Christopher J. Moran

IL-10R polymorphisms are associated with very-early-onset ulcerative colitis

Background:Interleukin-10 (IL-10) signaling genes are attractive inflammatory bowel disease (IBD) candidate genes as IL-10 restricts intestinal inflammation, IL-10 polymorphisms have been associated with IBD in genome-wide association studies, and mutations in IL-10 and IL-10 receptor (IL-10R) genes have been reported in immunodeficient children with severe infantile-onset IBD. Our objective was to determine if IL-10R polymorphisms were associated with early-onset IBD (EO-IBD) and very-early-onset IBD (VEO-IBD). Methods:Candidate-gene analysis of IL10RA and IL10RB was performed after initial sequencing of an infantile onset-IBD patient identified a novel homozygous mutation. The discovery cohort included 188 EO-IBD subjects and 188 healthy subjects. Polymorphisms associated with IBD in the discovery cohort were genotyped in an independent validation cohort of 422 EO-IBD subjects and 480 healthy subjects. Results:We identified a homozygous, splice-site point mutation in IL10RA in an infantile-onset IBD patient causing a premature stop codon (P206X) and IL-10 insensitivity. IL10RA and IL10RB sequencing in the discovery cohort identified five IL10RA polymorphisms associated with ulcerative colitis (UC) and two IL10RB polymorphisms associated with Crohns disease (CD). Of these polymorphisms, two IL10RA single nucleotide polymorphisms, rs2228054 and rs2228055, were associated with VEO-UC in the discovery cohort and replicated in an independent validation cohort (odds ratio [OR] 3.08, combined P = 2 x 10−4; and OR 2.93, P = 6 x 10−4, respectively). Conclusions:We identified IL10RA polymorphisms that confer risk for developing VEO-UC. Additionally, we identified the first splice site mutation in IL10RA resulting in infantile-onset IBD. This study expands the phenotype of IL10RA polymorphisms to include both severe arthritis and VEO-UC.

CRANIAL DURAL ARTERIOVENOUS FISTULAE: ASYMPTOMATIC CORTICAL VENOUS DRAINAGE PORTENDS LESS AGGRESSIVE CLINICAL COURSE

OBJECTIVECranial dural arteriovenous fistulae (dAVF) with cortical venous drainage (CVD) (Borden Types 2 and 3) are reported to carry a 15% annual risk of intracranial hemorrhage (ICH) or nonhemorrhagic neurological deficit (NHND). The purpose of this study was to compare the clinical course of Type 2 and 3 dAVFs that present with ICH or NHND with those that do not. METHODSTwenty-eight patients with Type 2 or 3 dAVFs were retrospectively evaluated. CVD was classified as asymptomatic (aCVD) if patients presented incidentally or with pulsatile tinnitus or orbital phenomena. CVD was classified as symptomatic (sCVD) if patients presented with ICH or NHND. Occurrence of new ICH or new or worsening NHND between diagnosis and disconnection of CVD or last follow-up (if not disconnected) was noted. Overall frequency of events was compared using Fishers exact test. Cumulative, event-free survival was compared using Kaplan-Meier analysis with log-rank testing. RESULTSOf 17 patients with aCVD, 1 (5.9%) developed ICH and none experienced NHND or death during the median 31.4-month follow-up period. Of 11 patients with sCVD, 2 (18.2%) developed ICH and 3 (27.3%) experienced new or worsened NHND over the median 9.7-month follow-up period. One of these patients subsequently died. Overall frequency of ICH or NHND was significantly lower in patients with aCVD versus sCVD (P = 0.022). Respective annual event rates were 1.4 versus 19.0%. aCVD patients had significantly higher cumulative event-free survival (P = 0.0016). CONCLUSIONCranial dAVFs with aCVD may have a less aggressive clinical course than those with sCVD.

Effect of antiplatelet therapy on thromboembolic complications of elective coil embolization of cerebral aneurysms.

BACKGROUND AND PURPOSE: Thromboembolic events are the most common complications of elective coil embolization of cerebral aneurysms. Administration of oral clopidogrel and/or aspirin could lower the thromboembolic complication rate. MATERIALS AND METHODS: Records over a 10-year period were reviewed in a retrospective cohort study. For 369 consecutive elective coil embolization procedures, 25 patients received no antiplatelet drugs, 86 received antiplatelet drugs only after embolization, and 258 received antiplatelet drugs before and after embolization. RESULTS: Symptomatic thromboembolic complications (transient ischemic attack or stroke within 60 days) occurred in 4 (16%) of 25 when no antiplatelet drugs were given, in 2 (2.3%) of 86 when antiplatelet drugs were administered only after embolization, and in 5 (1.9%) of 258 when antiplatelet drugs were administered before and after embolization. The lower symptomatic thromboembolic complication rate in the patients who received any antiplatelet therapy was statistically significant (P = .004). Clots were visible intraprocedurally in 5 (4.5%) of 111 when no antiplatelet drugs were administered before procedures and in 4 (1.6%) of 258 when they were (P value not significant). None of the 9 was symptomatic postprocedurally, but 7 were lysed or mechanically disrupted. Extracerebral hemorrhagic complications occurred in 0 (0%) of 25 when no antiplatelet drugs were given and in 11 (3.2%) of 344 when they were (P value not significant). CONCLUSION: Oral clopidogrel and/or aspirin significantly lowered the symptomatic thromboembolic complication rate of elective coil embolization of unruptured cerebral aneurysms. There were trends toward a lower rate of intraprocedural clot formation in patients given antiplatelet drugs before procedures and a higher hemorrhagic complication rate in patients given antiplatelet drugs. Benefits of antiplatelet therapy appear to outweigh risks.

Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function

The Wiskott-Aldrich syndrome protein (WASP) is a key cytoskeletal regulator of hematopoietic cells. Although WASP-knockout (WKO) mice have aberrant B-cell cytoskeletal responses, B-cell development is relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homolog of WASP, may serve some redundant functions with WASP in B cells. In the present study, we generated mice lacking WASP and N-WASP in B cells (conditional double knockout [cDKO] B cells) and show that cDKO mice had decreased numbers of follicular and marginal zone B cells in the spleen. Receptor-induced activation of cDKO B cells led to normal proliferation but a marked reduction of spreading compared with wild-type and WKO B cells. Whereas WKO B cells showed decreased migration in vitro and homing in vivo compared with wild-type cells, cDKO B cells showed an even more pronounced decrease in the migratory response in vivo. After injection of 2,4,6-trinitrophenol (TNP)-Ficoll, cDKO B cells had reduced antigen uptake in the splenic marginal zone. Despite high basal serum IgM, cDKO mice mounted a reduced immune response to the T cell-independent antigen TNP-Ficoll and to the T cell-dependent antigen TNP-keyhole limpet hemocyanin. Our results reveal that the combined activity of WASP and N-WASP is required for peripheral B-cell development and function.

Central Nervous System Lesions Biopsied or Treated by CT-Guided Needle Placement

Computed tomography has been utilized to guide a needle into central nervous system lesions as small as one centimeter in diameter. Direct puncture has drained many abscesses effectively, provided material for immediate Gram stain and subsequent culture, and permitted irrigation with appropriate antibioties, Multilocular cerebral lesions and loculated extracerebral fluid collections have been aspirated and treated with this technique. Aspiration of known cystic tumors has reduced their mass and obviated some palliative decompressions. Unresectable gliomas and metastases have been biopsied prior to chemotherapy or radiotherapy. Hemorrhage and other rare complications of biopsy may be detected and immediately treated.

Aneurysmal Subarachnoid Hemorrhage: DSA versus CT Angiography—Is the Answer Available?

The only acceptable modality for imaging patients with intracranial aneurysms is that which detects the aneurysm quickly, reliably, and safely and guides the prompt proper therapy; in my experience, conventional angiography with digital subtraction angiography techniques usually comes closest to that ideal.

Exome Sequencing Analysis Reveals Variants in Primary Immunodeficiency Genes in Patients With Very Early Onset Inflammatory Bowel Disease

BACKGROUND & AIMSnVery early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed at 5 years of age or younger, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development.nnnMETHODSnPatients with VEO-IBD and parents (when available) were recruited from the Childrens Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (age, 3 wk to 4 y) and 19xa0parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by postprocessing and variant calling. After functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency less than 0.1%, and scaled combined annotation-dependent depletion scores of 10 or less. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (nxa0= 45) or adult-onset Crohns disease (nxa0= 20) and healthy individuals (controls, nxa0= 145) were obtained from the University of Kiel, Germany, and used as control groups.nnnRESULTSnFour hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling more than 1 Mbp of coding sequence, were selected from the whole-exome data. Our analysis showed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19.nnnCONCLUSIONSnIn an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants.

Single-institution experience with matrix coils in the treatment of intracranial aneurysms: comparison with same-center outcomes with the use of platinum coils.

BACKGROUND AND PURPOSE: This study was undertaken to analyze the outcomes and treatment-related complications of the polyglycolic/polylactic acid (PGLA)-coated Matrix platinum coils in the treatment of intracranial aneurysms and compare these results with those derived from the same single-institutional experience with use of uncoated, bare platinum coils. MATERIALS AND METHODS: In this study, we compared 2 groups of patients in a retrospective fashion. The first group consisted of 70 consecutive patients who underwent 82 aneurysm treatments with Matrix coils during the 14-month period of study, from January 2003 to February 2004. We compared this cohort with 70 consecutive patients who underwent a total of 80 aneurysm treatments with bare platinum coils in the 12 months immediately preceding the use of PGLA-coated coils, from January through December 2002. We then recorded the treatment characteristics, angiographic outcomes, and any complications. RESULTS: There were similar baseline demographic characteristics between the 2 study groups except in age, anatomic location, and length of follow-up. The overall recurrence rate of aneurysms was 41% among the Matrix-treated group and 32% among the patients treated with bare platinum. Among the 42 patients treated with 100% Matrix, the rate of recurrence was 31%. Of the recurrences, 21% of the Matrix group, 19% of the 100% Matrix group, and 9% of the bare platinum group required retreatment. The overall rate of complications was 10% in the Matrix-treated group and 7% in the bare platinum group. There was not a statistically significant difference in the rate of recurrence of aneurysms or complications between the 2 groups. CONCLUSIONS: On the basis of our single-center experience, there is insufficient evidence to support the use of Matrix coils over bare platinum coils, given their disadvantages.

Computed Tomography of the Lumbar Thecal Sac

With a high resolution modification of a translate–rotate body scanner (EMI CT5005), radiologists may now demonstrate the epidmal fat, thecal sac, and axillary pouches of the lower thoracic, lumbar, and sacral spinal canal without using contrast agents. Preliminary results with a newer rotary motion scanner (EMI CT7070) suggest that this scanner achieves equally good delineation of intracanalicular anatomy.

Very early-onset inflammatory bowel disease: gaining insight through focused discovery.

Abstract:The pathogenesis of pediatric inflammatory bowel disease (IBD) is only partially understood. Strong evidence implicates a strong genetic component including high monozygotic twin concordance and familial disease phenotype concordance rates. Genome-wide association studies have identified associations between >160 genetic loci and the risk for developing IBD. The roles of implicated genes are largely immune-mediated, although other functions include cellular migration, oxidative stress, and carbohydrate metabolism. Additionally, growing literature describes monogenic causes of IBD that frequently present as infantile or very early-onset IBD. The interplay between IBD risk single nucleotide polymorphisms and rare genetic variants has yet to be determined. Studying patients with very early-onset IBD may elicit genetic factors that could be applied to broader populations of IBD. This review describes what is known about the genetic causes of very early-onset IBD and genetic strategies that may unravel more of the genetic causes of IBD.The pathogenesis of pediatric inflammatory bowel disease (IBD) is only partially understood. Strong evidence implicates a strong genetic component including high monozygotic twin concordance and familial disease phenotype concordance rates. Genome-wide association studies have identified associations between >160 genetic loci and the risk for developing IBD. The roles of implicated genes are largely immune-mediated, although other functions include cellular migration, oxidative stress, and carbohydrate metabolism. Additionally, growing literature describes monogenic causes of IBD that frequently present as infantile or very early-onset IBD. The interplay between IBD risk single nucleotide polymorphisms and rare genetic variants has yet to be determined. Studying patients with very early-onset IBD may elicit genetic factors that could be applied to broader populations of IBD. This review describes what is known about the genetic causes of very early-onset IBD and genetic strategies that may unravel more of the genetic causes of IBD.