standard deviation) ages in the groups 1, 2, 3, and 4 were 14.04 ± 5.10, 26.63 ± 4.71, 42.66 ± 3.92, and 61.65 ± 7.47 years, respectively. The central corneal thickness in all age groups was comparable. Maximum variance in CET parameters was seen in superior cornea.Conclusion:Central corneal thickness remains fairly stable over various age groups. The maximum variance in CET over age is seen in superior cornea. The findings from the Indian population correlate well with racially and geographically distinct subjects.