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1.  Somatic Mutations in Cerebral Cortical Malformations 
The New England journal of medicine  2014;371(8):733-743.
Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.
Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.
Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.
Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.)
PMCID: PMC4274952  PMID: 25140959
2.  Isolated Vitamin D Deficiency Is Not Associated with Nonthyroidal Illness Syndrome, but with Thyroid Autoimmunity 
The Scientific World Journal  2015;2015:239815.
Aim. This study aimed to compare thyroid functions, thyroid autoantibodies, and the existence of nonthyroidal illness syndrome (NTIS) according to vitamin D level. Materials and Methods. The study included age- and BMI-matched healthy volunteers with and without vitamin D deficiency. In addition, the nonthyroidal illness syndrome status was evaluated. Results. Anti-TPO positivity was significantly more common in those with severe and moderate vitamin D deficiency, as compared to those with a normal 25(OH)D level. Furthermore, TSH levels were significantly lower in those with severe and moderate vitamin D deficiency than in those with a normal 25(OH)D level. In addition, there was a significant weak inverse correlation between anti-TPO positivity and the 25(OH)D level and a positive correlation between the TSH level and 25(OH)D level. Only 1 thyroid function test result was compatible with NTIS among the participants with moderate vitamin D deficiency; therefore the difference was not significant. Conclusions. The prevalence of thyroid autoantibody positivity was higher in those with severe and moderate vitamin D deficiency than in those with a normal 25(OH)D level. Additional large-scale studies must be conducted to determine if vitamin D deficiency plays a causal role in the pathogenesis of Hashimoto's thyroiditis and NTIS.
PMCID: PMC4306373  PMID: 25654127
3.  Same-day colonoscopy preparation with Senna alkaloids and bisacodyl tablets: A pilot study 
World Journal of Gastroenterology : WJG  2014;20(41):15382-15386.
AIM: To evaluate the efficacy of same-day bowel preparation with Senna alkaloids combined with bisacodyl tablets in routine colonoscopy procedures.
METHODS: Between March and June 2013, a same-day bowel preparation was implemented in our endoscopy unit. The preparation consisted of a semi-liquid, fiber-free diet one day prior to the procedure, with two bisacodyl tablets after lunch and dinner, and 250 mL of Senna alkaloid with 1.5 L of drinking water at 6 am the day of the procedure. The quality control parameters of colonoscopy were evaluated and implemented according to the guidelines of the American Society for Gastrointestinal Endoscopy. The pre-procedure, during-procedure and post-procedure patient data were collected and analyzed: (1) pre-procedure (age, gender, comorbid diseases, colonoscopy indications, complete lack of compliance with the bowel preparation protocol); (2) during-procedure (sedation dose, duration of colonoscopy, withdrawal time, cecal intubation rate, polyp detection rate, Boston Bowel Preparation Scores and presence of foam and clear liquid); and (3) post-procedure (visual analogue scale score, pain during the procedure, patient satisfaction and premature withdrawal due to the insufficient bowel preparation).
RESULTS: A total of 75 patients were included in this study with a mean age of 54.64 ± 13.29 years; 53.3% (40/75) were female and 46.7% (35/75) were male. A complete lack of compliance with the bowel preparation protocol was seen in 6.7% of patients (5/75). The mean total duration of colonoscopy was 16.12 ± 6.51 min, and the mean withdrawal time was 8.89 ± 4.07 min. The cecal intubation rate was 93.8% (61/64) and the polyp detection rate was 40% (30/75). The mean Boston Bowel Preparation Score was 7.38 ± 1.81, with the following distribution: right colon, 2.34 ± 0.89; transverse colon, 2.52 ± 0.67; left colon, 2.52 ± 0.63. The mean visual analogue scale score was 4.59 ± 1.57. Due to insufficient bowel preparation, seven patients (7/75; 9.3%) were asked to repeat the procedure. Of these, five patients had poor or modest compliance with the protocol, and two patients reported constipation. Premature withdrawal due to insufficient bowel preparation was 2.7% (2/75). The overall satisfaction with the protocol was 86.7% (65/75), with patients reporting they would prefer the same protocol in a repeat procedure.
CONCLUSION: The same-day administration of Senna alkaloids appears to be a safe and effective bowel cleansing protocol for colonoscopy procedures.
PMCID: PMC4223273  PMID: 25386088
Bisacodyl; Bowel preparation; Colonoscopy; Same-day preparation; Senna alkaloid
4.  A Clinical Prediction Formula for Apnea-Hypopnea Index 
Objectives. There are many studies regarding unnecessary polysomnography (PSG) when obstructive sleep apnea syndrome (OSAS) is suspected. In order to reduce unnecessary PSG, this study aims to predict the apnea-hypopnea index (AHI) via simple clinical data for patients who complain of OSAS symptoms. Method. Demographic, anthropometric, physical examination and laboratory data of a total of 390 patients (290 men, average age 50 ± 11) who were subject to diagnostic PSG were obtained and evaluated retrospectively. The relationship between these data and the PSG results was analyzed. A multivariate linear regression analysis was performed step by step to identify independent AHI predictors. Results. Useful parameters were found in this analysis in terms of body mass index (BMI), waist circumference (WC), neck circumference (NC), oxygen saturation measured by pulse oximetry (SpO2), and tonsil size (TS) to predict the AHI. The formula derived from these parameters was the predicted AHI = (0.797 × BMI) + (2.286 × NC) − (1.272 × SpO2) + (5.114 × TS) + (0.314 × WC). Conclusion. This study showed a strong correlation between AHI score and indicators of obesity. This formula, in terms of predicting the AHI for patients who complain about snoring, witnessed apneas, and excessive daytime sleepiness, may be used to predict OSAS prior to PSG and prevent unnecessary PSG.
PMCID: PMC4199210  PMID: 25349613
5.  Both Maternal and Pup Genotype Influence Ultrasonic Vocalizations and Early Developmental Milestones in Tsc2+/− Mice 
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by tumor growth and neuropsychological symptoms such as autistic behavior, developmental delay, and epilepsy. While research has shed light on the biochemical and genetic etiology of TSC, the pathogenesis of the neurologic and behavioral manifestations remains poorly understood. TSC patients have a greatly increased risk of developmental delay and autism spectrum disorder, rendering the relationship between the two sets of symptoms an extremely pertinent issue for clinicians. We have expanded on previous observations of aberrant vocalizations in Tsc2+/− mice by testing vocalization output and developmental milestones systematically during the early postnatal period. In this study, we have demonstrated that Tsc2 haploinsufficiency in either dams or their pups results in a pattern of developmental delay in sensorimotor milestones and ultrasonic vocalizations.
PMCID: PMC4137560  PMID: 25165580
6.  Impaired Language Pathways in Tuberous Sclerosis Complex Patients with Autism Spectrum Disorders 
Cerebral Cortex (New York, NY)  2012;23(7):1526-1532.
The purpose of this study was to examine the relationship between language pathways and autism spectrum disorders (ASDs) in patients with tuberous sclerosis complex (TSC). An advanced diffusion-weighted magnetic resonance imaging (MRI) was performed on 42 patients with TSC and 42 age-matched controls. Using a validated automatic method, white matter language pathways were identified and microstructural characteristics were extracted, including fractional anisotropy (FA) and mean diffusivity (MD). Among 42 patients with TSC, 12 had ASD (29%). After controlling for age, TSC patients without ASD had a lower FA than controls in the arcuate fasciculus (AF); TSC patients with ASD had even a smaller FA, lower than the FA for those without ASD. Similarly, TSC patients without ASD had a greater MD than controls in the AF; TSC patients with ASD had even a higher MD, greater than the MD in those without ASD. It remains unclear why some patients with TSC develop ASD, while others have better language and socio-behavioral outcomes. Our results suggest that language pathway microstructure may serve as a marker of the risk of ASD in TSC patients. Impaired microstructure in language pathways of TSC patients may indicate the development of ASD, although prospective studies of language pathway development and ASD diagnosis in TSC remain essential.
PMCID: PMC3673171  PMID: 22661408
arcuate fasciculus; diffusion tensor imaging; neuroanatomy; tractography; white matter
7.  Diffusion tensor imaging and related techniques in tuberous sclerosis complex: review and future directions 
Future neurology  2013;8(5):583-597.
In this article, the authors aim to introduce the nonradiologist to diffusion tensor imaging (DTI) and its applications to both clinical and research aspects of tuberous sclerosis complex. Tuberous sclerosis complex is a genetic neurocutaneous syndrome with variable and unpredictable neurological comorbidity that includes refractory epilepsy, intellectual disability, behavioral abnormalities and autism spectrum disorder. DTI is a method for modeling water diffusion in tissue and can noninvasively characterize microstructural properties of the brain. In tuberous sclerosis complex, DTI measures reflect well-known pathological changes. Clinically, DTI can assist with detecting the epileptogenic tuber. For research, DTI has a putative role in identifying potential disease biomarkers, as DTI abnormalities of the white matter are associated with neurocognitive morbidity including autism. If indeed DTI changes parallel phenotypical changes related to the investigational treatment of epilepsy, cognition and behavior with mTOR inhibitors, it will facilitate future clinical trials.
PMCID: PMC3904372  PMID: 24489482
autism spectrum disorders; behavior; cognition; diffusion tensor imaging; epilepsy; MRI; mTOR serine–threonine kinases; tuberous sclerosis complex
8.  Characterizing the DIstribution of Anisotropic MicrO-structural eNvironments with Diffusion-weighted imaging (DIAMOND) 
Diffusion-weighted imaging (DWI) enables investigation of the brain microstructure by probing natural barriers to diffusion in tissues. In this work, we propose a novel generative model of the DW signal based on considerations of the tissue microstructure that gives rise to the diffusion attenuation. We consider that the DW signal can be described as the sum of a large number of individual homogeneous spin packets, each of them undergoing local 3-D Gaussian diffusion represented by a diffusion tensor. We consider that each voxel contains a number of large scale microstructural environments and describe each of them via a matrix-variate Gamma distribution of spin packets. Our novel model of DIstribution of Anisotropic MicrOstructural eNvironments in DWI (DIAMOND) is derived from first principles. It enables characterization of the extra-cellular space, of each individual white matter fascicle in each voxel and provides a novel measure of the microstructure heterogeneity. We determine the number of fascicles at each voxel with a novel model selection framework based upon the minimization of the generalization error. We evaluate our approach with numerous in-vivo experiments, with cross-testing and with pathological DW-MRI. We show that DIAMOND may provide novel biomarkers that captures the tissue integrity.
PMCID: PMC4029840  PMID: 24505801
9.  RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity 
The Journal of Clinical Investigation  2014;124(6):2774-2784.
Vascular malformations are linked to mutations in RAS p21 protein activator 1 (RASA1, also known as p120RasGAP); however, due to the global expression of this gene, it is unclear how these mutations specifically affect the vasculature. Here, we tested the hypothesis that RASA1 performs a critical effector function downstream of the endothelial receptor EPHB4. In zebrafish models, we found that either RASA1 or EPHB4 deficiency induced strikingly similar abnormalities in blood vessel formation and function. Expression of WT EPHB4 receptor or engineered receptors with altered RASA1 binding revealed that the ability of EPHB4 to recruit RASA1 is required to restore blood flow in EPHB4-deficient animals. Analysis of EPHB4-deficient zebrafish tissue lysates revealed that mTORC1 is robustly overactivated, and pharmacological inhibition of mTORC1 in these animals rescued both vessel structure and function. Furthermore, overexpression of mTORC1 in endothelial cells exacerbated vascular phenotypes in animals with reduced EPHB4 or RASA1, suggesting a functional EPHB4/RASA1/mTORC1 signaling axis in endothelial cells. Tissue samples from patients with arteriovenous malformations displayed strong endothelial phospho-S6 staining, indicating increased mTORC1 activity. These results indicate that deregulation of EPHB4/RASA1/mTORC1 signaling in endothelial cells promotes vascular malformation and suggest that mTORC1 inhibitors, many of which are approved for the treatment of certain cancers, should be further explored as a potential strategy to treat patients with vascular malformations.
PMCID: PMC4089464  PMID: 24837431
10.  The use of fibrin glue without surgery in the treatment of pilonidal sinus disease 
Pilonidal sinus disease is a common disabling condition affecting the natal clefts of the buttocks. We analyze the role of fibrin glue in the treatment of selected patients with pilonidal sinus disease. Forty patients diagnosed with pilonidal sinus disease at Vakif Gureba Training and Research Hospital were treated between December 2007 and December 2011. Recurrence was noted in four patients (10%). Ninety percent of patients had no recurrence one year later (95% confidence interval: 0.85-0.95). This procedure is suggested as a first line of treatment for patients with no prior history of infection and who have only one sinus orifice.
PMCID: PMC4057859  PMID: 24955180
Fibrin glue; pilonidal sinus
11.  A Mathematical Framework for the Registration and Analysis of Multi-Fascicle Models for Population Studies of the Brain Microstructure 
Diffusion tensor imaging (DTI) is unable to represent the diffusion signal arising from multiple crossing fascicles and freely diffusing water molecules. Generative models of the diffusion signal, such as multi-fascicle models, overcome this limitation by providing a parametric representation for the signal contribution of each population of water molecules. These models are of great interest in population studies to characterize and compare the brain microstructural properties. Central to population studies is the construction of an atlas and the registration of all subjects to it. However, the appropriate definition of registration and atlasing methods for multi-fascicle models have proven challenging. This paper proposes a mathematical framework to register and analyze multi-fascicle models. Specifically, we define novel operators to achieve interpolation, smoothing and averaging of multi-fascicle models. We also define a novel similarity metric to spatially align multi-fascicle models. Our framework enables simultaneous comparisons of different microstructural properties that are confounded in conventional DTI. The framework is validated on multi-fascicle models from 24 healthy subjects and 38 patients with tuberous sclerosis complex, 10 of whom have autism. We demonstrate the use of the multi-fascicle models registration and analysis framework in a population study of autism spectrum disorder.
PMCID: PMC3984609  PMID: 24235301
Diffusion magnetic resonance imaging (MRI); interpolation; microstructure; multi-fascicle; multi-tensor; population studies; registration
12.  A TSC signaling node at the peroxisome regulates mTORC1 and autophagy in response to ROS 
Nature cell biology  2013;15(10):1186-1196.
Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signaling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by PEX19 and PEX5, respectively, and peroxisome-localized TSC functioned as a Rheb GAP to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, abrogated peroxisome localization, Rheb GAP activity, and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS and peroxisome-localization deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for TSC in responding to ROS at the peroxisome, and identify the peroxisome as a signaling organelle involved in regulation of mTORC1.
PMCID: PMC3789865  PMID: 23955302
13.  Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis 
Molecular Autism  2014;5:16.
Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity.
To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis.
Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/−) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues.
Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/− mice mirror some, but not all, of the perturbed molecular pathways in the brain.
PMCID: PMC3940253  PMID: 24564913
Fragile X syndrome; Tuberous sclerosis; Autism; Cerebellum; Blood; Gene expression; Murine model
14.  Effect of orally administered simvastatin on prevention of postoperative adhesion in rats 
Aim: Formation of adhesions in the abdominal region appearing after abdominal pelvic surgery lead to infertility, chronic pelvic pain, intestinal obstructions, difficulty and morbidity at the following operations, and increased morbidity. The aim of our study is to examine the effectiveness of orally administered simvastatin on preventing the postoperative adhesion. Materials and methods: 20 male Wistar Albino rats weighing 230-250 gr were used. The rats were housed for 12 hours day and 12 hours night cycles in cages and were divided into two groups, namely study and control group. Microscopic evaluation of adhesion was assessed under 5 main topics which are the signs of inflammatory response; inflammation, activation, fibroblast activity, vascularity, presence of giant cell. Activation was scored as follows: (0) no activation, (1) while activation was accepted as present the score for other parameters was evaluated between 0 to 3 according to the increased severity. After evaluating all topics separately, the average of all scores has been assessed in both groups. Results: As a result of the macroscopic evaluation of postoperative intra-abdominal adhesions, the percentage of adhesion in simvastatin applied group was found to be 0.8 ± 0.17. This value was calculated as 0.6 ± 0.2 in the control group. Regarding the severity of adhesion, while in the simvastatin applied group the value was found to be 9.1 ± 4, in the control group it was 6.8 ± 3. The general adhesion score was found to be 7.7 ± 4.2 in simvastatin applied group and 5.1 ± 3.7 in control group. Conclusion: In this experimental study it was showed that orally administered simvastatin has no significant effect on preventing formation of postoperative adhesions.
PMCID: PMC3931595  PMID: 24600496
Surgery; adhesion; simvastatin
15.  An MRI Study of Cerebellar Volume in Tuberous Sclerosis Complex 
Pediatric neurology  2013;48(2):105-110.
The cerebellum plays an important role in motor learning and cognition, and structural cerebellar abnormalities have been associated with cognitive impairment. In tuberous sclerosis complex, neurological outcome is highly variable, and no consistent imaging or pathological determinant of cognition has been firmly established. The cerebellum calls for specific attention as mouse models of tuberous sclerosis complex have demonstrated a loss of cerebellar Purkinje cells and cases of human histological data have demonstrated a similar loss in patients. We hypothesized that there might be a common cerebellar finding in tuberous sclerosis complex that could be measured as morphometric changes with magnetic resonance imaging. Using a robust, automated image analysis procedure, we studied 36 patients with tuberous sclerosis complex and age-matched controls and observed significant volume loss among patients in the cerebellar cortices and vermis. Furthermore, this effect was strongest in a subgroup of 19 patients with a known, pathogenic mutation of the tuberous sclerosis 2 gene and impacted all cerebellar structures. We conclude that patients with tuberous sclerosis complex exhibit volume loss in the cerebellum, and this loss is larger and more widespread in patients with a tuberous sclerosis 2 mutation.
PMCID: PMC3763730  PMID: 23337002
16.  Prenatal rapamycin results in early and late behavioral abnormalities in wildtype C57Bl/6 mice 
Behavior genetics  2012;43(1):51-59.
Mammalian target of rapamycin (mTOR) signaling has been shown to be deregulated in a number of genetic, neurodevelopmental disorders including Tuberous Sclerosis Complex, Neurofibromatosis, Fragile X, and Rett syndromes. As a result, mTOR inhibitors, such as rapamycin and its analogs, offer potential therapeutic avenues for these disorders. Some of these disorders – such as Tuberous Sclerosis Complex – can be diagnosed prenatally. Thus, prenatal administration of these inhibitors could potentially prevent the development of the devastating symptoms associated with these disorders. To assess the possible detrimental effects of prenatal rapamycin treatment, we evaluated both early and late behavioral effects of a single rapamycin treatment at embryonic day 16.5 in wildtype C57Bl/6 mice. This treatment adversely impacted early developmental milestones as well as motor function in adult animals. Rapamycin also resulted in anxiety-like behaviors during both early development and adulthood but did not affect adult social behaviors. Together, these results indicate that a single, prenatal rapamycin treatment not only adversely affects early postnatal development but also results in long lasting negative effects, persisting into adulthood. These findings are of importance in considering prenatal administration of rapamycin and related drugs in the treatment of patients with neurogenetic, neurodevelopmental disorders.
PMCID: PMC3554236  PMID: 23229624
mTOR; tuberous sclerosis; embryonic; mouse
17.  The Role of Elastosonography in the Differentiation of Parotid Gland Lesions: Report of Three Cases and Review of the Literature 
Polish Journal of Radiology  2014;79:398-401.
The parotid gland is the mostly affected site among major salivary gland tumors in up to 85% of cases. Preoperative knowledge of the tumour nature is crucial since it influences the surgical procedure and patient’s morbidity, especially the risk of facial nerve palsy. Ultrasonography is commonly used as the first line imaging modality for the salivary gland lesions. A pitfall is that the histologic pleomorphism often reflects an imaging pleomorphism.
Case Report
Herein we aimed to present the role of elastosonography in three parotid lesions: a case of benign pleomorphic adenoma, a Wharthin’s tumour and a malignant parotid tumour.
Our findings show that malignant parotid lesion was the stiffest lesion according to elastosonography. Wharthin’s tumour demonstrated soft elastosonographic features. The pleomorphic adenoma was also interpreted as stiff by elastosonography suggesting that the elastosonographic features of pleomorphic adenoma may resemble those of malignant lesions limiting the utility of the technique.
PMCID: PMC4226314  PMID: 25386225
Elasticity Imaging Techniques; Parotid Neoplasms; Ultrasonography
18.  A gastrointestinal stromal tumor of the third portion of the duodenum treated by wedge resection: A case report 
A 65-year old woman was admitted to our hospital with abdominal pain. Computed tomography showed a tumor measuring about 3 cm in diameter with no metastatic lesion or signs of local infiltration. Gastroduodenal endoscopy revealed the presence of a submucosal tumor in the third portion of the duodenum and biopsy revealed tumor cells stained positive for c-kit. These findings were consistent with gastrointestinal stromal tumors (GISTs) and we performed a wedge resection of the duodenum, sparing the pancreas. The postoperative course was uneventful and she was discharged on day 6. Surgical margins were negative. Histology revealed a GIST with a diameter of 3.2 cm and < 5 mitoses/50 high power fields, indicating a low risk of malignancy. Therefore, adjuvant therapy with imatinib was not initiated. Wedge resection with primary closure is a surgical procedure that can be used to treat low malignant potential neoplasms of the duodenum and avoid extensive surgery, with significant morbidity and possible mortality, such as pancreatoduodenectomy.
PMCID: PMC3879418  PMID: 24392185
Gastrointestinal stromal tumor; Duodenum; Wedge resection; Surgery
19.  Homozygous PLCB1 Deletion Associated with Malignant Migrating Partial Seizures in Infancy 
Epilepsia  2012;53(8):10.1111/j.1528-1167.2012.03538.x.
Malignant migrating partial seizures in infancy (MMPEI) is an early onset epileptic encephalopathy with few known etiologies. We sought to identify a novel cause of MMPEI in a child with MMPEI whose healthy parents were consanguineous. We used array comparative genomic hybridization (CGH) to identify copy number variants (CNVs) genome-wide and long-range PCR to further delineate the breakpoints of a deletion found by CGH. The proband had an inherited homozygous deletion of chromosome 20p13, disrupting the promoter region and first three coding exons of the gene PLCB1. Additional MMPEI cases were screened for similar deletions or mutations in PLCB1 but did not harbor mutations. Our results suggest that loss of PLCβ1 function is one cause of MMPEI, consistent with prior studies in a Plcb1 knockout mouse model that develops early onset epilepsy. We provide novel insight into the molecular mechanisms underlying MMPEI and further implicate PLCB1 as a candidate gene for severe childhood epilepsies. This work highlights the importance of pursuing genetic etiologies for severe early onset epilepsy syndromes.
PMCID: PMC3851296  PMID: 22690784
Focal epilepsy; migrating partial seizures in infancy; genetics; phospholipase C beta 1 (PLCB1)
20.  The neuroprotective drug riluzole acts via small conductance Ca2+-activated K+ channels to ameliorate defects in Spinal Muscular Atrophy models 
Spinal muscular atrophy (SMA), a recessive neuromuscular disorder, is caused by diminished function of the Survival Motor Neuron (SMN) protein. To define the cellular processes pertinent to SMA, parallel genetic screens were undertaken in Drosophila and C. elegans SMA models to identify modifiers of the SMN loss of function phenotypes. One class of such genetic modifiers was the small conductance, Ca2+-activated K+ (SK) channels. SK channels allow efflux of potassium ions when intracellular calcium increases and can be activated by the neuroprotective drug riluzole. The latter is the only drug with proven, albeit modest, efficacy in the treatment of Amyotrophic Lateral Sclerosis (ALS). It is unclear if riluzole can extend lifespan or ameliorate symptoms in SMA patients as previous studies were limited and of insufficient power to draw any conclusions. The critical biochemical target of riluzole in motorneuron disease is not known, but the pharmacological targets of riluzole include SK channels. We examine here the impact of riluzole in two different SMA models. In vertebrate neurons, riluzole treatment restored axon outgrowth caused by diminished SMN. Additionally, riluzole ameliorated the neuromuscular defects in a C. elegans SMA model and SK channel function was required for this beneficial effect. We propose that riluzole improves motorneuron function by acting on SK channels and suggest that SK channels may be important therapeutic targets for SMA patients.
PMCID: PMC3652322  PMID: 23575853
21.  Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features 
Human Molecular Genetics  2012;21(19):4286-4300.
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with prominent brain manifestations due to mutations in either TSC1 or TSC2. Here, we describe novel mouse brain models of TSC generated using conditional hypomorphic and null alleles of Tsc2 combined with the neuron-specific synapsin I cre (SynIcre) allele. This allelic series of homozygous conditional hypomorphic alleles (Tsc2c-del3/c-del3SynICre+) and heterozygote null/conditional hypomorphic alleles (Tsc2k/c-del3SynICre+) achieves a graded reduction in expression of Tsc2 in neurons in vivo. The mice demonstrate a progressive neurologic phenotype including hunchback, hind limb clasp, reduced survival and brain and cortical neuron enlargement that correlates with a graded reduction in expression of Tsc2 in the two sets of mice. Both models also showed behavioral abnormalities in anxiety, social interaction and learning assays, which correlated with Tsc2 protein levels as well. The observations demonstrate that there are graded biochemical, cellular and clinical/behavioral effects that are proportional to the extent of reduction in Tsc2 expression in neurons. Further, they suggest that some patients with milder manifestations of TSC may be due to persistent low-level expression of functional protein from their mutant allele. In addition, they point to the potential clinical benefit of strategies to raise TSC2 protein expression from the wild-type allele by even modest amounts.
PMCID: PMC3441124  PMID: 22752306
22.  Targeted treatment trials for tuberous sclerosis and autism: no longer a dream 
Current opinion in neurobiology  2012;22(5):895-901.
Genetic disorders that present with a high incidence of autism spectrum disorders (ASD) offer tremendous potential both for elucidating the underlying neurobiology of ASD and identifying therapeutic drugs and/or drug targets. As a result, clinical trials for genetic disorders associated with ASD are no longer a hope for the future but rather an exciting reality whose time has come. Tuberous sclerosis complex (TSC) is one such genetic disorder that presents with ASD, epilepsy, and intellectual disability. Cell culture and mouse model experiments have identified the mTOR pathway as a therapeutic target in this disease. This review summarizes the advantages of using TSC as model of ASD and the recent advances in the translational and clinical treatment trials in TSC.
PMCID: PMC3715752  PMID: 22560338
23.  Effect of laparoscopic cholecystectomy techniques on postoperative pain: a prospective randomized study 
Minimally invasive surgical technics have benefits such as decreased pain, reduced surgical trauma, and increased potential to perform as day case surgery, and cost benefit. The primary aim of this prospective, randomized, controlled study was to compare the effects of single incision laparoscopic cholecystectomy (SILC) and conventional laparoscopic cholecystectomy (CLC) procedures regarding postoperative pain.
Ninety adult patients undergoing elective laparoscopic cholecystectomy were included in the study. Patients were randomized to either SILC or CLC. Patient characteristics, postoperative abdominal and shoulder pain scores, rescue analgesic use, and intraoperative and early postoperative complications were recorded.
A total of 83 patients completed the study. Patient characteristics, postoperative abdominal and shoulder pain scores and rescue analgesic requirement were similar between each group except with the lower abdominal pain score in CLC group at 30th minute (P = 0.04). Wound infection was seen in 1 patient in each group. Nausea occurred in 13 of 43 patients (30%) in the SILC group and 8 of 40 patients (20%) in the CLC group (P > 0.05). Despite ondansetron treatment, 6 patients in SILC group and 7 patients in CLC group vomited (P > 0.05).
In conclusion, in patients undergoing laparoscopic surgery, SILC or CLC techniques does not influence the postoperative pain and analgesic medication requirements. Our results also suggest that all laparoscopy patients suffer moderate and/or severe abdominal pain and nearly half of these patients also suffer from some form of shoulder pain.
PMCID: PMC3791356  PMID: 24106680
Laparoscopic cholecystectomy; Postoperative pain
24.  Solitary Fibrous Tumor of Neck Mimicking Cold Thyroid Nodule in 99m Tc Thyroid Scintigraphy 
Case Reports in Endocrinology  2013;2013:805745.
A 68-year-old man had a rapidly growing, painless neck mass, thought to be nodular goiter. Ultrasonography showed a giant, heterogeneous mass occupying the middle and superior poles and protruding outside of the left thyroid lobe. The results of the thyroid function tests were normal. Thyroid scintigraphy revealed a large hypoactive nodule in the left thyroid lobe. Complete surgical removal of tumor was performed and macroscopically demonstrated a well-demarked lesion outside the thyroid gland. Microscopically, the lesion was composed of fibroblast-like spindle cells in a patternless architecture and extensive stromal hyalinization. Immunohistochemistry showed positive reaction for CD34 in spindle cells and diffuse bcl-2 staining. The pathology was confirmed as solitary fibrous tumor. In the follow-up period after surgery, thyroid scintigraphy showed normal left thyroid lobe. Solitary fibrous tumor originated from or associated with thyroid gland is extremely rare. According to our knowledge, this is the first reported solitary fibrous tumor presenting like a cold thyroid nodule. This pathology must be considered for differential diagnosis of neck masses in the thyroid region.
PMCID: PMC3806406  PMID: 24194989
25.  Maximum A Posteriori Estimation of Isotropic High-Resolution Volumetric MRI from Orthogonal Thick-Slice Scans 
Thick-slice image acquisitions are sometimes inevitable in magnetic resonance imaging due to limitations posed by pulse sequence timing and signal-to-noise-ratio. The estimation of an isotropic high-resolution volume from thick-slice MRI scans is desired for improved image analysis and evaluation. In this article we formulate a maximum a posteriori (MAP) estimation algorithm for high-resolution volumetric MRI reconstruction. As compared to the previous techniques, this probabilistic formulation relies on a slice acquisition model and allows the incorporation of image priors. We focus on image priors based on image gradients and compare the developed MAP estimation approach to scattered data interpolation (SDI) and maximum likelihood reconstruction. The results indicate that the developed MAP estimation approach outperforms the SDI techniques and appropriate image priors may improve the volume estimation when the acquired thick-slice scans do not sufficiently sample the imaged volume. We also report applications in pediatric and fetal imaging.
PMCID: PMC3776306  PMID: 20879305
MAP estimation; super-resolution; volume reconstruction

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