Single-molecule analysis reveals widespread structural variation in multiple myeloma.

Multiple myeloma (MM), a malignancy of plasma cells, is characterized by widespread genomic heterogeneity and, consequently, differences in disease progression and drug response. Although recent large-scale sequencing studies have greatly improved our understanding of MM genomes, our knowledge about genomic structural variation in MM is attenuated due to the limitations of commonly used sequencing approaches. In this study, we present the application of optical mapping, a single-molecule, whole-genome analysis system, to discover new structural variants in a primary MM genome. Through our analysis, we have identified and characterized widespread structural variation in this tumor genome. Additionally, we describe our efforts toward comprehensive characterization of genome structure and variation by integrating our findings from optical mapping with those from DNA sequencing-based genomic analysis. Finally, by studying this MM genome at two time points during tumor progression, we have demonstrated an increase in mutational burden with tumor progression at all length scales of variation.

An integrative genomic approach identifies p73 and p63 as activators of miR-200 microRNA family transcription.

Although microRNAs (miRNAs) are important regulators of gene expression, the transcriptional regulation of miRNAs themselves is not well understood. We employed an integrative computational pipeline to dissect the transcription factors (TFs) responsible for altered miRNA expression in ovarian carcinoma. Using experimental data and computational predictions to define miRNA promoters across the human genome, we identified TFs with binding sites significantly overrepresented among miRNA genes overexpressed in ovarian carcinoma. This pipeline nominated TFs of the p53/p63/p73 family as candidate drivers of miRNA overexpression. Analysis of data from an independent set of 253 ovarian carcinomas in The Cancer Genome Atlas showed that p73 and p63 expression is significantly correlated with expression of miRNAs whose promoters contain p53/p63/p73 family binding sites. In experimental validation of specific miRNAs predicted by the analysis to be regulated by p73 and p63, we found that p53/p63/p73 family binding sites modulate promoter activity of miRNAs of the miR-200 family, which are known regulators of cancer stem cells and epithelial-mesenchymal transitions. Furthermore, in chromatin immunoprecipitation studies both p73 and p63 directly associated with the miR-200b/a/429 promoter. This study delineates an integrative approach that can be applied to discover transcriptional regulatory mechanisms in other biological settings where analogous genomic data are available.

Prevalence and Pattern of Ocular Diseases Among Children Aged 7-14 Years Visiting a Tertiary Care Teaching Hospital in Central India.

PURPOSE:  Ocular morbidity in children hinders their overall development. The prevalence and pattern vary amongst countries as well as within a country. Many ocular diseases if diagnosed and treated on time can prevent ocular morbidity in children to a large extent. The aim of this study is to determine the prevalence and pattern of ocular diseases in children (7-14 years) presenting to the All India Institute of Medical Sciences, Bhopal, a tertiary care teaching hospital in central India. METHODS:  This is a single-center, hospital-based cross-sectional study conducted from June 2018 to August 2019. A total of 1276 children between 7 and 14 years of age were included. A thorough ocular examination was done and a diagnosis was noted. Statistical analysis was performed using Microsoft Excel, Version 2013 (Microsoft Corp., Redmond, WA) and IBM SPSS Statistics for Windows, Version 23 (IBM Corp., Armonk, NY). A p-value of <0.05 was considered significant.  Results: Out of 1276 children, 505 (39.6%) were of 7-10 years while 771 (60.4%) were of 11-14 years. There were 563 females (44.1%) and 713 males (55.9%). The most common ocular morbidity was a refractive error, (653; 51.1%), it was significantly higher in the age group 11 to 14 years than in children of 7 to 10 years of age (p<0.03). The second most prevalent ocular morbidity was infection/inflammation of the adnexa (18.8%) of which males were affected more than females (p<0.0005). The other morbidities were squint and neuro-ophthalmological-related diseases (8.3%), followed by trauma (3%), congenital diseases (2.6%), amblyopia (2.4%), degenerative diseases (0.7%), neoplastic (< 0.01%), and miscellaneous disorders (1.6%). CONCLUSION: The majority of ocular disorders are preventable and treatable. The most common ocular morbidity in our study is refractive error. We recommend school-based screening programs for timely detection and correction of refractive error and to prevent amblyopia.

nhanesA: achieving transparency and reproducibility in NHANES research.

The National Health and Nutrition Examination Survey provides comprehensive data on demographics, sociology, health and nutrition. Conducted in 2-year cycles since 1999, most of its data are publicly accessible, making it pivotal for research areas like studying social determinants of health or tracking trends in health metrics such as obesity or diabetes. Assembling the data and analyzing it presents a number of technical and analytic challenges. This paper introduces the nhanesA R package, which is designed to assist researchers in data retrieval and analysis and to enable the sharing and extension of prior research efforts. We believe that fostering community-driven activity in data reproducibility and sharing of analytic methods will greatly benefit the scientific community and propel scientific advancements. Database URL: https://github.com/cjendres1/nhanes.

Anterior Chamber Biometric Parameters Associated With Intraocular Pressure Reduction After Phacoemulsification in Non-Glaucomatous Eyes With Open Angles.

BACKGROUND: Decreased intra-ocular pressure after cataract surgery has been reported in eyes with and without glaucoma with variable magnitude. It is influenced by the anatomical structure of the anterior chamber. Preoperative evaluation of anterior chamber parameters can help to predict the change in intra-ocular pressure postoperatively. OBJECTIVE: The objective of the study is to evaluate intraocular pressure (IOP) change after uneventful phacoemulsification in non-glaucomatous eyes with open angles and its correlation with preoperative anterior chamber parameters measured by anterior segment optical coherence tomography (AS-OCT). METHODS: In this hospital-based prospective observational study, we included consecutive patients without glaucoma and open angles on gonioscopy who had undergone uncomplicated phacoemulsification with intraocular lens implantation (IOL). IOP and anterior chamber biometric parameters were measured preoperatively and compared with parameters obtained three months post-operatively by AS-OCT. The change in IOP and its relation to the parameters, including anterior chamber angle (ACA), anterior chamber depth (ACD), angle opening distance 500 µm anterior to the scleral spur (AOD500), anterior chamber width (ACW), lens vault (LV), and trabecular iris space area (TISA500) were evaluated. The main outcome measure was a change in IOP after phacoemulsification in normal eyes. RESULTS: Sixty-four eyes of 64 patients were enrolled. The mean patient age was 58.5 ± 9.4 years. The average IOP reduction was 2.43±1.64 mm of Hg from a preoperative mean of 16.77±2.54 mmHg three months after phacoemulsification surgery. The mean AOD500 increased significantly (0.440 ± 0.07 to 0.522 ±0.092) from preoperatively to three months postoperatively (p < 0.001). Preoperative lens vault and preoperative IOP had a strong positive correlation with the change in IOP at three months (r-value = 0.606; p-value <0.001) and (r-value = 0.73; p-value <0.001). There was a significant negative correlation between pre-operative TISA and AOD with change in IOP at three months (r-value = -0.545; p-value <0.001) and (r-value = -0.69; p-value <0.01). CONCLUSION:  Phacoemulsification surgery results in IOP reduction in non-glaucomatous eyes. Pre-operative IOP, lens vault, AOD, and TISA were significant predictors for IOP reduction.

Sperm intrusion into the implantation-stage blastocyst and its potential biological significance.

The human embryo derives from fusion of oocyte and sperm, undergoes growth and differentiation, resulting in a blastocyst. To initiate implantation, the blastocyst hatches from the zona pellucida, allowing access from external inputs. Modelling of uterine sperm distribution indicates that 200-5000 sperm cells may reach the implantation-stage blastocyst following natural coitus. We show ultrastructural evidence of sperm cells intruding into trophectoderm cells of zona-free blastocysts obtained from the uterus of rhesus monkeys. Interaction between additional sperm and zona-free blastocyst could be an evolutionary feature yielding adaptive processes influencing the developmental fate of embryos. This process bears potential implications in pregnancy success, sperm competition and human health.

Visual performance and patient satisfaction with AcrySof® IQ Vivity® IOL: Experience from a tertiary care center in central India.

PURPOSE: To study the visual outcomes and patient satisfaction profile among patients post phacoemulsification with the Vivity intraocular lens (IOL) implantation. METHOD: This was a hospital-based, prospective, observational study cons isting of 64 study subjects who were followed up for 1 month to look for the objective and subjective aspects of visual outcomes of Vivity IOLs. Objective parameters included distance vision, intermediate vision, near vision, and contrast-sensitivity, whereas subjective parameters were assessed using the modified Catquest 9SF Questionnaire. RESULTS: Among the total study population, 82.5% were males and 17.5% were females, the most common age group was 41-50 years. In addition, 93.6% had a distance visual acuity of 6/9 or better, 93.7% had an intermediate vision of N18 or better, whereas 50.8% had a near vision of N18 or better. Good contrast sensitivity was reported among 79.4% of subjects, and 95.2% of study subjects were comfortable with distance vision, whereas 74.6% and 22.2% were comfortable with intermediate and near vision, respectively. Only two patients complained of glare, whereas none complained of halos and starbursts. A total of 88.8% of study subjects were satisfied with their postoperative visual outcomes, whereas 87.3% were willing to Vivity IOL in the other eye or were willing to refer this IOL to others. CONCLUSION: The study demonstrated a good distance and intermediate visual acuity post-Vivity IOL implantation, whereas near activities mostly required the use of near-addition glasses, though requiring lesser near-addition power.

Discovery of structural alterations in solid tumor oligodendroglioma by single molecule analysis.

BACKGROUND: Solid tumors present a panoply of genomic alterations, from single base changes to the gain or loss of entire chromosomes. Although aberrations at the two extremes of this spectrum are readily defined, comprehensive discernment of the complex and disperse mutational spectrum of cancer genomes remains a significant challenge for current genome analysis platforms. In this context, high throughput, single molecule platforms like Optical Mapping offer a unique perspective. RESULTS: Using measurements from large ensembles of individual DNA molecules, we have discovered genomic structural alterations in the solid tumor oligodendroglioma. Over a thousand structural variants were identified in each tumor sample, without any prior hypotheses, and often in genomic regions deemed intractable by other technologies. These findings were then validated by comprehensive comparisons to variants reported in external and internal databases, and by selected experimental corroborations. Alterations range in size from under 5 kb to hundreds of kilobases, and comprise insertions, deletions, inversions and compound events. Candidate mutations were scored at sub-genic resolution and unambiguously reveal structural details at aberrant loci. CONCLUSIONS: The Optical Mapping system provides a rich description of the complex genomes of solid tumors, including sequence level aberrations, structural alterations and copy number variants that power generation of functional hypotheses for oligodendroglioma genetics.

High-resolution human genome structure by single-molecule analysis.

Variation in genome structure is an important source of human genetic polymorphism: It affects a large proportion of the genome and has a variety of phenotypic consequences relevant to health and disease. In spite of this, human genome structure variation is incompletely characterized due to a lack of approaches for discovering a broad range of structural variants in a global, comprehensive fashion. We addressed this gap with Optical Mapping, a high-throughput, high-resolution single-molecule system for studying genome structure. We used Optical Mapping to create genome-wide restriction maps of a complete hydatidiform mole and three lymphoblast-derived cell lines, and we validated the approach by demonstrating a strong concordance with existing methods. We also describe thousands of new variants with sizes ranging from kb to Mb.

Study of rhino-orbital-cerebral mucormycosis and its correlates during COVID-19 pandemic in a tertiary eye care institute of central India.

PURPOSE: To evaluate factors associated with the occurrence of ROCM in COVID-19 patients and to compare its related parameters and outcomes between active and recovered COVID-19 groups. METHODS: A total of 35 patients of ROCM associated with COVID-19 (active and post-COVID-19) were included. This is an ambispective study with retrospective medical records review for COVID-19 analysis and prospective assessments of ROCM-associated COVID-19 during the second wave of the COVID-19 pandemic. The demographic data, clinical parameters, and outcome were recorded on MS excel sheet, and various parameters were compared between active and recovered COVID-19 groups. RESULTS: ROCM in recovered COVID-19 group was higher (57.1%) as compared to active COVID-19 (42.9%) (P = 1.00). High occurrence of ROCM was seen in those who had a history of hospitalization due to severity of COVID-19 (n 33, 94.28%), oxygen support (77.14), and received systemic steroids (82.9%). The most common comorbidity was diabetes mellitus (82.9%), and new-onset hyperglycemia was noticed in 17.1% of patients. Exenteration (28.6%) was performed in severe cases who had stage IV ROCM, bilateral, and CNS involvement (RR = 7.2, 95% CI: 2.91 to 18.00). The risk of globe exenteration was 1.35 (0.7-2.29) times higher in recovered COVID-19 group, and mortality was 1.76 (0.72-3.36) times higher in active COVID-19 group. CONCLUSION: Monitored use of systemic steroids and the prompt management of hyperglycemia in COVID-19 patients are important factors for favorable outcomes with reference to globe salvage and life-saving in ROCM associated with COVID-19. Even recovered COVID-19 patients should be observed for persistent hyperglycemia and occurrence of ROCM.

Age-related cataract - Prevalence, epidemiological pattern and emerging risk factors in a cross-sectional study from Central India.

Purpose: To study the epidemiological pattern, prevalence, types, and correlates of age-related cataracts in a tertiary care center in central India. Methods: This hospital-based single-center cross-sectional study was conducted on 2,621 patients diagnosed with cataracts for 3 years. Data pertaining to demography, socio-economic profile, cataract grading, cataract types, and associated risk factors were evaluated. Statistical analysis using unadjusted odds ratio (OR) and multivariate logistic regression was performed, with P-value <0.05 considered significant with the power of the study being 95%. Results: The commonest age group affected was 60-79 years, closely followed by the 40-59 years age group. The prevalence of nuclear sclerosis (NS), cortical (CC), and posterior subcapsular cataract (PSC) was found to be 65.2% (3,418), 24.6% (1,289), and 43.4% (2,276), respectively. Among mixed cataracts, (NS + PSC) had the highest prevalence of 39.8%. Smokers were found to have 1.17 times higher odds of developing NS than non-smokers. Diabetics had 1.12 times higher odds of developing NS cataracts and 1.04 times higher odds of developing CC. Patients with hypertension showed 1.27 times higher odds of developing NS and 1.32 times higher odds of developing CC. Conclusion: The prevalence of cataracts in the pre-senile age group (<60 years) was found to have increased significantly (35.7%). A higher prevalence of PSC (43.4%) was found in studied subjects, as compared to the data of previous studies. Smoking, diabetes, and hypertension were found to have a positive association with a higher prevalence of cataracts.

Rhino-orbito-cerebral mucormycosis and its resurgence during COVID-19 pandemic: A review.

This study aimed to review the current literature for epidemiology, pathogenesis, clinical spectrum and management of rhino-orbito-cerebral-mucormycosis (ROCM), especially highlighting the association between ROCM and COVID-19 disease and factors resulting in its resurgence during the pandemic. Mucormycosis is a rare, but an important emerging opportunistic fungal infection, often associated with high morbidity and mortality. ROCM is the commonest and also the most aggressive clinical form occurring in debilitated patients in conjunction with sinus or para-sinus involvement due to the propensity for contiguous spread. Recently ROCM has shown an unprecedented resurgence during the current pandemic. Reports from different parts of the world indicated an increased risk and incidence of ROCM in patients who had required hospital admission and have recovered from moderate-to-severe COVID-19 disease. A majority of mucormycosis cases have been reported from India. The presence of diabetes mellitus (DM) and use of corticosteroids for COVID-19 pneumonia were found to be the key risk factors, resulting in higher mortality. Amidst the ongoing pandemic, with the third wave already having affected most of the world, it becomes imperative to adopt a risk-based approach toward COVID-19 patients predisposed to developing ROCM. This could be based on the most recently published literature and emerging data from centers across the world. The present review intended to elucidate the causes that brought about the current spike in ROCM and the importance of its early detection and management to reduce mortality, loss of eye, and the need for mutilating debridement.

Case of leprosy mimicking preseptal cellulitis: a diagnostic dilemma.

A 36-year-old Asian man presented with swelling over the left frontal region involving the upper eyelids, with associated erythema and tenderness for 1 month duration. Clinically he was diagnosed as a case of preseptal cellulitis, however, the lesion did not improve on broad-spectrum systemic antibiotics. CT showed superficial soft tissue swelling in the forehead extending till the superior part of orbit. Histopathological assessment of the lesion revealed clusters of epithelioid cells with multinucleate giant cells in the dermis along with perivascular and periadnexal lymphocytic infiltrates, suggestive of leprosy. The patient was started on oral steroids with multidrug therapy, following which the patient showed early resolution of the lesion within 10 days of treatment. Leprosy is endemic in India, leprosy with reactional episodes mimics other inflammatory and infective etiologies making diagnosis difficult. Leprosy should be present in an ophthalmologist's diagnostic repertoire while dealing with periorbital swellings for early clinical diagnosis and favourable outcomes.

Ocular manifestations of RT-PCR-confirmed COVID-19 cases in a large database cross-sectional study.

OBJECTIVE: To evaluate ocular manifestations of reverse transcriptase (RT)-PCR-confirmed SARS-CoV-2-infected patients in a validated comparative model, and additionally to evaluate the correlation between severity of COVID-19 and ocular manifestations. METHODS AND ANALYSIS: In a prospective cross-sectional study, a total of 2400 subjects were enrolled over a period of 8 months. To eliminate bias of identical ocular symptom profile in other non-COVID-19 respiratory infections and to acquire a comparative model, 1200 COVID-19 RT-PCR-positive patients (group 1) and 1200 RT-PCR-negative patients (group 2) were included. Data collection included use of a prestructured tool and 'Google-forms', along with stratification of patients into 'mild, moderate, and severe' categories. Study subjects were evaluated for ocular manifestations by clinical examination and laboratory work-up. Univariate and multivariate logistic regression analyses were performed. RESULTS: 144 (12%) patients in group 1 had ocular symptoms as compared with 24 (2%) patients in group 2 (p<0.001). Ocular manifestations (symptoms and signs) comprising burning sensation (6.7%, p<0.001), foreign body sensation and irritation (7.0%, p<0.001), and conjunctival signs (2.7%, p<0.001) were found statistically significant in group 1 as compared with group 2. Ocular involvement increased in proportion to severity of COVID-19: mild (5.3%), moderate (24.6%) and severe (58.8%) (p=0.0006). CONCLUSION: The frequency of occurrence of ocular manifestations was higher in group 1 as opposed to group 2. Furthermore, the presence of ocular manifestations carried a direct correlation with severity of systemic disease and presence of comorbidities.

Corticosteroids in the Management of Infectious Keratitis: A Concise Review.

Microbial keratitis is devastating corneal morbidity with a variable spectrum of clinical manifestations depending on the infective etiology. Irrespective of the varied presentation delayed treatment can lead to severe visual impairment resulting from corneal ulceration, possible perforation, and subsequent scarring. Corticosteroids with a potent anti-inflammatory activity reduce host inflammation, thus minimizing resultant scarring while improving ocular symptoms. These potential effects of corticosteroids have been applied widely to treat various corneal diseases ranging from vernal keratoconjunctivitis to dry eye disease. However, antimicrobial therapy remains the mainstay of treatment in microbial keratitis, whereas the use of adjunctive topical corticosteroid therapy remains a matter of debate. Understandably, the use of topical corticosteroids is a double-edged sword with pros and cons in the treatment of microbial keratitis. Herein we review the rationale for and against the use and safety of topical corticosteroids in the treatment of infective keratitis. Important considerations, including type, dose, efficacy, the timing of initiation of corticosteroids, use of concomitant antimicrobial agents, and duration of corticosteroid therapy while prescribing corticosteroids for microbial keratitis, have been discussed. This review intends to provide new insights into the therapeutic utility of steroids as adjunctive treatment of corneal ulcer.

Epidemiology, clinical profile, management, and outcome of COVID-19-associated rhino-orbital-cerebral mucormycosis in 2826 patients in India - Collaborative OPAI-IJO Study on Mucormycosis in COVID-19 (COSMIC), Report 1.

Purpose: COVID-19-associated rhino-orbital-cerebral mucormycosis (ROCM) has reached epidemic proportion during India's second wave of COVID-19 pandemic, with several risk factors being implicated in its pathogenesis. This study aimed to determine the patient demographics, risk factors including comorbidities, and medications used to treat COVID-19, presenting symptoms and signs, and the outcome of management. Methods: This was a retrospective, observational study of patients with COVID-19-associated ROCM managed or co-managed by ophthalmologists in India from January 1, 2020 to May 26, 2021. Results: Of the 2826 patients, the states of Gujarat (22%) and Maharashtra (21%) reported the highest number of ROCM. The mean age of patients was 51.9 years with a male preponderance (71%). While 57% of the patients needed oxygen support for COVID-19 infection, 87% of the patients were treated with corticosteroids, (21% for > 10 days). Diabetes mellitus (DM) was present in 78% of all patients. Most of the cases showed onset of symptoms of ROCM between day 10 and day 15 from the diagnosis of COVID-19, 56% developed within 14 days after COVID-19 diagnosis, while 44% had delayed onset beyond 14 days. Orbit was involved in 72% of patients, with stage 3c forming the bulk (27%). Overall treatment included intravenous amphotericin B in 73%, functional endoscopic sinus surgery (FESS)/paranasal sinus (PNS) debridement in 56%, orbital exenteration in 15%, and both FESS/PNS debridement and orbital exenteration in 17%. Intraorbital injection of amphotericin B was administered in 22%. At final follow-up, mortality was 14%. Disease stage >3b had poorer prognosis. Paranasal sinus debridement and orbital exenteration reduced the mortality rate from 52% to 39% in patients with stage 4 disease with intracranial extension (p < 0.05). Conclusion: : Corticosteroids and DM are the most important predisposing factors in the development of COVID-19-associated ROCM. COVID-19 patients must be followed up beyond recovery. Awareness of red flag symptoms and signs, high index of clinical suspicion, prompt diagnosis, and early initiation of treatment with amphotericin B, aggressive surgical debridement of the PNS, and orbital exenteration, where indicated, are essential for successful outcome.

flowCore: a Bioconductor package for high throughput flow cytometry.

BACKGROUND: Recent advances in automation technologies have enabled the use of flow cytometry for high throughput screening, generating large complex data sets often in clinical trials or drug discovery settings. However, data management and data analysis methods have not advanced sufficiently far from the initial small-scale studies to support modeling in the presence of multiple covariates. RESULTS: We developed a set of flexible open source computational tools in the R package flowCore to facilitate the analysis of these complex data. A key component of which is having suitable data structures that support the application of similar operations to a collection of samples or a clinical cohort. In addition, our software constitutes a shared and extensible research platform that enables collaboration between bioinformaticians, computer scientists, statisticians, biologists and clinicians. This platform will foster the development of novel analytic methods for flow cytometry. CONCLUSION: The software has been applied in the analysis of various data sets and its data structures have proven to be highly efficient in capturing and organizing the analytic work flow. Finally, a number of additional Bioconductor packages successfully build on the infrastructure provided by flowCore, open new avenues for flow data analysis.

Age-related impairment of the transcriptional responses to oxidative stress in the mouse heart.

To investigate the transcriptional response to oxidative stress in the heart and how it changes with age, we examined the cardiac gene expression profiles of young (5-mo-old), middle-aged (15-mo-old), and old (25-mo-old) C57BL/6 mice treated with a single intraperitoneal injection of paraquat (50 mg/kg). Mice were killed at 0, 1, 3, 5, and 7 h after paraquat treatment, and the gene expression profile was obtained with high-density oligonucleotide microarrays. Of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle-aged mice, and 256 transcripts in the old mice displayed a significant change in mRNA levels (ANOVA, P < 0.01). Among these, a total of 55 transcripts were determined to be paraquat responsive for all age groups. Genes commonly induced in all age groups include those associated with stress, inflammatory, immune, and growth factor responses. Interestingly, only young mice displayed a significant increase in expression of all three isoforms of GADD45, a DNA damage-responsive gene. Additionally, the number of immediate early response genes (IEGs) found to be induced by paraquat was considerably higher in the younger animals. These results demonstrate that, at the transcriptional level, there is an age-related impairment of specific inducible pathways in the response to oxidative stress in the mouse heart.

Impairment of the transcriptional responses to oxidative stress in the heart of aged C57BL/6 mice.

To investigate the transcriptional response to oxidative stress in the heart and how it changes with age, we examined the cardiac gene expression profiles of young (5 months old), middle-aged (15 months old), and old (25 months old) C57BL/6 mice treated with a single intraperitoneal injection of paraquat (50 mg/kg). Mice were killed at 0, 1, 3, 5, and 7 hours after paraquat treatment, and the gene expression profile was obtained with high-density oligonucleotide microarrays. Of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle-aged mice, and 256 transcripts in the old mice displayed a significant change in mRNA levels (ANOVA, P <.01). Among these, a total of 55 transcripts were determined to be paraquat responsive for all age groups. Genes commonly induced in all age groups include those associated with stress, inflammatory, immune, and growth factor responses. Interestingly, only young mice displayed a significant increase in expression of all three isoforms of GADD45, a DNA damage-responsive gene. Additionally, the number of immediate early genes found to be induced by paraquat was considerably higher in the younger animals. These results demonstrate that, at the transcriptional level, there is an age-related impairment of specific inducible pathways in the response to oxidative stress in the mouse heart.