Characterization of m6A Modifiers and RNA Modifications in Uterine Fibroids.

Uterine leiomyoma or fibroids are prevalent noncancerous tumors of the uterine muscle layer, yet their origin and development remain poorly understood. We analyzed RNA expression profiles of 15 epigenetic mediators in uterine fibroids compared to myometrium using publicly available RNA sequencing (RNA-seq) data. To validate our findings, we performed RT-qPCR on a separate cohort of uterine fibroids targeting these modifiers confirming our RNA-seq data. We then examined protein profiles of key N6-methyladenosine (m6A) modifiers in fibroids and their matched myometrium, showing no significant differences in concordance with our RNA expression profiles. To determine RNA modification abundance, mRNA and small RNA from fibroids and matched myometrium were analyzed by ultra-high performance liquid chromatography-mass spectrometry identifying prevalent m6A and 11 other known modifiers. However, no aberrant expression in fibroids was detected. We then mined a previously published dataset and identified differential expression of m6A modifiers that were specific to fibroid genetic subtype. Our analysis also identified m6A consensus motifs on genes previously identified to be dysregulated in uterine fibroids. Overall, using state-of-the-art mass spectrometry, RNA expression, and protein profiles, we characterized and identified differentially expressed m6A modifiers in relation to driver mutations. Despite the use of several different approaches, we identified limited differential expression of RNA modifiers and associated modifications in uterine fibroids. However, considering the highly heterogenous genomic and cellular nature of fibroids, and the possible contribution of single molecule m6A modifications to fibroid pathology, there is a need for greater in-depth characterization of m6A marks and modifiers in a larger and diverse patient cohort.

Characterization of m6A modifiers and RNA modifications in uterine fibroids.

Uterine leiomyoma or fibroids are the most common prevalent noncancerous tumors of the uterine muscle layer. Common symptoms associated with fibroids include pelvic pain, heavy menstrual bleeding, anemia, and pelvic pressure. These tumors are a leading cause of gynecological care but lack long-term therapy as the origin and development of fibroids are not well understood. Several next-generation sequencing technologies have been performed to identify the underlying genetic and epigenetic basis of fibroids. However, there remains a systemic gap in our understanding of molecular and biological process that define uterine fibroids. Recent epitranscriptomics studies have unraveled RNA modifications that are associated with all forms of RNA and are thought to influence both normal physiological functions and the progression of diseases. We quantified RNA expression profiles by analyzing publicly available RNA-seq data for 15 known epigenetic mediators to identify their expression profile in uterine fibroids compared to myometrium. To validate our findings, we performed RT-qPCR on a separate cohort of uterine fibroids targeting these modifiers confirming our RNA-seq data. We then examined protein profiles of key m6A modifiers in fibroids and their matched myometrium. In concordance with our RNA expression profiles, no significant differences were observed in these proteins in uterine fibroids compared to myometrium. To determine abundance of RNA modifications, mRNA and small RNA from fibroids and matched myometrium were analyzed by UHPLC MS/MS. In addition to the prevalent N6-methyladenosine (m6A), we identified 11 other known modifiers but did not identify any aberrant expression in fibroids. We then mined a previously published dataset and identified differential expression of m6A modifiers that were specific to fibroid genetic sub-type. Our analysis also identified m6A consensus motifs on genes previously identified to be dysregulated in uterine fibroids. Overall, using state-of-the-art mass spectrometry, RNA expression and protein profiles, we characterized and identified differentially expressed m6A modifiers in relation to driver mutations. Despite the use of several different approaches, we identified limited differential expression of RNA modifiers and associated modifications in uterine fibroids. However, considering the highly heterogenous genomic and cellular nature of fibroids, and the possible contribution of single molecule m6A modifications to fibroid pathology, there is a need for greater in-depth characterization of m6A marks and modifiers in a larger and varied patient cohort.

Prevalence of depression and anxiety in older people in low- and middle- income countries in Africa, Asia and South America: A systematic review and meta-analysis.

BACKGROUND: There is rapid growth of older people in Low- and Middle- Income Countries (LMICs). The aim of this review was to assess the literature on prevalence of anxiety and depression in this demographic, which to our knowledge, has not yet been conducted. METHODS: Databases including Medline, PsychInfo, Embase, Scielo and African Journals Online were searched for terms including "mental disorders", "neurotic disorders", "mood disorders" and "anxiety disorders". Studies published between 1990 and 2020 providing data on older people (≥50 years) in LMICs (defined by World Bank Criteria) were included and quality-assessed. Meta-analysis was conducted on a subset of higher-quality studies to derive pooled prevalence estimates of depression. RESULTS: One hundred and forty relevant studies were identified, of which thirty-two were included in meta-analysis. One hundred and fifteen studies reported depression prevalence only, 19 reported both depression and anxiety, and six reported anxiety only. In all studies identified, depression prevalence ranged from 0.5 % to 62.7 %, and Generalised Anxiety Disorder prevalence ranged from 0.2 % to 32.2 %. The pooled prevalence of depression on meta-analysis was 10.5 % (95 % CI, 8.9 % - 11.2 %). Reported prevalence rates of depression were significantly different in studies using ICD-10 compared with DSM criteria, and between community and clinical settings. LIMITATIONS: The search strategy contained bias towards English language papers and high income country (HIC) publications. There is significant heterogeneity within the meta-analysis. DISCUSSION: A wide range of methodologies and clinical criteria are used in prevalence studies of depression and anxiety in older people. Studies using screening tools found higher prevalence rates; clinicians and researchers should ensure diagnosis is made with gold-standard clinical criteria. Meta-analysis data suggest that rates of depression are similar in older people in LMICs compared to HICs but mental healthcare resources are limited, suggesting a large potential treatment gap.

Enhancing the Resistive Switching Behavior of WORM Memory Devices Using D-π-A Based Ester-Flanked Quinolines.

Donor-Acceptor systems are highly appreciated in the field of organic memory devices due to their efficient charge transport within the systems. In this work, we have designed and synthesized a D-π-A system constituting ester-flanked quinolines and functionalized triarylamines (TAA) through a single-step cross-coupling reaction to fabricate memory devices via Write-Once Read-Many times (WORM) non-volatile memory. Structure-property relationships are reconnoitered for these conjugated D-π-A systems through a series of UV, fluorescence, XRD, DFT, and memory characterizations. The UV and CV data show efficient charge transfer with intramolecular charge transfer occurring at 407-417 nm and a short band gap of 2.56-2.65 eV. An enhancement in the resistive switching behavior of the memory devices is observed for the compounds with simple TAA-quinoline and tert-butylphenyl substituted TAA and fluorophenyl substituted quinoline due to balanced charge distribution in the compounds. This enhanced switching induces an on/off ratio of 103 by generating a highly ordered arrangement in the thin films. The HOMO, LUMO levels, and the ESP images together estimate a charge transfer and charge trapping as the plausible mechanism for the solution-processable WORM memory devices. The longer retention time (103  s) and lower threshold voltages (-1.21--2.12 V) of the devices makes them intriguing compounds for memory applications.

Role of TLR4 in the induction of inflammatory changes in adipocytes and macrophages.

In obesity, high levels of saturated fatty acids (SFAs) contribute to adipose tissue inflammation and dysfunction. Obesity-induced macrophage infiltration leads to insulin resistance, but the adipocyte itself may play a role in generating the inflammatory milieu. Given our recent findings of the role of TLR4 in myeloid biasing in obesity, we next investigated the role of TLR4 in adipocyte generated inflammatory responses to SFAs and lipopolysaccharides. We used WT and Tlr4-/- ear mesenchymal stem cell derived adipocytes (EMSC Ad) and bone marrow dendritic cells (BMDCs) to evaluate cell specific responses. Our work demonstrates a role for TLR4 in adipocyte- immune cell crosstalk and that SFA derived metabolites from adipocytes may induce proinflammatory stimulation of immune cells in a TLR4 independent manner.

Delaying clozapine: how long is too long?

BACKGROUND: Although clozapine is the most effective drug for treatment-resistant schizophrenia, its use remains restricted in clinical practice in India. The delay in initiating treatment with clozapine and its impact on disease outcome needs evaluation. AIM: To identify the implications of delaying clozapine initiation in clinical outcomes among people with treatment-resistant schizophrenia. METHODS: Subjects with treatment-resistant schizophrenia, stabilised on clozapine monotherapy, were recruited from the outpatient clinic of a general hospital psychiatry unit offering tertiary care services in Thrissur district, Kerala, India. A retrospective cohort design was employed, and information on duration of illness, total duration of treatment and duration of treatment with clozapine was collected. Present symptom status was measured using the Positive and Negative Syndrome Scale. Factors associated with higher symptom scores were analysed using an independent sample t test, Spearman correlation and multiple linear regression. RESULTS: Forty subjects stabilised on long-term clozapine therapy formed the study sample. The mean dose of clozapine used in the study population was 200 mg. The mean duration of antipsychotic treatment before starting clozapine was 89.3 months (7.4 years). The duration of treatment before starting clozapine was found to have a significant positive association with the total Positive and Negative Syndrome Scale score (correlation coefficient 0.40; p=0.01) and negative symptom score (correlation coefficient 0.33; p=0.04). The multiple regression analysis adjusting for covariates showed that the duration of treatment before starting clozapine was an independent factor associated with a higher negative symptom score in the Positive and Negative Syndrome Scale (slope ß=0.05; p=0.02; R2=0.27). CONCLUSION: Poor treatment outcomes in treatment-resistant schizophrenia could be secondary to a delay in initiating clozapine therapy.

Using fathers as a negative control exposure: Implications of measurement bias.

Negative control exposure analysis is a very effective tool in evaluating the effect of unmeasured confounding in observational epidemiological studies. Several biases, including recall bias, time-varying confounding factors, measurement bias and so on, can affect the credibility of negative control exposure analysis for causal interpretations. The article focuses on the implications of differential measurement error across exposed group and negative controls to causal interpretations on negative control exposure analysis.

Programming effects of maternal and gestational obesity on offspring metabolism and metabolic inflammation.

With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of this on offspring. The purpose of this study is to investigate the programming effects of maternal obesity during preconception and the preconception/gestational period on adiposity and adipose tissue inflammation in offspring using an animal model. Adult female C57Bl/6J mice were assigned either normal diet, high fat diet (HFD) prior to pregnancy, or HFD prior to and through pregnancy. Some offspring were maintained on normal diet while others started HFD later in life. Offspring were assessed for body composition and metabolic responses. Lipid storing tissues were evaluated for expansion and inflammation. Male offspring from the preconception group had the greatest weight gain, most subcutaneous adipose tissue, and largest liver mass when introduced to postnatal HFD. Male offspring of the preconception/gestation group had worsened glucose tolerance and an increase in resident (CD11c-) adipose tissue macrophages (ATMs) when exposed to postnatal HFD. Female offspring had no significant difference in any parameter between the diet treatment groups. In conclusion, this study demonstrates that prenatal and pregnancy windows have independent programming effects on offspring. Preconception exposure affects body composition and adiposity while gestation exposure affects metabolism and tissue immune cell phenotypes.

Reverse total shoulder arthroplasty using a trabecular metal glenoid base plate: functional and radiological outcomes at two to five years.

AIM: We present the medium-term clinical results of a reverse total shoulder arthroplasty with a trabecular metal glenoid base plate. PATIENTS AND METHODS: We reviewed 125 consecutive primary reverse total shoulder arthroplasties (RTSA) implanted in 124 patients for rotator cuff arthropathy. There were 100 women and 24 men in the study group with a mean age of 76 years (58 to 89). The mean follow-up was 32 months (24 to 60). No patient was lost to follow-up. RESULTS: There were statistically significant improvements in the mean range of movement and Oxford Shoulder Score (p < 0.001). Kaplan-Meier survivorship at five years was 96.7% (95% confidence interval 91.5 to 98.7) with aseptic glenoid failure as the end point. Radiologically, 63 shoulders (50.4%) showed no evidence of notching, 51 (40.8%) had grade 1 notching, ten (8.0%) had grade 2 notching and one (0.8%) had grade 4 notching. Radiolucency around the glenoid base plate was found in one patient (0.8%) and around the humeral stem in five (4.0%). In all, three RTSA (2.4%) underwent revision surgery for aseptic mechanical failure of the glenoid within 11 months of surgery due to malseating of the glenosphere. CONCLUSION: The clinical results of this large independent single unit series are comparable to those from previous series of RTSA reported in the literature. A trabecular metal base plate is safe and effective in the medium-term. Cite this article: Bone Joint J 2016;98-B:969-75.

A study of structural and functional connectivity in early Alzheimer's disease using rest fMRI and diffusion tensor imaging.

BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative condition where in early diagnosis and interventions are key policy priorities in dementia services and research. We studied the functional and structural connectivity in mild AD to determine the nature of connectivity changes that coexist with neurocognitive deficits in the early stages of AD. METHODS: Fifteen mild AD subjects and 15 cognitively healthy controls (CHc) matched for age and gender, underwent detailed neurocognitive assessment and magnetic resonance imaging (MRI) of resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Rest fMRI was analyzed using dual regression approach and DTI by voxel wise statistics. RESULTS: Patients with mild AD had significantly lower functional connectivity (FC) within the default mode network and increased FC within the executive network. The mild AD group scored significantly lower in all domains of cognition compared with CHc. But fractional anisotropy did not significantly (p < 0.05) differ between the groups. CONCLUSION: Resting state functional connectivity alterations are noted during initial stages of cognitive decline in AD, even when there are no significant white matter microstructural changes.

The use of shoulder scoring systems and outcome measures in the UK.

INTRODUCTION: In future, outcomes following shoulder surgery may be subject to public survey. Many outcome measures exist but we do not know whether there is a consensus between shoulder surgeons in the UK. The aim of this study was to survey the preferred outcome measures used by National Health Service (NHS) shoulder surgeons operating in the UK. METHODS: A total of 350 shoulder surgeons working in NHS hospitals were asked to complete a short written questionnaire regarding their use of scoring systems and outcome measures. Questionnaires were sent and responses were received by post. RESULTS: Overall, 217 responses were received (62%). Of the respondents, 171 (79%) use an outcome measure in their shoulder practice while 46 (21%) do not. There were 118 surgeons (69%) who use more than one outcome measure. The Oxford shoulder score was most commonly used by 150 surgeons (69%), followed by the Constant score with 106 (49%), the Oxford shoulder instability score with 82 (38%), and the Disabilities of the Arm, Shoulder and Hand score with 54 (25%). The less commonly used outcome measures were the SF-36® and SF-12® health questionnaires with 19 (9%), the University of California at Los Angeles activity score with 8 (4%), the American Shoulder and Elbow Surgeons shoulder assessment form with 8 (4%) and the EQ-5D™ with 10 (3%). Conclusions Validated outcome measures should be adopted by all practising surgeons in all specialties. This will allow better assessment of treatments in addition to assessment of surgical performance in a transparent way.

Profilin-2 increased expression and its altered interaction with ß-actin in the striatum of 3-nitropropionic acid-induced Huntington's disease in rats.

Subacute systemic treatment with 3-nitropropionic acid (3-NP) causes specific lesions in the cortex and the striatum, and Huntington's disease behavioral phenotypes in rats. We investigated differentially expressed genes in the striatum, and examined status of a highly expressed huntingtin interacting protein, profilin 2 (Pfn2) in relation to 3-NP-induced striatal neurodegeneration, employing both in vivo animal model and in vitro primary striatal neuronal cultures. Golgi staining of 3-NP-treated rat brain revealed significantly altered dendritic spine morphology and decreased spine density in the cortex and the striatum, as compared to the control. We employed suppression subtractive hybridization (SSH) method to screen differentially expressed genes during striatal neurodegeneration in these animals. Forward and reverse SSH provided a library of 188 clones, which were used for reverse northern dot blot analysis to identify greatly altered striatal-specific genes. Sequence analysis of the clones identified 23 genes, expressions of which were ⩾1.5-fold changed (16 up-regulated) in the striatum of 3-NP-treated rats. Immunoprecipitation assay showed decreased binding of Pfn2 with ß-actin, the level of which remained unaffected in the striata and cortices of 3-NP-treated rats. Primary cultures of striatal glutamic acid decarboxylase-65/67 immunopositive GABAergic neurons revealed loss of co-existence of Pfn2 and ß-actin in fluorescence imaging studies following 3-NP treatment for 24h. Since Pfn2 is known to regulate dendritic spine dynamics by interacting with ß-actin, the reduction in its binding affinity to Pfn2 following 3-NP neurotoxic insult, and the accompanying aberrations of the dendritic spine structure and loss of spine density in striatal neurons suggest that Pfn2 may be involved in neurodegeneration in 3-NP-treated rat model of HD.

Scrub typhus presenting as an acute abdomen.

Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi, which presents as an acute febrile illness with headache, myalgia, breathlessness, and an eschar, a pathognomonic sign, in a varying proportion of patients. However, this illness can present unusually with fever and severe abdominal pain mimicking acute abdomen. A careful search for an eschar in all patients with an acute febrile illness would provide a valuable diagnostic clue and avoid unnecessary investigations and surgical exploration.

Randomized clinical trial of yoga-based intervention in residents from elderly homes: Effects on cognitive function.

CONTEXT: Elderly have increased risk for cognitive impairment and dementia. Yoga therapy may be helpful in elderly to improve cognitive function. AIMS: We examined the benefits of yoga-based intervention compared with waitlist control group on cognitive function in the residents of elderly homes. SETTINGS AND DESIGN: Single blind controlled study with block randomization of elderly homes. MATERIALS AND METHODS: Study sample included yoga group (n=62) and waitlist group (n=58). A total of 87 subjects (yoga=44, waitlist=43) completed the study period of 6 months. Yoga group received daily yoga sessions for 1 month, weekly until 3(rd) month and encouraged to continue unsupervised until 6 months. They were assessed on Rey's Auditory Verbal Learning Test (RAVLT), Rey's complex figure test (CFT), Wechsler's Memory Scale (WMS)-digit and spatial span, Controlled Oral Word Association (COWA) test, Stroop Color Word Interference Test and Trail Making Test A and B at baseline and at the end of 6(th) month. STATISTICAL ANALYSIS: Paired t-test and analysis of covariance (ANCOVA) to compare the difference in neuropsychological test scores. RESULTS: Yoga group showed significant improvement in immediate and delayed recall of verbal (RAVLT) and visual memory (CFT), attention and working memory (WMS-spatial span), verbal fluency (COWA), executive function (Stroop interference) and processing speed (Trail Making Test-A) than waitlist group at the end of 6 months after correcting for corresponding baseline score and education. CONCLUSION: Yoga based-intervention appears beneficial to improve several domains of cognitive function in elderly living in residential care homes. Study findings need to be interpreted after considering methodological limitations like lack of active comparison group.

Effects of yoga intervention on sleep and quality-of-life in elderly: A randomized controlled trial.

CONTEXT: Yoga as a life-style practice has demonstrated beneficial effects. The role of yoga in the elderly for such benefits merits investigation. AIMS: The aim of this study is to examine the effects of yoga intervention on quality-of-life (QOL) and sleep quality in the elderly living in old age homes. SETTINGS AND DESIGN: Single blind controlled study with block randomization of elderly homes. MATERIALS AND METHODS: A total of 120 subjects from nine elderly homes were randomized in to yoga group (n=62) and waitlist group (n=58). Subjects in the yoga group were given yoga intervention daily for 1 month and weekly until 3 months and were encouraged to practice yoga without supervision until for 6 months. Subjects in waitlist group received no intervention during this period. Subjects were evaluated with World Health Organization Quality of Life (WHOQOL)-BREF for measuring QOL and Pittsburgh Sleep Quality Index for sleep quality in the baseline and after 6 months. STATISTICAL ANALYSIS: Independent t-test and repeated measures analysis of covariance respectively was used to measure the difference in outcome measures between the two groups at baseline and after the study period. RESULTS: Subjects in the yoga group had significantly higher number of years of formal education. Subjects in the yoga group had significant improvement in all the domains of QOL and total sleep quality after controlling for the effect of baseline difference in education between the two groups. CONCLUSION: Yoga intervention appears to improve the QOL and sleep quality of elderly living in old age homes. There is a need for further studies overcoming the limitations in this study to confirm the benefits of yoga for elderly in QOL and sleep quality.

Parkinson's disease cybrids, differentiated or undifferentiated, maintain morphological and biochemical phenotypes different from those of control cybrids.

SH-SY5Y, control, and Parkinson's disease (PD) cybrids prepared from an Indian population were differentiated using retinoic acid (RA) for understanding their dopaminergic characteristics and neuritogenesis. Undifferentiated control and PD cybrids exhibited higher levels of TH mRNA, but lower c-RET expression, short neurites, low neuritic density, and low proportion of cells with neurites compared with the undifferentiated parent cell line, SH-SY5Y. The expression levels of DAT and Ptx3 were similar to SH-SY5Y. PD cybrids showed poor viability and lower differentiating potency than SH-SY5Y or control cybrids. RA treatment for 6 days elevated c-RET expression and corrected the neuritic morphology of the control, but not of PD cybrids. Cell viability was found to be reduced in differentiated control and PD cybrids. TH expression level was significantly elevated in SH-SY5Y following RA treatment, but not in both the cybrids. In differentiated control and PD cybrids, the TH immunofluorescence intensity was significantly lower compared with SH-SY5Y cells. MitoTracker Green fluorescence intensity of the mitochondria was higher in differentiated PD cybrids. Dopamine released into the medium was unaffected in the differentiated SH-SY5Y or in the control cybrids but was significantly elevated in PD cybrids. These results suggest that PD cybrids, differentiated or undifferentiated, maintained morphological and biochemical phenotypes significantly different from those of the control cybrids, or the differentiated SH-SY5Y cells, and therefore could be an ideal cellular model of the disease for pharmacological screening of drugs and for investigation of the pathophysiology of PD.

Nitric oxide synthase inhibitors protect against rotenone-induced, oxidative stress mediated parkinsonism in rats.

Rotenone is known to cause progressive dopaminergic neuronal loss in rodents, but it remains unclear how this mitochondrial complex-I inhibitor mediates neurodegeneration specific to substantia nigra pars compacta (SNpc). One of the proposed mechanisms is increased free radical generation owing to mitochondrial electron transport chain dysfunction following complex-I inhibition. The present study examined the role of nitric oxide (NO) and hydroxyl radicals (OH) in mediating rotenone-induced dopaminergic neurotoxicity. Indications of NO involvement are evidenced by inducible nitric oxide synthase (NOS) over-expression, and increased NADPH-diaphorase staining in SNpc neurons 96h following rotenone administration. Treatment of these animals with specific neuronal NOS inhibitor, 7-nitroindazole (7-NI) and non-specific NOS inhibitor, N-ω-nitro-l-argenine methyl ester (l-NAME) caused reversal of rotenone-induced striatal dopamine depletion, and attenuation of the neurotoxin-induced decrease in the number of tyrosine hydroxylase immunoreactive neurons in SNpc, as well as in apomorphine and amphetamine-induced unilateral rotations. Interestingly, the study also demonstrated the contribution of OH in mediating rotenone nigral toxicity since there appeared a significant generation of the reactive oxygen species in vivo 24h following rotenone administration, a copious loss of reduced and oxidized glutathione, and increased superoxide dismutase and catalase activities in the cytosolic fractions of the ipsilateral SNpc area on the 5th day. An OH scavenging capacity of 7-NI and l-NAME in a Fenton-like reaction, as well as complete reversal of the rotenone-induced increases in the antioxidant enzyme activities, and the loss in reduced and oxidized glutathione contents in the SNpc supported OH involvement in rotenone-induced dopaminergic neurotoxicity. While these results strongly suggest the contribution of both OH and NO, resulting in acute oxidative stress culminating in dopaminergic neurodegeneration caused by rotenone, the course of events indicated generation of OH as the primary event in the neurotoxic processes.

ApoE4 and late onset depression in Indian population.

OBJECTIVE: ApoE4 is a 'risk factor' for cognitive disorders like Alzheimer's dementia, and Late Onset Depression (LOD) is a forerunner of dementia. There is thus a need to study the association between ApoE4 allele and LOD. METHOD: The study assessed the frequency of ApoE4 allele in 31 cases of LOD above the age of 50 years and 31 matched controls. The subjects were assessed on various clinical parameters towards diagnosis. RESULTS: There was a significant association between the ApoE4 allele and LOD in comparison to controls (Odd's ratio=4.7, Confidence Interval=1.12 to 19.79, P=0.035). ApoE4 allele had no association with the age of onset of depression, cognitive functions and severity of LOD. CONCLUSION: Individuals with LOD have a significantly higher frequency of the ApoE4 allele. In other words, elderly in India with an ApoE4 allele have 4.7 times more risk of developing depression in old age. Within LOD group there is no difference between those with and without ApoE4 accordingly in age of onset of depression, cognitive functions and severity of LOD.