Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program.

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.

Childhood autism in India: A case-control study using tract-based spatial statistics analysis.

CONTEXT: Autism is a serious behavioral disorder among young children that now occurs at epidemic rates in developing countries like India. We have used tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI) measures to investigate the microstructure of primary neurocircuitry involved in autistic spectral disorders as compared to the typically developed children. OBJECTIVE: To evaluate the various white matter tracts in Indian autistic children as compared to the controls using TBSS. MATERIALS AND METHODS: Prospective, case-control, voxel-based, whole-brain DTI analysis using TBSS was performed. The study included 19 autistic children (mean age 8.7 years ± 3.84, 16 males and 3 females) and 34 controls (mean age 12.38 ± 3.76, all males). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) values were used as outcome variables. RESULTS: Compared to the control group, TBSS demonstrated multiple areas of markedly reduced FA involving multiple long white matter tracts, entire corpus callosum, bilateral posterior thalami, and bilateral optic tracts (OTs). Notably, there were no voxels where FA was significantly increased in the autism group. Increased RD was also noted in these regions, suggesting underlying myelination defect. The MD was elevated in many of the projections and association fibers and notably in the OTs. There were no significant changes in the AD in these regions, indicating no significant axonal injury. There was no significant correlation between the FA values and Childhood Autism Rating Scale. CONCLUSION: This is a first of a kind study evaluating DTI findings in autistic children in India. In our study, DTI has shown a significant fault with the underlying intricate brain wiring system in autism. OT abnormality is a novel finding and needs further research.

Diffusion tensor imaging in evaluation of posterior fossa tumors in children on a 3T MRI scanner.

CONTEXT: Primary intracranial tumors in children are commonly located in the posterior fossa. Conventional MRI offers limited information regarding the histopathological type of tumor which is essential for better patient management. AIMS: The purpose of the study was to evaluate the usefulness of advanced MR imaging techniques like diffusion tensor imaging (DTI) in distinguishing the various histopathological types of posterior fossa tumors in children. SETTINGS AND DESIGN: DTI was performed on a 3T MRI scanner in 34 untreated children found to have posterior fossa lesions. MATERIALS AND METHODS: Using third party software, various DTI parameters [apparent diffusion coefficient (ADC), fractional anisotropy (FA), radial diffusivity, planar index, spherical index, and linear index] were calculated for the lesion. STATISTICAL ANALYSIS USED: Data were subjected to statistical analysis [analysis of variance (ANOVA)] using SPSS 15.0 software. RESULTS: We observed significant correlation (P < 0.01) between ADC mean and maximum, followed by radial diffusivity (RD) with the histopathological types of the lesions. Rest of the DTI parameters did not show any significant correlation in our study. CONCLUSIONS: The results of our study support the hypothesis that most cellular tumors and those with greater nuclear area like medulloblastoma would have the lowest ADC values, as compared to less cellular tumors like pilocytic astrocytoma.

Shear Bond Strength of Repaired Composites Using Surface Treatments and Repair Materials: An In vitro Study.

BACKGROUND: Enhancement of bond strength between new and old composite usually requires increased surface roughness of old composite to promote mechanical interlocking and subsequent coating with bonding agents to improve surface wetting and chemical bonding. So this study was carried out to evaluate and compare the effects of different surface treatments and repair materials on the shear bond strength (SBS) of composite repairs The mode of failure of repaired composites whether cohesive or adhesive was also evaluated. MATERIALS AND METHODS: The substrates for 60 composite specimens were fabricated and aged with water treatment and subjected to various surface treatments. The surface treatment regimens used in the study were: No surface treatment, abraded with diamond bur, air abraded (sandblasted) with 50 µ aluminum oxide particles. Specimens were then repaired with fresh composite using either Clearfil(™) repair or all-bond two adhesive systems. Specimens were water stored, thermocycled and tested for SBS using universal testing machine. Fractured specimens were then examined under stereomicroscope to determine the mode of failure. RESULTS: It was clearly showed that surface roughening of the aged composite substrate with air abrasion, followed by the application of Clearfil(™) repair adhesive system (Group IIIa) yielded the highest repair bond strength (32.3 ± 2.2 MPa). CONCLUSION: Surface treatment with air abrasion followed by bonding with Clearfil(™) repair adhesive system can be attempted clinically for the repair of composite restorations.

Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1α interaction with cofactors p300/CBP.

PURPOSE: The hypoxia-inducible factor-1 (HIF-1) plays a critical role in tumor adaptation to hypoxia, and its elevated expression correlates with poor prognosis and treatment failure in patients with cancer. In this study, we determined whether 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1, the lead inhibitor in a novel class of arylsulfonamide inhibitors of the HIF-1 pathway, had antitumorigenic properties in vivo and further defined its mechanism of action. EXPERIMENTAL DESIGN: We studied the inhibitory effect of systemic KCN1 delivery on the growth of human brain tumors in mice. To define mechanisms of KCN1 anti-HIF activities, we examined its influence on the assembly of a functional HIF-1α/HIF-1ß/p300 transcription complex. RESULTS: KCN1 specifically inhibited HIF reporter gene activity in several glioma cell lines at the nanomolar level. KCN1 also downregulated transcription of endogenous HIF-1 target genes, such as VEGF, Glut-1, and carbonic anhydrase 9, in a hypoxia-responsive element (HRE)-dependent manner. KCN1 potently inhibited the growth of subcutaneous malignant glioma tumor xenografts with minimal adverse effects on the host. It also induced a temporary survival benefit in an intracranial model of glioma but had no effect in a model of melanoma metastasis to the brain. Mechanistically, KCN1 did not downregulate the levels of HIF-1α or other components of the HIF transcriptional complex; rather, it antagonized hypoxia-inducible transcription by disrupting the interaction of HIF-1α with transcriptional coactivators p300/CBP. CONCLUSIONS: Our results suggest that the new HIF pathway inhibitor KCN1 has antitumor activity in mouse models, supporting its further translation for the treatment of human tumors displaying hypoxia or HIF overexpression.

"Mixed germ cell testicular tumor" in an adult female.

The androgen insensitivity (testicular feminization) syndrome was described by Morris in phenotypic females with 46XY karyotype, presenting with primary amenorrhea, adequate breast development, and absent or scanty pubic or axillary hair. Gonads consist usually of seminiferous tubules without spermatogenesis. These patients have a 5-10% risk of developing germ cell tumors, usually after the complete development of secondary female sexual characteristics. We hereby report a case considered as a female with married life of 15 years, who was operated for severe abdominal pain. Phenotype characters were that of female. Microscopic examination of the tumor from the abdomen revealed germinoma and yolk sac tumor with adjacent seminiferous tubules. Karyotyping showed 46XY. Final diagnosis of malignant mixed germ cell tumor in androgen insensitivity syndrome was made. Surveillance may be the most appropriate option when these conditions are initially diagnosed in adulthood to prevent development of germ cell tumors.

Role of multidetector computed tomography in evaluating complications following endovascular repair of aortic aneurysm.

OBJECTIVE: To study the role of multidetector computed tomography (MDCT) in evaluating various complications following endovascular stenting of aortic aneurysms. MATERIALS AND METHODS: Over a period of 2 years (June 2005 to June 2007), 50 patients with aortic aneurysm on computed tomography (CT) angiogram were prospectively studied. Images were acquired on a 64 slice multidetector row CT scanner (GE-LightSpeed VCT) after intravenous administration of nonionic iodinated contrast. Nineteen patients underwent endovascular stent-graft repair based on their medical and surgical risk factors. Stent-graft related complications were recorded by CT angiography and analyzed using descriptive statistics. RESULTS: Most common complication related to the endovascular stent-graft placement was endoleak (44.4%), followed by puncture site hematoma (27.8%), thrombotic occlusion of a limb of the bifurcated stent graft, kinking of the stent-graft, and difficult catheterization with intimal tear in the common iliac artery were 5.6% each. Poststent diameter of the aneurysm was an important predictor of endoleaks. All the patients with either increase or no change in the aneurysm size had endoleaks. CONCLUSION: MDCT angiography is an important modality in identifying, describing, and following up the various complications following endovascular repair of aortic aneurysms, endoleaks being the most common complication. Decrease in the poststent diameter of the aneurysm suggested a good outcome.

"MacCallum Plaque of the Heart": A Medicolegal Case.

Mural endocardial lesions can be seen as MacCallum plaques in rheumatic heart disease. These plaques appear as map-like areas of thickened, roughened, and wrinkled part of the endocardium in the left atrium. Perhaps they are caused by regurgitant jets of blood flow, due to incompetence of the mitral valve. Although MacCallum plaques are one of the characteristic features in rheumatic heart disease, they are very uncommon in recent times. We hereby report a case of an adolescent female with RHD, who was working as a housemaid in a doctor's house for a few months, and suddenly developed respiratory tract infection and cardiac failure. She died on the fourth day of admission. A medicolegal autopsy was conducted, as her relatives accused her master of sexual assault. On autopsy it was seen that the mitral valves were narrowed, showing multiple vegetations. MacCallum plaque was seen in the dilated left atrium. Hence, it is presented here for educative purposes.

Radiofrequency ablation for accessory pathways: success and variants.

INTRODUCTION: Radiofrequency ablation (RFA) is currently being advocated as the first line of therapy for symptomatic and drug refractory arrhythmias mediated by accessory pathways (APs). However, a large database on RFA for APs from India is still lacking. METHODS: Four hundred thirty-four patients (298 males, (69%)), with APs who underwent RF ablation between January, 1998 and May, 2001 were included. The success and variants were evaluated retrospectively from the data. RESULTS: The mean age was 36 +/- 11 years. There were 314 (73%) patients with WPW syndrome while the other 120 (27%) had concealed APs. Documented tachycardia was noted in 406 (91%) patients. Forty-six (11%) patients had associated structural heart disease (Ebstein's anomaly in 18). The procedure was successful in 414 (97%) of 425 patients in whom it was attempted. Of those unsuccessful, five had epicardial APs, four had multiple APs and two had immediate recurrence of APs. RFA was not attempted in nine parahissian pathways. Additional mechanisms were seen in 48 (11%) patients with WPW syndrome (14 (4.4%) AV nodal reentrant tachycardias, 16 (5%) additional concealed APs and 18 (5.7%) multiple APs). Coronary sinus diverticulum were detected in 23 (7.3%) patients, and Mahaim-like APs were diagnosed in 24 (6\8%) patients. The procedural and fluoroscopy time was 96 +/- 41 and 19 +/- 13 minutes, respectively. There were no deaths; three patients developed pericardial tamponade, which was promptly treated by pericardiocentesis. CONCLUSION: Radiofrequency ablation is a safe and effective treatment for AP mediated tachycardia, especially for younger patients and children in whom life-long drug therapy may not be best option.