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BACKGROUND: Glucose-dependent insulinotropic polypeptide receptor (Gipr) gene expression has been reported in mouse spermatids and Gipr knockout male mice have previously been reported to have decreased in vitro fertilization, although the role of Gipr signaling in male mouse fertility is not well understood. OBJECTIVES: The purposes of these studies were to determine the role of glucose-dependent insulinotropic polypeptide receptor in male fertility using Gipr knockout mice and anti-glucose-dependent insulinotropic polypeptide receptor antibody-treated wild-type mice and to determine if the expression of Gipr in mouse testes is similar in non-human and human primates. METHODS AND MATERIALS: Adiponectin promoter-driven Gipr knockout male mice (GiprAdipo-/- ) were assessed for in vitro and in vivo fertility, sperm parameters, and testicular histology. CD1 male mice were administered an anti-glucose-dependent insulinotropic polypeptide receptor antibody (muGIPR-Ab) prior to and during mating for assessment of in vivo fertility and sperm parameters. Expression of Gipr/GIPR mRNA in the mouse, cynomolgus monkey, and human testes was assessed by in situ hybridization methods using species-specific probes. RESULTS: GiprAdipo-/- male mice are infertile in vitro and in vivo, despite normal testis morphology, sperm counts, and sperm motility. In contrast, administration of muGIPR-Ab to CD1 male mice did not impact fertility. While Gipr mRNA expression is detectable in the mouse testes, GIPR mRNA expression is not detectable in monkey or human testes. DISCUSSION: The infertility of GiprAdipo-/- male mice correlated with the lack of Gipr expression in the testis and/or adipocyte tissue. However, as administration of muGIPR-Ab did not impact the fertility of adult male mice, it is possible that the observations in genetically deficient male mice are related to Gipr deficiency during development. CONCLUSION: Our data support a role for Gipr expression in the mouse testis during the development of sperm fertilization potential, but based on gene expression data, a similar role for glucose-dependent insulinotropic polypeptide receptor in non-human primate or human male fertility is unlikely.
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Polipéptido Inhibidor Gástrico , Testículo , Animales , Femenino , Fertilidad , Polipéptido Inhibidor Gástrico/genética , Polipéptido Inhibidor Gástrico/metabolismo , Expresión Génica , Humanos , Macaca fascicularis/genética , Macaca fascicularis/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de la Hormona Gastrointestinal , Motilidad Espermática , Testículo/metabolismoRESUMEN
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 bispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters. BW loss is greater with GIPR-Ab/GLP-1 than with GIPR-Ab or a control antibody conjugate, suggesting synergistic effects. GIPR-Ab/GLP-1 also reduces the respiratory exchange ratio in DIO mice. Simultaneous receptor binding and rapid receptor internalization by GIPR-Ab/GLP-1 amplify endosomal cAMP production in recombinant cells expressing both receptors. This may explain the efficacy of the bispecific molecules. Overall, our GIPR-Ab/GLP-1 molecules promote BW loss, and they may be used for treating obesity.
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Peso Corporal/fisiología , Péptido 1 Similar al Glucagón/metabolismo , Obesidad/metabolismo , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Animales , Polipéptido Inhibidor Gástrico/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Prueba de Tolerancia a la Glucosa/métodos , Haplorrinos/metabolismo , Ratones ObesosRESUMEN
Distal radius fractures are among the most common injuries to the upper extremity and have a bimodal distribution in younger male patients and older women. Young men suffer from high-energy injuries and older women from fragility fractures. Approximately 50% of these are intra-articular. Timely and appropriate treatment usually will lead to an acceptable outcome, but loss of congruity of the articular surface remains a difficult problem to manage. We report here on the case of a 16-year-old boy with malunion of the radial articular surface with lack of motion and pain. He was managed by replacing the displaced and damaged segment of the radial articular surface with a vascularized osteochondral graft from the proximal phalanx of the great toe. This matched the shape of this portion of the radius quite well, and he has had improvements in motion and pain in the 10 months since that time. The donor site has not caused him any difficulty to date.
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Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.
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Adipocitos/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/uso terapéutico , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Peso Corporal/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/metabolismo , Polipéptido Inhibidor Gástrico/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/patología , Receptores de la Hormona Gastrointestinal/deficiencia , Receptores de la Hormona Gastrointestinal/metabolismoRESUMEN
Glucose-dependent insulinotropic polypeptide receptor (GIPR) is associated with obesity in human genome-wide association studies. Similarly, mouse genetic studies indicate that loss of function alleles and glucose-dependent insulinotropic polypeptide overexpression both protect from high-fat diet-induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when codosed or molecularly combined with glucagon-like peptide-1 analogs preclinically. Here, we review the current literature on GIPR, including biology, human and mouse genetics, and pharmacology of both agonists and antagonists, discussing the similarities and differences between the 2 approaches. Despite opposite approaches being investigated preclinically and clinically, there may be viability of both agonists and antagonists for the treatment of obesity, and we expect this area to continue to evolve with new clinical data and molecular and pharmacological analyses of GIPR function.
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Fármacos Antiobesidad/uso terapéutico , Terapia Molecular Dirigida , Obesidad/tratamiento farmacológico , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Animales , Estudio de Asociación del Genoma Completo , Humanos , Ratones , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Obesidad/genética , Receptores de la Hormona Gastrointestinal/genética , Receptores de la Hormona Gastrointestinal/fisiologíaRESUMEN
Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic ß-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.
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Receptor del Péptido 1 Similar al Glucagón/agonistas , Obesidad/tratamiento farmacológico , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Adipocitos/metabolismo , Animales , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Dieta , Quimioterapia Combinada , Conducta Alimentaria , Polipéptido Inhibidor Gástrico/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/farmacología , Péptidos Similares al Glucagón/uso terapéutico , Humanos , Fragmentos Fc de Inmunoglobulinas/farmacología , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Liraglutida/farmacología , Liraglutida/uso terapéutico , Ratones Obesos , Obesidad/patología , Primates , Receptores de la Hormona Gastrointestinal/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Respiración , Aumento de Peso/efectos de los fármacos , Pérdida de Peso/efectos de los fármacosRESUMEN
OBJECTIVE: Regulation of fatty acid (FA) metabolism is central to adipocyte dysfunction during diet-induced obesity (DIO). Long-chain acyl-CoA synthetase-4 (ACSL4) has been hypothesized to modulate the metabolic fates of polyunsaturated FA (PUFA), including arachidonic acid (AA), but the in vivo actions of ACSL4 are unknown. The purpose of our studies was to determine the in vivo role of adipocyte ACSL4 in regulating obesity-associated adipocyte dysfunction. METHODS: We developed a novel mouse model with adipocyte-specific ablation of ACSL4 (Ad-KO) using loxP Cre recombinase technology. Metabolic phenotyping of Ad-KO mice relative to their floxed littermates (ACSL4floxed) was performed, including body weight and body composition over time; insulin and glucose tolerance tests; and energy expenditure, activity, and food intake in metabolic cages. Adipocytes were isolated for ex vivo adipocyte oxygen consumption by Clark electrode and lipidomics analysis. In vitro adipocyte analysis including oxygen consumption by Seahorse and real-time PCR analysis were performed to confirm our in vivo findings. RESULTS: Ad-KO mice were protected against DIO, adipocyte death, and metabolic dysfunction. Adipocytes from Ad-KO mice fed high-fat diet (HFD) had reduced incorporation of AA into phospholipids (PL), free AA, and levels of the AA lipid peroxidation product 4-hydroxynonenal (4-HNE). Additionally, adipocytes from Ad-KO mice fed HFD had reduced p53 activation and increased adipocyte oxygen consumption (OCR), which we demonstrated are direct effects of 4-HNE on adipocytes in vitro. CONCLUSION: These studies are the first to elucidate ACSL4's in vivo actions to regulate the incorporation of AA into PL and downstream effects on DIO-associated adipocyte dysfunction. By reducing the incorporation of AA into PL and free fatty acid pools in adipocytes, Ad-KO mice were significantly protected against HFD-induced increases in adipose and liver fat accumulation, adipocyte death, gonadal white adipose tissue (gWAT) inflammation, and insulin resistance (IR). Additionally, deficiency of adipocyte ACSL4 expression in mice fed a HFD resulted in increased gWAT adipocyte OCR and whole body energy expenditure (EE).
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Adipocitos/metabolismo , Coenzima A Ligasas/genética , Obesidad/metabolismo , Células 3T3 , Adipocitos/patología , Adiposidad , Animales , Células Cultivadas , Coenzima A Ligasas/metabolismo , Dieta Alta en Grasa/efectos adversos , Femenino , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/patología , Consumo de Oxígeno , Fosfolípidos/metabolismoRESUMEN
BACKGROUND: Burn patients are prone to infections which often necessitate broad antibiotic coverage. Vancomycin is a common antibiotic after burn injury and is administered alone (V), or in combination with imipenem-cilastin (V/IC) or piperacillin-tazobactam (V/PT). Sparse reports indicate that the combination V/PT is associated with increased renal dysfunction. The purpose of this study was to evaluate the short-term impact of the three antibiotic administration types on renal dysfunction. METHODS: All pediatric and adult patients admitted to our centers between 2004 and 2016 with a burn injury were included in this retrospective review if they met the criteria of exposition to either V, V/IC, or V/PT for at least 48 h, had normal baseline creatinine, and no pre-existing renal dysfunction. Creatinine was monitored for 7 days after initial exposure; the absolute and relative increase was calculated, and patient renal outcomes were classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria depending on creatinine increases and estimated creatinine clearance. Secondary endpoints (demographic and clinical data, incidences of septicemia, and renal replacement therapy) were analyzed. Antibiotic doses were modeled in logistic and linear multivariable regression models to predict categorical KDIGO events and relative creatinine increase. RESULTS: Out of 1449 patients who were screened, 718 met the inclusion criteria, 246 were adults, and 472 were children. Between the study cohorts V, V/IC, and V/PT, patient characteristics at admission were comparable. V/PT administration was associated with a statistically higher serum creatinine, and lower creatinine clearance compared to patients receiving V alone or V/IC in adults and children after burn injury. The incidence of KDIGO stages 1, 2, and 3 was higher after V/PT treatment. In children, the incidence of KDIGO stage 3 following administration of V/PT was greater than after V/IC. In adults, the incidence of renal replacement therapy was higher after V/PT compared with V or V/IC. Multivariate modeling demonstrated that V/PT is an independent predictor of renal dysfunction. CONCLUSION: Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in pediatric and adult burn patients when compared to vancomycin alone or vancomycin plus imipenem-cilastin. The mechanism of this increased nephrotoxicity remains elusive and warrants further scientific evaluation.
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Lesión Renal Aguda/etiología , Quemaduras/tratamiento farmacológico , Ácido Penicilánico/análogos & derivados , Vancomicina/efectos adversos , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/fisiopatología , Adolescente , Adulto , Análisis de Varianza , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Niño , Preescolar , Cilastatina/administración & dosificación , Cilastatina/efectos adversos , Cilastatina/uso terapéutico , Combinación Cilastatina e Imipenem , Estudios de Cohortes , Creatinina/análisis , Creatinina/sangre , Combinación de Medicamentos , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/normas , Femenino , Humanos , Imipenem/administración & dosificación , Imipenem/efectos adversos , Imipenem/uso terapéutico , Incidencia , Infecciones/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Ácido Penicilánico/administración & dosificación , Ácido Penicilánico/efectos adversos , Ácido Penicilánico/uso terapéutico , Piperacilina/administración & dosificación , Piperacilina/efectos adversos , Piperacilina/uso terapéutico , Combinación Piperacilina y Tazobactam , Estudios Retrospectivos , Texas/epidemiología , Vancomicina/administración & dosificación , Vancomicina/uso terapéuticoRESUMEN
Nonmelanoma skin cancers are the most common skin cancers in the United States and the most common malignancies afflicting the head and neck region. Reconstruction of resulting defects has significant aesthetic and functional implications, and plastic surgeons are frequently consulted for reconstruction. Reconstruction can be accomplished via a multitude of approaches spanning the reconstructive ladder, and the approach should be individualized based upon both patient-related and defect-related factors. Here the authors propose a simplified approach to facial reconstruction broken down by aesthetic region.
RESUMEN
OBJECTIVE: The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform. METHODS: To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5 (-/-) ). RESULTS: Ablation of ACSL5 reduced ACSL activity by â¼80% in jejunal mucosa, â¼50% in liver, and â¼37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5 (-/-) , as compared to control ACSL5 (loxP/loxP) , mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5 (-/-) had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5 (-/-) mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (â¼16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (â¼13-fold) were increased in ACSL5 (-/-) as compared to ACSL5 (loxP/loxP) . Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1α) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5 (-/-) mice as compared to control mice. CONCLUSIONS: In summary, ACSL5 (-/-) mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance.
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BACKGROUND: Fibrin glue has widespread use in multiple fields of surgery. There have been numerous studies on the use of fibrin glue in facelifts, with no consensus regarding differences in outcomes. OBJECTIVES: This study compared the risk of hematoma, seroma, and the 24-hour drainage volume in all published prospective controlled trials. METHODS: A MEDLINE search of English-language articles on fibrin glue and rhytidectomy published up to July 2013 yielded 49 citations. After screening, we examined 7 relevant controlled trials. The DerSimonian and Laird random-effects model was used to perform the meta-analysis. RESULTS: Seven controlled trials measuring the outcomes of fibrin glue in facelifts were used to estimate the pooled relative risk of complications and confidence intervals. Hematoma formation was four times less likely with the use of fibrin glue (relative risk 0.25, P = .002). There was no significant reduction in seroma formation (relative risk 0.56, P = .19). There was not enough data to properly measure 24-hour drainage and ecchymoses. CONCLUSIONS: This analysis suggests that fibrin glue reduces the rates of hematoma formation, but does not significantly reduce the rates of seroma development. LEVEL OF EVIDENCE: 3 Therapeutic.
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Adhesivo de Tejido de Fibrina/administración & dosificación , Ritidoplastia/métodos , Adhesivos Tisulares/administración & dosificación , Drenaje/métodos , Hematoma/epidemiología , Hematoma/etiología , Humanos , Complicaciones Posoperatorias/epidemiología , Ritidoplastia/efectos adversos , Seroma/epidemiología , Seroma/etiologíaRESUMEN
Currently, there is no consensus regarding how to determine the optimal surgical procedure for a patient with velopharyngeal incompetence (VPI) post-primary palate repair. The purpose of the present study was to assess the effect of preoperative velar closing ratio (VCR) and lateral wall movement (LWM) on nasal emission and hypernasality after Furlow double-opposing Z-plasty. A retrospective analysis involving patients with VPI post-primary palatoplasty whose VPI was treated with double-opposing Z-plasty by a single surgeon was performed. Ten consecutive patients with VPI postpalatoplasty were reviewed. Videonasendoscopy, videofluoroscopy and perceptual speech examinations were performed preoperatively and postoperatively. VCR improved from an mean of 0.5 preoperatively (range 0.1 to 0.95) to 0.9 postoperatively (range 0.55 to 1.0). Postoperative mean LWM was 0.5 (range 0.3 to 0.9), unchanged from preoperative ratings. A trend toward an inverse relationship between preoperative VCR and improvement in hypernasality and resolution of nasal emission was observed. No relationship was noted between the degree of preoperative LWM and mean improvement in hypernasality. However, patients with worse preoperative LWM experienced better resolution of nasal emission postoperatively.
Il n'y a pas de consensus pour déterminer l'intervention chirurgicale optimale chez un patient présentant une insuffisance vélopharyngée (IVP) après une réparation palatine primaire. La présente étude visait à évaluer l'effet du ratio de fermeture vélaire (RFV) et de mouvement des parois latérales (MPL) sur l'émission nasale et l'hypernasalité après une plastie en Z en double opposition selon Furlow. Les chercheurs ont procédé à une analyse rétrospective de patients qui avaient subi une palatoplastie primaire et qui présentaient une IVP traitée par un chirurgien par une plastie en Z en double opposition. Ils ont examiné dix patients consécutifs ayant une IVP après leur palatoplastie. Ils ont effectué une vidéo-endoscopie nasale, une vidéo-fluoroscopie et des examens orthophoniques perceptuels avant et après l'opération. Le RFV s'est amélioré d'une moyenne de 0,5 avant l'opération (plage de 0,1 à 0,95) à une moyenne de 0,9 après l'opération (plage de 0,55 à 1,0). Le MPL moyen après l'opération était de 0,5 (plage de 0,3 à 0,9), identique aux mesures préopératoires. Les chercheurs ont observé une tendance inversement proportionnelle entre le RFV préopératoire, l'amélioration de la nasalité et la résolution de l'émission nasale. Ils n'ont pas remarqué de relation entre le degré préopératoire de MPL et l'amélioration moyenne de l'hypernasalité. Cependant, les patients dont le MPL était plus prononcé avant l'opération présentaient une meilleure résolution de l'émission nasale après l'opération.
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Vascular tumors and malformations are unique in that affected cells exhibit disrupted angiogenesis. The current treatment options often yield suboptimal results. New insight into the genetics and molecular basis of vascular anomalies may pave the way for potential development of targeted therapy. The authors review the genetic and molecular basis of vascular anomalies and common associated syndromes.
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Normocephalic pancraniosynostosis is a rare variant of craniosynostosis associated with delayed presentation and elevated intracranial pressure. We present 2 cases of normocephalic pancraniosynostosis highlighting the common clinical course, radiographic findings, and intraoperative findings seen in children with normocephalic pancraniosynostosis.