Kosambi-Cartan-Chern perspective on chaos: Unveiling hidden attractors in nonlinear autonomous systems.

This article confronts the formidable task of exploring chaos within hidden attractors in nonlinear three-dimensional autonomous systems, highlighting the lack of established analytical and numerical methodologies for such investigations. As the basin of attraction does not touch the unstable manifold, there are no straightforward numerical processes to detect those attractors and one has to implement special numerical and analytical strategies. In this article we present an alternative approach that allows us to predict the basin of attraction associated with hidden attractors, overcoming the existing limitations. The method discussed here is based on the Kosambi-Cartan-Chern theory which enables us to conduct a comprehensive theoretical analysis by means of evaluating geometric invariants and instability exponents, thereby delineating the regions encompassing chaotic and periodic zones. Our analytical predictions are thoroughly validated by numerical results.

De-glutathionylases: The resilient underdogs to keep neurodegeneration at bay.

Proteins become S-glutathionylated as a result of the derivatization of their cysteine thiols with the thiolate anion derivative of glutathione; this process is frequently linked to diseases and protein misbehavior. Along with the other well-known oxidative modifications like S-nitrosylation, S-glutathionylation has quickly emerged as a major contributor to a number of diseases, with a focus on neurodegeneration. The immense clinical significance of S-glutathionylation in cell signaling and the genesis of diseases are progressively coming to light with advanced research, which is also creating new opportunities for prompt diagnostics that utilize this phenomenon. In-depth investigation in recent years has revealed other significant deglutathionylases in addition to glutaredoxin, necessitating the hunt for their specific substrates. The precise catalytic mechanisms of these enzymes must also be understood, along with how the intracellular environment affects their impact on protein conformation and function. These insights must then be extrapolated to the understanding of neurodegeneration and the introduction of novel and clever therapeutic approaches to clinics. Clarifying the importance of the functional overlap of glutaredoxin and other deglutathionylases and examining their complementary functions as defense systems in the face of stress are essential prerequisites for predicting and promoting cell survival under high oxidative/nitrosative stress.

Post-treatment symptomatic improvement of the eastern Indian ADHD probands is influenced by CYP2D6 genetic variations.

OBJECTIVES: Symptomatic remediation from attention deficit hyperactivity disorder (ADHD)-associated traits is achieved by treatment with methylphenidate (MPH)/atomoxetine (ATX). We have analyzed the association of functional CYP2D6 variations, rs1065852, rs3892097, rs1135840, and rs1058164, with ADHD in the Indian subjects. METHODS: Subjects were recruited following the Diagnostic and Statistical Manual for Mental Disorders. Trait scores were obtained from the Conner's Parents Rating Scale-Revised. After obtaining informed consent, blood was collected for DNA isolation, and genotyping was performed by PCR or TaqMan-based methods. Probands were treated with MPH or ATX based on age, symptoms, and drug availability. Treatment outcome was assessed using a structured questionnaire. Data obtained was analyzed to identify the association of CYP2D6 variations and the SLC6A3 rs28363170 with the treatment outcome. RESULTS: The frequency of rs1135840 "G" and rs1065852 "G" was higher in the male ADHD probands. Bias in parental transmission (p=0.007) and association with higher trait scores were observed for rs1065852 "A". Independent influence of rs1065852 on ADHD was also observed. Probands carrying rs1065852 'GG', rs1135840 'CG', and rs28363170 10R exhibited significant symptomatic improvement with MPH, while probands with rs1135840 'CC' and rs28363170 9R showed improvement after ATX treatment. CONCLUSIONS: ADHD probands having specific CYP2D6 genetic variations respond differentially to pharmaceutical intervention.

Genetic aetiology of Down syndrome birth: novel variants of maternal DNMT3B and RFC1 genes increase risk of meiosis II nondisjunction in the oocyte.

The aim of the present work was to explore the intriguing association of maternal folate regulator gene polymorphisms and mutations with the incidence of chromosome 21 nondisjunction and Down syndrome birth. We tested polymorphisms/mutations of DNMT3B and RFC1 genes for their association with meiotic errors in oocyte among the 1215 Down syndrome child-bearing women and 900 controls. We observed that 23 out of 31 variants of DNMT3B and RFC1 exhibited an association with meiosis II nondisjunction in maternal age-independent manner. Additionally, we have reported 17 novel mutations and 1 novel polymorphic variant that are unique to the Indian Bengali speaking cohort and increased odds in favour of meiosis II nondisjunction. We hypothesize that the risk variants and mutations of DNMT3B and RFC1 genes may cause reduction in two or more recombination events and also cause peri-centromeric single exchange that increases the risk of nondisjunction at any age of women. In silico analyses predicted the probable damages of the transcripts or proteins from the respective genes owing to the said polymorphisms. These findings from the largest population sample tested ever revealed that mutations/polymorphisms of the genes DNMT3B and RFC1 impair recombination that leads to chromosome 21 nondisjunction in the oocyte at meiosis II stage and bring us a significant step closer towards understanding the aetiology of chromosome 21 nondisjunction and birth of a child with Down syndrome to women at any age.

Effectiveness of neurofeedback training, behaviour management including attention enhancement training and medication in children with attention-deficit/hyperactivity disorder - A comparative follow up study.

BACKGROUND: Attention Deficit/ Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental psychiatric disorders of childhood. Treatment of ADHD includes medications and Behavioural interventions. Neurofeedback, a type of biofeedback, has been found to be useful in ADHD. It helps patients to control their brain waves consciously. However, it is not yet conclusive if it is efficacious in comparison to behavioural management training and medication. AIM: To compare the efficacy of neurofeedback training, behaviour management including attention enhancement training and medication in children with ADHD. METHOD: Ninety children between 6 and 12 years with ADHD were taken and randomly divided into 3 treatment groups equally- neurofeedback, behaviour management and medication (methylphenidate). Conners 3-P Short Scale was applied for baseline assessment. The respective interventions were given and follow up was done at the end of 3 months by using Conners 3-P Short scale to assess the improvement in the symptoms. There were 6 dropouts, the final sample size was 84. RESULTS: The medication group showed the greatest reduction of symptoms in inattention, hyperactivity, executive functioning domain (core symptoms of ADHD). No statistically significant difference was observed between Neurofeedback and Behaviour Management in these domains. Learning problems improved in all three groups, neurofeedback being the most effective followed by medication. Both Neurofeedback and Medication groups showed similar effect which was higher than the Behavioural Management group in Peer Relation. CONCLUSION: Improvement in core ADHD symptoms have been observed with all 3 interventions with medication showing the greatest improvement Neurofeedback has been superior for learning problems. Thus, Neurofeedback can be an independent or combined intervention tool for children with ADHD in outpatient department of Psychiatry.

Evaluation of potency of the selected bioactive molecules from Indian medicinal plants with MPro of SARS-CoV-2 through in silico analysis.

BACKGROUND: The recent outbreak of the novel SARS-CoV-2 across the globe and the absence of specific drug against this virus lead the scientific community to look into some alternative indigenous treatments. India as a hub of Ayurvedic and medicinal plants can shed light on its treatment using specific active bio-molecules from these plants. OBJECTIVES: Keeping our herbal resources in mind, we were interested to inquire whether some phytochemicals from Indian spices and medicinal plants can be used as alternative therapeutic agents in contrast to synthetic drugs. MATERIALS AND METHODS: We used in silico molecular docking approach to test whether bioactive molecules of herbal origin such as hyperoside, nimbaflavone, ursolic acid, 6-gingerol, 6-shogaol and 6-paradol, curcumin, catechins and epigallocatechin, α-Hederin, piperine could bind and potentially block the Mproenzyme of the SARS-CoV-2 virus. RESULTS: Ursolic acid showed the highest docking score (-8.7 kcal/mol) followed by hyperoside (-8.6 kcal/mol), α-Hederin (-8.5 kcal/mol) and nimbaflavone (-8.0 kcal/mol). epigallocatechin, catechins, and curcumin also exhibited high binding affinity (Docking score -7.3, -7.1 and -7.1 kcal/mol) with the Mpro. The remaining tested phytochemicals exhibited moderate binding and inhibitory effects. CONCLUSION: This finding provides a basis for biochemical assay of tested bioactive molecules on SARS-CoV-2 virus.

Understanding etiology of chromosome 21 nondisjunction from gene × environment models.

Maternal risk factors and their interactions with each other that associate chromosome 21 nondisjunction are intriguing and need incisive study to be resolved. We determined recombination profile of nondisjoined chromosome 21 and maternal genotypes for four selected polymorphic variants from the folate regulators genes stratifying the women according to the origin of segregation error and age at conception. We conducted association study for genotype and maternal addiction to smokeless chewing tobacco, usually chopped tobacco leaves or paste of tobacco leaves with the incidence of Down syndrome birth. Additionally, we designed various logistic regression models to explore the effects of maternal genotype, maternal habit of smokeless chewing tobacco, maternal age at conception and all possible interactions among them on chromosome 21 nondisjunction. We found folate regulator gene mutations are associated with maternal meiosis II error. Regression models revealed smokeless chewing tobacco and folate polymorphic/mutant risk genotype interact with each other to increase the risk of reduced and single peri-centromeric recombination events on chromosome 21 that nondisjoined at meiosis II in the oocytes and the effect is maternal age independent. We inferred maternal folate polymorphic/mutant risk genotypes and habit of smokeless chewing tobacco interact with each other and increase the risk of meiosis II error in oocytes in maternal age-independent manner.

Deep-sea shipwrecks represent island-like ecosystems for marine microbiomes.

Biogeography of macro- and micro-organisms in the deep sea is, in part, shaped by naturally occurring heterogeneous habitat features of geological and biological origin such as seeps, vents, seamounts, whale and wood-falls. Artificial features including shipwrecks and energy infrastructure shape the biogeographic patterns of macro-organisms; how they influence microorganisms is unclear. Shipwrecks may function as islands of biodiversity for microbiomes, creating a patchwork of habitats with influence radiating out into the seabed. Here we show microbiome richness and diversity increase as a function of proximity to the historic deep-sea shipwreck Anona in the Gulf of Mexico. Diversity and richness extinction plots provide evidence of an island effect on microbiomes. A halo of core taxa on the seabed was observed up to 200 m away from the wreck indicative of the transition zone from shipwreck habitat to the surrounding environment. Transition zones around natural habitat features are often small in area compared to what was observed at Anona indicating shipwrecks may exert a large sphere of influence on seabed microbiomes. Historic shipwrecks are abundant, isolated habitats with global distribution, providing a means to explore contemporary processes shaping biogeography on the seafloor. This work is a case study for how built environments impact microbial biodiversity and provides new information on how arrival of material to the seafloor shapes benthic microbiomes.

The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte.

Altered patterns of recombination on 21q have long been associated with the nondisjunction chromosome 21 within oocytes and the increased risk of having a child with Down syndrome. Unfortunately the genetic etiology of these altered patterns of recombination have yet to be elucidated. We for the first time genotyped the gene MCM9, a candidate gene for recombination regulation and DNA repair in mothers with or without children with Down syndrome. In our approach, we identified the location of recombination on the maternal chromosome 21 using short tandem repeat markers, then stratified our population by the origin of meiotic error and age at conception. We observed that twenty-five out of forty-one single nucleotide polymorphic sites within MCM9 exhibited an association with meiosis I error (N = 700), but not with meiosis II error (N = 125). This association was maternal age-independent. Several variants exhibited aprotective association with MI error, some were neutral. Maternal age stratified characterization of cases revealed that MCM9 risk variants were associated with an increased chance of reduced recombination on 21q within oocytes. The spatial distribution of single observed recombination events revealed no significant change in the location of recombination among women harbouring MCM9 risk, protective, or neutral variant. Additionally, we identified a total of six novel polymorphic variants and two novel alleles that were either risk imparting or protective against meiosis I nondisjunction. In silico analyses using five different programs suggest the risk variants either cause a change in protein function or may alter the splicing pattern of transcripts and disrupt the proportion of different isoforms of MCM9 products within oocytes. These observations bring us a significant step closer to understanding the molecular basis of recombination errors in chromosome 21 nondisjunction within oocytes that leads to birth of child with Down syndrome.

Self-assembly of surfactants: An overview on general aspects of amphiphiles.

Surfactants are molecules (ionic or nonionic) that upon adsorption at the air-water interface reduce surface tension of water. Therefore, surfactants are surface-active agents. Surfactants are normally amphiphilic molecules with a long hydrocarbon tail and a polar head group. The head group may be anionic, cationic or nonionic and accordingly the surfactants are classified as anionic, cationic or nonionic. There are some surface-active amphiphilic molecules that contain both anionic and cationic centers at the head group. These are called zwitterionic surfactants. Surfactants can also have two hydrocarbon chains attached to a polar head and are called double chain surfactants. Also, surfactants containing two hydrophobic and two hydrophilic groups, called "gemini" surfactants. The gemini surfactants can be thought of "twin" surfactants as being made up of two typical surfactant molecules chemically linked at or near the head group. Amphiphilic molecules can also have two head groups (both anionic, both cationic or one anionic and the other cationic) joined by hydrophobic spacer. These types of molecules are termed "bola-amphiphiles" commonly known as "bolaforms". Surface activity of these molecules depends on both the hydrocarbon chain length and the nature of head group(s). Amphiphiles with longer hydrocarbon chains are found to be more surface-active compared to those having shorter hydrocarbon tail. It is observed that amphiphiles with fluorocarbon chain are more surface-active than those with hydrocarbon chain. This is because the fluorocarbon chain is more hydrophobic than hydrocarbon chain.

Eye movement tracking in pediatric obsessive compulsive disorder.

Till date researchers have elucidated the neurobiological substrates in OCD using methods like neuroimaging. However, a potential biomarker is still elusive. The present study is an attempt to identify a potential biomarker in pediatric OCD using eye tracking. The present study measured pro-saccade and anti-saccade parameters in 36 cases of pediatric OCD and 31 healthy controls. There was no significant difference between cases and controls in the error rate, peak velocity, position gain and latency measures in both pro-saccade and anti-saccade eye tracking tasks. With age, anti-saccades become slower in velocity, faster in response and more accurate irrespective of disorder status of the child. Pro-saccades also show a similar effect that is less prominent than anti-saccades. Gain measures more significantly vary with age in children with OCD than the controls, whereas latency measures positively correlated with age in children with OCD as opposed to being negatively correlated in the controls. Findings of this study do not support any of the eye tracking measures as putative diagnostic bio-markers in OCD. However, latency and gain parameters across different age groups in anti-saccade tasks need to be explored in future studies.

A Self-Deleting AAV-CRISPR System for In Vivo Genome Editing.

Adeno-associated viral (AAV) vectors packaging the CRISPR-Cas9 system (AAV-CRISPR) can efficiently modify disease-relevant genes in somatic tissues with high efficiency. AAV vectors are a preferred delivery vehicle for tissue-directed gene therapy because of their ability to achieve sustained expression from largely non-integrating episomal genomes. However, for genome editizng applications, permanent expression of non-human proteins such as the bacterially derived Cas9 nuclease is undesirable. Methods are needed to achieve efficient genome editing in vivo, with controlled transient expression of CRISPR-Cas9. Here, we report a self-deleting AAV-CRISPR system that introduces insertion and deletion mutations into AAV episomes. We demonstrate that this system dramatically reduces the level of Staphylococcus aureus Cas9 protein, often greater than 79%, while achieving high rates of on-target editing in the liver. Off-target mutagenesis was not observed for the self-deleting Cas9 guide RNA at any of the predicted potential off-target sites examined. This system is efficient and versatile, as demonstrated by robust knockdown of liver-expressed proteins in vivo. This self-deleting AAV-CRISPR system is an important proof of concept that will help enable translation of liver-directed genome editing in humans.

Risk of Down syndrome birth: Consanguineous marriage is associated with maternal meiosis-II nondisjunction at younger age and without any detectable recombination error.

Consanguineous marriage was examined as a risk factor for Down syndrome birth. We genotyped Down syndrome family trios using short tandem repeat markers on 21q-to interpret the parental and meiotic stage of origin of errors as well as to record recombination profile along long arm of chromosome 21. We then compared nonconsanguineous (N = 811) group with-the consanguineous (N =157) marriages. We report for the first time that consanguineous marriage is associated with an increased risk for nondisjunction of chromosome 21 in oocytes-during the second meiotic division. We observed the absence of recombination more frequently in younger mothers in nonconsanguineous meiosis I cases. This was in contrast to an equal distribution of nonrecombinant cases across the age categories in the meiosis I consanguineous group. Moreover, the non-consanguineous group exhibited preferential telomeric recombination in meiosis I error among younger women and centromeric recombination in meiosis II errors in older women. In contrast, the consanguineous group exhibited medially placed recombination events in both meiosis I and meiosis II nondisjunction errors. Additionally, we recorded reduced maternal age at conception in the-consanguineous group. These findings suggest novel risk factors associated that increase the risk of chromosome 21 nondisjunction in the families with consanguinity.

Regeneration of plantlets through somatic embryogenesis from root derived calli of Hibiscus sabdariffa L. (Roselle) and assessment of genetic stability by flow cytometry and ISSR analysis.

Induction of somatic embryogenesis and complete plantlet regeneration from callus culture of Hibiscus sabdariffa L. var. HS4288 has been made. Leaf and root explants were cultured on Murashige and Skoog (MS) and Driver-Kuniyuki Walnut (DKW) basal media supplemented with different concentrations of synthetic auxins and cytokinins. Root explants on DKW medium supplemented with 2.26µM 2, 4-Dichlorophenoxyacetic acid (2, 4-D) and 4.65µM kinetin (KIN) induced highest percentage (70%) of embryogenic calli. Average number of globular embryos per root derived callus produced within 6 weeks of culture initiation on MS media with different plant growth regulators (PGRs) ranged from 2.27±0.12 to 8.80±0.17 and that of cotyledonary embryos ranged from 0.00 to 2.53±0.20. On DKW medium comparatively more globular embryos (2.70±0.15 to 14.53±0.23) and cotyledonary embryos (0.00 to 8.90±0.17) were produced than that of MS medium. Regeneration of complete plantlets was highest (76.67%) when embryogenic calli with mature somatic embryos were grown on DKW medium containing 2.32µM KIN and 2.22µM 6-Benzyladenine (BA). Plants were primarily hardened in humidity, temperature and light controlled chamber and finally in a greenhouse showed 70% survival ability. Different stages of somatic embryogenesis process in the root derived embryogenic calli were elaborated in detail by morphological, histological and SEM study. The data were statistically analyzed by Duncan Multiple range test (p ≤ 0.05) and Principal component analysis (PCA). Flow cytometry and Inter-simple sequence repeats (ISSR) marker analysis confirmed that there was no genetic variation within the regenerated plants.

Taxon-Driven Functional Shifts Associated with Storm Flow in an Urban Stream Microbial Community.

Urban streams are susceptible to stormwater and sewage inputs that can impact their ecological health and water quality. Microbial communities in streams play important functional roles, and their composition and metabolic potential can help assess ecological state and water quality. Although these environments are highly heterogenous, little is known about the influence of isolated perturbations, such as those resulting from rain events on urban stream microbiota. Here, we examined the microbial community composition and diversity in an urban stream during dry and wet weather conditions with both 16S rRNA gene sequencing across multiple years and shotgun metagenomics to more deeply analyze a single storm flow event. Metagenomics was used to assess population-level dynamics as well as shifts in the microbial community taxonomic profile and functional potential before and after a substantial rainfall. The results demonstrated general trends present in the stream under storm flow versus base flow conditions and also highlighted the influence of increased effluent flow following rain in shifting the stream microbial community from abundant freshwater taxa to those more associated with urban/anthropogenic settings. Shifts in the taxonomic composition were also linked to changes in functional gene content, particularly for transmembrane transport and organic substance biosynthesis. We also observed an increase in relative abundance of genes encoding degradation of organic pollutants and antibiotic resistance after rain. Overall, this study highlighted some differences in the microbial community of an urban stream under storm flow conditions and showed the impact of a storm flow event on the microbiome from an environmental and public health perspective.IMPORTANCE Urban streams in various parts of the world are facing increased anthropogenic pressure on their water quality, and storm flow events represent one such source of complex physical, chemical, and biological perturbations. Microorganisms are important components of these streams from both ecological and public health perspectives. Analysis of the effect of perturbations on the stream microbial community can help improve current knowledge on the impact such chronic disturbances can have on these water resources. This study examines microbial community dynamics during rain-induced storm flow conditions in an urban stream of the Chicago Area Waterway System. Additionally, using shotgun metagenomics we identified significant shifts in the microbial community composition and functional gene content following a high-rainfall event, with potential environment and public health implications. Previous work in this area has focused on specific genes/organisms or has not assessed immediate storm flow impact.

Genetic variants of the folate metabolic system and mild hyperhomocysteinemia may affect ADHD associated behavioral problems.

An etiologically complex disorder, Attention Deficit Hyperactivity Disorder (ADHD), is often associated with various levels of cognitive deficit. Folate/vitamin B9 is crucial for numerous biochemical pathways including neural stem cell proliferation and differentiation, regulation of gene expression, neurotransmitter synthesis, myelin synthesis and repair, etc. and a scarcity has often been linked to cognitive deficit. Our pilot study in the field revealed significant association of few genetic variants with ADHD. Mild hyperhomocysteinemia and vitamin B12 deficiency was also noticed in the probands. In the present study additional genetic variants, folate and vitamin B6, which may affect folate-homocysteine metabolic pathway, were investigated in 866 individuals including nuclear families with ADHD probands (N=221) and ethnically matched controls (N=286) to find out whether ADHD associated traits are affected by these factors. Population based analysis revealed significant over representation of MTRR rs1801394 "G" allele and "GG" genotype in all as well as male probands. Stratified analysis showed significantly higher frequency of RFC1 rs1051266 and BHMT rs3733890 "AG" genotypes in full term and prematurely delivered ADHD probands respectively. Probands with rs1801394 "GG" genotype and BHMT rs3733890 "G" allele showed association with hyperhomocysteinemia. MTHFR rs1801131, MTR rs1805087 and BHMT rs3733890 also showed association with ADHD index. While rs1051266, rs1801131, and rs1805087 showed association with behavioral problems, rs3733890 was associated with ODD score. Conduct problem exhibited association with RFC1 rs1051266, MTHFR rs1801133 and MTRR rs1801394. Gene-gene interaction analysis revealed positive synergistic interactions between rs1051266, rs1801131 and rs1801394 in the probands as compared to the controls. It can be inferred from the data obtained that folate system genetic variants and mild hyperhomocysteimenia may affect ADHD associated traits by attenuating folate metabolism.

Oppositional defiant disorder: current insight.

Oppositional defiant disorder (ODD) is diagnosed broadly on the basis of frequent and persistent angry or irritable mood, argumentativeness/defiance, and vindictiveness. Since its inception in the third Diagnostic and Statistical Manual of Mental Disorders, epidemiological and longitudinal studies have strongly suggested a distinct existence of ODD that is different from other closely related externalizing disorders, with different course and outcome and possibly discrete subtypes. However, several issues, such as symptom threshold, dimensional versus categorical conceptualization, and sex-specific symptoms, are yet to be addressed. Although ODD was found to be highly heritable, no genetic polymorphism has been identified with confidence. There has been a definite genetic overlap with other externalizing disorders. Studies have begun to explore its epigenetics and gene-environment interaction. Neuroimaging findings converge to implicate various parts of the prefrontal cortex, amygdala, and insula. Alteration in cortisol levels has also been demonstrated consistently. Although a range of environmental factors, both familial and extrafamilial, have been studied in the past, current research has combined these with other biological parameters. Psychosocial treatment continues to be time-tested and effective. These include parental management training, school-based training, functional family therapy/brief strategic family therapy, and cognitive behavior therapy. Management of severe aggression and treatment of co-morbid disorders are indications for pharmacotherapy. In line with previous conceptualization of chronic irritability as a bipolar spectrum abnormality, most studies have explored antipsychotics and mood stabilizers in the management of aggression, with limited effects.

Adolescent-onset X-linked Adrenoleukodystrophy Presenting as Treatment-resistant Bipolar Disorder.

A small proportion of bipolar disorder of adolescent onset can be secondary to underlying neurological disorder (secondary mania). We report a case of treatment-resistant mania secondary to cerebral form of adrenoleukodystrophy of adolescent onset. This case demonstrates the need for clinicians to be alert to the possibility of rare neurological diseases that can present with psychiatric manifestations.

Pilot study indicate role of preferentially transmitted monoamine oxidase gene variants in behavioral problems of male ADHD probands.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is an etiologically complex childhood onset neurobehavioral disorder characterized by age-inappropriate inattention, hyperactivity, and impulsivity. Symptom severity varies widely and boys are diagnosed more frequently than girls. ADHD probands were reported to have abnormal transmissions of dopamine, serotonin, and/or noradrenaline. Monoamine oxidase A (MAOA) and B (MAOB), mitochondrial outer membrane bound two isoenzymes, mediate degradation of these neurotransmitters and thus regulating their circulating levels. Case-control analyses in different populations, including Indians, suggested involvement of MAOA and MAOB genes in the etiology of ADHD. Due to high heritability rate of ADHD, we tested familial transmission of MAOA and MAOB variants to ADHD probands in 190 nuclear families having ADHD probands from Indo-Caucasoid ethnicity. METHODS: Subjects were recruited following the Diagnostic and Statistical Manual of Mental Disorders-4th edition (DSM-IV). Appropriate scales were used for measuring the behavioral traits in probands. Genotyping was performed through PCR-based amplification of target sites followed by DNA-sequencing and/or gel-electrophoresis. Data obtained were analyzed by family based statistical methods. RESULTS: Out of 58 variants present in the analyzed sites only 15 were found to be polymorphic (30 bp-uVNTR, rs5906883, rs1465107, rs1465108, rs5905809, rs5906957, rs6323, rs1137070 from MAOA and rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324, rs3027440 from MAOB). Statistically significant maternal transmission of alleles to male probands was observed for MAOA rs5905809 'G' (p = 0.04), rs5906957 'A' (p = 0.04), rs6323 'G' (p = 0.0001) and MAOB rs56220155 'A' (p = 0.002), rs2283728 'C' (p = 0.0008), rs2283727 'C' (p = 0.0008), rs3027441 'T' (p = 0.003), rs6324 'C' (p = 0.003), rs3027440 'T' (p = 0.0002). Significantly preferential maternal transmissions of different haplotype combinations to male probands were also noticed (p < 0.05), while female probands did not reveal such transmission bias. Behavioral traits of male probands exhibited significant association with gene variants. Age of the mother at pregnancy also revealed association with risk variants of male probands. CONCLUSIONS: It may be inferred that the MAOA and MAOB variants may contribute to the etiology of ADHD in the Indo-Caucasoid population and could be responsible for higher occurrence of ADHD in the boys.

Leukodystrophy Presenting as Hyperactivity and Bipolarity with Uncommon Adverse Drug Reaction.

Leukodystrophy is a group of demyelinating neurodegenerative diseases of brain with varied presentation and multiple etiologies. Prognosis is predominantly dismal. Misdiagnosis and wrong treatment are common in this group of rare neurological disorders, especially when it presents with psychiatric symptoms. In this case, importance of neurological and radiological evaluation and need for high diagnostic suspicion in treatment-resistant psychiatric disorders is highlighted.