Disrupted IRF6-NME1/2 Complexes as a Cause of Cleft Lip/Palate.

Mutations and common polymorphisms in interferon regulatory factor 6 ( IRF6) are associated with both syndromic and nonsyndromic forms of cleft lip/palate (CLP). To date, much of the focus on this transcription factor has been on identifying its direct targets and the gene regulatory network in which it operates. Notably, however, IRF6 is found predominantly in the cytoplasm, with its import into the nucleus tightly regulated like other members of the IRF family. To provide further insight into the role of IRF6 in the pathogenesis of CLP, we sought to identify direct IRF6 protein interactors using a combination of yeast 2-hybrid screens and co-immunoprecipitation assays. Using this approach, we identified NME1 and NME2, well-known regulators of Rho-type GTPases, E-cadherin endocytosis, and epithelial junctional remodeling, as bona fide IRF6 partner proteins. The NME proteins co-localize with IRF6 in the cytoplasm of primary palatal epithelial cells in vivo, and their interaction with IRF6 is significantly enhanced by phosphorylation of key serine residues in the IRF6 C-terminus. Furthermore, CLP associated IRF6 missense mutations disrupt the ability of IRF6 to bind the NME proteins and result in elevated activation of Rac1 and RhoA, compared to wild-type IRF6, when ectopically expressed in 293T epithelial cells. Significantly, we also report the identification of 2 unique missense mutations in the NME proteins in patients with CLP (NME1 R18Q in an IRF6 and GRHL3 mutation-negative patient with van der Woude syndrome and NME2 G71V in a patient with nonsyndromic CLP). Both variants disrupted the ability of the respective proteins to interact with IRF6. The data presented suggest an important role for cytoplasmic IRF6 in regulating the availability or localization of the NME1/2 complex and thus the dynamic behavior of epithelia during lip/palate development.

Quality of life and outcomes for femoral hernia repair: does laparoscopy have an advantage?

BACKGROUND: Due to their relative scarcity and to limit single-center bias, multi-center data are needed to study femoral hernias. The aim of this study was to evaluate outcomes and quality of life (QOL) following laparoscopic vs. open repair of femoral hernias. METHODS: The International Hernia Mesh Registry was queried for femoral hernia repairs. Laparoscopic vs. open techniques were assessed for outcomes and QOL, as quantified by the Carolinas Comfort Scale (CCS), preoperatively and at 1, 6, 12, and 24 months postoperatively. Outcomes were evaluated using the standard statistical analysis. RESULTS: A total of 80 femoral hernia repairs were performed in 73 patients: 37 laparoscopic and 43 open. There was no difference in mean age (54.7 ± 14.6 years), body mass index (24.2 ± 3.8 kg/m2), gender (60.3 % female), or comorbidities (p > 0.05). The hernias were recurrent in 21 % of the cases with an average of 1.23 ± 0.6 prior repairs (p > 0.1). Preoperative CCS scores were similar for both groups and indicated that 59.7 % of patients reported pain and 46.4 % had movement limitations (p > 0.05). Operative time was equivalent (47.2 ± 21.2 vs. 45.9 ± 14.8 min, p = 0.82). There was no difference in postoperative complications, with an overall 8.2 % abdominal wall complications rate (p > 0.05). The length of stay was shorter in the laparoscopic group (0.5 ± 0.6 vs. 1.3 ± 1.6 days, p = 0.02). Follow-up was somewhat longer in the open group (23.8 ± 10.2 vs. 17.3 ± 10.9 months, p = 0.02). There was one recurrence, which was in the laparoscopic group (3.1 vs. 0 %, p = 0.4). QOL outcomes at all time points demonstrated no difference for pain, movement limitation, or mesh sensation. Postoperative QOL scores improved for both groups when compared to preoperative scores. CONCLUSION: In this prospective international multi-institution study of 80 femoral hernia repairs, no difference was found for operative times, long-term outcomes, or QOL in the treatment of femoral hernias when comparing laparoscopic vs. open techniques. After repair, QOL at all time-points postoperatively improved compared to QOL scores preoperatively for laparoscopic and open femoral hernia repair. While international data supports improved outcomes with laparoscopic approach for femoral hernia repair, no data had existed prior to this study on the difference of approach impacting QOL. In the setting where recurrence and complication rates are equal after femoral hernia repair for either approach, surgeons should perform the technique with which they are most confident, as the operative approach does not appear to change QOL outcomes after femoral hernia repair.

Massively Increased Caries Susceptibility in an Irf6 Cleft Lip/Palate Model.

Patients with cleft lip/palate (CLP) have been reported, in some studies, to exhibit an increased prevalence of caries, although the underlying cause for this increase is unknown. In genetically defined mouse models, studies of postnatal sequelae associated with CLP have been hampered by neonatal lethality. Using a conditional targeting approach, we ablated the major CLP gene Irf6 only in the late embryonic oral epithelium ( Irf6 cKO), bypassing the role of the gene in lip and palate morphogenesis and thus ensuring survival to adulthood. We report that Irf6 cKO mice present with 1) dysplastic salivary glands due to disruptions of epithelial junctional complexes, likely secondary to elevated activation of RHO GTPases, and 2) increased salivary cell proliferation. These changes result in significantly reduced saliva flow rate and buffering capacity and increased mucus acidity. A marked decrease in expression of CCL27, one of the major mucosal and skin cytokines, was found that correlated with increased bacterial colonization of the oral cavity with the cariogenic pathogen Streptococcus mutans and other bacteria. When placed on a high-sugar diet, Irf6 cKO mice show a 35-fold increase in presentation and severity of dental caries as compared with wild-type control mice. Strikingly, within the 8-wk test period, many molars extensively dissolved, and there was progressive loss of the alveolar bone, likely as a result of increased colonization of periodontal pathogens. These data provide the first mechanistic insight into the heightened caries susceptibility associated with CLP and indicate a direct role for the major CLP gene Irf6 in salivary gland development and a significant role in regulating oral immunity. Our data suggest that careful evaluation of salivary gland function and the implementation of early oral health preventive strategies are warranted to reduce the burden of dental care in this at-risk population.

Full Spectrum of Postnatal Tooth Phenotypes in a Novel Irf6 Cleft Lip Model.

Clefting of the lip, with or without palatal involvement (CLP), is associated with a higher incidence of developmental tooth abnormalities, including hypodontia and supernumerary teeth, aberrant crown and root morphologies, and enamel defects, although the underlying mechanistic link is poorly understood. As most CLP genes are expressed throughout the oral epithelium, the authors hypothesized that the expression of CLP genes may persist in the dental epithelium and thus, in addition to their earlier role in labiopalatine development, may play an important functional role in subsequent tooth patterning and amelogenesis. To address this, the authors generated a unique conditional knockout model involving the major CLP gene, Irf6, that overcomes the previously reported perinatal lethality to enable assessment of any posteruption dental phenotypes. A dental epithelium-specific Irf6 conditional knockout (Irf6-cKO) mouse was generated via a Pitx2-Cre driver line. Dental development was analyzed by microcomputed tomography, scanning electron microscopy, histology, immunohistochemistry, and quantitative polymerase chain reaction. Irf6-cKO mice displayed variable hypodontia, occasional supernumerary incisors and molars, as well as crown and root patterning anomalies, including peg-shaped first molars and taurodontic and C-shaped mandibular second molars. Enamel density was reduced in preeruption Irf6-cKO mice, and some shearing of enamel rods was noted in posteruption incisors. There was also rapid attrition of Irf6-cKO molars following eruption. Histologically, Irf6-cKO ameloblasts exhibited disturbances in adhesion and polarity, and delayed enamel formation was confirmed immunohistochemically. Altered structure of Hertwig's epithelial root sheath was also observed. These data support a role for IRF6 in tooth number, crown and root morphology and amelogenesis that is likely due to a functional role of Irf6 in organization and polarity of epithelial cell types. This data reinforce the notion that various isolated tooth defects could be considered part of the CLP spectrum in relatives of an affected individual.

Risk factors for postoperative sepsis in laparoscopic gastric bypass.

INTRODUCTION: Postoperative sepsis is a rare but serious complication following elective surgery. The purpose of this study was to identify the rate of postoperative sepsis following elective laparoscopic gastric bypass (LGBP) and to identify patients' modifiable, preoperative risk factors. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried from 2005 to 2013 for factors associated with the development of postoperative sepsis following elective LGBP. Patients who developed sepsis were compared to those who did not. Results were analyzed using the Chi-square test for categorical variables and Wilcoxon two-sample test for continuous variables. A multivariate logistic regression analysis was utilized to calculate adjusted odds ratios for factors contributing to sepsis. RESULTS: During the study period, 66,838 patients underwent LGBP. Of those, 546 patients developed postoperative sepsis (0.82%). The development of sepsis was associated with increased operative time (161 ± 77.8 vs. 135.10 ± 56.5 min; p < 0.0001) and a greater number of preoperative comorbidities, including diabetes (39.6 vs. 30.6%; p < 0.0001), hypertension requiring medication (65.2 vs. 54%; p < 0.0001), current tobacco use (16.7 vs. 11.5%; p = 0.0002), and increased pack-year history of smoking (8.6 ± 18.3 vs. 5.6 ± 14.2; p = 0.0006), and the Charlson Comorbidity Index (0.51 ± 0.74 vs. 0.35 ± 0.57, p < 0.0001). Sepsis resulted in an increased length of stay (10.1 ± 14.4 vs. 2.4 ± 4.8 days; p < 0.0001) and a 30 times greater chance of 30-day mortality (4.03 vs. 0.11%, p < 0.0001). Multivariate logistic regression analysis showed that current smokers had a 63% greater chance of developing sepsis compared to non-smokers, controlling for age, race, gender, BMI, and CCI score (OR 1.63, 95% CI 1.23-2.14; p = 0.0006). CONCLUSIONS: Laparoscopic gastric bypass is uncommonly associated with postoperative sepsis. When it occurs, it portends a 30 times increased risk of death. A patient history of diabetes, hypertension, and increasing pack-years of smoking portend an increased risk of sepsis. Current smoking status, a preoperative modifiable risk factor, is independently associated with the chance of postoperative sepsis. Preoperative patient optimization and risk reduction should be a priority for elective surgery, and patients should be encouraged to stop smoking prior to gastric bypass.

Laparoscopic appendectomy and cholecystectomy versus open: a study in 1999 pregnant patients.

BACKGROUND: When pregnant patients require surgery, whether to perform an operation open or laparoscopic is often debated. We evaluated the impact of laparoscopy for common general surgical problems in pregnancy to determine safety and trends in operative approach over time. METHODS: Pregnant patients undergoing appendectomy or cholecystectomy were identified using the National Surgical Quality Improvement Program (NSQIP) database. We analyzed demographics, operative characteristics, and outcomes. Univariate comparison and multivariate regression analysis (MVA) were performed adjusting for confounding factors: age, body mass index (BMI), diabetes, and smoking, and an additional MVA was performed for perforated cases. RESULTS: A total of 1999 pregnant patients between 2005 and 2012 were evaluated. Of 1335 appendectomies, 894 were performed laparoscopically (LA) and 441 open (OA). For 664 cholecystectomies, 606 were laparoscopic (LC) and 58 open (OC). There were no deaths. For LA versus OA, patient characteristics were not different {age: 27.7 vs. 28.2 years, p = 0.19; diabetes: 1.8 vs. 0.9%, p = 0.24; smoking: 19 vs. 16.1%, p = 0.2} except for BMI (27.9 vs. 28.4 kg/m(2); p = 0.03). LA had shorter operative times (ORT), length of stay (LOS), and fewer postoperative complications compared to OA. In MVA, difference between approaches remained statistically significant for ORT (<0.0001), LOS (<0.01), and wound complications (<0.01). MVA was performed for perforated cases alone: LA had equal ORT (p = 0.19) yet shorter LOS (p = <0.001). The majority of LA were performed in the last 4 years versus the first 4 years (61 vs. 39%, p < 0.001). For LC versus OC, patient characteristics were not different: age (28.3 vs. 28.7 years; p = 0.33), BMI (31.4 vs. 33.2 kg/m(2), p = 0.25), diabetes (2.8 vs. 3.5%, p = 0.68), and smoking (21.1 vs. 25.9%, p = 0.4). LC had a shorter ORT, LOS, and fewer postoperative complications than OC. In MVA, the difference between approaches remained statistically significant for ORT (<0.0001), LOS (<0.0001), and minor complications (<0.01). In MVA for cholecystitis with perforation, no difference was seen for LOS, ORT, or postoperative complications (p > 0.05). The percentage of LC cases appeared to increase over time (89 vs. 93%, p = 0.06). CONCLUSION: While fetal events are unknown, LA and LC in pregnant patients demonstrated shorter ORT, LOS, and reduced complications and were performed more frequently over time. Even in perforated cases, laparoscopy appears safe in pregnant patients.

Automated Detection of 3D Landmarks for the Elimination of Non-Biological Variation in Geometric Morphometric Analyses.

Landmark-based morphometric analyses are used by anthropologists, developmental and evolutionary biologists to understand shape and size differences (eg. in the cranioskeleton) between groups of specimens. The standard, labor intensive approach is for researchers to manually place landmarks on 3D image datasets. As landmark recognition is subject to inaccuracies of human perception, digitization of landmark coordinates is typically repeated (often by more than one person) and the mean coordinates are used. In an attempt to improve efficiency and reproducibility between researchers, we have developed an algorithm to locate landmarks on CT mouse hemi-mandible data. The method is evaluated on 3D meshes of 28-day old mice, and results compared to landmarks manually identified by experts. Quantitative shape comparison between two inbred mouse strains demonstrate that data obtained using our algorithm also has enhanced statistical power when compared to data obtained by manual landmarking.

A new tool for quantifying and characterizing asymmetry in bilaterally paired structures.

This paper introduces a new tool to quantify and characterize asymmetry in bilaterally paired structures. This method uses deformable registration to produce a dense vector field describing the point correspondences between two images of bilaterally paired structures. The deformation vector field properties are clustered to detect and describe regions of relevant asymmetry. Three methods are provided to analyze the asymmetries: the global asymmetry score uses cluster features to quantify overall asymmetry, the local asymmetry score quantifies asymmetry in user-defined regions of interest, and the asymmetry similarity measure quantifies pairwise similarity of individual asymmetry. The scores and image distances generated by this tool are shown to correlate highly with asymmetry ratings assigned by an expert.

The ontology of craniofacial development and malformation for translational craniofacial research.

We introduce the Ontology of Craniofacial Development and Malformation (OCDM) as a mechanism for representing knowledge about craniofacial development and malformation, and for using that knowledge to facilitate integrating craniofacial data obtained via multiple techniques from multiple labs and at multiple levels of granularity. The OCDM is a project of the NIDCR-sponsored FaceBase Consortium, whose goal is to promote and enable research into the genetic and epigenetic causes of specific craniofacial abnormalities through the provision of publicly accessible, integrated craniofacial data. However, the OCDM should be usable for integrating any web-accessible craniofacial data, not just those data available through FaceBase. The OCDM is based on the Foundational Model of Anatomy (FMA), our comprehensive ontology of canonical human adult anatomy, and includes modules to represent adult and developmental craniofacial anatomy in both human and mouse, mappings between homologous structures in human and mouse, and associated malformations. We describe these modules, as well as prototype uses of the OCDM for integrating craniofacial data. By using the terms from the OCDM to annotate data, and by combining queries over the ontology with those over annotated data, it becomes possible to create "intelligent" queries that can, for example, find gene expression data obtained from mouse structures that are precursors to homologous human structures involved in malformations such as cleft lip. We suggest that the OCDM can be useful not only for integrating craniofacial data, but also for expressing new knowledge gained from analyzing the integrated data.

Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients.

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

Simulated Colonoscopy Objective Performance Evaluation (SCOPE): a non-computer-based tool for assessment of endoscopic skills.

BACKGROUND: The Simulated Colonoscopy Objective Performance Evaluation (SCOPE) was developed to fill the need for a lower-cost, non-virtual-reality (VR)-based assessment tool. This study aimed to evaluate the ability of SCOPE to assess endoscopic skills objectively. METHODS: Four tasks were created using the Kyoto Kagaku colonoscopy model (Kyoto Kagaku Co., Ltd., Kyoto, Japan). The SCOPE tasks included Scope Manipulation (SM) requiring torque and tip deflection to align a shape in the colon with a matching shape on the monitor; Tool Targeting (TT) requiring coordination with biopsy forceps to contact a metal target; Loop Management (LM) requiring prevention, recognition, and reduction of a redundant sigmoid colon with navigation to the cecum; and Mucosal Inspection (MI) requiring identification of simulated polyps during withdrawal and retroflexion. Key performance metrics were identified, and a normalized scoring system was developed. For the study, 35 subjects were stratified into three cohorts based on colonoscopy experience: novice (0-50 colonoscopies; n = 11), intermediate (51-139 colonoscopies; n = 13), and experienced (>140 colonoscopies; n = 11). The subjects performed two trials of all four tasks. RESULTS: Across all four tasks, the experienced endoscopists (E) consistently outperformed the intermediates (I), who in turn outperformed the novices (N). The mean normalized scores with 95 % confidence intervals (CI) are as follows: SM: N (54; range, 26-82), I (92; range, 79-106), E (106; range, 93-118) (p = 0.0006). TT: N (40; range, 24-55), I (77; range, 63-91), E (88; range, 72-105) (p < 0.0001). LM: N (51; range, 24-79), I (80; range, 59-101), E (101; range, 98-105) (p = 0.003). MI: N (73; range, 53-92), I (85; range, 76-95), E (100; range, 91-108) (p = 0.013). Total score: N (218; range, 155-280), I (335; range, 299-371), E (395; range, 371-419) (p < 0.0001). The test-retest reliability (0.6) for the expert total score was respectable. CONCLUSIONS: The validity evidence from this study shows that scores on SCOPE tasks can differentiate between groups expected to have different levels of technical skill. This model shows promise as a low-technology tool for objective assessment or training of endoscopic skills.

A landmark-free framework for the detection and description of shape differences in embryos.

This paper introduces a new method to quantify and characterize shape changes during early facial development without the use of landmarks. Landmarks are traditionally used in morphometric analysis, but very few can be identified reliably across all stages of embryonic development. This method uses deformable registration to produce a dense vector field describing the point correspondences between two images. Low and mid-level features are extracted from the deformable vector field to find regions of organized differences that are biologically relevant. These methods are shown to detect regions of difference when evaluated on chick embryo images warped with small magnitude deformations in regions critical to midfacial development.

Rives-Stoppa incisional hernia repair combined with laparoscopic separation of abdominal wall components: a novel approach to complex abdominal wall closure.

BACKGROUND: The Rives-Stoppa incisional hernia repair is the gold standard for mesh repair of complex incisional hernias. The risk of infection can be reduced if fascia is closed over the prosthetic mesh. Fascial closure in large defects may require extensive dissection and can result in devascularization of the overlying skin and denervation of the abdominal wall musculature. Laparoscopic components separation minimizes these risks while facilitating anterior fascial closure. The combined technique of Rives-Stoppa repair augmented by laparoscopic separation of abdominal wall components has not previously been reported. METHODS: We retrospectively reviewed our initial experience with this combined technique for incisional hernia repair. A Rives-Stoppa incisional hernia repair is performed with mesh placed in the retromuscular position. If the anterior fascia cannot be closed, a laparoscopic separation of abdominal wall components is performed to facilitate fascial closure without creation of skin flaps. RESULTS: Six patients were identified. Three patients developed hernias following laparotomy from severe injuries sustained during combat. The other patients included hernia after esophagectomy, retroperitoneal liposarcoma resection, and complicated diverticulitis. Average defect size was 270 cm(2). Complete primary fascial closure anterior to the mesh was achieved in 66% of the patients. No mortalities occurred and at short term follow-up no incisional hernia recurrences have developed. Early post operative complications included a superficial skin infection not involving mesh and a recurrent enterocutaneous fistula. CONCLUSIONS: The authors conclude that Rives-Stoppa repair augmented by laparoscopic components separation is an innovative method for reconstruction of complex abdominal wall defects. Laparoscopic components separation allows fascial closure to be achieved anterior to the mesh in large incisional hernias, which may reduce wound infection rates.

Do Craniosynostosis syndrome phenotypes with both FGFR2 and TWIST mutations have a worse clinical outcome?

We present three cases with both FGFR2 mutations and novel TWIST sequence variants. The clinical outcome in this cohort is compared with that in individuals with a single mutation.

Multidisciplinary management of Opitz G BBB syndrome.

Opitz G BBB syndrome is a rare condition characterized by the 3 major anomalies of hypertelorism, cleft lip and palate, and hypospadias, although there may be other associated anomalies. The underlying genetic causes are complex and consist of both X-linked recessive and autosomal dominant forms of the disorder. Previously, there have been publications on the underlying genetics and case reports, but there have been few reports regarding the long-term outcome. The aim in this study was to review the range of clinical presentation and evaluate outcomes of the multidisciplinary management of a cohort of patients with Opitz G BBB syndrome. In a 25-year period, 7 patients with Opitz G BBB syndrome were managed by the Australian Craniofacial Unit (ACFU), 5 male and 2 female. Most of the patients are now reaching skeletal maturity. Each one presented with a range of severity in the triad of hypertelorism, cleft lip and palate, and hypospadias anomalies. The males all exhibited the triad of anomalies, while the females both had hypertelorism, only 1 had isolated cleft palate, and neither had any genitourinary anomalies. Each patient underwent multidisciplinary assessment to make a treatment plan for staged management of different anomalies. Plan for surgical corrections of facial anomalies were performed according to the unit's protocol management of both hypertelorism and cleft lip and palate, but the presence of these coexisting anomalies required adjustment of the standard protocol of management of cleft lip and palate. In conclusion, we recommend that patients with Opitz G BBB syndrome require careful evaluation, and management of the anomalies should be in a coordinated manner by a multidisciplinary team.

Taking it to the max: the genetic and developmental mechanisms coordinating midfacial morphogenesis and dysmorphology.

The rapid proliferative expansion and complex morphogenetic events that coordinate the development of the face underpin the sensitivity of this structure to genetic and environmental insult and provide an explanation for the high incidence of midfacial malformation. Most notable of these malformations is cleft lip with or without cleft palate (CLP) that, with an incidence of between one in 600 and one in 1000 live births, is the fourth most common congenital disorder in humans. Despite the obvious global impact of the disorder and some recent progress in identifying causative genes for some prominent syndromal forms, our knowledge of the key genetic factors contributing to the more common isolated cases of CLP is still remarkably patchy. The current understanding of the molecular and cellular processes that orchestrate morphogenesis of the midface, with emphasis on events leading to fusion of the lip and primary palate, is detailed in this review. The roles of crucial factors identified from relevant animal model systems, including BMP4 and SHH, and the likely events perturbed by key genes pinpointed in human studies [such as PVRL1, IRF6p63, MID1, MSX1, and PTCH1] are discussed in this light. New candidates for human CLP genes are also proposed.

Measures of folding applied to the development of the human fetal brain.

Previous work has suggested the existence of differences between the cerebral cortex of normal individuals, and those of patients with diseases such as epilepsy and schizophrenia. These shape abnormalities may be of developmental origin. Improved shape measures could provide useful tools for neuroscience research and patient diagnosis. We consider the theoretically desirable properties of measures of brain shape. We have implemented seven measures, three from the neuroscience literature, and four new to this field. Three of the measures are zero-order and four are second-order with respect to the surface. We validate the measures using simple geometrical shapes, and a collection of magnetic resonance scans of ten histologically normal ex vivo fetal brains with gestational ages from 19-42 weeks. We then apply the measures to MR scans from two histologically abnormal ex vivo brains. We demonstrate that our implementation of the measures is sensitive to anatomical variability rather than to the discreteness of the image data. All the measures were sensitive to changes in shape during fetal development. Several of the measures could distinguish between the normal and abnormal fetal brains. We propose a multivariate approach to studying the shape of the cerebral cortex, in which both zero-order and second-order measures are used to quantify folding.

Posterior circulation stroke in childhood: risk factors and recurrence.

OBJECTIVE: To ascertain whether posterior circulation stroke in children has distinctive clinical or radiologic features. METHODS: Patients were identified retrospectively from two pediatric neurology centers. Clinical details were ascertained by chart review, and radiologic data were reviewed by three neuroradiologists. RESULTS: Twenty-two cases were identified (17 boys). Twenty children had evidence of vertebrobasilar arterial abnormalities, which were multifocal in 12. The etiology of these was vertebral artery dissection in 10 cases and unclear in the remaining 10. Cardiac abnormalities were rare (n = 4). Other risk factors for stroke in childhood were hypertension (n = 9), the thermolabile methylene tetrahydrofolate reductase gene mutation (n = 4), and the factor V Leiden mutation (n = 2). Two children had subluxation of the upper cervical spine at the extreme of normal limits. In follow-up for 6 months to 11 years (median 4 years), five patients had further strokes and seven had TIA. Overall, 12 patients had no residual neurologic deficits. CONCLUSIONS: The male preponderance, frequency of arterial dissection, rarity of cardiac embolism, and >20% recurrence were notable. Cerebral angiography is usually indicated if a definitive diagnosis is not made on MRI. Additional investigations should include echocardiography and cervical spine radiography in flexion and extension.

Magnetic resonance imaging findings within 5 days of status epilepticus in childhood.

The nature of the relationships between status epilepticus, acute hippocampal injury, mesial temporal sclerosis (MTS) and temporal lobe epilepsy remains unclear. The aim of this study was to investigate whether generalized status epilepticus is associated with brain abnormalities, especially in the mesial temporal lobe, within 5 days of the acute event. Such changes may be the first part of a causative pathophysiological sequence relating status epilepticus and MTS. Thirty-five children with a history of status epilepticus, including 21 with a history of prolonged febrile convulsion (PFC), underwent qualitative and quantitative MRI investigations within 5 days of the acute episode. Quantitative assessments of the hippocampus included T(2) relaxometry and hippocampal volumetry. Hippocampal volumes were large in patients with PFC when compared with controls. In addition, T(2) relaxation time was elevated in patients with PFC compared with control subjects during the first 2 days of the acute event. No difference was observed in patients examined 3-5 days after the event. Patients with afebrile status epilepticus had a variety of imaging abnormalities including elevated hippocampal T(2) values, but no evidence of hippocampal enlargement. PFC is associated with hippocampal abnormalities, consistent with hippocampal oedema, whilst non-febrile status epilepticus is not. A systematic longitudinal study is required to characterize the evolution of these abnormalities and to determine whether any patient develops MTS.