Search

Abstract Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative.

Summary: The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrophy probands. A total of 858 probands were collected from 26 centers, of whom 722 carried no or one pathogenic ABCA4 variant, while 136 cases carried two ABCA4 alleles, one of which was a frequent mild variant, suggesting that deep-intronic variants (DIVs) or other cis-modifiers might have been missed. After single molecule molecular inversion probes (smMIPs)-based sequencing of the complete 128-kb ABCA4 locus, the effect of putative splice variants was assessed in vitro by midigene splice assays in HEK293T cells. The breakpoints of copy number variants (CNVs) were determined by junction PCR and Sanger sequencing. ABCA4 sequence analysis solved 207 of 520 (39.8%) naive or unsolved cases and 70 of 202 (34.7%) monoallelic cases, while additional causal variants were identified in 54 of 136 (39.7%) probands carrying two variants. Seven novel DIVs and six novel non-canonical splice site variants were detected in a total of 35 alleles and characterized, including the c.6283-321C>G variant leading to a complex splicing defect. Additionally, four novel CNVs were identified and characterized in five alleles. These results confirm that smMIPs-based sequencing of the complete ABCA4 gene provides a cost-effective method to genetically solve retinopathy cases and that several rare structural and splice altering defects remain undiscovered in Stargardt disease cases.

Hepatocellular carcinoma (HCC) is primary hepatic malignancy with a high incidence of recurrence. The risk of recurrence directly correlates to patient’s overall prognosis. Management of advanced HCC involves a combination of surgical resection, locoregional therapy, and systemic treatment. Distant metastases are rare, and intraventricular cardiac metastases are even more infrequent. This brief review details an illustrative case of cardiac metastasis after curative treatment of primary HCC and then summarizes the literature on risk factors, treatment options, and patient prognosis in the setting of distant metastases from HCC. Prognosis of metastasis to the heart is generally poor, and available evidence emphasizes the importance of maintaining regular posttreatment screening for metastases in patients with HCC. Given the variable presentation and high risk of recurrence, it is critical to have individualized multimodality treatment plans.

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.

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 HbA1C analysis of selected individuals, 100 individuals were grouped into group I (above 5.7) and group II (below 5.7). Ultrasonographic measurements (length (L), 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 (L), we found a low-positive relationship. Similarly, for right (L, TD, DLM, DDM) and left (TD, DDM) parotid glands with HbA1C, we found a low-positive relationship, whereas for left parotid gland (L, DLM) with HbA1C, 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 HbA1C 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.

The salivary fluid has an old history of study, but its physiological importance has only been recognized recently. In the past 50 years, the pace of salivary research has accelerated with the advent of new techniques that illuminated the biochemical and physicochemical properties of saliva. The interest in saliva increased, further, with the finding that saliva is filled with hundreds of components that might serve to detect systemic diseases and/or act as an evidence of exposure to various harmful substances as well as provide biomarkers of health and disease. The role of saliva in the diagnosis as well as monitoring of glycemic control has, also, been attracting attention of clinical researchers in recent times although results have been conflicting. To conclude, saliva is a whole, diverse fluid that serves various purposes discussed in detail in the literature. The recent introduction of molecular biology opens up, once again, new vistas and a new search of the role of salivary fluid as a potential diagnostic tool which has an added advantage of being noninvasive. The present review presents such insight into the possible use of salivary fluid as a potential diagnostic and prognostic tool for the search of numerous diseases as well as for monitoring the treatment outcomes and assesses prognosis in such varied states of derangements of metabolic functions.

Objectives: To assess the alveolar bone density by fractal dimension (FD) analysis in radiovisiograph of postmenopausal women of mandibular posterior region and to correlate FD values with t-scores of quantitative ultrasound of the calcaneus bone. Materials and Methods: This study, approved by the institutional review board, included 40 participants, aged 45–60 years divided into two groups. Twenty postmenopausal women with osteoporosis comprised group 1, and 20 postmenopausal women without osteoporosis comprised group 2 based on bone mineral density assessment of ultrasound of the calcaneus bone. Digital dental radiograph of mandibular first molar were obtained and used for assessing alveolar bone density by FD analysis and were correlated with t-scores of ultrasound of calcaneus bone. Results: The mean FD values were evaluated using SPSS 14 version software, and were found to be 1.738 and 1.867 for group 1 and group 2, respectively, which was statistically significant (P < 0.001). However, correlation between t-scores and FD values within the study group was not found to be statistically significant (P > 0.05). Conclusion: FD analysis using direct digital periapical radiographs is a novel method, which can be used for early diagnosis of osteoporosis in the alveolar bone.

Hereditary sensory and autonomic neuropathies (HSANs) are a group of disorders characterized by insensitivity to noxious stimuli and autonomic dysfunction, associated with pathological abnormalities of the peripheral nerves. Five types of HSAN have been reported in literature, out of which Type V known as congenital insensitivity to pain (CIP) is a rare autosomal recessive condition. Self-mutilation is an invariable feature of this disorder, involving the teeth and orofacial structures. This case report describes a case of a 6-year-old girl with CIP brought by her parents for prostheses to replace her self-extracted primary teeth.

Introduction: Chronic renal failure (CRF) is an important health problem worldwide with a tendency of annual progression. Renal failure could alter the balance of the stomatognathic system, thus conditioning the prevalence of oral diseases at its different stages. Researchers estimate that up to 90% of renal patients show oral manifestations and a wide range of bony anomalies accounting for 92% of the patients. Aims and Objectives: The aim and objective of this study was to evaluate radiographic manifestations in CRF patients and compare the findings between the stages of CRF. Materials and Methods: A longitudinal study on fifty CRF patients was conducted. Patients were divided into three stages depending on the severity of renal failure. Orthopantomograph was taken for all the subjects. Results: The study showed that 88% of the study group had positive radiographic findings. Stage IV renal failure patients had more severe manifestations as compared to Stages II and III. Conclusion: Majority of the patients had positive radiographic findings which can be one of the diagnostic markers in CRF patients.

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 ABCA4, DMD, and TMC1 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 ABCA4, DMD, and TMC1 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.

BACKGROUND AND AIM:Pancreatic cancer is one of the common cancers in US and is associated with high mortality and morbidity. The objectives of our study were to look at the recent trends in the number of hospitalizations with pancreatic cancer. METHODS:We identified patients with a discharge diagnosis of pancreatic cancer in the National Inpatient Sample from 2007 to 2011 using International Classification of Diseases-Clinical Modification, 9th revision (ICD-9-CM) codes. We looked at the yearly trend in the hospitalizations with pancreatic cancer and the outcomes which included length of stay (LOS), hospital charges and in-hospital mortality. We also performed multivariate analysis to look for the predictors of mortality. RESULTS:There were 450, 414 patients with discharge diagnosis of pancreatic cancer. There was 18% increase in hospitalizations with pancreatic cancer in 2011 compared to 2007. Most of the patients were Caucasian (63%) with the mean age of 68 ± 0.14 years, had Medicare (57%) as primary insurance, were from Southern region (35%) and had higher Charlson Comorbidity Index (CCI) (87% with CCI > = 5). 6% underwent Whipple's procedure in the index hospitalization. After the adjustment for inflation, the mean hospital charges increased from $ 47,331 in 20007 to $ 53, 854 in 2011 (p = 0.01). LOS decreased from 7.31 ± 0.11 days in 2007 to 6.70 ± 0.09 days in 2011 (

Introduction: The styloid process (SP) is an anatomical structure whose clinical importance is not well understood. Aims and Objectives: This study aimed to study the type of SP as per Langlais′ classification and to assess the feasibility of digital panoramic radiographs in measuring the length of SP. Materials and Methods: Eighty digital panoramic radiographs of patients with dental problems were retrieved from archives of our department as soft copies. The radiographs were taken using a digital panoramic system. The radiographic length of SP was measured on both sides using measurement toolbars on accompanying analysis software. The type of elongation patterns of SP was classified as per Langlais′ classification. Finally, the data were subjected to statistical analysis. Results: The average length of the left and right side SPs was 29.1882 ± 6.86 and 28.16 ± 6.44, respectively. Majority of patients were found to be asymptomatic, and Langlais′ Type I elongated SP was more common than others. Conclusion: Digital panoramic radiographs are valuable tools in early detection of elongated SP. Digital radiographs help in avoiding a misdiagnosis of tonsillar pain or pain of dental, pharyngeal, or muscular region.

Aims and Objectives: Thalassemia is the most common gene disorder caused by mutations that decrease the rate of synthesis of α- or β-globin chains. Every year approximately 100,000 children with thalassemia major are born the world over, of which 10,000 are born in India. This study aimed to compare the radiographic findings of jaws and teeth, as well as crown body and root lengths of the mandibular first permanent molar in thalassemia major patients. Materials and Methods: Panoramic radiographs of 50 thalassemia major patients and 50 controls were made. The radiological changes in the jaws and teeth and the dimensional changes in the teeth were evaluated and compared between the two groups. Two observers were involved in evaluating the specific changes and findings were subjected to statistical analysis using chi-square test (χ2 ) test. Differences in crown body height, root length, and crown:root (C:R) ratio were found using independent t-test. Results: A significant difference was found between the two groups in the occurrence of short spiky roots, taurodontism, faint lamina dura, large bone marrow spaces, obliteration of maxillary sinus (haziness), indistinct inferior alveolar canal, thin mandibular cortex (P < 0.001), nutrient canals (P < 0.02), and between mean crown body and root values of the two groups (P < 0.05). However, there was no statistically significant difference in prominent antegonial notch (P = 0.860) and C:R ratio (P = 0.989). Conclusion: Taurodonts, short spiky roots, thin mandibular cortex, enlarged bone marrow spaces, and obliterated maxillary sinuses were found to occur with high frequency in thalassemia major, followed by indistinct inferior alveolar canal and attenuated lamina dura.

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.

Objective: To study the clinical types and association of psychological factors in patients with Oral Lichen Planus (OLP). Materials and Methods: An analytical age- and sex-matched study involved 30 patients with oral lichen planus (group 1) and 30 control subjects (group 2). We applied the following psychometric tests to both groups: General Health Questionnaire (GHQ) and Hospital Anxiety and Depression Scale (HADS). Results: The patients with OLP were found to exhibit statistically significant higher anxiety, insomnia, and social dysfunction with the tests that were used (GHQ 24 and HADS) than the control group (P > 0.05). The study group likewise exhibited greater depression and somatic symptoms. The mean total of the GHQ and HAD scores were found to be higher in the study group than in the controls (P > 0.05). Among the various types of OLP, patients with the erosive type had higher mean scores for anxiety and insomnia, social dysfunction and depression. Conclusion: In most patients psychiatric morbidity was strongly associated with OLP, which could support its role in the etiopathogenesis of the disease. The higher scores of the General Health Questionnaire and Hospital Anxiety and Depression Scale gave an insight into the hypothesis that psychological factors are associated with the causation of OLP.

Juvenile ossifying fibroma is considered a unique entity occurring primarily in children and adolescents. Although a benign neoplasm of bone origin, it is an aggressive variant of ossifying fibroma of the jaws. On account of the variable clinical behavior, a highly aggressive nature, and a high tendency for recurrence, early detection and prompt treatment is required. This report presents a case of juvenile ossifying fibroma in an eight-year-old girl, who reported to our institution with a gradually progressive swelling on the left side of her face since nine months, with typical clinical, radiological, and histopathological features.

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.

Background:The diagnosis of malignant and potentially malignant epithelial lesions of the oral mucosa cannot be based solely on clinical findings. Therefore, histologic evaluation of a representative biopsy specimen is necessary. However the site for the biopsy is always a subjective choice that sometimes raises doubts about its representativeness. Colposcopy, a well-known gynecological diagnostic procedure, is helpful in the selection of these epithelial dysplasia areas depending upon the vascular pattern. Hence, this study assesses the role of colposcopic examination in the selectionof biopsy sites for carcinomas of the buccal mucosa.Methods: This study included 30 patients between the ages of 30-60 years who were clinically diagnosed with carcinoma of the buccal mucosa and a control group that consisted of 25 healthy, age-matched individuals. For each subject, a thorough clinical examination followed by colposcopic assessment was performed. The most representative site was selected for biopsy from the involved buccal mucosa. The biopsy specimens that measured 6 mm were obtained by punch biopsy and subjected to histopathologic examination. The histopathologic findings were then compared in the two cases.Results: The sensitivity and specificity of biopsies performed on the basis of clinical criteria was found to be more appropriate compared to biopsies directed through colposcopic examination.Conclusion: From the study, it was concluded that clinical criterion was found to be more appropriate for the selection of biopsy specimens in cases of carcinoma of the buccal mucosa.

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