10 research outputs found

    Histological and Immunohistochemical Analyses Used to Study Craniosynostosis in Pediatric Patients

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    Craniosynostosis is a condition in which one or more of the sutures of the skull grow together (fuse) earlier than normal in infants. Sutures are large gaps located at the bony plates or joints of the head. Craniosynostosis causes the skull to expand and grow in the direction of any normal open suture, creating craniofacial complications, such as drooping eyelids and abnormal intracranial pressure, head shape, or brain morphology. This premature fusion or ossification of sutures affects approximately 300-500 live births in 1,000,000 (Kolpakova-Hart et al., 2008) with considerable variation in phenotype, depending on which suture(s) is involved. Corrective surgery can be performed to reshape the skull and eliminate the symptom(s) present in the infant. There is no known cause of craniosynostosis or direct pattern of heritability from parent to affected infant and the condition can appear syndromically (associated with syndrome or condition) or non-syndromically. However, the majority of cases reported are sporadic, non-syndromic cases, in which pediatric patients suffer from premature fusion of only one suture (Levi et al., 2012). In the current prospective study, histological and/or immunohistochemical analyses have been conducted on sagittal synostoses as well as patent (normal open suture) tissue from the skulls of three pediatric patients. Patient surgeries were performed at Akron Children’s Hospital. The studies were begun to understand more completely the underlying etiology and possible risk factors of non-syndromic craniosynostosis. Histological staining, including toluidine blue, hematoxylin and eosin, and picrosirius red counterstained with alcian blue, has been performed for qualitatively describing tissue and cell architectural shapes and gross morphology. Immunohistochemical analysis has also been performed to study the presence of osterix, a transcription factor essential for osteoblast differentiation and bone formation. Analytical results of this work are ongoing

    Kruppel-like factor 15 is required for the cardiac adaptive response to fasting.

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    Cardiac metabolism is highly adaptive in response to changes in substrate availability, as occur during fasting. This metabolic flexibility is essential to the maintenance of contractile function and is under the control of a group of select transcriptional regulators, notably the nuclear receptor family of factors member PPARα. However, the diversity of physiologic and pathologic states through which the heart must sustain function suggests the possible existence of additional transcriptional regulators that play a role in matching cardiac metabolism to energetic demand. Here we show that cardiac KLF15 is required for the normal cardiac response to fasting. Specifically, we find that cardiac function is impaired upon fasting in systemic and cardiac specific Klf15-null mice. Further, cardiac specific Klf15-null mice display a fasting-dependent accumulation of long chain acylcarnitine species along with a decrease in expression of the carnitine translocase Slc25a20. Treatment with a diet high in short chain fatty acids relieves the KLF15-dependent long chain acylcarnitine accumulation and impaired cardiac function in response to fasting. Our observations establish KLF15 as a critical mediator of the cardiac adaptive response to fasting through its regulation of myocardial lipid utilization

    Short-chain diet rescues the KLF15-dependent attenuation of cardiac function in response to fasting.

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    <p>(A) qPCR analysis of expression of transporter genes in MHC-Cre vs. KLF15-cKO under fed vs. 48 hour fasting conditions. *P<0.05 vs. Cre Fed, **P<0.05 vs. CKO Fed, # P<0.05 vs. Cre Fast. Values normalized to <i>Ppib</i>. (B) <i>Slc25a20</i> expression (qPCR) in MHC-Cre vs. KLF15-cKO under fed vs. 48 hour fasting conditions. *P<0.05 vs. Cre Fed, **P<0.05 vs. CKO Fed, # P<0.05 vs. Cre Fast. Values normalized to <i>Ppib</i>. (C) Western blot analysis of CACT levels in MHC-Cre vs KLF15-cKO under fed and 48 hour fasting conditions. α-tubulin used as loading control. (D) Quantification of data in C (n = 3 per group). Two-tailed Student's <i>t</i>-test for unpaired data was used. *P<0.05. (E) Left ventricular fractional shortening from echocardiography performed in control (MHC-Cre) vs. KLF15-cKO under fed vs. 48 hours fasting conditions following 10 weeks of short-chain fatty acid diet, (n = 10). (F) Representative echocardiography image from MHC-Cre vs. KLF15-cKO following 48 hours fasting and 10 weeks of short-chain fatty acid diet. (G) Tabular representation of echocardiography data in MHC-Cre vs. KLF15-cKO under fed vs. 48 hour fasting conditions following 10 weeks of short-chain fatty acid diet.</p

    Cardiac specific deletion of KLF15 alters tissue and plasma levels of free fatty acids and triglycerides.

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    <p>Cardiac FFA (A) and TG (B) levels in control (MHC-Cre) vs. KF15-cKO following 48 hours fasting, (n = 5), *P<0.05 vs. Cre Fed, **P<0.05 vs. CKO Fed, # P<0.05 vs. Cre Fast. Plasma FFA (C) and TG (D) levels in control (MHC-Cre) vs. KLF15-cKO following 48 hours fasting, (n = 5), *P<0.05 vs. Cre Fed, **P<0.05 vs. CKO Fed, # P<0.05 vs. Cre Fast.</p

    Cardiac specific deletion of KLF15 alters lipid profile.

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    <p>Metabolomic analysis of long chain acylcarnitines in cardiac tissue from control (MHC-Cre) vs. KLF15-cKO with and without 48 hour fast, (n = 5), *P<0.05 by one-way analysis of variance (ANOVA) with the Tukey post hoc test.</p

    Cardiac KLF15 is required for the heart’s functional adaptation in response to fasting.

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    <p>(A) Left ventricular fractional shortening from echocardiography performed in control (MHC-Cre) vs KLF15-cKO under fed vs. 48 hours fasting conditions, (n = 5), *P<0.05 vs. MHC-Cre Fast. (B) Representative echocardiography image from MHC-Cre vs. KLF15-cKO following a 48 hour fast. (C) Tabular representation of echocardiography data in MHC-Cre vs. KLF15-cKO under fed vs. 48 hour fasting conditions.</p

    Systemic KLF15 is required for the heart’s functional adaptation in response to fasting.

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    <p>(A) Left ventricular fractional shortening from echocardiography performed in wild-type (WT) vs. systemic <i>Klf15</i>-null (<i>Klf15-/-</i>) under fed vs. 48 hours fasting conditions, (n = 5), *P,0.05 vs. WT Fast. (B) Representative echocardiography image from WT vs. <i>Klf15-/-</i> following a 48 hour fast. (C) Tabular representation of echocardiography data in WT vs. <i>Klf15-/-</i> under fed vs. 48 hour fasting conditions.</p
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