Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation

Background

Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD.

Methods

We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD.

Results

We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p?=?1.85?×?10^?03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten “CNV positive” trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4.

Conclusions

Our findings suggest that rare CNVs may contribute to the etiology of OCD.

     

Providing more through less: current methods of retraction in SIMIS and NOTES cholecystectomy

Background

As the field of minimally invasive surgery continues to develop, surgeons are confronted with the challenge of performing conventional laparoscopic surgeries through fewer incisions while maintaining the same degree of safety and surgical efficiency. Most of these methods involve elimination of the ports previously designated for retraction. As a result, minimally invasive surgeons have been forced to develop minimally invasive and ingenious methods for providing adequate retraction for these procedures. Herein we present our experience using endoloops and internal retractors to provide retraction during Single Incision Minimally Invasive Surgery (SIMIS) and Natural Orifice Transluminal Endoscopic Surgery (NOTES) cholecystectomy. We also present a review of the alternative retraction methods currently being employed for these surgeries.

Methods

SIMIS was performed on 20 patients and NOTES was performed on 5 patients at our institution. Endoloops or internal retractors were used to provide retraction for all SIMIS procedures. Internal retractors provided retraction for all NOTES procedures.

Results

Successful cholecystectomy was accomplished in all cases. One SIMIS surgery required conversion to standard laparoscopy due to complex anatomy. There were no intraoperative complications. Although adequate retraction was accomplished in all cases, the internal retractors were found to provide superior and more versatile retraction compared to that of endoloops.

Conclusion

Adequate retraction greatly simplifies SIMIS and NOTES surgery. Endograb internal retractors were easy to use and were found to provide optimal retraction and exposure during these procedures without complications.     

Acute infantile bilateral striatal necrosis: single-photon emission computed tomography (SPECT) imaging and review

Acute infantile bilateral striatal necrosis is a rarely described acute neurological syndrome associated with radiological findings. Its etiology and pathogenic mechanisms are unknown. Clinically, the syndrome usually follows respiratory illnesses and presents with an array of neurological findings, including axial ataxia, grimacing, mutism, head nodding, and high-pitched cry. This study follows a child with acute infantile bilateral striatal necrosis both clinically and radiologically. In addition, for the first time, the authors describe the serial findings of single-photon emission computed tomography (SPECT) from onset of illness through 20 months. Their findings indicate an initial insult apparent on both magnetic resonance imaging and SPECT localized to the basal ganglia, which, although improved over time, does not fully regress. The residual lesion on SPECT was clinically associated with only mild attention deficit disorder and no motor pathology. The authors review the published literature concerning acute infantile bilateral striatal necrosis and suggest possible mechanisms of this poorly understood and probably underreported condition.     

Rare CpG island methylator phenotype in ulcerative colitis-associated neoplasias

BACKGROUND & AIMS: We previously reported that a high degree of age-related methylation was found in both the dysplastic and nondysplastic mucosa of patients with ulcerative colitis (UC). Whether this translates into hypermethylation in UC-associated cancers (UC-Cs) is not known. METHODS: We evaluated the methylation status of 11 genes (MINT1, 2, 31, hMLH1, p16, p14, MGMT, HPP1, SFRP1, ERalpha, and LINE-1) in 48 UC-Cs, 21 UC-associated dysplasias, and 69 sporadic colorectal cancers (S-CRCs) using a quantitative bisulfite pyrosequencing analysis. RESULTS: Methylation levels in UC-Cs were lower than S-CRCs for all the genes except MGMT. A methylation index based on the average of Z-scores, for type C (cancer-specific genes: MINT1, MINT2, MINT31, hMLH1, p16, and p14) was -.97 in UC-Cs and .92 in S-CRCs (P = .009). That of type A (age-related genes: HPP1, SFRP1, and ERalpha) was -1.97 in UC-Cs and 1.24 in S-CRCs (P < .001). We observed a significant difference in the incidence of CpG island methylator phenotype between UC-Cs and S-CRCs (8 of 48 [17%] and 26 of 69 [38%]; P = .022). UC-associated dysplasias had significantly higher methylation of type A gene than UC-Cs (Z-score: .07 and -1.97, respectively; P < .001). By contrast, global DNA methylation measured using a LINE-1 assay was significantly higher in UC-Cs than in S-CRCs (58.2% vs 51.0%, P < .001). CONCLUSIONS: DNA methylation alterations are uncommon in UC cancers. Given that both genetic and epigenetic changes are common in UC mucosa and dysplasias, we speculate that the genetic changes lead to a more aggressive clinical course than epigenetic changes.     

Bisphosphonate-related osteonecrosis of the jaw: clinical correlations with computerized tomography presentation

The aim of this study was to correlate clinical and computerized tomography (CT) features of bisphosphonate-related osteonecrosis of the jaws (BRONJ). All ONJ patients for whom there was complete CT scan imaging were eligible. Selected clinical parameters retrieved from their medical records were analyzed for correlation with CT parameters. The clinical presentation of BRONJ was supported by findings in CT imaging in 78.3%. The lesion’s size on CT correlated with the presence of purulent secretion (p?=?0.03). When sequestrum was present, the median lesion’s size on CT was relatively big (28 mm, range 21–43 mm). The mandibular canal cortex was never breached. CT has reasonable detection competence for diagnosing BRONJ. Purulent secretion indicates the likelihood that a more extensive involvement will be displayed on CT. A large lesion on CT should raise the index of suspicion for sequestrum. The CT appearance of a continuous cortex of the mandibular canal may serve as a differential parameter between BRONJ and metastasis to the jaw.