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.
arcuate fasciculus; diffusion tensor imaging; neuroanatomy; tractography; white matter
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.
autism spectrum disorders; behavior; cognition; diffusion tensor imaging; epilepsy; MRI; mTOR serine–threonine kinases; tuberous sclerosis complex
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.
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.
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.
Fibrin glue; pilonidal sinus
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.
Diffusion magnetic resonance imaging (MRI); interpolation; microstructure; multi-fascicle; multi-tensor; population studies; registration
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.
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.
Fragile X syndrome; Tuberous sclerosis; Autism; Cerebellum; Blood; Gene expression; Murine model
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.
Surgery; adhesion; simvastatin
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.
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.
mTOR; tuberous sclerosis; embryonic; mouse
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.
Gastrointestinal stromal tumor; Duodenum; Wedge resection; Surgery
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.
Focal epilepsy; migrating partial seizures in infancy; genetics; phospholipase C beta 1 (PLCB1)
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.
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.
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.
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.
Laparoscopic cholecystectomy; Postoperative pain
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.
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.
MAP estimation; super-resolution; volume reconstruction
The olive tree (Olea europaea L.) is a diploid (2n = 2x = 46) outcrossing species mainly grown in the Mediterranean area, where it is the most important oil-producing crop. Because of its economic, cultural and ecological importance, various DNA markers have been used in the olive to characterize and elucidate homonyms, synonyms and unknown accessions. However, a comprehensive characterization and a full sequence of its transcriptome are unavailable, leading to the importance of an efficient large-scale single nucleotide polymorphism (SNP) discovery in olive. The objectives of this study were (1) to discover olive SNPs using next-generation sequencing and to identify SNP primers for cultivar identification and (2) to characterize 96 olive genotypes originating from different regions of Turkey.
Next-generation sequencing technology was used with five distinct olive genotypes and generated cDNA, producing 126,542,413 reads using an Illumina Genome Analyzer IIx. Following quality and size trimming, the high-quality reads were assembled into 22,052 contigs with an average length of 1,321 bases and 45 singletons. The SNPs were filtered and 2,987 high-quality putative SNP primers were identified. The assembled sequences and singletons were subjected to BLAST similarity searches and annotated with a Gene Ontology identifier. To identify the 96 olive genotypes, these SNP primers were applied to the genotypes in combination with amplified fragment length polymorphism (AFLP) and simple sequence repeats (SSR) markers.
This study marks the highest number of SNP markers discovered to date from olive genotypes using transcriptome sequencing. The developed SNP markers will provide a useful source for molecular genetic studies, such as genetic diversity and characterization, high density quantitative trait locus (QTL) analysis, association mapping and map-based gene cloning in the olive. High levels of genetic variation among Turkish olive genotypes revealed by SNPs, AFLPs and SSRs allowed us to characterize the Turkish olive genotype.
Adipocytokines are important mediators of interorgan crosstalk in metabolic regulation. Thyroid diseases have effects on metabolism and inflammation. The mechanism of these effects is not clear. Recently, there are several reports suggesting this interrelation between adipocytokines and thyroid dysfunction. In this review, we summarize this relation according to the literature.
Diffusion magnetic resonance imaging has been used extensively to probe the white matter in vivo. Typically, the raw diffusion images are used to reconstruct a diffusion tensor image (DTI). The in-capacity of DTI to represent crossing fibers leaded to the development of more sophisticated diffusion models. Among them, multi-fiber models represent each fiber bundle independently, allowing the direct extraction of diffusion features for population analysis. However, no method exists to properly register multi-fiber models, seriously limiting their use in group comparisons. This paper presents a registration and atlas construction method for multi-fiber models. The validity of the registration is demonstrated on a dataset of 45 subjects, including both healthy and unhealthy subjects. Morphometry analysis and tract-based statistics are then carried out, proving that multi-fiber models registration is better at detecting white matter local differences than single tensor registration.
Diffusion Imaging; Multi-Fiber Models; Registration; White Matter
Monosymptomatic nocturnal enuresis is a common disorder seen in childhood, and many factors play a role in its etiopathology to varying degrees. The aim of our study was to investigate the possible association between nocturnal enuresis and 24-h blood pressure profiles of enuretic children.
A total of 45 children ranging in age from 6 to 15 years with monosymptomatic nocturnal enuresis and 22 age-matched healthy controls were enrolled in our study. The blood pressure measurement was made at 30-min intervals during a 24-h period via an ambulatory blood pressure measurement device. Both groups underwent medical tests that included a complete blood count, blood biochemistry profile, urinalysis and blood renin–aldosterone levels, and all study subjects received an abdominal ultrasound.
Statistically significant high nocturnal blood pressure levels were observed in our patients with monosymptomatic nocturnal enuresis compared with the control group (p < 0.05). The mean values of the day-to-night difference (dipping) in the systolic and diastolic blood pressure of the patients were significantly lower than those of control group (p < 0.05).
Nocturnal enuresis should not only be accepted as a urinary system disorder. Possible systemic causative factors have to be examined, especially in patients that are resistant to first-line therapy. Based on the results of our study, we deduce that one of the factors that plays a role in the pathogenesis of enuresis nocturna is a non-dipping blood pressure profile (the “non-dipping” phenomenon).
Nocturnal enuresis; Children; Blood pressure; Non-dipping phenomenon
Fatty acid binding protein 4 (FABP4) plays an important role in regulation of glucose and lipid homeostasis as well as inflammation through its actions in adipocytes and macrophages. FABP4 is also expressed in a subset of endothelial cells, but its role in this cell type is not known. We found that FABP4-deficient human umbilical vein endothelial cells (HUVECs) demonstrate a markedly increased susceptibility to apoptosis as well as decreased migration and capillary network formation. Aortic rings from FABP4−/− mice demonstrated decreased angiogenic sprouting, which was recovered by reconstitution of FABP4. FABP4 was strongly regulated by mTORC1 and inhibited by Rapamycin. FABP4 modulated activation of several important signaling pathways in HUVECs, including downregulation of P38, eNOS, and stem cell factor (SCF)/c-kit signaling. Of these, the SCF/c-kit pathway was found to have a major role in attenuated angiogenic activity of FABP4-deficient ECs as provision of exogenous SCF resulted in a significant recovery in cell proliferation, survival, morphogenesis, and aortic ring sprouting. These data unravel a novel pro-angiogenic role for endothelial cell-FABP4 and suggest that it could be exploited as a potential target for diseases associated with pathological angiogenesis.
Angiogenesis; Endothelial cells; FABP4; Rapamycin; c-Kit; Stem cell factor