Next-generation therapeutics for rare genetic disorders.

The therapeutic potential of the human genome has been explored through the development of next-generation therapeutics, which have had a high impact on treating genetic disorders. Classical treatments have traditionally focused on common diseases that require repeated treatments. However, with the recent advancements in the development of nucleic acids, utilizing DNA and RNA to modify or correct gene expression in genetic disorders, there has been a paradigm shift in the treatment of rare diseases, offering more potential one-time cure options. Advanced technologies that use CRISPR-Cas 9, antisense oligonucleotides, siRNA, miRNA, and aptamers are promising tools that have achieved successful breakthroughs in the treatment of various genetic disorders. The advancement in the chemistry of these molecules has improved their efficacy, reduced toxicity, and expanded their clinical use across a wide range of tissues in various categories of human disorders. However, challenges persist regarding the safety and efficacy of these advanced technologies in translating into clinical practice. This review mainly focuses on the potential therapies for rare genetic diseases and considers how next-generation techniques enable drug development to achieve long-lasting curative effects through gene inhibition, replacement, and editing.

Mosaic variegated aneuploidy syndrome 2 with biallelic novel CEP57 splice site variation in Indian siblings: Expanding the clinical and molecular spectrum.

Mosaic variegated aneuploidy syndrome 2 (MVA2) (MIM# 614114) is a rare autosomal recessive condition caused by biallelic loss of function variants in the CEP57 gene. MVA2 is characterized by a variable phenotype ranging from poor growth to facial dysmorphism, short stature and congenital heart defects. Only 11 families and 5 pathogenic variants of MVA2 have been described so far. Intragenic duplication of 11 nucleotides (c.915_925dup11) in homozygous or compound heterozygous state is the commonest genetic aberration (10/13). We describe the first Indian family with two siblings with a novel homozygous splice site variant (c.382+2T>C) in CEP57. Molecular characterization demonstrated skipping of exon 3 due to the variant with protein modeling predicting subsequent complete loss of function. This is the first report of a splice site variation in CEP57 leading to MVA2.

Isochromosome Xq and the risk of metabolic comorbidities in Turner syndrome.

BACKGROUND AND AIM: Subjects with Turner syndrome (TS) are at increased risk of metabolic disorders. The objective of this study is to evaluate the prevalence of metabolic abnormalities in TS and compare the metabolic profiles of subjects with respect to their X chromosome dosage. METHODS: Sixty-four TS subjects with a mean age of 19 ± 4.9 years were included, and the prevalence of metabolic abnormalities was assessed. Out of these, 54 age and body mass index-matched TS subjects were divided into two groups based on karyotype: 45,X and 45,X/46,XX (group I; n = 33) and 46,X,i(X)(q10) and 45,X/46,X,i(X)(q10) (group II; n = 21). They were compared for blood pressure, fasting plasma glucose, homeostasis model assessment (HOMA) of insulin resistance (IR) and ß cell function (HOMA-ß), lipid profile, and percent total body fat mass (PTBFM) to assess if an extra copy of Xq contributes to a different metabolic profile. RESULTS: The prevalence of impaired fasting glucose was 7.8%. 12% of subjects had higher systolic blood pressure (SBP), and 16% had higher diastolic blood pressure for age. 53% had a deranged lipid profile. Significant differences were noted in the two groups, with higher prevalence in group II vs. group I for SBP (p = 0.03), low-density lipoprotein cholesterol (LDL-c) (p = 0.03), and PTBFM (p = 0.02). When we applied a multiple regression analysis for these outcome variables while adjusting for potential confounders known to influence the cardiometabolic risk profile in TS, karyotype no longer remained a significant independent variable. CONCLUSION: Extra copies of Xq do not contribute to an adverse metabolic risk profile.

Cannabis-induced obsessive-compulsive disorder: Is it a paradox?

The case of a 22-year-old man with cannabis-induced obsessive-compulsive disorder (OCD) is described in this case report. There is ample literature available regarding cannabis-induced psychotic and mood symptoms but there is dearth of literature about cannabis association with OCD. The importance of recognising cannabis-induced OCD is emphasized, given that in literature, it can be used in ameliorating OCD in a few studies. Nevertheless, further research is needed to explore the neurobiological underpinning of both cannabis abuse and OCD to find out the link and complex interplay between addictive, impulsive and compulsive behaviours before using it as a treatment option.

Attitudes towards coronavirus (COVID-19) vaccine and sources of information across diverse ethnic groups in the UK: a qualitative study from June to October 2020.

OBJECTIVES: Across diverse ethnic groups in the UK, explore attitudes and intentions towards COVID-19 vaccination and sources of COVID-19 information. DESIGN: Remote qualitative interviews and focus groups (FGs) conducted June-October 2020 before UK COVID-19 vaccine approval. Data were transcribed and analysed through inductive thematic analysis and mapped to the Theoretical Domains Framework. SETTING: England and Wales. PARTICIPANTS: 100 participants from 19 self-identified ethnic groups. RESULTS: Mistrust and doubt were reported across ethnic groups. Many participants shared concerns about perceived lack of information about COVID-19 vaccine safety and efficacy. There were differences within each ethnic group, with factors such as occupation and perceived health status influencing intention to accept a vaccine once made available. Across ethnic groups, participants believed that public contact occupations, older adults and vulnerable groups should be prioritised for vaccination. Perceived risk, social influences, occupation, age, comorbidities and engagement with healthcare influenced participants' intentions to accept vaccination once available. All Jewish FG participants intended to accept, while all Traveller FG participants indicated they probably would not.Facilitators to COVID-19 vaccine uptake across ethnic groups included: desire to return to normality and protect health and well-being; perceived higher risk of infection; evidence of vaccine safety and efficacy; vaccine availability and accessibility.COVID-19 information sources were influenced by social factors and included: friends and family; media and news outlets; research literature; and culture and religion. Participants across most different ethnic groups were concerned about misinformation or had negative attitudes towards the media. CONCLUSIONS: During vaccination rollout, including boosters, commissioners and providers should provide accurate information, authentic community outreach and use appropriate channels to disseminate information and counter misinformation. Adopting a context-specific approach to vaccine resources, interventions and policies and empowering communities has potential to increase trust in the programme.

Daily waiting time management for modern radiation oncology department in Indian perspective.

Introduction: Radiation therapy is one of the most technically sophisticated branch of medical sciences which caters to very ill patients, some of whom may be terminally ill. Since patients are treated on an outpatient basis which requires daily visit to hospital for a number of days, it can make them sensitive toward any increase in waiting time for their radiation treatment. This could be a source of stress for them. However, given the technical sophistication involved and varied clinical profile of patients, some amount of delay is inevitable. Aim & Objective: To compile and suggest strategies to manage patient waiting time in Radiation oncology department to achieve optimum patient' satisfaction. Method: The radiation oncologists in different institutes of the country were interviewed telephonically and were asked about the practices followed in their institutes/ departments in managing the patient waiting time during radiation treatment. The best practices being followed and the suggestions were compiled. Conclusion: Now it is being recognized that meticulous management of waiting time could go a long way in driving patient's satisfaction. Twoway communications are the best strategy. Apart from this many provisions could be made in waiting area as per institutional preferences and protocol to engage patient in waiting area of radiation treatment facility.

Public views of and reactions to the COVID-19 pandemic in England: a qualitative study with diverse ethnicities.

OBJECTIVES: To explore public reactions to the COVID-19 pandemic across diverse ethnic groups. DESIGN: Remote qualitative interviews and focus groups in English or Punjabi. Data were transcribed and analysed through inductive thematic analysis. SETTING: England and Wales, June to October 2020. PARTICIPANTS: 100 participants from 19 diverse 'self-identified' ethnic groups. RESULTS: Dismay, frustration and altruism were reported across all ethnic groups during the first 6-9 months of the COVID-19 pandemic. Dismay was caused by participants' reported individual, family and community risks, and loss of support networks. Frustration was caused by reported lack of recognition of the efforts of ethnic minority groups (EMGs), inaction by government to address COVID-19 and inequalities, rule breaking by government advisors, changing government rules around: border controls, personal protective equipment, social distancing, eating out, and perceived poor communication around COVID-19 and the Public Health England COVID-19 disparities report (leading to reported increased racism and social isolation). Altruism was felt by all, in the resilience of National Health Service (NHS) staff and their communities and families pulling together. Data, participants' suggested actions and the behaviour change wheel informed suggested interventions and policies to help control COVID-19. CONCLUSION: To improve trust and compliance future reports or guidance should clearly explain any stated differences in health outcomes by ethnicity or other risk group, including specific messages for these groups and concrete actions to minimise any risks. Messaging should reflect the uncertainty in data or advice and how guidance may change going forward as new evidence becomes available. A contingency plan is needed to mitigate the impact of COVID-19 across all communities including EMGs, the vulnerable and socially disadvantaged individuals, in preparation for any rise in cases and for future pandemics. Equality across ethnicities for healthcare is essential, and the NHS and local communities will need to be supported to attain this.

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis.

INTRODUCTION: Nonimmune hydrops fetalis (NIHF) has varied etiology. We assessed the etiological spectrum and evaluated the utility of fetal whole exome sequencing (fWES) for the diagnosis of NIHF. METHODS: In this prospective cohort study, we evaluated antenatally diagnosed fetuses with NIHF between July 2018 and December 2019 according to the routine diagnostic algorithm. Fetuses that remained undiagnosed after routine NIHF workup were subjected to fetal chromosomal microarray and/or WES. Pregnancies were followed up for clinical outcomes. RESULTS: Of the 45 fetuses, consanguinity and recurrent hydrops fetalis were observed in 13.3% (6/45) and 28.8% (13/45), respectively. Overall, an etiological diagnosis was possible in 75.5% (34/45) of fetuses, while the cause remained unknown in 24.4% (11/45). A genetic etiology was identified in 46.6% (21/45): aneuploidy and monogenic disorders in 28.8% (13/45) and 17.8% (8/45), respectively. fWES on 19 fetuses detected disease-causing variants in 42.1% (8/19). Nine novel variants were detected in RAPSN, ASCC1, NEB, PKD1L1, GUSB, and PIEZO1. Only 8.8% (4/45) of the cohort survived without morbidity. CONCLUSIONS: This study describes the etiological spectrum and the disease-causing variants in an Indian cohort of hydropic fetuses.

Impact of parental origin of X-chromosome on clinical and biochemical profile in Turner syndrome.

Objectives To evaluate if the parental origin of X-chromosome has an impact on the phenotype and biochemical profile in Turner syndrome (TS). Result of the previous studies have been equivocal and could be attributable to the multicentric study design with different experts examining heterogeneous TS population of various ethnic background. Methods A cross-sectional single center study from Northern India. Fifty nine diagnosed subjects of TS and their parents participated in the study. Parental origin of intact X-chromosome was determined using 12 highly polymorphic short tandem repeats (STR) on X-chromosome. For the evaluation of parent-of-origin effects, typical phenotypic traits including congenital malformations, anthropometry, body composition by dual energy X-ray absorptiometry (DXA) and biochemical profile were compared. Clinical stigmata of TS in all subjects were examined by a single expert. Results The intact X-chromosome was of maternal origin (Xm) in 49.1% subjects while 50.9% had paternal origin (Xp). Skeletal anomalies were more common in Xm group, out of which prevalence of short neck and short fourth metatarsal reached statistical significance (p=0.04 and 0.01 respectively). A strong correlation was observed between subject's baseline height standard deviation score (Ht SDS) and paternal height (r=0.593, p<0.001), maternal height (r=0.564, p<0.001) and mid-parental height (MPH) (r=0.372, p=0.047) in Xp group. This effect was not seen in Xm subjects whose baseline Ht SDS showed no significant correlation with maternal height, paternal height or MPH. No differences were detected between the groups with regard to biochemical profile or body composition. Conclusions We speculate that the differences in skeletal anomalies and height correlations between Xm and Xp groups could be due to the modifying effect of epigenetic signature on short stature homeobox (SHOX) gene of Xm. SHOX gene is not modified on Xp thereby explaining the paucity of skeletal changes and height correlations in Xp subjects.

Evaluation of thrombospondin-1 gene polymorphisms in corneal allograft rejection in Asian Indian patients.

Purpose: To evaluate the frequency and the association of Thrombospondin 1 (THBS1) gene single nucleotide polymorphisms (SNPs) in Asian Indian patients with optical full thickness corneal grafting surgery. Methods: Prospective case-control analysis of optical penetrating keratoplasty patients with and without immune rejection and controls for genotyping of 3 THBS1 gene SNPs (rs1478604 A>G; rs2228261 C>T; rs2228262 A>G) by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS PCR). Results: Among 58 patients [45 with immune allograft rejection (DNA isolation was possible in 38 samples) and 13 without immune corneal allograft rejection] and 65 controls, allele frequencies observed for rs1478604 (A>G) are A: 69.7% and 72.6%, G: 30.2% and 27.3%; for rs2228261 (C>T) are T: 70.2% and 62.3%, C: 29.7% and 37.6%; and for rs2228262 (A>G) A: 97.4% and 98.4%; G 2.5% and 1.5% respectively. Genotype frequencies were rs1478604 (A>G) AA: 57.8% and 59.3%, AG 23.6% and 26.5%; GG 18.4% and 14%; for rs2228261 (C>T) TT: 40.5% and 33.8%, TC: 59% and 56.9%, CC: 0% and 9.2%; for rs2228262 (A>G) AA: 94.8% and 96.8%, AG: 5.1% and 3.1% in rejection and controls respectively. The allele and genotype frequency for the 3 described THSB1 SNPs did not show any difference between the corneal graft immune rejection patients and controls. Conclusion: Asian Indian population evaluated for THBS1 gene SNPs by ARMS PCR genotyping in Asian Indian population did not show any genetic association to immune rejection occurrence in our study.

Neuroprotective effect of Reinwardtia indica against scopolamine induced memory-impairment in rat by attenuating oxidative stress.

Reinwardtia indica belongs to Linaceae family and used as a folk medicine in Asian countries. Traditionally, it has been used in the treatment of paralysis and anti-microbial in wound healing, etc. The current study was undertaken in order to investigate the antioxidant and memory protective effect of the alcoholic (99.90%) (AERI) and hydro-alcoholic (70:30) leaves extract (HAERI) of Reinwardtia indica, against scopolamine-induced memory impairment in animals and also tried to determine the possible mechanism of action. In addition, phytochemical profiling of alcoholic leaves extract was also conducted through gas chromatography-mass spectrometry (GC-MS/MS). Rats were pretreated with AERI, HAERI (dose 250 and 500 mg/kg) and Donepezil (standard drug) along with scopolamine (1 mg/kg) for a period of 14 days followed by different test like elevated plus maze, passive avoidance, and Morris water maze to assess learning and memory ability. Acetylcholine levels, acetylcholinesterase (AChE), antioxidant enzymes (SOD, CAT & GSH), histopathology of the brain and biochemical test were also performed at the end of the treatment period. The scopolamine treatment resulted in learning and memory deficits which were partially and significantly ameliorated by the AERI at higher dose among other doses of extracts. The AERI at higher dose also counteracted the scopolamine-induced decrease in acetylcholine levels, increase in AChE activity, and decrease in antioxidant enzymes activities. No significant changes observed in the biochemical estimation of all dose of extracts. Histology of brain tissue showed the marked cellular changes in only scopolamine treated group while the standard, AERI and HAERI treated group were showing less damage at hippocampus region of the brain. The phytochemicals found after chemical profiling through GC-MS also supported the activity because of the presence of chemicals already reported for the neuroprotective, memory-enhancing and antioxidant activity, etc. The results demonstrated that the ability of the AERI at higher dose among all doses of extracts has more potential to revert the scopolamine-induced learning and memory deficits in rats by attenuating the decreased level of acetylcholine and antioxidant enzymes.

Acute and sub-acute toxicity study of hydro-alcoholic leaves extract of Reinwardtia indica in rats.

The present study was to assess the toxicity of hydro alcoholic leaves extract of Reinwardtia indica in Charles foster rats through an acute and sub-acute study. In the acute study, rats were treated orally with single dose and for sub-acute study different doses were given orally for 28 consecutive days. At the dose of 2000 mg/kg satellite group was also used for 6 weeks as per OECD guidelines-407. General behavioral parameters were assessed in acute toxicity and found no mortality or exterior signs of toxicity. While in the sub-acute study; biochemical, hematological and histopathology along with the body weight, food, and water consumptions parameters were screened in the animals after 14 & 28 days. The study reveals the insignificant (P < 0.05) change in treated group in comparison to the control. The hydroalcoholic leaves extract of Reinwardtia indica was found non-toxic up to 5000 mg/kg in acute study whereas up to 2000 mg/kg dose level in the sub-acute study.

Toxicity assessment of the alcoholic leaves extract of Reinwardtia indica

The present study aimed to evaluate the safety of the alcoholic leaves extract of Reinwardtia indica in Charles foster rats through an acute and sub-acute oral administration.For assessment of acute oral toxicity test, ratswere orally treated with single dose of the alcoholic leaves extract of Reinwardtia indica at the doses of 50, 250, 500, 1000 2000 and 5000 mg/kg. In sub-acute toxicity study, using the OECD guidelines no. 407, the extract was administered at the doses of 50, 250, 500, 1000, 2000 mg/kg/day for 28 consecutive days and at the dose of 2000 mg/kg satellite group also used for 6 weeks.In acute toxicity above mentioned doses neither showed mortality nor exterior signs of toxicity. In sub-acute, study no significant changes found in haematological and biochemical level ofthe treated rat after 14 days and 28 days in comparison to control. The histopathology of rat brain, kidney, liver, and heart also showed the no cellular changes after extract treated rat.The alcoholic leaves extract of Reinwardtia indica was found non-toxic in single drug dose administration up to 5000 mg/kg (acute study) and in sub-acute administration up to 2000 mg/kg.

Intramolecular trapping of ammonium ylides with N-benzoylbenzotriazoles in aqueous medium: direct access to the pseudoindoxyl scaffold.

The present work documents an operationally simple, clean and practical method for accessing the 2,2-disubstituted indolin-3-one (pseudoindoxyl) scaffold. The rhodium carbenoid mediated reaction between N-o-alkylamino benzoylbenzotriazoles and aryl diazoacetates occurs smoothly in water and exploits the leaving group ability of the benzotriazole moiety to install the carbonyl function in the product. Other highlights of the methodology are a wide substrate scope and experimental practicality given the re-use of the benzotriazole byproduct for starting material preparation.

Correlation of Mandibular Foramen to Occlusal Plane as a Clinical Guide for Inferior Alveolar Nerve Block in Children: A Digital Panoramic Radiographic Study.

AIM: The study aimed to correlate the position of mandibular foramen with occlusal plane as a clinical guide for inferior alveolar nerve block (IANB) injection in children from 3 to 13 years of age. MATERIALS AND METHODS: The study was carried out on 180 children visiting our department and required orthopantomogram as a routine diagnostic aid. Mandibular casts were obtained and radiographs were digitally analyzed to obtain linear and angular measurements. STATISTICAL ANALYSIS: The measurements were correlated with the position of mandibular foramen with Karl Pearson's correlation test. RESULTS: The results of the study suggest that the needle for IANB should be placed below the occlusal plane in 3-4-year-old children (1.26 mm approximately), almost at the level of occlusal plane in 5-7 years (0.33 mm), above the occlusal plane in 7-9 years (1.54 mm), 9-12 years (1.64 mm), 11-12 years (1.98 mm), and 12-13 years (2.9 mm), respectively. The distance of the mandibular foramen from anterior border of mandible was greater than that from posterior border. The gonial angle values decrease with increasing age. CONCLUSION: The bony landmarks within the jaws keep changing their relative positions along with the skeletal growth. It is therefore necessary to modify the placement of needle during local anesthesia techniques with advancing age.

Antioxidant and Antiapoptotic effect of aqueous extract of Pueraria tuberosa (Roxb. Ex Willd.) DC. On streptozotocin-induced diabetic nephropathy in rats.

BACKGROUND: Oxidative stress and renal apoptosis play a significant role in the progression of diabetic nephropathy. The tubers of Pueraria tuberosa (Roxb. ex Willd.) DC. has been traditionally used as anti-ageing and health promotive tonic. The purpose of this study was to investigate its nephroprotective effect and mechanism via antioxidant and antiapoptotic potential in Streptozotocin-induced diabetic nephropathy (DN) in rats. METHODS: The chemical composition of aqueous extract of Pueraria tuberosa (PTY-2r) was analyzed by gas chromatography-mass spectrometry (GC-MS). Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) (55 mg/kg body weight) in rats. After 60 days, the rats were randomly divided into 3 groups (n = 6/each group), namely DN control (DN) group-2, DN rats treated with PTY-2r at the dose of 50 mg/100 g, group-3 and 100 mg/100 g, group-4 p.o. for 20 days. The normal rats were chosen as a normal control (NC) group-1. PTY-2r was orally given to the rats for 20 days. Reactive oxygen species (ROS), lipid peroxidation (LPO) and the activity of ROS-scavenging enzymes - superoxide dismutase (SOD), catalase (CAT) & glutathione peroxidase (GPx) were determined in the kidney tissue of DN rats. The expression of apoptosis-related proteins was measured by immunofluorescence. RESULTS: GC-MS analysis of PTY-2r indicated the presence of 37 compounds among them 5-Hydroxymethylfurfural (17.80%), 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one (17.03%), n-Hexadecanoic acid (5.18%) and 9-Octadecenoic acid (Z) - (6.69%) were found in the higher amount. A significant increase in ROS and LPO was observed along with the decreased activity of antioxidant enzymes, responsible for oxidative stress in the kidney of DN rats. Since, high oxidative stress induces apoptosis in target cells, as shown by significantly decreased expression of Bcl-2 along with increased expression of Bax, active Caspase-3 & cleaved PARP-1 in DN control rats, suggesting apoptosis. The PTY-2r treatment significantly raised the activity of antioxidant enzymes, suppressed oxidative stress and apoptosis thus, prevented urinary albumin excretion in a dose-dependent manner. CONCLUSIONS: The findings suggest that PTY-2r exerted the nephroprotective potential against STZ induced DN rats via suppressing oxidative stress and apoptosis due to the presence of different bioactive compounds. ᅟ.

Pueraria tuberosa extract inhibits iNOS and IL-6 through suppression of PKC-α and NF-kB pathway in diabetes-induced nephropathy.

OBJECTIVES: Inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to explore the anti-inflammatory role of PTY-2r (extracted from Pueraria tuberosa), on streptozotocin (STZ)-induced DN rats. METHODS: Diabetes was induced by intraperitoneal injection of STZ (55mg/kg) in rats. After 60 days, the rats were randomly divided into three groups (n = 6/each group), namely DN control group 2, DN rats treated with PTY-2r at dose of 100 mg/100 g, group 3 and 50 mg/100 g, group 4, p.o for 20 days. The normal rats were chosen as a normal control (NC) group 1. KEY FINDINGS: In DN rats, the expression of iNOS and inflammatory cytokines (IL-6 and TNF-α) was significantly increased. Raised expression of PKC-α was also found. As NF-kB is the main transcription factor for the inflammatory response-mediated progression of DN, variation in NF-kB expression and its activated phosphorylated derivative (pNF-kB) were also evaluated and increase in expression was obtained in the kidney of DN rats. PTY-2r treatment significantly reversed these changes in dose-dependent manner. CONCLUSIONS: This study suggested that the nephroprotective effect of PTY-2r is possibly due to downregulation of PKC-α and NF-kB pathway and normalizing the expression of inflammatory cytokines and iNOS in the kidney of DN rats.

Cyclin dependent kinase inhibitor 2A/B gene deletions are markers of poor prognosis in Indian children with acute lymphoblastic leukemia.

BACKGROUND: Cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) genes are implicated in many malignancies including acute lymphoblastic leukemia (ALL). These tumor suppressor genes, with a key regulatory role in cell cycle are located on chromosome 9p21.3. Previous studies involving CDKN2A/B gene deletions have shown mixed associations with survival outcome in childhood ALL. PROCEDURE: Hundred and four newly diagnosed children with ALL (1-14 years) were enrolled in this study. Genomic DNA from pretreatment bone marrow/peripheral blood samples of these children was investigated for copy number alterations in CDKN2A/B genes using multiplex ligation dependent probe amplification assay. Immunophenotype subtyping and cytogenetic and molecular analysis of ALL was performed at start of induction chemotherapy in all children. Children were monitored for response to prednisolone (Day 8), complete morphological remission, and minimal residual disease at the end of induction. The minimum postinduction follow-up period was 6 months. RESULTS: CDKN2A/B deletions were seen in 19.8% (18/91) of B lineage acute lymphoblastic leukemia (B-ALL) and 38.5% (5/13) of T lineage acute lymphoblastic leukemia (T-ALL). Monoallelic CDKN2A/B deletions were found in 61.1% of total deletions in B-ALL while all the children with T-ALL harbored biallelic deletions. The prevalence of CDKN2A/B gene deletions was found to be significantly higher in older children (P = 0.002), in those with higher leukocyte count (P = 0.037), and in National Cancer Institute high risk group patients (P = 0.001) in the B-ALL subgroup. Hazard ratio was significantly high for children with CDKN2A/B deletions in total cohort (P = 0.004). Children with CDKN2A/B deletion had significantly lesser event free survival (P = 0.03). CONCLUSIONS: CDKN2A/B deletions were significantly more prevalent in T-ALL subgroup and were found to have higher hazard ratio and lesser event free survival in total cohort in our study.

Cognitive Deficits in Schizophrenia: Understanding the Biological Correlates and Remediation Strategies.

Cognitive deficits are one of the core symptoms of schizophrenia that evolve during the course of schizophrenia, after being originated even before the onset of illness. Existing pharmacological and biological treatment modalities fall short to meet the needs to improve the cognitive symptoms; hence, various cognitive remediation strategies have been adopted to address these deficits. Research evidences suggest that cognitive remediation measures improve the functioning, limit disability bettering the quality of life. The functional outcomes of cognitive remediation in schizophrenia are resultant of neurobiological changes in specific brain areas. Recent years witnessed significant innovations in cognitive remediation strategies in schizophrenia. This comprehensive review highlights the biological correlates of cognitive deficits in schizophrenia and the remedial measures with evidence base.