Publications by authors named "Mubeen Khan"

39 Publications

Oral health status among transgender young adults: a cross-sectional study.

BMC Oral Health 2021 Nov 12;21(1):575. Epub 2021 Nov 12.

Oral Diagnostic and Surgical Sciences Division, UWA Dental School, The University of Western Australia, 17 Monash Avenue, Nedlands, WA, 6009, Australia.

Background: Transgender and gender nonconforming (TGNC) people are a marginalized set of the population that continues to experience health care inequalities. This study aimed to assess oral health parameters including Candida growth and intensity among TGNC adults.

Methods: This cross-sectional study recruited two subgroups: 40 transgender and 40 control adults. Consented participants were interviewed and clinically examined. Data using the WHO oral health assessment forms were obtained. Samples for Candida growth and intensity analysis were collected from the dorsum surface of the tongue.

Results: 27.5% of the transgender group was HIV seropositive. Oral nicotine stomatitis and leukoplakia are reported to be the most prevalent intra-oral lesions showing a prevalence of 27.5% and 20%, respectively. The dental and periodontal health parameters of the transgender group were worse than those of the control group. The intensity of Candida colonies was significantly higher in the test group (p = 0.014).

Conclusion: Poor oral health and significant oral mucosal disorders were reported in transgender adults that have shown a higher rate of behavioral risk factors such as tobacco and alcohol consumption. Further longitudinal studies in different world regions are warranted to understand the barriers to good oral health in transgender adults and how to implement effective prevention and management strategies.
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http://dx.doi.org/10.1186/s12903-021-01945-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588739PMC
November 2021

PRPH2 mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease.

Hum Mutat 2021 Dec 20;42(12):1521-1547. Epub 2021 Sep 20.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Mutations in PRPH2, encoding peripherin-2, are associated with the development of a wide variety of inherited retinal diseases (IRDs). To determine the causality of the many PRPH2 variants that have been discovered over the last decades, we surveyed all published PRPH2 variants up to July 2020, describing 720 index patients that in total carried 245 unique variants. In addition, we identified seven novel PRPH2 variants in eight additional index patients. The pathogenicity of all variants was determined using the ACMG guidelines. With this, 107 variants were classified as pathogenic, 92 as likely pathogenic, one as benign, and two as likely benign. The remaining 50 variants were classified as variants of uncertain significance. Interestingly, of the total 252 PRPH2 variants, more than half (n = 137) were missense variants. All variants were uploaded into the Leiden Open source Variation and ClinVar databases. Our study underscores the need for experimental assays for variants of unknown significance to improve pathogenicity classification, which would allow us to better understand genotype-phenotype correlations, and in the long-term, hopefully also support the development of therapeutic strategies for patients with PRPH2-associated IRD.
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http://dx.doi.org/10.1002/humu.24275DOI Listing
December 2021

In ANCA-associated vasculitis, avacopan was superior to prednisone taper for sustained remission.

Ann Intern Med 2021 07 6;174(7):JC79. Epub 2021 Jul 6.

University of Texas McGovern Medical School, Houston, Texas, USA (M.M.K., D.A.M.).

Source Citation: Jayne DRW, Merkel PA, Schall TJ, et al. N Engl J Med. 2021;384:599-609. 33596356.
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http://dx.doi.org/10.7326/ACPJ202107200-079DOI Listing
July 2021

Benchmarking deep learning splice prediction tools using functional splice assays.

Hum Mutat 2021 Jul 20;42(7):799-810. Epub 2021 May 20.

Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Hereditary disorders are frequently caused by genetic variants that affect pre-messenger RNA splicing. Though genetic variants in the canonical splice motifs are almost always disrupting splicing, the pathogenicity of variants in the noncanonical splice sites (NCSS) and deep intronic (DI) regions are difficult to predict. Multiple splice prediction tools have been developed for this purpose, with the latest tools employing deep learning algorithms. We benchmarked established and deep learning splice prediction tools on published gold standard sets of 71 NCSS and 81 DI variants in the ABCA4 gene and 61 NCSS variants in the MYBPC3 gene with functional assessment in midigene and minigene splice assays. The selection of splice prediction tools included CADD, DSSP, GeneSplicer, MaxEntScan, MMSplice, NNSPLICE, SPIDEX, SpliceAI, SpliceRover, and SpliceSiteFinder-like. The best-performing splice prediction tool for the different variants was SpliceRover for ABCA4 NCSS variants, SpliceAI for ABCA4 DI variants, and the Alamut 3/4 consensus approach (GeneSplicer, MaxEntScacn, NNSPLICE and SpliceSiteFinder-like) for NCSS variants in MYBPC3 based on the area under the receiver operator curve. Overall, the performance in a real-time clinical setting is much more modest than reported by the developers of the tools.
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http://dx.doi.org/10.1002/humu.24212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360004PMC
July 2021

A Cross-Sectional Study on Ultrasonographic Measurements of Parotid Glands in Type 2 Diabetes Mellitus.

Int J Dent 2021 2;2021:5583412. Epub 2021 Mar 2.

Department of Medicine, Bangalore Medical College and Research Institute, Bangalore 560001, India.

Background: Diabetes mellitus is a metabolic disease which is seen increasing globally and is diagnosed and monitored on basis of invasive blood investigations. Salivary glands are affected in diabetes mellitus. The objective of this study was to assess ultrasonographic measurements of parotid glands and correlate with the glycosylated hemoglobin levels in type 2 diabetic mellitus and duration of type 2 diabetic mellitus and treatment regimens.

Materials And Methods: This study was conducted on 50 subjects of type 2 diabetes mellitus and on 50 healthy controls. After HbA analysis of selected individuals, 100 individuals were grouped into group I (above 5.7) and group II (below 5.7). Ultrasonographic measurements (length (), transverse dimension (TD), depth lateral to the mandible (DLM), and depth dorsal to the mandible (DDM)) of bilateral parotid glands were calculated. Statistical analysis was done using the chi-square test of significance and Spearman correlation coefficients.

Results: On correlation with measurement of right (L, DLM, DDM) and left (TD, DLM, DDM) of parotid glands with duration of type 2 diabetes mellitus, we found a moderate positive relationship, whereas as for right (TD) and left (), we found a low-positive relationship. Similarly, for right (L, TD, DLM, DDM) and left (TD, DDM) parotid glands with HbA, we found a low-positive relationship, whereas for left parotid gland (L, DLM) with HbA, we found a moderate positive relationship. The mean DLM of right and left parotids in the insulin group was found to be slightly more than that in the combined group which was statistically insignificant.

Conclusion: Ultrasonographic measurements of parotid glands were found to be higher in study subjects as compared to control subjects, and they increased with increased HbA levels; also, there was no difference in treatment regimen. Ultrasonography could be a prospective diagnostic test for detection and monitoring of diabetes mellitus, and still further studies are required for this.
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http://dx.doi.org/10.1155/2021/5583412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943275PMC
March 2021

Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease.

JAMA Ophthalmol 2020 10;138(10):1035-1042

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

Importance: The mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management.

Objective: To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1.

Design, Setting, And Participants: Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020.

Main Outcomes And Measures: Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed.

Results: A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P = .02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P = .005).

Conclusions And Relevance: This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.2990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441467PMC
October 2020

Detailed Phenotyping and Therapeutic Strategies for Intronic ABCA4 Variants in Stargardt Disease.

Mol Ther Nucleic Acids 2020 Sep 12;21:412-427. Epub 2020 Jun 12.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Stargardt disease is a progressive retinal disorder caused by bi-allelic mutations in the ABCA4 gene that encodes the ATP-binding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease.
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http://dx.doi.org/10.1016/j.omtn.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352060PMC
September 2020

Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.

Genet Med 2020 07 20;22(7):1235-1246. Epub 2020 Apr 20.

Bartiméus Diagnostic Center for Complex Visual Disorders, Zeist, The Netherlands.

Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands.

Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays.

Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband.

Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
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http://dx.doi.org/10.1038/s41436-020-0787-4DOI Listing
July 2020

In or Out? New Insights on Exon Recognition through Splice-Site Interdependency.

Int J Mol Sci 2020 03 26;21(7). Epub 2020 Mar 26.

Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

Noncanonical splice-site mutations are an important cause of inherited diseases. Based on in vitro and stem-cell-based studies, some splice-site variants show a stronger splice defect than expected based on their predicted effects, suggesting that other sequence motifs influence the outcome. We investigated whether splice defects due to human-inherited-disease-associated variants in noncanonical splice-site sequences in , , and could be rescued by strengthening the splice site on the other side of the exon. Noncanonical 5'- and 3'-splice-site variants were selected. Rescue variants were introduced based on an increase in predicted splice-site strength, and the effects of these variants were analyzed using in vitro splice assays in HEK293T cells. Exon skipping due to five variants in noncanonical splice sites of exons in , , and could be partially or completely rescued by increasing the predicted strengths of the other splice site of the same exon. We named this mechanism "splicing interdependency", and it is likely based on exon recognition by splicing machinery. Awareness of this interdependency is of importance in the classification of noncanonical splice-site variants associated with disease and may open new opportunities for treatments.
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http://dx.doi.org/10.3390/ijms21072300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177576PMC
March 2020

ABCA4-Associated Stargardt Disease.

Klin Monbl Augenheilkd 2020 Mar 3;237(3):267-274. Epub 2020 Feb 3.

Department of Human Genetics, Radboudumc, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Autosomal recessive Stargardt disease (STGD1) is associated with variants in the gene. The phenotypes range from early-onset STGD1, that clinically resembles severe cone-rod dystrophy, to intermediate STGD1 and late-onset STGD1. These different phenotypes can be correlated with different combinations of variants which can be classified according to their degree of severity. A significant fraction of STGD1 cases, particularly late-onset STGD1 cases, were shown to carry only a single variant. A frequent coding variant (p.Asn1868Ile) was recently identified which - in combination with a severe variant - is generally associated with late-onset STGD1. In addition, an increasing number of rare deep-intronic variants have been found and some of these are also associated with late-onset STGD1. The effect of these and other variants on RNA was tested using assays in human kidney cells using specially designed midigenes. With stem cells and photoreceptor progenitor cells derived from patient skin or blood cells, retina-specific splice defects can be assessed. With expert clinical examination to distinguish STGD1 cases from other maculopathies, as well as in-depth genomics and transcriptomics data, it is now possible to identify both mutant alleles in > 95% of cases.
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http://dx.doi.org/10.1055/a-1057-9939DOI Listing
March 2020

No Association Linking Short-Term Proton Pump Inhibitor Use to Dementia: Systematic Review and Meta-analysis of Observational Studies.

Am J Gastroenterol 2020 05;115(5):671-678

Division of Gastroenterology and Hepatology, University of Tennessee College of Medicine, Memphis, Tennessee, USA.

Introduction: Long-term use of proton pump inhibitors (PPIs) has been associated with a wide variety of potentially serious adverse effects including a possible increased risk of dementia. Studies evaluating this association have reached divergent conclusions. We aimed to evaluate this proposed association further and to assess the quality of the evidence in its support.

Methods: We searched MEDLINE, EMBASE, ISI Web of Science, and Cochrane databases for studies examining a link between PPI use and dementia, up to February 2019. Studies reporting summary results as hazard ratio (HR) or odds ratio (OR) were pooled using the DerSimonian and Laird random-effects model for meta-analyses. Methodological quality of individual observational studies was assessed using the Newcastle-Ottawa scale and the overall quality of evidence rated as per the GRADE approach.

Results: We identified and included 11 observational studies comprising 642,949 subjects; 64% were women. Most studies were short-term ranging from 5 to 10 years. There were 158,954 PPI users and 483,995 nonusers. For studies summarizing data as adjusted HR, pooled HR for all causes of dementia was 1.10 (0.88-1.37); for Alzheimer dementia only, it was 1.06 (0.72-1.55). For studies summarizing data as adjusted OR, pooled OR for all causes of dementia was 1.03 (0.84-1.25) and for Alzheimer dementia only 0.96 (0.82-1.11). Per Newcastle-Ottawa scale assessment, 10 studies were of high quality and 1 was of moderate quality. By applying GRADE methodology, quality of evidence for both outcomes was very low.

Discussion: We found no evidence to support the proposed association between PPI use and an increased risk of dementia. PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.
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http://dx.doi.org/10.14309/ajg.0000000000000500DOI Listing
May 2020

Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles.

Invest Ophthalmol Vis Sci 2019 10;60(13):4249-4256

Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1).

Methods: Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253+43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769-784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs).

Results: Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253+43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253+43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5%-39.6%) and c.4253+43G>A (35.8%-43.1%) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253+43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15% of the total mRNA (i.e., ∼30% of the c.769-784C>T allele alone).

Conclusions: Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene.
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http://dx.doi.org/10.1167/iovs.19-27524DOI Listing
October 2019

Identification of splice defects due to noncanonical splice site or deep-intronic variants in ABCA4.

Hum Mutat 2019 12 3;40(12):2365-2376. Epub 2019 Sep 3.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.

Pathogenic variants in the ATP-binding cassette transporter A4 (ABCA4) gene cause a continuum of retinal disease phenotypes, including Stargardt disease. Noncanonical splice site (NCSS) and deep-intronic variants constitute a large fraction of disease-causing alleles, defining the functional consequences of which remains a challenge. We aimed to determine the effect on splicing of nine previously reported or unpublished NCSS variants, one near exon splice variant and nine deep-intronic variants in ABCA4, using in vitro splice assays in human embryonic kidney 293T cells. Reverse transcription-polymerase chain reaction and Sanger sequence analysis revealed splicing defects for 12 out of 19 variants. Four deep-intronic variants create pseudoexons or elongate the upstream exon. Furthermore, eight NCSS variants cause a partial deletion or skipping of one or more exons in messenger RNAs. Among the 12 variants, nine lead to premature stop codons and predicted truncated ABCA4 proteins. At least two deep-intronic variants affect splice enhancer and silencer motifs and, therefore, these conserved sequences should be carefully evaluated when predicting the outcome of NCSS and deep-intronic variants.
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http://dx.doi.org/10.1002/humu.23890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899986PMC
December 2019

Cost-effective molecular inversion probe-based ABCA4 sequencing reveals deep-intronic variants in Stargardt disease.

Hum Mutat 2019 10 18;40(10):1749-1759. Epub 2019 Jun 18.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: Stargardt disease (STGD1) is caused by biallelic mutations in ABCA4, but many patients are genetically unsolved due to insensitive mutation-scanning methods. We aimed to develop a cost-effective sequencing method for ABCA4 exons and regions carrying known causal deep-intronic variants.

Methods: Fifty exons and 12 regions containing 14 deep-intronic variants of ABCA4 were sequenced using double-tiled single molecule Molecular Inversion Probe (smMIP)-based next-generation sequencing. DNAs of 16 STGD1 cases carrying 29 ABCA4 alleles and of four healthy persons were sequenced using 483 smMIPs. Thereafter, DNAs of 411 STGD1 cases with one or no ABCA4 variant were sequenced. The effect of novel noncoding variants on splicing was analyzed using in vitro splice assays.

Results: Thirty-four ABCA4 variants previously identified in 16 STGD1 cases were reliably identified. In 155/411 probands (38%), two causal variants were identified. We identified 11 deep-intronic variants present in 62 alleles. Two known and two new noncanonical splice site variants showed splice defects, and one novel deep-intronic variant (c.4539+2065C>G) resulted in a 170-nt mRNA pseudoexon insertion (p.[Arg1514Lysfs*35,=]).

Conclusions: smMIPs-based sequence analysis of coding and selected noncoding regions of ABCA4 enabled cost-effective mutation detection in STGD1 cases in previously unsolved cases.
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http://dx.doi.org/10.1002/humu.23787DOI Listing
October 2019

ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.

Genet Med 2019 08 23;21(8):1761-1771. Epub 2019 Jan 23.

Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.

Purpose: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability.

Methods: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4.

Results: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells.

Conclusion: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.
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http://dx.doi.org/10.1038/s41436-018-0420-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752479PMC
August 2019

Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides.

Genet Med 2019 08 15;21(8):1751-1760. Epub 2019 Jan 15.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability.

Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.

Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.

Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.
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http://dx.doi.org/10.1038/s41436-018-0414-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752325PMC
August 2019

SHROOM3-FYN Interaction Regulates Nephrin Phosphorylation and Affects Albuminuria in Allografts.

J Am Soc Nephrol 2018 11 19;29(11):2641-2657. Epub 2018 Oct 19.

Division of Nephrology, Department of Medicine and

Background: We previously showed that the presence of a CKD-associated locus in SHROOM3 in a donor kidney results in increased expression of SHROOM3 (an F-actin-binding protein important for epithelial morphogenesis, via rho-kinase [ROCK] binding); this facilitates TGF-b signaling and allograft fibrosis. However, other evidence suggests Shroom3 may have a protective role in glomerular development.

Methods: We used human data, Shroom3 knockdown podocytes, and inducible shRNA-mediated knockdown mice to study the role of Shroom3 in adult glomeruli.

Results: Expression data from the Nephroseq database showed glomerular and nonglomerular had opposing associations with renal function in CKD biopsy samples. In human allografts, homozygosity at rs17319721, the SHROOM3 locus linked with lower GFR, was associated with reduced albuminuria by 2 years after transplant. Although our previous data showed reduced renal fibrosis with tubular Shroom3 knockdown, this study found that glomerular but not tubular Shroom3 knockdown induced albuminuria. Electron microscopy revealed diffuse foot process effacement, and glomerular RNA-sequencing showed enrichment of tyrosine kinase signaling and podocyte actin cytoskeleton pathways in knockdown mice. Screening SHROOM3-interacting proteins identified FYN (a src-kinase) as a candidate.We confirmed the interaction of endogenous SHROOM3 with FYN in human podocytes via a critical Src homology 3-binding domain, distinct from its ROCK-binding domain. Shroom3-Fyn interaction was required in vitro and in vivo for activation of Fyn kinase and downstream nephrin phosphorylation in podocytes. SHROOM3 knockdown altered podocyte morphology, cytoskeleton, adhesion, and migration.

Conclusions: We demonstrate a novel mechanism that may explain SHROOM3's dichotomous associations in glomerular versus nonglomerular compartments in CKD.
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http://dx.doi.org/10.1681/ASN.2018060573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218856PMC
November 2018

Identification and Analysis of Genes Associated with Inherited Retinal Diseases.

Methods Mol Biol 2019 ;1834:3-27

Department of Human Genetics, Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

Inherited retinal diseases (IRDs) display a very high degree of clinical and genetic heterogeneity, which poses challenges in finding the underlying defects in known IRD-associated genes and in identifying novel IRD-associated genes. Knowledge on the molecular and clinical aspects of IRDs has increased tremendously in the last decade. Here, we outline the state-of-the-art techniques to find the causative genetic variants, with special attention for next-generation sequencing which can combine molecular diagnostics and retinal disease gene identification. An important aspect is the functional assessment of rare variants with RNA and protein effects which can only be predicted in silico. We therefore describe the in vitro assessment of putative splice defects in human embryonic kidney cells. In addition, we outline the use of stem cell technology to generate photoreceptor precursor cells from patients' somatic cells which can subsequently be used for RNA and protein studies. Finally, we outline the in silico methods to interpret the causality of variants associated with inherited retinal disease and the registry of these variants.
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http://dx.doi.org/10.1007/978-1-4939-8669-9_1DOI Listing
April 2019

Identification and Rescue of Splice Defects Caused by Two Neighboring Deep-Intronic ABCA4 Mutations Underlying Stargardt Disease.

Am J Hum Genet 2018 04 8;102(4):517-527. Epub 2018 Mar 8.

Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 EN Nijmegen, the Netherlands. Electronic address:

Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal-recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. By generating photoreceptor precursor cells (PPCs) from fibroblasts obtained from individuals with STGD1, we demonstrated that two neighboring deep-intronic ABCA4 variants (c.4539+2001G>A and c.4539+2028C>T) result in a retina-specific 345-nt pseudoexon insertion (predicted protein change: p.Arg1514Leufs36), likely due to the creation of exonic enhancers. Administration of antisense oligonucleotides (AONs) targeting the 345-nt pseudoexon can significantly rescue the splicing defect observed in PPCs of two individuals with these mutations. Intriguingly, an AON that is complementary to c.4539+2001G>A rescued the splicing defect only in PPCs derived from an individual with STGD1 with this but not the other mutation, demonstrating the high specificity of AONs. In addition, a single AON molecule rescued splicing defects associated with different neighboring mutations, thereby providing new strategies for the treatment of persons with STGD1. As many genes associated with human genetic conditions are expressed in specific tissues and pre-mRNA splicing may also rely on organ-specific factors, our approach to investigate and treat splicing variants using differentiated cells derived from individuals with STGD1 can be applied to any tissue of interest.
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http://dx.doi.org/10.1016/j.ajhg.2018.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985352PMC
April 2018

midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease.

Genome Res 2018 01 21;28(1):100-110. Epub 2017 Nov 21.

Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

Stargardt disease is caused by variants in the gene, a significant part of which are noncanonical splice site (NCSS) variants. In case a gene of interest is not expressed in available somatic cells, small genomic fragments carrying potential disease-associated variants are tested for splice abnormalities using in vitro splice assays. We recently discovered that when using small minigenes lacking the proper genomic context, in vitro results do not correlate with splice defects observed in patient cells. We therefore devised a novel strategy in which a bacterial artificial chromosome was employed to generate midigenes, splice vectors of varying lengths (up to 11.7 kb) covering almost the entire gene. These midigenes were used to analyze the effect of all 44 reported and three novel NCSS variants on pre-mRNA splicing. Intriguingly, multi-exon skipping events were observed, as well as exon elongation and intron retention. The analysis of all reported NCSS variants in allowed us to reveal the nature of aberrant splicing events and to classify the severity of these mutations based on the residual fraction of wild-type mRNA. Our strategy to generate large overlapping splice vectors carrying multiple exons, creating a toolbox for robust and high-throughput analysis of splice variants, can be applied to all human genes.
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http://dx.doi.org/10.1101/gr.226621.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749174PMC
January 2018

Colposcopy in oral epithelial dysplasia: seeing the unseen, a pilot study.

J Cancer Res Ther 2014 Jul-Sep;10(3):563-70

Department of Oral Medicine and Radiology, Government Dental College and Research Institute, Bangalore, Karnataka, India.

Context: The diagnosis of malignant and potentially malignant epithelial lesions of oral mucosa cannot be based solely on clinical findings. The histologic evaluation of a representative biopsy specimen thus becomes necessary. The site for biopsy, however, is always a subjective choice that sometimes raises doubts about its representativeness. So far, no simple and reliable method is available for the selection of the most appropriate area for biopsy. Colposcopy is helpful in the selection of these sites of epithelial dysplasia depending upon the vascular patterns.

Aims: The study was planned to assess the role of colposcopic examination in the selection of biopsy site in patients with varying grades of oral epithelial dysplasia at various sites.

Settings And Design: Fifty patients between the ages of 30-60 years clinically diagnosed with leukoplakia and carcinoma buccal mucosa were included in the study.

Materials And Methods: For each of the subject, a thorough clinical examination followed by colposcopic assessment was carried out for the selection of biopsy site from the involved mucosa. The histopathological findings were then compared in the two cases and results analyzed.

Statistical Analysis Used: The statistical analysis was done using paired t-test.

Results: In our study, sensitivity and specificity for the selection of biopsy site by colposcopic examination came out to be higher for leukoplakia than carcinoma buccal mucosa patients.

Conclusions: It was concluded that colposcopic examination was found more significant in the selection of biopsy site for leukoplakia patients while clinical criterion was found to be more appropriate for carcinoma buccal mucosa cases.
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http://dx.doi.org/10.4103/0973-1482.137957DOI Listing
June 2015

Parry Romberg syndrome with localized scleroderma: A case report.

J Clin Exp Dent 2014 Jul 1;6(3):e313-6. Epub 2014 Jul 1.

Post Graduate Student. Department of Oral Medicine and Radiology, Government Dental College and Research Institute, Bangalore, Karnataka, India.

Parry Romberg syndrome(PRS) is a rare acquired poorly understood neurocutaneous syndrome of unknown etiology characterized by slow progressive atrophic changes commonly affecting one half of the face. The exact incidence and etiology towards the syndrome remains unclear. Apart from the multifactorial etiology proposed, the possible primary cause is mainly attributed to the cerebral disturbance of the fat metabolism. The syndrome overlaps with "en coup de sabre" morphea, with an ill defined relationship existing between the two. Parry Romberg Syndrome is an invalidating lesion that may be associated with different neurological, cutaneous, ocular, dental and autoimmune abnormalities. This report presents one rare case of 22 years old female patient with Parry Romberg syndrome associated with localized scleroderma, accompanied by a brief review of literature with classical clinical, radiographic, histological findings and the treatment of progressive hemifacial atrophy. Key words:Parry Romberg syndrome, progressive facial hemiatrophy, morphea, localized scleroderma.
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http://dx.doi.org/10.4317/jced.51409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134867PMC
July 2014

Colposcopy: gynecological vision in viewing oral lesions.

Indian J Pathol Microbiol 2014 Apr-Jun;57(2):223-30

Department of Oral Medicine and Radiology, Government Dental College and Research Institute, Bangalore, Karnataka, India.

Context: The diagnosis of malignant and potentially malignant epithelial lesions of the oral mucosa cannot be based solely on clinical findings. The histologic evaluation of a representative biopsy specimen thus becomes necessary. The site for biopsy however is always a subjective choice that sometimes raises doubts about its representativeness. So far, no simple and reliable method is available for the selection of the most appropriate area for biopsy. Colposcopy is helpful in the selection of these sites of epithelial dysplasia depending upon the vascular patterns.

Aims: This study was planned to assess the role of Colposcopic examination in the selection of biopsy site in patients with varying grades of oral epithelial dysplasia at various sites.

Settings And Design: One hundred and eighty patients between the ages of 30 and 60 years clinically diagnosed with leukoplakia and carcinoma buccal mucosa were included in the study.

Materials And Methods: For each of the subjects, a thorough clinical examination followed by Colposcopic assessment was carried out for the selection of biopsy site from the involved mucosa. The histopathological findings were then compared in the two cases and results analyzed.

Statistical Analysis Used: The statistical analysis was performed using a paired t-test.

Results: In our study, sensitivity and specificity for the selection of biopsy site by Colposcopic examination was found to be higher for leukoplakia than for carcinoma buccal mucosa.

Conclusions: It was concluded that Colposcopic examination was found to be significant in the selection of biopsy site for leukoplakia while clinical criterion was found to be more appropriate for carcinoma buccal mucosa cases.
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http://dx.doi.org/10.4103/0377-4929.134672DOI Listing
April 2015

Phenytoin, folic acid and gingival enlargement: Breaking myths.

Contemp Clin Dent 2014 Jan;5(1):59-66

Department of Clinical Biochemistry, Bangalore Medical College and Research Institute, Bangalore, Karnataka, India.

Background: Epilepsy is described as a chronic neurological disorder characterized by recurrent seizures of cerebral origin, presenting with episodes of sensory, motor or autonomic phenomenon with or, without loss of consciousness. A recent meta-analysis of published and unpublished studies puts an overall prevalence rate of epilepsy in India at 5.59 per 1,000 populations. There have been studies that report clinical benefits of the use of folic acid as an adjuvant to the anti-epileptic therapy in the prevention of anti-epileptic drug induced gingival enlargement. However, studies conducted in the past have also reported precipitation of epileptic attacks in patients on folic acid adjuvant therapy due to fall in sera levels of phenytoin due to drug interactions. The study was planned to investigate the association of phenytoin induced gingival enlargement and sera levels of folic acid in epileptic patients on phenytoin therapy so as to justify the use of folic acid as a routine adjuvant to the usual anti-epileptic therapy to prevent this inevitable adverse effect without destabilizing the ongoing regimen leading to the precipitation of seizures in an otherwise stable patient (breakthrough seizures).

Materials And Methods: A total of 100 patients between the ages 18 and 50 years were clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of serum folic acid levels and gingival enlargement was performed prior to the start of and after 1 year of phenytoin therapy.

Statistical Analysis Used: The statistical analysis was carried out using t-test and the baseline serum folate levels and the serum folate levels obtained after 1 year of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula.

Results: The results of the study confirmed a significant association between low serum folate levels with increasing severity as well as an early onset of phenytoin induced gingival enlargement.

Conclusions: The results of the study suggest a higher incidence of gingival enlargement with an early onset and increased severity in phenytoin treated epileptic patients with a positive correlation with falling serum folic acid levels as the duration of the therapy increases.
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http://dx.doi.org/10.4103/0976-237X.128666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012119PMC
January 2014

Clinical, radiographic, and histologic presentation of fibrodentinosarcoma.

Quintessence Int 2014 Feb;45(2):169-72

A general dental practitioner should be familiar with certain rare odontogenic entities like fibrodentinosarcoma, which can occur with unerupted or impacted teeth. The knowledge of such rare pathologies usually associated with unerupted/ impacted teeth aids in the early recognition and correct management of these entities, which are often asymptomatic. One such rare, diverse tumor is ameloblastic fibrodentinosarcoma (AFDS), characterized only by sporadic case reports in the literature. It is important to describe the features of this odontogenic entity to general dental practitioners for successful management and to reduce patient morbidity. This report presents a case of AFDS in a 17-year-old woman who reported to our department with a swelling of the right mandible that was associated with an unerupted tooth. The clinical, radiographic, and histologic findings of AFDS are presented, providing the details necessary to assist the primary dental clinical team in management of AFDS.
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http://dx.doi.org/10.3290/j.qi.a30991DOI Listing
February 2014

Carbetocin at elective Cesarean delivery: a sequential allocation trial to determine the minimum effective dose.

Can J Anaesth 2014 Mar 27;61(3):242-8. Epub 2013 Nov 27.

Department of Anesthesia and Pain Management, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Room 781, Toronto, ON, M5G 1X5, Canada.

Purpose: The purpose of this study was to determine the intravenous dose of carbetocin required to produce effective uterine contraction in 90% of females (ED90) undergoing elective Cesarean delivery (CD) under spinal anesthesia.

Methods: We conducted a double-blind dose-finding study of carbetocin. Forty females undergoing elective CD received carbetocin intravenously upon delivery of the fetus. The dose of carbetocin for each patient was determined according to a biased-coin up-and-down sequential allocation scheme designed to cluster doses close to ED90. The initial dose was 10 μg, with increments/decrements of 5 μg. The anesthesiologist, obstetrician, and patient were blinded to the dose. The obstetrician assessed the uterine tone at one-minute intervals for five minutes after carbetocin administration. In case of unsatisfactory tone, additional uterotonics were administered. The primary outcome was requirement for additional intraoperative uterotonics. Secondary outcomes were postoperative requirement for additional uterotonics within 24 hr of delivery, estimated blood loss and side effects.

Results: The ED90 of carbetocin was 14.8 μg (95% confidence interval 13.7 to 15.8). Thirty-seven patients (92.5%) had adequate uterine tone with no requirement of additional intraoperative uterotonics. Two patients (5%) required postoperative uterotonics within 24 hr. The overall mean (SD) estimated blood loss was 786 (403) mL and the overall incidence of hypotension (decrease in systolic blood pressure ≥ 20% baseline) was 37.5%.

Conclusion: Based on our study, the ED90 of carbetocin at elective CD is less than one-fifth the currently recommended dose of 100 μg. This study was registered at clinicaltrials.gov (NCT-01651130).
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http://dx.doi.org/10.1007/s12630-013-0082-9DOI Listing
March 2014

A study on gingival enlargement and folic acid levels in phenytoin-treated epileptic patients: Testing hypotheses.

Surg Neurol Int 2013 3;4:133. Epub 2013 Oct 3.

Department of Oral Medicine and Radiology, Government Dental College and Research Institute, Bangalore, Karnataka, India.

Background: There have been studies that report clinical benefits of the use of folic acid as an adjuvant to the antiepileptic therapy in the prevention of antiepileptic drug-induced gingival enlargement. However, studies in the past have also reported precipitation of epileptic attacks in patients on folic acid adjuvant therapy due to fall in sera levels of phenytoin due to drug interactions. The study was planned to investigate the association of phenytoin-induced gingival enlargement and sera levels of folic acid in epileptic patients on phenytoin therapy. The statistical analysis was done using t-test and the baseline serum folate levels and the serum folate levels obtained after 6 months of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula.

Methods: A total of 25 patients aged between 18 and 50 years, clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of serum folic acid levels and gingival enlargement was done prior to the start of and after 6 months of phenytoin therapy.

Results: The results of the study confirmed a significant association between low serum folate levels with increasing severity as well as an early onset of phenytoin-induced gingival enlargement.

Conclusions: The results of the study suggest a higher incidence of gingival enlargement in phenytoin treated epileptic patients with a positive correlation with falling serum folic acid levels as the duration of the therapy increases.
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http://dx.doi.org/10.4103/2152-7806.119232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814993PMC
November 2013

Management of oral submucous fibrosis by two different drug regimens: A comparative study.

Dent Res J (Isfahan) 2013 Jul;10(4):527-32

Department of Oral Medicine and Radiology, ITS Centre for Dental Studies and Research, Muradnagar, Ghaziabad, India.

Background: Oral Submucous Fibrosis (OSF) is a precancerous condition of the oral mucosa. Existing treatments give only temporary symptomatic relief. Colchicine is an ancient drug with anti-fibrotic and anti-inflammatory properties. We planned to study the effects of colchicine in the management of oral submucous fibrosis.

Materials And Methods: Fifty OSF patients were divided randomly into two groups and treated for 12 weeks. Group 1-Patients were administered tablet colchicine orally, 0.5 mg twice daily and 0.5 ml intralesional injection Hyaluronidase 1,500 IU into each buccal mucosa once a week. Group 2-Patients were administered 0.5 ml intralesional injection Hyaluronidase 1,500 IU and 0.5 ml intralesional injection Hydrocortisone acetate 25 mg/ml in each buccal mucosa once a week alternatively. Student's t test and analysis of variance (ANOVA) were used to compare pre and post treatment results. P<0.05 was considered as significant.

Results: Thirty-three percent in group 1 got relief from burning sensation in the second week. Inter group comparisons of increase in mouth opening and reduction in histological parameters indicated that group 1 patients responded better than group 2.

Conclusion: These encouraging results should prompt further clinical trials with colchicine alone on a larger sample size to broaden the therapeutic usefulness of the drug in the management of OSF.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793419PMC
July 2013

Cardiopulmonary exercise testing in major urological surgery: an old test; a new perspective; a potential application.

BJU Int 2013 Aug;112(4):E232-3

Department of Anaesthesia, Guys and St. Thomas' Hospital, UK.

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http://dx.doi.org/10.1111/bju.12352DOI Listing
August 2013

Psychiatric morbidity among patients with oral submucous fibrosis: a controlled study.

Oral Health Dent Manag 2013 Jun;12(2):85-94

Department of Oral Medicine and Radiology, Dr Syamala Reddy Dental College Hospital and Research Centre, Bangalore, Karnataka, India.

Aim: The study aimed to evaluate the association between oral submucous fibrosis (OSF) and psychiatric morbidity in a controlled manner.

Methods: Matched patients were divided into three groups: Those with areca nut chewing habits with OSF (Group 1; n=50); those with areca nut chewing habits without OSF (Group 2; n=50); those without areca habits and with dental problems other than OSF (Group 3; n=50). The Mini International Neuropsychiatric Interview was used to assess psychiatric morbidity. Dependence to areca products was also assessed.

Results: Sixteen (32%) Group 1 patients had psychiatric morbidity compared to one (2%) in Group 2 and two (4%) in Group 3 (P<0.001). Further, psychiatric morbidity was significantly higher among patients with advanced stages of OSF. In Groups 1 and 2, 49 (98%) and 47 (94%) patients, respectively, had dependence on areca products.

Conclusion: This study has suggested the association of substantial psychiatric morbidity among patients with OSF. In addition to mandatory psychiatric management of these patients, future research should be targeted at a prospective evaluation of a cause and effect relationship as well as at psychiatric interventions.
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June 2013
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