Wallerian Degeneration Beyond the Corticospinal Tracts: Conventional and Advanced MRI Findings.

PubMed

Chen, Yin Jie; Nabavizadeh, Seyed Ali; Vossough, Arastoo; Kumar, Sunil; Loevner, Laurie A; Mohan, Suyash

2017-05-01

Wallerian degeneration (WD) is defined as progressive anterograde disintegration of axons and accompanying demyelination after an injury to the proximal axon or cell body. Since the 1980s and 1990s, conventional magnetic resonance imaging (MRI) sequences have been shown to be sensitive to changes of WD in the subacute to chronic phases. More recently, advanced MRI techniques, such as diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI), have demonstrated some of earliest changes attributed to acute WD, typically on the order of days. In addition, there is increasing evidence on the value of advanced MRI techniques in providing important prognostic information related to WD. This article reviews the utility of conventional and advanced MRI techniques for assessing WD, by focusing not only on the corticospinal tract but also other neural tracts less commonly thought of, including corticopontocerebellar tract, dentate-rubro-olivary pathway, posterior column of the spinal cord, corpus callosum, limbic circuit, and optic pathway. The basic anatomy of these neural pathways will be discussed, followed by a comprehensive review of existing literature supported by instructive clinical examples. The goal of this review is for readers to become more familiar with both conventional and advanced MRI findings of WD involving important neural pathways, as well as to illustrate increasing utility of advanced MRI techniques in providing important prognostic information for various pathologies. Copyright © 2016 by the American Society of Neuroimaging.

The spinocerebellar ataxia 2 locus is located within a 3-cm interval on chromosome 12q23-24.1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allotey, R.; Twells, R.; Cemal, C.

1995-07-01

The autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders characterized by a predominantly cerebellar syndrome of onset with gait ataxia, dysarthria, dysmetria, and dysdiadochokinesia. Pathologically, the disorders are characterized by premature neuronal loss in the cerebellar cortex and the inferior olivary and pontine nuclei, with degeneration of the spinal cord. We have previously assigned the spinocerebellar ataxia 2 locus to chromosome 12q23-24.1, within a 31-cM interval flanked by the loci D12S58 and PLA2. Linkage to SCA2 has been demonstrated in pedigrees from Europe, Japan, and North America, the latter serving to refine the candidate regionmore » to a 16-cM interval. We report here genetic analysis undertaken between SCA2 and nine microsatellite loci known to span 8 cM within this interval. 12 refs., 2 figs., 1 tab.« less

Properties of the Nucleo-Olivary Pathway: An In Vivo Whole-Cell Patch Clamp Study

PubMed Central

Bazzigaluppi, Paolo; Ruigrok, Tom; Saisan, Payam; De Zeeuw, Chris I.; de Jeu, Marcel

2012-01-01

The inferior olivary nucleus (IO) forms the gateway to the cerebellar cortex and receives feedback information from the cerebellar nuclei (CN), thereby occupying a central position in the olivo-cerebellar loop. Here, we investigated the feedback input from the CN to the IO in vivo in mice using the whole-cell patch-clamp technique. This approach allows us to study how the CN-feedback input is integrated with the activity of olivary neurons, while the olivo-cerebellar system and its connections are intact. Our results show how IO neurons respond to CN stimulation sequentially with: i) a short depolarization (EPSP), ii) a hyperpolarization (IPSP) and iii) a rebound depolarization. The latter two phenomena can also be evoked without the EPSPs. The IPSP is sensitive to a GABAA receptor blocker. The IPSP suppresses suprathreshold and subthreshold activity and is generated mainly by activation of the GABAA receptors. The rebound depolarization re-initiates and temporarily phase locks the subthreshold oscillations. Lack of electrotonical coupling does not affect the IPSP of individual olivary neurons, nor the sensitivity of its GABAA receptors to blockers. The GABAergic feedback input from the CN does not only temporarily block the transmission of signals through the IO, it also isolates neurons from the network by shunting the junction current and re-initiates the temporal pattern after a fixed time point. These data suggest that the IO not only functions as a cerebellar controlled gating device, but also operates as a pattern generator for controlling motor timing and/or learning. PMID:23029495

MICROLESIONS OF THE INFERIOR OLIVE REDUCE VESTIBULAR MODULATION OF PURKINJE CELL COMPLEX AND SIMPLE SPIKES IN MOUSE CEREBELLUM

PubMed Central

Barmack, N.H.; Yakhnitsa, V.

2011-01-01

Cerebellar Purkinje cells have two distinct action potentials: Complex spikes (CSs) are evoked by single climbing fibers that originate from the contralateral inferior olive. Simple spikes (SSs) are often ascribed to mossy fiber---granule cell---parallel fiber inputs to Purkinje cells. Although generally accepted, this view lacks experimental support. Vestibular stimulation independently activates primary afferent mossy fibers and tertiary afferent climbing fibers that project to theuvula-nodulus (folia 8-10). CSs and SSs normally discharge antiphasically during sinusoidal roll-tilt. When CSs increase, SSs decrease. We tested the relative independence of these pathways in mice by making electrolytic microlesions of the two inferior olivary nuclei from which vestibular climbing fibers originate; the β-nucleus and dorsomedial cell column (DMCC). This reduced vestibular climbing fiber signaling to the contralateral folia 8-10, while leaving intact vestibular primary and secondary afferent mossy fibers. We recorded from Purkinje cells and interneurons in folia 8-10, identified by juxtacellular labeling with neurobiotin. Microlesions of the inferior olive increased the spontaneous discharge of SSs in contralateral folia 8-10, but blocked their modulation during vestibular stimulation. The vestibularly-evoked discharge of excitatory cerebellar interneurons (granule cells and unipolar brush cells) was not modified by olivary microlesions. The modulated discharge of stellate cells, but not Golgi cells was reduced by olivary microlesions. We conclude that vestibular modulation of CSs and SSs depends on intact climbing fibers. The absence of vestibularly-modulated SSs following olivary microlesions reflects the loss of climbing fiber-evoked stellate cell discharge. PMID:21734274

GABAergic inhibition shapes frequency tuning and modifies response properties in the superior olivary nucleus of the leopard frog.

PubMed

Zheng, W; Hall, J C

2000-01-01

The role of gamma-aminobutyric acid (GABA)ergic inhibition in shaping the excitatory frequency tuning of 74 neurons in the superior olivary nucleus of the leopard frog, Rana pipiens, was studied using iontophoretic application of the GABA(A) receptor antagonist, bicuculline methiodide. For 37 neurons, bicuculline application broadened and/or changed the configuration of the excitatory frequency-tuning curve. Results indicate that GABA-mediated inhibition not only sharpens the tuning curves of neurons but also plays a critical role in creating new frequency tuning properties in the superior olivary nucleus. Bicuculline application affected other neuronal response properties as well. Spontaneous firing rate increased 11-338% for 18 of 59 neurons. For 32 of 58 neurons there was an increase in stimulus-evoked discharge rate and a change in rate-level function. There was no qualitative effect on the discharge pattern of 60 neurons, though 2 tonically responding neurons did show an increase (> 30%) in response duration. Additional roles for GABAergic inhibition in monaural signal analysis are discussed.

Neuroanatomical dysmorphology of the medial superior olivary nucleus in sudden fetal and infant death

PubMed Central

Lavezzi, Anna M.; Matturri, Luigi

2012-01-01

This study expands our understanding of the organization of the human caudal pons, providing a morphologic characterization of the medial superior olivary nucleus (MSO), component of the superior olivary complex (SOC) that plays an important role in the processing of acoustic information. We examined victims of sudden unexplained fetal and infant death and controls (n = 75), from 25 gestational weeks to 8 months of postnatal age, by complete autopsy and in-depth autonomic nervous system histological examination, particularly of the MSO nucleus, the focus of this study. Peculiar cytoarchitectural features of the MSO nucleus were found in sudden death cases, such as hypoplasia/agenesis and immature hypercellularity, frequently related to dysgenesis of contiguous structures involved in respiratory rhythm-generating circuit, in particular to hypoplasia of the retrotrapezoid and the facial nuclei. We propose the involvement of this nucleus in more important functions than those related to hearing, as breathing and, more extensively, all the vital activities. Besides, we highlight the fundamental role of the maternal smoking in pregnancy as etiological factor in the dysmorphic neuroanatomical development of the MSO nucleus. PMID:23205011

Neurophysiological aspects of peripheral neuropathies.

PubMed

MacKenzie, R A; Skuse, N F; Lethlean, A K

1976-01-01

1. Eighty-eight intrafascicular neural recordings were obtained in 10 normal subjects, 5 patients with axonal degeneration and 11 patients with demyelinating neuropathy. 2. Stimulus levels required for perception and fibre activation were higher in neuropathic subjects. Fibres transmitting touch perception had significantly lower conduction velocities in both patient groups, but were very much lower in the group with demyelinating neuropahty than the group with axonal degeneration. Maximum electrical stimulation evoked dispersed fibre responses in the axonal degeneration group and more dispersed, slowly conducting fibre potentials in the demyelinating group. In patients with hypertrophic Charcot-Marie-Tooth disorder, usually only a small group of slowly conducting low amplitude potentials was recorded. 3. Delivery of a train of supramaximal stimuli caused prolongation of latency and dispersion of fibre potentials in all microneurographic recordings. The changes were significantly greater in the axonal neuropathy group than in normals, and recovery was slower. The demyelinating neuropathies showed significantly greater changes than both the normal and the axonal neuropathy groups, and post-tetanic conduction slowing became even more marked after limb temperature was raised. 4. Surface SAP recordings showed normal refractory period in chronic axonal neuropathy but significant latency prolongation occurred in demyelinating neuropathy. 5. It is concluded that both receptor and nerve fibre abnormalities contribute to sensory dysfunction in degenerative and demyelinating neuropathies.

A case of idiopathic hypertrophic pachymeningitis presenting with chronic headache and multiple cranial nerve palsies: A case report.

PubMed

Huang, Yuanyuan; Chen, Jun; Gui, Li

2017-07-01

Idiopathic hypertrophic pachymeningitis (IHP) is a rare condition, characterized by a chronic fibrosing inflammatory process usually involving either the intracranial or spinal dura mater, but rarely both. Here, we report a rare case of IHP affecting both the intracranial and spinal dura mater. We also discussed the diagnosis, management, and outcome of IHP. We reviewed the case of a 60-year-old woman presenting with chronic headache, multiple cranial nerve palsies and gait disturbance. Magnetic resonance imaging (MRI) of her head revealed thickened and contrast-enhanced dura in the craniocervical region as well as obstructive hydrocephalus and cerebellar tonsillar herniation. The patient had a suboccipital craniectomy and posterior decompression through C1 plus a total laminectomy. The dura was partially resected to the extent of the bony decompression, and a duroplasty was performed. Microscopic examination of the surgically resected sample showed chronic inflammatory changes, lymphoplasmacytic cell infiltration, fibrous tissue hyperplasia, and hyaline degeneration. Blood tests to evaluate the secondary causes of hypertrophic pachymeningitis (HP) were unremarkable. Steroid was used to treat suspected IHP. Postoperatively, the patient showed gradual improvement in her headache, glossolalia, and bucking. Prior to discharge, a follow-up MRI showed improvement of the dura mater thickening. IHP is a chronic inflammatory disorder of the dura mater that usually causes neurological deficits. Clinical manifestations of IHP, MRI findings, and laboratory abnormalities are the essential components for making an accurate diagnosis. When the radiological or laboratory evaluation is uncertain, but neurological deficits are present, a prompt surgical approach should be considered. Postoperative steroid therapy and close observation for recurrence are necessary to ensure a good long-term outcome.

Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature.

PubMed

Mazurova, Stella; Magner, Martin; Kucerova-Vidrova, Vendula; Vondrackova, Alzbeta; Stranecky, Viktor; Pristoupilova, Anna; Zamecnik, Josef; Hansikova, Hana; Zeman, Jiri; Tesarova, Marketa; Honzik, Tomas

2017-07-01

Cardiomyopathy is a common manifestation in neonates and infants with mitochondrial disorders. In this study, we report two cases manifesting with fatal mitochondrial hypertrophic cardiomyopathy, which include the third known patient with thymidine kinase 2 deficiency and the ninth patient with alanyl-tRNA synthetase 2 deficiency. The girl with thymidine kinase 2 deficiency had hypertrophic cardiomyopathy together with regression of gross motor development at the age of 13 months. Neurological symptoms and cardiac involvement progressed into severe myopathy, psychomotor arrest, and cardiorespiratory failure at the age of 22 months. The imaging methods and autoptic studies proved that she suffered from unique findings of leucoencephalopathy, severe, mainly cerebellar neuronal degeneration, and hepatic steatosis. The girl with alanyl-tRNA synthetase 2 deficiency presented with cardiac failure and underlying hypertrophic cardiomyopathy within 12 hours of life and subsequently died at 9 weeks of age. Muscle biopsy analyses demonstrated respiratory chain complex I and IV deficiencies, and histological evaluation revealed massive mitochondrial accumulation and cytochrome c oxidase-negative fibres in both cases. Exome sequencing in the first case revealed compound heterozygozity for one novel c.209T>C and one previously published c.416C>T mutation in the TK2 gene, whereas in the second case homozygozity for the previously described mutation c.1774C>T in the AARS2 gene was determined. The thymidine kinase 2 mutations resulted in severe mitochondrial DNA depletion (to 12% of controls) in the muscle. We present, for the first time, severe leucoencephalopathy and hepatic steatosis in a patient with thymidine kinase 2 deficiency and the finding of a ragged red fibre-like image in the muscle biopsy in a patient with alanyl-tRNA synthetase 2 deficiency.

IL-1β mediating high mobility group box protein-1 expression in condylar chondrocyte during temporomandibular joint inflammation.

PubMed

Li, Cheng; Cai, Hengxing; Meng, Qinggong; Feng, Yaping; Guo, Huilin; Fang, Wei; Long, Xing

2016-08-01

Temporomandibular joint (TMJ) osteoarthritis(OA)characterized with cartilage degen-eration is associated with inflammation. High mobility group box chromosomal protein-1(HMGB-1)is a potent mediator of inflammation and the trigger of OA. The expression of HMGB-1 in TMJ OA was uncovered, but the role of HMGB-1 in TMJ cartilage degeneration is not fully understood. In this study, the regulation of HMGB-1 in TMJ condylar cartilage was revealed. A complete Freund's adjuvant (CFA)-induced TMJ inflammation animal model was employed and the expression of HMGB-1 was detected at 1st, 2nd, and 6th weeks by immunohistochemistry. TMJ condylar chondrocytes were incubated with IL-1β (10 and 40 ng/ml) at 24, 48, and 72 h, and the translocation and protein level of HMGB-1 were evaluated by immunofluorescence and Western blot. Nuclear HMGB-1 staining was predominantly located in chondrocytes of both the fibrosis and proliferative zones in healthy TMJ. 1st week and 2nd week after CFA injection, immunoreaction could be detected in the cytoplasms of HMGB-1-positive cells and cartilage matrix especially in hypertrophic zone. At 6th week after CFA injection, cartilage matrix expression was disappeared and the cytoplasm expression of HMGB-1 was very weak in hypertrophic zone. HMGB-1 was translocated from the nucleus to the cytoplasm at 48 h after incubated with IL-1β (10 ng/ml and 40 ng/ml). The protein level of HMGB-1 was increased after stimulation and had a peak at 48 h. HMGB-1 might be associated with TMJ inflammation and OA. Insight into the role of HMGB-1 in TMJ inflammation is helpful to add the new knowledge into the pathogenesis of TMJ OA. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Precerebellar and vestibular nuclei of the short-beaked echidna (Tachyglossus aculeatus).

PubMed

Ashwell, K W S; Paxinos, G; Watson, C R R

2007-09-01

The monotremes are a unique group of living mammals, which diverged from the line leading to placental mammals at least 125 million years ago. We have examined the organization of pontine, inferior olivary, lateral reticular and vestibular nuclei in the brainstem of the short-beaked echidna (Tachyglossus aculeatus) to determine if the cyto- and chemoarchitecture of these nuclei are similar to that in placental mammals and marsupials. We have used Nissl staining in conjunction with enzyme-histochemistry for acetylcholinesterase, cytochrome oxidase and NADPH diaphorase as well as immunohistochemistry for non-phosphorylated neurofilament protein (SMI-32 antibody) and calcium binding proteins (parvalbumin, calbindin, calretinin). Homologies could be established between the arch shaped inferior olivary complex of the echidna and the principal, dorsal and medial accessory subdivisions of the therian inferior olivary complex. The pontine nuclei of the echidna included basilar and reticulotegmental components with similar cyto- and chemarchitectural features to therians and there were magnocellular and subtrigeminal components of the lateral reticular nucleus, also as seen in therians. Subdivisions and chemoarchitecture of the vestibular complex of the echidna were both similar to that region in rodents. In all three precerebellar nuclear groups studied and in the vestibular nucleus organization, the cyto- and chemoarchitecture of the echidna was very similar to that seen in therian mammals and no "primitive" or "reptilian" features were evident.

TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions

PubMed Central

Zieba, Jennifer; Forlenza, Kimberly Nicole; Khatra, Jagteshwar Singh; Sarukhanov, Anna; Duran, Ivan; Rigueur, Diana; Lyons, Karen M.; Cohn, Daniel H.; Merrill, Amy E.; Krakow, Deborah

2016-01-01

Spondylocarpotarsal synostosis (SCT) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in Filamin B (FLNB). FLNB acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems, yet the disease mechanisms for SCT remain unclear. Employing a Flnb knockout mouse, we found morphologic and molecular evidence that the intervertebral discs (IVDs) of Flnb–/–mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the IVD, particularly the annulus fibrosus (AF). In Flnb–/–mice, the AF cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue. We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFβ signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf. These findings indicate that FLNB is involved in attenuation of TGFβ/BMP signaling and influences AF cell fate. Furthermore, we demonstrate that the IVD disruptions in Flnb–/–mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration. PMID:27019229

Human mesenchymal stem cell differentiation to NP-like cells in chitosan-glycerophosphate hydrogels.

PubMed

Richardson, Stephen M; Hughes, Nesta; Hunt, John A; Freemont, Anthony J; Hoyland, Judith A

2008-01-01

Intervertebral disc (IVD) degeneration is one of the major causes of low back pain. As current clinical treatments are aimed at restoring biomechanical function and providing symptomatic relief, interest in methods focused on biological repair has increased. Several tissue engineering approaches using different cell types and hydrogels/scaffolds have been proposed. Owing to the unsuitable nature of degenerate cells for tissue engineering attention has focused on the use of mesenchymal stem cells (MSCs). Additionally, while rigid scaffolds have been demonstrated to allow MSC differentiation to the chondrocyte-like cells of the IVD, hydrogels are being increasingly studied as they allow minimally invasive implantation without extensive damage to the IVD. Here, we have studied the temperature-sensitive hydrogel chitosan-glycerophosphate (C/Gp), seeded with human MSCs and cultured for 4 weeks in standard medium. We have analysed the gene and protein expression profile of the MSCs and compared it to that of both nucleus pulposus (NP) cells and articular chondrocytes cultured in C/Gp. Gene expression analysis for chondrocytic-cell marker genes demonstrated differentiation of MSCs to a phenotype which showed similarities to both articular chondrocytes and NP cells. Conventional PCR demonstrated a lack of expression of osteogenic marker genes and the hypertrophic marker gene type X collagen. MSCs also secreted both proteoglycans and collagens in a ratio, which more closely resembled that of NP cells than articular chondrocytes. These results therefore suggest that MSC-seeded C/Gp gels could be used clinically for the regeneration of the degenerate human IVD.

MRI features of cervical articular process degenerative joint disease in Great Dane dogs with cervical spondylomyelopathy.

PubMed

Gutierrez-Quintana, Rodrigo; Penderis, Jacques

2012-01-01

Cervical spondylomyelopathy or Wobbler syndrome commonly affects the cervical vertebral column of Great Dane dogs. Degenerative changes affecting the articular process joints are a frequent finding in these patients; however, the correlation between these changes and other features of cervical spondylomyelopathy are uncertain. We described and graded the degenerative changes evident in the cervical articular process joints from 13 Great Danes dogs with cervical spondylomyelopathy using MR imaging, and evaluated the relationship between individual features of cervical articular process joint degeneration and the presence of spinal cord compression, vertebral foraminal stenosis, intramedullary spinal cord changes, and intervertebral disc degenerative changes. Degenerative changes affecting the articular process joints were common, with only 13 of 94 (14%) having no degenerative changes. The most severe changes were evident between C4-C5 and C7-T1 intervertebral spaces. Reduction or loss of the hyperintense synovial fluid signal on T2-weighted MR images was the most frequent feature associated with articular process joint degenerative changes. Degenerative changes of the articular process joints affecting the synovial fluid or articular surface, or causing lateral hypertrophic tissue, were positively correlated with lateral spinal cord compression and vertebral foraminal stenosis. Dorsal hypertrophic tissue was positively correlated with dorsal spinal cord compression. Disc-associated spinal cord compression was recognized less frequently. © 2011 Veterinary Radiology & Ultrasound.

Determination of multidirectional myocardial deformations in cats with hypertrophic cardiomyopathy by using two-dimensional speckle-tracking echocardiography.

PubMed

Suzuki, Ryohei; Mochizuki, Yohei; Yoshimatsu, Hiroki; Teshima, Takahiro; Matsumoto, Hirotaka; Koyama, Hidekazu

2017-12-01

Objectives Hypertrophic cardiomyopathy, a primary disorder of the myocardium, is the most common cardiac disease in cats. However, determination of myocardial deformation with two-dimensional speckle-tracking echocardiography in cats with various stages of hypertrophic cardiomyopathy has not yet been reported. This study was designed to measure quantitatively multidirectional myocardial deformations of cats with hypertrophic cardiomyopathy. Methods Thirty-two client-owned cats with hypertrophic cardiomyopathy and 14 healthy cats serving as controls were enrolled and underwent assessment of myocardial deformation (peak systolic strain and strain rate) in the longitudinal, radial and circumferential directions. Results Longitudinal and radial deformations were reduced in cats with hypertrophic cardiomyopathy, despite normal systolic function determined by conventional echocardiography. Cats with severely symptomatic hypertrophic cardiomyopathy also had lower peak systolic circumferential strain, in addition to longitudinal and radial strain. Conclusions and relevance Longitudinal and radial deformation may be helpful in the diagnosis of hypertrophic cardiomyopathy. Additionally, the lower circumferential deformation in cats with severe hypertrophic cardiomyopathy may contribute to clinical findings of decompensation, and seems to be related to severe cardiac clinical signs. Indices of multidirectional myocardial deformations by two-dimensional speckle-tracking echocardiography may be useful markers and help to distinguish between cats with hypertrophic cardiomyopathy and healthy cats. Additionally, they may provide more detailed assessment of contractile function in cats with hypertrophic cardiomyopathy.

Phenotypic behavior of C2C12 myoblasts upon expression of the dystrophy-related caveolin-3 P104L and TFT mutants.

PubMed

Fanzani, Alessandro; Stoppani, Elena; Gualandi, Laura; Giuliani, Roberta; Galbiati, Ferruccio; Rossi, Stefania; Fra, Anna; Preti, Augusto; Marchesini, Sergio

2007-10-30

Caveolin-3 (Cav-3) is the main scaffolding protein present in myofiber caveolae. We transfected C2C12 myoblasts with dominant negative forms of Cav-3, P104L or DeltaTFT, respectively, which cause the limb-girdle muscular dystrophy 1-C. Both these forms triggered Cav-3 loss during C2C12 cell differentiation. The P104L mutation reduced myofiber formation by impaired AKT signalling, accompanied by dramatic expression of the E3 ubiquitin ligase Atrogin. On the other hand, the DeltaTFT mutation triggered hypertrophic myotubes sustained by prolonged AKT activation, but independent of increased levels of follistatin and interleukin 4 expression. These data suggest that separated mutations within the same dystrophy-related gene may cause muscle degeneration through different mechanisms.

In vivo mouse inferior olive neurons exhibit heterogeneous subthreshold oscillations and spiking patterns

PubMed Central

Khosrovani, S.; Van Der Giessen, R. S.; De Zeeuw, C. I.; De Jeu, M. T. G.

2007-01-01

In vitro whole-cell recordings of the inferior olive have demonstrated that its neurons are electrotonically coupled and have a tendency to oscillate. However, it remains to be shown to what extent subthreshold oscillations do indeed occur in the inferior olive in vivo and whether its spatiotemporal firing pattern may be dynamically generated by including or excluding different types of oscillatory neurons. Here, we did whole-cell recordings of olivary neurons in vivo to investigate the relation between their subthreshold activities and their spiking behavior in an intact brain. The vast majority of neurons (85%) showed subthreshold oscillatory activities. The frequencies of these subthreshold oscillations were used to distinguish four main olivary subtypes by statistical means. Type I showed both sinusoidal subthreshold oscillations (SSTOs) and low-threshold Ca2+ oscillations (LTOs) (16%); type II showed only sinusoidal subthreshold oscillations (13%); type III showed only low-threshold Ca2+ oscillations (56%); and type IV did not reveal any subthreshold oscillations (15%). These subthreshold oscillation frequencies were strongly correlated with the frequencies of preferred spiking. The frequency characteristics of the subthreshold oscillations and spiking behavior of virtually all olivary neurons were stable throughout the recordings. However, the occurrence of spontaneous or evoked action potentials modified the subthreshold oscillation by resetting the phase of its peak toward 90°. Together, these findings indicate that the inferior olive in intact mammals offers a rich repertoire of different neurons with relatively stable frequency settings, which can be used to generate and reset temporal firing patterns in a dynamically coupled ensemble. PMID:17895389

Development of a Porcine Full-Thickness Burn Hypertrophic Scar Model and Investigation of the Effects of Shikonin on Hypertrophic Scar Remediation

PubMed Central

Deng, Xingwang; Chen, Qian; Qiang, Lijuan; Chi, Mingwei; Xie, Nan; Wu, Yinsheng; Yao, Ming; Zhao, Dan; Ma, Jiaxiang; Zhang, Ning; Xie, Yan

2018-01-01

Hypertrophic scars formed after burns remain a challenge in clinical practice. Development of effective scar therapies relies on validated animal models that mimic human hypertrophic scars. A consistent porcine full-thickness burn hypertrophic scar model has yet to be developed. We have previously reported that Shikonin induces apoptosis and reduces collagen production in hypertrophic scar fibroblasts in vitro and may therefore hold potential as a novel scar remediation therapy. In this study, we aimed to validate the potential of Shikonin on scar remediation in vivo. A novel porcine hypertrophic scar model was created after full-thickness burn wounds, and the effect of Shikonin on scar remediation was investigated. Clinical scar assessments, histology, and immunohistochemistry were used to evaluate scar appearance, morphology, and protein expression. Eight weeks after scar formation, clinical scar assessment indicated that the score of hypertrophic scars treated with Shikonin was significantly lower than that of the control group. Hypertrophic scars treated with Shikonin appeared flat, pink, and pliable. In addition, histological analysis indicated that hypertrophic scars treated with Shikonin exhibited reduced thickness of the epidermis and dermis, thin and even epithelial layers, reduced numbers of keratinocytes, uniform distribution of fibroblasts, and a parallel and loose arrangement of collagen fibers in the dermis. Moreover, immunohistochemical analysis indicated that Shikonin inhibited the expression of p63, cytokeratin 10, alpha-smooth muscle actin, transforming growth factor-beta 1, and collagen I, which play important roles in hypertrophic scar formation. Based on these results, we conclude that Shikonin has potential as a novel scar therapy. PMID:29922164

Subcollicular projections to the auditory thalamus and collateral projections to the inferior colliculus.

PubMed

Schofield, Brett R; Mellott, Jeffrey G; Motts, Susan D

2014-01-01

Experiments in several species have identified direct projections to the medial geniculate nucleus (MG) from cells in subcollicular auditory nuclei. Moreover, many cochlear nucleus cells that project to the MG send collateral projections to the inferior colliculus (IC) (Schofield et al., 2014). We conducted three experiments to characterize projections to the MG from the superior olivary and the lateral lemniscal regions in guinea pigs. For experiment 1, we made large injections of retrograde tracer into the MG. Labeled cells were most numerous in the superior paraolivary nucleus, ventral nucleus of the trapezoid body, lateral superior olivary nucleus, ventral nucleus of the lateral lemniscus, ventrolateral tegmental nucleus, paralemniscal region and sagulum. Additional sources include other periolivary nuclei and the medial superior olivary nucleus. The projections are bilateral with an ipsilateral dominance (66%). For experiment 2, we injected tracer into individual MG subdivisions. The results show that the subcollicular projections terminate primarily in the medial MG, with the dorsal MG a secondary target. The variety of projecting nuclei suggest a range of functions, including monaural and binaural aspects of hearing. These direct projections could provide the thalamus with some of the earliest (i.e., fastest) information regarding acoustic stimuli. For experiment 3, we made large injections of different retrograde tracers into one MG and the homolateral IC to identify cells that project to both targets. Such cells were numerous and distributed across many of the nuclei listed above, mostly ipsilateral to the injections. The prominence of the collateral projections suggests that the same information is delivered to both the IC and the MG, or perhaps that a common signal is being delivered as a preparatory indicator or temporal reference point. The results are discussed from functional and evolutionary perspectives.

Subcollicular projections to the auditory thalamus and collateral projections to the inferior colliculus

PubMed Central

Schofield, Brett R.; Mellott, Jeffrey G.; Motts, Susan D.

2014-01-01

Experiments in several species have identified direct projections to the medial geniculate nucleus (MG) from cells in subcollicular auditory nuclei. Moreover, many cochlear nucleus cells that project to the MG send collateral projections to the inferior colliculus (IC) (Schofield et al., 2014). We conducted three experiments to characterize projections to the MG from the superior olivary and the lateral lemniscal regions in guinea pigs. For experiment 1, we made large injections of retrograde tracer into the MG. Labeled cells were most numerous in the superior paraolivary nucleus, ventral nucleus of the trapezoid body, lateral superior olivary nucleus, ventral nucleus of the lateral lemniscus, ventrolateral tegmental nucleus, paralemniscal region and sagulum. Additional sources include other periolivary nuclei and the medial superior olivary nucleus. The projections are bilateral with an ipsilateral dominance (66%). For experiment 2, we injected tracer into individual MG subdivisions. The results show that the subcollicular projections terminate primarily in the medial MG, with the dorsal MG a secondary target. The variety of projecting nuclei suggest a range of functions, including monaural and binaural aspects of hearing. These direct projections could provide the thalamus with some of the earliest (i.e., fastest) information regarding acoustic stimuli. For experiment 3, we made large injections of different retrograde tracers into one MG and the homolateral IC to identify cells that project to both targets. Such cells were numerous and distributed across many of the nuclei listed above, mostly ipsilateral to the injections. The prominence of the collateral projections suggests that the same information is delivered to both the IC and the MG, or perhaps that a common signal is being delivered as a preparatory indicator or temporal reference point. The results are discussed from functional and evolutionary perspectives. PMID:25100950

A prospective study of time to healing and hypertrophic scarring in paediatric burns: every day counts.

PubMed

Chipp, Elizabeth; Charles, Lisa; Thomas, Clare; Whiting, Kate; Moiemen, Naiem; Wilson, Yvonne

2017-01-01

It is commonly accepted that burns taking longer than 3 weeks to heal have a much higher rate of hypertrophic scarring than those which heal more quickly. However, some of our patients develop hypertrophic scars despite healing within this 3-week period. We performed a prospective study of 383 paediatric burns treated non-operatively at a regional burns centre over a 2-year period from May 2011 to April 2013. Scar assessment was performed by a senior burns therapist using the Vancouver Scar Scale. Overall rates of hypertrophic scarring were 17.2%. Time to healing was the strongest predictor of developing hypertrophic scarring, and the earliest hypertrophic scar developed in a patient who was healed after 8 days. The risk of hypertrophic scarring was multiplied by 1.138 for every additional day taken for the burn wound to heal. There was a trend towards higher rates of hypertrophic scarring in non-white skin types but this did not reach statistical significance. The risk of hypertrophic scarring increases with every day and, therefore, every effort should be made to get the wound healed as quickly as possible, even within the traditional 3-week period usually allowed for healing. We believe that the traditional dogma of aiming for healing within 3 weeks is overly simplistic and should be abandoned: in paediatric burns, every day counts. Not applicable.

An unusual ST-segment elevation: apical hypertrophic cardiomyopathy shows the ace up its sleeve.

PubMed

de Santis, Francesco; Pergolini, Amedeo; Zampi, Giordano; Pero, Gaetano; Pino, Paolo Giuseppe; Minardi, Giovanni

2013-01-01

Apical hypertrophic cardiomyopathy is part of the broad clinical and morphologic spectrum of hypertrophic cardiomyopathy. We report a patient with electrocardiographic abnormalities in whom acute coronary syndrome was excluded and apical hypertrophic cardiomyopathy was demonstrated by careful differential diagnosis. Copyright © 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Comparative peptidomic profile between human hypertrophic scar tissue and matched normal skin for identification of endogenous peptides involved in scar pathology.

PubMed

Li, Jingyun; Chen, Ling; Li, Qian; Cao, Jing; Gao, Yanli; Li, Jun

2018-08-01

Endogenous peptides recently attract increasing attention for their participation in various biological processes. Their roles in the pathogenesis of human hypertrophic scar remains poorly understood. In this study, we used liquid chromatography-tandem mass spectrometry to construct a comparative peptidomic profiling between human hypertrophic scar tissue and matched normal skin. A total of 179 peptides were significantly differentially expressed in human hypertrophic scar tissue, with 95 upregulated and 84 downregulated peptides between hypertrophic scar tissue and matched normal skin. Further bioinformatics analysis (Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis) indicated that precursor proteins of these differentially expressed peptides correlate with cellular process, biological regulation, cell part, binding and structural molecule activity ribosome, and PPAR signaling pathway occurring during pathological changes of hypertrophic scar. Based on prediction database, we found that 78 differentially expressed peptides shared homology with antimicrobial peptides and five matched known immunomodulatory peptides. In conclusion, our results show significantly altered expression profiles of peptides in human hypertrophic scar tissue. These peptides may participate in the etiology of hypertrophic scar and provide beneficial scheme for scar evaluation and treatments. © 2017 Wiley Periodicals, Inc.

Squamous Cell Carcinoma Arising in Hypertrophic Lichen Planus: A Review and Analysis of 38 Cases.

PubMed

Knackstedt, Thomas J; Collins, Lindsey K; Li, Zhongze; Yan, Shaofeng; Samie, Faramarz H

2015-12-01

Hypertrophic lichen planus is a chronic variant of lichen planus with controversial malignant association. To describe and analyze the relationship of squamous cell carcinoma (SCC) and hypertrophic lichen planus. A retrospective chart review of patients with hypertrophic lichen planus and SCC was performed at the authors' institution. Thereafter, scientific databases were searched for articles reporting cases of SCC arising in hypertrophic lichen planus. Patient demographics, immune status, lichen planus features, and SCC data points were extracted for each patient and evaluated. Thirty-eight cases of SCC in hypertrophic lichen planus occurred in 16 women, average age: 61.4, and 22 men, average age: 51.3, after a lag time of 88 days to 40 years. Squamous cell carcinoma was uniformly located on the lower extremity. Men had larger SCC than women (p = .027) and a significantly longer lag time to SCC development (p = .002). Long lag time was associated with a smaller SCC size (p = .032). In the past, hypertrophic lichen planus and SCC have been considered isolated diseases. Based on an increasing number of cases, the association between hypertrophic lichen planus and keratinocyte malignancies warrants surveillance.

Long-pulsed neodymium:yttrium-aluminum-garnet laser treatment for hypertrophic port-wine stains on the lips.

PubMed

Kono, Taro; Frederick Groff, William; Chan, Henry H; Sakurai, Hiroyuki; Yamaki, Takashi

2009-03-01

Pulsed dye laser (PDL) treatment of hypertrophic port-wine stains (PWSs) on the lips has demonstrated poor efficacy and a potential risk of dyspigmentation. PDL-resistant hypertrophic PWS may require treatment with deeper penetrating lasers such as a 1064-nm neodymium:yttrium-aluminum-garnet (Nd:YAG) laser. The objective of this clinical study was to evaluate the efficacy and safety of a Nd:YAG laser for the treatment of hypertrophic PWSs on the lips. Ten patients (four were male and six were female) with hypertrophic PWSs on the lips were recruited in this study. Eight patients showed good to excellent improvement without complications. In conclusion, the Nd:YAG laser is safe and effective for treating hypertrophic PWSs on the lips.

The Size of the Radial Tuberosity is Not Related to the Occurrence of Distal Biceps Tendon Ruptures: A Case-Control Study.

PubMed

Kodde, Izaäk F; van den Bekerom, Michel P J; Mulder, Paul G H; Eygendaal, Denise

2016-01-01

Hypertrophic changes at the radial tuberosity have traditionally been related to distal biceps tendon degeneration and rupture. From supination to pronation of the forearm, the space available for the distal biceps tendon between de lateral ulna and radial bicipital tuberosity (RBT) decreases by almost 50%. A hypertrophic change at the radial tuberosity further reduces this space with impingement of the distal biceps tendon as a result. The purpose of this study was to evaluate whether the size of the RBT plays a role in the pathophysiology of distal biceps tendon ruptures. Twenty-two consecutive patients with a surgically proven distal biceps tendon rupture were matched to controls, in a 1:1 ratio. The size of the RBT was expressed as a ratio of the maximum diameter of the radius at the RBT to the diameter of the diaphysis just distal to the RBT (RD ratio), measured on standard radiographs of the elbow. The RD ratio of patients and matched controls were compared. The mean RD ratio in control group was 1.25 and not significantly different from the mean 1.30 in the group of patients with a distal biceps tendon rupture. Each 0.1 point increase in RD ratio results in an estimated 60% increase of the rupture odds, which was not significant either. Based on the RD ratio on conventional radiographs of the elbow, there was no significant difference in RBT size between patients with a distal biceps tendon rupture and matched controls without biceps tendon pathology.

Visualization of living terminal hypertrophic chondrocytes of growth plate cartilage in situ by differential interference contrast microscopy and time-lapse cinematography.

PubMed

Farnum, C E; Turgai, J; Wilsman, N J

1990-09-01

The functional unit within the growth plate consists of a column of chondrocytes that passes through a sequence of phases including proliferation, hypertrophy, and death. It is important to our understanding of the biology of the growth plate to determine if distal hypertrophic cells are viable, highly differentiated cells with the potential of actively controlling terminal events of endochondral ossification prior to their death at the chondro-osseous junction. This study for the first time reports on the visualization of living hypertrophic chondrocytes in situ, including the terminal hypertrophic chondrocyte. Chondrocytes in growth plate explants are visualized using rectified differential interference contrast microscopy. We record and measure, using time-lapse cinematography, the rate of movement of subcellular organelles at the limit of resolution of this light microscopy system. Control experiments to assess viability of hypertrophic chondrocytes include coincubating organ cultures with the intravital dye fluorescein diacetate to assess the integrity of the plasma membrane and cytoplasmic esterases. In this system, all hypertrophic chondrocytes, including the very terminal chondrocyte, exist as rounded, fully hydrated cells. By the criteria of intravital dye staining and organelle movement, distal hypertrophic chondrocytes are identical to chondrocytes in the proliferative and early hypertrophic cell zones.

Penile agenesis and congenital hypertrophic pyloric stenosis: an association or a random coexistence?

PubMed

Yagmurlu, Aydin; Vargun, Rahsan; Gollu, Gulnur; Gokcora, I Haluk

2004-01-01

A neonate with penile agenesis and congenital hypertrophic pyloric stenosis is presented. The patterns of associated anomalies with penile agenesis, and those of congenital hypertrophic pyloric stenosis are discussed.

Nonsurgical management of hypertrophic scars: evidence-based therapies, standard practices, and emerging methods.

PubMed

Atiyeh, Bishara S

2007-01-01

Hypertrophic scars, resulting from alterations in the normal processes of cutaneous wound healing, are characterized by proliferation of dermal tissue with excessive deposition of fibroblast-derived extracellular matrix proteins, especially collagen, over long periods, and by persistent inflammation and fibrosis. Hypertrophic scars are among the most common and frustrating problems after injury. As current aesthetic surgical techniques become more standardized and results more predictable, a fine scar may be the demarcating line between acceptable and unacceptable aesthetic results. However, hypertrophic scars remain notoriously difficult to eradicate because of the high recurrence rates and the incidence of side effects associated with available treatment methods. This review explores the various treatment methods for hypertrophic scarring described in the literature including evidence-based therapies, standard practices, and emerging methods, attempting to distinguish those with clearly proven efficiency from anecdotal reports about therapies of doubtful benefits while trying to differentiate between prophylactic measures and actual treatment methods. Unfortunately, the distinction between hypertrophic scar treatments and keloid treatments is not obvious in most reports, making it difficult to assess the efficacy of hypertrophic scar treatment.

Recent Understandings of Biology, Prophylaxis and Treatment Strategies for Hypertrophic Scars and Keloids

PubMed Central

Jang, Yong Ju

2018-01-01

Hypertrophic scars and keloids are fibroproliferative disorders that may arise after any deep cutaneous injury caused by trauma, burns, surgery, etc. Hypertrophic scars and keloids are cosmetically problematic, and in combination with functional problems such as contractures and subjective symptoms including pruritus, these significantly affect patients’ quality of life. There have been many studies on hypertrophic scars and keloids; but the mechanisms underlying scar formation have not yet been well established, and prophylactic and treatment strategies remain unsatisfactory. In this review, the authors introduce and summarize classical concepts surrounding wound healing and review recent understandings of the biology, prevention and treatment strategies for hypertrophic scars and keloids. PMID:29498630

Post-burn hypertrophic scars are characterized by high levels of IL-1β mRNA and protein and TNF-α type I receptors.

PubMed

Salgado, Rosa M; Alcántara, Luz; Mendoza-Rodríguez, C Adriana; Cerbón, Marco; Hidalgo-González, Christian; Mercadillo, Patricia; Moreno, Luis M; Alvarez-Jiménez, Ricardo; Krötzsch, Edgar

2012-08-01

Post-burn hypertrophic scars are characterized by increased collagen synthesis and hyperplasia, and may be associated with erythema, pain, dysesthesia, pruritus, and skin border elevation. Although the etiopathogenesis of hypertrophic scarring remains unclear, proinflammatory and profibrogenic cytokines are known to play an important role in general skin dysfunction. This study assessed mRNA expression, proteins, and type I receptors of tumor necrosis factor-alpha (TNF-α) and interleukin 1-beta (IL-1β) in normal skin, normotrophic and post-burn hypertrophic scars. Skin biopsies were obtained from 10 hypertrophic and 9 normotrophic scars, and 4 normal skin sites. Only post-burn scars covering more than 10% of the body were included. Ex vivo histopathological analysis evaluated scar maturity, in situ hybridization assessed mRNA expression, and cytokine protein and cytokine/cell colocalization were performed using single- and double-label immunohistochemistry, respectively. IL-1β is overexpressed in hypertrophic scars at the post-transcriptional level, associated primarily with keratinocytes and CD1a(+) cells. Type I receptors for TNF-α are overexpressed in blood vessels of hypertrophic scars. The coordinated overexpression of IL-1β and TNF-α type I receptor may maintain the fibrogenic phenotypes of hypertrophic scars, even those in "remission". Copyright © 2011 Elsevier Ltd and ISBI. All rights reserved.

[Gene mutation and clinical phenotype analysis of patients with Noonan syndrome and hypertrophic cardiomyopathy].

PubMed

Liu, X H; Ding, W W; Han, L; Liu, X R; Xiao, Y Y; Yang, J; Mo, Y

2017-10-02

Objective: To analyze the gene mutations and clinical features of patients with Noonan syndrome and hypertrophic cardiomyopathy. Method: Determined the mutation domain in five cases diagnosed with Noonan syndrome and hypertrophic cardiomyopathy and identified the relationship between the mutant domain and hypertrophic cardiomyopathy by searching relevant articles in pubmed database. Result: Three mutant genes (PTPN11 gene in chromosome 12, RIT1 gene in chromosome 1 and RAF1 gene in chromosome 3) in five cases all had been reported to be related to hypertrophic cardiomyopathy. The reported hypertrophic cardiomyopathy relevant genes MYPN, MYH6 and MYBP3 had also been found in case 1 and 2. Patients with same gene mutation had different clinical manifestations. Both case 4 and 5 had RAF1 mutation (c.770C>T). However, case 4 had special face, low IQ, mild pulmonary artery stenosis, and only mild ventricular hypertrophy. Conclusion: Noonan syndrome is a genetic heterogeneity disease. Our study identified specific gene mutations that could result in Noonan syndrome with hypertrophic cardiomyopathy through molecular biology methods. The results emphasize the importance of gene detection in the management of Noonan syndrome.

Food habits of Bald Eagles breeding in the Arizona desert

Treesearch

Teryl G. Grubb

1995-01-01

Of 1814 foraging attempts, prey captures, or nest deliveries by Bald Eagles (Haliaeetus leucocephalus) in 14 Arizona breeding areas during 1983-1985, 1471 observations were identifiable to at least class: fish (76%), mammal (18%), bird (4%), and reptile/amphibian (2%). Forty-five species were recorded: catfish (Ictalurus punctatus, Pylodictis olivaris), suckers (...

En1 directs superior olivary complex neuron positioning, survival, and expression of FoxP1.

PubMed

Altieri, Stefanie C; Jalabi, Walid; Zhao, Tianna; Romito-DiGiacomo, Rita R; Maricich, Stephen M

2015-12-01

Little is known about the genetic pathways and transcription factors that control development and maturation of central auditory neurons. En1, a gene expressed by a subset of developing and mature superior olivary complex (SOC) cells, encodes a homeodomain transcription factor important for neuronal development in the midbrain, cerebellum, hindbrain and spinal cord. Using genetic fate-mapping techniques, we show that all En1-lineal cells in the SOC are neurons and that these neurons are glycinergic, cholinergic and GABAergic in neurotransmitter phenotype. En1 deletion does not interfere with specification or neural fate of these cells, but does cause aberrant positioning and subsequent death of all En1-lineal SOC neurons by early postnatal ages. En1-null cells also fail to express the transcription factor FoxP1, suggesting that FoxP1 lies downstream of En1. Our data define important roles for En1 in the development and maturation of a diverse group of brainstem auditory neurons. Copyright © 2015 Elsevier Inc. All rights reserved.

Making sense of hypertrophic scar: a role for nerves.

PubMed

Scott, Jeffrey R; Muangman, Pornprom; Gibran, Nicole S

2007-01-01

Healed partial thickness wounds including burns and donor sites cause hypertrophic scar formation and patient discomfort. For many patients with hypertrophic scars, pruritus is the most distressing symptom, which leads to wound excoriation and chronic wound formation. In spite of the clinical significance of abnormal innervation in scars, the nervous system has been largely ignored in the pathophysiology of hypertrophic scars. Evidence that neuropeptides contribute to inflammatory responses to injury include inflammatory cell chemotaxis, cytokine and growth factor production. The neuropeptide substance P, which is released from nerve endings after injury, induces inflammation and mediates angiogenesis, keratinocyte proliferation, and fibrogenesis. Substance P activity is tightly regulated by neutral endopeptidase (NEP), a membrane bound metallopeptidase that degrades substance P at the cell membrane. Altered substance P levels may contribute to impaired cutaneous healing responses associated with diabetes mellitus or hypertrophic scar formation. Topical application of exogenous substance P or an NEP inhibitor enhances wound closure kinetics in diabetic murine wounds suggesting that diabetic wounds have insufficient substance P levels to promote a neuroinflammatory response necessary for normal wound repair. Conversely, increased nerve numbers and neuropeptide levels with reduced NEP levels in human and porcine hypertrophic scar samples suggest that excessive neuropeptide activity induces exuberant inflammation in hypertrophic scars. Given these observations about the role of neuropeptides in cutaneous repair, neuronal modulation of repair processes at two extremes of abnormal wound healing, chronic non-healing ulcers in type II diabetes mellitus and hypertrophic scars in deep partial thickness wounds, may provide therapeutic targets.

Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling.

PubMed

Ni, Yan G; Berenji, Kambeez; Wang, Na; Oh, Misook; Sachan, Nita; Dey, Asim; Cheng, Jun; Lu, Guangrong; Morris, David J; Castrillon, Diego H; Gerard, Robert D; Rothermel, Beverly A; Hill, Joseph A

2006-09-12

Cellular hypertrophy requires coordinated regulation of progrowth and antigrowth mechanisms. In cultured neonatal cardiomyocytes, Foxo transcription factors trigger an atrophy-related gene program that counters hypertrophic growth. However, downstream molecular events are not yet well defined. Here, we report that expression of either Foxo1 or Foxo3 in cardiomyocytes attenuates calcineurin phosphatase activity and inhibits agonist-induced hypertrophic growth. Consistent with these results, Foxo proteins decrease calcineurin phosphatase activity and repress both basal and hypertrophic agonist-induced expression of MCIP1.4, a direct downstream target of the calcineurin/NFAT pathway. Furthermore, hearts from Foxo3-null mice exhibit increased MCIP1.4 abundance and a hypertrophic phenotype with normal systolic function at baseline. Together, these results suggest that Foxo proteins repress cardiac growth at least in part through inhibition of the calcineurin/NFAT pathway. Given that hypertrophic growth of the heart occurs in multiple contexts, our findings also suggest that certain hypertrophic signals are capable of overriding the antigrowth program induced by Foxo. Consistent with this, multiple hypertrophic agonists triggered inactivation of Foxo proteins in cardiomyocytes through a mechanism requiring the PI3K/Akt pathway. In addition, both Foxo1 and Foxo3 are phosphorylated and consequently inactivated in hearts undergoing hypertrophic growth induced by hemodynamic stress. This study suggests that inhibition of the calcineurin/NFAT signaling cascade by Foxo and release of this repressive action by the PI3K/Akt pathway are important mechanisms whereby Foxo factors govern cell growth in the heart.

Neurotoxicity of carbonyl sulfide in F344 rats following inhalation exposure for up to 12 weeks.

PubMed

Morgan, Daniel L; Little, Peter B; Herr, David W; Moser, Virginia C; Collins, Bradley; Herbert, Ronald; Johnson, G Allan; Maronpot, Robert R; Harry, G Jean; Sills, Robert C

2004-10-15

Carbonyl sulfide (COS), a high-priority Clean Air Act chemical, was evaluated for neurotoxicity in short-term studies. F344 rats were exposed to 75-600 ppm COS 6 h per day, 5 days per week for up to 12 weeks. In rats exposed to 500 or 600 ppm for up to 4 days, malacia and microgliosis were detected in numerous neuroanatomical regions of the brain by conventional optical microscopy and magnetic resonance microscopy (MRM). After a 2-week exposure to 400 ppm, rats were evaluated using a functional observational battery. Slight gait abnormality was detected in 50% of the rats and hypotonia was present in all rats exposed to COS. Decreases in motor activity, and forelimb and hindlimb grip strength were also detected. In rats exposed to 400 ppm for 12 weeks, predominant lesions were in the parietal cortex area 1 (necrosis) and posterior colliculus (neuronal loss, microgliosis, hemorrhage), and occasional necrosis was present in the putamen, thalamus, and anterior olivary nucleus. Carbonyl sulfide specifically targeted the auditory system including the olivary nucleus, nucleus of the lateral lemniscus, and posterior colliculus. Consistent with these findings were alterations in the amplitude of the brainstem auditory evoked responses (BAER) for peaks N3, P4, N4, and N5 that represented changes in auditory transmission between the anterior olivary nucleus to the medial geniculate nucleus in animals after exposure for 2 weeks to 400 ppm COS. A concentration-related decrease in cytochrome oxidase activity was detected in the posterior colliculus and parietal cortex of exposed rats as early as 3 weeks. Cytochrome oxidase activity was significantly decreased at COS concentrations that did not cause detectable lesions, suggesting that disruption of the mitochondrial respiratory chain may precede these brain lesions. Our studies demonstrate that this environmental air contaminant has the potential to cause a wide spectrum of brain lesions that are dependent on the degree and duration of exposure.

Substance P levels and neutral endopeptidase activity in acute burn wounds and hypertrophic scar.

PubMed

Scott, Jeffrey R; Muangman, Pornprom R; Tamura, Richard N; Zhu, Kathy Q; Liang, Zhi; Anthony, Joanne; Engrav, Loren H; Gibran, Nicole S

2005-04-01

Substance P, a cutaneous neuroinflammatory mediator released from peripheral nerves, plays a role in responses to injury. Neutral endopeptidase is a cell membrane-bound metallopeptidase enzyme that regulates substance P activity. The question of substance P involvement in hypertrophic scar development has been based on observations that hypertrophic scars have increased numbers of nerves. The authors hypothesized that hypertrophic scar has greater substance P levels and decreased neutral endopeptidase activity compared with uninjured skin and acute partial-thickness burns, which may contribute to an exuberant response to injury. The authors obtained small skin samples of deep partial-thickness burns (n = 7; postburn days 7 to 78) and uninjured skin (n = 14) from patients (eight male patients and six female patients; 2 to 71 years old) undergoing burn wound excision. Hypertrophic scar samples were obtained from six patients (three male patients and three female patients; 8 to 47 years old) undergoing surgical excision 13 to 64 months after burn injury. Protein concentrations were determined using a bicinchoninic acid assay. Substance P concentration was determined by means of indirect enzyme-linked immunosorbent assay. Neutral endopeptidase activity was measured using an enzymatic assay that quantifies a fluorescent degradation product, methoxy-2-naphthylamine (MNA). Substance P and neutral endopeptidase data were standardized to sample weight. Substance P levels were greater in hypertrophic scar (3506 pg/g) compared with uninjured skin (1698 pg/g; p < 0.03) and burned skin (958 pg/g; p < 0.01). Hypertrophic scar samples had decreased neutral endopeptidase enzyme activity (8.8 pM MNA/hour/microg) compared with normal skin (16.3 pM MNA/hour/microg; p < 0.05). Acute burn wounds (27.9 pM MNA/hour/microg) demonstrated increased neutral endopeptidase enzyme activity (p < 0.05). Increased substance P concentration in hypertrophic scar correlates with histologic findings of increased nerve numbers in hypertrophic scar samples. Decreased neutral endopeptidase enzyme activity in hypertrophic scar may contribute to increased available substance P that may result in an exuberant neuroinflammatory response.

Perforating elastic fibers ('elastic fiber trapping') in the differentiation of keratoacanthoma, conventional squamous cell carcinoma and pseudocarcinomatous epithelial hyperplasia.

PubMed

Shah, Kabeer; Kazlouskaya, Viktoryia; Lal, Karan; Molina, David; Elston, Dirk M

2014-02-01

Keratoacanthoma (KA), an epithelial neoplasm occurring in sun-exposed skin of the elderly, is considered a well-differentiated form of conventional squamous cell carcinoma (SCC) that often follows a course of spontaneous regression. Distinguishing KA from conventional SCC or pseudocarcinomatous epithelial hyperplasia ensures proper diagnosis, treatment and management. For some time, perforating elastic fibers have been utilized in differentiating KA from SCC. This phenomenon may also occur in association with scars and hypertrophic lupus erythematosus (LE). To assess the diagnostic utility of perforating elastic fibers, we compared their incidence in KA, SCC, scars with overlying pseudocarcinomatous hyperplasia, hypertrophic LE, hypertrophic lichen planus (LP) and lichen simplex chronicus (LSC). A retrospective case search identified 359 lesions and the presence of perforating elastic fibers was evaluated using routinely stained sections. This phenomenon was documented in all studied groups except hypertrophic LP. The incidence was found to be 71% in KA, 37% in SCC, and was lowest in inflammatory conditions with associated pseudocarcinomatous hyperplasia (hypertrophic LP 0%, hypertrophic LE 5.9% and LSC 28.2%). The observed frequency in pseudocarcinomatous hyperplasia overlying scars (57.8%) vs. KA (71%) was not statistically different. Although elastic fiber trapping has potential value as a diagnostic criterion for KA, dermatopathologists should consider its limitations. Its diagnostic utility was greatest in distinguishing KA from hypertrophic LE and hypertrophic LP. Conversely, elastic trapping is not helpful differentiating pseudocarcinomatous hyperplasia from recurrent/persistent KA following surgery. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical efficacy of utilizing Ultrapulse CO2 combined with fractional CO2 laser for the treatment of hypertrophic scars in Asians-A prospective clinical evaluation.

PubMed

Lei, Ying; Li, Shi Feng; Yu, Yi Ling; Tan, Jun; Gold, Michael H

2017-06-01

Hypertrophic scarring is seen regularly. Tissue penetration of laser energy into hypertrophic scars using computer defaults from some lasers may be insufficient and penetration not enough. We have developed a treatment with an interrupted laser "drilling" by the Ultrapulse CO 2 (Manual Fractional Technology, MFT) and, a second pass, with fractional CO 2 . The MFT with fractional CO 2 lasers to treat hypertrophic scars is evaluated. A total of 158 patients with hypertrophic scars had three sessions of MFT with fractional CO 2 laser at 3-month intervals. Evaluations made before and 6 months after the 3rd treatment: (1) the Vancouver Scar Scale (VSS), (2) the University of North Carolina (UNC) Scar Scale, and (3) a survey of patient satisfaction. All data were analyzed using a t-test before and after treatment. The VSS score decreased from 9.35 to 3.12 (P<.0001), and the UNC Scar Scale score decreased from 8.03 to 1.62 (P<.0001). The overall satisfaction rate was 92%. No long-term complications occurred in the clinical trial. The interrupted laser drilling by MFT and a fractional CO2 laser had profound effects on the hypertrophic scars treated. It works by increasing the penetration depth of the CO 2 laser in the scar tissue, exerting more precise effects on the hypertrophic scars. MFT combined with fractional CO 2 laser has the potential to be a major advance in the treatment of hypertrophic scars. © 2017 Wiley Periodicals, Inc.

The activity of N-acetyl-β-d-hexosaminidase A and B and β-glucuronidase in nasal polyps and hypertrophic nasal concha.

PubMed

Chojnowska, Sylwia; Minarowska, Alina; Waszkiewicz, Napoleon; Kępka, Alina; Zalewska-Szajda, Beata; Gościk, Elżbieta; Kowal, Krzysztof; Olszewska, Ewa; Konarzewska-Duchnowska, Emilia; Minarowski, Łukasz; Zwierz, Krzysztof; Ładny, Jerzy Robert; Szajda, Sławomir Dariusz

2014-01-01

Nasal polyps and hypertrophic lower nasal conchae are common disorders of nasal cavity. The majority of etiopathogenetic theories indicate inflammatory background of polyps and hypertrophic concha. N-acetyl-β-D-hexosaminidase and β-glucuronidase are lysosomal exoglycosidases revealing accelerated activity in inflammatory processes. The aim of the study was to evaluate the catabolism of glycoconjugates in nasal polyps and hypertrophic nasal concha basing on the activity of N-acetyl-β-D-hexosaminidase (HEX) and β-glucuronidase (GLU). Material consisted of nasal polyps taken from 40 patients during polypectomy in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and hypertrophic lower nasal conchae taken from 20 patients during mucotomy. The activity of HEX, HEX A, HEX B and GLU in supernatant of homogenates of nasal polyps and hypertrophic lower nasal concha tissues has been estimated using colorimetric method. Statistically significant decrease has been observed in concentration of the activity (per 1mg of tissue) of HEX (p<0.05), HEX B (p<0.001) and specific activity (per 1mg of protein) of HEX B (p<0.001) in nasal polyps tissue in comparison to hypertrophic lower nasal conchae tissue. Decrease in the activity and specific activity concentration of the majority of examined lysosomal exoglycosidases (increasing in inflammations) in comparison to hypertrophic lower nasal conchae suggests electrolytes disorders and questions the inflammatory background of nasal polyps. Copyright © 2013 Polish Otorhinolaryngology - Head and Neck Surgery Society. Published by Elsevier Urban & Partner Sp. z.o.o. All rights reserved.

MR Imaging in Hypertrophic Cardiomyopathy: From Magnet to Bedside.

PubMed

Bogaert, Jan; Olivotto, Iacopo

2014-11-01

Hypertrophic cardiomyopathy ( HCM hypertrophic cardiomyopathy ), the most common genetically transmitted cardiac disorder, has been the focus of extensive research over the past 50 years. HCM hypertrophic cardiomyopathy is a multifaceted disease with highly heterogeneous genetic background, phenotypic expression, clinical presentation, and long-term outcome. Though most patients have an indolent course with a life expectancy comparable to that of the general population, early diagnosis and accurate risk profiling are essential to identify the sizeable subset at increased risk of sudden cardiac death or disease progression and heart failure-related complications, requiring aggressive management options. Imaging has a central role in the diagnosis and prognostic assessment of HCM hypertrophic cardiomyopathy patients, as well as screening of potentially affected family members. In this context, magnetic resonance (MR) imaging has recently emerged as an ideal complement to transthoracic echocardiography. Its multiparametric approach, fusing spatial, contrast, and temporal resolution, provides the clinician with detailed characterization of the HCM hypertrophic cardiomyopathy phenotype and assessment of its functional consequences including causes and site of dynamic obstruction, presence and extent of myocardial perfusion abnormalities, and fibrosis. Moreover, MR is key in differentiating HCM hypertrophic cardiomyopathy from "phenocopies"-that is, hearts with similar morphology but profoundly different etiology, such as amyloid or Anderson-Fabry disease. Long term, the incremental information provided by MR is relevant to planning of septal reduction therapies, identification of the early stages of end-stage progression, and stratification of arrhythmic risk. The aim of this review is to depict the increasingly important role of MR imaging in relation to the complexity of HCM hypertrophic cardiomyopathy , highlighting its role in clinical decision making.

Foxo Transcription Factors Blunt Cardiac Hypertrophy by Inhibiting Calcineurin Signaling

PubMed Central

Ni, Yan G.; Berenji, Kambeez; Wang, Na; Oh, Misook; Sachan, Nita; Dey, Asim; Cheng, Jun; Lu, Guangrong; Morris, David J.; Castrillon, Diego H.; Gerard, Robert D.; Rothermel, Beverly A.; Hill, Joseph A.

2014-01-01

Background Cellular hypertrophy requires coordinated regulation of progrowth and antigrowth mechanisms. In cultured neonatal cardiomyocytes, Foxo transcription factors trigger an atrophy-related gene program that counters hypertrophic growth. However, downstream molecular events are not yet well defined. Methods and Results Here, we report that expression of either Foxo1 or Foxo3 in cardiomyocytes attenuates calcineurin phosphatase activity and inhibits agonist-induced hypertrophic growth. Consistent with these results, Foxo proteins decrease calcineurin phosphatase activity and repress both basal and hypertrophic agonist-induced expression of MCIP1.4, a direct downstream target of the calcineurin/NFAT pathway. Furthermore, hearts from Foxo3-null mice exhibit increased MCIP1.4 abundance and a hypertrophic phenotype with normal systolic function at baseline. Together, these results suggest that Foxo proteins repress cardiac growth at least in part through inhibition of the calcineurin/NFAT pathway. Given that hypertrophic growth of the heart occurs in multiple contexts, our findings also suggest that certain hypertrophic signals are capable of overriding the antigrowth program induced by Foxo. Consistent with this, multiple hypertrophic agonists triggered inactivation of Foxo proteins in cardiomyocytes through a mechanism requiring the PI3K/Akt pathway. In addition, both Foxo1 and Foxo3 are phosphorylated and consequently inactivated in hearts undergoing hypertrophic growth induced by hemodynamic stress. Conclusions This study suggests that inhibition of the calcineurin/NFAT signaling cascade by Foxo and release of this repressive action by the PI3K/Akt pathway are important mechanisms whereby Foxo factors govern cell growth in the heart. PMID:16952979

MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria.

PubMed

Chatterjee, Aindrila; Seyfferth, Janine; Lucci, Jacopo; Gilsbach, Ralf; Preissl, Sebastian; Böttinger, Lena; Mårtensson, Christoph U; Panhale, Amol; Stehle, Thomas; Kretz, Oliver; Sahyoun, Abdullah H; Avilov, Sergiy; Eimer, Stefan; Hein, Lutz; Pfanner, Nikolaus; Becker, Thomas; Akhtar, Asifa

2016-10-20

A functional crosstalk between epigenetic regulators and metabolic control could provide a mechanism to adapt cellular responses to environmental cues. We report that the well-known nuclear MYST family acetyl transferase MOF and a subset of its non-specific lethal complex partners reside in mitochondria. MOF regulates oxidative phosphorylation by controlling expression of respiratory genes from both nuclear and mtDNA in aerobically respiring cells. MOF binds mtDNA, and this binding is dependent on KANSL3. The mitochondrial pool of MOF, but not a catalytically deficient mutant, rescues respiratory and mtDNA transcriptional defects triggered by the absence of MOF. Mof conditional knockout has catastrophic consequences for tissues with high-energy consumption, triggering hypertrophic cardiomyopathy and cardiac failure in murine hearts; cardiomyocytes show severe mitochondrial degeneration and deregulation of mitochondrial nutrient metabolism and oxidative phosphorylation pathways. Thus, MOF is a dual-transcriptional regulator of nuclear and mitochondrial genomes connecting epigenetics and metabolism. Copyright © 2016 Elsevier Inc. All rights reserved.

[Toxoplasmosis in patients with lymphoid hyperplasia of the head and neck].

PubMed

Yariktaş, Murat; Demirci, Mustafa; Döner, Fehmi; Kaya, Selçuk; Doğru, Harun

2004-01-01

To investigate the incidence of toxoplasmosis in patients with lymphoid hyperplasia of the head and neck. In this study, 53 patients (32 males, 21 females; mean age 11.2+/-4.3 years, range 5 to 22) were investigated. There were hypertrophic tonsillitis in 13 patients, hypertrophic tonsillitis and adenoid hyperplasia in 22 patients, adenoid hyperplasia in 10 patients, and lymphadenopathy of the neck in eight patients. In venous blood samples, IgM and IgG antibodies for Toxoplasma gondii were investigated with the enzyme-linked immunoabsorbent assay (Axsym, Abbott). Positive IgG was determined in 23 patients (48%) with hypertrophic tonsillitis (n=6), hypertrophic tonsillitis and adenoid hyperplasia (n=10), adenoid hyperplasia (n=3), and lymphadenopathy of the neck (n=4). Positive IgM was determined in 5 patients (9.4%) with hypertrophic tonsillitis (n=1), hypertrophic tonsillitis and adenoid hyperplasia (n=1), and lymphadenopathy of the neck (n=3). Toxoplasmosis, which is known to cause lymphadenopathy, may be a reason for lymphadenopathy of the neck. Toxoplasmosis should be considered in the differential diagnosis of untreated patients with tonsillitis, adenoid hyperplasia, and chronic neck lymphadenopathy.

Auditory Evoked Potentials from the Frog Eighth Nerve

DTIC Science & Technology

1989-09-01

superior olivary nucleus 6, 10-100 ms in torus semicircularis’ 2,4’ 14, 1618, 30-120 ms in thalamus 7’ 1,13,14, and greater than 30 ms in telencephalon 12...899. 12 Mudry, K.M. and Capranica, R.R., Evoked auditory activity within the telencephalon of the bullfrog (Rana catesbeiana), Brain Res., 182 (1980

Characterization of T-cell subsets infiltrating post-burn hypertrophic scar tissues.

PubMed

Castagnoli, C; Trombotto, C; Ondei, S; Stella, M; Calcagni, M; Magliacani, G; Alasia, S T

1997-01-01

In this study, skin-infiltrating cells were characterized in both the active and remission phases of post-burn hypertrophic scar biopsies. Immunohistochemistry examination of active phase samples showed an abundant presence of Langerhans cells, T cells, macrophages, a low presence of natural killer cells and the lack of B lymphocytes. In active hypertrophic scars T lymphocytes infiltrate deep into the superficial dermis and are also observed in the epidermis: CD3+ cells were present at about 222 +/- 107 per 0.25 mm2. In particular the analysis of lymphocyte subpopulations showed that CD4+ T cells predominate in the dermis as well as in the epidermis of active hypertrophic scars whereas CD8+ cells were less well represented (CD4/CD8 ratio is 2.06). This distribution was also shown in remission phase samples and in normotrophic scar specimens, although the lymphocyte number was significantly lower. Approximately 70 per cent of T lymphocytes present in the tissue involved in active phase hypertrophic scar samples were activated (positive with anti-HLA-DR and IL-2 receptor antibodies) which is significantly higher than remission phase hypertrophic and normotrophic scars, in which positivity was 40 and 38 per cent, respectively. Upon activation, the lesional lymphocytes release several cytokines, locally and transiently, that interact with specific receptors in response to different stimulation. Central to the immune hypothesis of hypertrophic scars is that some of the T-cell lymphokines act on keratinocytes, fibroblasts and other cell types to induce changes characteristic of these scars. The presence and close proximity of activated T lymphocytes and antigen-presenting cells of various phenotypes in both the epidermis and dermis of hypertrophic tissues provides strong circumstantial evidence of a local immune response. However, the manner in which T cells achieve and maintain their activated state in hypertrophic tissues is not yet known, and both antigen-dependent and independent mechanisms may contribute.

Idiopathic hypertrophic pachymeningitis presenting with occipital neuralgia.

PubMed

Auboire, Laurent; Boutemy, Jonathan; Constans, Jean Marc; Le Gallou, Thomas; Busson, Philippe; Bienvenu, Boris

2015-03-01

Although occipital neuralgia is usually caused by degenerative arthropathy, nearly 20 other aetiologies may lead to this condition. We present the first case report of hypertrophic pachymeningitis revealed by isolated occipital neuralgia. Idiopathic hypertrophic pachymeningitis is a plausible cause of occipital neuralgia and may present without cranial-nerve palsy. There is no consensus on the treatment for idiopathic hypertrophic pachymeningitis, but the usual approach is to start corticotherapy and then to add immunosuppressants. When occipital neuralgia is not clinically isolated or when a first-line treatment fails, another disease diagnosis should be considered. However, the cost effectiveness of extended investigations needs to be considered.

Hypertrophic osteoarthropathy, spider naevi and oestrogen hyperexcretion associated with adenocarcinoma.

PubMed Central

Brear, S. G.; Edwards, J. D.; Rademaker, M.; Doyle, L.

1985-01-01

We describe two patients with hypertrophic osteoarthropathy, spider naevi and elevated 24 h urinary oestrogen excretion associated with an adenocarcinoma. In one of the patients, the spider naevi and the clinical signs of hypertrophic osteoarthropathy disappeared and the 24 h urinary oestrogen returned to normal following removal of the tumour. Images Figure 1 PMID:4059145

A new treatment of hypertrophic and keloid scars with combined triamcinolone and verapamil: a retrospective study.

PubMed

Kant, S B; van den Kerckhove, E; Colla, C; Tuinder, S; van der Hulst, R R W J; Piatkowski de Grzymala, A A

2018-01-01

Since the management of keloid and hypertrophic scars still remains a difficult clinical problem, there is need for adequate, effective therapy. In this study, we explored for the first time the efficacy and the potential synergetic effect of combined triamcinolone and verapamil for the treatment of hypertrophic and keloid scars. The objective was to assess the efficacy of combined intralesional triamcinolone and verapamil therapy for hypertrophic and keloid scars. Fifty-eight patients with hypertrophic scars ( n  = 31) and keloid scars ( n  = 27) were included. A specific injection therapy scheme was applied. Five follow-up moments were chosen, with a maximum follow-up of nearly 2 years. The effects of combination therapy on scar pliability, thickness, relief, vascularization, surface area, pain, and pruritus were examined by means of the Patient and Observer Scar Assessment Scale (POSAS). Our results reveal a fast and abiding improvement of both keloid and hypertrophic scars after treatment with the combination therapy. All POSAS components showed a reduction in scar score, while scar relief, pain, itchiness, and surface area improved significantly ( P  < 0.05) in keloids. Significant improvement in hypertrophic scars was found in scar pigmentation, vascularization, pliability, thickness, pain, and surface area. Overall POSAS scores revealed statistically significant decreases between baseline and 3-4 months, 4-6 months, and >12 months after start of therapy in both keloids and hypertrophic scars. This study reveals that combined therapy of triamcinolone and verapamil results in overall significant scar improvement with a long-term stable result.Level of evidence: Level IV, therapeutic study.

Update on hypertrophic scar treatment

PubMed Central

Rabello, Felipe Bettini; Souza, Cleyton Dias; Júnior, Jayme Adriano Farina

2014-01-01

Scar formation is a consequence of the wound healing process that occurs when body tissues are damaged by a physical injury. Hypertrophic scars and keloids are pathological scars resulting from abnormal responses to trauma and can be itchy and painful, causing serious functional and cosmetic disability. The current review will focus on the definition of hypertrophic scars, distinguishing them from keloids and on the various methods for treating hypertrophic scarring that have been described in the literature, including treatments with clearly proven efficiency and therapies with doubtful benefits. Numerous methods have been described for the treatment of abnormal scars, but to date, the optimal treatment method has not been established. This review will explore the differences between different types of nonsurgical management of hypertrophic scars, focusing on the indications, uses, mechanisms of action, associations and efficacies of the following therapies: silicone, pressure garments, onion extract, intralesional corticoid injections and bleomycin. PMID:25141117

Topical modalities for treatment and prevention of postsurgical hypertrophic scars.

PubMed

Foo, Chong Wee; Tristani-Firouzi, Payam

2011-08-01

There is no universally accepted treatment regimen and no evidence-based literature to guide management of hypertrophic scars. This article summarizes the existing literature regarding topical treatments such as silicone gel sheeting and ointment, onion extract, vitamin E, pressure garment therapy, massage therapy, and topical imiquimod 5% cream in the management of hypertrophic scars. 2011 Elsevier Inc. All rights reserved.

Down Syndrome with Complete Atrioventricular Septal Defect, Hypertrophic Cardiomyopathy, and Pulmonary Vein Stenosis.

PubMed

Mahadevaiah, Guruprasad; Gupta, Manoj; Ashwath, Ravi

2015-10-01

The prevalence of congenital heart disease in infants with Down syndrome is 40%, compared with 0.3% in children who have normal chromosomes. Atrioventricular and ventricular septal defects are often associated with chromosomal aberrations, such as in trisomy 21, whereas hypertrophic cardiomyopathy is chiefly thought to be secondary to specific gene mutations. We found only one reported case of congenital hypertrophic cardiomyopathy and atrioventricular septal defect in an infant with Down syndrome. Here, we report atrioventricular septal defect, hypertrophic cardiomyopathy, and pulmonary vein stenosis in a neonate with Down syndrome-an apparently unique combination. In addition, we discuss the relevant medical literature.

Clinical Presentation and Natural History of Hypertrophic Cardiomyopathy in RASopathies.

PubMed

Calcagni, Giulio; Adorisio, Rachele; Martinelli, Simone; Grutter, Giorgia; Baban, Anwar; Versacci, Paolo; Digilio, Maria Cristina; Drago, Fabrizio; Gelb, Bruce D; Tartaglia, Marco; Marino, Bruno

2018-04-01

RASopathies are a heterogeneous group of genetic syndromes characterized by mutations in genes that regulate cellular processes, including proliferation, differentiation, survival, migration, and metabolism. Excluding congenital heart defects, hypertrophic cardiomyopathy is the most frequent cardiovascular defect in patients affected by RASopathies. A worse outcome (in terms of surgical risk and/or mortality) has been described in a specific subset of Rasopathy patients with early onset, severe hypertrophic cardiomyopathy presenting with heart failure. New short-term therapy with a mammalian target of rapamycin inhibitor has recently been used to prevent heart failure in these patients with a severe form of hypertrophic cardiomyopathy. Copyright © 2017 Elsevier Inc. All rights reserved.

Cardiovascular magnetic resonance in the evaluation of hypertrophic and infiltrative cardiomyopathies.

PubMed

O'Hanlon, Rory; Pennell, Dudley J

2009-07-01

There is often considerable phenotypic overlap in hypertrophic and infiltrative cardiomyopathies. This overlap creates difficulties, when using routine imaging modalities, in arriving at a conclusive diagnosis. Cardiovascular magnetic resonance (CMR) can make diagnosis easier and more certain. Used with gadolinium contrast agent for tissue characterization, CMR offers a superior field of view and temporal resolution, enabling clinicians to make more confident assessments of etiology. CMR may also be a useful modality for stratifying risk and monitoring treatment responses over time in patients with hypertrophic or infiltrative cardiomyopathies. This article highlights the role of CMR in the assessment and, if relevant, the risk stratification of hypertrophic and infiltrative cardiomyopathies.

Effects of downregulation of S100A8 protein expression on cell cycle and apoptosis of fibroblasts derived from hypertrophic scars.

PubMed

Yaundong, Lv; Dongyan, Wang; Lijun, Hao; Zhibo, Xiao

2014-01-01

Uncontrolled growth and lack of apoptosis in fibroblasts derived from a hypertrophic scar play an important role in pathology. The authors explore the contribution of S100A8 overexpression to the phenotype of cells and discuss how the downregulation of S100A8 could inhibit the growth and induce apoptosis of fibroblasts derived from hypertrophic scars. Fibroblasts were harvested from hypertrophic scar tissue in 8 patients treated with small interfering RNA against S100A8 in an in vitro culture. The effects of silencing S100A8 were analyzed by Western blot. Cellular proliferation and apoptosis were detected by flow cytometry. Fibroblasts treated with small interfering RNA targeting S100A8 showed a significant decrease in S100A8 protein 48 hours after treatment. They also proliferated significantly slower and showed more apoptosis than control fibroblasts. Inhibition of S100A8 resulted in significant growth reduction and apoptosis acceleration in fibroblasts derived from hypertrophic scars. Manipulation of S100A8 protein expression by gene silencing may represent something new in the treatment of hypertrophic scarring.

Differential and exclusive diagnosis of diseases that resemble keloids and hypertrophic scars.

PubMed

Ogawa, Rei; Akaishi, Satoshi; Hyakusoku, Hiko

2009-06-01

Previous articles suggested the presence of various kinds of malignant tumors that resemble keloid or hypertrophic scar, including dermatofibrosarcoma protuberans, trichilemmal carcinoma, and keloidal basal cell carcinoma. Thus, we studied our cases that were diagnosed with diseases other than keloid or hypertrophic scar. From April 2003 to March 2007, we examined 378 patients self diagnosed with keloid or hypertrophic scar.We detected 4 other diseases (1.06%) in the group of patients. All tumors were benign: apocrine cystadenoma, adult-onset juvenile xanthogranuloma, mixed tumor, and chronic folliculitis. Our study led us to the conclusion that differential or exclusive diagnosis of diseases similar to keloid and hypertrophic scar is important. We found the following considerations important in the examination of keloid or hypertrophic scar: (1) biopsy should be conducted in anomalous cases because malignant disease may be the original or secondary problem, (2) steroid injection should be performed only after careful consideration because malignancy or infections may be present, (3) careful differential diagnosis is particularly challenging in African-Americans because skin and tumor color are often similar, and (4) the presence of bacterial or fungal infection should be investigated.

Repair of bone defects in vivo using tissue engineered hypertrophic cartilage grafts produced from nasal chondrocytes.

PubMed

Bardsley, Katie; Kwarciak, Agnieska; Freeman, Christine; Brook, Ian; Hatton, Paul; Crawford, Aileen

2017-01-01

The regeneration of large bone defects remains clinically challenging. The aim of our study was to use a rat model to use nasal chondrocytes to engineer a hypertrophic cartilage tissue which could be remodelled into bone in vivo by endochondral ossification. Primary adult rat nasal chondrocytes were isolated from the nasal septum, the cell numbers expanded in monolayer culture and the cells cultured in vitro on polyglycolic acid scaffolds in chondrogenic medium for culture periods of 5-10 weeks. Hypertrophic differentiation was assessed by determining the temporal expression of key marker genes and proteins involved in hypertrophic cartilage formation. The temporal changes in the genes measured reflected the temporal changes observed in the growth plate. Collagen II gene expression increased 6 fold by day 7 and was then significantly downregulated from day 14 onwards. Conversely, collagen X gene expression was detectable by day 14 and increased 100-fold by day 35. The temporal increase in collagen X expression was mirrored by increases in alkaline phosphatase gene expression which also was detectable by day 14 with a 30-fold increase in gene expression by day 35. Histological and immunohistochemical analysis of the engineered constructs showed increased chondrocyte cell volume (31-45 μm), deposition of collagen X in the extracellular matrix and expression of alkaline phosphatase activity. However, no cartilage mineralisation was observed in in vitro culture of up to 10 weeks. On subcutaneous implantation of the hypertrophic engineered constructs, the grafts became vascularised, cartilage mineralisation occurred and loss of the proteoglycan in the matrix was observed. Implantation of the hypertrophic engineered constructs into a rat cranial defect resulted in angiogenesis, mineralisation and remodelling of the cartilage tissue into bone. Micro-CT analysis indicated that defects which received the engineered hypertrophic constructs showed 38.48% in bone volume compared to 7.01% in the control defects. Development of tissue engineered hypertrophic cartilage to use as a bone graft substitute is an exciting development in regenerative medicine. This is a proof of principal study demonstrating the potential of nasal chondrocytes to engineer hypertrophic cartilage which will remodel into bone on in vivo transplantation. This approach to making engineered hypertrophic cartilage grafts could form the basis of a new potential future clinical treatment for maxillofacial reconstruction. Copyright © 2016. Published by Elsevier Ltd.

Characteristic brain MRI findings in ataxia-neuropathy spectrum related to POLG mutation

PubMed Central

Henao, Adriana I; Pira, Sonia; Vargas, Sergio A; Montoya, Jorge; Castillo, Mauricio

2016-01-01

Patients with mutations in the polymerase gamma gene (POLG) may present with progressive ataxia and in such situations neuroimaging findings may suggest the diagnosis. Herein we report a patient with a POLG gene W748S homozygous mutation and characteristic lesions in the thalamus, cerebellum and inferior olivary nucleus seen on magnetic resonance imaging. PMID:26755490

Characteristic brain MRI findings in ataxia-neuropathy spectrum related to POLG mutation.

PubMed

Henao, Adriana I; Pira, Sonia; Herrera, Diego A; Vargas, Sergio A; Montoya, Jorge; Castillo, Mauricio

2016-02-01

Patients with mutations in the polymerase gamma gene (POLG) may present with progressive ataxia and in such situations neuroimaging findings may suggest the diagnosis. Herein we report a patient with a POLG gene W748S homozygous mutation and characteristic lesions in the thalamus, cerebellum and inferior olivary nucleus seen on magnetic resonance imaging. © The Author(s) 2016.

Expression of inorganic phosphate/vesicular glutamate transporters (BNPI/VGLUT1 and DNPI/VGLUT2) in the cerebellum and precerebellar nuclei of the rat.

PubMed

Hisano, Setsuji; Sawada, Kazuhiko; Kawano, Michihiro; Kanemoto, Mizuki; Xiong, Guoxiang; Mogi, Koichi; Sakata-Haga, Hiromi; Takeda, Jun; Fukui, Yoshihiro; Nogami, Haruo

2002-10-30

Expression of inorganic phosphate/vesicular glutamate transporters (BNPI/VGLUT1 and DNPI/VGLUT2) was studied in the cerebellum and precerebellar nuclei of rats using immunohistochemistry and in situ hybridization. DNPI/VGLUT2-stained mossy fibers were principally seen in the vermis (lobules I and VIII-X) and flocculus, whereas BNPI/VGLUT1-stained mossy fibers were localized throughout the cortex. Some vermal and floccular mossy fibers were stained for both transporters. High levels of DNPI/VGLUT2 mRNA hybridization signals were demonstrated in many neurons throughout the vestibular nuclear complex as well as the lateral reticular, external cuneate, inferior olivary and deep cerebellar nuclei. Significant BNPI/VGLUT1 mRNA signals were demonstrated in the lateral reticular nucleus and vestibular nuclear complex but not in the inferior olivary nucleus, indicating that climbing fibers have DNPI/VGLUT2 only. These results show that DNPI/VGLUT2 is expressed preferentially to vestibulo-, reticulo- and cuneocerebellar neurons, some of which also possess BNPI/VGLUT1, suggesting some differential and co-operative functions between DNPI/VGLUT2 and BNPI/VGLUT1 in the cerebellum.

Structural Changes and Lack of HCN1 Channels in the Binaural Auditory Brainstem of the Naked Mole-Rat (Heterocephalus glaber).

PubMed

Gessele, Nikodemus; Garcia-Pino, Elisabet; Omerbašić, Damir; Park, Thomas J; Koch, Ursula

2016-01-01

Naked mole-rats (Heterocephalus glaber) live in large eu-social, underground colonies in narrow burrows and are exposed to a large repertoire of communication signals but negligible binaural sound localization cues, such as interaural time and intensity differences. We therefore asked whether monaural and binaural auditory brainstem nuclei in the naked mole-rat are differentially adjusted to this acoustic environment. Using antibody stainings against excitatory and inhibitory presynaptic structures, namely the vesicular glutamate transporter VGluT1 and the glycine transporter GlyT2 we identified all major auditory brainstem nuclei except the superior paraolivary nucleus in these animals. Naked mole-rats possess a well structured medial superior olive, with a similar synaptic arrangement to interaural-time-difference encoding animals. The neighboring lateral superior olive, which analyzes interaural intensity differences, is large and elongated, whereas the medial nucleus of the trapezoid body, which provides the contralateral inhibitory input to these binaural nuclei, is reduced in size. In contrast, the cochlear nucleus, the nuclei of the lateral lemniscus and the inferior colliculus are not considerably different when compared to other rodent species. Most interestingly, binaural auditory brainstem nuclei lack the membrane-bound hyperpolarization-activated channel HCN1, a voltage-gated ion channel that greatly contributes to the fast integration times in binaural nuclei of the superior olivary complex in other species. This suggests substantially lengthened membrane time constants and thus prolonged temporal integration of inputs in binaural auditory brainstem neurons and might be linked to the severely degenerated sound localization abilities in these animals.

Experimental Study of 5-fluorouracil Encapsulated Ethosomes Combined with CO2 Fractional Laser to Treat Hypertrophic Scar.

PubMed

Zhang, Zhen; Chen, Jun; Huang, Jun; Wo, Yan; Zhang, Yixin; Chen, Xiangdong

2018-01-18

This study is designed to explore permeability of ethosomes encapsulated with 5-florouracil (5-FU) mediated by CO 2 fractional laser on hypertrophic scar tissues. Moreover, therapeutic and duration effect of CO 2 fractional laser combined with 5-FU encapsulated ethosomes in rabbit ear hypertrophic scar model will be evaluated. The permeated amount of 5-FU and retention contents of 5-FU were both determined by high-performance liquid chromatography (HPLC). Fluorescence intensities of ethosomes encapsulated with 5-FU (5E) labeled with Rodanmin 6GO (Rho) were measured by confocal laser scanning microscopy (CLSM). The permeability promotion of 5E labeled with Rho in rabbit ear hypertrophic scar mediated by CO 2 fractional laser was evaluated at 0 h, 6 h, 12 h, 24 h, 3 days and 7 days after the irradiation. The opening rates of the micro-channels were calculated according to CLSM. The therapeutic effect of 5EL was evaluated on rabbit ear hypertrophic scar in vivo. Relative thickness of rabbit ear hypertrophic scar before and after the treatment was measured by caliper method. Scar elevation index (SEI) of rabbit ear hypertrophic scar was measured using H&E staining. The data showed that the penetration amount of 5EL group was higher than 5E group (4.15 ± 2.22 vs. 0.73 ± 0.33; p < 0.05) after 1-h treatment. Additionally, the penetration amount of 5EL was higher than that of the 5E group (107.61 ± 13.27 vs. 20.73 ± 3.77; p < 0.05) after 24-h treatment. The retention contents of the 5EL group also showed higher level than 5E group (24.42 ± 4.37 vs.12.25 ± 1.64; p < 0.05). The fluorescence intensity of Rho in hypertrophic scar tissues of the 5EL group was higher than that of the 5E group at different time points (1, 6, and 24 h). The opening rates of the micro-channels were decreased gradually within 24 h, and micro-channels were closed completely 3 days after the irradiation by CO 2 fractional laser. The relative thickness and SEI of rabbit ear hypertrophic scar after 7 days of treatment in the 5EL group were significantly lower than the 5E group. CO 2 fractional laser combined with topical 5E can be effective in the treatment of hypertrophic scar in vivo and supply a novel therapy method for human hypertrophic scar.

Metastases of Hepatocellular Carcinoma Misdiagnosed as Isolated Hypertrophic Cardiomyopathy.

PubMed

Greco, Assunta; De Masi, Roberto; Orlando, Stefania; Metrangolo, Antonio; Zecca, Vittorio; Morciano, Giancarlo; De Donno, Antonella; Bagordo, Francesco; Piccinni, Giancarlo

At present, cardiac metastasis of hepatocellular carcinoma is rarely mentioned in the literature. We report a hepatocellular carcinoma patient with cardiac metastasis misdiagnosed as hypertrophic cardiomyopathy in 2011. Two years later, on presentation of syncope, an abnormal ventricular septal size was recorded by ultrasound scan, and was subsequently shown by magnetic resonance imaging to be a tumour lesion. A myocardial biopsy confirmed infiltration of hepatocellular carcinoma. This observation underlines the risk of hepatocellular carcinoma cardiac metastasis, manifested in its infiltrative form as hypertrophic cardiomyopathy. In conclusion, we suggest that the ultrasound appearance of hypertrophic cardiomyopathy in hepatocellular carcinoma patients should be seen as a "red flag" and recommend the introduction of magnetic resonance imaging assessment of transplant candidates.

Asn391Thr Mutation of β-Myosin Heavy Chain in a Hypertrophic Cardiomyopathy Family.

PubMed

Feng, Xiaotong; He, Tingting; Wang, Ji-Gang; Zhao, Peng

2018-05-30

The present study was performed to identify the genetic abnormalities in a family with familial hypertrophic cardiomyopathy.Peripheral blood samples were collected from 22 members of a Chinese family with hypertrophic cardiomyopathy and 307 healthy controls. A total of 26 candidate pathogenic genes were analyzed in the proband using targeted capture sequencing. Identified mutations were analyzed using Sanger sequencing in all family members and healthy controls.A missense mutation (c.1172A>C, p. Asn391Thr) in exon 12 of MYH7 was identified in eight family members, among which six of them were hypertrophic cardiomyopathy carriers. Three carriers presented with cardiac dysfunction. Four members of this pedigree died suddenly, three of whom were diagnosed with hypertrophic cardiomyopathy.From the results of this study, we concluded that the Asn391Thr mutation of MYH7 is a malignant mutation for HCM and that mutation carriers should get effective treatment to prevent sudden death.

Enhanced secretion of TIMP-1 by human hypertrophic scar keratinocytes could contribute to fibrosis.

PubMed

Simon, Franck; Bergeron, Daniele; Larochelle, Sébastien; Lopez-Vallé, Carlos A; Genest, Hervé; Armour, Alexis; Moulin, Véronique J

2012-05-01

Hypertrophic scars are a pathological process characterized by an excessive deposition of extracellular matrix components. Using a tissue-engineered reconstructed human skin (RHS) method, we previously reported that pathological keratinocytes induce formation of a fibrotic dermal matrix. We further investigated keratinocyte action using conditioned media. Results showed that conditioned media induce a similar action on dermal thickness similar to when an epidermis is present. Using a two-dimensional electrophoresis technique, we then compared conditioned media from normal or hypertrophic scar keratinocytes and determined that TIMP-1 was increased in conditioned media from hypertrophic scar keratinocytes. This differential profile was confirmed using ELISA, assaying TIMP-1 presence on media from monolayer cultured keratinocytes and from RHS. The dermal matrix of these RHS was recreated using mesenchymal cells from three different origins (skin, wound and hypertrophic scar). The effect of increased TIMP-1 levels on dermal fibrosis was also validated independently from the mesenchymal cell origin. Immunodetection of TIMP-1 showed that this protein was increased in the epidermis of hypertrophic scar biopsies. The findings of this study represent an important advance in understanding the role of keratinocytes as a direct potent modulator for matrix degradation and scar tissue remodeling, possibly through inactivation of MMPs. Copyright © 2011 Elsevier Ltd and ISBI. All rights reserved.

An immunohistochemical and ultrastructural study of the pericellular matrix of uneroded hypertrophic chondrocytes in the mandibular condyle of aged c-src-deficient mice.

PubMed

Shibata, Shunichi; Baba, Otto; Oda, Tsuyoshi; Yokohama-Tamaki, Tamaki; Qin, Chunlin; Butler, William T; Sakakura, Yasunori; Takano, Yoshiro

2008-03-01

Previous studies indicate that hypertrophic chondrocytes can transdifferentiate or dedifferentiate and redifferentiate into bone cells during the endochondral bone formation. Mandibular condyle in aged c-src-deficient mice has incremental line-like striations consisting of cartilaginous and non-cartilaginous layers, and the former contains intact hypertrophic chondrocytes in uneroded lacunae. The purpose of this study is to determine the phenotype changes of uneroded hypertrophic chondrocytes. Immunohistochemical and ultrastructural examinations of the pericellular matrix of hypertrophic chondrocytes in the upper, middle, and lower regions of the mandibular condyle were conducted in aged c-src-deficient mice, using several antibodies of cartilage/bone marker proteins. Co-localisation of aggrecan, type I collagen, and dentin matrix protein-1 (DMP-1) or matrix extracellular phosphoprotein (MEPE) was detected in the pericellular matrix of the middle region. Ultrastructurally, granular substances in the pericellular matrix of the middle region were the remains of upper region chondrocytes, which were mixed with thick collagen fibrils. In the lower region, the width of the pericellular matrix and the amount of collagen fibrils were increased. Versican, type I collagen, DMP-1, and MEPE were detected in the osteocyte lacunae. Additionally, DMP-1 and MEPE were detected in the pericellular matrix of uneroded hypertrophic chondrocytes located in the lower, peripheral region of the mandibular condyle in younger c-src-deficient mice, but not in the aged wild-type mice. These results indicate that long-term survived, uneroded hypertrophic chondrocytes, at least in a part, acquire osteocytic characteristics.

Therapeutic effects of liposome-enveloped Ligusticum chuanxiong essential oil on hypertrophic scars in the rabbit ear model.

PubMed

Zhang, Hong; Ran, Xia; Hu, Chang-Ling; Qin, Lu-Ping; Lu, Ying; Peng, Cheng

2012-01-01

Hypertrophic scarring, a common proliferative disorder of dermal fibroblasts, results from an overproduction of fibroblasts and excessive deposition of collagen. Although treatment with surgical excision or steroid hormones can modify the symptoms, numerous treatment-related complications have been described. In view of this, we investigated the therapeutic effects of essential oil (EO) from rhizomes of Ligusticum chuanxiong Hort. (Umbelliferae) on formed hypertrophic scars in a rabbit ear model. EO was prepared as a liposomal formulation (liposome-enveloped essential oil, LEO) and a rabbit ear model with hypertrophic scars was established. LEO (2.5, 5, and 10%) was applied once daily to the scars for 28 days. On postoperative day 56, the scar tissue was excised for masson's trichrome staining, detection of fibroblast apoptosis, assays of the levels of collagens I and III, and analysis of the mRNA expression of matrix metalloproteinase-1 (MMP-1), caspase-3 and -9, and transforming growth factor beta 1 (TGF-β(1)). In addition, the scar elevation index (SEI) was also determined. As a result, LEO treatment significantly alleviated formed hypertrophic scars on rabbit ears. The levels of TGF-β(1), MMP-1, collagen I, and collagen III were evidently decreased, and caspase -3 and -9 levels and apoptosis cells were markedly increased in the scar tissue. SEI was also significantly reduced. Histological findings exhibited significant amelioration of the collagen tissue. These results suggest that LEO possesses the favorable therapeutic effects on formed hypertrophic scars in the rabbit ear model and may be an effective cure for human hypertrophic scars.

In situ hybridization and immunohistochemistry of bone sialoprotein and secreted phosphoprotein 1 (osteopontin) in the developing mouse mandibular condylar cartilage compared with limb bud cartilage

PubMed Central

Shibata, Shunichi; Fukada, Kenji; Suzuki, Shoichi; Ogawa, Takuya; Yamashita, Yasuo

2002-01-01

Mandibular condylar cartilage is often classified as a secondary cartilage, differing from the primary cartilaginous skeleton in its rapid progress from progenitor cells to hypertrophic chondrocytes. In this study we used in situ hybridization and immunohistochemistry to investigate whether the formation of primary (tibial) and secondary (condylar) cartilage also differs with respect to the expression of two major non-collagenous glycoproteins of bone matrix, bone sialoprotein (BSP) and secreted phosphoprotein 1 (Spp1, osteopontin). The mRNAs for both molecules were never expressed until hypertrophic chondrocytes appeared. In the tibial cartilage, hypertrophic chondrocytes first appeared at E14 and the expression of BSP and Spp1 mRNAs was detected in the lower hypertrophic cell zone, but the expression of BSP mRNA was very weak. In the condylar cartilage, hypertrophic chondrocytes appeared at E15 as soon as cartilage tissue appeared. The mRNAs for both molecules were expressed in the newly formed condylar cartilage, although the proteins were not detected by immunostaining; BSP mRNA in the condylar cartilage was more extensively expressed than that in the tibial cartilage at the corresponding stage (first appearance of hypertrophic cell zone). Endochondral bone formation started at E15 in the tibial cartilage and at E16 in the condylar cartilage. At this stage (first appearance of endochondral bone formation), BSP mRNA was also more extensively expressed in the condylar cartilage than in the tibial cartilage. The hypertrophic cell zone in the condylar cartilage rapidly extended during E15–16. These results indicate that the formation process of the mandibular condylar cartilage differs from that of limb bud cartilage with respect to the extensive expression of BSP mRNA and the rapid extension of the hypertrophic cell zone at early stages of cartilage formation. Furthermore, these results support the hypothesis that, in vivo, BSP promotes the initiation of mineralization. PMID:12033735

FGF2 High Molecular Weight Isoforms Contribute to Osteoarthropathy in Male Mice

PubMed Central

Meo Burt, Patience; Xiao, Liping; Dealy, Caroline; Fisher, Melanie C.

2016-01-01

Humans with X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of the disease, develop severe osteoarthropathy and the precise factors that contribute to this joint degeneration remain largely unknown. Fibroblast growth factor 2 (FGF2) is a key regulatory growth factor in osteoarthritis. Although there are multiple FGF2 isoforms the potential involvement of specific FGF2 isoforms in joint degradation has not been investigated. Mice that overexpress the high molecular weight FGF2 isoforms in bone (HMWTg mice) phenocopy Hyp mice and XLH subjects and Hyp mice overexpress the HMWFGF2 isoforms in osteoblasts and osteocytes. Given that Hyp mice and XLH subjects develop osteoarthropathies we examined whether HMWTg mice also develop knee joint degeneration at 2, 8, and 18 mo compared with VectorTg (control) mice. HMWTg mice developed spontaneous osteoarthropathy as early as age 2 mo with thinning of subchondral bone, osteophyte formation, decreased articular cartilage thickness, abnormal mineralization within the joint, increased cartilage degradative enzymes, hypertrophic markers, and angiogenesis. FGF receptors 1 and 3 and fibroblast growth factor 23 were significantly altered compared with VectorTg mice. In addition, gene expression of growth factors and cytokines including bone morphogenetic proteins, Insulin like growth factor 1, Interleukin 1 beta, as well as transcription factors Sex determining region Y box 9, hypoxia inducible factor 1, and nuclear factor kappa B subunit 1 were differentially modulated in HMWTg compared with VectorTg. This study demonstrates that overexpression of the HMW isoforms of FGF2 in bone results in catabolic activity in joint cartilage and bone that leads to osteoarthropathy. PMID:27732085

Alteration of glycine receptor immunoreactivity in the auditory brainstem of mice following three months of exposure to radiofrequency radiation at SAR 4.0 W/kg.

PubMed

Maskey, Dhiraj; Kim, Hyung Gun; Suh, Myung-Whan; Roh, Gu Seob; Kim, Myeung Ju

2014-08-01

The increasing use of mobile communication has triggered an interest in its possible effects on the regulation of neurotransmitter signals. Due to the close proximity of mobile phones to hearing-related brain regions during usage, its use may lead to a decrease in the ability to segregate sounds, leading to serious auditory dysfunction caused by the prolonged exposure to radiofrequency (RF) radiation. The interplay among auditory processing, excitation and inhibitory molecule interactions plays a major role in auditory function. In particular, inhibitory molecules, such a glycine, are predominantly localized in the auditory brainstem. However, the effects of exposure to RF radiation on auditory function have not been reported to date. Thus, the aim of the present study was to investigate the effects of exposure to RF radiation on glycine receptor (GlyR) immunoreactivity (IR) in the auditory brainstem region at 835 MHz with a specific absorption rate of 4.0 W/kg for three months using free-floating immunohistochemistry. Compared with the sham control (SC) group, a significant loss of staining intensity of neuropils and cells in the different subdivisions of the auditory brainstem regions was observed in the mice exposed to RF radiation (E4 group). A decrease in the number of GlyR immunoreactive cells was also noted in the cochlear nuclear complex [anteroventral cochlear nucleus (AVCN), 31.09%; dorsal cochlear nucleus (DCN), 14.08%; posteroventral cochlear nucleus (PVCN), 32.79%] and the superior olivary complex (SOC) [lateral superior olivary nucleus (LSO), 36.85%; superior paraolivary nucleus (SPN), 24.33%, medial superior olivary nucleus (MSO), 23.23%; medial nucleus of the trapezoid body (MNTB), 10.15%] of the mice in the E4 group. Auditory brainstem response (ABR) analysis also revealed a significant threshold elevation of in the exposed (E4) group, which may be associated with auditory dysfunction. The present study suggests that the auditory brainstem region is susceptible to chronic exposure to RF radiation, which may affect the function of the central auditory system.

Oxygen consumption of keloids and hypertrophic scars.

PubMed

Ichioka, Shigeru; Ando, Taichi; Shibata, Masahiro; Sekiya, Naomi; Nakatsuka, Takashi

2008-02-01

The oxygen consumption of keloids and hypertrophic scars has never been quantitatively presented, although abnormal metabolic conditions must be associated with their pathophysiology. We invented an original measurement system equipped with a Clark oxygen electrode for ex vivo samples. The measurement of a mouse wound-healing model revealed immature repairing tissues consumed more oxygen than mature tissues. This finding is in accord with the current thinking and supported the validity of our measurement system. The analysis of fresh human samples clearly demonstrated the high oxygen consumption rate of keloid hypertrophic scars and the comparatively low consumption of mature scars. A high oxygen consuming potential, as well as insufficient oxygen diffusion, may possibly contribute to the pathophysiology of keloids and hypertrophic scars.

Zinc-finger protein 418 overexpression protects against cardiac hypertrophy and fibrosis

PubMed Central

Huang, Zirui; Zhu, Zhilin; Xu, Chunli; Teng, Lin; He, Ling; Gu, Chen; Yi, Cai

2017-01-01

Background This study aimed to investigated the effect and mechanism of zinc-finger protein 418 (ZNF418) on cardiac hypertrophy caused by aortic banding (AB), phenylephrine (PE) or angiotensin II (Ang II) in vivo and in vitro. Methods The expression of ZNF418 in hearts of patients with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) and AB-induced cardiac hypertrophy mice, as well as in Ang II- or PE-induced hypertrophic primary cardiomyocytes was detected by western blotting. Then, the expression of ZNF418 was up-regulated or down-regulated in AB-induced cardiac hypertrophy mice and Ang II -induced hypertrophic primary cardiomyocytes. The hypertrophic responses and fibrosis were evaluated by echocardiography and histological analysis. The mRNA levels of hypertrophy markers and fibrotic markers were detected by RT-qPCR. Furthermore, the phosphorylation and total levels of c-Jun were measured by western blotting. Results ZNF418 was markedly down-regulated in hearts of cardiac hypertrophy and hypertrophic primary cardiomyocytes. Down-regulated ZNF418 exacerbated the myocyte size and fibrosis, moreover increased the mRNA levels of ANP, BNP, β-MHC, MCIP1.4, collagen 1a, collagen III, MMP-2 and fibronection in hearts of AB-treated ZNF418 knockout mice or Ang II-treated cardiomyocytes with AdshZNF418. Conversely, these hypertrophic responses were reduced in the ZNF418 transgenic (TG) mice treated by AB and the AdZNF418-transfected primary cardiomyocytes treated by Ang II. Additionally, the deficiency of ZNF418 enhanced the phosphorylation level of c-jun, and overexpression of ZNF418 suppressed the phosphorylation level of c-jun in vivo and in vitro. Conclusion ZNF418 maybe attenuate hypertrophic responses by inhibiting the activity of c-jun/AP-1. PMID:29065170

Morphologic and Histologic Comparison of Hypertrophic Scar in Nude Mice, T-Cell Receptor, and Recombination Activating Gene Knockout Mice.

PubMed

Momtazi, Moein; Ding, Jie; Kwan, Peter; Anderson, Colin C; Honardoust, Dariush; Goekjian, Serge; Tredget, Edward E

2015-12-01

Proliferative scars in nude mice have demonstrated morphologic and histologic similarities to human hypertrophic scar. Gene knockout technology provides the opportunity to study the effect of deleting immune cells in various disease processes. The authors' objective was to test whether grafting human skin onto T-cell receptor (TCR) αβ-/-γδ-/-, recombination activating gene (RAG)-1-/-, and RAG-2γ-/-c-/- mice results in proliferative scars consistent with human hypertrophic scar and to characterize the morphologic, histologic, and cellular changes that occur after removing immune cells. Nude TCRαβ-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice (n = 20 per strain) were grafted with human skin and euthanized at 30, 60, 120, and 180 days. Controls (n = 5 per strain) were autografted with mouse skin. Scars and normal skin were harvested at each time point. Sections were stained with hematoxylin and eosin, Masson's trichrome, and immunohistochemistry for anti-human leukocyte antigen-ABC, α-smooth muscle actin, decorin, and biglycan. TCRαβ-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice grafted with human skin developed firm, elevated scars with histologic and immunohistochemical similarities to human hypertrophic scar. Autografted controls showed no evidence of pathologic scarring. Knockout animals demonstrated a capacity for scar remodeling not observed in nude mice where reductions in α-smooth muscle actin staining pattern and scar thickness occurred over time. Human skin transplanted onto TCRαβ-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice results in proliferative scars with morphologic and histologic features of human hypertrophic scar. Remodeling of proliferative scars generated in knockout animals is analogous to changes in human hypertrophic scar. These animal models may better represent the natural history of human hypertrophic scar.

The rare association of tetralogy of Fallot with hypertrophic cardiomyopathy. Report of 2 neonatal patients.

PubMed Central

Lewin, M B; Towbin, J A; Thapar, M K; Dreyer, W J; Feltes, T F

1997-01-01

Although tetralogy of Fallot is commonly associated with other congenital heart defects, it is rarely found in conjunction with hypertrophic cardiomyopathy. We describe the cases of 2 neonates with this rare condition, both of whom required surgical intervention during infancy. Because hypertrophic cardiomyopathy is frequently familial, and tetralogy of Fallot is commonly found in patients diagnosed with chromosomal anomalies, we speculate about a possible genetic cause for this association. PMID:9339511

Effect of HMME-PDT with different parameters in rabbit ear model: a possible way for hypertrophic scarring

NASA Astrophysics Data System (ADS)

Cai, Hong; Gu, Ying; Zeng, Jing; Li, Shao-ran; Sun, Qiang; Wang, Ying; Shi, Dong-wen; Zhang, Lu-yong

2007-11-01

Background and Objective: Hypertrophic scar is a pathological scar that grows aberrantly by excessive deposition of collagens in the dermis. It is known that photodynamic therapy (PDT) contributes to a variety of diseases, however, the use of inhibiting scar formation has not been fully explored. The purpose of this study is to investigate the effect of HMME-PDT (Photodynamic therapy induced by Hematoporphyrin Monomethyl Ether) with different parameters on hypertrophic scar in rabbit ear. Materials and Methods: After the placement of 7-mm diameter dermal wounds on each ear, the acute model of dermal hypertrophic scar in the New Zealand white rabbits was established. Scar wounds were randomly separated into 2 groups: the experimental group received HMME-PDT with different parameters, and the control group received no special treatment. Specimens were harvested from scar wounds on postoperative day 28. Scar and hypertrophic index (HI) were observed by haematoxylin-eosin staining. Results: Compared with the control group, scar formation was inhibited by HMME-PDT in the experimental group with parameters as follows: photosensitizer dose 10mg/kg, power density 20mw/cm2, fluence 5J/cm2, meanwhile, HI was decreased significantly. Conclusion: HMME-PDT may play a role in inhibiting hypertrophic scarring in rabbit ear. The biological effect is determined by the dose of photosensitizer, interval between the injection of photosensitizer and irradiation, power density and energy fluence.

Variations in gap junctional intercellular communication and connexin expression in fibroblasts derived from keloid and hypertrophic scars.

PubMed

Lu, Feng; Gao, JianHua; Ogawa, Rei; Hyakusoku, Hiko

2007-03-01

Expression of connexins and other constituent proteins of gap junctions along with gap junctional intercellular communication are involved in cellular development and differentiation processes. In addition, an increasing number of hereditary skin disorders appear to be linked to connexins. Therefore, in this report, the authors studied in vitro gap junctional intercellular communication function and connexin expression in fibroblasts derived from keloid and hypertrophic scar patients. Fibroblasts harvested from each of six keloid and hypertrophic scar patients were used for this study. Gap junctional intercellular communication function was investigated using the gap fluorescence recovery after photobleaching method, and expression of connexin proteins was studied using quantitative confocal microscopic analyses. Compared with normal skin, a decreased level of gap junctional intercellular communication was seen in fibroblasts derived from hypertrophic scar tissue, whereas an extremely low gap junctional intercellular communication level was detected in fibroblasts derived from keloid tissue. We also detected little connexin 43 (Cx43) protein localized in fibroblasts derived from keloids. Moreover, Cx43 protein levels were much lower in fibroblasts derived from hypertrophic scars than in those derived from normal skin. The authors' data suggest that the loss of gap junctional intercellular communication and connexin expression may affect intercellular recognition and thus break the proliferation and apoptosis balance in fibroblasts derived from keloid and hypertrophic scar tissue.

Ablative fractional laser treatment for hypertrophic scars: comparison between Er:YAG and CO2 fractional lasers.

PubMed

Choi, Jae Eun; Oh, Ga Na; Kim, Jong Yeob; Seo, Soo Hong; Ahn, Hyo Hyun; Kye, Young Chul

2014-08-01

Nonablative fractional photothermolysis has been reported to show early promise in the treatment of hypertrophic scars, but there are few reports on ablative fractional photothermolysis for the treatment of hypertrophic scars. To evaluate and compare the efficacy and safety of Er:YAG fractional laser (EYFL) and CO2 fractional laser (CO2FL) for treatment of hypertrophic scars. Thirteen patients with hypertrophic scars were treated with 2,940 nm EYFL, and ten were treated with 10,600 nm CO2FL. An independent physician evaluator assessed the treatment outcomes using Vancouver scar scale (VSS) and 5-point grading scale (grade 0, no improvement; grade 1, 1-25%; grade 2, 26-50%; grade 3, 51-75%; grade 4, 76-100% improvement). Patients are queried about their subjective satisfaction with the treatment outcomes. After the final treatment, average percentage changes of VSS were 28.2% for EYFL and 49.8% for CO2FL. Improvement was evident in terms of pliability, while insignificant in terms of vascularity and pigmentation. Based on physician's global assessment, mean grade of 1.8 for EYFL and 2.7 for CO2FL was achieved. Patient's subjective satisfaction scores paralleled the physician's objective evaluation. CO2FL is a potentially effective and safe modality for the treatment of hypertrophic scars, particularly in terms of pliability.

Auditory Spatial Perception: Auditory Localization

DTIC Science & Technology

2012-05-01

cochlear nucleus, TB – trapezoid body, SOC – superior olivary complex, LL – lateral lemniscus, IC – inferior colliculus. Adapted from Aharonson and...Figure 5. Auditory pathways in the central nervous system. LE – left ear, RE – right ear, AN – auditory nerve, CN – cochlear nucleus, TB...fibers leaving the left and right inner ear connect directly to the synaptic inputs of the cochlear nucleus (CN) on the same (ipsilateral) side of

The etiology of essential tremor: Genes versus environment.

PubMed

Hopfner, Franziska; Helmich, Rick C

2018-01-01

Essential tremor (ET) is characterized by bilateral upper limb action tremor. Here we review the pathophysiology (cerebral mechanisms) and etiology (genetic and environmental risk factors) of ET. We reviewed the literature (until June 2017) by searching PubMed for relevant papers. The pathophysiology of ET involves oscillatory activity in the cortico-olivo-cerebello-thalamic circuit, evidenced by electrophysiological and metabolic imaging. Possible underlying mechanisms include GABA-ergic dysfunction, cerebellar neurodegeneration, olivary dysfunction, or a combination. Genetic studies have examined affected ET families (linkage studies and whole-exome sequencing studies). These studies revealed several chromosomal regions and genes associated with ET, but the findings have not been replicated across different ET families. Genetic studies also assessed the sporadic occurrence of ET using genome wide genotyping of single nucleotide polymorphisms (SNP's) and candidate gene studies. Several SNP's are associated with ET, and this has been replicated across different cohorts. Interestingly, some of the involved genes are linked to the cerebellum and inferior olive. Environmental studies point to an association between ET and beta-carboline alkaloids (such as harmane), which have been found in the cerebellum. Genetic and environmental risk factors may influence cerebellar and/or olivary function, resulting in abnormal cortico-olivo-cerebello-thalamic activity, and ultimately ET. Copyright © 2017 Elsevier Ltd. All rights reserved.

Embryonic Origins of the Mouse Superior Olivary Complex

PubMed Central

Howell, David M.; Spirou, George A.; Mathers, Peter H.

2014-01-01

Many areas of the central nervous system are organized into clusters of cell groups, with component cell groups exhibiting diverse but related functions. One such cluster, the superior olivary complex (SOC), is located in the ventral auditory brainstem in mammals. The SOC is an obligatory contact point for most projection neurons of the ventral cochlear nucleus and plays central roles in many aspects of monaural and binaural information processing. Despite their important interrelated functions, little is known about the embryonic origins of SOC nuclei, due in part to a paucity of developmental markers to distinguish individual cell groups. In this report, we present a collection of novel markers for the developing SOC nuclei in mice, including the transcription factors FoxP1, MafB, and Sox2, and the lineage-marking transgenic line En1-Cre. We use these definitive markers to examine the rhombic lip and rhombomeric origins of SOC nuclei and demonstrate that they can serve to uniquely identify SOC nuclei and subnuclei in newborn pups. The markers are also useful in identifying distinct nuclear domains within the presumptive SOC as early as embryonic day (E) 14.5, well before morphological distinction of individual nuclei is evident. These findings indicate that the mediolateral and dorsoventral position of SOC nuclei characteristic of the adult brainstem is established during early neurogenesis. PMID:23303740

Extracorporeal shock wave therapy with low-energy flux density inhibits hypertrophic scar formation in an animal model.

PubMed

Zhao, Jing-Chun; Zhang, Bo-Ru; Hong, Lei; Shi, Kai; Wu, Wei-Wei; Yu, Jia-Ao

2018-04-01

Hypertrophic scar is characterized by excessive deposits of collagen during skin wound healing, which could become a challenge to clinicians. This study assessed the effects of the extracorporeal shock wave therapy (ESWT) on hypertrophic scar formation and the underlying gene regu-lation. A rabbit ear hypertrophic scar model was generated and randomly divided into three groups: L-ESWT group to receive L-ESWT (energy flux density of 0.1 mJ/mm2), H-ESWT (energy flux density of 0.2 mJ/mm2) and sham ESWT group (S-ESWT). Hypertrophic scar tissues were then collected and stained with hematoxylin and eosin (H&E) and Masson's trichrome staining, respectively, to assess scar elevation index (SEI), fibroblast density and collagen fiber arrangement. Expression of cell proliferation marker proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were assessed using RT-PCR and immunohistochemistry in hypertrophic scar tissues. H&E staining sections showed significant reduction of SEI and fibroblast density in both ESWT treatment groups compared to S-ESWT, but there was no dramatic difference between L-ESWT and H-ESWT groups. Masson's trichrome staining showed that collagen fibers were more slender and broader and oriented in parallel to skin surface after administration of ESWT compared to control tissues. At the gene level, PCNA‑positive fibroblasts and α-SMA-positive myofibroblasts were significantly decreased after L-ESWT or H-ESWT compared to the controls. Furthermore, there was no significant difference in expression of PCNA mRNA between L-ESWT or H-ESWT and S-ESWT, whereas expression of α-SMA mRNA significantly decreased in L-ESWT compared to that of H-ESWT and S-ESWT (P=0.002 and P=0.030, respectively). In conclusion, L-ESWT could be effective on suppression of hypertrophic scar formation by inhibition of scar elevation index and fibroblast density as well as α-SMA expression in hypertrophic scar tissues of the rabbit model.

Association between ventricular filling patterns and the extent of late enhancement on magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

PubMed

De Zan, M; Carrascosa, P; Deviggiano, A; Capunay, C; Rodríguez-Granillo, G A

To explore the relationship between ventricular filling curves and the extent of late enhancement on cardiac magnetic resonance imaging (MRI) in patients with hypertrophic cardiomyopathy. We retrospectively included consecutive patients with suspected and/or confirmed hypertrophic cardiomyopathy and a control group of patients matched for age and sex who underwent cardiac MRI with evaluation of late enhancement. Among other determinations, we evaluated the following parameters on cine sequences: peak filling rate, time to the first peak filling rate, and filling rate normalized to the filling volume. Late enhancement was observed in 29 (73%) of the 40 patients with hypertrophic cardiomyopathy. The normalized peak filling rate was significantly lower in patients with late enhancement (4.9 ± 1.6 in those with hypertrophic cardiomyopathy positive for late enhancement vs. 5.8 ± 2.2 in those with hypertrophic cardiomyopathy negative for late enhancement vs. 6.3 ± 1.5 in controls, p = 0.008) and the time to peak filling was longer in patients with late enhancement (540.6 ± 89.7 ms vs. 505.5 ± 99.3 ms in those with hypertrophic cardiomyopathy negative for late enhancement vs. 486.9 ± 86.3 ms in controls, p = 0.02). When the population was stratified into three groups in function of the normalized peak filling rate, significant differences were observed among groups for age (p = 0.002), mean wall thickness (p = 0.036), and myocardial mass (p = 0.046) and atrial dimensions, whereas no significant differences with respect to late enhancement were seen. In patients with hypertrophic cardiomyopathy, we found a significant association between ventricular filling patterns and age, wall thicknesses, and atrial dimensions, but not with the extent of late enhancement. Copyright © 2016 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis.

PubMed

Ogawa, Rei

2017-03-10

Keloids and hypertrophic scars are caused by cutaneous injury and irritation, including trauma, insect bite, burn, surgery, vaccination, skin piercing, acne, folliculitis, chicken pox, and herpes zoster infection. Notably, superficial injuries that do not reach the reticular dermis never cause keloidal and hypertrophic scarring. This suggests that these pathological scars are due to injury to this skin layer and the subsequent aberrant wound healing therein. The latter is characterized by continuous and histologically localized inflammation. As a result, the reticular layer of keloids and hypertrophic scars contains inflammatory cells, increased numbers of fibroblasts, newly formed blood vessels, and collagen deposits. Moreover, proinflammatory factors, such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α are upregulated in keloid tissues, which suggests that, in patients with keloids, proinflammatory genes in the skin are sensitive to trauma. This may promote chronic inflammation, which in turn may cause the invasive growth of keloids. In addition, the upregulation of proinflammatory factors in pathological scars suggests that, rather than being skin tumors, keloids and hypertrophic scars are inflammatory disorders of skin, specifically inflammatory disorders of the reticular dermis. Various external and internal post-wounding stimuli may promote reticular inflammation. The nature of these stimuli most likely shapes the characteristics, quantity, and course of keloids and hypertrophic scars. Specifically, it is likely that the intensity, frequency, and duration of these stimuli determine how quickly the scars appear, the direction and speed of growth, and the intensity of symptoms. These proinflammatory stimuli include a variety of local, systemic, and genetic factors. These observations together suggest that the clinical differences between keloids and hypertrophic scars merely reflect differences in the intensity, frequency, and duration of the inflammation of the reticular dermis. At present, physicians cannot (or at least find it very difficult to) control systemic and genetic risk factors of keloids and hypertrophic scars. However, they can use a number of treatment modalities that all, interestingly, act by reducing inflammation. They include corticosteroid injection/tape/ointment, radiotherapy, cryotherapy, compression therapy, stabilization therapy, 5-fluorouracil (5-FU) therapy, and surgical methods that reduce skin tension.

[Hypertrophic cardiomyopathy: an intraoperative death case analysis and substantiation of the standards of perioperative anesthetic management in a non-cardiosurgery clinic].

PubMed

Fedosiuk, Roman N; Shchupachynska, Liliia O

2018-01-01

The article is based on the case analysis of a sudden and unexpected intraoperative death of a 51-year-old female patient with hypertrophic cardiomyopathy, who was undergoing a non-cardiac operation in a non-cardiosurgery clinic, from acute precipitation of left ventricular outflow tract obstruction provoked by surgery and anesthesia. It emphasizes the importance of raising non-cardiac anesthesiologists' awareness of the issue and having clear standards of pre-operative evaluation and perioperative management of patients with hypertrophic cardiomyopathy in order to avoid fatal medical errors. A literature review on the disease with an accent on anesthesia-related issues is also given, and four standards of perioperative anesthetic management of patients with hypertrophic cardiomyopathy presenting for non-cardiac surgery in general hospital settings are developed and offered.

[Scarlet fever with multisystem organ failure and hypertrophic gastritis].

PubMed

Sandrini, J; Beucher, A-B; Kouatchet, A; Lavigne, C

2009-05-01

Scarlet fever is a rare disease in adult patients. We report a patient in whom scarlet fever was associated with hypertrophic gastritis and multiple organ failure. A 62-year-old woman presented with septic shock and multiple organ failure. Bacteriological survey was negative. Abdominal tomodensitometry showed an hypertrophic gastritis. Histological analysis demonstrated a non specific gastritis without any tumoral sign. Cefotaxime and amoxicillin led to improvement and hypertrophic gastritis progressively resolved. A sandpaper rash over the body with finger desquamation, elevation of antistreptolysin O and a recent contact with an infected grandson led to the diagnosis of scarlet fever. Due to antibiotic prescription, scarlet fever is now uncommon. Although classical, ENT or gastroenteritis presentations may be puzzling for the diagnosis of scarlet fever. As 150 years ago, diagnosis of scarlet fever is still a clinical challenge.

Delayed-enhanced cardiac MRI for differentiation of Fabry's disease from symmetric hypertrophic cardiomyopathy.

PubMed

De Cobelli, Francesco; Esposito, Antonio; Belloni, Elena; Pieroni, Maurizio; Perseghin, Gianluca; Chimenti, Cristina; Frustaci, Andrea; Del Maschio, Alessandro

2009-03-01

Fabry's disease may be difficult to differentiate from symmetric hypertrophic cardiomyopathy. Our aim was to compare the myocardial location and distribution patterns of delayed enhancement between patients with Fabry's disease who are affected by symmetric myocardial hypertrophy and patients with symmetric hypertrophic cardiomyopathy in order to identify a specific sign to best differentiate the two diseases. Patients with Fabry's disease-related hypertrophy showed left ventricular (LV) delayed enhancement with a typical and consistently found pattern characterized by the involvement of the inferolateral basal or mid basal segments and a mesocardial distribution that spared the subendocardium. This pattern seems to be specific to Fabry's disease; in fact, patients with symmetric hypertrophic cardiomyopathy had variable locations and distributions of delayed enhancement. These observations may contribute to identifying Fabry's disease as a specific cause of symmetric hypertrophy.

The presence of lysylpyridinoline in the hypertrophic cartilage of newly hatched chicks

NASA Technical Reports Server (NTRS)

Orth, M. W.; Martinez, D. A.; Cook, M. E.; Vailas, A. C.

1993-01-01

The presence of lysylpyridinoline (LP) as a nonreducible cross-link in appreciable quantities has primarily been limited to the mineralized tissues, bone and dentin. However, the results reported here show that LP is not only present in the hypertrophic cartilage of the tibiotarsus isolated from newly hatched broiler chicks, but it is approx. 4-fold as concentrated as hydroxylysylpyridinoline (HP). Bone and articular cartilage surrounding the hypertrophic cartilage do not contain measurable quantities of LP. Purified LP has a fluorescent scan similar to purified HP and literature values, confirming that we indeed were measuring LP. Also, the cartilage lesion produced by immature chondrocytes from birds with tibial dyschondroplasia had LP but the HP:LP ratio was > 1. Thus, the low HP:LP ratio could be a marker for hypertrophic cartilage in avians.

Effect of botulinum toxin type A on transforming growth factor beta1 in fibroblasts derived from hypertrophic scar: a preliminary report.

PubMed

Xiao, Zhibo; Zhang, Fengmin; Lin, Weibin; Zhang, Miaobo; Liu, Ying

2010-08-01

Hypertrophic scar is a common dermal disease. Numerous treatments are currently available but they do not always yield excellent therapeutic results. Hence, alternatives are needed. Recent basic and clinical research has shown that botulinum toxin type A (BTXA) has antihypertrophic scar properties but the molecular mechanism for this action is unknown. The aim of this study was to explore the effect of BTXA on transforming growth factor beta1 (TGF-beta1) in fibroblasts derived from hypertrophic scar and further elucidate its actual mechanism. Fibroblasts were isolated from tissue specimens of hypertrophic scar. Fibroblasts were treated with BTXA and the difference in proliferation between treated and nontreated cells was analyzed through the MTT method from the first to the fifth day after treatment. Proteins of TGF-beta1 were checked using ELISA in fibroblasts with BTXA and without BTXA from the first to the fifth day. The growth of the fibroblast treated with BTXA was obviously slower than that of the fibroblast without BTXA treatment (p < 0.01), which showed that BTXA effectively inhibited the growth of fibroblasts. Proteins of TGF-beta1 between fibroblasts with BTXA and fibroblasts without BTXA are statistically significant (p < 0.01). These results suggest that BTXA effectively inhibited the growth of fibroblasts derived from hypertrophic scar and in turn caused a decrease in TGF-beta1 protein, indicating that BTXA-based therapies for hypertrophic scar are promising and worth investigating further.

[Wound healing is still a game of " blind men and an elephant"].

PubMed

Han, C M

2016-10-20

The wound healing includes non-healing and overhealing of the wounds. The results of wound healing are well known by people such as non-healing of the diabetic ulcer or hypertrophic scar after deep burn. In this issue, three papers involve in wound healing, one about autologous adipose-derived mesenchymal stem cells injected into wound or scar of rabbit ear, one about severe hypoxia and hypoalbuminemia inducing human hypertrophic scar derived fibroblast apoptosis in vitro, and another about the dysfunction of protein kinase B/mammalian target of rapamycin signaling pathway contributing to the pathophysiological characteristics of diabetic skin and non-healing wound. The basic problem of hypertrophic scar study is lacking an ideal animal model. Although rabbit ear model or red Duroc pig model has been used widely for study on hypertrophic scar, they can not fully represent human dermal fibrosis after deep trauma on the skin. I recommend A novel nude mouse model of hypertrophic scarring using scratched full thickness human skin grafts recently published in Advances in Wound Care to the readers. The author emphasizes that the wound healing study is still in the situation like the game of " blind men and an elephant" .

Enhanced in Vivo Delivery of 5-Fluorouracil by Ethosomal Gels in Rabbit Ear Hypertrophic Scar Model

PubMed Central

Wo, Yan; Zhang, Zheng; Zhang, Yixin; Zhang, Zhen; Wang, Kan; Mao, Xiaohui; Su, Weijie; Li, Ke; Cui, Daxiang; Chen, Jun

2014-01-01

Applying Ethosomal Gels (EGs) in transdermal drug delivery systems has evoked considerable interest because of their good water-solubility and biocompatibility. However, there has not been an explicit description of applying EGs as a vehicle for hypertrophic scars treatment. Here, a novel transdermal EGs loaded with 5-fluorouracil (5-FU EGs) was successfully prepared and characterized. The stability assay in vitro revealed that 5-FU EGs stored for a period of 30 days at 4 ± 1 °C had a better size stability than that at 25 ± 1 °C. Furthermore, using confocal laser scanning microscopy, EGs labeled with Rhodamine 6 G penetrated into the deep dermis of the hypertrophic scar within 24 h in the rabbit ear hypertrophic model suggested that the EGs were an optional delivery carrier through scar tissues. In addition, the value of the Scar Elevation Index (SEI) of 5-FU EGs group in the rabbit ear scar model was lower than that of 5-FU Phosphate Buffered Saline gel and Control groups. To conclude, these results suggest that EGs delivery system loaded 5-fluorouracil is a perfect candidate drug for hypertrophic scars therapy in future. PMID:25501333

The Metabolome in Finnish Carriers of the MYBPC3-Q1061X Mutation for Hypertrophic Cardiomyopathy.

PubMed

Jørgenrud, Benedicte; Jalanko, Mikko; Heliö, Tiina; Jääskeläinen, Pertti; Laine, Mika; Hilvo, Mika; Nieminen, Markku S; Laakso, Markku; Hyötyläinen, Tuulia; Orešič, Matej; Kuusisto, Johanna

2015-01-01

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the metabolome to the echocardiographic parameters. 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation. Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle.

Genetics Home Reference: familial hypertrophic cardiomyopathy

MedlinePlus

... Savithri GR, Kumar MS, Narasimhan C, Nallari P. Molecular genetics of familial hypertrophic cardiomyopathy (FHC). J Hum Genet. ... 5(11):747. Citation on PubMed Kimura A. Molecular genetics and pathogenesis of cardiomyopathy. J Hum Genet. 2016 ...

Techniques for Optimizing Surgical Scars, Part 2: Hypertrophic Scars and Keloids.

PubMed

Potter, Kathryn; Konda, Sailesh; Ren, Vicky Zhen; Wang, Apphia Lihan; Srinivasan, Aditya; Chilukuri, Suneel

2017-01-01

Surgical management of benign or malignant cutaneous tumors may result in noticeable scars that are of great concern to patients, regardless of sex, age, or ethnicity. Techniques to optimize surgical scars are discussed in this three-part review. Part 2 focuses on scar revision for hypertrophic and keloids scars. Scar revision options for hypertrophic and keloid scars include corticosteroids, bleomycin, fluorouracil, verapamil, avotermin, hydrogel scaffold, nonablative fractional lasers, ablative and fractional ablative lasers, pulsed dye laser (PDL), flurandrenolide tape, imiquimod, onion extract, silicone, and scar massage.

Retinal projections in the short-tailed fruit bat, Carollia perspicillata, as studied using the axonal transport of cholera toxin B subunit: Comparison with mouse.

PubMed

Scalia, Frank; Rasweiler, John J; Danias, John

2015-08-15

To provide a modern description of the Chiropteran visual system, the subcortical retinal projections were studied in the short-tailed fruit bat, Carollia perspicillata, using the anterograde transport of eye-injected cholera toxin B subunit, supplemented by the silver-impregnation of anterograde degeneration following eye removal, and compared with the retinal projections of the mouse. The retinal projections were heavily labeled by the transported toxin in both species. Almost all components of the murine retinal projection are present in Carollia in varying degrees of prominence and laterality. The projections: to the superior colliculus, accessory optic nuclei, and nucleus of the optic tract are predominantly or exclusively contralateral; to the dorsal lateral geniculate nucleus and posterior pretectal nucleus are predominantly contralateral; to the ventral lateral geniculate nucleus, intergeniculate leaflet, and olivary pretectal nucleus have a substantial ipsilateral component; and to the suprachiasmatic nucleus are symmetrically bilateral. The retinal projection in Carollia is surprisingly reduced at the anterior end of the dorsal lateral geniculate and superior colliculus, suggestive of a paucity of the relevant ganglion cells in the ventrotemporal retina. In the superior colliculus, in which the superficial gray layer is very thin, the projection is patchy in places where the layer is locally absent. Except for a posteriorly located lateral terminal nucleus, the other accessory optic nuclei are diminutive in Carollia, as is the nucleus of the optic tract. In both species the cholera toxin labeled sparse groups of apparently terminating axons in numerous regions not listed above. A question of their significance is discussed. © 2015 Wiley Periodicals, Inc.

Echocardiography Differences Between Athlete's Heart Hearth and Hypertrophic Cardiomyopathy.

PubMed

Kreso, Amir; Barakovic, Fahir; Medjedovic, Senad; Halilbasic, Amila; Klepic, Muhamed

2015-10-01

Among long term athletes there is always present hypertrophy of the left ventricle walls as well as increased cardiac mass. These changes are the result of the heart muscle adaptation to load during the years of training, which should not be considered as pathology. In people suffering from hypertrophic cardiomyopathy (HCM), there is also present hypertrophy of the left ventricle walls and increased mass of the heart, but these changes are the result of pathological changes in the heart caused by a genetic predisposition for the development HCM of. Differences between myocardial hypertrophy in athletes and HCM are not clearly differentiated and there are always dilemmas between pathological and physiological hypertrophy. The goal of the study is to determine and compare the echocardiographic cardiac parameters of longtime athletes to patients with hypertrophic cardiomyopathy. The study included 60 subjects divided into two groups: active athletes and people with hypertrophic cardiomyopathy. Mean values of IVSd recorded in GB is IVSd=17.5 mm (n=20, 95% CI, 16.00-19.00 mm), while a significantly smaller mean value is recorded in GA, IVSd=10.0 mm (n=40, 95% CI, 9.00-11.00 mm). The mean value of the left ventricle in diastole (LVDd) recorded in the GA is LVDd=51 mm (n=40; 95% CI, 48.00 to 52.00 mm), while in the group with hypertrophic cardiomyopathy (GB) mean LVDd value is 42 mm (n=20; 95% CI, 40.00 to 48.00 mm). The mean value of the rear wall of the left ventricle (LVPWd) recorded in the GA is LVDd=10 mm (n=40; 95% CI, 9.00-10.00 mm) while in the group with hypertrophic cardiomyopathy (GB) mean LVDd is 14 mm (n=20; 95% CI, 12.00 to 16.00 mm). The mean of the left ventricle during systole (LVSD) observed in GA is LVSD=34 mm (n=40; 95% CI, 32.00 to 36.00 mm), while in the group with hypertrophic cardiomyopathy (GB) mean LVSD is 28 mm (n=20; 95% CI, 24.00 to 28.83 mm). The mean ejection fraction (EF%) observed in GA is EF=60% (n=40; 95% CI, 56.41 to 63.00%), while in the group with hypertrophic cardiomyopathy (GB) mean EF value is 69% (n=20; 95% CI, 62.00 to 70.83 mm). Somewhat higher mean diastolic left ventricular function (E/A) was observed in GA, E/A=1.76±0.15, and lower average values in the group with hypertrophic cardiomyopathy: (GB) E/A=0.78±0.02. Mean values of parameters intraventricular septum thickness in diastole (IVSd), the thickness of the rear wall of the left ventricle (LVPWd), the diameter of the left ventricle during systole (LVSD) were statistically different between groups of athletes (GA) compared to the group of patients with hypertrophic cardiomyopathy (GB).

Developing a Mouse Model of Sensory and Cognitive Deficits for Multiple Sclerosis

DTIC Science & Technology

2012-07-01

ABRs and otoacoustic emissions. More sophisticates measures, such as neural processing of binaural responses are typically performed in rats, guinea...ears we are able to calculate the binaural component of the EEGs for comparison of wild type and Claudin 11 knockout responses. We are awaiting the...knockout of the Claudin 11 gene. 2. Development of a novel anesthesia protocol to measure binaural auditory signals in the superior olivary complex of

Scar massage for hypertrophic burns scarring-A systematic review.

PubMed

Ault, P; Plaza, A; Paratz, J

2018-02-01

Scar massage is used in burn units globally to improve functional and cosmetic outcomes of hypertrophic scarring following a burn, however, the evidence to support this therapy is unknown. To review the literature and assess the efficacy of scar massage in hypertrophic burn scars. MEDLINE, PubMed, Embase, CINAHL and the Cochrane Library were searched using the key words "burn", "burn injury", "thermal injury" and "scar", "hypertrophic scar" and "massage", "manipulation", "soft tissue mobilisation", "soft tissue manipulation". The articles were scored by the assessors using the Physiotherapy Evidence Database (PEDro) scale and outcome measures on range of motion (ROM), cosmesis (vascularity, pliability, height), pain scores, pruritus, and psychological measures of depression and anxiety were extracted. Eight publications were included in the review with 258 human participants and 15 animal subjects who received scar massage following a thermal injury resulting in hypertrophic scarring. Outcome measures that demonstrated that scar massage was effective included scar thickness as measured with ultrasonography (p=0.001; g=-0.512); depression (Centre for Epidemiologic Studies - Depression [CES-D]) (p=0.031; g=-0.555); pain as measured with Visual Analogue Scale (VAS) (p=0.000; g=-1.133) and scar characteristics including vascularity (p=0.000; g=-1.837), pliability (p=0.000; g=-1.270) and scar height (p=0.000; g=-2.054). Outcome measures that trended towards significance included a decrease in pruritus (p=0.095; g=-1.157). It appears that there is preliminary evidence to suggest that scar massage may be effective to decrease scar height, vascularity, pliability, pain, pruritus and depression in hypertrophic burns scaring. This review reflects the poor quality of evidence and lack of consistent and valid scar assessment tools. Controlled, clinical trials are needed to develop evidence-based guidelines for scar massage in hypertrophic burns scarring. Copyright © 2017 Elsevier Ltd and ISBI. All rights reserved.

The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APP(SW) mice.

PubMed

Wegiel, J; Wang, K C; Imaki, H; Rubenstein, R; Wronska, A; Osuchowski, M; Lipinski, W J; Walker, L C; LeVine, H

2001-01-01

Ultrastructural reconstruction of 27 fibrillar plaques in different stages of formation and maturation was undertaken to characterize the development of fibrillar plaques in the brains of human APP(SW) transgenic mice (Tg2576). The study suggests that microglial cells are not engaged in Abeta removal and plaque degradation, but in contrast, are a driving force in plaque formation and development. Fibrillar Abeta deposition at the amyloid pole of microglial cells appears to initiate three types of neuropil response: degeneration of neurons, protective activation of astrocytes, and attraction and activation of microglial cells sustaining plaque growth. Enlargement of neuronal processes and synapses with accumulation of degenerated mitochondria, dense bodies, and Hirano-type bodies is the marker of toxic injury of neurons by fibrillar Abeta. Separation of amyloid cores from neurons and degradation of amyloid cores by cytoplasmic processes of hypertrophic astrocytes suggest the protective and defensive character of astrocytic response to fibrillar Abeta. The growth of cored plaque from a small plaque with one microglial cell with an amyloid star and a few dystrophic neurites to a large plaque formed by several dozen microglial cells seen in old mice is the effect of attraction and activation of microglial cells residing outside of the plaque perimeter. This mechanism of growth of plaques appears to be characteristic of cored plaques in transgenic mice. Other features in mouse microglial cells that are absent in human brain are clusters of vacuoles, probably of lysosomal origin. They evolve into circular cisternae and finally into large vacuoles filled with osmiophilic, amorphous material and bundles of fibrils that are poorly labeled with antibody to Abeta. Microglial cells appear to release large amounts of fibrillar Abeta and accumulate traces of fibrillar Abeta in a lysosomal pathway.

Hypertrophic scarring: the greatest unmet challenge following burn injury

PubMed Central

Finnerty, Celeste C; Jeschke, Marc G; Branski, Ludwik K; Barret, Juan P.; Dziewulski, Peter; Herndon, David N

2017-01-01

Summary Improvements in acute burn care have enabled patients to survive massive burns which would have once been fatal. Now up to 70% of patients develop hypertrophic scars following burns. The functional and psychosocial sequelae remain a major rehabilitative challenge, decreasing quality of life and delaying reintegration into society. The current approach is to optimise the healing potential of the burn wound using targeted wound care and surgery in order to minimise the development of hypertrophic scarring. This approach often fails, and modulation of established scar is continued although the optimal indication, timing, and combination of therapies have yet to be established. The need for novel treatments is paramount, and future efforts to improve outcomes and quality of life should include optimisation of wound healing to attenuate or prevent hypertrophic scarring, well-designed trials to confirm treatment efficacy, and further elucidation of molecular mechanisms to allow development of new preventative and therapeutic strategies. PMID:27707499

Comparative effect of topical silicone gel and topical tretinoin cream for the prevention of hypertrophic scar and keloid formation and the improvement of scars.

PubMed

Kwon, S Y; Park, S D; Park, K

2014-08-01

Numerous modalities have been used to treat keloids and hypertrophic scars; however, optimal treatment has not yet been established. Therefore, prevention is the mainstay. Recently, silicone gel and tretinoin cream have been shown to be useful for the prevention of hypertrophic scars and keloids. However, there has been no comparative study of the two topical agents thus far. To determine and compare the effectiveness of silicone gel and tretinoin cream for the prevention of hypertrophic scars and keloids resulting from postoperative wounds and for scar improvement. This study included 26 patients with 44 different wounds. The postoperative wounds were divided into two treatment groups and one control group. The patients in the first and second treatment group applied silicone gel and tretinoin cream, respectively, twice a day on their wounds after their stitches were removed. In contrast, the control group patients did not apply anything. We used the Modified Vancouver Scar Scale to quantitatively examine the effectiveness of silicone gel and tretinoin cream just after stitches removal, and at 4, 8, 12 and 24 weeks after removal of the stitches. The silicone gel and tretinoin cream effectively prevented hypertrophic scars and keloids and improved scar effects in the two treatment groups compared with those in the control group. However, no significant difference was noted between the two treatment groups. To prevent hypertrophic scars and keloids and improve scars after surgery, application of a silicone gel or a tretinoin cream to the wounds is needed. © 2013 European Academy of Dermatology and Venereology.

The histone acetyltransferase MOF overexpression blunts cardiac hypertrophy by targeting ROS in mice.

PubMed

Qiao, Weiwei; Zhang, Weili; Gai, Yusheng; Zhao, Lan; Fan, Juexin

2014-06-13

Imbalance between histone acetylation/deacetylation critically participates in the expression of hypertrophic fetal genes and development of cardiac hypertrophy. While histone deacetylases play dual roles in hypertrophy, current evidence reveals that histone acetyltransferase such as p300 and PCAF act as pro-hypertrophic factors. However, it remains elusive whether some histone acetyltransferases can prevent the development of hypertrophy. Males absent on the first (MOF) is a histone acetyltransferase belonging to the MYST (MOZ, Ybf2/Sas3, Sas2 and TIP60) family. Here in this study, we reported that MOF expression was down-regulated in failing human hearts and hypertrophic murine hearts at protein and mRNA levels. To evaluate the roles of MOF in cardiac hypertrophy, we generated cardiac-specific MOF transgenic mice. MOF transgenic mice did not show any differences from their wide-type littermates at baseline. However, cardiac-specific MOF overexpression protected mice from transverse aortic constriction (TAC)-induced cardiac hypertrophy, with reduced radios of heart weight (HW)/body weight (BW), lung weight/BW and HW/tibia length, decreased left ventricular wall thickness and increased fractional shortening. We also observed lower expression of hypertrophic fetal genes in TAC-challenged MOF transgenic mice compared with that of wide-type mice. Mechanically, MOF overexpression increased the expression of Catalase and MnSOD, which blocked TAC-induced ROS and ROS downstream c-Raf-MEK-ERK pathway that promotes hypertrophy. Taken together, our findings identify a novel anti-hypertrophic role of MOF, and MOF is the first reported anti-hypertrophic histone acetyltransferase. Copyright © 2014 Elsevier Inc. All rights reserved.

Hypertrophic Cardiomyopathy: Practical Steps for Preventing Sudden Death.

ERIC Educational Resources Information Center

Maron, Barry J.

2002-01-01

Hypertrophic cardiomyopathy (HCM) is a rare cause of death among athletes, with deaths occurring in young, apparently healthy people. Differentiating HCM from conditioning hypertrophy is challenging. Routine detection involves family history, physical examination, electrocardiography, and echocardiography. Keys to differential diagnosis include…

Hypertrophic Cardiomyopathy Association

MedlinePlus

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Incomplete form of Primary Hypertrophic Osteoarthropathy (Touraine-Solente-Gole Syndrome) Masquerading as Polyartrhalgia Diagnosed in Technetium-99m-Methylene Diphosphonate Scintigraphy: An Interesting Case Report.

PubMed

Sivathapandi, Thangalakshmi; Amalachandran, Jaykanth; Simon, Shelley; Elangovan, Indirani

2018-01-01

The primary hypertrophic osteoarthropathy (PHOA) (pachydermoperiostosis) is a rare genetic/hereditary disease characterized by skin changes (pachydermia), clubbing of fingers and periosteal thickening (periostitis) with sub-periosteal new bone formation. Here we describe a case of an adolescent male who presented with clubbing and polyarthralgia. On evaluation with scintigraphy and SPECT-CT, he was diagnosed to have incomplete form of PHOA(skeletal manifestations without skin changes). The identification of incomplete form of primary hypertrophic osteoarthropathy which can be easily misdiagnosed as rheumatoid arthritis is discussed here.

Hypertrophic Pachymeningitis and the Syndrome of Inappropriate Antidiuretic Hormone Secretion: Coincidence or Cause?

PubMed

Harsch, Igor Alexander; Schiffer, Anne; Konturek, Peter C

2017-01-01

To investigate a potential cause of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). A 70-year-old female patient had nausea and collapsed. Although euvolemic, pathological laboratory findings showed hyponatremia and hypoosmolality, and cerebral magnetic resonance imaging showed hypertrophic pachymeningitis. Secondary hypertrophic pachymeningitis was excluded. Other nonneurological reasons for SIADH were also excluded. Moderate fluid restriction restored an almost normal serum osmolality and sodium. This case of SIADH was conservatively treated with moderate fluid restriction that almost restored normal serum osmolality and sodium levels. © 2017 S. Karger AG, Basel.

Hypertrophic Pachymeningitis and the Syndrome of Inappropriate Antidiuretic Hormone Secretion: Coincidence or Cause?

PubMed Central

Harsch, Igor Alexander; Schiffer, Anne; Konturek, Peter C.

2017-01-01

Objective To investigate a potential cause of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Clinical Presentation and Intervention A 70-year-old female patient had nausea and collapsed. Although euvolemic, pathological laboratory findings showed hyponatremia and hypoosmolality, and cerebral magnetic resonance imaging showed hypertrophic pachymeningitis. Secondary hypertrophic pachymeningitis was excluded. Other nonneurological reasons for SIADH were also excluded. Moderate fluid restriction restored an almost normal serum osmolality and sodium. Conclusion This case of SIADH was conservatively treated with moderate fluid restriction that almost restored normal serum osmolality and sodium levels. PMID:28245481

The effect of burn rehabilitation massage therapy on hypertrophic scar after burn: a randomized controlled trial.

PubMed

Cho, Yoon Soo; Jeon, Jong Hyun; Hong, Aram; Yang, Hyeong Tae; Yim, Haejun; Cho, Yong Suk; Kim, Do-Hern; Hur, Jun; Kim, Jong Hyun; Chun, Wook; Lee, Boung Chul; Seo, Cheong Hoon

2014-12-01

To evaluate the effect of burn rehabilitation massage therapy on hypertrophic scar after burn. One hundred and forty-six burn patients with hypertrophic scar(s) were randomly divided into an experimental group and a control group. All patients received standard rehabilitation therapy for hypertrophic scars and 76 patients (massage group) additionally received burn scar rehabilitation massage therapy. Both before and after the treatment, we determined the scores of visual analog scale (VAS) and itching scale and assessed the scar characteristics of thickness, melanin, erythema, transepidermal water loss (TEWL), sebum, and elasticity by using ultrasonography, Mexameter(®), Tewameter(®), Sebumeter(®), and Cutometer(®), respectively. The scores of both VAS and itching scale decreased significantly in both groups, indicating a significant intragroup difference. With regard to the scar characteristics, the massage group showed a significant decrease after treatment in scar thickness, melanin, erythema, TEWL and a significant intergroup difference. In terms of scar elasticity, a significant intergroup difference was noted in immediate distension and gross skin elasticity, while the massage group significant improvement in skin distensibility, immediate distension, immediate retraction, and delayed distension. Our results suggest that burn rehabilitation massage therapy is effective in improving pain, pruritus, and scar characteristics in hypertrophic scars after burn. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

Osteogenic Treatment Initiating a Tissue-Engineered Cartilage Template Hypertrophic Transition.

PubMed

Fu, J Y; Lim, S Y; He, P F; Fan, C J; Wang, D A

2016-10-01

Hypertrophic chondrocytes play a critical role in endochondral bone formation as well as the progress of osteoarthritis (OA). An in vitro cartilage hypertrophy model can be used as a platform to study complex molecular mechanisms involved in these processes and screen new drugs for OA. To develop an in vitro cartilage hypertrophy model, we treated a tissue-engineered cartilage template, living hyaline cartilaginous graft (LhCG), with osteogenic medium for hypertrophic induction. In addition, endothelial progenitor cells (EPCs) were seeded onto LhCG constructs to mimic vascular invasion. The results showed that osteogenic treatment significantly inhibited the synthesis of endostatin in LhCG constructs and enhanced expression of hypertrophic marker-collagen type X (Col X) and osteogenic markers, as well as calcium deposition in vitro. Upon subcutaneous implantation, osteogenic medium-treated LhCG constructs all stained positive for Col X and showed significant calcium deposition and blood vessel invasion. Col X staining and calcium deposition were most obvious in osteogenic medium-treated only group, while there was no difference between EPC-seeded and non-seeded group. These results demonstrated that osteogenic treatment was of the primary factor to induce hypertrophic transition of LhCG constructs and this model may contribute to the establishment of an in vitro cartilage hypertrophy model.

Changes in VEGF and nitric oxide after deep dermal injury in the female, red Duroc pig-further similarities between female, Duroc scar and human hypertrophic scar.

PubMed

Zhu, Kathy Q; Engrav, Loren H; Armendariz, Rebecca; Muangman, Pornprom; Klein, Matthew B; Carrougher, Gretchen J; Deubner, Heike; Gibran, Nicole S

2005-02-01

Despite decades of research, our understanding of human hypertrophic scar is limited. A reliable animal model could significantly increase our understanding. We previously confirmed similarities between scarring in the female, red, Duroc pig and human hypertrophic scarring. The purpose of this study was to: (1) measure vascular endothelial growth factor (VEGF) and nitric oxide (NO) levels in wounds on the female Duroc; and (2) to compare the NO levels to those reported for human hypertrophic scar. Shallow and deep wounds were created on four female Durocs. VEGF levels were measured using ELISA and NO levels with the Griess reagent. VEGF and NO levels were increased in deep wounds at 10 days when compared to shallow wounds (p < 0.05). At 15 weeks, VEGF and NO levels had returned to the level of shallow wounds. At 21 weeks, VEGF and NO levels had declined below baseline levels in deep wounds and the NO levels were significantly lower (p < 0.01). We found that VEGF and NO exhibit two distinctly different temporal patterns in shallow and deep wounds on the female Durocs. Furthermore, NO is decreased in female, Duroc scar as it is in human, hypertrophic scar further validating the usefulness of the model.

Laterally Versus Medially Projecting Spinothalamic Neurons and their Axon Collaterals to the Periaqueductal Gray and Medullary Reticular Formation in the Rat

DTIC Science & Technology

1987-06-30

nucleus reticularis gigantocellularis. No distinct tracts were reported in the brainstem as far rostral as the superior olivary complex. At the level...that stimulation of the PAG 12 activates neurons which project to the MRF, specifically the nucleus reticularis gigantocellularis, nucleus ... reticularis magnocellularis and the nucleus raphe magnus. Neurons in the raphe magnus receive convergent input from the PAG and other MRF regions and, via

The Interior Olivary Complex of Guinea Pig: Cytoarchitecture and Cellular Morphology

DTIC Science & Technology

1986-01-01

The oscillatory phenomenon ap- dye -coupling [471 between 1.0. cells might have been pre- peared in a sampling of neurons from all of the...information derived from injections of the ing of multiple cells from the Lucifer yellow injection into fluorescent dye Lucifer yellow revealed that...aggregates of only one 1.0. neuron [41. The early Golgi analyses also rv- inferior olive neurons are dye -coupled, presumably through vealed at least two

Use of bilidase for the treatment of experimental hypertrophic postburn cicatrices.

PubMed

Loladze, M; Alibegashvili, M; Turmanidze, Ts; Iashvili, B; Kutivadze, D; Chanishvili, T

2005-01-01

The efficiency of bilidase (hyaluronidase preparation) was studied in guinea pigs with experimental postburn cicatrices. Bilidase promoted normalization of the structure and histochemical picture of new cicatricial tissue. The drug can be used for the treatment of hypertrophic postburn cicatrices.

Sarcomeric hypertrophic cardiomyopathy: genetic profile in a Portuguese population.

PubMed

Brito, Dulce; Miltenberger-Miltenyi, Gabriel; Vale Pereira, Sónia; Silva, Doroteia; Diogo, António Nunes; Madeira, Hugo

2012-09-01

Sarcomeric hypertrophic cardiomyopathy has heterogeneous phenotypic expressions, of which sudden cardiac death is the most feared. A genetic diagnosis is essential to identify subjects at risk in each family. The spectrum of disease-causing mutations in the Portuguese population is unknown. Seventy-seven unrelated probands with hypertrophic cardiomyopathy were systematically screened for mutations by PCR and sequencing of five sarcomeric genes: MYBPC3, MYH7, TNNT2, TNNI3 and MYL2. Familial cosegregation analysis was performed in most patients. Thirty-four different mutations were identified in 41 (53%) index patients, 71% with familial hypertrophic cardiomyopathy. The most frequently involved gene was MYBPC3 (66%) with 22 different mutations (8 novel) in 27 patients, followed by MYH7 (22%), TNNT2 (12%) and TNNI3 (2.6%). In three patients (7%), two mutations were found in MYBPC3 and/or MYH7. Additionally, 276 relatives were screened, leading to the identification of a mean of three other affected relatives for each pedigree with the familial form of the disease. Disease-associated mutations were identified mostly in familial hypertrophic cardiomyopathy, corroborating the idea that rarely studied genes may be implicated in sporadic forms. Private mutations are the rule, MYBPC3 being the most commonly involved gene. Mutations in MYBPC3 and MYH7 accounted for most cases of sarcomere-related disease. Multiple mutations in these genes may occur, which highlights the importance of screening both. The detection of novel mutations strongly suggests that all coding regions should be systematically screened. Genotyping in hypertrophic cardiomyopathy enables a more precise diagnosis of the disease, with implications for risk stratification and genetic counseling. Copyright © 2011 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Pressure garment therapy alone and in combination with silicone for the prevention of hypertrophic scarring: randomized controlled trial with intraindividual comparison.

PubMed

Steinstraesser, Lars; Flak, Ewa; Witte, Bernd; Ring, Andrej; Tilkorn, Daniel; Hauser, Jörg; Langer, Stefan; Steinau, Hans-Ulrich; Al-Benna, Sammy

2011-10-01

Published trials evaluating pressure garment and/or silicone therapy as a treatment for hypertrophic burn scarring are of poor quality and highly susceptible to bias. The authors' aim was to compare the efficacy of pressure garment therapy alone and in combination with silicone gel sheet or spray therapy for the prevention of hypertrophic scarring. The authors conducted an open, single-center, randomized controlled study with intraindividual comparison of study preparations and control to standard treatment. Forty-three consecutive patients with two comparable areas of split-thickness graft burn wounds were recruited into the study, and 38 patients were followed up for 18 months. All patients received compression garments and were randomized to one of two treatment groups: (1) self-drying silicone spray and compression versus compression alone and (2) silicone sheeting and compression versus compression alone. Clinical assessment, measurement of scar redness, height, and photographic documentation of each treated area were performed at different visits over an 18-month follow-up period. Significance was tested using repeated-measures analyses and Wilcoxon paired-sample signed rank tests. Use of pressure garment therapy alone produced results equivalent to those of combined silicone and pressure garment therapy in the prevention of hypertrophic scars. The efficacy of silicone spray therapy was comparable to that of silicone gel sheet therapy in the prevention of hypertrophic scars. Patients treated with silicone spray had fewer side effects when compared with the silicone sheet group. Multimodal therapy with silicone and pressure garment therapy failed to prevent hypertrophic scars beyond that observed with pressure garment therapy alone. Therapeutic, II.

Minimal extracorporeal circulation (MECC) does not result in less hypertrophic scar formation as compared to conventional extracorporeal circulation (CECC) with dexamethasone.

PubMed

Soykan, E A; Butzelaar, L; de Kroon, T L; Beelen, R H J; Ulrich, M M W; Mink van der Molen, A B; Niessen, F B

2014-05-01

Cardiopulmonary bypass surgery is associated with a systemic inflammatory response through the interaction of air, blood and synthetic components in the bypass system and the physical trauma of surgery. An alternative cardiopulmonary bypass system, minimal extracorporeal circulation (MECC), has shown promising results in terms of reducing the inflammatory response. We hypothesized that this system may reduce pathological excessive scarring. To study this assumption, the effects of MECC and the effects of conventional extracorporeal circulation (CECC) with dexamethasone on skin scarring were compared in a standardized wound-healing model. Pre-sternal scars were evaluated prospectively at four and 12 months postoperatively. The height and width of the scars were measured, using a slide caliper and sonography. The scars were scored using the validated Patient and Observer Scar Assessment Scale. Additional risk factors for hypertrophic scar formation were identified by means of a questionnaire. During surgery, MECC was used in 45 patients and CECC/dexamethasone in 42 patients. Four months postoperatively, 22 patients of the MECC group (49%) and 18 patients in the CECC/dexamethasone group (43%) had developed hypertrophic scars. Twelve months postoperatively, the hypertrophic scars in four patients of the MECC group and in two patients of the CECC/dexamethasone group had become normotrophic. In 18 patients of the MECC group (38%) and 16 patients of the CECC group (41%) the scars remained hypertrophic at 12 months. These differences between the two groups were not statistically significant. MECC does not reduce hypertrophic scar formation compared with CECC with dexamethasone, but its use is more beneficial than the use of CECC/dexamethasone because of the circulatory and immunological advantages and because treatment with dexamethasone can be omitted.

Comparative effect and safety of verapamil in keloid and hypertrophic scar treatment: a meta-analysis.

PubMed

Li, Zhouna; Jin, Zhehu

2016-01-01

Keloids and hypertrophic scars are the most common types of pathological scarring. Traditionally, keloids have been considered as a result of aberrant wound healing, involving excessive fibroblast participation that is characterized by hyalinized collagen bundles. However, the usefulness of this characterization has been questioned. In recent years, studies have reported the appropriate use of verapamil for keloids and hypertrophic scars. Searches were conducted on the databases Medline, Embase, Cochrane, PubMed, and China National Knowledge Infrastructure from 2006 to July 2016. State12.0 was used for literature review, data extraction, and meta-analysis. Treatment groups were divided into verapamil and nonverapamil group. Nonverapamil group includes steroids and intense pulsed light (IPL) therapy. Total effective rates include cure rate and effective rate. Cure: skin lesions were completely flattened, became soft and symptoms disappeared. Efficacy: skin lesions subsided, patient significantly reduced symptoms. Inefficient definition of skin was progression free or became worse. Random-effects model was used for the meta-analysis. Six studies that included 331 patients with keloids and hypertrophic scars were analyzed. Analysis of the total effective rate of skin healing was performed. The total effective rates in the two groups were 54.07% (verapamil) and 53.18% (nonverapamil), respectively. The meta-analysis showed that there was no difference between the two groups. We also compared the adverse reactions between the verapamil treatment group and the steroids treatment group in two studies, and the result indicated that the verapamil group showed less adverse reactions. There were no differences between the application of verapamil and nonverapamil group in keloids and hypertrophic scars treatment. Verapamil could act as an effective alternative modality in the prevention and treatment of keloid and hypertrophic scars. A larger number of studies are required to confirm our conclusion.

Identification of sirtuin 1 as a promising therapeutic target for hypertrophic scars

PubMed Central

Bai, Xiao‐Zhi; Liu, Jia‐Qi; Yang, Long‐Long; Fan, Lei; He, Ting; Su, Lin‐Lin; Shi, Ji‐Hong; Tang, Chao‐Wu

2016-01-01

Background and Purpose Sirtuin1 (SIRT1), the founding member of mammalian class III histone deacetylases, is reported to be a drug target involved in fibrotic diseases. However, whether it is an effective drug target in hypertrophic scar treatment is still not known. Experimental Approach In the present study, we observed that SIRT1 localized to both the epidermis and the dermis of skin tissues by immunohistochemistry. After knock‐down of SIRT1 by shRNA or up‐regulating SIRT1 by resveratrol, the expression of α‐SMA, Col1 and Col3 in fibroblasts were detected by western blots. A mouse excision wound healing model was used to observe the changes in collagen fibre associated with the different expression levels of SIRT1. Key Results SIRT1 expression was inhibited in hypertrophic scar tissue. The down‐regulation of SIRT1 resulted in an increased expression of α‐SMA, Col1 and Col3 in hypertrophic scar‐derived fibroblasts. In contrast, the up‐regulation of SIRT1 not only inhibited the expression of α‐SMA, Col1 and Col3 in hypertrophic scar‐derived fibroblasts but also blocked the activation of TGFβ1‐induced normal skin‐derived fibroblasts. In the mouse model of wound healing, the deletion of SIRT1 resulted in denser collagen fibres and a more disordered structure, whereas resveratrol treatment led to a more organized and thinner collagen fibre, which was similar to that observed during normal wound healing. Conclusions and Implications The results revealed that SIRT1 negatively regulates TGFβ1‐induced fibroblast activation and inhibits excessive scar formation and is, therefore, a promising drug target for hypertrophic scar formation. PMID:26891034

Effects of platelet rich plasma and chondrocyte co-culture on MSC chondrogenesis, hypertrophy and pathological responses

PubMed Central

Ramezanifard, Rouhallah; Kabiri, Mahboubeh; Hanaee Ahvaz, Hana

2017-01-01

Regarding the inadequate healing capability of cartilage tissue, cell-based therapy is making the future of cartilage repair and regeneration. Mesenchymal stem cells (MSC) have shown great promise in cartilage regeneration. However, a yet-unresolved issue is the emergence of hypertrophic and pathologic markers during in vitro MSC chondrogenesis. Articular chondrocytes (AC) can suppress the undesired hypertrophy when co-cultured with MSC. On the other hand, platelet rich plasma (PRP), is considered potentially effective for cartilage repair and in-vitro chondrogenesis. We thus aimed to harness chondro-promotive effects of PRP and hypertrophic-suppressive effects of AC:MSC co-culture to achieve a more functional cartilage neo-tissue. We used PRP or conventional-differentiation chondrogenic media (ConvDiff) in MSC mono-cultures and AC:MSC co-cultures. We assessed gene expression of chondrogenic and hypertrophic markers using real-time RT-PCR and immunostaining. Alkaline-phosphatase activity (ALP) and calcium content of the pellets were quantified. We also measured VEGF and TNF-α secretion via ELISA. We showed PRP had higher chondrogenic potential (in mRNA and protein level) and hypertrophic-suppressive effects than Conv-Diff (mRNA level). Co-culturing reduced ALP while PRP increased calcium deposition. In all four groups, TNF-α was down-regulated compared to MSC controls, with co-cultures receiving ConvDiff media secreting the least. Meanwhile, the only group with increased VEGF secretion was PRP-mono-cultures. We observed synergistic effects for PRP and AC:MSC co-culture in enhancing chondrogenesis. Inclusion of AC reduced hypertrophic markers and angiogenic potential in PRP groups. We thus propose that combination of PRP and co-culture would favor chondrogenesis while alleviate but not totally eradicate undesired hypertrophic and pathologic responses. PMID:28900383

Hypertrophic Cardiomyopathy in Athletes: Catching a Killer.

ERIC Educational Resources Information Center

Maron, Barry J.

1993-01-01

A leading cause of sudden death among young athletes, hypertrophic cardiomyopathy (HCM) does not always present cardiac signs and symptoms. Echocardiography offers the most effective means for diagnosis. Some patients require pharmaceutical or surgical intervention. Patients with HCM should not engage in organized competitive sports or…

Quantification of regional nonuniformity and paradoxical intramural mechanics in hypertrophic cardiomyopathy by high frame rate ultrasound myocardial strain mapping.

PubMed

Sengupta, Partho P; Mehta, Vimal; Arora, Ramesh; Mohan, Jagdish C; Khandheria, Bijoy K

2005-07-01

This study tested the hypothesis that linear mapping of regional myocardial strain comprehensively assesses variations in regional myocardial function in hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy is characterized by disorganized myocardial architecture that results in spatial and temporal nonuniformity of regional function. Left ventricular deformation was quantified in 20 patients with hypertrophic cardiomyopathy and compared with 25 age- and sex-matched control subjects. Abnormalities in subendocardial strain ranged from reduced longitudinal shortening to paradoxical systolic lengthening and delayed regional longitudinal contractions that were often located in small subsegmental areas. These variations were underestimated significantly by arbitrary measurements compared with linear mapping, in which a region of interest was moved across the longitudinal length of left ventricle (difference of peak and least strain, 10.7% +/- 5.1% vs 17% +/- 5.5%; P < .001). Echocardiographic assessment of variations in regional strain requires careful mapping and may be inappropriately assessed if left ventricular segments are sampled at arbitrary focal locations.

FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program

PubMed Central

Ionescu, Andreia; Kozhemyakina, Elena; Nicolae, Claudia; Kaestner, Klaus H.; Olsen, Bjorn R.; Lassar, Andrew B.

2012-01-01

During endochondral ossification small immature chondrocytes enlarge to form hypertrophic chondrocytes, which express collagen X. In this work, we demonstrate that FoxA factors are induced during chondrogenesis, bind to conserved binding sites in the collagen X enhancer, and can promote the expression of a collagen X-luciferase reporter in both chondrocytes and fibroblasts. In addition, we demonstrate by both gain and loss of function analyses that FoxA factors play a crucial role driving the expression of both endogenous collagen X and other hypertrophic chondrocyte-specific genes. Mice engineered to lack expression of both FoxA2 and FoxA3 in their chondrocytes display defects in chondrocyte hypertrophy, alkaline phosphatase expression, and mineralization in their sternebrae and in addition exhibit postnatal dwarfism that is coupled to significantly decreased expression of both collagen X and MMP13 in their growth plates. Together, our findings indicate that FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program. PMID:22595668

Scar Management of the Burned Hand

PubMed Central

Sorkin, Michael; Cholok, David; Levi, Benjamin

2017-01-01

Unimpaired hand function is critical in almost all activities of daily living. Burn injury can result in hypertrophic scar formation that can lead to debilitating functional deficits and poor aesthetic outcomes. Initial algorithms of acute burn management involve early debridement and skin grafting and early mobilization to prevent formation of hypertrophic scarring and ultimately digit contractures. While non-operative modalities in the early phase of scar maturation are critical to minimize hypertrophic scar formation, surgical management is often indicated in order to restore hand function. The essential tenant of operative scar management is release of tension, which can often be achieved through local tissue rearrangement. Laser therapy has emerged as a central pillar of subsequent scar rehabilitation with several modalities that address scar texture, color, pruritis and thickness. These can be utilized in conjunction with local corticosteroid treatment and other emerging modalities to modulate the scar and achieve optimal hand function. These treatment tools provide an effective resource for the reconstructive surgeon to treat hypertrophic hand scars. PMID:28363297

Evaluation of the effect of fractional CO2 laser on histopathological picture and TGF-β1 expression in hypertrophic scar.

PubMed

Makboul, Mohamed; Makboul, Rania; Abdelhafez, Assem Hk; Hassan, Safaa Said; Youssif, Sherif M

2014-09-01

Hypertrophic scar is a form of abnormal wound healing process in which tissue repair regulating mechanism is disrupted. Transforming growth factor β1 has a particular importance in the fibrotic scarring response. Treatment of hypertrophic scar included many chemical, physical, and surgical options. Fractional CO2 laser devices have gained acceptance as a way for managing hypertrophic scar. Aims of this study are: (a) to determine the clinical and histopathological effects of fractional CO2 laser on hypertrophic scar, (b) to evaluate the expression pattern of transforming growth factor-β1 (TGF-β1) as an important fibrogenic factor before and 6 months after fractional CO2 laser treatment. Forty patients of hypertrophic scar were selected, each patient was treated by four sessions with 1 month apart with fractional CO2 laser. Vancouver Scar Scale (VSS) was used to assess the patients before and after laser treatment. Skin biopsy was taken from eight cases before and 3 months after four fractional CO2 laser sessions and four normal skin control biopsies. All were assessed by hematoxylin-eosin (H&E), Masson's trichrome, Van Gieson and immunohistochemical (IHC) staining with TGF-β1. The epidermal thickness was assessed before and after treatment by image analyzing system software. There was statistically significant difference in VSS before and after fractional CO2 laser (P > 0.001). The epidermal thickness showed significant increase after laser treatment (P > 0.001), and there was also thinning in stratum corneum and replacement of the irregular collagen bands with organized new collagen fibrils as demonstrated by H&E and the other special stains. The study also showed significant decrease in TGF-β1 expression after laser therapy (P = 0.008). Fractional CO2 laser could be considered as a good way for hypertrophic scar management. It normalizes dermal collagen as imaged by histopathological picture and the change in TGF-β1 expression. © 2014 Wiley Periodicals, Inc.

Myectomy and LA-to-LV Conduit for Severe Calcific Mitral Stenosis and Hypertrophic Cardiomyopathy.

PubMed

Meghji, Zahara; Nguyen, Anita; Geske, Jeffrey B; Schaff, Hartzell V

2018-02-26

Severe calcific mitral valve stenosis can rarely occur concomitantly with obstructive hypertrophic cardiomyopathy. In these patients, surgical decalcification of the stenotic mitral valve followed by mitral valve replacement carries significant operative risk and may result in paravalvular leakage, atrioventricular groove disruption, and excessive bleeding. We report the first 2 cases of obstructive hypertrophic cardiomyopathy with severe calcific mitral valve stenosis successfully treated with concomitant transaortic septal myectomy and bypass of the stenotic mitral valve using a valved left atrium to left ventricular conduit. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Management of an asymptomatic patient with the apical variant of hypertrophic cardiomyopathy.

PubMed

Trojan, Meghan K Borden; Biederman, Robert W

2017-07-01

Healthcare professionals are faced with challenging decisions regarding patient evaluation and management on a daily basis. Once a diagnosis is made, additional challenges include how to proceed with the management. Here, we present an eighty-two-year-old female who was incidentally diagnosed with the apical variant of hypertrophic cardiomyopathy on a transthoracic echocardiogram. She was found to have newly diagnosed atrial fibrillation, but was otherwise asymptomatic from a cardiomyopathy standpoint. No specific guidelines exist for this patient population. Therefore, how does one proceed with the management of an asymptomatic patient with the apical variant of hypertrophic cardiomyopathy? © 2017, Wiley Periodicals, Inc.

Risk factors for hypertrophic burn scar pain, pruritus, and paresthesia development.

PubMed

Xiao, Yongqiang; Sun, Yu; Zhu, Banghui; Wang, Kangan; Liang, Pengfei; Liu, Wenjun; Fu, Jinfeng; Zheng, Shiqing; Xiao, Shichu; Xia, Zhaofan

2018-05-02

Hypertrophic scar pain, pruritus, and paresthesia symptoms are major and particular concerns for burn patients. However, because no effective and satisfactory methods exist for their alleviation, the clinical treatment for these symptoms is generally considered unsatisfactory. Therefore, their risk factors should be identified and prevented during management. We reviewed the medical records of 129 post-burn hypertrophy scar patients and divided them into two groups for each of three different symptoms based on the University of North Carolina "4P" Scar Scale: patients with scar pain requiring occasional or continuous pharmacological intervention (HSc pain, n=75) vs. patients without such scar pain (No HSc pain, n=54); patients with scar pruritus requiring occasional or continuous pharmacological intervention (HSc pruritus, n=63) vs. patients without such scar pruritus (No HSc pruritus, n=66); patients with scar paresthesia that influenced the patients' daily activities (HSc paresthesia, n=31) vs. patients without such scar paresthesia (No HSc paresthesia, n=98). Three multivariable logistic regression models were built, respectively, to identify the risk factors for hypertrophic burn scar pain, pruritus, and paresthesia development. Multivariable analysis showed that hypertrophic burn scar pain development requiring pharmacological intervention was associated with old age (odds ratio [OR]=1.046; 95% confidence interval [CI], 1.011-1.082, p=0.009), high body mass index(OR=1.242; 95%CI,1.068-1.445, p=0.005), 2-5-mm-thick post-burn hypertrophic scars (OR=3.997; 95%CI, 1.523-10.487; p=0.005), and 6-12-month post-burn hypertrophic scars (OR=4.686; 95%CI; 1.318-16.653; p=0.017). Hypertrophic burn scar pruritus development requiring pharmacological intervention was associated with smoking (OR=3.239; 95%CI, 1.380-7.603; p=0.007), having undergone surgical operation (OR=2.236; 95%CI, 1.001-4.998; p=0.049), and firm scars (OR=3.317; 95%CI, 1.237-8.894; p=0.017). Finally, hypertrophic burn scar paresthesia development which affected the patients' daily activities was associated with age (OR=1.038; 95%CI, 1.002-1.075; p=0.040), fire burns (OR=0.041; 95%CI, 0.005-0.366; p=0.004, other burns vs. flame burns), and banding and contracture scars (OR=4.705; 95%CI, 1.281-17.288, p=0.020). This article is protected by copyright. All rights reserved. © 2018 by the Wound Healing Society.

Altering the architecture of tissue engineered hypertrophic cartilaginous grafts facilitates vascularisation and accelerates mineralisation.

PubMed

Sheehy, Eamon J; Vinardell, Tatiana; Toner, Mary E; Buckley, Conor T; Kelly, Daniel J

2014-01-01

Cartilaginous tissues engineered using mesenchymal stem cells (MSCs) can be leveraged to generate bone in vivo by executing an endochondral program, leading to increased interest in the use of such hypertrophic grafts for the regeneration of osseous defects. During normal skeletogenesis, canals within the developing hypertrophic cartilage play a key role in facilitating endochondral ossification. Inspired by this developmental feature, the objective of this study was to promote endochondral ossification of an engineered cartilaginous construct through modification of scaffold architecture. Our hypothesis was that the introduction of channels into MSC-seeded hydrogels would firstly facilitate the in vitro development of scaled-up hypertrophic cartilaginous tissues, and secondly would accelerate vascularisation and mineralisation of the graft in vivo. MSCs were encapsulated into hydrogels containing either an array of micro-channels, or into non-channelled 'solid' controls, and maintained in culture conditions known to promote a hypertrophic cartilaginous phenotype. Solid constructs accumulated significantly more sGAG and collagen in vitro, while channelled constructs accumulated significantly more calcium. In vivo, the channels acted as conduits for vascularisation and accelerated mineralisation of the engineered graft. Cartilaginous tissue within the channels underwent endochondral ossification, producing lamellar bone surrounding a hematopoietic marrow component. This study highlights the potential of utilising engineering methodologies, inspired by developmental skeletal processes, in order to enhance endochondral bone regeneration strategies.

Altering the Architecture of Tissue Engineered Hypertrophic Cartilaginous Grafts Facilitates Vascularisation and Accelerates Mineralisation

PubMed Central

Sheehy, Eamon J.; Vinardell, Tatiana; Toner, Mary E.; Buckley, Conor T.; Kelly, Daniel J.

2014-01-01

Cartilaginous tissues engineered using mesenchymal stem cells (MSCs) can be leveraged to generate bone in vivo by executing an endochondral program, leading to increased interest in the use of such hypertrophic grafts for the regeneration of osseous defects. During normal skeletogenesis, canals within the developing hypertrophic cartilage play a key role in facilitating endochondral ossification. Inspired by this developmental feature, the objective of this study was to promote endochondral ossification of an engineered cartilaginous construct through modification of scaffold architecture. Our hypothesis was that the introduction of channels into MSC-seeded hydrogels would firstly facilitate the in vitro development of scaled-up hypertrophic cartilaginous tissues, and secondly would accelerate vascularisation and mineralisation of the graft in vivo. MSCs were encapsulated into hydrogels containing either an array of micro-channels, or into non-channelled ‘solid’ controls, and maintained in culture conditions known to promote a hypertrophic cartilaginous phenotype. Solid constructs accumulated significantly more sGAG and collagen in vitro, while channelled constructs accumulated significantly more calcium. In vivo, the channels acted as conduits for vascularisation and accelerated mineralisation of the engineered graft. Cartilaginous tissue within the channels underwent endochondral ossification, producing lamellar bone surrounding a hematopoietic marrow component. This study highlights the potential of utilising engineering methodologies, inspired by developmental skeletal processes, in order to enhance endochondral bone regeneration strategies. PMID:24595316

Mitral valve disease—morphology and mechanisms

PubMed Central

Levine, Robert A.; Hagége, Albert A.; Judge, Daniel P.; Padala, Muralidhar; Dal-Bianco, Jacob P.; Aikawa, Elena; Beaudoin, Jonathan; Bischoff, Joyce; Bouatia-Naji, Nabila; Bruneval, Patrick; Butcher, Jonathan T.; Carpentier, Alain; Chaput, Miguel; Chester, Adrian H.; Clusel, Catherine; Delling, Francesca N.; Dietz, Harry C.; Dina, Christian; Durst, Ronen; Fernandez-Friera, Leticia; Handschumacher, Mark D.; Jensen, Morten O.; Jeunemaitre, Xavier P.; Le Marec, Hervé; Le Tourneau, Thierry; Markwald, Roger R.; Mérot, Jean; Messas, Emmanuel; Milan, David P.; Neri, Tui; Norris, Russell A.; Peal, David; Perrocheau, Maelle; Probst, Vincent; Pucéat, Michael; Rosenthal, Nadia; Solis, Jorge; Schott, Jean-Jacques; Schwammenthal, Ehud; Slaugenhaupt, Susan A.; Song, Jae-Kwan; Yacoub, Magdi H.

2016-01-01

Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease. PMID:26483167

Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling

PubMed Central

Urbano, Francisco J.; Leznik, Elena; Llinás, Rodolfo R.

2007-01-01

Modafinil (Provigil, Modiodal), an antinarcoleptic and mood-enhancing drug, is shown here to sharpen thalamocortical activity and to increase electrical coupling between cortical interneurons and between nerve cells in the inferior olivary nucleus. After irreversible pharmacological block of connexin permeability (i.e., by using either 18β-glycyrrhetinic derivatives or mefloquine), modafinil restored electrotonic coupling within 30 min. It was further established that this restoration is implemented through a Ca2+/calmodulin protein kinase II-dependent step. PMID:17640897

Intracellular Membrane and Synaptic Properties in Medial Preoptic Slices Containing the Sexually Dimorphic Nucleus of the Rat

DTIC Science & Technology

1992-01-01

these events appear to be LTS potentials, as originally described in other central regions (Jahnsen and Llings 1984). In some media preoptic neurons, LTS...Kelly, J.S. An intracellular study of grafted and in situ preoptic area neurones in brain slices from normal and hypogonadal mice. J Physiol. 423: 111... central nervous system function. Science 242: 1654-1664, 1988. Llings, R., and Yarom, Y. Electrophysiology of mammalian inferior olivary neurons in vitro

Age and growth of flathead catfish, Pylodictus olivaris rafinesque, in the Altamaha River system, Georgia

USGS Publications Warehouse

Grabowski, T.B.; Isely, J.J.; Weller, R.R.

2004-01-01

Flathead catfish were introduced to the Altamaha River system, Georgia in the 1970's. We determined the length-weight relationship, Von Bertalanffy growth parameters, and back calculated lengths by examining the sagittal otoliths of 331 individuals captured from this population. We found that there were no sex related differences in length weight relationship or Von Bertalanffy growth parameters. Flathead catfish in the Altamaha River system grow at about the same rate as individuals in other introduced populations.

Hypertrophic osteopathy secondary to metastatic ovarian adenocarcinoma in a mare.

PubMed

Browne, Nimet S; Scarratt, William K; Robertson, John

2016-12-01

A 10-year-old Andalusian mare was presented for evaluation of weight loss, increasing periods of recumbency, and swelling of the lower limbs. Radiographs revealed severe palisading to solid periosteal new bone formation in numerous locations. Necropsy revealed a metastatic malignant adenocarcinoma of ovarian origin with secondary hypertrophic osteopathy.

Anaesthetic management of severe hypertrophic obstructive cardiomyopathy with bronchial asthma for emergency caesarean section.

PubMed

Rajesh, M C; Varma, Ravi; Lima, P; Ramdas, E K

2012-10-01

A 39-year-old primi and a known case of hypertrophic obstructive cardiomyopathy presented for emergency lower segment caesarean section. She was also an asthmatic with a recent exacerbation. She underwent uneventful lower segment caesarean section under general anaesthesia with lumbar epidural analgesia for postoperative pain relief. Anaesthetic agents and techniques were selected to suit the haemodynamic profile of severe hypertrophic obstructive cardiomyopathy in pregnancy. The case has been reported because of successful outcome in an emergency scenario with such high intraventricular gradients and omissions in the case so that it will be of benefit to readers who may happen to land up in similar situations.

A Child With a Burn-Related Foot and Ankle Contracture Treated With Multiple Modalities.

PubMed

Yelvington, Miranda; Scoggins, Michelle; White, Leslie

2017-01-01

The presence of hypertrophic scars, which cross lower extremity joints, can often result in decreased range of motion, limitations in functional mobility, and gait deviations. This article reviews a case and describes a multimodal treatment approach. A 6-year-old girl developed aggressive hypertrophic scars following a burn injury. A multimodal treatment approach, including splinting, elastomers, and physical therapy, was developed. Rapid improvements were demonstrated in measured objective outcomes. Early multimodal intervention, in addition to range of motion, stretching, massage, and compression garments, is recommended when treating hypertrophic scars. This case suggests that further study into a multimodal treatment approach may be beneficial to develop a standardized protocol for more efficient scar management.

Hypertrophic Cardiomyopathy Associated with Mid-cavity Obstruction and High Left Intraventricular Pressure

PubMed Central

A. Bejiqi, Ramush; J. Retkoceri, Ragip; Sh. Bejiqi, Hana

2011-01-01

We report a case of a child, with a rare form of the idiopathic hypertrophic cardiomyopathy, associated with mid-cavity obstruction and high intraventricular peak pressure. Cardiomyopathy, diagnosed antenataly, was followed postnataly and, despite of a lot echocardiographic findings - the growing, development and clinical signs are minimal. PMID:23407799

An abnormal Ca2+ response in mutant sarcomere protein–mediated familial hypertrophic cardiomyopathy

PubMed Central

Fatkin, Diane; McConnell, Bradley K.; Mudd, James O.; Semsarian, Christopher; Moskowitz, Ivan G.P.; Schoen, Frederick J.; Giewat, Michael; Seidman, Christine E.; Seidman, J.G.

2000-01-01

Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (αMHC403/+), when treated with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca2+ concentrations in wild-type cardiac myocytes; αMHC403/+ myocytes failed to respond. Pretreatment with a Ca2+-channel antagonist abrogated diastolic Ca2+ changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated αMHC403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca2+ responses that initiate a hypertrophic response. These data define an important Ca2+-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease. PMID:11104788

Review of the female Duroc/Yorkshire pig model of human fibroproliferative scarring

PubMed Central

Zhu, Kathy Q.; Carrougher, Gretchen J.; Gibran, Nicole S.; Isik, F. Frank; Engrav, Loren H.

2010-01-01

Hypertrophic scarring after burns is an unsolved problem and remains as devastating today as it was in the 40s and it may be that the main reason for this is the lack of an accepted, useful animal model. The female, red Duroc pig was described as a model of hypertrophic scarring nearly 30 years ago but then vanished from the literature. This seemed strange since the authors reported that 12 of 12 pigs developed thick scar. In the mid 90s we explored the model and found that, indeed, the red Duroc pig does make thick scar. Other authors have established that the Yorkshire pig does not heal in this fashion so there is the possibility of a same species control. We have continued to explore the Duroc/Yorkshire model and herein describe our experiences. Is it a perfect model of hypertrophic scarring? No. Is it a useful model of hypertrophic scarring? Time will tell. We have now obtained gene expression data from the Duroc/Yorkshire model and analysis is underway. PMID:17727465

Investigating β-adrenergic-induced cardiac hypertrophy through computational approach: classical and non-classical pathways.

PubMed

Khalilimeybodi, Ali; Daneshmehr, Alireza; Sharif-Kashani, Babak

2018-07-01

The chronic stimulation of β-adrenergic receptors plays a crucial role in cardiac hypertrophy and its progression to heart failure. In β-adrenergic signaling, in addition to the well-established classical pathway, Gs/AC/cAMP/PKA, activation of non-classical pathways such as Gi/PI3K/Akt/GSK3β and Gi/Ras/Raf/MEK/ERK contribute in cardiac hypertrophy. The signaling network of β-adrenergic-induced hypertrophy is very complex and not fully understood. So, we use a computational approach to investigate the dynamic response and contribution of β-adrenergic mediators in cardiac hypertrophy. The proposed computational model provides insights into the effects of β-adrenergic classical and non-classical pathways on the activity of hypertrophic transcription factors CREB and GATA4. The results illustrate that the model captures the dynamics of the main signaling mediators and reproduces the experimental observations well. The results also show that despite the low portion of β2 receptors out of total cardiac β-adrenergic receptors, their contribution in the activation of hypertrophic mediators and regulation of β-adrenergic-induced hypertrophy is noticeable and variations in β1/β2 receptors ratio greatly affect the ISO-induced hypertrophic response. The model results illustrate that GSK3β deactivation after β-adrenergic receptor stimulation has a major influence on CREB and GATA4 activation and consequent cardiac hypertrophy. Also, it is found through sensitivity analysis that PKB (Akt) activation has both pro-hypertrophic and anti-hypertrophic effects in β-adrenergic signaling.

Mitral stenosis and hypertrophic obstructive cardiomyopathy: An unusual combination.

PubMed

Hong, Joonhwa; Schaff, Hartzell V; Ommen, Steve R; Abel, Martin D; Dearani, Joseph A; Nishimura, Rick A

2016-04-01

Systolic anterior motion of mitral valve (MV) leaflets is a main pathophysiologic feature of left ventricular outflow tract (LVOT) obstruction in hypertrophic obstructive cardiomyopathy. Thus, restricted leaflet motion that occurs with MV stenosis might be expected to minimize outflow tract obstruction related to systolic anterior motion. From January 1993 through February 2015, we performed MV replacement and septal myectomy in 12 patients with mitral stenosis and hypertrophic obstructive cardiomyopathy at Mayo Clinic Hospital in Rochester, Minn. Preoperative data, echocardiographic images, operative records, and postoperative outcomes were reviewed. Mean (standard deviation) age was 70 (7.6) years. Preoperative mean (standard deviation) maximal LVOT pressure gradient was 75.0 (35.0) mm Hg; MV gradient was 13.7 (2.8) mm Hg. From echocardiographic images, 4 mechanisms of outflow tract obstruction were identified: systolic anterior motion without severe limitation in MV leaflet excursion, severe limitation in MV leaflet mobility with systolic anterior motion at the tip of the MV anterior leaflet, septal encroachment toward the LVOT, and MV displacement toward the LVOT by calcification. Mitral valve replacement and extended septal myectomy relieved outflow gradients in all patients, with no death or serious morbidity. Patients with mitral stenosis and hypertrophic obstructive cardiomyopathy have multiple LVOT obstruction mechanisms, and MV replacement may not be adequate treatment. We favor septal myectomy and MV replacement in this complex subset of hypertrophic obstructive cardiomyopathy. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Remission of recurrent gastrointestinal bleeding after septal reduction therapy in patients with hypertrophic obstructive cardiomyopathy-associated acquired von Willebrand syndrome.

PubMed

Blackshear, J L; Stark, M E; Agnew, R C; Moussa, I D; Safford, R E; Shapiro, B P; Waldo, O A; Chen, D

2015-02-01

Gastrointestinal hemorrhage is considered to be a severe complication of von Willebrand disease. The optimal therapy for acquired von Willebrand syndrome and severe gastrointestinal bleeding with hypertrophic cardiomyopathy is undefined. Seventy-seven patients (median age, 67 years; interquartile range [IQR], 56-75 years; 49% women) with hypertrophic cardiomyopathy underwent von Willebrand factor multimer testing and acquisition of bleeding history. Bleeding was detected in 27 (36%) (median age, 74 years; IQR 66-76 years; 74% women), 20 with gastrointestinal bleeding, including 11 women with transfusion dependence. In these 11 women, the median duration of transfusion dependency was 36 months (IQR 18-44 months), and the median number of transfusions required was 25 (IQR 20-38). Two patients had undergone bowel resection for bleeding, one of them twice. Seven patients showed angiodysplasia, and the remainder had no endoscopic lesion. Bleeding recurred after bowel surgery or endoscopic intervention and medical therapy for hypertrophic cardiomyopathy in 10 of 11 patients. Two patients had septal myectomy, and six patients underwent alcohol septal ablation. With the exception of one patient in whom a significant gradient persisted after septal ablation, after the periprocedural period, patients after septal reduction therapy remained free of recurrent bleeding and need for transfusions. Acquired von Willebrand syndrome is common in hypertrophic cardiomyopathy. Gastrointestinal bleeding often recurs after endoscopic therapy, but may be relieved by structural cardiac repair. © 2014 International Society on Thrombosis and Haemostasis.

Cytoarchitectural and functional abnormalities of the inferior colliculus in sudden unexplained perinatal death.

PubMed

Lavezzi, Anna M; Pusiol, Teresa; Matturri, Luigi

2015-02-01

The inferior colliculus is a mesencephalic structure endowed with serotonergic fibers that plays an important role in the processing of acoustic information. The implication of the neuromodulator serotonin also in the aetiology of sudden unexplained fetal and infant death syndromes and the demonstration in these pathologies of developmental alterations of the superior olivary complex (SOC), a group of pontine nuclei likewise involved in hearing, prompted us to investigate whether the inferior colliculus may somehow contribute to the pathogenetic mechanism of unexplained perinatal death. Therefore, we performed in a wide set of fetuses and infants, aged from 33 gestational weeks to 7 postnatal months and died of both known and unknown cause, an in-depth anatomopathological analysis of the brainstem, particularly of the midbrain. Peculiar neuroanatomical and functional abnormalities of the inferior colliculus, such as hypoplasia/structural disarrangement and immunonegativity or poor positivity of serotonin, were exclusively found in sudden death victims, and not in controls. In addition, these alterations were frequently related to dysgenesis of connected structures, precisely the raphé nuclei and the superior olivary complex, and to nicotine absorption in pregnancy. We propose, on the basis of these results, the involvement of the inferior colliculus in more important functions than those related to hearing, as breathing and, more extensively, all the vital activities, and then in pathological conditions underlying a sudden death in vulnerable periods of the autonomic nervous system development, particularly associated to harmful risk factors as cigarette smoking.

Retinal ganglion cell projections to the hamster suprachiasmatic nucleus, intergeniculate leaflet, and visual midbrain: bifurcation and melanopsin immunoreactivity

NASA Technical Reports Server (NTRS)

Morin, Lawrence P.; Blanchard, Jane H.; Provencio, Ignacio

2003-01-01

The circadian clock in the suprachiasmatic nucleus (SCN) receives direct retinal input via the retinohypothalamic tract (RHT), and the retinal ganglion cells contributing to this projection may be specialized with respect to direct regulation of the circadian clock. However, some ganglion cells forming the RHT bifurcate, sending axon collaterals to the intergeniculate leaflet (IGL) through which light has secondary access to the circadian clock. The present studies provide a more extensive examination of ganglion cell bifurcation and evaluate whether ganglion cells projecting to several subcortical visual nuclei contain melanopsin, a putative ganglion cell photopigment. The results showed that retinal ganglion cells projecting to the SCN send collaterals to the IGL, olivary pretectal nucleus, and superior colliculus, among other places. Melanopsin-immunoreactive (IR) ganglion cells are present in the hamster retina, and some of these cells project to the SCN, IGL, olivary pretectal nucleus, or superior colliculus. Triple-label analysis showed that melanopsin-IR cells bifurcate and project bilaterally to each SCN, but not to the other visual nuclei evaluated. The melanopsin-IR cells have photoreceptive characteristics optimal for circadian rhythm regulation. However, the presence of moderately widespread bifurcation among ganglion cells projecting to the SCN, and projection by melanopsin-IR cells to locations distinct from the SCN and without known rhythm function, suggest that this ganglion cell type is generalized, rather than specialized, with respect to the conveyance of photic information to the brain. Copyright 2003 Wiley-Liss, Inc.

Cytoarchitectural and Functional Abnormalities of the Inferior Colliculus in Sudden Unexplained Perinatal Death

PubMed Central

Lavezzi, Anna M.; Pusiol, Teresa; Matturri, Luigi

2015-01-01

Abstract The inferior colliculus is a mesencephalic structure endowed with serotonergic fibers that plays an important role in the processing of acoustic information. The implication of the neuromodulator serotonin also in the aetiology of sudden unexplained fetal and infant death syndromes and the demonstration in these pathologies of developmental alterations of the superior olivary complex (SOC), a group of pontine nuclei likewise involved in hearing, prompted us to investigate whether the inferior colliculus may somehow contribute to the pathogenetic mechanism of unexplained perinatal death. Therefore, we performed in a wide set of fetuses and infants, aged from 33 gestational weeks to 7 postnatal months and died of both known and unknown cause, an in-depth anatomopathological analysis of the brainstem, particularly of the midbrain. Peculiar neuroanatomical and functional abnormalities of the inferior colliculus, such as hypoplasia/structural disarrangement and immunonegativity or poor positivity of serotonin, were exclusively found in sudden death victims, and not in controls. In addition, these alterations were frequently related to dysgenesis of connected structures, precisely the raphé nuclei and the superior olivary complex, and to nicotine absorption in pregnancy. We propose, on the basis of these results, the involvement of the inferior colliculus in more important functions than those related to hearing, as breathing and, more extensively, all the vital activities, and then in pathological conditions underlying a sudden death in vulnerable periods of the autonomic nervous system development, particularly associated to harmful risk factors as cigarette smoking. PMID:25674737

Inferior olive mirrors joint dynamics to implement an inverse controller.

PubMed

Alvarez-Icaza, Rodrigo; Boahen, Kwabena

2012-10-01

To produce smooth and coordinated motion, our nervous systems need to generate precisely timed muscle activation patterns that, due to axonal conduction delay, must be generated in a predictive and feedforward manner. Kawato proposed that the cerebellum accomplishes this by acting as an inverse controller that modulates descending motor commands to predictively drive the spinal cord such that the musculoskeletal dynamics are canceled out. This and other cerebellar theories do not, however, account for the rich biophysical properties expressed by the olivocerebellar complex's various cell types, making these theories difficult to verify experimentally. Here we propose that a multizonal microcomplex's (MZMC) inferior olivary neurons use their subthreshold oscillations to mirror a musculoskeletal joint's underdamped dynamics, thereby achieving inverse control. We used control theory to map a joint's inverse model onto an MZMC's biophysics, and we used biophysical modeling to confirm that inferior olivary neurons can express the dynamics required to mirror biomechanical joints. We then combined both techniques to predict how experimentally injecting current into the inferior olive would affect overall motor output performance. We found that this experimental manipulation unmasked a joint's natural dynamics, as observed by motor output ringing at the joint's natural frequency, with amplitude proportional to the amount of current. These results support the proposal that the cerebellum-in particular an MZMC-is an inverse controller; the results also provide a biophysical implementation for this controller and allow one to make an experimentally testable prediction.

Colocalization of vesicular glutamate transporters in the rat superior olivary complex.

PubMed

Billups, Brian

Vesicular glutamate transporters (VGLUTs) are responsible for the accumulation of the excitatory neurotransmitter glutamate into synaptic vesicles. It is currently controversial whether the two isoforms found in glutamatergic neurons, VGLUT1 and VGLUT2, are present at the same synapse or have entirely complementary patterns of distribution. Using fluorescent immunohistochemistry, this study examines the colocalization of these two transporters in the rat superior olivary complex (SOC) between postnatal day (P) 5 and 29. The medial and lateral superior olives (MSO; LSO) stain for both VGLUT1 and VGLUT2 at all ages studied, with VGLUT1 levels doubling over this developmental period and VGLUT2 levels remaining unchanged. The ventral nucleus of the trapezoid body (VNTB) strongly labels only for VGLUT2, despite the fact that glutamatergic synapses are present that are formed from collaterals of axons that go on to form synapses containing both VGLUT1 and VGLUT2. Principal neurons of the medial nucleus of the trapezoid body (MNTB) are surrounded by the calyx of Held presynaptic terminal, which is large enough to allow examination of VGLUT localization within a synapse. Throughout its postnatal developmental period a single calyx synapse contains both VGLUT1 and VGLUT2. Whereas VGLUT1 levels are greatly up-regulated from P5 to P29, VGLUT2 levels remain high. As the abundance of VGLUT determines the quantal size, this up-regulation will increase excitatory postsynaptic currents (EPSCs) and have influences on synaptic physiology.

Duodenal Bulb Mucosa with Hypertrophic Gastric Oxyntic Heterotopia in Patients with Zollinger Ellison Syndrome

PubMed Central

Kohan, Emil; Oh, David; Wang, Hank; Hazany, Salar; Ohning, Gordon; Pisegna, Joseph R.

2009-01-01

Objectives. Zollinger-Ellison Syndrome (ZES) results in hypersecretion of gastric acid (via gastrinoma) leading to peptic ulcers, diarrhea, and abdominal pain. We describe the novel discovery of hypertrophic, heterotopic gastric mucosa in the proximal duodenal bulb in patients with ZES, which we hypothesize results in an increased incidence of postbulbar ulcers in patients with ZES (a mechanism previously unreported). We determined the incidence of the novel finding of duodenal gastric oxyntic hypertrophic heterotopia (GOH) in patients with ZES. Methods. Seven patients with ZES were enrolled. The diagnosis of ZES was established by hypergastrinemia, gastric acid hypersecretion, and a positive secretin test or based on biopsy specimens (evaluated via tissue staining). Basal acid output (BAO) and baseline gastrin secretion were determined by established methods. Endoscopic examinations with methylene blue staining and biopsy of the gastric and duodenal mucosa were conducted in all patients every 3–6 months for an average of 5 years. Results. The duodenal mucosa demonstrated hypertrophic GOH in 5 out of 7 patients with ZES and an intact stomach and duodenum. Biopsies from the bowel mucosa demonstrated patchy replacement of surface epithelium by gastric-type epithelium with hypertrophic oxyntic glands in the lamina propria in 5 patients. Two of the patients had no evidence of GOH in the duodenal bulb. Patients with GOH had an average serum gastrin level of 1245 pg/mL and BAO of 2.92 mEq/hr versus 724 pg/mL and 0.8 mEq/hr in patients without GOH. Conclusions. This study demonstrated the presence of duodenal mucosa with GOH in 5 out of 7 patients with ZES and an intact stomach and duodenum. The presence of hypertrophic and heterotopic gastric mucosa is proposed to result from increased gastrin levels and may contribute to the increased incidence of postbulbar ulcers in these patients. PMID:19587828

A New 4D Trajectory-Based Approach Unveils Abnormal LV Revolution Dynamics in Hypertrophic Cardiomyopathy

PubMed Central

Madeo, Andrea; Piras, Paolo; Re, Federica; Gabriele, Stefano; Nardinocchi, Paola; Teresi, Luciano; Torromeo, Concetta; Chialastri, Claudia; Schiariti, Michele; Giura, Geltrude; Evangelista, Antonietta; Dominici, Tania; Varano, Valerio; Zachara, Elisabetta; Puddu, Paolo Emilio

2015-01-01

The assessment of left ventricular shape changes during cardiac revolution may be a new step in clinical cardiology to ease early diagnosis and treatment. To quantify these changes, only point registration was adopted and neither Generalized Procrustes Analysis nor Principal Component Analysis were applied as we did previously to study a group of healthy subjects. Here, we extend to patients affected by hypertrophic cardiomyopathy the original approach and preliminarily include genotype positive/phenotype negative individuals to explore the potential that incumbent pathology might also be detected. Using 3D Speckle Tracking Echocardiography, we recorded left ventricular shape of 48 healthy subjects, 24 patients affected by hypertrophic cardiomyopathy and 3 genotype positive/phenotype negative individuals. We then applied Generalized Procrustes Analysis and Principal Component Analysis and inter-individual differences were cleaned by Parallel Transport performed on the tangent space, along the horizontal geodesic, between the per-subject consensuses and the grand mean. Endocardial and epicardial layers were evaluated separately, different from many ecocardiographic applications. Under a common Principal Component Analysis, we then evaluated left ventricle morphological changes (at both layers) explained by first Principal Component scores. Trajectories’ shape and orientation were investigated and contrasted. Logistic regression and Receiver Operating Characteristic curves were used to compare these morphometric indicators with traditional 3D Speckle Tracking Echocardiography global parameters. Geometric morphometrics indicators performed better than 3D Speckle Tracking Echocardiography global parameters in recognizing pathology both in systole and diastole. Genotype positive/phenotype negative individuals clustered with patients affected by hypertrophic cardiomyopathy during diastole, suggesting that incumbent pathology may indeed be foreseen by these methods. Left ventricle deformation in patients affected by hypertrophic cardiomyopathy compared to healthy subjects may be assessed by modern shape analysis better than by traditional 3D Speckle Tracking Echocardiography global parameters. Hypertrophic cardiomyopathy pathophysiology was unveiled in a new manner whereby also diastolic phase abnormalities are evident which is more difficult to investigate by traditional ecocardiographic techniques. PMID:25875818

Comparative effect and safety of verapamil in keloid and hypertrophic scar treatment: a meta-analysis

PubMed Central

Li, Zhouna; Jin, Zhehu

2016-01-01

Background Keloids and hypertrophic scars are the most common types of pathological scarring. Traditionally, keloids have been considered as a result of aberrant wound healing, involving excessive fibroblast participation that is characterized by hyalinized collagen bundles. However, the usefulness of this characterization has been questioned. In recent years, studies have reported the appropriate use of verapamil for keloids and hypertrophic scars. Methods Searches were conducted on the databases Medline, Embase, Cochrane, PubMed, and China National Knowledge Infrastructure from 2006 to July 2016. State12.0 was used for literature review, data extraction, and meta-analysis. Treatment groups were divided into verapamil and nonverapamil group. Nonverapamil group includes steroids and intense pulsed light (IPL) therapy. Total effective rates include cure rate and effective rate. Cure: skin lesions were completely flattened, became soft and symptoms disappeared. Efficacy: skin lesions subsided, patient significantly reduced symptoms. Inefficient definition of skin was progression free or became worse. Random-effects model was used for the meta-analysis. Results Six studies that included 331 patients with keloids and hypertrophic scars were analyzed. Analysis of the total effective rate of skin healing was performed. The total effective rates in the two groups were 54.07% (verapamil) and 53.18% (nonverapamil), respectively. The meta-analysis showed that there was no difference between the two groups. We also compared the adverse reactions between the verapamil treatment group and the steroids treatment group in two studies, and the result indicated that the verapamil group showed less adverse reactions. Conclusion There were no differences between the application of verapamil and nonverapamil group in keloids and hypertrophic scars treatment. Verapamil could act as an effective alternative modality in the prevention and treatment of keloid and hypertrophic scars. A larger number of studies are required to confirm our conclusion. PMID:27877046

Effect of Moderate-Intensity Exercise Training on Peak Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy: A Randomized Clinical Trial.

PubMed

Saberi, Sara; Wheeler, Matthew; Bragg-Gresham, Jennifer; Hornsby, Whitney; Agarwal, Prachi P; Attili, Anil; Concannon, Maryann; Dries, Annika M; Shmargad, Yael; Salisbury, Heidi; Kumar, Suwen; Herrera, Jonathan J; Myers, Jonathan; Helms, Adam S; Ashley, Euan A; Day, Sharlene M

2017-04-04

Formulating exercise recommendations for patients with hypertrophic cardiomyopathy is challenging because of concern about triggering ventricular arrhythmias and because a clinical benefit has not been previously established in this population. To determine whether moderate-intensity exercise training improves exercise capacity in adults with hypertrophic cardiomyopathy. A randomized clinical trial involving 136 patients with hypertrophic cardiomyopathy was conducted between April 2010 and October 2015 at 2 academic medical centers in the United States (University of Michigan Health System and Stanford University Medical Center). Date of last follow-up was November 2016. Participants were randomly assigned to 16 weeks of moderate-intensity exercise training (n = 67) or usual activity (n = 69). The primary outcome measure was change in peak oxygen consumption from baseline to 16 weeks. Among the 136 randomized participants (mean age, 50.4 [SD, 13.3] years; 42% women), 113 (83%) completed the study. At 16 weeks, the change in mean peak oxygen consumption was +1.35 (95% CI, 0.50 to 2.21) mL/kg/min among participants in the exercise training group and +0.08 (95% CI, -0.62 to 0.79) mL/kg/min among participants in the usual-activity group (between-group difference, 1.27 [95% CI, 0.17 to 2.37]; P = .02). There were no occurrences of sustained ventricular arrhythmia, sudden cardiac arrest, appropriate defibrillator shock, or death in either group. In this preliminary study involving patients with hypertrophic cardiomyopathy, moderate-intensity exercise compared with usual activity resulted in a statistically significant but small increase in exercise capacity at 16 weeks. Further research is needed to understand the clinical importance of this finding in patients with hypertrophic cardiomyopathy, as well as the long-term safety of exercise at moderate and higher levels of intensity. clinicaltrials.gov Identifier: NCT01127061.

Incidence, degree, and development of graft hypertrophy 24 months after matrix-induced autologous chondrocyte implantation: association with clinical outcomes.

PubMed

Ebert, Jay R; Smith, Anne; Fallon, Michael; Butler, Rodney; Nairn, Robert; Breidahl, William; Wood, David J

2015-09-01

Graft hypertrophy is a common occurrence after periosteal, collagen-covered and matrix-induced autologous chondrocyte implantation (MACI). The purpose of this study was to investigate the incidence, development, and degree of graft hypertrophy at 24 months after MACI. The hypothesis was that graft hypertrophy would not be associated with clinical outcome at 24 months. Case series, Level of evidence, 4. This study was undertaken in 180 consecutive patients (113 male, 67 female) after MACI in the knee. All patients were assessed clinically using the Knee injury and Osteoarthritis Outcome Score (KOOS) and underwent magnetic resonance imaging (MRI) at 3, 12, and 24 months after surgery. The incidence of hypertrophy relevant to anatomic graft site was investigated, as was the progressive change in hypertrophic studies postoperatively. The degree of tissue overgrowth in hypertrophic cases was investigated, as was its association with patient clinical outcome at 24 months after surgery. Of the 180 patients, 50 demonstrated a hypertrophic graft at 1 or more postoperative time points. This included 9 grafts (5.0%) at 3 months and 32 grafts (18.7%) at 12 months. At 24 months, 47 grafts (26.1%)-43 (32.1%) tibiofemoral and 4 (8.7%) patellofemoral-were hypertrophic. Patients with hypertrophic grafts at 24 months (n = 47) were younger (P = .051), they had a lower body mass index (BMI; P = .069), and significantly fewer of them had patellofemoral grafts (P = .007) compared with patients who had grafts with full (100%) tissue infill (n = 61). There were no significant differences in any of the KOOS subscales between patients with graft hypertrophy or full (100%) tissue infill at 24 months after surgery, while the severity of graft hypertrophy was not associated with KOOS subscales at 24 months. Hypertrophic grafts after MACI were common and continued to develop through to 24 months after surgery. Hypertrophic growth was associated with being younger and having a lower BMI, was more common on the femoral condyles, and overall was not associated with clinical outcome at 24 months after surgery. However, further research with longer term follow-up is required to evaluate the effect of persistent hypertrophy on graft stability and to assess the use of early surgical intervention to prevent such failure. © 2015 The Author(s).

Mesenchymal Stem Cells and Cardiomyocytes Interplay to Prevent Myocardial Hypertrophy

PubMed Central

Tan, Xueying; Zhang, Yong; Li, Xingda; Wang, Xinyue; Zhu, Jiuxin; Wang, Yang; Yang, Fan; Wang, Baoqiu; Liu, Yanju; Xu, Chaoqian; Pan, Zhenwei; Wang, Ning; Yang, Baofeng

2015-01-01

Bone marrow-derived mesenchymal stem cells (BMSCs) have emerged as a promising therapeutic strategy for cardiovascular disease. However, there is no evidence so far that BMSCs can heal pathological myocardial hypertrophy. In this study, BMSCs were indirectly cocultured with neonatal rat ventricular cardiomyocytes (NRVCs) in vitro or intramyocardially transplanted into hypertrophic hearts in vivo. The results showed that isoproterenol (ISO)-induced typical hypertrophic characteristics of cardiomyocytes were prevented by BMSCs in the coculture model in vitro and after BMSC transplantation in vivo. Furthermore, activation of the Ca2+/calcineurin/nuclear factor of activated T cells cytoplasmic 3 (NFATc3) hypertrophic pathway in NRVCs was abrogated in the presence of BMSCs both in vitro and in vivo. Interestingly, inhibition of vascular endothelial growth factor (VEGF) release from BMSCs, but not basic fibroblast growth factor and insulin-like growth factor 1, abolished the protective effects of BMSCs on cardiomyocyte hypertrophy. Consistently, VEGF administration attenuated ISO-induced enlargement of cellular size; the upregulation of atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain expression; and the activation of Ca2+/calcineurin/NFATc3 hypertrophic pathways, and these pathways can be abrogated by blocking VEGFR-1 in cardiomyocytes, indicating that VEGF receptor 1 is involved in the antihypertrophic role of VEGF. We further found that the ample VEGF secretion contributing to the antihypertrophic effects of BMSCs originates from the crosstalk of BMSCs and cardiac cells but not BMSCs or cardiomyocytes alone. Interplay of mesenchymal stem cells with cardiomyocytes produced synergistic effects on VEGF release. In summary, crosstalk between mesenchymal stem cells and cardiomyocytes contributes to the inhibition of myocardial hypertrophy via inhibiting Ca2+/calcineurin/NFATc3 hypertrophic pathways in cardiac cells. These results provide the first evidence for the treatment of myocardial hypertrophy using BMSCs. Significance This study found that mesenchymal stem cells may crosstalk with cardiomyocytes, which causes a synergistic vascular endothelial growth factor (VEGF) release from both kinds of cells and then inhibits pathological cardiac remodeling following hypertrophic stimulation in cardiomyocytes in vitro and in vivo. Blockage of VEGF release from bone marrow-derived mesenchymal stem cells (BMSCs) abolishes the antihypertrophic actions of BMSCs in vitro and in vivo. On the contrary, VEGF administration attenuates hypertrophic signaling of calcineurin/ nuclear factor of activated T cell cytoplasmic 3 signal pathways. This study provides the first evidence for the treatment of myocardial hypertrophy using BMSCs. PMID:26586774

Hypertrophic osteopathy associated with renal pelvis transitional cell carcinoma in a dog

PubMed Central

Grillo, Thais P.; Brandão, Cláudia V.S.; Mamprim, Maria J.; de Jesus, Carlos M.N.; Santos, Taizha C.; Minto, Bruno W.

2007-01-01

A 6-year-old male, Belgian shepherd dog was presented with lethargy, oliguria, hematuria, and reluctance to move. The dog developed hypertrophic osteopathy secondary to renal pelvis transitional cell carcinoma. A nephrectomy was performed and after a year, the dog was completely asymptomatic, and no evidence of metastatic disease was present. PMID:17824162

Left ventricular assist device implantation in a patient who had previously undergone apical myectomy for hypertrophic cardiomyopathy.

PubMed

Cho, Yang Hyun; Deo, Salil V; Topilsky, Yan; Grogan, Martha A; Park, Soon J

2012-03-01

Apical hypertrophy is a rare variant of hypertropic cardiomyopathy. These patients may present with end-stage congestive heart failure subsequent to long standing diastolic dysfunction. We report the technique for left ventricular assist device insertion in a patient with previous apical myectomy for hypertrophic cardiomyopathy. © 2012 Wiley Periodicals, Inc.

Hypertrophic gastropathy with gastric adenocarcinoma: Menetrier's disease and lymphocytic gastritis?

PubMed Central

Mosnier, J F; Flejou, J F; Amouyal, G; Gayet, B; Molas, G; Henin, D; Potet, F

1991-01-01

Lymphocytic gastritis is a form of gastric inflammation characterised by a pronounced increase in lymphocytes in gastric surface and foveolar epithelium. Lymphocytic gastritis is often associated with endoscopic evidence of 'varioliform gastritis'. Lymphocytic gastritis has recently been reported to be associated with other forms of hypertrophic gastropathies. We present a case of hypertrophic gastropathy with gastric adenocarcinoma, with both Menetrier's disease and lymphocyte gastritis. Immunohistochemical studies showed that the intraepithelial lymphocytes were predominantly alpha/beta T cells as in the normal stomach and not gamma/delta T cells as in coeliac sprue. This case together with the six recently published cases suggests that Menetrier's disease and lymphocytic gastritis may be part of the same disease spectrum. Images Figure 1 Figure 2 PMID:1773969

HYPERTROPHIC PYLORIC STENOSIS

PubMed Central

Gans, Stephen L.

1959-01-01

Hypertrophic pyloric stenosis, a relatively common condition, is caused by hyperplasia of the musculature of the pylorus. The diagnosis is made by a history of projectile vomiting and failure to gain weight, the observation of gastric peristaltic waves, and the palpation of a pyloric “tumor.” A method of palpating this tumor is described in detail. Roentgenological studies are rarely indicated. Pylorotomy for treatment of hypertrophic pyloric stenosis was not successful until the development of necessary supporting measures. Preparation for operation consists of intravenous administration of fluids and electrolytes and sometimes serum or whole blood. The position of the tumor governs the choice between two different incisions. The operative procedure herein described is essentially that devised by Ramstedt many years ago, with modifications to facilitate the procedure. PMID:13651960

The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy

PubMed Central

Spudich, James A.

2015-01-01

No matter how many times one explores the structure of the myosin molecule, there is always something new to discover. Here, I describe the myosin mesa, a structural feature of the motor domain that has the characteristics of a binding domain for another protein, possibly myosin-binding protein C (MyBP-C). Interestingly, many well-known hypertrophic cardiomyopathy (HCM) mutations lie along this surface and may affect the putative interactions proposed here. A potential unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy is discussed here. It involves increased power output of the cardiac muscle as a result of HCM mutations causing the release of inhibition by myosin binding protein C. PMID:25619247

Matrix Metalloproteinases Are Differentially Regulated and Responsive to Compression Therapy in a Red Duroc Model of Hypertrophic Scar.

PubMed

Travis, Taryn E; Ghassemi, Pejhman; Prindeze, Nicholas J; Moffatt, Lauren T; Carney, Bonnie C; Alkhalil, Abdulnaser; Ramella-Roman, Jessica C; Shupp, Jeffrey W

2018-01-01

Objective: Proteins of the matrix metalloproteinases family play a vital role in extracellular matrix maintenance and basic physiological processes in tissue homeostasis. The function and activities of matrix metalloproteinases in response to compression therapies have yet to be defined. Here, a swine model of hypertrophic scar was used to profile the transcription of all known 26 matrix metalloproteinases in scars treated with a precise compression dose. Methods: Full-thickness excisional wounds were created. Wounds underwent healing and scar formation. A subset of scars underwent 2 weeks of compression therapy. Biopsy specimens were preserved, and microarrays, reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry were performed to characterize the transcription and expression of various matrix metalloproteinase family members. Results: Microarray results showed that 13 of the known 26 matrix metalloproteinases were differentially transcribed in wounds relative to the preinjury skin. The predominant upregulation of these matrix metalloproteinases during early wound-healing stages declined gradually in later stages of wound healing. The use of compression therapy reduced this decline in 10 of the 13 differentially regulated matrix metalloproteinases. Further investigation of MMP7 using reverse transcription-polymerase chain reaction confirmed the effect of compression on transcript levels. Assessment of MMP7 at the protein level using Western blotting and immunohistochemistry was concordant. Conclusions: In a swine model of hypertrophic scar, the application of compression to hypertrophic scar attenuated a trend of decreasing levels of matrix metalloproteinases during the process of hypertrophic wound healing, including MMP7, whose enzyme regulation was confirmed at the protein level.

Lichen planus hypertrophicus of the vulva - a rare entity.

PubMed

Job, Anupa Mary; Kaimal, Sowmya

2017-09-01

Vulvovaginal lichen planus is a type of chronic inflammatory dermatosis of the vulva, usually seen as a part of widespread lichen planus. The common clinical types of vulval lichen planus include papulosquamous, erosive and pigmented types. Hypertrophic lichen planus of the vulva is a rare entity. We report a case of hypertrophic lichen planus of the vulva which clinically simulated genital warts.

Modeling hypertrophic IP3 transients in the cardiac myocyte.

PubMed

Cooling, Michael; Hunter, Peter; Crampin, Edmund J

2007-11-15

Cardiac hypertrophy is a known risk factor for heart disease, and at the cellular level is caused by a complex interaction of signal transduction pathways. The IP3-calcineurin pathway plays an important role in stimulating the transcription factor NFAT which binds to DNA cooperatively with other hypertrophic transcription factors. Using available kinetic data, we construct a mathematical model of the IP3 signal production system after stimulation by a hypertrophic alpha-adrenergic agonist (endothelin-1) in the mouse atrial cardiac myocyte. We use a global sensitivity analysis to identify key controlling parameters with respect to the resultant IP3 transient, including the phosphorylation of cell-membrane receptors, the ligand strength and binding kinetics to precoupled (with G(alpha)GDP) receptor, and the kinetics associated with precoupling the receptors. We show that the kinetics associated with the receptor system contribute to the behavior of the system to a great extent, with precoupled receptors driving the response to extracellular ligand. Finally, by reparameterizing for a second hypertrophic alpha-adrenergic agonist, angiotensin-II, we show that differences in key receptor kinetic and membrane density parameters are sufficient to explain different observed IP3 transients in essentially the same pathway.

Topical Silicone Sheet Application in the Treatment of Hypertrophic Scars and Keloids.

PubMed

Westra, Iris; Pham, Hth; Niessen, Frank B

2016-10-01

Objective: Since the early 1980s, topical silicone sheets have been used in the treatment of hypertrophic scars and keloids.This study aimed to determine the optimal duration and application of these sheets. Design: multi-centered therapeutic study. Setting and participants: A total of 224 patients were included in this study; 205 patients with hypertrophic scars and 19 patients with keloids. Patients received treatment with a topical silicone sheet. Treated scars varied in age, ranging from two weeks to 62 years and treatment time ranged from one month to 16 months. Assessment of the scars was performed by the use of standardized study forms and digital photography. Measurements: Skin therapists objectively assessed the scars on its color, thickness, and elasticity. Patients themselves subjectively assessed their perception of their scar and their experience with the usage of the topical silicone sheet. Results: After applying the topical silicone sheet, all scars, regardless of type of scar and maturity, improved significantly in color, thickness, and elasticity. Conclusion: In this study, treatment with the topical silicone sheet showed significant improvement on both hypertrophic scars and keloids. Best results were reached when the silicone sheet was applied at least four hours per day.

Efficacy of IPL device combined with intralesional corticosteroid injection for the treatment of keloids and hypertrophic scars with regards to the recovery of skin barrier function: A pilot study.

PubMed

Kim, Dong Young; Park, Hyun Sun; Yoon, Hyun-Sun; Cho, Soyun

2015-10-01

Keloids and hypertrophic scars are prevalent and psychologically distressful dermatologic conditions. Various treatment modalities have been tried but without complete success by any one method. We evaluated the efficacy of a combination of intense pulsed light (IPL) device and intralesional corticosteroid injection for the treatment of keloids and hypertrophic scars with respect to the recovery of skin barrier function. Totally 52 Korean patients were treated by the combined treatment at 4-8-week intervals. Using digital photographs, changes in scar appearance were assessed with modified Vancouver Scar Scale (MVSS), physicians' global assessment (PGA) and patient's satisfaction score. In 12 patients, the stratum corneum (SC) barrier function was assessed by measuring transepidermal water loss (TEWL) and SC capacitance. Most scars demonstrated significant clinical improvement in MVSS, PGA and patient's satisfaction score after the combined therapy. A significant decrease of TEWL and elevation of SC capacitance were also documented after the treatment. The combination therapy (IPL + corticosteroid injection) not only improves the appearance of keloids and hypertrophic scars but also increases the recovery level of skin hydration status in terms of the skin barrier function.

Use of calcium channel blockers in hypertrophic cardiomyopathy.

PubMed

Lorell, B H

1985-02-22

Recent studies in patients with either obstructive or nonobstructive hypertrophic cardiomyopathy have suggested that increased resistance to diastolic filling of the stiff left ventricle may be an important mechanism contributing to symptoms. These observations have led to exploration of the effects of calcium channel blockers on systolic and diastolic function in patients with hypertrophic cardiomyopathy. Acute hemodynamic studies using verapamil and nifedipine have shown that these agents tend to cause: (1) a slight fall in systemic arterial pressure and reflex increase in heart rate; (2) a reduction in left ventricular outflow gradient in most but not all patients; and (3) variable effect on left-side heart filling pressures. In contrast to beta-adrenergic blockers, these hemodynamic effects are not associated with depression of systolic function, but appear to be related to improved left ventricular distensibility. Clinical trials have suggested that long-term administration of verapamil in patients with hypertrophic cardiomyopathy promotes improvement in symptomatic status and exercise tolerance in many but not all patients; similar results have been reported in preliminary studies using nifedipine. Potential major adverse effects include depression of sinoatrial activity and atrioventricular conduction with verapamil, and marked hypotension and, rarely, pulmonary edema with both verapamil and nifedipine.

Treatment Strategies for Hypopigmentation in the Context of Burn Hypertrophic Scars

PubMed Central

Carney, Bonnie C.; McKesey, Jacqueline P.; Rosenthal, Dean S.

2018-01-01

Dyspigmentation in burn scars can contribute to the development of psychosocial complications after injury and can be detrimental to social reintegration and quality of life for burn survivors. Although treatments for skin lightening to treat hyperpigmentation have been well reviewed in the literature, skin-darkening strategies to treat hypopigmentation have not. The following potential treatment options in the context of burn hypertrophic scar will be discussed: use of the melanocyte-keratinocyte transplantation procedure, use of ectopic synthetic analogues of alpha-melanocyte stimulating hormone to initiate melanogenesis, and use of FK506 to induce melanogenesis. A proposed future direction of research in laser-assisted drug delivery of inducers of local melanin production, with the hope of developing a targeted, effective approach to dyspigmentation in hypertrophic scar is also discussed. PMID:29464168

Tangeretin Improves Glucose Uptake in a Coculture of Hypertrophic Adipocytes and Macrophages by Attenuating Inflammatory Changes.

PubMed

Shin, Hye-Sun; Kang, Seong-Il; Ko, Hee-Chul; Park, Deok-Bae; Kim, Se-Jae

2017-03-01

Obesity is characterized by a state of chronic low-grade inflammation and insulin resistance, which are aggravated by the interaction between hypertrophic adipocytes and macrophages. In this study, we investigated the effects of tangeretin on inflammatory changes and glucose uptake in a coculture of hypertrophic adipocytes and macrophages. Tangeretin decreased nitric oxide production and the expression of interleukin (IL)-6, IL-1β, tumor necrosis factor-α, inducible nitric oxide synthase, and cyclooxygenase-2 in a coculture of 3T3-L1 adipocytes and RAW 264.7 cells. Tangeretin also increased glucose uptake in the coculture system, but did not affect the phosphorylation of insulin receptor substrate (IRS) and Akt. These results suggest that tangeretin improves insulin resistance by attenuating obesity-induced inflammation in adipose tissue.

Hypertrophic cardiomyopathy.

PubMed

Santos Mateo, Juan José; Sabater Molina, María; Gimeno Blanes, Juan Ramón

2018-06-08

Hypertrophic cardiomyopathy is the most common inherited cardiovascular disease. It is characterized by increased ventricular wall thickness and is highly complex due to its heterogeneous clinical presentation, several phenotypes, large number of associated causal mutations and broad spectrum of complications. It is caused by mutations in sarcomeric proteins, which are identified in up to 60% of cases of the disease. Clinical manifestations of Hypertrophic Cardiomyopathy include shortness of breath, chest pain, palpitations and syncope, which are related to the onset of diastolic dysfunction, left ventricular outflow tract obstruction, ischemia, atrial fibrillation and abnormal vascular responses. It is associated with an increased risk of sudden cardiac death, heart failure and thromboembolic events. In this article, we discuss the diagnostic and therapeutic aspects of this disease. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Biventricular non-compaction hypertrophic cardiomyopathy in association with congenital complete heart block and type I mitochondrial complex deficiency.

PubMed

Dhar, Ranjana; Reardon, William; McMahon, Colin J

2015-06-01

We report a baby girl with an antenatal diagnosis of biventricular non-compaction and complete heart block detected at 22 weeks' gestation. Postnatal echocardiography confirmed severe biventricular non-compaction hypertrophic cardiomyopathy, multiple muscular ventricular septal defects, and mild-moderate pulmonary valve stenosis. Skeletal muscle biopsy confirmed complex 1 mitochondrial respiratory chain deficiency. An epicardial VVI pacemaker was implanted on day 3 of life and revised at 7 years of age. She remains stable at 8 years of age following pacing and medical treatment with carvedilol, aspirin, co-enzyme Q10, and carnitine. This represents the first report of biventricular non-compaction hypertrophic phenotype in association with congenital complete heart block and complex 1 mitochondrial respiratory chain deficiency in a child.

Hypertrophic Scars: Are Vitamins and Inflammatory Biomarkers Related with the Pathophysiology of Wound Healing?

PubMed

Correia-Sá, Inês; Serrão, Paula; Marques, Marisa; Vieira-Coelho, Maria A

2017-12-01

Hypertrophic scars are a consequence of wound healing. The objective of the present study is to evaluate vitamin D and inflammatory biomarker plasma levels during wound healing. A prospective study was performed in patients (n = 63) submitted to body contouring surgery. Blood samples were collected before (t 0 ) and 5 days after surgery (t 5 ). Blood cell count, protein inflammatory biomarkers, and circulating plasma levels of 25(OH)D, vitamin A and vitamin E were quantified. Six months after surgery, scars were evaluated and classified as normal or hypertrophic. At the end of the study, 73% of the patients developed a normal scar (control group, n = 46) and 27% of the patients presented hypertrophic scars (HT group, n = 17). The patients in the HT group presented higher eosinophil (0.145 × 10 9 /L vs. 0.104 × 10 9 /L, p = 0.028) and basophil count (0.031 × 10 9 /L vs. 0.22 × 10 9 /L, p = 0.049) and C-reactive protein levels (6.12 mg/L vs. 2.30 mg/L, p = 0.015) in t 0 than the patients in the control group. At t 5 , the patients in the HT group showed a decrease in neutrophil (3.144 × 10 9/L vs. 4.03 × 10 9 /L, p = 0.031) and an increase in basophil (0.024 × 10 9 /L vs. 0.015 × 10 9 /L, p = 0.005) and lymphocyte count (1.836 × 10 9 /L vs. 1.557 × 10 9 /L; p = 0.028). Before surgery, vitamin D plasma levels were found to be decreased by almost 50% (23.52 ng/mL vs. 15.46 ng/mL, p = 0.031) in the patients who developed hypertrophic scars. Thirty-one percent of the patients submitted to bariatric surgery had more hypertrophic scars, versus 24% of the patients with no previous bariatric surgery. There is a different systemic inflammatory profile response in the patients during the formation of hypertrophic scars. Vitamin D plasma levels are marked reduced in these patients. Considering the powerful anti-inflammatory effect of vitamin D, these findings could be related.

Verrucous Lichen Planus: A Rare Presentation of a Common Condition

PubMed Central

Audhya, Moutusi; Varughese, Jenny S.; Nakhwa, Yuti C.

2014-01-01

Lichen planus is a chronic papulosquamous dermatoses in which both skin and mucosae are involved. There are various morphological forms of lichen planus. Hypertrophic lichen planus is one of the rare clinical variants. Herein, we report a very unusual presentation of hypertrophic lichen planus. A similar presentation has not been reported in literature yet, to the best of our knowledge. PMID:25386324

A crying baby: not simply infant colic.

PubMed

Onesimo, Roberta; Giorgio, Valentina; Monaco, Serena; Fundarò, Carlo

2012-08-21

Hypertrophic pyloric stenosis is a relatively common condition, but atypical presentations can present a diagnostic challenge. We describe the case of a 9-week-old Latin male infant who presented with a 2-day history of intermittent crying and poor feeding. He was suspected to have intussusception but was affected by and successfully treated for hypertrophic pyloric stenosis. Diagnostic tools of atypical HPS cases are discussed.

In-the-bag decentration of an intraocular lens in a patient with a tendency to hypertrophic scarring

PubMed Central

Joshi, Rajesh Subhash

2016-01-01

Summary We report a case of rapid anterior lens capsular contraction leading to decentration of a hydrophilic acrylic lens with stiff haptics (Rayner design). To our knowledge, this is the first report to investigate early capsular contraction with folding of the haptic over the optic in a patient with a tendency toward hypertrophic scar formation. PMID:27330480

Left ventricular hypertrophy diagnosed after a stroke: a case report.

PubMed

Umeojiako, Wilfred Ifeanyi; Kanyal, Ritesh

2018-03-22

Stroke is a recognized clinical course of hypertrophic cardiomyopathy. This interesting case showed notable difference on the electrocardiogram of a patient 4 months prior to suffering a stroke and 10 days after suffering a stroke. The pre-stroke electrocardiogram showed atrial fibrillation with a narrow QRS complex, while the post-stroke electrocardiogram showed marked left ventricular hypertrophy. Left ventricular hypertrophy was diagnosed using the Sokolow-Lyon indices. The development of left ventricular hypertrophy a few days after suffering a stroke has not previously been reported. An 83-year-old white British woman with a background history of permanent atrial fibrillation, hypertension, and previous stroke attended the emergency department with a 2-day history of exertional dyspnea, and chest tightness. On examination, she had bibasal crepitations with a systolic murmur loudest at the apex. In-patient investigations include an electrocardiogram, blood tests, chest X-ray, contrast echocardiogram, coronary angiogram, and cardiovascular magnetic resonance imaging. An electrocardiogram showed atrial fibrillation, with inferolateral T wave inversion, and left ventricular hypertrophy. A chest X-ray showed features consistent with pulmonary edema. A contrast echocardiogram showed marked hypertrophy of the mid to apical left ventricle, appearance consistent with apical hypertrophic cardiomyopathy. Coronary angiography showed eccentric shelf-type plaque with non-flow-limiting stenosis in the left coronary artery main stem. Cardiovascular magnetic resonance imaging reported findings highly suggestive of apical hypertrophic cardiomyopathy. Our patient was treated and discharged on rivaroxaban, bisoprolol, and atorvastatin with a follow-up in the cardiomyopathy outpatient clinic. Electrocardiogram diagnosis of left ventricular hypertrophy led to the diagnosis of apical hypertrophic cardiomyopathy in this patient. Left ventricular hypertrophy was only evident a few days after our patient suffered a stroke. The underlying mechanisms responsible for this remain unclear. Furthermore, differential diagnosis of hypertrophic cardiomyopathy should be considered in people with electrocardiogram criteria for left ventricular hypertrophy. Cardiovascular magnetic resonance imaging is an important diagnostic tool in identifying causes of left ventricular hypertrophy. Family screening should be recommended in patients with new diagnosis of hypertrophic cardiomyopathy.

Synemin acts as a regulator of signalling molecules during skeletal muscle hypertrophy.

PubMed

Li, Zhenlin; Parlakian, Ara; Coletti, Dario; Alonso-Martin, Sonia; Hourdé, Christophe; Joanne, Pierre; Gao-Li, Jacqueline; Blanc, Jocelyne; Ferry, Arnaud; Paulin, Denise; Xue, Zhigang; Agbulut, Onnik

2014-11-01

Synemin, a type IV intermediate filament (IF) protein, forms a bridge between IFs and cellular membranes. As an A-kinase-anchoring protein, it also provides temporal and spatial targeting of protein kinase A (PKA). However, little is known about its functional roles in either process. To better understand its functions in muscle tissue, we generated synemin-deficient (Synm(-) (/-)) mice. Synm(-) (/-) mice displayed normal development and fertility but showed a mild degeneration and regeneration phenotype in myofibres and defects in sarcolemma membranes. Following mechanical overload, Synm(-) (/-) mice muscles showed a higher hypertrophic capacity with increased maximal force and fatigue resistance compared with control mice. At the molecular level, increased remodelling capacity was accompanied by decreased myostatin (also known as GDF8) and atrogin (also known as FBXO32) expression, and increased follistatin expression. Furthermore, the activity of muscle-mass control molecules (the PKA RIIα subunit, p70S6K and CREB1) was increased in mutant mice. Finally, analysis of muscle satellite cell behaviour suggested that the absence of synemin could affect the balance between self-renewal and differentiation of these cells. Taken together, our results show that synemin is necessary to maintain membrane integrity and regulates signalling molecules during muscle hypertrophy. © 2014. Published by The Company of Biologists Ltd.

Correlation between Gene Expression and Osteoarthritis Progression in Human.

PubMed

Zhong, Leilei; Huang, Xiaobin; Karperien, Marcel; Post, Janine N

2016-07-14

Osteoarthritis (OA) is a multifactorial disease characterized by gradual degradation of joint cartilage. This study aimed to quantify major pathogenetic factors during OA progression in human cartilage. Cartilage specimens were isolated from OA patients and scored 0-5 according to the Osteoarthritis Research Society International (OARSI) guidelines. Protein and gene expressions were measured by immunohistochemistry and qPCR, respectively. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used to detect apoptotic cells. Cartilage degeneration in OA is a gradual progress accompanied with gradual loss of collagen type II and a gradual decrease in mRNA expression of SOX9, ACAN and COL2A1. Expression of WNT antagonists DKK1 and FRZB was lost, while hypertrophic markers (RUNX2, COL10A1 and IHH) increased during OA progression. Moreover, DKK1 and FRZB negatively correlated with OA grading, while RUNX2 and IHH showed a significantly positive correlation with OA grading. The number of apoptotic cells was increased with the severity of OA. Taken together, our results suggested that genetic profiling of the gene expression could be used as markers for staging OA at the molecular level. This helps to understand the molecular pathology of OA and may lead to the development of therapies based on OA stage.

Ephrin-B2 Reverse Signaling Is Required for Topography but Not Pattern Formation of Lateral Superior Olivary Inputs to the Inferior Colliculus

PubMed Central

Wallace, Matthew M.; Kavianpour, Sarah M.; Gabriele, Mark L.

2014-01-01

Graded and modular expressions of Eph-ephrins are known to provide positional information for the formation of topographic maps and patterning in the developing nervous system. Previously we have shown that ephrin-B2 is expressed in a continuous gradient across the tonotopic axis of the central nucleus of the inferior colliculus (CNIC), whereas patterns are discontinuous and modular in the lateral cortex of the IC (LCIC). The present study explores the involvement of ephrin-B2 signaling in the development of projections to the CNIC and LCIC arising from the lateral superior olivary nuclei (LSO) prior to hearing onset. Anterograde and retrograde fluorescent tracing methods in neonatal fixed tissue preparations were used to compare topographic mapping and the establishment of LSO layers/modules in wild-type and ephrin-B2lacZ/+ mice (severely compromised reverse signaling). At birth, pioneer LSO axons occupy the ipsilateral IC in both groups but are delayed contralaterally in ephrin-B2lacZ/+ mutants. By the onset of hearing, both wild-type and mutant projections form discernible layers bilaterally in the CNIC and modular arrangements within the ipsilateral LCIC. In contrast, ephrin-B2lacZ/+ mice lack a reliable topography in LSO-IC projections, suggesting that fully functional ephrin-B2 reverse signaling is required for normal projection mapping. Taken together, these ephrin-B2 findings paired with known coexpression of EphA4 suggest the importance of these signaling proteins in establishing functional auditory circuits prior to experience. PMID:23042409

Early segregation of layered projections from the lateral superior olivary nucleusto the central nucleus of the inferior colliculus in the neonatal cat

PubMed Central

Gabriele, Mark L.; Shahmoradian, Sarah H.; French, Christopher C.; Henkel, Craig K.we; McHaffie, John G.

2007-01-01

The central nucleus of the inferior colliculus (IC) is a laminated structure that receives multiple converging afferent projections. These projections terminate in a layered arrangement and are aligned with dendritic arbors of the predominant disc-shaped neurons, forming fibrodendritic laminae. Within this structural framework, inputs terminate in a precise manner, establishing a mosaic of partially overlapping domains that likely define functional compartments. Although several of these patterned inputs have been described in the adult, relatively little is known about their organization prior to hearing onset. The present study used the lipophilic carbocyanine dyes DiI and DiD to examine the ipsilateral and contralateral projections from the lateral superior olivary (LSO) nucleus to the IC in a developmental series of paraformaldehyde-fixed kitten tissue. By birth, the crossed and uncrossed projections had reached the IC and were distributed across the frequency axis of the central nucleus. At this earliest postnatal stage, projections already exhibited a characteristic banded arrangement similar to that described in the adult. The heaviest terminal fields of the two inputs were always complementary in nature, with the ipsilateral input appearing slightly denser. This early arrangement of interdigitating ipsilateral and contralateral LSO axonal bands that occupy adjacent sublayers supports the idea that the initial establishment of this highly organized mosaic of inputs that defines distinct synaptic domains within the IC occurs largely in the absence of auditory experience. Potential developmental mechanisms that may shape these highly ordered inputs prior to hearing onset are discussed. PMID:17850770

Ephrin-B2 reverse signaling is required for topography but not pattern formation of lateral superior olivary inputs to the inferior colliculus.

PubMed

Wallace, Matthew M; Kavianpour, Sarah M; Gabriele, Mark L

2013-05-01

Graded and modular expressions of Eph-ephrins are known to provide positional information for the formation of topographic maps and patterning in the developing nervous system. Previously we have shown that ephrin-B2 is expressed in a continuous gradient across the tonotopic axis of the central nucleus of the inferior colliculus (CNIC), whereas patterns are discontinuous and modular in the lateral cortex of the IC (LCIC). The present study explores the involvement of ephrin-B2 signaling in the development of projections to the CNIC and LCIC arising from the lateral superior olivary nuclei (LSO) prior to hearing onset. Anterograde and retrograde fluorescent tracing methods in neonatal fixed tissue preparations were used to compare topographic mapping and the establishment of LSO layers/modules in wild-type and ephrin-B2(lacZ/+) mice (severely compromised reverse signaling). At birth, pioneer LSO axons occupy the ipsilateral IC in both groups but are delayed contralaterally in ephrin-B2(lacZ/+) mutants. By the onset of hearing, both wild-type and mutant projections form discernible layers bilaterally in the CNIC and modular arrangements within the ipsilateral LCIC. In contrast, ephrin-B2(lacZ/+) mice lack a reliable topography in LSO-IC projections, suggesting that fully functional ephrin-B2 reverse signaling is required for normal projection mapping. Taken together, these ephrin-B2 findings paired with known coexpression of EphA4 suggest the importance of these signaling proteins in establishing functional auditory circuits prior to experience. Copyright © 2012 Wiley Periodicals, Inc.

Synchronicity and Rhythmicity of Purkinje Cell Firing during Generalized Spike-and-Wave Discharges in a Natural Mouse Model of Absence Epilepsy

PubMed Central

Kros, Lieke; Lindeman, Sander; Eelkman Rooda, Oscar H. J.; Murugesan, Pavithra; Bina, Lorenzo; Bosman, Laurens W. J.; De Zeeuw, Chris I.; Hoebeek, Freek E.

2017-01-01

Absence epilepsy is characterized by the occurrence of generalized spike and wave discharges (GSWDs) in electrocorticographical (ECoG) recordings representing oscillatory activity in thalamocortical networks. The oscillatory nature of GSWDs has been shown to be reflected in the simple spike activity of cerebellar Purkinje cells and in the activity of their target neurons in the cerebellar nuclei, but it is unclear to what extent complex spike activity is implicated in generalized epilepsy. Purkinje cell complex spike firing is elicited by climbing fiber activation and reflects action potential firing in the inferior olive. Here, we investigated to what extent modulation of complex spike firing is reflected in the temporal patterns of seizures. Extracellular single-unit recordings in awake, head-restrained homozygous tottering mice, which suffer from a mutation in the voltage-gated CaV2.1 calcium channel, revealed that a substantial proportion of Purkinje cells (26%) showed increased complex spike activity and rhythmicity during GSWDs. Moreover, Purkinje cells, recorded either electrophysiologically or by using Ca2+-imaging, showed a significant increase in complex spike synchronicity for both adjacent and remote Purkinje cells during ictal events. These seizure-related changes in firing frequency, rhythmicity and synchronicity were most prominent in the lateral cerebellum, a region known to receive cerebral input via the inferior olive. These data indicate profound and widespread changes in olivary firing that are most likely induced by seizure-related activity changes in the thalamocortical network, thereby highlighting the possibility that olivary neurons can compensate for pathological brain-state changes by dampening oscillations. PMID:29163057

Characterization of the superior olivary complex of Canis lupus domesticus.

PubMed

Fech, Tatiana; Calderón-Garcidueñas, Lilian; Kulesza, Randy J

2017-08-01

The superior olivary complex (SOC) is a collection of brainstem auditory nuclei which play essential roles in the localization of sound sources, temporal coding of vocalizations and descending modulation of the cochlea. Notwithstanding, the SOC nuclei vary considerably between species in accordance with the auditory needs of the animal. The canine SOC was subjected to anatomical and physiological examination nearly 50 years ago and was then virtually forgotten. Herein, we aimed to characterize the nuclei of the canine SOC using quantitative morphometrics, estimation of neuronal number, histochemistry for perineuronal nets and immunofluorescence for the calcium binding proteins calbindin and calretinin. We found the principal nuclei to be extremely well developed: the lateral superior olive (LSO) contained over 20,000 neurons and the medial superior olive (MSO) contained over 15,000 neurons. In nearly all non-chiropterian terrestrial mammals, the MSO exists as a thin, vertical column of neurons. The canine MSO was folded into a U-shaped contour and had associated with the ventromedial tip a small, round collection of neurons we termed the tail nucleus of the MSO. Further, we found evidence within the LSO, MSO and medial nucleus of the trapezoid body (MNTB) for significant morphological variations along the mediolateral or rostrocaudal axes. Finally, the majority of MNTB neurons were calbindin-immunopositive and associated with calretinin-immunopositive calyceal terminals. Together, these observations suggest the canine SOC complies with the basic plan of the mammalian SOC but possesses a number of unique anatomical features. Copyright © 2017 Elsevier B.V. All rights reserved.

Arterial compression of the retro-olivary sulcus of the medulla in essential hypertension: a multivariate analysis.

PubMed

Coffee, Robert E; Nicholas, Joyce S; Egan, Brent M; Rumboldt, Zoran; D'Agostino, Sabino; Patel, Sunil J

2005-11-01

Pulsatile arterial compression (AC) of the ventrolateral medulla (VLM) has been postulated to cause neurogenically mediated essential hypertension (EHTN). We aimed to establish whether the association between AC of specifically the retro-olivary sulcus (ROS) of the VLM and EHTN was significant, while controlling for other risks associated with EHTN. Case-control study. Posterior fossa magnetic resonance imaging scans of 131 subjects, including 58 subjects with EHTN and 73 normotensives, were reviewed to determine the presence of AC in the ROS. The history of other risk factors for EHTN was obtained by reviewing medical records. Multivariate logistic regression analysis of these data shows a significant association between AC in the ROS (right and/or left) and EHTN [odds ratio (OR) = 3.03, 95% confidence interval (CI) = 1.30, 7.06]. This analysis was done controlling for other known EHTN risk factors such as age, race, sex, diabetes, and obesity. A secondary analysis also controlling for these variables shows that AC of both the right and left ROS are independently associated with EHTN (right AC: OR = 5.04, 95% CI = 1.33, 19.17; left AC: OR = 3.39, 95% CI = 1.20, 9.60). In this retrospective study of subjects with EHTN and normotensive controls that had undergone magnetic resonance imaging of the posterior fossa, AC of the ROS on either side of the medulla is a significant independent risk factor in EHTN. Further studies are required to determine whether this is true for the general population of patients with neurogenically mediated EHTN.

Feeding ecology and energetic relationships with habitat of blue catfish, Ictalurus furcatus, and flathead catfish, Pylodictis olivaris, in the lower Mississippi River, U.S.A.

USGS Publications Warehouse

Eggleton, M.A.; Schramm, H.L.

2004-01-01

We examined feeding of blue catfish, Ictalurus furcatus, and flathead catfish, Pylodictis olivaris, collected from floodplain lake, secondary (side) river channel, and main river channel habitats in the lower Mississippi River (LMR), U.S.A. We described the feeding ecology of two large river catfish species within the context of whether off-channel habitats in the LMR (i.e., floodplain lakes and secondary channels) potentially provided energetic benefits to these fishes as purported in contemporary theory on the ecology of large rivers. We used diet composition and associated caloric densities of prey consumed as indicators of energetic benefit to catfishes. Differences in diet among habitats were strong for blue catfish, but weak for flathead catfish; consumed foods generally differed among habitats in caloric (energy) content. Caloric densities of consumed foods were generally greatest in floodplain lakes, least in the main river channel, and intermediate in secondary river channels. Strong between-year variation in diet was observed, but only for blue catfish. Blue catfish fed disproportionately on lower-energy zebra mussels in the main river channel during 1997, and higher-energy chironomids and oligochaetes in floodplain lakes during 1998. Results suggested that although off-channel habitats potentially provided greater energetic return to catfishes in terms of foods consumed, patterns of feeding and subsequent energy intake may vary annually. Energetic benefits associated with off-channel habitats as purported under contemporary theory (e.g., the 'flood-pulse concept') may not be accrued by catfishes every year in the LMR.

Functional characterization of TRAP1-like protein involved in modulating fibrotic processes mediated by TGF-β/Smad signaling in hypertrophic scar fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, X.; Department of Pediatric Surgery, Shanghai Children’s Medical Center, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127; Chu, J.

2015-03-15

The transforming growth factor-β1 (TGF-β)-mediated signaling pathway is believed to be closely associated with wound healing and scar formation, in which TRAP1-like protein (TLP) plays a role in regulating the balance of Smad2 vs. Smad3 signaling. Our previous study revealed the relation between TLP and collagen synthesis in normal human skin fibroblasts. Here, we present a detailed analysis of the effects of TLP on the process of hypertrophic scar formation and contraction. To explore and verify a contribution of TLP to the pathological mechanism of hypertrophic scar fibroblasts (HSFb), we constructed lentiviral vectors that either overexpressed TLP or encoded smallmore » hairpin RNAs (shRNAs) targeting TLP, then we transfected them into HSFb. TLP knockdown in HSFb resulted in reduced levels of cell contraction, type I and type III collagen mRNA transcripts and protein expression, and higher levels of fibronectin (FN) compared to control groups. In addition, knockdown of TLP promoted the phosphorylation of Smad3 but repressed Smad2 and Erk-1/2 phosphorylation in human hypertrophic scar fibroblasts compared to control groups. The reduction of TLP did not interfere with HSF proliferative ability, but exogenous TLP cooperated with TGF-β1 to increase cell viability. Together, our findings demonstrate evidence for a contribution of TLP expression in hypertrophic scar formation and contraction. - Highlights: • TLP acted different roles in the activating of Smad2- and Smad3-dependent signaling. • TLP may induce TGF-β1-mediated collagens expression through Smad signalings and MAPK signaling. • TLP may enhance HSFb contraction by increasing the expression of α-SMA. • Exogenous TLP can cooperate with TGF-β1 to increase cell viability.« less

Immunolocalization of type X collagen in normal fetal and adult osteoarthritic cartilage with monoclonal antibodies.

PubMed

Girkontaite, I; Frischholz, S; Lammi, P; Wagner, K; Swoboda, B; Aigner, T; Von der Mark, K

1996-09-01

For studies on processing and tissue distribution of type X collagen, monoclonal antibodies were prepared against human recombinant collagen type X (hrCol X) and tested by ELISA, immunoblotting and immunohistology. Forty-two clones were obtained which were grouped into four different subsets based on their reactivity against native and denatured hrCol X, pepsin-treated hrCol X, and the C-terminal NC-1 domain. Here we present results obtained with four monoclonal antibodies: Clone X 53, a representative of group I, binds with high affinity to both native and pepsin-digested hrCol X but with low affinity to the NC-1 dimer; monoclonal antibodies of group II and III recognized native and denatured hrCol X but not NC-1; antibodies of group II, but not III, reacted to some extent with pepsin treated hrCol X; one antibody (X 34) was obtained that reacted strongly with the isolated NC-1 dimer and native hrCol X but not with the NC-1 monomer or pepsin-digested hrCol X (group IV). Antibodies of all groups stained specifically the hypertrophic zone of fetal human epiphyseal cartilage. Mab X 53 stained the peri- and extracellular matrix of hypertrophic chondrocytes in the lower hypertrophic zone and in the calcified cartilage core in endochondral bone trabecules, while clone X 34 stained intracellularly and the pericellular matrix. All other tissues or cells of the epiphysis were negative. Antibody X 53 reacted also with canine, murine and guinea pig hypertrophic cartilage in tissue sections, but not with bovine or porcine type X collagen. In sections of osteoarthritic cartilage, clusters of hypertrophic chondrocytes in the deep zone were stained, confirming previous observations on enhanced chondrocyte hypertrophy and type X collagen expression in osteoarthritic articular cartilage.

Src homology 2 domain-containing phosphatase 2 (Shp2) is a component of the A-kinase-anchoring protein (AKAP)-Lbc complex and is inhibited by protein kinase A (PKA) under pathological hypertrophic conditions in the heart.

PubMed

Burmeister, Brian T; Taglieri, Domenico M; Wang, Li; Carnegie, Graeme K

2012-11-23

AKAP-Lbc is a scaffold protein that coordinates cardiac hypertrophic signaling. AKAP-Lbc interacts with Shp2, facilitating its regulation by PKA. AKAP-Lbc integrates PKA and Shp2 signaling in the heart. Under pathological hypertrophic conditions Shp2 is phosphorylated by PKA, and phosphatase activity is inhibited. Inhibition of Shp2 activity through AKAP-Lbc-anchored PKA is a previously unrecognized mechanism that may promote pathological cardiac hypertrophy. Pathological cardiac hypertrophy (an increase in cardiac mass resulting from stress-induced cardiac myocyte growth) is a major factor underlying heart failure. Our results identify a novel mechanism of Shp2 inhibition that may promote cardiac hypertrophy. We demonstrate that the tyrosine phosphatase, Shp2, is a component of the A-kinase-anchoring protein (AKAP)-Lbc complex. AKAP-Lbc facilitates PKA phosphorylation of Shp2, which inhibits its protein-tyrosine phosphatase activity. Given the important cardiac roles of both AKAP-Lbc and Shp2, we investigated the AKAP-Lbc-Shp2 interaction in the heart. AKAP-Lbc-tethered PKA is implicated in cardiac hypertrophic signaling; however, mechanism of PKA action is unknown. Mutations resulting in loss of Shp2 catalytic activity are also associated with cardiac hypertrophy and congenital heart defects. Our data indicate that AKAP-Lbc integrates PKA and Shp2 signaling in the heart and that AKAP-Lbc-associated Shp2 activity is reduced in hypertrophic hearts in response to chronic β-adrenergic stimulation and PKA activation. Thus, while induction of cardiac hypertrophy is a multifaceted process, inhibition of Shp2 activity through AKAP-Lbc-anchored PKA is a previously unrecognized mechanism that may promote compensatory cardiac hypertrophy.

Hypertrophic Effects of Concentric vs. Eccentric Muscle Actions: A Systematic Review and Meta-analysis.

PubMed

Schoenfeld, Brad J; Ogborn, Dan I; Vigotsky, Andrew D; Franchi, Martino V; Krieger, James W

2017-09-01

Schoenfeld, BJ, Ogborn, DI, Vigotsky, AD, Franchi, MV, and Krieger, JW. Hypertrophic effects of concentric vs. eccentric muscle actions: A systematic review and meta-analysis. J Strength Cond Res 31(9): 2599-2608, 2017-Controversy exists as to whether different dynamic muscle actions produce divergent hypertrophic responses. The purpose of this paper was to conduct a systematic review and meta-analysis of randomized controlled trials comparing the hypertrophic effects of concentric vs. eccentric training in healthy adults after regimented resistance training (RT). Studies were deemed eligible for inclusion if they met the following criteria: (a) were an experimental trial published in an English-language refereed journal; (b) directly compared concentric and eccentric actions without the use of external implements (i.e., blood pressure cuffs) and all other RT variables equivalent; (c) measured morphologic changes using biopsy, imaging (magnetic resonance imaging, computerized tomography, or ultrasound), bioelectrical impedance, and/or densitometry; (d) had a minimum duration of 6 weeks; and (e) used human participants without musculoskeletal injury or any health condition that could directly, or through the medications associated with the management of said condition, be expected to impact the hypertrophic response to resistance exercise. A systematic literature search determined that 15 studies met inclusion criteria. Results showed that eccentric muscle actions resulted in a greater effect size (ES) compared with concentric actions, but results did not reach statistical significance (ES difference = 0.25 ± 0.13; 95% confidence interval: -0.03 to 0.52; p = 0.076). The mean percent change in muscle growth across studies favored eccentric compared with concentric actions (10.0% vs. 6.8, respectively). The findings indicate the importance of including eccentric and concentric actions in a hypertrophy-oriented RT program, as both have shown to be effective in increasing muscle hypertrophy.

Augmentation plating in hypertrophic non-union after nail fixation of femoral shaft fracture compared with exchange plating.

PubMed

Jiang, Liangjun; Pan, Zhijun; Zheng, Qiang

2014-01-01

Augmentation plating has been used successfully to treat hypertrophic non-union after nail fixation. This study compared the efficacy of augmentation plating and exchange plating for treating hypertrophic non-union of femoral shaft fracture after intramedullary nail fixation. A total of 12 patients received augmentation plating and 15 patients received exchange plating as treatment for femoral shaft hypertrophic non-union. The procedures were conducted at our medical centre between January 2005 and January 2012. Clinical follow-up was conducted at 2 weeks, 1 month and then monthly until union was achieved to compare union time, operation time, bleeding and complications between the two groups. All patients underwent follow-up examinations until fracture union was achieved. The average length of follow-up time after the second treatment was (18.37 ± 3.28) months. The time needed for union was (4.17 ± 0.94) months in the augmentation plating group and (5.33 ± 1.72) months in the exchange plating group. The operation time was (90.00 ± 17.58) minutes in the augmentation plating group and (160.00 ± 25.35) minutes in the exchange plating group. The amount of blood loss during the operation was (270.00 ± 43.32) ml in the augmentation plating group and (530.00 ± 103.65) ml in the exchange plating group. Both groups showed significant difference (P < 0.05) in their results. No complications were reported after the second operation. Augmentation plating after nail fixation could remove local rotation instability, facilitate simple operation, create minimal damage and enable exercise for early functional recovery. Therefore, augmentation plating is excellent for treating hypertrophic non-union after nail fixation in femoral shaft fracture.

Effect of P144® (Anti-TGF-β) in an "In Vivo" Human Hypertrophic Scar Model in Nude Mice.

PubMed

Qiu, Shan Shan; Dotor, Javier; Hontanilla, Bernardo

2015-01-01

Hypertrophic scars are one of the most important complications in surgery due to their cosmetic and functional impairments. Previous studies in tissue fibrotic disorders have shown promising results by inhibiting the biological activity effect of Transforming Growth Factor-beta 1 (TGF-β1). The aim of the current study was to determine the clinical effect of the inhibition of TGF-β1 signaling in human hypertrophic scars implanted in nude mice by topical application of an inhibitor of TGF-β1 (P144®). A total of 30 human hypertrophic scars were implanted in 60 nude mice. The animals were divided in two groups, group A (placebo) and group B (treatment). Group C (basal) was considered as the preimplanted scar samples and they were not implanted in the nude mice. After the shedding period, topical application of a lipogel containing placebo (group A) or P144 (group B) was daily administered during two weeks. The animals were sacrificed upon completion of the study. Total area, thickness and collagen fibers area were measure and compared across all groups. Immunohistochemistry was also performed in order to quantify collagen type I and type III and elastic fiber expressions present in the dermis. Successful shedding was achieved in 83,3% of the xenografts. The mean time for shedding was 35±5.4 days. Statistically significant differences were found in the total area, collagen fibers area and thickness between the groups. Increased elastic fibers and decreased collagen I were found in the P144-treated group compared to the basal group. Topical application of an inhibitor of TGF-β1 may promote scar maturation and clinical improvement of hypertrophic scar morphology features in an "in vivo" model in nude mice after two weeks of treatment.

Lmcd1/Dyxin, a novel Z-disc associated LIM protein, mediates cardiac hypertrophy in vitro and in vivo.

PubMed

Frank, Derk; Frauen, Robert; Hanselmann, Christiane; Kuhn, Christian; Will, Rainer; Gantenberg, Johanne; Füzesi, Laszlo; Katus, Hugo A; Frey, Norbert

2010-10-01

To identify new mediators of cardiac hypertrophy, we performed a genome-wide mRNA screen of stretched neonatal rat cardiomyocytes (NRCMs). In addition to known members of the hypertrophic gene program, we found the novel sarcomeric Z-disc LIM protein Lmcd1/Dyxin markedly upregulated. Consistently, Lmcd1 was also induced in several mouse models of myocardial hypertrophy suggesting a causal role in cardiac hypertrophy. We overexpressed Lmcd1 in NRCM, which led to cardiomyocyte hypertrophy and induction of the hypertrophic gene program. Likewise, the calcineurin-responsive gene RCAN1-4 was found significantly upregulated. Conversely, knockdown of Lmcd1 blunted the response to hypertrophic stimuli such as stretch and phenylephrine (PE), suggesting that Lmcd1 is required for the hypertrophic response. Furthermore, PE-mediated activation of calcineurin was completely blocked by knockdown of Lmcd1. To confirm these results in vivo, we generated transgenic mice with cardiac-restricted overexpression of Lmcd1. Despite normal cardiac function, adult transgenic mice displayed significant cardiac hypertrophy, again accompanied by induction of hypertrophic marker genes such as ANF and alpha-skeletal actin. Likewise, Rcan1-4 was found upregulated. Moreover, when crossed with transgenic mice overexpressing constitutionally active calcineurin, Lmcd1 transgenic mice revealed an exacerbated cardiomyopathic phenotype with depressed contractile function and further increased cardiomyocyte hypertrophy. We show that the novel z-disc protein Lmcd1/Dyxin is significantly upregulated in several models of cardiac hypertrophy. Lmcd1/Dyxin potently induces cardiomyocyte hypertrophy both in vitro and in vivo, while knockdown of this molecule prevents hypertrophy. Mechanistically, Lmcd1/Dyxin appears to signal through the calcineurin pathway. Lmcd1/Dyxin may thus represent an attractive target for novel antihypertrophic strategies. Copyright 2010 Elsevier Ltd. All rights reserved.

Identification of novel biomarker candidates for hypertrophic cardiomyopathy and other cardiovascular diseases leading to heart failure.

PubMed

Rehulkova, H; Rehulka, P; Myslivcova Fucikova, A; Stulik, J; Pudil, R

2016-11-23

In-depth proteome discovery analysis represents new strategy in an effort to identify novel reliable specific protein markers for hypertrophic cardiomyopathy and other life threatening cardiovascular diseases. To systematically identify novel protein biomarkers of cardiovascular diseases with high mortality we employed an isobaric tag for relative and absolute quantitation (iTRAQ) proteome technology to make comparative analysis of plasma samples obtained from patients suffering from non-obstructive hypertrophic cardiomyopathy, stable dilated cardiomyopathy, aortic valve stenosis, chronic stable coronary artery disease and stable arterial hypertension. We found 128 plasma proteins whose abundances were uniquely regulated among the analyzed cardiovascular pathologies. 49 of them have not been described yet. Additionally, application of statistical exploratory analyses of the measured protein profiles indicated the relationship in pathophysiology of the examined cardiovascular pathologies.

Collagen-Proteoglycan Relationships in Epiphyseal Cartilage

PubMed Central

Eisenstein, Reuben; Larsson, Sven-Erik; Sorgente, Nino; Kuettner, Klaus E.

1973-01-01

Columnar and hypertrophic zones of calf scapular cartilage were studied before and after extraction with 3 M guanidinium chloride (GuCl) and digestion with enzymes which degrade various components of the extracellular matrix. Morphologic and chemical analysis suggests that there are at least two anatomic pools of proteoglycan in this tissue. One, which resides between collagen fibrils, is extractable with GuCl. Another appears attached to collagen by strong bonds and is apparently not extractable with GuCl. This type of collagen-proteoglycan relationship is possibly restricted to epiphyseal cartilage. The morphology of the lacuna is different in the columnar and hypertrophic zones. Proteoglycans in the distal hypertrophic zone are less resistant to GuCl extraction. ImagesFig 9Fig 10Fig 11Fig 1Fig 2Fig 3Fig 4Fig 5Fig 6Fig 7Fig 8 PMID:4357177

Right ventricle myectomy.

PubMed

Borisov, Konstantin V

2017-07-01

Right ventricular (RV) hypertrophy is common in patients with hypertrophic cardiomyopathy (HCM), and is associated with more severe disease. Conventional surgical strategies such as the traditional Morrow procedure pose a particularly high risk to patients with severe hypertrophy and RV obstruction, for whom the most appropriate therapeutic approach has not yet been established. We have proposed a new technique for surgical correction in patients with hypertrophic obstructive cardiomyopathy and severe hypertrophy, which involves approaching the area of obstruction by entering through the conal part of the RV. This novel technique provides effective elimination of biventricular obstruction and the precise removal of the areas of septal fibrosis in patients with hypertrophic obstructive cardiomyopathy. The current literature review analyzes the indications and various techniques for performing a RV myectomy, and presents the results of follow-up assessments in patients with biventricular obstruction and severe hypertrophy.

A case of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome presenting with hypertrophic pachymeningitis.

PubMed

Shiraishi, Wataru; Hayashi, Shintaro; Iwanaga, Yasutaka; Murai, Hiroyuki; Yamamoto, Akifumi; Kira, Jun-ichi

2015-02-15

A 43-year-old woman with a 3-year history of headache, fever, and swelling of the forehead, presented to our hospital. A general examination revealed palmar and plantar pustules. Blood analyses showed an elevated white blood cell count, C-reactive protein level, and erythrocyte sedimentation rate. Brain MRI revealed a partially thickened cranial bone with gadolinium enhancement, and also abnormally enhanced dura mater. Bone scintigraphy showed involvement of the cranial bone and bilateral sternoclavicular joints. Palmar skin biopsy indicated palmoplantar pustulosis. From these results, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome with associated hypertrophic pachymeningitis was diagnosed. After corticosteroid therapy and tonsillectomy, the clinical symptoms and radiological abnormalities were improved. Clinicians should be aware of SAPHO as a potential unusual cause of hypertrophic pachymeningitis. Copyright © 2014 Elsevier B.V. All rights reserved.

Arterial hypertension and hypertrophic pulmonary osteopathy associated with aortic valvular endocarditis in a dog.

PubMed

Vulgamott, J C; Clark, R G

1980-08-01

A 5-year-old spayed female Doberman Pinscher was referred for clinical evaluation following two acute episodes of lameness, lethargy, and respiratory dyspnea. The femoral pulse had a bounding "water-hammer" quality. Arterial blood pressures were 280 mm of Hg to greater than 300 mm of Hg during systole and approximately 40 mm of Hg during diastole. Systolic blood pressure was lowered to 210 mm of Hg, using prazosin. Radiography revealed extensive pulmonary interstitial markings and smooth subperiosteal expansions of the long bones indicative of hypertrophic pulmonary osteopathy. Despite symptomatic treatment, the dog's health gradually deteriorated, and it died 9 days after referral. Necropsy revealed vegetative endocarditis of the aortic valve. Insufficiency of the aortic valve was believed to be responsible for the systolic hypertension and the hypertrophic pulmonary osteopathy.

Cardiac magnetic resonance in myocardial disease.

PubMed

Sechtem, U; Mahrholdt, H; Vogelsberg, H

2007-12-01

For a number of patients it is difficult to diagnose the cause of cardiac disease. In such patients cardiac magnetic resonance is useful for helping to make a differential diagnosis between ischaemic and dilated cardiomyopathy; identifying patients with myocarditis; diagnosing cardiac involvement in sarcoidosis and Chagas' disease; identifying patients with unusual forms of hypertrophic cardiomyopathy and those with continuing myocardial damage; and defining the sequelae of ablation treatment for hypertrophic obstructive cardiomyopathy.

Syncope in the young athlete: Assessment of prognosis in subjects with hypertrophic cardiomyopathy.

PubMed

Magalhães-Ribeiro, Carlos; Freitas, João

2016-01-01

Syncope is a common but concerning event in young athletes. Although mostly due to benign reflex causes, syncope may be arrhythmic and precede sudden cardiac death. Efforts must therefore be made to distinguish post-exertional syncope from syncope during exercise, which can be an ominous sign of a possible underlying heart disease, such as hypertrophic cardiomyopathy. Prevention requires cooperation between physician and athlete, in order to identify individuals at risk and to protect them from sudden death. Solving this diagnostic dilemma may lead to recommendations for athletes to be cleared to play or disqualified from competitive sports, and presents challenging and controversial decisions to the health care provider that can prove difficult to implement. Although exercise contributes to physical and psychological well-being, there are insufficient data to indicate whether an athlete with hypertrophic cardiomyopathy diagnosed after a syncopal episode can safely resume competitive physical activity. The purpose of this study was to review the literature on syncope in young athletes and its relationship to individuals with hypertrophic cardiomyopathy, in order to enable accurate assessment of prognosis and the possibility of resuming competitive sports. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Tissue Engineering Whole Bones Through Endochondral Ossification: Regenerating the Distal Phalanx.

PubMed

Sheehy, Eamon J; Mesallati, Tariq; Kelly, Lara; Vinardell, Tatiana; Buckley, Conor T; Kelly, Daniel J

2015-01-01

Novel strategies are urgently required to facilitate regeneration of entire bones lost due to trauma or disease. In this study, we present a novel framework for the regeneration of whole bones by tissue engineering anatomically shaped hypertrophic cartilaginous grafts in vitro that subsequently drive endochondral bone formation in vivo. To realize this, we first fabricated molds from digitized images to generate mesenchymal stem cell-laden alginate hydrogels in the shape of different bones (the temporomandibular joint [TMJ] condyle and the distal phalanx). These constructs could be stimulated in vitro to generate anatomically shaped hypertrophic cartilaginous tissues that had begun to calcify around their periphery. Constructs were then formed into the shape of the distal phalanx to create the hypertrophic precursor of the osseous component of an engineered long bone. A layer of cartilage engineered through self-assembly of chondrocytes served as the articular surface of these constructs. Following chondrogenic priming and subcutaneous implantation, the hypertrophic phase of the engineered phalanx underwent endochondral ossification, leading to the generation of a vascularized bone integrated with a covering layer of stable articular cartilage. Furthermore, spatial bone deposition within the construct could be modulated by altering the architecture of the osseous component before implantation. These findings open up new horizons to whole limb regeneration by recapitulating key aspects of normal bone development.

Intralesional cryotherapy for hypertrophic scars and keloids: a review

PubMed Central

O’Boyle, Ciaran P; Shayan-Arani, Holleh; Hamada, Maha Wagdy

2017-01-01

Introduction: Hypertrophic and keloid scarring remain notoriously troublesome for patients to tolerate and frustratingly difficult for clinicians to treat. Many different treatment modalities exist, signifying the failure of any method to achieve consistently excellent results. Intralesional cryotherapy is a relatively recent development that uses a double lumen needle, placed through the core of a keloid or hypertrophic scar, to deliver nitrogen vapour, which freezes the scar from its core, outwards. Methods: This article provides a comprehensive review of the literature on intralesional cryotherapy for hypertrophic scars and keloids. A systematic review or meta-analysis was not possible, since the existing articles did not permit this. Results: A search of English language, peer-reviewed literature was carried out. The evidence base was found to be low (level 4). In addition, much of the published evidence comes from a very few groups. Despite this, consistent findings from case series suggest that the technique is safe and achieves good scar reduction with very few treatments. Adverse effects include depigmentation, recurrence and pain. Pain and recurrence appear to be uncommon and depigmentation may be temporary. Discussion: Well-constructed, prospectively recruited comparative trials are absent from the literature. These are strongly encouraged, in order to strengthen general confidence in this technique and in the repeatability of outcomes reported thus far. PMID:29799581

Evidence based management for paediatric burn: new approaches and improved scar outcomes.

PubMed

Kishikova, Lyudmila; Smith, Matthew D; Cubison, Tania C S

2014-12-01

Little evidence has been produced on the best practice for managing paediatric burns. We set out to develop a formal approach based on the finding that hypertrophic scarring is related to healing-time, with durations under 21 days associated with improved scar outcome. Incorporating new advances in burn care, we compared outcomes under the new approach to a cohort treated previously. Our study was a retrospective cross-sectional case note study, with demographic, treatment and outcome information collected. The management and outcome of each case was assessed and compared against another paediatric burns cohort from 2006. 181 burns presenting across a six month period were analysed (2010 cohort) and compared to 337 children from a previous cohort from 2006. Comparison of patients between cohorts showed an overall shift towards shorter healing-times in the 2010 cohort. A lower overall rate of hypertrophic scarring was seen in the 2010 cohort, and for corresponding healing-times after injury, hypertrophic scarring rates were halved in comparison to the 2006 cohort. We demonstrate that the use of a structured approach for paediatric burns has improved outcomes with regards to healing-time and hypertrophic scarring rate. This approach allows maximisation of healing potential and implements aggressive prophylactic measures. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

A porcine deep dermal partial thickness burn model with hypertrophic scarring.

PubMed

Cuttle, Leila; Kempf, Margit; Phillips, Gael E; Mill, Julie; Hayes, Mark T; Fraser, John F; Wang, Xue-Qing; Kimble, Roy M

2006-11-01

We developed a reproducible model of deep dermal partial thickness burn injury in juvenile Large White pigs. The contact burn is created using water at 92 degrees C for 15s in a bottle with the bottom replaced with plastic wrap. The depth of injury was determined by a histopathologist who examined tissue sections 2 and 6 days after injury in a blinded manner. Upon creation, the circular wound area developed white eschar and a hyperaemic zone around the wound border. Animals were kept for 6 weeks or 99 days to examine the wound healing process. The wounds took between 3 and 5 weeks for complete re-epithelialisation. Most wounds developed contracted, purple, hypertrophic scars. On measurement, the thickness of the burned skin was approximately 1.8 times that of the control skin at week 6 and approximately 2.2 times thicker than control skin at 99 days after injury. We have developed various methods to assess healing wounds, including digital photographic analysis, depth of organising granulation tissue, immunohistochemistry, electron microscopy and tensiometry. Immunohistochemistry and electron microscopy showed that our porcine hypertrophic scar appears similar to human hypertrophic scarring. The development of this model allows us to test and compare different treatments on burn wounds.

Myocardial diseases of animals.

PubMed Central

Van Vleet, J. F.; Ferrans, V. J.

1986-01-01

In this review we have attempted a comprehensive compilation of the cardiac morphologic changes that occur in spontaneous and experimental myocardial diseases of animals. Our coverage addresses diseases of mammals and birds and includes these diseases found in both domesticated and wild animals. A similar review of the myocardial diseases in this broad range of animal species has not been attempted previously. We have summarized and illustrated the gross, microscopic, and ultrastructural alterations for these myocardial diseases; and, whenever possible, we have reviewed their biochemical pathogenesis. We have arranged the myocardial diseases for presentation and discussion according to an etiologic classification with seven categories. These include a group of idiopathic or primary cardiomyopathies recognized in man (hypertrophic, dilated, and restrictive types) and a large group of secondary cardiomyopathies with known causes, such as inherited tendency; nutritional deficiency; toxicity; physical injury and shock; endocrine disorders, and myocarditides of viral, bacterial, and protozoal causation. Considerable overlap exists between each of the etiologic groups in the spectrum of pathologic alterations seen in the myocardium. These include various degenerative changes, myocyte necrosis, and inflammatory lesions. However, some diseases show rather characteristic myocardial alterations such as vacuolar degeneration in anthracycline cardiotoxicity, myofibrillar lysis in furazolidone cardiotoxicity, calcification in calcinosis of mice, glycogen accumulation in the glycogenoses, lipofuscinosis in cattle, fatty degeneration in erucic acid cardiotoxicity, myofiber disarray in hypertrophic cardiomyopathy, and lymphocytic inflammation with inclusion bodies in canine parvoviral myocarditis. The myocardial diseases represent the largest group in the spectrum of spontaneous cardiac diseases of animals. Pericardial and endocardial diseases and congential cardiac diseases are seen less frequently; and, in contrast to man, coronary artery disease and myocardial ischemia are rather infrequent in animals. The present review shows clearly that the spectrum of myocardial diseases in animals is enlarging and that many newly recognized diseases are emerging and assuming considerable importance. For example, various heritable cardiomyopathies have recently been described in the KK mouse, cattle, and rats. Increasingly recognized myocardial diseases include cardiomyopathies in cats, dogs, and birds; anthracycline cardiotoxicity; furazolidone cardiotoxicity; ionophore cardiotoxicity; myocardial damage associated with central nervous system injuries; myocardial hypertrophy in Images Figure 1 Figure 2 Figure 45 Figure 46 Figure 47 Figure 48 Figure 61 Figure 62 Figure 63 Figure 64 Figure 79 Figure 75 Figure 76 Figure 77 Figure 78 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 Figure 23 Figure 24 Figure 25 Figure 26 Figure 27 Figure 28 Figure 29 & 30 Figure 31 Figure 32 Figure 33 Figure 34 Figure 35 Figure 36 Figure 37 Figure 38 Figure 39 Figure 40 Figure 41 Figure 42 Figure 43 Figure 44 Figure 49 Figure 50 Figure 51 Figure 52 Figure 53 Figure 54 Figure 55 Figure 56 Figure 57 Figure 58 Figure 59 Figure 60 Figure 65 Figure 66 Figure 67 Figure 68 Figure 69 Figure 70 Figure 71 & 72 Figure 73 & 74 PMID:3524254

[Gastric adenomyoma clinically simulating hypertrophic pyloric stenosis].

PubMed

Sánchez García, S; Rubio Solís, D; Anes González, G; González Sánchez, S

2016-01-01

Gastric adenomyomas are extremely uncommon benign tumors in children. On histologic examination, these tumors have an epithelial component similar to pancreatic ducts. We present a case of a pyloric adenomyoma that clinically simulated hypertrophic pyloric stenosis in a newborn girl. Imaging tests, fundamentally magnetic resonance imaging, were very important in the characterization and diagnosis of this entity. Copyright © 2016 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Hypertrophic neuropathy in Noonan syndrome with multiple lentigines.

PubMed

Maridet, Claire; Sole, Guilhem; Morice-Picard, Fanny; Taieb, Alain

2016-06-01

RASopathies comprise several genetic syndromes with mainly cardio-facial-cutaneous manifestations. We report a patient with Noonan syndrome with multiple lentigines (NSML) due to a PTPN11 (p.Thr468Met) mutation associated with hypertrophic neuropathy of lumbar plexus in an adult woman, initially referred for neuropathic pain. Differential diagnosis of neurofibromatosis type 1 (NF1) and other RASopathies is difficult without molecular testing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Up-to-date approach to manage keloids and hypertrophic scars: A useful guide

PubMed Central

Arno, Anna I.; Gauglitz, Gerd G.; Barret, Juan P.; Jeschke, Marc G.

2014-01-01

Keloids and hypertrophic scars occur anywhere from 30 to 90% of patients, and are characterized by pathologically excessive dermal fibrosis and aberrant wound healing. Both entities have different clinical and histochemical characteristics, and unfortunately still represent a great challenge for clinicians due to lack of efficacious treatments. Current advances in molecular biology and genetics reveal new preventive and therapeutical options which represent a hope to manage this highly prevalent, chronic and disabling problem, with long-term beneficial outcomes and improvement of quality of life. While we wait for these translational clinical products to be marketed, however, it is imperative to know the basics of the currently existing wide array of strategies to deal with excessive scars: from the classical corticotherapy, to the most recent botulinum toxin and lasers. The main aim of this review paper is to offer a useful up-to-date guideline to prevent and treat keloids and hypertrophic scars. PMID:24767715

Calcification of in vitro developed hypertrophic cartilage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tacchetti, C.; Quarto, R.; Campanile, G.

1989-04-01

We have recently reported that dedifferentiated cells derived from stage 28-30 chick embryo tibiae, when transferred in suspension culture in the presence of ascorbic acid, develop in a tissue closely resembling hypertrophic cartilage. Ultrastructural examination of this in vitro formed cartilage showed numerous matrix vesicles associated with the extracellular matrix. In the present article we report that the in vitro developed hypertrophic cartilage undergoes calcification. We indicate a correlation between the levels of alkaline phosphatase activity and calcium deposition at different times of development. Following the transfer of cells into suspension culture and an initial lag phase, the level ofmore » alkaline phosphatase activity rapidly increased. In most experiments the maximum of activity was reached after 5 days of culture. When alkaline phosphatase activity and /sup 45/Ca deposition were measured in the same experiment, we observed that the increase in alkaline phosphatase preceded the deposition of nonwashable calcium deposits in the cartilage.« less

Abnormal cardiac response to exercise in a murine model of familial hypertrophic cardiomyopathy.

PubMed

Nguyen, Lan; Chung, Jessica; Lam, Lien; Tsoutsman, Tatiana; Semsarian, Christopher

2007-07-10

Clinical outcome in familial hypertrophic cardiomyopathy (FHC) may be influenced by modifying factors such as exercise. Transgenic mice which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), develop all the characteristic phenotypic features of FHC. To study the modifying effect of exercise in early disease, mice underwent swimming exercise at an early age prior to the development of the FHC phenotype. In non-transgenic and cTnI-wt mice, swimming resulted in a significant increase in left ventricular wall thickness and contractility on echocardiography, consistent with a physiological hypertrophic response to exercise. In contrast, cTnI-G203S mice showed no increase in these parameters, indicating an abnormal response to exercise. The lack of a physiological response to exercise may indicate an important novel mechanistic insight into the role of exercise in triggering adverse events in FHC.

Left Atrial trajectory impairment in Hypertrophic Cardiomyopathy disclosed by Geometric Morphometrics and Parallel Transport

NASA Astrophysics Data System (ADS)

Piras, Paolo; Torromeo, Concetta; Re, Federica; Evangelista, Antonietta; Gabriele, Stefano; Esposito, Giuseppe; Nardinocchi, Paola; Teresi, Luciano; Madeo, Andrea; Chialastri, Claudia; Schiariti, Michele; Varano, Valerio; Uguccioni, Massimo; Puddu, Paolo E.

2016-10-01

The analysis of full Left Atrium (LA) deformation and whole LA deformational trajectory in time has been poorly investigated and, to the best of our knowledge, seldom discussed in patients with Hypertrophic Cardiomyopathy. Therefore, we considered 22 patients with Hypertrophic Cardiomyopathy (HCM) and 46 healthy subjects, investigated them by three-dimensional Speckle Tracking Echocardiography, and studied the derived landmark clouds via Geometric Morphometrics with Parallel Transport. Trajectory shape and trajectory size were different in Controls versus HCM and their classification powers had high AUC (Area Under the Receiving Operator Characteristic Curve) and accuracy. The two trajectories were much different at the transition between LA conduit and booster pump functions. Full shape and deformation analyses with trajectory analysis enabled a straightforward perception of pathophysiological consequences of HCM condition on LA functioning. It might be worthwhile to apply these techniques to look for novel pathophysiological approaches that may better define atrio-ventricular interaction.

Effect of Body Mass Index on Exercise Capacity in Patients With Hypertrophic Cardiomyopathy.

PubMed

Larsen, Carolyn M; Ball, Caroline A; Hebl, Virginia B; Ong, Kevin C; Siontis, Konstantinos C; Olson, Thomas P; Ackerman, Michael J; Ommen, Steve R; Allison, Thomas G; Geske, Jeffrey B

2018-01-01

The objective of this study was to evaluate the relation between body mass index (BMI), exercise capacity, and symptoms in patients with hypertrophic cardiomyopathy (HC) and to utilize results of cardiopulmonary exercise tests (CPX) and transthoracic echocardiograms to understand the mechanism(s) of reduced exercise capacity across body mass index groups. Over a 6-year period, 510 consecutive patients with HC seen at a tertiary referral center underwent (CPX) and a transthoracic echocardiogram. Increasing BMI was associated with decreased exercise capacity as assessed by peak VO 2 (ml/kg/min). However, the prevalence of cardiac impairment did not vary by BMI group. In conclusion, these findings suggest that in some patients with hypertrophic cardiomyopathy, cardiac impairment is not the primary cause of exercise limitation and weight loss may result in improved exercise capacity. Copyright © 2017 Elsevier Inc. All rights reserved.

Stress relaxation of swine growth plate in semi-confined compression: depth dependent tissue deformational behavior versus extracellular matrix composition and collagen fiber organization.

PubMed

Amini, Samira; Mortazavi, Farhad; Sun, Jun; Levesque, Martin; Hoemann, Caroline D; Villemure, Isabelle

2013-01-01

Mechanical environment is one of the regulating factors involved in the process of longitudinal bone growth. Non-physiological compressive loading can lead to infantile and juvenile musculoskeletal deformities particularly during growth spurt. We hypothesized that tissue mechanical behavior in sub-regions (reserve, proliferative and hypertrophic zones) of the growth plate is related to its collagen and proteoglycan content as well as its collagen fiber orientation. To characterize the strain distribution through growth plate thickness and to evaluate biochemical content and collagen fiber organization of the three histological zones of growth plate tissue. Distal ulnar growth plate samples (N = 29) from 4-week old pigs were analyzed histologically for collagen fiber organization (N = 7) or average zonal thickness (N = 8), or trimmed into the three average zones, based on the estimated thickness of each histological zone, for biochemical analysis of water, collagen and glycosaminoglycan content (N = 7). Other samples (N = 7) were tested in semi-confined compression under 10% compressive strain. Digital images of the fluorescently labeled nuclei were concomitantly acquired by confocal microscopy before loading and after tissue relaxation. Strain fields were subsequently calculated using a custom-designed 2D digital image correlation algorithm. Depth-dependent compressive strain patterns and collagen content were observed. The proliferative and hypertrophic zone developed the highest axial and transverse strains, respectively, under compression compared to the reserve zone, in which the lowest axial and transverse strains arose. The collagen content per wet mass was significantly lower in the proliferative and hypertrophic zones compared to the reserve zone, and all three zones had similar glycosaminoglycan and water content.Polarized light microscopy showed that collagen fibers were mainly organized horizontally in the reserve zone and vertically aligned with the growth direction in the proliferative and hypertrophic zones. Higher strains were developed in growth plate areas (proliferative and hypertrophic) composed of lower collagen content and of vertical collagen fiber organization. The stiffer reserve zone, with its higher collagen content and collagen fibers oriented to restrain lateral expansion under compression, could play a greater role of mechanical support compared to the proliferative and hypertrophic zones, which could be more susceptible to be involved in an abnormal growth process.

Sleep-Disordered Breathing in Hypertrophic Cardiomyopathy

PubMed Central

Somers, Virend K.

2014-01-01

Sleep-disordered breathing (SDB) may be a treatable risk factor in patients with hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy. Evidence suggests a high prevalence of SDB in HCM. We summarize the pathophysiology of SDB as it relates to hypertension, coronary artery disease, atrial fibrillation, and sudden cardiac death in patients with HCM. The implications regarding the care of patients with HCM and SDB are discussed as well as the knowledge deficits needing further exploration. PMID:25010966

Correlation of Electrocardiographic Changes with Cardiac Magnetic Resonance Findings in Patients with Hypertrophic Cardiomyopathy

PubMed Central

Paixão, Gabriela Miana de Mattos; Veronesi, Horácio Eduardo; da Silva, Halsted Alarcão Gomes Pereira; de Alencar Neto, José Nunes; Maldi, Carolina de Paulo; Aguiar Filho, Luciano de Figueiredo; Pinto, Ibrahim Masciarelli Francisco; de França, Francisco Faustino de Albuquerque Carneiro; Correia, Edileide de Barros

2018-01-01

Background Electrocardiogram is the initial test in the investigation of heart disease. Electrocardiographic changes in hypertrophic cardiomyopathy have no set pattern, and correlates poorly with echocardiographic findings. Cardiac magnetic resonance imaging has been gaining momentum for better assessment of hypertrophy, as well as the detection of myocardial fibrosis. Objectives To correlate the electrocardiographic changes with the location of hypertrophy in hypertrophic cardiomyopathy by cardiac magnetic resonance. Methods This descriptive cross-sectional study evaluated 68 patients with confirmed diagnosis of hypertrophic cardiomyopathy by cardiac magnetic resonance. The patients’ electrocardiogram was compared with the location of the greatest myocardial hypertrophy by cardiac magnetic resonance. Statistical significance level of 5% and 95% confidence interval were adopted. Results Of 68 patients, 69% had septal hypertrophy, 21% concentric and 10% apical hypertrophies. Concentric hypertrophy showed the greatest myocardial fibrosis mass (p < 0.001) and the greatest R wave size in D1 (p = 0.0280). The amplitudes of R waves in V5 and V6 (p = 0.0391, p = 0.0148) were higher in apical hypertrophy, with statistical significance. Apical hypertrophy was also associated with higher T wave negativity in D1, V5 and V6 (p < 0.001). Strain pattern was found in 100% of the patients with apical hypertrophy (p < 0.001). Conclusion The location of myocardial hypertrophy by cardiac magnetic resonance can be correlated with electrocardiographic changes, especially for apical hypertrophy. PMID:29538524

Ablation of hypertrophic septum using radiofrequency energy: an alternative for gradient reduction in patient with hypertrophic obstructive cardiomyopathy?

PubMed

Riedlbauchová, Lucie; Janoušek, Jan; Veselka, Josef

2013-06-01

Alcohol septal ablation and surgical myectomy represent accepted therapeutic options for treatment of symptomatic patients with hypertrophic obstructive cardiomyopathy. Long-term experience with radiofrequency ablation of arrhythmogenic substrates raised a question if this technique might be effective for left ventricular outflow tract (LVOT) gradient reduction. We report on a 63-year-old patient with recurrence of symptoms 1 year after alcohol septal ablation (ASA) leading originally to a significant reduction of both symptoms and gradient. Due to a new increase of gradient in the LVOT up to 200 mm Hg with corresponding worsening of symptoms and due to refusal of surgical myectomy by the patient, endocardial radiofrequency ablation of the septal hypertrophy (ERASH) was indicated. Radiofrequency ablation was performed in the LVOT using irrigated-tip ablation catheter; the target site was identified using intracardiac echocardiography and electroanatomical CARTO mapping. ERASH caused an immediate gradient reduction due to hypokinesis of the ablated septum. At 2-month follow-up exam, significant clinical improvement was observed, together with persistent gradient reduction assessed with Doppler echocardiography. Echocardiography and magnetic resonance revealed persistent septal hypokinesis and slight thinning of the ablated region. Septal ablation using radiofrequency energy may be a promising alternative or adjunct to the treatment of hypertrophic obstructive cardiomyopathy. Intracardiac echocardiography and electroanatomical CARTO mapping enable exact lesion placement and preservation of atrioventricular conduction.

Prevention of hypertrophic scars and keloids by the prophylactic use of topical silicone gel sheets following a surgical procedure in an office setting.

PubMed

Gold, M H; Foster, T D; Adair, M A; Burlison, K; Lewis, T

2001-07-01

Topical silicone gel sheeting has been used for more than 20 years to help reduce the size of hypertrophic scars and keloids. Its clinical efficacy and safety is well established. To determine whether topical silicone gel sheeting can be used to prevent hypertrophic scars and keloids from forming following dermatologic skin surgery. Patients undergoing skin surgery were stratified into two groups: those with no history of abnormal scarring (low-risk group) and those with a history of abnormal scarring (high-risk group). Following the procedure, patients within each group were randomized to receive either routine postoperative care or topical silicone gel sheeting (48 hours after surgery). Patients were followed for 6 months. In the low-risk group, there were no statistical differences between individuals using routine postoperative care or using topical silicone gel sheets. In the high-risk group, there was a statistical difference (39% versus 71%) between patients who did not develop abnormal scars and used topical silicone gel sheeting and patients who developed abnormal scars after routine postoperative treatment. Those individuals having a scar revision procedure also showed a statistical difference if topical silicone gel sheeting was used following surgery. Topical silicone gel sheeting, with a 20-year history of satisfaction in dermatology, now appears to be useful in the prevention of hypertrophic scars and keloids in patients undergoing scar revision.

Porous decellularized tissue engineered hypertrophic cartilage as a scaffold for large bone defect healing.

PubMed

Cunniffe, Gráinne M; Vinardell, Tatiana; Murphy, J Mary; Thompson, Emmet M; Matsiko, Amos; O'Brien, Fergal J; Kelly, Daniel J

2015-09-01

Clinical translation of tissue engineered therapeutics is hampered by the significant logistical and regulatory challenges associated with such products, prompting increased interest in the use of decellularized extracellular matrix (ECM) to enhance endogenous regeneration. Most bones develop and heal by endochondral ossification, the replacement of a hypertrophic cartilaginous intermediary with bone. The hypothesis of this study is that a porous scaffold derived from decellularized tissue engineered hypertrophic cartilage will retain the necessary signals to instruct host cells to accelerate endogenous bone regeneration. Cartilage tissue (CT) and hypertrophic cartilage tissue (HT) were engineered using human bone marrow derived mesenchymal stem cells, decellularized and the remaining ECM was freeze-dried to generate porous scaffolds. When implanted subcutaneously in nude mice, only the decellularized HT-derived scaffolds were found to induce vascularization and de novo mineral accumulation. Furthermore, when implanted into critically-sized femoral defects, full bridging was observed in half of the defects treated with HT scaffolds, while no evidence of such bridging was found in empty controls. Host cells which had migrated throughout the scaffold were capable of producing new bone tissue, in contrast to fibrous tissue formation within empty controls. These results demonstrate the capacity of decellularized engineered tissues as 'off-the-shelf' implants to promote tissue regeneration. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Hypertrophic and dilated cardiomyopathy: four decades of basic research on muscle lead to potential therapeutic approaches to these devastating genetic diseases.

PubMed

Spudich, James A

2014-03-18

With the advent of technologies to obtain the complete sequence of the human genome in a cost-effective manner, this decade and those to come will see an exponential increase in our understanding of the underlying genetics that lead to human disease. And where we have a deep understanding of the biochemical and biophysical basis of the machineries and pathways involved in those genetic changes, there are great hopes for the development of modern therapeutics that specifically target the actual machinery and pathways altered by individual mutations. Prime examples of such a genetic disease are those classes of hypertrophic and dilated cardiomyopathy that result from single amino-acid substitutions in one of several of the proteins that make up the cardiac sarcomere or from the truncation of myosin binding protein C. Hypertrophic cardiomyopathy alone affects ∼1 in 500 individuals, and it is the leading cause of sudden cardiac death in young adults. Here I describe approaches to understand the molecular basis of the alterations in power output that result from these mutations. Small molecules binding to the mutant sarcomeric protein complex should be able to mitigate the effects of hypertrophic and dilated cardiomyopathy mutations at their sources, leading to possible new therapeutic approaches for these genetic diseases. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Species-specific differences in adaptive phenotypic plasticity in an ecologically relevant trophic trait: hypertrophic lips in Midas cichlid fishes.

PubMed

Machado-Schiaffino, Gonzalo; Henning, Frederico; Meyer, Axel

2014-07-01

The spectacular species richness of cichlids and their diversity in morphology, coloration, and behavior have made them an ideal model for the study of speciation and adaptive evolution. Hypertrophic lips evolved repeatedly and independently in African and Neotropical cichlid radiations. Cichlids with hypertrophic lips forage predominantly in rocky crevices and it has been hypothesized that mechanical stress caused by friction could result in larger lips through phenotypic plasticity. To test the influence of the environment on the size and development of lips, we conducted a series of breeding and feeding experiments on Midas cichlids. Full-sibs of Amphilophus labiatus (thick-lipped) and Amphilophus citrinellus (thin-lipped) each were split into a control group which was fed food from the water column and a treatment group whose food was fixed to substrates. We found strong evidence for phenotypic plasticity on lip area in the thick-lipped species, but not in the thin-lipped species. Intermediate phenotypic values were observed in hybrids from thick- and thin-lipped species reared under "control" conditions. Thus, both a genetic, but also a phenotypic plastic component is involved in the development of hypertrophic lips in Neotropical cichlids. Moreover, species-specific adaptive phenotypic plasticity was found, suggesting that plasticity is selected for in recent thick-lipped species. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

Relation between thallium-201/iodine 123-BMIPP subtraction and fluorine 18 deoxyglucose polar maps in patients with hypertrophic cardiomyopathy.

PubMed

Ito, Y; Hasegawa, S; Yamaguchi, H; Yoshioka, J; Uehara, T; Nishimura, T

2000-01-01

Clinical studies have shown discrepancies in the distribution of thallium-201 and iodine 123-beta-methyl-iodophenylpentadecanoic acid (BMIPP) in patients with hypertrophic cardiomyopathy (HCM). Myocardial uptake of fluorine 18 deoxyglucose (FDG) is increased in the hypertrophic area in HCM. We examined whether the distribution of a Tl-201/BMIPP subtraction polar map correlates with that of an FDG polar map. We normalized to maximum count each Tl-201 and BMIPP bull's-eye polar map of 6 volunteers and obtained a standard Tl-201/BMIPP subtraction polar map by subtracting a normalized BMIPP bull's-eye polar map from a normalized Tl-201 bull's-eye polar map. The Tl-201/BMIPP subtraction polar map was then applied to 8 patients with HCM (mean age 65+/-12 years) to evaluate the discrepancy between Tl-201 and BMIPP distribution. We compared the Tl-201/BMIPP subtraction polar map with an FDG polar map. In patients with HCM, the Tl-201/BMIPP subtraction polar map showed a focal uptake pattern in the hypertrophic area similar to that of the FDG polar map. By quantitative analysis, the severity score of the Tl-201/BMIPP subtraction polar map was significantly correlated with the percent dose uptake of the FDG polar map. These results suggest that this new quantitative method may be an alternative to FDG positron emission tomography for the routine evaluation of HCM.

The Corticofugal Effects of Auditory Cortex Microstimulation on Auditory Nerve and Superior Olivary Complex Responses Are Mediated via Alpha-9 Nicotinic Receptor Subunit

PubMed Central

Aedo, Cristian; Terreros, Gonzalo; León, Alex; Delano, Paul H.

2016-01-01

Background and Objective The auditory efferent system is a complex network of descending pathways, which mainly originate in the primary auditory cortex and are directed to several auditory subcortical nuclei. These descending pathways are connected to olivocochlear neurons, which in turn make synapses with auditory nerve neurons and outer hair cells (OHC) of the cochlea. The olivocochlear function can be studied using contralateral acoustic stimulation, which suppresses auditory nerve and cochlear responses. In the present work, we tested the proposal that the corticofugal effects that modulate the strength of the olivocochlear reflex on auditory nerve responses are produced through cholinergic synapses between medial olivocochlear (MOC) neurons and OHCs via alpha-9/10 nicotinic receptors. Methods We used wild type (WT) and alpha-9 nicotinic receptor knock-out (KO) mice, which lack cholinergic transmission between MOC neurons and OHC, to record auditory cortex evoked potentials and to evaluate the consequences of auditory cortex electrical microstimulation in the effects produced by contralateral acoustic stimulation on auditory brainstem responses (ABR). Results Auditory cortex evoked potentials at 15 kHz were similar in WT and KO mice. We found that auditory cortex microstimulation produces an enhancement of contralateral noise suppression of ABR waves I and III in WT mice but not in KO mice. On the other hand, corticofugal modulations of wave V amplitudes were significant in both genotypes. Conclusion These findings show that the corticofugal modulation of contralateral acoustic suppressions of auditory nerve (ABR wave I) and superior olivary complex (ABR wave III) responses are mediated through MOC synapses. PMID:27195498

Mechanisms contributing to cluster formation in the inferior olivary nucleus in brainstem slices from postnatal mice

PubMed Central

Kølvraa, Mathias; Müller, Felix C; Jahnsen, Henrik; Rekling, Jens C

2014-01-01

Abstract The inferior olivary nucleus (IO) in in vitro slices from postnatal mice (P5.5–P15.5) spontaneously generates clusters of neurons with synchronous calcium transients, and intracellular recordings from IO neurons suggest that electrical coupling between neighbouring IO neurons may serve as a synchronizing mechanism. Here, we studied the cluster-forming mechanism and find that clusters overlap extensively with an overlap distribution that resembles the distribution for a random overlap model. The average somatodendritic field size of single curly IO neurons was ∼6400 μm2, which is slightly smaller than the average IO cluster size. Eighty-seven neurons with overlapping dendrites were estimated to be contained in the principal olive mean cluster size, and about six non-overlapping curly IO neurons could be contained within the largest clusters. Clusters could also be induced by iontophoresis with glutamate. Induced clusters were inhibited by tetrodotoxin, carbenoxelone and 18β-glycyrrhetinic acid, suggesting that sodium action potentials and electrical coupling are involved in glutamate-induced cluster formation, which could also be induced by activation of N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Spikelets and a small transient depolarizing response were observed during glutamate-induced cluster formation. Calcium transients spread with decreasing velocity during cluster formation, and somatic action potentials and cluster formation are accompanied by large dendritic calcium transients. In conclusion, cluster formation depends on gap junctions, sodium action potentials and spontaneous clusters occur randomly throughout the IO. The relative slow signal spread during cluster formation, combined with a strong dendritic influx of calcium, may signify that active dendritic properties contribute to cluster formation. PMID:24042500

The nucleus of the optic tract (NOT) and the dorsal terminal nucleus (DTN) of opossums (Didelphis marsupialis aurita).

PubMed

Vargas, C D; Volchan, E; Nasi, J P; Bernardes, R F; Rocha-Miranda, C E

1996-01-01

Wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) was injected unilaterally into the pretectocollicular region of opossums (Didelphis marsupialis aurita), primarily to investigate the existence of a commissural subcortical pathway but also to reveal afferents and efferents of the nucleus of the optic tract (NOT) and dorsal terminal nucleus (DTN) in this species. Labelled cells and terminals were observed in the contralateral NOT-DTN. Furthermore, HRP was injected bilaterally in the region of the inferior olive (IO) to verify if the distribution of labelled cells in the NOT-DTN overlapped the region of commissural labelled cells. The two subpopulations of retrogradely labelled cells coincided, being distributed within the retinal terminal field attributed to the NOT-DTN, as revealed by contralateral eye injections of HRP. The commissural cells were located slightly more ventral than the olivary cells in the optic tract. The pretectocollicular WGA-HRP injections also labelled cells and terminals bilaterally in the lateral terminal nucleus (LTN), interstitial nucleus of the superior fasciculus, posterior fibers (INSFp), ventral lateral geniculate nucleus (vLGN), and superior colliculus (SC) and ipsilaterally in the medial terminal nucleus (MTN). In addition, further caudally, labelled cells and terminals were observed bilaterally in the nuclei prepositus hypoglossi (PH) and in the medial (MVN) and lateral (LVN) vestibular nuclei. Labelled terminals were found in the ipsilateral nucleus reticularis tegmenti pontis (NRTP) and in the IO with ipsilateral predominance. This study allowed an anatomical delimitation of the NOT-DTN in this opossum species, as defined by the olivary and commissural subpopulations, as well as a hodological evaluation of this region. The existence of some common anatomical aspects with other mammalian species is discussed.

Differential distribution of vesicular glutamate transporters in the rat cerebellar cortex.

PubMed

Hioki, H; Fujiyama, F; Taki, K; Tomioka, R; Furuta, T; Tamamaki, N; Kaneko, T

2003-01-01

The chemical organization of excitatory axon terminals in the rat cerebellar cortex was examined by immunocytochemistry and in situ hybridization histochemistry of vesicular glutamate transporters 1 and 2 (VGluT1 and VGluT2). Chemical depletion of the inferior olivary complex neurons by 3-acetylpyridine treatment almost completely removed VGluT2 immunoreactivity from the molecular layer, leaving VGluT1 immunoreactivity apparently intact. On the other hand, neuronal deprivation of the cerebellar cortex by kainic acid injection induced a large loss of VGluT1 immunoreactivity in the molecular layer. In the cerebellar granular layer, both VGluT1 and VGluT2 immunoreactivities were found in mossy fiber terminals, and the two immunoreactivities were mostly colocalized in single-axon terminals. Signals for mRNA encoding VGluT2 were found in the inferior olivary complex, and those for VGluT1 and VGluT2 mRNAs were observed in most brainstem precerebellar nuclei sending mossy fibers, such as the pontine, pontine tegmental reticular, lateral reticular and external cuneate nuclei. These results indicate that climbing and parallel fibers selectively use VGluT2 and VGluT1, respectively, whereas mossy fibers apply both VGluT1 and VGluT2 together to accumulate glutamate into synaptic vesicles. Since climbing-fiber and parallel-fiber terminals are known to make depressing and facilitating synapses, respectively, VGluT1 and VGluT2 might have distinct properties associated with those synaptic characteristics. Thus, it would be the next interesting issue to determine whether mossy-fiber terminals co-expressing VGluT1 and VGluT2 show synaptic facilitation or depression.

A rodent model for artificial gravity: VOR adaptation and Fos expression.

PubMed

Kaufman, Galen; Weng, Tianxiang; Ruttley, Tara

2005-01-01

Vestibulo-ocular reflex (VOR) adaptation and brainstem Fos expression as a result of short radius cross-coupling stimuli were investigated to find neural correlates of the inherent Coriolis force asymmetry from an artificial gravity (AG) environment. Head-fixed gerbils (Meriones unguiculatus, N=79) were exposed, in the dark, to 60--90 minutes of cross-coupled rotations, combinations of pitch (or roll) and yaw rotation, while binocular horizontal, vertical, and torsional eye position were determined using infrared video-oculography. Centripetal acceleration in combination with angular cross-coupling was also studied. Simultaneous sinusoidal rotations in two planes (yaw with roll or pitch) provided a net symmetrical stimulus for the right and left labyrinths. In contrast, a constant velocity yaw rotation during sinusoidal roll or pitch provided the asymmetric stimulus model for AG. We found orthogonally oriented half-cycle VOR gain changes. The results depended on the direction of horizontal rotation during asymmetrical cross-coupling, and other aspects of the stimulus, including the phase relationship between the two rotational inputs, the symmetry of the stimulus, and training. Fos expression also revealed laterality differences in the prepositus and inferior olivary C subnucleus. In contrast the inferior olivary beta and ventrolateral outgrowth were labeled bilaterally. Additional cross-coupling dependent labeling was found in the flocculus, hippocampus, and several cortical regions, including the perirhinal and temporal association cortices. Analyses showed significant differences across the brain regions for several factors (symmetry, rotation velocity and direction, the presence of centripetal acceleration or a visual surround, and training). Finally, animals compensating from a unilateral surgical labyrinthectomy who received multiple cross-coupling training sessions had improved half-cycle VOR gain in the ipsilateral eye with head rotation toward the intact side. We hypothesize that cross-coupling vestibular training can benefit aspects of motor recovery or performance.

Systemic depletion of macrophages in the subacute phase of wound healing reduces hypertrophic scar formation.

PubMed

Zhu, Zhensen; Ding, Jie; Ma, Zengshuan; Iwashina, Takashi; Tredget, Edward E

2016-07-01

Hypertrophic scars are caused by trauma or burn injuries to the deep dermis and can cause cosmetic disfigurement and psychological issues. Studies suggest that M2-like macrophages are pro-fibrotic and contribute to hypertrophic scar formation. A previous study from our lab showed that M2 macrophages were present in developing hypertrophic scar tissues in vivo at 3-4 weeks after wounding. In this study, the effect of systemic macrophage depletion on scar formation was explored at subacute phase of wound healing. Thirty-six athymic nude mice that received human skin transplants were randomly divided into macrophage depletion group and control group. The former received intraperitoneal injections of clodronate liposomes while the controls received sterile saline injections on day 7, 10, and 13 postgrafting. Wound area, scar thickness, collagen abundance and collagen bundle structure, mast cell infiltration, myofibroblast formation, M1, and M2 macrophages together with gene expression of M1 and M2 related factors in the grafted skin were investigated at 2, 4, and 8 weeks postgrafting. The transplanted human skin from the control group developed contracted, elevated, and thickened scars while the grafted skin from the depletion group healed with significant less contraction and elevation. Significant reductions in myofibroblast number, collagen synthesis, and hypertrophic fiber morphology as well as mast cell infiltration were observed in the depletion group compared to the control group. Macrophage depletion significantly reduced M1 and M2 macrophage number in the depletion group 2 weeks postgrafting as compared to the control group. These findings suggest that systemic macrophage depletion in subacute phase of wound healing reduces scar formation, which provides evidence for the pro-fibrotic role of macrophages in fibrosis of human skin as well as insight into the potential benefits of specifically depleting M2 macrophages in vivo. © 2016 by the Wound Healing Society.

Effects of silicone gel on burn scars.

PubMed

Momeni, Mahnoush; Hafezi, Farhad; Rahbar, Hossein; Karimi, Hamid

2009-02-01

To study the efficacy of silicone gel applied to hypertrophic burn scars, in reducing scar interference with normal function and improving cosmesis. A randomised, double-blind, placebo-controlled trial involving 38 people with hypertrophic burn scars. Each scar was divided into two segments; silicone gel sheet was applied randomly to one of the two and placebo to the other. Participants were seen again after 1 and 4 months. Their data and wound characteristics were collected using the Vancouver scar scale. The median age of participants was 22 years (1.5-60 years) and 16 were male; 4 did not attend follow-up and were excluded from the study. There were no significant differences in baseline characteristics. Although after 1 month all scar scale measures were lower in treated areas, only the vascularity scale was significantly different between the two areas. After 4 months, all scale measures were significantly lower in the silicone gel group than in the control group, except for the pain score. Silicone gel is an effective treatment for hypertrophic burn scars.

[Functional regulation of genome with peptide bioregulators by hypertrophic cardiomyopathy (by patients and relatives)].

PubMed

Dzhokhadze, T A; Buadze, T Zh; Gaĭozishvili, M N; Rogava, M A; Lazhava, T A

2013-12-01

In this paper, a comparative study of the functional genome indicators using lymphocyte cultures of patients with hypertrophic cardiomyopathy (HCM) and their first relatives. Studies conducted both in intact cultures and cultures exposed to the influence of peptide - bioregulators Epithalon, Vilon and Livagen. Last (Livagen) tested at separate and joint application with cobalt chloride salt. As indicated according to the results of the analysis, the cells of the individuals with HCM and their first relatives were characterized by higher frequency of spontaneous quantitative - structural disorders in comparison with the cells of healthy individuals. The findings suggest a different effect of bioregulators. The most effective protective action in relation normalization of functional parameters of the genome shows Epithalon for lowering the level of chromosomal instability in patients with hypertrophic cardiomyopathy and relatives of patients with HCM. On the basis of identified protective action Epithalon concludes prospects of its application in the development of preventive measures for individuals at increased risk of morbidity HCM.

Hypertrophic Cranial Pachymeningitis and Skull Base Osteomyelitis by Pseudomonas Aeruginosa: Case Report and Review of the Literature

PubMed Central

Caldas, Ana Rita; Brandao, Mariana; Paula, Filipe Seguro; Castro, Elsa; Farinha, Fatima; Marinho, Antonio

2012-01-01

Hypertrophic cranial pachymeningitis (HCP) is an uncommon disorder characterized by localized or diffuse thickening of the dura mater, and it usually presents with multiple cranial neurophaties. It has been associated with a variety of inflammatory, infectious, traumatic, toxic and neoplasic diseases, when no specific cause is found the process is called idiopathic. The infectious cases occur in patients under systemic immunosuppression, which have an evident contiguous source or those who have undergone neurosurgical procedures. We describe a case of a 62-year-old immunosuppressed woman with diabetes and rheumatoid arthritis, which had HCP and osteomyelitis of the skull base caused by pseudomonas aeruginosa, presenting with headache and diplopia. We believe this is the second documented case of pachymeningitis secondary to this microorganism. As a multifactorial disease, it is essencial to determine the specific causative agent of HCP before making treatment decisions, and great care is needed with immunocompromised patients. Keywords Pseudomonas aeruginosa; Hypertrophic pachymeningitis; Ophtalmoplegia, optical neuropathy; Osteomyelitis; Skull base PMID:22505989

Early detection of myocardial dysfunction using two-dimensional speckle tracking echocardiography in a young cat with hypertrophic cardiomyopathy

PubMed Central

Mochizuki, Yohei; Yoshimatsu, Hiroki; Niina, Ayaka; Teshima, Takahiro; Matsumoto, Hirotaka; Koyama, Hidekazu

2018-01-01

Case summary A 5-month-old intact female Scottish Fold cat was presented for cardiac evaluation. Careful auscultation detected a slight systolic murmur (Levine I/VI). The findings of electrocardiography, thoracic radiography, non-invasive blood pressure measurements and conventional echocardiographic studies were unremarkable. However, two-dimensional speckle tracking echocardiography revealed abnormalities in myocardial deformations, including decreased early-to-late diastolic strain rate ratios in longitudinal, radial and circumferential directions, and deteriorated segmental systolic longitudinal strain. At the follow-up examinations, the cat exhibited echocardiographic left ventricular hypertrophy and was diagnosed with hypertrophic cardiomyopathy using conventional echocardiography. Relevance and novel information This is the first report on the use of two-dimensional speckle tracking echocardiography for the early detection of myocardial dysfunction in a cat with hypertrophic cardiomyopathy; the myocardial dysfunction was detected before the development of hypertrophy. The findings from this case suggest that two-dimensional speckle tracking echocardiography can be useful for myocardial assessment when conventional echocardiographic and Doppler findings are ambiguous. PMID:29449957

Family communication in a population at risk for hypertrophic cardiomyopathy.

PubMed

Batte, Brittany; Sheldon, Jane P; Arscott, Patricia; Huismann, Darcy J; Salberg, Lisa; Day, Sharlene M; Yashar, Beverly M

2015-04-01

Encouraging family communication is an integral component of genetic counseling; therefore, we sought to identify factors impacting communication to family members at risk for Hypertrophic Cardiomyopathy (HCM). Participants (N = 383) completed an online survey assessing: 1) demographics (gender, genetic test results, HCM family history, and disease severity); 2) illness representations; 3) family functioning and cohesiveness; 4) coping styles; 5) comprehension of HCM autosomal dominant inheritance; and 6) communication of HCM risk information to at-risk relatives. Participants were a national sample of individuals with HCM, recruited through the Hypertrophic Cardiomyopathy Association. Data from 183 participants were analyzed using a logistic regression analysis, with family communication as a dichotomous dependent variable. We found that female gender and higher comprehension of autosomal dominant inheritance were significant predictors of participants' communication of HCM risk information to all their siblings and children. Our results suggest that utilizing interventions that promote patient comprehension (e.g., a teaching-focused model of genetic counseling) are important and may positively impact family communication within families with HCM.

Up-to-date approach to manage keloids and hypertrophic scars: a useful guide.

PubMed

Arno, Anna I; Gauglitz, Gerd G; Barret, Juan P; Jeschke, Marc G

2014-11-01

Keloids and hypertrophic scars occur anywhere from 30 to 90% of patients, and are characterized by pathologically excessive dermal fibrosis and aberrant wound healing. Both entities have different clinical and histochemical characteristics, and unfortunately still represent a great challenge for clinicians due to lack of efficacious treatments. Current advances in molecular biology and genetics reveal new preventive and therapeutical options which represent a hope to manage this highly prevalent, chronic and disabling problem, with long-term beneficial outcomes and improvement of quality of life. While we wait for these translational clinical products to be marketed, however, it is imperative to know the basics of the currently existing wide array of strategies to deal with excessive scars: from the classical corticotherapy, to the most recent botulinum toxin and lasers. The main aim of this review paper is to offer a useful up-to-date guideline to prevent and treat keloids and hypertrophic scars. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy*.

PubMed

Richardson, Kenneth E; Tannous, Paul; Berenji, Kambeez; Nolan, Bridgid; Bayless, Kayla J; Davis, George E; Rothermel, Beverly A; Hill, Joseph A

2005-12-01

There is great interest in deciphering mechanisms of maladaptive remodeling in cardiac hypertrophy in the hope of affording clinical benefit. Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rac1 and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about the interaction-if any-between these important signaling molecules in hypertrophic heart disease. In this study, we examined the molecular interplay among these molecules, finding that Rho family guanosine triphosphatase signaling occurs either downstream of calcineurin or as a required, parallel pathway. It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition blocks hypertrophy, and we report here that "statin" therapy effectively suppresses small G protein activation and blunts hypertrophic growth in vitro and in vivo. Importantly, despite significant suppression of hypertrophy, clinical and hemodynamic markers remained compensated, suggesting that the hypertrophic growth induced by this pathway is not required to maintain circulatory performance.

Are Human Peripheral Nerves Sensitive to X-Ray Imaging?

PubMed Central

Scopel, Jonas Francisco; de Souza Queiroz, Luciano; O’Dowd, Francis Pierce; Júnior, Marcondes Cavalcante França; Nucci, Anamarli; Hönnicke, Marcelo Gonçalves

2015-01-01

Diagnostic imaging techniques play an important role in assessing the exact location, cause, and extent of a nerve lesion, thus allowing clinicians to diagnose and manage more effectively a variety of pathological conditions, such as entrapment syndromes, traumatic injuries, and space-occupying lesions. Ultrasound and nuclear magnetic resonance imaging are becoming useful methods for this purpose, but they still lack spatial resolution. In this regard, recent phase contrast x-ray imaging experiments of peripheral nerve allowed the visualization of each nerve fiber surrounded by its myelin sheath as clearly as optical microscopy. In the present study, we attempted to produce high-resolution x-ray phase contrast images of a human sciatic nerve by using synchrotron radiation propagation-based imaging. The images showed high contrast and high spatial resolution, allowing clear identification of each fascicle structure and surrounding connective tissue. The outstanding result is the detection of such structures by phase contrast x-ray tomography of a thick human sciatic nerve section. This may further enable the identification of diverse pathological patterns, such as Wallerian degeneration, hypertrophic neuropathy, inflammatory infiltration, leprosy neuropathy and amyloid deposits. To the best of our knowledge, this is the first successful phase contrast x-ray imaging experiment of a human peripheral nerve sample. Our long-term goal is to develop peripheral nerve imaging methods that could supersede biopsy procedures. PMID:25757086

Retrograde transport of (/sup 3/H)-D-aspartate label by cochlear and vestibular efferent neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwarz, D.W.; Schwarz, I.E.

1988-01-01

(/sup 3/H)-D-aspartic acid was injected into the inner ear of rats. After a six hour survival time, labeled cells were found at all locations known to contain efferent cochlear or vestibular neurons. Most labeled neurons were found in the ipsilateral lateral superior olivary nucleus (LSO), although both ventral nuclei of the trapezoid body (VTB), group E, and the caudal pontine reticular nucleus (CPR) just adjacent to the ascending limb of the facial nerve also contained labeled cells. Because not all efferent neurons in the rat could be previously shown to be cholinergic, aspartate and glutamate are efferent transmitter candidates.

Abnormalities in the basement membrane structure promote basal keratinocytes in the epidermis of hypertrophic scars to adopt a proliferative phenotype.

PubMed

Yang, Shaowei; Sun, Yexiao; Geng, Zhijun; Ma, Kui; Sun, Xiaoyan; Fu, Xiaobing

2016-05-01

The majority of studies on scar formation have mainly focused on the dermis and little is known of the involvement of the epidermis. Previous research has demonstrated that the scar tissue-derived keratinocytes are different from normal cells at both the genetic and cell biological levels; however, the mechanisms responsible for the fundamental abnormalities in keratinocytes during scar development remain elusive. For this purpose, in this study, we used normal, wound edge and hypertrophic scar tissue to examine the morphological changes which occur during epidermal regeneration as part of the wound healing process and found that the histological structure of hypertrophic scar tissues differed from that of normal skin, with a significant increase in epidermal thickness. Notably, staining of the basement membrane (BM) appeared to be absent in the scar tissues. Moreover, immunofluorescence staining for cytokeratin (CK)10, CK14, CK5, CK19 and integrin-β1 indicated the differential expression of cell markers in the epidermal keratinocytes among the normal, wound edge and hypertrophic scar tissues, which corresponded with the altered BM structures. By using a panel of proteins associated with BM components, we validated our hypothesis that the BM plays a significant role in regulating the cell fate decision of epidermal keratinocytes during skin wound healing. Alterations in the structure of the BM promote basal keratinocytes to adopt a proliferative phenotype both in vivo and in vitro.

Abnormalities in the basement membrane structure promote basal keratinocytes in the epidermis of hypertrophic scars to adopt a proliferative phenotype

PubMed Central

YANG, SHAOWEI; SUN, YEXIAO; GENG, ZHIJUN; MA, KUI; SUN, XIAOYAN; FU, XIAOBING

2016-01-01

The majority of studies on scar formation have mainly focused on the dermis and little is known of the involvement of the epidermis. Previous research has demonstrated that the scar tissue-derived keratinocytes are different from normal cells at both the genetic and cell biological levels; however, the mechanisms responsible for the fundamental abnormalities in keratinocytes during scar development remain elusive. For this purpose, in this study, we used normal, wound edge and hypertrophic scar tissue to examine the morphological changes which occur during epidermal regeneration as part of the wound healing process and found that the histological structure of hypertrophic scar tissues differed from that of normal skin, with a significant increase in epidermal thickness. Notably, staining of the basement membrane (BM) appeared to be absent in the scar tissues. Moreover, immunofluorescence staining for cytokeratin (CK)10, CK14, CK5, CK19 and integrin-β1 indicated the differential expression of cell markers in the epidermal keratinocytes among the normal, wound edge and hypertrophic scar tissues, which corresponded with the altered BM structures. By using a panel of proteins associated with BM components, we validated our hypothesis that the BM plays a significant role in regulating the cell fate decision of epidermal keratinocytes during skin wound healing. Alterations in the structure of the BM promote basal keratinocytes to adopt a proliferative phenotype both in vivo and in vitro. PMID:26986690

Treatment of hypertrophic scars and keloids using intense pulsed light (IPL).

PubMed

Erol, O Onur; Gurlek, Ali; Agaoglu, Galip; Topcuoglu, Ela; Oz, Hayat

2008-11-01

Keloids and hypertrophic scars are extremely disturbing to patients, both physically and psychologically. This study prospectively assessed the safety and efficacy of intense pulsed light (IPL) on scars originating from burns, trauma, surgery, and acne. Hypertrophic scars in 109 patients, originating from surgical incisions (n = 55), traumatic cuts (traffic accidents) (n = 24), acne scars (n = 6), keloids (n = 5), and burns (n = 19), were treated using an IPL Quantum device. Treatment was administered at 2-4-week intervals, and patients received an average of 8 treatments (range = 6-24). Using digital photographs, Changes in scar appearance were assessed by two physicians who were blinded to the study patients and treatments. The photographs were graded on a scale of 0 to 4 (none, minimal, moderate, good, excellent) for improvement in overall clinical appearance and reduction in height, erythema, and hardness. An overall clinical improvement in the appearance of scars and reductions in height, erythema, and hardness were seen in the majority of the patients (92.5%). Improvement was excellent in 31.2% of the patients, good in 25.7%, moderate in 34%, and minimal in 9.1%. Over half the patients had good or excellent improvement. In the preventive IPL treatment group, 65% had good to excellent improvement in clinical appearance. Patient satisfaction was very high. This study suggests that IPL is effective not only in improving the appearance of hypertrophic scars and keloids regardless of their origin, but also in reducing the height, redness, and hardness of scars.

Fractional microplasma radiofrequency technology for non-hypertrophic post-burn scars in Asians: A prospective study of 95 patients.

PubMed

Wang, Shen; Mi, Jing; Li, Qingfeng; Jin, Rui; Dong, Jiying

2017-08-01

Laser and other energy devices are emerging, minimally invasive treatments for scars. Among the various techniques, fractional microplasma radiofrequency technology (FMRT) has proven to be an effective treatment option for various types of scars and skin conditions such as rhytids, striae distensae, and hyperpigmentation. This prospective clinical trial was designed to evaluate the efficacy and safety of FMRT for treating non-hypertrophic post-burn scars in the Asian population. All patients underwent three to five treatment sessions at various intervals of 8-16 weeks. The Patient and Observer Scar Assessment Scales (POSAS) [20] were used to evaluate changes in burn scars pre-and post-FMRT treatment. A total of 95 patients completed the study. The overall response rate was 86.3% (82/95). The total POSAS scores before and after 6 months of treatment were 53.41 ± 6.28 and 46.35 ± 5.30, respectively. There was statistically significant improvement in scar color, thickness, and pliability. There was no improvement in vascularization, pain, or itching. Complications included prolonged post-inflammatory hyperpigmentation, acne eruption, herpes simplex eruption, and abnormal hair growth. No severe adverse events, such as acute skin infection, hypertrophic scarring, or depigmentation, were observed. FMRT is an efficacious, safe treatment for non-hypertrophic burn scars in the Asian population. Lasers Surg. Med. 49:563-569, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Evidence-Based Scar Management: How to Improve Results with Technique and Technology.

PubMed

Khansa, Ibrahim; Harrison, Bridget; Janis, Jeffrey E

2016-09-01

Scars represent the visible sequelae of trauma, injury, burn, or surgery. They may induce distress in the patient because of their aesthetically unpleasant appearance, especially if they are excessively raised, depressed, wide, or erythematous. They may also cause the patient symptoms of pain, tightness, and pruritus. Numerous products are marketed for scar prevention or improvement, but their efficacy is unclear. A literature review of high-level studies analyzing methods to prevent or improve hypertrophic scars, keloids, and striae distensae was performed. The evidence from these articles was analyzed to generate recommendations. Each intervention's effectiveness at preventing or reducing scars was rated as none, low, or high, depending on the strength of the evidence for that intervention. For the prevention of hypertrophic scars, silicone, tension reduction, and wound edge eversion seem to have high efficacy, whereas onion extract, pulsed-dye laser, pressure garments, and scar massage have low efficacy. For the treatment of existing hypertrophic scars, silicone, pulsed-dye laser, CO2 laser, corticosteroids, 5-fluorouracil, bleomycin, and scar massage have high efficacy, whereas onion extract and fat grafting seem to have low efficacy. For keloid scars, effective adjuncts to excision include corticosteroids, mitomycin C, bleomycin, and radiation therapy. No intervention seems to have significant efficacy in the prevention or treatment of striae distensae. Although scars can never be completely eliminated in an adult, this article presents the most commonly used, evidence-based methods to improve the quality and symptoms of hypertrophic scars, as well as keloid scars and striae distensae.

Opuntia Extract Reduces Scar Formation in Rabbit Ear Model: A Randomized Controlled Study.

PubMed

Fang, Quan; Huang, Chunlan; You, Chuangang; Ma, Shaolin

2015-12-01

The purpose of this article is to investigate the effect of Opuntia stricta H (Cactaceae) extract on suppression of hypertrophic scar on ventral surface wounds of rabbit ears. Full thickness skin defection was established in a rabbit ear to simulate hypertrophic scar. Opuntia extract was sprayed on the wounds in the experimental group, and normal saline was used in the control group. After the wounds healed with scar formation, the hypertrophic scar tissue was harvested on days 22, 39, and 54 for histological analysis. The expression of type I and type III collagen and matrix metalloproteinase-1 (MMP-1) were evaluated by immunohistochemistry and real-time quantitative polymerase chain reaction. The results indicated that the scar of the control group is more prominent compared with the opuntia extract group. The expression of type I collagen in the opuntia extract group was lower than the control group, while type III collagen in opuntia extract group gradually increased and exceeded control group. The expression of MMP-1 decreased in the opuntia extract group, while the control group increased over time, but the amount of MMP-1 was much higher than that in the control group on day 22. In conclusion, opuntia extract reduces hypertrophic scar formation by means of type I collagen inhibition, and increasing type III collagen and MMP-1.T he novel application of opuntia extract may lead to innovative and effective antiscarring therapies. © The Author(s) 2015.

Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA.

PubMed

Cui, Huanhuan; Schlesinger, Jenny; Schoenhals, Sophia; Tönjes, Martje; Dunkel, Ilona; Meierhofer, David; Cano, Elena; Schulz, Kerstin; Berger, Michael F; Haack, Timm; Abdelilah-Seyfried, Salim; Bulyk, Martha L; Sauer, Sascha; Sperling, Silke R

2016-04-07

DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo

PubMed Central

Passier, Robert; Zeng, Hong; Frey, Norbert; Naya, Francisco J.; Nicol, Rebekka L.; McKinsey, Timothy A.; Overbeek, Paul; Richardson, James A.; Grant, Stephen R.; Olson, Eric N.

2000-01-01

Hypertrophic growth is an adaptive response of the heart to diverse pathological stimuli and is characterized by cardiomyocyte enlargement, sarcomere assembly, and activation of a fetal program of cardiac gene expression. A variety of Ca2+-dependent signal transduction pathways have been implicated in cardiac hypertrophy, but whether these pathways are independent or interdependent and whether there is specificity among them are unclear. Previously, we showed that activation of the Ca2+/calmodulin-dependent protein phosphatase calcineurin or its target transcription factor NFAT3 was sufficient to evoke myocardial hypertrophy in vivo. Here, we show that activated Ca2+/calmodulin-dependent protein kinases-I and -IV (CaMKI and CaMKIV) also induce hypertrophic responses in cardiomyocytes in vitro and that CaMKIV overexpressing mice develop cardiac hypertrophy with increased left ventricular end-diastolic diameter and decreased fractional shortening. Crossing this transgenic line with mice expressing a constitutively activated form of NFAT3 revealed synergy between these signaling pathways. We further show that CaMKIV activates the transcription factor MEF2 through a posttranslational mechanism in the hypertrophic heart in vivo. Activated calcineurin is a less efficient activator of MEF2-dependent transcription, suggesting that the calcineurin/NFAT and CaMK/MEF2 pathways act in parallel. These findings identify MEF2 as a downstream target for CaMK signaling in the hypertrophic heart and suggest that the CaMK and calcineurin pathways preferentially target different transcription factors to induce cardiac hypertrophy. PMID:10811847

Mast cells and angiogenesis in wound healing.

PubMed

Gaber, Mohamed A; Seliet, Iman A; Ehsan, Nermin A; Megahed, Mohamed A

2014-02-01

To investigate the role of mast cells and vascular endothelial growth factor (VEGF) as a mediator of angiogenesis to promote wound healing in surgical and pathological scars. The study was carried out on 40 patients who presented with active scar lesions. They were subdivided into 4 groups. They included granulation tissue (10 cases), surgical scar (10 cases), hypertrophic scar (10 cases), and keloid scar (10 cases). Also 10 healthy volunteers of the same age and sex were selected as a control group. Skin biopsies were taken from the patients and the control group. Skin biopsies from clinically assessed studied groups were processed for routine histology and embedded in paraffin. Four sections were prepared from each paraffin block. The first section was stained with hematoxylin and eosin for histological evaluation. The second and third sections were processed for immunostaining of mast cells that contain chymase (MCCs) and mast cells that contain tryptase (MCTs). The fourth section was processed for immunostaining of VEGF. MCCs exhibited mild expression in normal tissue, granulation tissue, and surgical, hypertrophic and keloid scars. MCTs exhibited mild expression in normal tissue, granulation tissue and keloid, whereas moderate expression was exhibited in hypertrophic and surgical scars. VEGF expression was absent in normal tissue, mild in keloid, surgical and hypertrophic scars, and moderate in keloids and granulation tissue. Mast cell expression variation among different scar types signals the pathological evolution of the lesion, and hence may guide the need for therapeutic intervention.

Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring

PubMed Central

Xue, Meilang; Jackson, Christopher J.

2015-01-01

Significance: When a cutaneous injury occurs, the wound heals via a dynamic series of physiological events, including coagulation, granulation tissue formation, re-epithelialization, and extracellular matrix (ECM) remodeling. The final stage can take many months, yet the new ECM forms a scar that never achieves the flexibility or strength of the original tissue. In certain circumstances, the normal scar is replaced by pathological fibrotic tissue, which results in hypertrophic or keloid scars. These scars cause significant morbidity through physical dysfunction and psychological stress. Recent Advances and Critical Issues: The cutaneous ECM comprises a complex assortment of proteins that was traditionally thought to simply provide structural integrity and scaffolding characteristics. However, recent findings show that the ECM has multiple functions, including, storage and delivery of growth factors and cytokines, tissue repair and various physiological functions. Abnormal ECM reconstruction during wound healing contributes to the formation of hypertrophic and keloid scars. Whereas adult wounds heal with scarring, the developing foetus has the ability to heal wounds in a scarless fashion by regenerating skin and restoring the normal ECM architecture, strength, and function. Recent studies show that the lack of inflammation in fetal wounds contributes to this perfect healing. Future Directions: Better understanding of the exact roles of ECM components in scarring will allow us to produce therapeutic agents to prevent hypertrophic and keloid scars. This review will focus on the components of the ECM and their role in both physiological and pathological (hypertrophic and keloid) cutaneous scar formation. PMID:25785236

Combined pulsed dye laser and fiberoptic Nd-YAG laser for the treatment of hypertrophic port wine stain.

PubMed

Radmanesh, Mohammed; Radmanesh, Ramin

2017-10-01

The hypertrophic Port Wine Stain (PWS) is only partially and superficially treated with the Pulsed dye laser (PDL) because of its limited depth of penetration. We used combined PDL and fiberoptic 1444-nm Nd-YAG laser to treat a case with hypertrophic PWS. After tumescent anesthesia, few holes were made by a 16-gauge needle on different sides of the lesion. The fiberoptic tip of 1444-nm Nd-YAG laser was inserted within the holes and was pushed forward while triggering. In a fan pattern and by a back and forth movement, the subcutaneous and deep dermal areas were coagulated. The skin and outer mucosal surfaces were then treated by PDL. The fiberoptic system used was Accusculpt 1444-nm Nd-YAG laser (Lutronic lasers, South Korea), and the PDL used was 585 nm Nlite system (Chromogenex UK). The parameters used for PDL were fluence = 9 Joules/cm 2 and the spot size was 5 mm. The parameters used for fiberoptic 1444-nm Nd-YAG laser were: Pulse rate = 30 Hz, pulse energy = 300 mJ, power = 6 W, and the total energy = 4000 J for the whole face and mucosa. Little sign of regression and moderate purpura were detected immediately after combined fiberoptic Nd-YAG and PDL therapy. The lesion gradually regressed within 4 months with satisfactory color and volume change. Combined fiberoptic Nd-YAG laser and PDL can be used for the treatment of deeper and superficial layers of hypertrophic PWS.

Evaluation of non-Gaussian diffusion in cardiac MRI.

PubMed

McClymont, Darryl; Teh, Irvin; Carruth, Eric; Omens, Jeffrey; McCulloch, Andrew; Whittington, Hannah J; Kohl, Peter; Grau, Vicente; Schneider, Jürgen E

2017-09-01

The diffusion tensor model assumes Gaussian diffusion and is widely applied in cardiac diffusion MRI. However, diffusion in biological tissue deviates from a Gaussian profile as a result of hindrance and restriction from cell and tissue microstructure, and may be quantified better by non-Gaussian modeling. The aim of this study was to investigate non-Gaussian diffusion in healthy and hypertrophic hearts. Thirteen rat hearts (five healthy, four sham, four hypertrophic) were imaged ex vivo. Diffusion-weighted images were acquired at b-values up to 10,000 s/mm 2 . Models of diffusion were fit to the data and ranked based on the Akaike information criterion. The diffusion tensor was ranked best at b-values up to 2000 s/mm 2 but reflected the signal poorly in the high b-value regime, in which the best model was a non-Gaussian "beta distribution" model. Although there was considerable overlap in apparent diffusivities between the healthy, sham, and hypertrophic hearts, diffusion kurtosis and skewness in the hypertrophic hearts were more than 20% higher in the sheetlet and sheetlet-normal directions. Non-Gaussian diffusion models have a higher sensitivity for the detection of hypertrophy compared with the Gaussian model. In particular, diffusion kurtosis may serve as a useful biomarker for characterization of disease and remodeling in the heart. Magn Reson Med 78:1174-1186, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.

Dihydrotestosterone in prostatic hypertrophy

PubMed Central

Siiteri, Pentti K.; Wilson, Jean D.

1970-01-01

To explore the relation between androgens and prostatic hypertrophy in man, the concentrations of testosterone, dihydrotestosterone, and androstenedione and the rate of conversion of testosterone to dihydrotestosterone have been measured in normal and hypertrophic prostate tissue. First, a double isotope derivative technique was adapted for the measurement of tissue androgen content in 15 normal and 10 hypertrophic prostates. Although there was no significant difference in the content of androstenedione and testosterone between the two types of tissue, the content of dihydrotestosterone was significantly greater in the hypertrophic tissue (0.60 ±0.10 μg/100 g) than in the normal glands (0.13 ±0.05 μg/100 g). Second, a regional study was performed in three normal prostates and four glands with early hypertrophy, and it was demonstrated that the dihydrotestosterone content was two and three fold greater in the periurethral area where prostatic hypertrophy usually commences than in the outer regions of the gland. Finally, the rate of conversion of testosterone to dihydrotestosterone has been measured under standardized conditions in tissue slices from 4 normal and 20 hypertrophic prostates. There was no significant difference in the rate of dihydrotestosterone formation between the two types of gland (6.0 ±0.8 and 7.8 ±0.5 μμmoles/15 mg of tissue per hr). While the mechanism by which dihydrotestosterone accumulation occurs remains unexplained, it is possible that the local accumulation of dihydrotestosterone may be involved in the pathogenesis of prostatic hypertrophy in man. Images PMID:4194768

Radiofrequency ablation of fast ventricular tachycardia causing an ICD storm in an infant with hypertrophic cardiomyopathy.

PubMed

Ergul, Yakup; Ozyilmaz, Isa; Bilici, Meki; Ozturk, Erkut; Haydin, Sertaç; Guzeltas, Alper

2018-04-01

An implantable cardioverter defibrillator (ICD) storm involves very frequent arrhythmia episodes and ICD shocks, and it is associated with poor short-term and long-term prognosis. Radiofrequency catheter ablation can be used as an effective rescue treatment for patients with an ICD storm. To our knowledge, this is the first report of an infant with hypertrophic cardiomyopathy presenting with an ICD storm and undergoing successful radiofrequency catheter ablation salvage treatment for the fast left posterior fascicular ventricular tachycardia. © 2017 Wiley Periodicals, Inc.

Cadmium-induced oxidative stress and histological damage in the myocardium. Effects of a soy-based diet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferramola, Mariana L.; Pérez Díaz, Matías F.F.; Honoré, Stella M.

Cd exposure has been associated to an augmented risk for cardiovascular disease. We investigated the effects of 15 and 100 ppm of Cd on redox status as well as histological changes in the rat heart and the putative protective effect of a soy-based diet. Male Wistar rats were separated into 6 groups and treated during 60 days as follows: groups (1), (2) and (3) were fed a casein-based diet; groups (4), (5) and (6), a soy-based diet; (1) and (4) were given tap water; (2) and (5) tap water containing 15 ppm of Cd{sup 2+}; and (3) and (6) tapmore » water containing 100 ppm of Cd{sup 2+}. Serum lipid peroxides increased and PON-1 activity decreased in group (3). Lipoperoxidation also increased in the heart of all intoxicated groups; however protein oxidation only augmented in (3) and reduced glutathione levels diminished in (2) and (3). Catalase activity increased in groups (3) and (6) while superoxide dismutase activity increased only in (6). Glutathione peroxidase activity decreased in groups (3) and (6). Nrf2 expression was higher in groups (3) and (6), and MTI expression augmented in (3). Histological examination of the heart tissue showed the development of hypertrophic and fusion of cardiomyocytes along with foci of myocardial fiber necrosis. The transmission electron microscopy analysis showed profound ultra-structural damages. No protection against tissue degeneration was observed in animals fed the soy-based diet. Our findings indicate that even though the intake of a soy-based diet is capable of ameliorating Cd induced oxidative stress, it failed in preventing cardiac damage. -- Highlights: ► Cd intoxication produces extracellular and ultrastructural damage in the myocardium. ► The intake of a soy-based diet ameliorated Cd-induced oxidative stress. ► Cd-induced myocardial damage wasn't prevented by the intake of a soy-based diet. ► Cd-induced myocardial degeneration may not be caused by oxidative stress generation. ► Histology evaluation is needed to establish the extent of Cd-induced cardiac damage.« less

Treatment of keloids and hypertrophic scars with dermojet injections of bleomycin: a preliminary study.

PubMed

Saray, Yasemin; Güleç, A Tülin

2005-09-01

Numerous treatment modalities have been used to treat keloids and hypertrophic scars, but the optimal treatment has not been established. The aim of this study was to determine the efficacy and safety of intralesional jet injection of bleomycin as therapy for keloids and hypertrophic scars that are unresponsive to intralesional steroid injection. The study included 14 patients with 15 keloids or hypertrophic scars that had not responded to a minimum of three intralesional injections of triamcinolone acetonide. Multiple jet injections of 0.1 ml of bleomycin (1.5 IU/ml) were administered to each lesion, with injection sites spaced 0.5 mm apart. Injections were repeated each month. Scar height was measured, and scar pliability and erythema were scored at baseline and then monthly during the treatment and follow-up periods. Patients' self-assessments of subjective symptoms (pruritus and pain) were also scored. Clinical improvement was defined primarily on the basis of scar height reduction (percentage reduction from baseline), and was classified using the following scale: complete flattening (100%), highly significant flattening (> 90%), significant flattening (75-90%), moderate flattening (50-75%), and minimal flattening (< 50%). Pre- and post-treatment mean values for scar height, scar pliability, erythema, pruritus and pain were statistically compared. The number of sessions required to successfully treat the lesions ranged from two to six. Eleven lesions (73.3%) showed complete flattening, one (6.7%) showed highly significant flattening, two (13.3%) showed significant flattening, and one scar (6.7%) showed moderate flattening. The mean scar height was significantly lower, and the mean scores for scar pliability and erythema were significantly better at the end of treatment (P < 0.001, P < 0.001 and P < 0.001, respectively). The mean scores for pruritus and pain also improved significantly (P < 0.001 and P = 0.01, respectively). The observed side-effects were hyperpigmentation (four lesions) and skin atrophy (three lesions). No recurrences were noted during follow up (mean duration of 19 months). Intralesional jet injection of bleomycin is an effective and safe method of treating keloids and hypertrophic scars that are unresponsive to intralesional steroid therapy.

Logistics of building a laser practice for the treatment of hypertrophic burn scars.

PubMed

Hultman, Charles Scott; Edkins, Renee E; Cairns, Bruce A; Meyer, Anthony A

2013-05-01

Although lasers can improve burn scars, such treatment has not been adopted universally, due to operational challenges starting a practice and the perception that such a program is not financially viable. We report the logistics of building a laser practice for the treatment of hypertrophic burn scars. We analyzed the clinical, operational, and financial components of our laser practice, focusing on treatment of hypertrophic burn scars, using pulsed dye laser, fractional CO2 laser, and intense pulsed light. Cases were performed in an operating room, with anesthesia, after preauthorization. We examined professional charges and collections, case time, variable and indirect expenses, and breakeven volumes. Our practice grew as follows: 2008, 1 case; 2009, 44 cases; 2010, 169 cases; and 2011, 415 cases. Overall collection rate was 32.1%. Expenses incurred by the provider, per 8-hour session, included laser rental/lease ($2375), personnel salaries ($1900), and physician overhead ($808), for a total cost of $5083. Mean charge was $1642 per case; mean collection was $527 per case. Median case time (procedure plus turnover) was 40 minutes. In this model, breakeven volume is 9.7 cases per day; breakeven time is 49.7 minutes. Provider profit margin for 10 cases per day, or 83% capacity utilization, is $187 per day (income - expenses = $5270 - $5083). Despite high costs associated with starting and operating a laser practice for the treatment of hypertrophic burn scars, a sustainable enterprise can be achieved when the provider has accrued enough volume to batch cases over an entire day. Critical to achieving breakeven is preauthorization, controlling overhead, and efficient throughput.

[Idiopathic hypertrophic pachymeningitis: a case report].

PubMed

Vargas-Bellina, V; Saavedra-Pastor, H; Alvarado-Rosales, M; Porras-Carrión, M; Cjuno-Pinto, R; Gonzales-Quispe, I; Alban-Zapata, G

Hypertrophic pachymeningitis is a clinical condition that is caused by a diffuse or localised thickening of the dura mater. It predominantly affects males and manifests as chronic headache, with or without association to neurological manifestations, such as paralysis of the cranial nerves, cerebellar ataxia and neuro-ophthalmic complications. A 61-year-old male, with no relevant past history, who, one month before admission, had begun to suffer from right frontotemporal headache that irradiated to the ipsilateral orbital region and was more pronounced at night. A week later he was affected by a decrease in visual acuity in the right eye and two weeks later he noted the presence of right palpebral ptosis, while the headaches increased. The examination showed: right palpebral ptosis with global ophthalmoparesis with predominance of adduction and abduction, and diminished photomotor reflex in the right eye. The visual acuity of the right eye was reduced and the palpebral fissure was 0 in the right eye. The fundus oculi was normal. Infectious and non-infectious causations of meningitis were precluded. Magnetic resonance imaging revealed a diffuse thickening of the supratentorial and infratentorial meninges, as well as diffuse uptake of the paramagnetic substance; thickening of the mucus in both paranasal maxillary sinuses was also observed. A meningeal biopsy study confirmed the existence of hypertrophic pachymeningitis. Treatment was established with prednisone and the clinical symptoms improved. Idiopathic hypertrophic pachymeningitis is an underdiagnosed condition that must be taken into consideration in cases of patients with a history of subacute or chronic meningitis in which infectious and non-infectious causations have been precluded, and high-dose steroid treatment must be established.

Is the evaluation of the anterior inferior iliac spine (AIIS) in the AP pelvis possible? Analysis of conventional X-rays and 3D-CT reconstructions.

PubMed

Krueger, David R; Windler, Markus; Geßlein, Markus; Schuetz, Michael; Perka, Carsten; Schroeder, Joerg H

2017-07-01

A hypertrophic AIIS has been identified as a cause for extraarticular hip impingement and is classified according to Hetsroni using 3D-CT reconstructions. The role of the conventional AP pelvis X-ray, which is the first standard imaging step for the evaluation of hip pain, has not been investigated yet. AP pelvis X-rays and 3D-CT reconstructions of patients were evaluated regarding their morphology of the AIIS. The conventional X-rays were categorized into three groups according to the projection of the AIIS: above (A) or below (B) the acetabular sourcil or even exceeding the anterior acetabular rim (C). They were compared to the morphologic types in the 3D-CT reconstruction (Hetsroni type I-III). Ninety patients with an equal distribution of type A, B or C projection in the AP pelvis were evaluated and compared to the morphology in the 3D-CT reconstruction. The projection of the AIIS below the acetabular sourcil (B + C) showed only moderate sensitivity (0.76) and specificity (0.64) for a hypertrophic AIIS (Hetsroni type II + III), but if the AIIS exceeds the anterior rim, all cases showed a hypertrophic AIIS in the 3D-CT reconstructions (Hetsroni type II + III). Distinct differentiation of the AIIS morphology in the AP pelvis is not possible, but the projection of the AIIS below the anterior acetabular rim represented a hypertrophic AIIS in all cases and should, therefore, be critically investigated for a relevant AIIS impingement.

Voltage dependent potassium channel remodeling in murine intestinal smooth muscle hypertrophy induced by partial obstruction.

PubMed

Liu, Dong-Hai; Huang, Xu; Guo, Xin; Meng, Xiang-Min; Wu, Yi-Song; Lu, Hong-Li; Zhang, Chun-Mei; Kim, Young-chul; Xu, Wen-Xie

2014-01-01

Partial obstruction of the small intestine causes obvious hypertrophy of smooth muscle cells and motility disorder in the bowel proximate to the obstruction. To identify electric remodeling of hypertrophic smooth muscles in partially obstructed murine small intestine, the patch-clamp and intracellular microelectrode recording methods were used to identify the possible electric remodeling and Western blot, immunofluorescence and immunoprecipitation were utilized to examine the channel protein expression and phosphorylation level changes in this research. After 14 days of obstruction, partial obstruction caused obvious smooth muscle hypertrophy in the proximally located intestine. The slow waves of intestinal smooth muscles in the dilated region were significantly suppressed, their amplitude and frequency were reduced, whilst the resting membrane potentials were depolarized compared with normal and sham animals. The current density of voltage dependent potassium channel (KV) was significantly decreased in the hypertrophic smooth muscle cells and the voltage sensitivity of KV activation was altered. The sensitivity of KV currents (IKV) to TEA, a nonselective potassium channel blocker, increased significantly, but the sensitivity of IKv to 4-AP, a KV blocker, stays the same. The protein levels of KV4.3 and KV2.2 were up-regulated in the hypertrophic smooth muscle cell membrane. The serine and threonine phosphorylation levels of KV4.3 and KV2.2 were significantly increased in the hypertrophic smooth muscle cells. Thus this study represents the first identification of KV channel remodeling in murine small intestinal smooth muscle hypertrophy induced by partial obstruction. The enhanced phosphorylations of KV4.3 and KV2.2 may be involved in this process.

Choline Protects Against Cardiac Hypertrophy Induced by Increased After-load

PubMed Central

Zhao, Yilei; Wang, Chen; Wu, Jianwei; Wang, Yan; Zhu, Wenliang; Zhang, Yong; Du, Zhimin

2013-01-01

Background: Although inadequate intake of essential nutrient choline has been known to significantly increase cardiovascular risk, whether additional supplement of choline offering a protection against cardiac hypertrophy remain unstudied. Methods: The effects of choline supplements on pathological cardiac hypertrophic growth induced by transverse aorta constriction (TAC) for three weeks and cardiomyocyte hypertrophy in cultured cells induced by isoproterenol (ISO) 10 μM for 48 h stimulation were investigated. Western blot analysis and real-time PCR were used to determine the expression of ANP, BNP, β-MHC, miR-133a and Calcineurin. Results: Administration of 14 mg/kg choline to mice undergone TAC effectively attenuated the cardiac hypertrophic responses, as indicated by the reduced heart weight, left ventricular weight, ventricular thickness, and reduced expression of biomarker genes of cardiac hypertrophy. This anti-hypertrophic efficacy was reproduced in a cellular model of cardiomyocyte hypertrophy induced by isoproterenol in cultured neonatal cardiomyocytes. Our results further showed that choline rescued the aberrant downregulation of the muscle-specific microRNA miR-133a expression, a recently identified anti-hypertrophic factor, and restored the elevated calcineurin protein level, the key signaling molecule for the development of cardiac hypertrophy. These effects of choline were abolished by the M3 mAChR-specific antagonist 4-DAMP. Conclusion: Our study unraveled for the first time the cardioprotection of choline against cardiac hypertrophy, with correction of expression of miR-133a and calcineurin as a possible mechanism. Our findings suggest that choline supplement may be considered for adjunct anti-hypertrophy therapy. PMID:23493786

Clinical Profile and Prognosis of Left Ventricular Apical Aneurysm in Hypertrophic Cardiomyopathy.

PubMed

Xiao, Yan; Wang, Lin-Ping; Yang, Yan-Kun; Tian, Tao; Yang, Kun-Qi; Sun, Xin; Jiang, Yong; Liu, Ya-Xin; Zhou, Xian-Liang; Li, Jian-Jun

2016-01-01

Hypertrophic cardiomyopathy with left ventricular apical aneurysm is a unique entity with diverse manifestations and varied prognoses among races. This study evaluated the prevalence, clinical characteristics and outcomes of apical aneurysm in Chinese patients with hypertrophic cardiomyopathy. Consecutive patients with apical aneurysm were recruited from 1,844 patients with HCM treated at our hospital from 2002-2013. Basic clinical data and follow-up data were collected and analyzed. Apical aneurysm was identified in 24 patients (1.3%) (mean age: 52 ± 14 years). We identified an hourglass-shaped (71%) or distally hypertrophic (29%) left ventricle and found mural thrombi and nonsustained and sustained ventricular tachycardia in 11 (46%), 4 (17%) and 9 (38%) patients, respectively. During follow-up (5.0 ± 3.4 years [range: 1-14 years]), following were the clinical adverse events experienced by 14 patients (58%) (annual rate: 11.7%): sudden cardiac death (n = 4), appropriate discharge of an implantable cardioverter-defibrillator (n = 4), progressive heart failure (n = 4) or heart failure-related death (n = 1) and stroke (n = 4). The 4 patients who underwent aneurysmectomy had no adverse events. Patients with SCD had a lower ejection fraction (P = 0.004) and a larger left ventricular end-diastolic diameter (P < 0.001) than nonoperated survivors. Apical aneurysm is not rare in patients with HCM and it confers an extremely poor prognosis. Early aggressive therapies should be considered for this entity and prophylactic aneurysmectomy may be an option. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Phospholipase Cϵ Scaffolds to Muscle-specific A Kinase Anchoring Protein (mAKAPβ) and Integrates Multiple Hypertrophic Stimuli in Cardiac Myocytes*

PubMed Central

Zhang, Lianghui; Malik, Sundeep; Kelley, Grant G.; Kapiloff, Michael S.; Smrcka, Alan V.

2011-01-01

To define a role for phospholipase Cϵ (PLCϵ) signaling in cardiac myocyte hypertrophic growth, PLCϵ protein was depleted from neonatal rat ventricular myocytes (NRVMs) using siRNA. NRVMs with PLCϵ depletion were stimulated with endothelin (ET-1), norepinephrine, insulin-like growth factor-1 (IGF-1), or isoproterenol and assessed for development of hypertrophy. PLCϵ depletion dramatically reduced hypertrophic growth and gene expression induced by all agonists tested. PLCϵ catalytic activity was required for hypertrophy development, yet PLCϵ depletion did not reduce global agonist-stimulated inositol phosphate production, suggesting a requirement for localized PLC activity. PLCϵ was found to be scaffolded to a muscle-specific A kinase anchoring protein (mAKAPβ) in heart and NRVMs, and mAKAPβ localizes to the nuclear envelope in NRVMs. PLCϵ-mAKAP interaction domains were defined and overexpressed to disrupt endogenous mAKAPβ-PLCϵ complexes in NRVMs, resulting in significantly reduced ET-1-dependent NRVM hypertrophy. We propose that PLCϵ integrates multiple upstream signaling pathways to generate local signals at the nucleus that regulate hypertrophy. PMID:21550986

Increased intracellular proteolysis reduces disease severity in an ER stress-associated dwarfism.

PubMed

Mullan, Lorna A; Mularczyk, Ewa J; Kung, Louise H; Forouhan, Mitra; Wragg, Jordan Ma; Goodacre, Royston; Bateman, John F; Swanton, Eileithyia; Briggs, Michael D; Boot-Handford, Raymond P

2017-10-02

The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture. Depending on the nature of the mutation, CBZ application stimulated proteolysis of misfolded collagen X by either autophagy or proteasomal degradation, thereby reducing intracellular accumulation of mutant collagen. In MCDS mice expressing the Col10a1.pN617K mutation, CBZ reduced the MCDS-associated expansion of the growth plate hypertrophic zone, attenuated enhanced expression of ER stress markers such as Bip and Atf4, increased bone growth, and reduced skeletal dysplasia. CBZ produced these beneficial effects by reducing the MCDS-associated abnormalities in hypertrophic chondrocyte differentiation. Stimulation of intracellular proteolysis using CBZ treatment may therefore be a clinically viable way of treating the ER stress-associated dwarfism MCDS.

A novel mutation of the beta myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy.

PubMed

Wang, Juan; Xu, Shi-Jie; Zhou, Hua; Wang, Li-Jie; Hu, Bo; Fang, Fang; Zhang, Xu-Min; Luo, Yi-Wei; He, Xiao-Yan; Zhuang, Shao-Wei; Li, Xin-Ming; Liu, Zhong-Ming; Hu, Da-Yi

2009-09-01

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder and shows high variability in genetic heterogeneity and phenotypic characteristics. The genetic etiology responsible for HCM in many individuals remains unclear. This instigation was sought to identify novel genetic determinants for familial hypertrophic cardiomyopathy. Six unrelated Chinese families with HCM were studied. For each of the 13 established HCM-susceptibility genes, 3 to 5 microsatellite markers were selected to perform genotyping and haplotype analysis. The linked genes were sequenced. Haplotype analyses on candidate genetic loci revealed cosegregation of the gene beta-myosin heavy chain (MYH7) with HCM in a single family. A novel double heterozygous missense mutation of Ala26Val plus Arg719Trp in MYH7 was subsequently identified by sequencing in this family and was associated with a severe phenotype of HCM. The novel double mutation of Ala26Val plus Arg719Trp in MYH7 identified in a Chinese family highlights the remarkable genetic heterogeneity of HCM, which provides important information for genetic counseling, accurate diagnosis, prognostic evaluation, and appropriate clinical management. Copyright 2009 Wiley Periodicals, Inc.

Intrinsic electrical properties of mammalian neurons and CNS function: a historical perspective

PubMed Central

Llinás, Rodolfo R.

2014-01-01

This brief review summarizes work done in mammalian neuroscience concerning the intrinsic electrophysiological properties of four neuronal types; Cerebellar Purkinje cells, inferior olivary cells, thalamic cells, and some cortical interneurons. It is a personal perspective addressing an interesting time in neuroscience when the reflex view of brain function, as the paradigm to understand global neuroscience, began to be modified toward one in which sensory input modulates rather than dictates brain function. The perspective of the paper is not a comprehensive description of the intrinsic electrical properties of all nerve cells but rather addresses a set of cell types that provide indicative examples of mechanisms that modulate brain function. PMID:25408634

Hypertrophic Cardiomyopathy: New Evidence Since the 2011 American Cardiology of Cardiology Foundation and American Heart Association Guideline.

PubMed

Fraiche, Ariane; Wang, Andrew

2016-07-01

Since publication of the 2011 American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy (HCM), more recent studies offer greater insights about this condition. With increased recognition of the role of sarcomere protein mutations and myocardial structural abnormalities in the pathophysiology of this disease, new evidence offers potential improvements for the management of patients with HCM. In this review of studies published since 2011, we highlight several studies that may impact diagnostic considerations, risk stratification, and treatment of symptoms in HCM.

Focal giant cell cardiomyopathy with Beckwith-Wiedemann syndrome.

PubMed

Kapur, S; Kuehl, K S; Midgely, F M; Chandra, R S

1985-01-01

Cardiac involvement in Beckwith-Wiedemann syndrome is mostly limited to mild cardiomegaly. Although these patients have visceromegaly, macroglossia, gigantism, and adrenal cytomegaly, no significant myocardial changes have been described. An infant with dysmorphic features of this syndrome had supraventricular tachycardia since birth. Nodular lesions were present in the right atrium. Morphologically these lesions were composed of hypertrophic myocardial fibers admixed with multinucleated giant cells of myogenic origin. The exact nature of these lesions remains undetermined. It is postulated that hypertrophic myocardial cells may represent cardiac cytomegaly as a manifestation of the accelerated growth potential of cells seen with this syndrome.

Electrocardiogram and Imaging: An Integrated Approach to Arrhythmogenic Cardiomyopathies.

PubMed

Savino, Ketty; Bagliani, Giuseppe; Crusco, Federico; Padeletti, Margherita; Lombardi, Massimo

2018-06-01

Cardiovascular imaging has radically changed the management of patients with arrhythmogenic cardiomyopathies. This article focuses on the role of echocardiography and MRI in the diagnosis of these structural diseases. Cardiomyopathies with hypertrophic pattern (hypertrophic cardiomyopathy, restrictive cardiomyopathies, amyloidosis, Anderson-Fabry disease, and sarcoidosis), cardiomyopathies with dilated pattern, inflammatory cardiac diseases, and right ventricular arrhythmogenic cardiomyopathy are analyzed. Finally, anatomic predictors of arrhythmias and sudden cardiac death are discussed. Each paragraph is attended by clinical cases that are discussed on the electrocardiogram, after integrated with the anatomic, functional, and hemodynamic modifications of cardiovascular imaging. Copyright © 2018 Elsevier Inc. All rights reserved.

Myoadenylate deaminase deficiency, hypertrophic cardiomyopathy and gigantism syndrome.

PubMed

Skyllouriotis, M L; Marx, M; Bittner, R E; Skyllouriotis, P; Gross, M; Wimmer, M

1997-07-01

We report a 20-year-old man with gigantism syndrome, hypertrophic cardiomyopathy, muscle weakness, exercise intolerance, and severe psychomotor retardation since childhood. Histochemical and biochemical analysis of skeletal muscle biopsy revealed myoadenylate deaminase deficiency; molecular genetic analysis confirmed the diagnosis of primary (inherited) myoadenylate deaminase deficiency. Plasma, urine, and muscle carnitine concentrations were reduced. L-Carnitine treatment led to gradual improvement in exercise tolerance and cognitive performance; plasma and tissue carnitine levels returned to normal, and echocardiographic evidence of left ventricular hypertrophy disappeared. The combination of inherited myoadenylate deaminase deficiency, gigantism syndrome and carnitine deficiency has not previously been described.

Concomitant idiopathic hypertrophic spinal pachymeningitis and Guillain-Barré syndrome in a patient: coincidence or a triggering mechanism?

PubMed

Olubajo, Farouk; Yermakova, Tatyana; Highley, J Robin; Arzoglou, Vasileios

2017-09-01

Idiopathic hypertrophic spinal pachymeningitis (IHSP), a rare diffuse inflammatory thickening of the dura mater, and Guillain-Barré syndrome (GBS) are known entities but they have never been reported as concomitant diagnoses. To their knowledge, the authors present the first reported case in the international literature with supportive evidence for both IHSP (based on MRI, intraoperative, and histological findings) and GBS (based on history, clinical examination, and electrophysiological findings). They review the literature on IHSP and the diagnostic criteria for GBS, with the view of identifying a possible causative connection.

Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial.

PubMed

Axelsson, Anna; Iversen, Kasper; Vejlstrup, Niels; Ho, Carolyn; Norsk, Jakob; Langhoff, Lasse; Ahtarovski, Kiril; Corell, Pernille; Havndrup, Ole; Jensen, Morten; Bundgaard, Henning

2015-02-01

No medical treatment has been reliably shown to halt or reverse disease progression in hypertrophic cardiomyopathy, but the results of several pilot studies have suggested beneficial effects of angiotensin II receptor blockers on left ventricular hypertrophy and fibrosis, which are predictive of an adverse outcome. We aimed to assess the effect of the angiotensin II receptor blocker losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. In this single-centre, randomised, double-blind, placebo-controlled trial, adult patients (aged 18 years and older) with obstructive or non-obstructive hypertrophic cardiomyopathy were randomly assigned via computer-based system to losartan (100 mg per day) or placebo for 12 months. Patients and investigators were masked to assigned treatment. The primary endpoint was change in left ventricular mass as assessed by cardiac magnetic resonance imaging (CMR) or CT. Efficacy analyses were done in the modified intention-to-treat population (all patients with data available at the 12-month follow-up). The trial is registered with ClinicalTrials.gov, number NCT01447654. Between Dec 1, 2011, and May 1, 2013, 318 patients were screened. 133 patients (mean age 52 years [SD 13], 35% women) consented and were randomly assigned to placebo (n=69) or losartan (n=64). 124 (93%) patients completed the study and were included in the modified intention-to-treat analysis for the primary endpoint. After 12 months we noted no significant difference in the change in left ventricular mass between the placebo group and the losartan group (mean difference 1 g/m(2), 95% CI -3 to 6; p=0·60). A decrease in systolic blood pressure in the losartan group (from mean 127 mm Hg [SD 12] to 121 mm Hg [14]; p=0·0001) confirmed drug compliance; blood pressure did not decrease in the placebo group. Two (2%) patients, both in the placebo group, died from sudden cardiac death during follow-up. In the losartan group, one (1%) patient had angioedema, one (1%) had deterioration of renal function, and one (1%) had hyperkalaemia. Treatment was well tolerated by patients with left ventricular outflow obstruction at baseline. Our findings challenge the generally held view that angiotensin II receptor blockers reduce cardiac hypertrophy. Treatment with losartan was safe, suggesting that it can be used for other indications in patients with hypertrophic cardiomyopathy, irrespective of obstructive physiology. Additional studies are needed to assess the effect of angiotensin II receptor blockers in preclinical hypertrophic cardiomyopathy-eg, in genotype-positive but phenotype-negative individuals. Copyright © 2015 Elsevier Ltd. All rights reserved.

Stage-specific control of connective tissue growth factor (CTGF/CCN2) expression in chondrocytes by Sox9 and beta-catenin.

PubMed

Huang, Bau-Lin; Brugger, Sean M; Lyons, Karen M

2010-09-03

CCN2/connective tissue growth factor is highly expressed in hypertrophic chondrocytes and is required for chondrogenesis. However, the transcriptional mechanisms controlling its expression in cartilage are largely unknown. The activity of the Ccn2 promoter was, therefore, investigated in osteochondro-progenitor cells and hypertrophic chondrocytes to ascertain these mechanisms. Sox9 and T-cell factor (TCF) x lymphoid enhancer factor (LEF) factors contain HMG domains and bind to related consensus sites. TCF x LEF factors are normally repressive but when bound to DNA in a complex with beta-catenin become activators of gene expression. In silico analysis of the Ccn2 proximal promoter identified multiple consensus TCF x LEF elements, one of which was also a consensus binding site for Sox9. Using luciferase reporter constructs, the TCF x LEF x Sox9 site was found to be involved in stage-specific expression of Ccn2. Luciferase, electrophoretic mobility shift assay (EMSA), and ChIP analysis revealed that Sox9 represses Ccn2 expression by binding to the consensus TCF x LEF x Sox9 site. On the other hand, the same assays showed that in hypertrophic chondrocytes, TCF x LEF x beta-catenin complexes occupy the consensus TCF x LEF x Sox9 site and activate Ccn2 expression. Furthermore, transgenic mice in which lacZ expression is driven under the control of the proximal Ccn2 promoter revealed that the proximal Ccn2 promoter responded to Wnt signaling in cartilage. Hence, we propose that differential occupancy of the TCF x LEF x Sox9 site by Sox9 versus beta-catenin restricts high levels of Ccn2 expression to hypertrophic chondrocytes.

Hypertrophic Stimulation Increases β-actin Dynamics in Adult Feline Cardiomyocytes

PubMed Central

Balasubramanian, Sundaravadivel; Mani, Santhosh K.; Kasiganesan, Harinath; Baicu, Catalin C.; Kuppuswamy, Dhandapani

2010-01-01

The myocardium responds to hemodynamic stress through cellular growth and organ hypertrophy. The impact of cytoskeletal elements on this process, however, is not fully understood. While α-actin in cardiomyocytes governs muscle contraction in combination with the myosin motor, the exact role of β-actin has not been established. We hypothesized that in adult cardiomyocytes, as in non-myocytes, β-actin can facilitate cytoskeletal rearrangement within cytoskeletal structures such as Z-discs. Using a feline right ventricular pressure overload (RVPO) model, we measured the level and distribution of β-actin in normal and pressure overloaded myocardium. Resulting data demonstrated enriched levels of β-actin and enhanced translocation to the Triton-insoluble cytoskeletal and membrane skeletal complexes. In addition, RVPO in vivo and in vitro hypertrophic stimulation with endothelin (ET) or insulin in isolated adult cardiomyocytes enhanced the content of polymerized fraction (F-actin) of β-actin. To determine the localization and dynamics of β-actin, we adenovirally expressed GFP-tagged β-actin in isolated adult cardiomyocytes. The ectopically expressed β-actin-GFP localized to the Z-discs, costameres, and cell termini. Fluorescence recovery after photobleaching (FRAP) measurements of β-actin dynamics revealed that β-actin at the Z-discs is constantly being exchanged with β-actin from cytoplasmic pools and that this exchange is faster upon hypertrophic stimulation with ET or insulin. In addition, in electrically stimulated isolated adult cardiomyocytes, while β-actin overexpression improved cardiomyocyte contractility, immunoneutralization of β-actin resulted in a reduced contractility suggesting that β-actin could be important for the contractile function of adult cardiomyocytes. These studies demonstrate the presence and dynamics of β-actin in the adult cardiomyocyte and reinforce its usefulness in measuring cardiac cytoskeletal rearrangement during hypertrophic stimulation. PMID:20635003

Hypertrophic stimulation increases beta-actin dynamics in adult feline cardiomyocytes.

PubMed

Balasubramanian, Sundaravadivel; Mani, Santhosh K; Kasiganesan, Harinath; Baicu, Catalin C; Kuppuswamy, Dhandapani

2010-07-12

The myocardium responds to hemodynamic stress through cellular growth and organ hypertrophy. The impact of cytoskeletal elements on this process, however, is not fully understood. While alpha-actin in cardiomyocytes governs muscle contraction in combination with the myosin motor, the exact role of beta-actin has not been established. We hypothesized that in adult cardiomyocytes, as in non-myocytes, beta-actin can facilitate cytoskeletal rearrangement within cytoskeletal structures such as Z-discs. Using a feline right ventricular pressure overload (RVPO) model, we measured the level and distribution of beta-actin in normal and pressure overloaded myocardium. Resulting data demonstrated enriched levels of beta-actin and enhanced translocation to the Triton-insoluble cytoskeletal and membrane skeletal complexes. In addition, RVPO in vivo and in vitro hypertrophic stimulation with endothelin (ET) or insulin in isolated adult cardiomyocytes enhanced the content of polymerized fraction (F-actin) of beta-actin. To determine the localization and dynamics of beta-actin, we adenovirally expressed GFP-tagged beta-actin in isolated adult cardiomyocytes. The ectopically expressed beta-actin-GFP localized to the Z-discs, costameres, and cell termini. Fluorescence recovery after photobleaching (FRAP) measurements of beta-actin dynamics revealed that beta-actin at the Z-discs is constantly being exchanged with beta-actin from cytoplasmic pools and that this exchange is faster upon hypertrophic stimulation with ET or insulin. In addition, in electrically stimulated isolated adult cardiomyocytes, while beta-actin overexpression improved cardiomyocyte contractility, immunoneutralization of beta-actin resulted in a reduced contractility suggesting that beta-actin could be important for the contractile function of adult cardiomyocytes. These studies demonstrate the presence and dynamics of beta-actin in the adult cardiomyocyte and reinforce its usefulness in measuring cardiac cytoskeletal rearrangement during hypertrophic stimulation.

Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis.

PubMed

Sugden, P H; Fuller, S J; Weiss, S C; Clerk, A

2008-03-01

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3alpha and GSK3beta) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3alpha(Ser21) and GSK3beta(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3beta, rather than GSK3alpha. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, beta-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bvarepsilon. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes.

Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis

PubMed Central

Sugden, P H; Fuller, S J; Weiss, S C; Clerk, A

2008-01-01

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3α and GSK3β) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3α(Ser21) and GSK3β(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3β, rather than GSK3α. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, β-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bɛ. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes. PMID:18204489

Suppressed inflammatory gene expression during human hypertrophic scar compared to normotrophic scar formation.

PubMed

van den Broek, Lenie J; van der Veer, Willem M; de Jong, Etty H; Gibbs, Susan; Niessen, Frank B

2015-08-01

Hypertrophic scar formation is a result of adverse cutaneous wound healing. The pathogenesis of hypertrophic scar formation is still poorly understood. A problem next to the lack of suitable animal models is that often normal skin is compared to hypertrophic scar (HTscar) and not to normotrophic scar (NTscar) tissue. Another drawback is that often only one time period after wounding is studied, while scar formation is a dynamic process over a period of several months. In this study, we compared the expression of genes involved in inflammation, angiogenesis and extracellular matrix (ECM) formation and also macrophage infiltration in biopsies obtained before and up to 52 weeks after standard surgery in five patients who developed HTscar and six patients who developed NTscar. It was found that HTscar formation coincided with a prolonged decreased expression of inflammatory genes (TNFα, IL-1α, IL-1RN, CCL2, CCL3, CXCL2, CXCR2, C3 and IL-10) and an extended increased expression of ECM-related genes (PLAU, Col3A1, TGFβ3). This coincided with a delayed but prolonged infiltration of macrophages (type 2) in HTscar tissue compared to NTscar tissue. These findings were supported by immunohistochemical localization of proteins coding for select genes named above. Our study emphasizes that human cutaneous wound healing is a dynamic process that is needed to be studied over a period of time rather than a single point of time. Taken together, our results suggest innate immune stimulatory therapies may be a better option for improving scar quality than the currently used anti-inflammatory scar therapies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Disease-associated changes in the expression of ion channels, ion receptors, ion exchangers and Ca{sup 2+}-handling proteins in heart hypertrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zwadlo, Carolin; Borlak, Juergen

2005-09-15

The molecular pathology of cardiac hypertrophy is multifactorial with transcript regulation of ion channels, ion exchangers and Ca{sup 2+}-handling proteins being speculative. We therefore investigated disease-associated changes in gene expression of various ion channels and their receptors as well as ion exchangers, cytoskeletal proteins and Ca{sup 2+}-handling proteins in normotensive and spontaneously hypertensive (SHR) rats. We also compared experimental findings with results from hypertrophic human hearts, previously published (Borlak, J., and Thum, T., 2003. Hallmarks of ion channel gene expression in end-stage heart failure. FASEB J. 17, 1592-1608). We observed significant (P < 0.05) induction in transcript level of ATP-drivenmore » ion exchangers (Atp1A1, NCX-1, SERCA2a), ion channels (L-type Ca{sup 2+}-channel, K{sub ir}3.4, Na{sub v}1.5) and RyR-2 in hypertrophic hearts, while gene expression was repressed in diseased human hearts. Further, the genes coding for calreticulin and calmodulin, PMCA 1 and 4 as well as {alpha}-skeletal actin were significantly (P < 0.05) changed in hypertrophic human heart, but were unchanged in hypertrophic left ventricles of the rat heart. Notably, transcript level of {alpha}- and {beta}-MHC, calsequestrin, K{sub ir}6.1 (in the right ventricle only), phospholamban as well as troponin T were repressed in both diseased human and rat hearts. Our study enabled an identification of disease-associated candidate genes. Their regulation is likely to be the result of an imbalance between pressure load/stretch force and vascular tonus and the observed changes may provide a rational for the rhythm disturbances observed in patients with cardiac hypertrophy.« less

Evidence Suggesting that the Cardiomyocyte Circadian Clock Modulates Responsiveness of the Heart to Hypertrophic Stimuli in Mice

PubMed Central

Durgan, David J.; Tsai, Ju-Yun; Grenett, Maximiliano H.; Pat, Betty M.; Ratcliffe, William F.; Villegas-Montoya, Carolina; Garvey, Merissa E.; Nagendran, Jeevan; Dyck, Jason R.B.; Bray, Molly S.; Gamble, Karen L.; Gimble, Jeffrey M.; Young, Martin E.

2011-01-01

Circadian dyssynchrony of an organism (at the whole body level) with its environment, either through light/dark cycle or genetic manipulation of clock genes, augments various cardiometabolic diseases. The cardiomyocyte circadian clock has recently been shown to influence multiple myocardial processes, ranging from transcriptional regulation and energy metabolism, to contractile function. We therefore reasoned that chronic dyssychrony of the cardiomyocyte circadian clock with its environment would precipitate myocardial maladaptation to a circadian challenge (simulated shift work; SSW). To test this hypothesis, 2 and 20 month old wild-type and CCM (Cardiomyocyte Clock Mutant; a model with genetic temporal suspension of the cardiomyocyte circadian clock at the active-to-sleep phase transition) mice were subjected to chronic (16-wks) bi-weekly 12-hr phase shifts in the light/dark cycle (i.e., SSW). Assessment of adaptation/maladaptation at whole body homeostatic, gravimetric, humoral, histological, transcriptional, and cardiac contractile function levels revealed essentially identical responses between wild-type and CCM littermates. However, CCM hearts exhibit increased bi-ventricular weight, cardiomyocyte size, and molecular markers of hypertrophy (anf, mcip1) independent of aging and/or SSW. Similarly, a second genetic model of selective temporal suspension of the cardiomyocyte circadian clock (Cardiomyocyte-specific BMAL1 Knockout [CBK] mice) exhibits increased bi-ventricular weight and mcip1 expression. Wild-type mice exhibit 5-fold greater cardiac hypertrophic growth (and 6-fold greater anf mRNA induction) when challenged with the hypertrophic agonist isoproterenol at the active-to-sleep phase transition, relative to isoproterenol administration at the sleep-to-active phase transition. This diurnal variation was absent in CCM mice. Collectively, these data suggest that the cardiomyocyte circadian clock likely influences responsiveness of the heart to hypertrophic stimuli. PMID:21452915

PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulates G-protein-coupled receptor kinase 5 (GRK5)-induced cardiac hypertrophy in vitro.

PubMed

Yeh, Szu-Tsen; Zambrano, Cristina M; Koch, Walter J; Purcell, Nicole H

2018-05-25

PH domain leucine-rich repeat protein phosphatase (PHLPP) is a serine/threonine phosphatase that has been shown to regulate cell growth and survival through dephosphorylation of several members of the AGC family of kinases. G-protein-coupled receptor kinase 5 (GRK5) is an AGC kinase that regulates phenylephrine (PE)-induced cardiac hypertrophy through its noncanonical function of directly targeting proteins to the nucleus to regulate transcription. Here we investigated the possibility that the PHLPP2 isoform can regulate GRK5-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes (NRVMs). We show that removal of PHLPP2 by siRNA induces hypertrophic growth of NRVMs as measured by cell size changes at baseline, potentiated PE-induced cell size changes, and re-expression of fetal genes atrial natriuretic factor and brain natriuretic peptide. Endogenous GRK5 and PHLPP2 were found to interact in NRVMs, and PE-induced nuclear accumulation of GRK5 was enhanced upon down-regulation of PHLPP2. Conversely, overexpression of PHLPP2 blocked PE-induced hypertrophic growth, re-expression of fetal genes, and nuclear accumulation of GRK5, which depended on its phosphatase activity. Finally, using siRNA against GRK5, we found that GRK5 was necessary for the hypertrophic response induced by PHLPP2 knockdown. Our findings demonstrate for the first time a novel regulation of GRK5 by the phosphatase PHLPP2, which modulates hypertrophic growth. Understanding the signaling pathways affected by PHLPP2 has potential for new therapeutic targets in the treatment of cardiac hypertrophy and failure. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Stromal cell-derived factor 1 regulates the actin organization of chondrocytes and chondrocyte hypertrophy.

PubMed

Murata, Koichi; Kitaori, Toshiyuki; Oishi, Shinya; Watanabe, Naoki; Yoshitomi, Hiroyuki; Tanida, Shimei; Ishikawa, Masahiro; Kasahara, Takashi; Shibuya, Hideyuki; Fujii, Nobutaka; Nagasawa, Takashi; Nakamura, Takashi; Ito, Hiromu

2012-01-01

Stromal cell-derived factor 1 (SDF-1/CXCL12/PBSF) plays important roles in the biological and physiological functions of haematopoietic and mesenchymal stem cells. This chemokine regulates the formation of multiple organ systems during embryogenesis. However, its roles in skeletal development remain unclear. Here we investigated the roles of SDF-1 in chondrocyte differentiation. We demonstrated that SDF-1 protein was expressed at pre-hypertrophic and hypertrophic chondrocytes in the newly formed endochondral callus of rib fracture as well as in the growth plate of normal mouse tibia by immunohistochemical analysis. Using SDF-1(-/-) mouse embryo, we histologically showed that the total length of the whole humeri of SDF-1(-/-) mice was significantly shorter than that of wild-type mice, which was contributed mainly by shorter hypertrophic and calcified zones in SDF-1(-/-) mice. Actin cytoskeleton of hypertrophic chondrocytes in SDF-1(-/-) mouse humeri showed less F-actin and rounder shape than that of wild-type mice. Primary chondrocytes from SDF-1(-/-) mice showed the enhanced formation of philopodia and loss of F-actin. The administration of SDF-1 to primary chondrocytes of wild-type mice and SDF-1(-/-) mice promoted the formation of actin stress fibers. Organ culture of embryonic metatarsals from SDF-1(-/-) mice showed the growth delay, which was recovered by an exogenous administration of SDF-1. mRNA expression of type X collagen in metatarsals and in primary chondrocytes of SDF-1(-/-) mouse embryo was down-regulated while the administration of SDF-1 to metatarsals recovered. These data suggests that SDF-1 regulates the actin organization and stimulates bone growth by mediating chondrocyte hypertrophy.

11β-HSD1 reduces metabolic efficacy and adiponectin synthesis in hypertrophic adipocytes.

PubMed

Koh, Eun Hee; Kim, Ah-Ram; Kim, Hyunshik; Kim, Jin Hee; Park, Hye-Sun; Ko, Myoung Seok; Kim, Mi-Ok; Kim, Hyuk-Joong; Kim, Bum Joong; Yoo, Hyun Ju; Kim, Su Jung; Oh, Jin Sun; Woo, Chang-Yun; Jang, Jung Eun; Leem, Jaechan; Cho, Myung Hwan; Lee, Ki-Up

2015-06-01

Mitochondrial dysfunction in hypertrophic adipocytes can reduce adiponectin synthesis. We investigated whether 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression is increased in hypertrophic adipocytes and whether this is responsible for mitochondrial dysfunction and reduced adiponectin synthesis. Differentiated 3T3L1 adipocytes were cultured for up to 21 days. The effect of AZD6925, a selective 11β-HSD1 inhibitor, on metabolism was examined. db/db mice were administered 600 mg/kg AZD6925 daily for 4 weeks via gastric lavage. Mitochondrial DNA (mtDNA) content, mRNA expression levels of 11 β -H sd1 and mitochondrial biogenesis factors, adiponectin synthesis, fatty acid oxidation (FAO), oxygen consumption rate and glycolysis were measured. Adipocyte hypertrophy in 3T3L1 cells exposed to a long duration of culture was associated with increased 11 β -Hsd1 mRNA expression and reduced mtDNA content, mitochondrial biogenesis factor expression and adiponectin synthesis. These cells displayed reduced mitochondrial respiration and increased glycolysis. Treatment of these cells with AZD6925 increased adiponectin synthesis and mitochondrial respiration. Inhibition of FAO by etomoxir blocked the AZD6925-induced increase in adiponectin synthesis, indicating that 11β-HSD1-mediated reductions in FAO are responsible for the reduction in adiponectin synthesis. The expression level of 11 β -Hsd1 was higher in adipose tissues of db/db mice. Administration of AZD6925 to db/db mice increased the plasma adiponectin level and adipose tissue FAO. In conclusion, increased 11β-HSD1 expression contributes to reduced mitochondrial respiration and adiponectin synthesis in hypertrophic adipocytes. © 2015 Society for Endocrinology.

Evaluation of soft tissue hypertrophy at the retro-odontoid space in patients with Chiari malformation type I on magnetic resonance imaging.

PubMed

Hayashi, Yasuhiko; Oishi, Masahiro; Sasagawa, Yasuo; Kita, Daisuke; Kozaka, Kazuto; Nakada, Mitsutoshi

2018-06-02

Chiari malformation type I (CM-I) is a well-known hindbrain disorder in which the cerebellar tonsils protrude through the foramen magnum. The soft tissues, including the transverse ligament and the tectorial membrane at the retro-odontoid space, can compress the cervicomedullary junction if they become hypertrophic. Twenty-two symptomatic CM-I patients (aged 5 to 19 years) were treated between 2007 and 2017 at our institute. The retro-odontoid soft tissue was evaluated using T2-weighted magnetic resonance imaging. Anterior-posterior (AP) distances and cranio-caudal (CC) distances of the soft tissue were measured in CM-I patients and 48 normal control children. Modified clivo-axial angles (CAA) were also evaluated as the index of ventral compression of the cervicomedullary junction. Of the 18 patients treated with foramen magnum decompression (FMD), 16 patients improved postoperatively, while the condition of 2 remained unchanged. The AP distances in the CM-I group (6.0 mm) were significantly larger than those in the control group (3.5 mm), whereas there were no apparent differences in the CC distances. Modified CAAs were obviously smaller in the CM-I group (131.5°) than in the control group (146.9°). Moreover, the AP distances were significantly reduced postoperatively (5.5 mm), though the other parameters did not change significantly. The retro-odontoid soft tissue in symptomatic CM-I patients can be hypertrophic enough to compress the cervicomedullary junction ventrally even if there are no combined osseous anomalies. FMD works to reduce the hypertrophic changes significantly, suggesting that downward tonsil movement might participate in hypertrophic soft tissue formation at the retro-odontoid space. Copyright © 2018 Elsevier Inc. All rights reserved.

Transneuronal pathways to the vestibulocerebellum

NASA Technical Reports Server (NTRS)

Kaufman, G. D.; Mustari, M. J.; Miselis, R. R.; Perachio, A. A.

1996-01-01

The alpha-herpes virus (pseudorabies, PRV) was used to observe central nervous system (CNS) pathways associated with the vestibulocerebellar system. Retrograde transneuronal migration of alpha-herpes virions from specific lobules of the gerbil and rat vestibulo-cerebellar cortex was detected immunohistochemically. Using a time series analysis, progression of infection along polyneuronal cerebellar afferent pathways was examined. Pressure injections of > 20 nanoliters of a 10(8) plaque forming units (pfu) per ml solution of virus were sufficient to initiate an infectious locus which resulted in labeled neurons in the inferior olivary subnuclei, vestibular nuclei, and their afferent cell groups in a progressive temporal fashion and in growing complexity with increasing incubation time. We show that climbing fibers and some other cerebellar afferent fibers transported the virus retrogradely from the cerebellum within 24 hours. One to three days after cerebellar infection discrete cell groups were labeled and appropriate laterality within crossed projections was preserved. Subsequent nuclei labeled with PRV after infection of the flocculus/paraflocculus, or nodulus/uvula, included the following: vestibular (e.g., z) and inferior olivary nuclei (e.g., dorsal cap), accessory oculomotor (e.g., Darkschewitsch n.) and accessory optic related nuclei, (e.g., the nucleus of the optic tract, and the medial terminal nucleus); noradrenergic, raphe, and reticular cell groups (e.g., locus coeruleus, dorsal raphe, raphe pontis, and the lateral reticular tract); other vestibulocerebellum sites, the periaqueductal gray, substantia nigra, hippocampus, thalamus and hypothalamus, amygdala, septal nuclei, and the frontal, cingulate, entorhinal, perirhinal, and insular cortices. However, there were differences in the resulting labeling between infection in either region. Double-labeling experiments revealed that vestibular efferent neurons are located adjacent to, but are not included among, flocculus-projecting supragenual neurons. PRV transport from the vestibular labyrinth and cervical muscles also resulted in CNS infections. Virus propagation in situ provides specific connectivity information based on the functional transport across synapses. The findings support and extend anatomical data regarding vestibulo-olivo-cerebellar pathways.

Interactive coupling of electronic and optical man-made devices to biological systems

NASA Astrophysics Data System (ADS)

Ozden, Ilker

Fireflies blink synchronously, lasers are "mode-locked" for amplification, cardiac pacemaker cells maintain a steady heartbeat, and crickets chirps get in step. These are examples of coupled oscillators. Coupled non-linear limit-cycle oscillator models are used extensively to provide information about the collective behavior of many physical and biological systems. Depending on the system parameters, namely, the coupling coefficient and the time delay in the coupling, these coupled limit-cycle oscillator exhibit several interesting phenomena; they either synchronize to a common frequency, or oscillate completely independent of each other, or drag each other to a standstill i.e., show "amplitude death". Many neuronal systems exhibit synchronized limit-cycle oscillations in network of electrically coupled cells. The inferior olivary (IO) neuron is an example of such a system. The inferior olive has been widely studied by neuroscientists as it exhibits spontaneous oscillations in its membrane potential, typically in the range of 1--10 Hz. Located in the medulla, the inferior olive is believed to form the neural basis for precise timing and learning in motor circuits by making strong synaptic connections onto Purkinjee cells in the cerebellum. In this thesis work, we report on work, which focuses on the implementation and study of coupling of a biological circuit, which is the inferior olivary system, with a man-made electronic oscillator, the so-called Chua's circuit. We were able to study the interaction between the two oscillators over a wide range coupling conditions. With increasing coupling strength, the oscillators become phase-locked, or synchronized, but with a phase relationship which is either in- or out-of-phase depending on the detailed adjustment in the coupling. Finally, the coupled system reaches the conditions for amplitude death, a rather fundamental result given that the interaction has taken place between purely biological and man-made circuit elements.

Collateralization of cerebellar output to functionally distinct brainstem areas. A retrograde, non-fluorescent tracing study in the rat

PubMed Central

Ruigrok, Tom J. H.; Teune, Thea M.

2014-01-01

The organization of the cerebellum is characterized by a number of longitudinally organized connection patterns that consist of matching olivo-cortico-nuclear zones. These entities, referred to as modules, have been suggested to act as functional units. The various parts of the cerebellar nuclei (CN) constitute the output of these modules. We have studied to what extent divergent and convergent patterns in the output of the modules to four, functionally distinct brain areas can be recognized. Two retrograde tracers were injected in various combinations of the following nuclei: the red nucleus (RN), as a main premotor nucleus; the prerubral area, as a main supplier of afferents to the inferior olive (IO); the nucleus reticularis tegmenti pontis (NRTP), as a main source of cerebellar mossy fibers; and the IO, as the source of climbing fibers. For all six potential combinations three cases were examined. All nine cases with combinations that involved the IO did not, or hardly, resulted in double labeled neurons. In contrast, all other combinations resulted in at least 10% and up to 67% of double labeled neurons in cerebellar nuclear areas where both tracers were found. These results show that the cerebellar nuclear neurons that terminate within the studied areas represent basically two intermingled populations of projection cells. One population corresponds to the small nucleo-olivary neurons whereas the other consists of medium- to large-sized neurons which are likely to distribute their axons to several other areas. Despite some consistent differences between the output patterns of individual modules we propose that modular cerebellar output to premotor areas such as the RN provides simultaneous feedback to both the mossy fiber and the climbing fiber system and acts in concert with a designated GABAergic nucleo-olivary circuit. These features seem to form a basic characteristic of cerebellar operation. PMID:24600356

Effects of surgical lesions on choline acetyltransferase activity in the cat cochlea.

PubMed

Frilling, Mark J; Wiet, Gregory J; Godfrey, Donald A; Parli, Judy A; Dunn, Jon D; Ross, C David

2017-12-01

Although it is well established that the choline acetyltransferase (ChAT, the enzyme for acetylcholine synthesis) in the mammalian cochlea is associated with its olivocochlear innervation, the distribution of this innervation in the cochlea varies somewhat among mammalian species. The quantitative distribution of ChAT activity in the cochlea has been reported for guinea pigs and rats. The present study reports the distribution of ChAT activity within the organ of Corti among the three turns of the cat cochlea and the effects of removing olivocochlear innervation either by a lateral cut aimed to totally transect the left olivocochlear bundle or a more medial cut additionally damaging the superior olivary complex on the same side. Similarly to results for guinea pig and rat, the distribution of ChAT activity in the cat outer hair cell region showed a decrease from base to apex, but, unlike in the guinea pig and rat, the cat inner hair cell region did not. As in the rat, little ChAT activity was measured in the outer supporting cell region. As previously reported for whole cat cochlea and for rat cochlear regions, transection of the olivocochlear bundle resulted in almost total loss of ChAT activity in the hair cell regions of the cat cochlea. Lesions of the superior olivary complex resulted in loss of ChAT activity in the inner hair cell region of all cochlear turns only on the lesion side but bilateral losses in the outer hair cell region of all turns. The results are consistent with previous evidence that virtually all cholinergic synapses in the mammalian cochlea are associated with its olivocochlear innervation, that the olivocochlear innervation to the inner hair cell region is predominantly ipsilateral, and that the olivocochlear innervation to the outer hair cells is bilateral. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuronal regulation of tendon homoeostasis

PubMed Central

Ackermann, Paul W

2013-01-01

The regulation of tendon homoeostasis, including adaptation to loading, is still not fully understood. Accumulating data, however, demonstrates that in addition to afferent (sensory) functions, the nervous system, via efferent pathways which are associated with through specific neuronal mediators plays an active role in regulating pain, inflammation and tendon homeostasis. This neuronal regulation of intact-, healing- and tendinopathic tendons has been shown to be mediated by three major groups of molecules including opioid, autonomic and excitatory glutamatergic neuroregulators. In intact healthy tendons the neuromediators are found in the surrounding structures: paratenon, endotenon and epitenon, whereas the proper tendon itself is practically devoid of neurovascular supply. This neuroanatomy reflects that normal tendon homoeostasis is regulated from the tendon surroundings. After injury and during tendon repair, however, there is extensive nerve ingrowth into the tendon proper, followed by a time-dependent emergence of sensory, autonomic and glutamatergic mediators, which amplify and fine-tune inflammation and regulate tendon regeneration. In tendinopathic condition, excessive and protracted presence of sensory and glutamatergic neuromediators has been identified, suggesting involvement in inflammatory, nociceptive and hypertrophic (degenerative) tissue responses. Under experimental and clinical conditions of impaired (e.g. diabetes) as well as excessive (e.g. tendinopathy) neuromediator release, dysfunctional tendon homoeostasis develops resulting in chronic pain and gradual degeneration. Thus there is a prospect that in the future pharmacotherapy and tissue engineering approaches targeting neuronal mediators and their receptors may prove to be effective therapies for painful, degenerative and traumatic tendon disorders. PMID:23718724

The role of inhibition by phosphocitrate and its analogue in chondrocyte differentiation and subchondral bone advance in Hartley guinea pigs

PubMed Central

Sun, Yubo; Kiraly, Alex J.; Cox, Michael; Mauerhan, David R.; Hanley, Edward N.

2018-01-01

Phosphocitrate (PC) and its analogue, PC-β ethyl ester, inhibit articular cartilage degeneration in Hartley guinea pigs. However, the underlying molecular mechanisms remain unclear. The present study aimed to investigate the hypothesis that PC exerted its disease-modifying effect on osteoarthritis (OA), in part, by inhibiting a molecular program similar to that in the endochondral pathway of ossification. The results demonstrated that severe proteoglycan loss occurred in the superficial and middle zones, as well as in the calcified zone of articular cartilage in the Hartley guinea pigs. Subchondral bone advance was greater in the control Hartley guinea pigs compared with PC- or PC analogue-treated guinea pigs. Resorption of cartilage bars or islands and vascular invasion in the growth plate were also greater in the control guinea pigs compared with the PC- or PC analogue-treated guinea pigs. The levels of matrix metalloproteinase-13 and type X collagen within the articular cartilage and growth plate were significantly increased in the control guinea pigs compared with PC-treated guinea pigs (P<0.05). These results indicated that articular chondrocytes in Hartley guinea pigs exhibited a hypertrophic phenotype and recapitulated a developmental molecular program similar to the endochondral pathway of ossification. Activation of this molecular program resulted in resorption of calcified articular cartilage and subchondral bone advance. This suggests that PC and PC analogues exerted their OA disease-modifying activity, in part, by inhibiting this molecular program. PMID:29545850

Sahlgrenska Cardiomyopathy Project

ClinicalTrials.gov

2018-05-15

Dilated Cardiomyopathies; Hypertrophic Cardiomyopathy; Restrictive Cardiomyopathy; Arrhythmogenic Right Ventricular Cardiomyopathy; Myocarditis; Sarcoidosis With Myocarditis; Giant Cell Myocarditis; Amyloidosis; Heart (Manifestation)

Echocardiography and cardiac MRI in mutation-negative hypertrophic cardiomyopathy in an older patient: a case defining the need for ICD.

PubMed

Rodriguez, Fatima; Degnan, Kathleen O; Seidman, Christine E; Mangion, Judy R

2014-08-01

We report the case of a 67-year-old man with hypertrophic cardiomyopathy who presented for a second opinion about implantable cardio-defibrillator (ICD) placement after a witnessed syncopal episode. Despite his older age, being mutation-negative, and having a maximal septal thickness of 2.2 cm on echocardiography, he demonstrated rapid progression of myocardial fibrosis on cardiac MRI, correlating to ventricular tachyarrhythmias and syncope. We review the role of echocardiography and cardiac MRI in optimizing medical care for such patients who may not otherwise meet criteria for an ICD placement or further interventions. © 2014, Wiley Periodicals, Inc.

Cardiac magnetic resonance in hypertrophic cardiomyopathy: current state of the art.

PubMed

Kwon, Deborah H; Desai, Milind Y

2010-01-01

Hypertrophic cardiomyopathy is a complex disorder with significant heterogeneity in clinical characteristics and natural history. Traditionally, the diagnosis has been based on clinical assessment and echocardiography; however, persistent challenges in its noninvasive evaluation remain. Hence, improved diagnostic techniques could lead to better risk stratification of patients, which would potentially identify patients likely to benefit from effective therapies. Recent studies have demonstrated the increasing utility of cardiac magnetic resonance in the management of this disease. With the increasing utilization of genetics, cardiac magnetic resonance is likely to play an even more important role in discerning the subtle morphologic differences seen in such patients with similar genotypic profiles.

NEW MOLECULAR MEDICINE-BASED SCAR MANAGEMENT STRATEGIES

PubMed Central

Arno, Anna I; Gauglitz, Gerd G; Barret, Juan P; Jeschke, Marc G

2014-01-01

Keloids and hypertrophic scars are prevalent disabling conditions with still suboptimal treatments. Basic science and molecular-based medicine research has contributed to unravel new bench-to-bedside scar therapies, and to dissect the complex signaling pathways involved. Peptides such as transforming growth factor beta (TGF-β) superfamily, with SMADs, Ski, SnoN, Fussels, endoglin, DS-Sily, Cav-1p, AZX100, thymosin-β4 and other related molecules may emerge as targets to prevent and treat keloids and hypertrophic scars. The aim of this review is to describe the basic complexity of these new molecular scar management strategies, and point out new fibrosis research lines. PMID:24438742

Case Studies

PubMed Central

Danielson, John R.; Walter, Robert J.

2005-01-01

Objective: The purpose of this report is to present the results of a preliminary treatment regimen for hypertrophic scars combining topical 2% salicylic acid cream (Avosil) with an overlay of hydrogel dressing (Avogel). Methods: The study group consisted of 3 patients with symptomatic hypertrophic scars: 2 presternal and 1 on the inner thigh. Scars were divided into 3 equal-size areas: (1) untreated control, (2) hydrogel alone, and (3) 2% salicylic acid with hydrogel cover. Treatments were applied every 8 to 12 hours and a Velcro appliance was employed to cover the area during treatment. The total length of treatment was 60 days. Results: At the end of the 60-day treatment protocol, the area treated with 2% salicylic acid and hydrogel was asymptomatic. In contrast, the hydrogel-treated and untreated control areas remained erythematous and symptomatic for burning pain and pruritis. Conclusion: This small study suggests the efficacy of combined salicylic acid and hydrogel therapy in the treatment of hypertrophic scars. More extensive studies of scar treatment with salicylic acid and hydrogel are needed. These studies must be larger in scope to carefully document the spectrum of patient responses and should include methods for evaluating alterations in the levels of different inflammatory mediators. PMID:16921411

Comparison of efficacy of silicone gel, silicone gel sheeting, and topical onion extract including heparin and allantoin for the treatment of postburn hypertrophic scars.

PubMed

Karagoz, Huseyin; Yuksel, Fuat; Ulkur, Ersin; Evinc, Rahmi

2009-12-01

We compared the efficacy of silicone gel (Scarfade), silicone gel sheet (Epi-Derm), and topical onion extract including heparin and allantoin (Contractubex) for the treatment of hypertrophic scars. Forty-five postburn scars were included in the study. Patients with scars less than 6 months from injury were assigned at random to three groups each containing 15 scars, and their treatment was continued for 6 months. Scars were treated with Scarfade, Epiderm and Contractubex. Scar assessment was performed at the beginning of the treatment, and at the end of the sixth month when the treatment was completed by using the Vancouver scar scale. The difference between before and after treatment scores for each three groups was statistically significant. The difference between Scarfade group and Epi-Derm group was not significant; however, the differences of the other groups (Scarfade-Contractubex, Epiderm-Contractubex) were significant. Silicone products, either in gel or sheet, are superior to Contractubex in the treatment of the hypertrophic scar. The therapist should select the most appropriate agent according to the patient's need and guidelines of these signs.

Imaging findings of intestinal tuberculosis.

PubMed

Engin, Gulgun; Balk, Emre

2005-01-01

Intestinal tuberculosis (TB) has 3 main forms: ulcerative, hypertrophic or ulcerohypertrophic, and fibrous stricturing. In the ulcerative form, barium examination reveals thickened folds, spasticity, and shallow ulcers involving the cecum and terminal ileum. Computerized tomography shows preferential thickening of the ileocecal valve and medial wall of the cecum as well as a few small regional nodes. In the hypertrophic or ulcerohypertrophic form, a hyperplastic reaction is seen in the exophytic masses around the ulcerated lumen on computed tomography. An inflammatory mass that extends into adjacent muscle suggests TB. In the sclerotic form, the main reaction is fibrosis with single or multiple short strictures. The cecum classically becomes amputated, conical, shrunken, and retracted. In comparison, Crohn's disease (CD) has a rather uniform and lesser thickening of the bowel wall. Mural stratification, vascular jejunization or the comb sign, and mesenteric fibrofatty proliferation are seen only in CD. The hypertrophic form may also mimic malignant neoplasms, such as lymphoma or carcinoma. Cecal carcinoma rarely extends beyond the ileocecal valve, however. In lymphoma, it can be seen as a greater degree of wall thickness with aneurysmatic dilation of the intestinal lumen. Single or multiple strictures are also seen as a CD complication. Advanced skip lesions adjacent to the stricture are usually diagnostic for CD.

Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes.

PubMed

Sabbagh, Yves; Carpenter, Thomas O; Demay, Marie B

2005-07-05

Rickets is seen in association with vitamin D deficiency and in several genetic disorders associated with abnormal mineral ion homeostasis. Studies in vitamin D receptor (VDR)-null mice have demonstrated that expansion of the late hypertrophic chondrocyte layer, characteristic of rickets, is secondary to impaired apoptosis of these cells. The observation that normalization of mineral ion homeostasis in the VDR-null mice prevents rachitic changes suggests that rickets is secondary to hypocalcemia, hypophosphatemia, or hyperparathyroidism, rather than impaired VDR action. To determine which of these abnormalities is responsible for impaired chondrocyte apoptosis and subsequent rachitic changes, two additional models were examined: diet-induced hypophosphatemia/hypercalcemia and hypophosphatemia secondary to mutations in the Phex gene. The former model is associated with suppressed parathyroid hormone levels as a consequence of hypercalcemia. The latter model demonstrates normal calcium and parathyroid hormone levels, but 1,25-dihydroxyvitamin D levels that are inappropriately low for the degree of hypophosphatemia. Our studies demonstrate that normal phosphorus levels are required for growth plate maturation and implicate a critical role for phosphate-regulated apoptosis of hypertrophic chondrocytes via activation of the caspase-9-mediated mitochondrial pathway.

Hypertrophic osteopathy associated with mycotic pneumonia in two juvenile elk (Cervus elaphus).

PubMed

Ferguson, Nicole M; Lévy, Michel; Ramos-Vara, José A; Baird, Debra K; Wu, Ching Ching

2008-11-01

Two yearling bull elk (cervus claphus) from the same farm developed anorexia, weight loss, and lameness. On physical examination, both elk were thin and showed diffuse swelling of all lower limbs. Radiographs of the lower limbs showed periosteal thickening of the distal extremities, consistent with hypertrophic osteopathy. Thoracic radiographs indicated the presence of pulmonary nodules. Cytologic evaluations of tracheal washes on both elk were consistent with inflammation. Acid-fast stains on both samples were negative. Because of the poor prognosis, both elk were euthanized. At necropsy, the carpal, metacarpal, tarsal, and metatarsal bones, as well as the radius, ulna, and tibia had thickening of cortical bone. There were multiple encapsulated nodules throughout the lungs, lymph nodes, and kidney, and smaller nodules in the myocardium. On microscopic examination, these nodules contained myriads of hyphae, and immunohistochemistry for Aspergillus sp. was strongly positive. Aspergillus fumigatus was isolated from affected tissue in 1 elk. Necropsy findings in both elk were consistent with disseminated fungal granulomas and periosteal hyperostosis. This case presents the first description of hypertrophic osteopathy in elk. The source of infection was undetermined, but inhalation of spores from contaminated feed or bedding was suspected.

Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway.

PubMed

Pennanen, Christian; Parra, Valentina; López-Crisosto, Camila; Morales, Pablo E; Del Campo, Andrea; Gutierrez, Tomás; Rivera-Mejías, Pablo; Kuzmicic, Jovan; Chiong, Mario; Zorzano, Antonio; Rothermel, Beverly A; Lavandero, Sergio

2014-06-15

Cardiomyocyte hypertrophy has been associated with diminished mitochondrial metabolism. Mitochondria are crucial organelles for the production of ATP, and their morphology and function are regulated by the dynamic processes of fusion and fission. The relationship between mitochondrial dynamics and cardiomyocyte hypertrophy is still poorly understood. Here, we show that treatment of cultured neonatal rat cardiomyocytes with the hypertrophic agonist norepinephrine promotes mitochondrial fission (characterized by a decrease in mitochondrial mean volume and an increase in the relative number of mitochondria per cell) and a decrease in mitochondrial function. We demonstrate that norepinephrine acts through α1-adrenergic receptors to increase cytoplasmic Ca(2+), activating calcineurin and promoting migration of the fission protein Drp1 (encoded by Dnml1) to mitochondria. Dominant-negative Drp1 (K38A) not only prevented mitochondrial fission, it also blocked hypertrophic growth of cardiomyocytes in response to norepinephrine. Remarkably, an antisense adenovirus against the fusion protein Mfn2 (AsMfn2) was sufficient to increase mitochondrial fission and stimulate a hypertrophic response without agonist treatment. Collectively, these results demonstrate the importance of mitochondrial dynamics in the development of cardiomyocyte hypertrophy and metabolic remodeling. © 2014. Published by The Company of Biologists Ltd.

Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure

PubMed Central

Rothermel, Beverly A.; Berenji, Kambeez; Tannous, Paul; Kutschke, William; Dey, Asim; Nolan, Bridgid; Yoo, Ki-Dong; Demetroulis, Elaine; Gimbel, Michael; Cabuay, Barry; Karimi, Mohsen; Hill, Joseph A.

2014-01-01

Hypertrophic growth of the myocardium occurs in most forms of heart failure and may contribute to the pathogenesis of the failure state. Little is known about the regulatory mechanisms governing the often-coexisting phenotypes of hypertrophy, systolic failure, and diastolic stiffness that characterize clinical disease. We hypothesized that intracellular signaling pathways are differentially activated by graded degrees of hemodynamic stress. To test this, we developed models of graded pressure stress in mice and used them to directly compare compensated hypertrophy and pressure-overload heart failure. Surgical interventions were designed to be similar, on either side of a threshold separating compensated from decompensated responses. Our findings revealed two dramatically different hypertrophic phenotypes with only modest differences in the activation of relevant intracellular signaling pathways. Furthermore, we uncovered a functional requirement of calcineurin signaling in each model such that calcineurin suppression blunted hypertrophic growth. Remarkably, in each case, suppression of calcineurin signaling was not associated with clinical deterioration or increased mortality. Profiles of stress-response signaling and Ca2+ handling differ between the steady-state, maintenance phases of load-induced cardiac hypertrophy and failure. This information may be useful in identifying novel targets of therapy in chronic disease. PMID:16033866

Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure.

PubMed

Rothermel, Beverly A; Berenji, Kambeez; Tannous, Paul; Kutschke, William; Dey, Asim; Nolan, Bridgid; Yoo, Ki-Dong; Demetroulis, Elaine; Gimbel, Michael; Cabuay, Barry; Karimi, Mohsen; Hill, Joseph A

2005-09-21

Hypertrophic growth of the myocardium occurs in most forms of heart failure and may contribute to the pathogenesis of the failure state. Little is known about the regulatory mechanisms governing the often-coexisting phenotypes of hypertrophy, systolic failure, and diastolic stiffness that characterize clinical disease. We hypothesized that intracellular signaling pathways are differentially activated by graded degrees of hemodynamic stress. To test this, we developed models of graded pressure stress in mice and used them to directly compare compensated hypertrophy and pressure-overload heart failure. Surgical interventions were designed to be similar, on either side of a threshold separating compensated from decompensated responses. Our findings revealed two dramatically different hypertrophic phenotypes with only modest differences in the activation of relevant intracellular signaling pathways. Furthermore, we uncovered a functional requirement of calcineurin signaling in each model such that calcineurin suppression blunted hypertrophic growth. Remarkably, in each case, suppression of calcineurin signaling was not associated with clinical deterioration or increased mortality. Profiles of stress-response signaling and Ca2+ handling differ between the steady-state, maintenance phases of load-induced cardiac hypertrophy and failure. This information may be useful in identifying novel targets of therapy in chronic disease.

Variability of NT-proBNP and Its Relationship with Inflammatory Status in Patients with Stable Essential Hypertension: A 2-Year Follow-Up Study

PubMed Central

Roselló-Lletí, Esther; Calabuig, Jose R.; Morillas, Pedro; Cortés, Raquel; Martínez-Dolz, Luis; Almenar, Luis; González-Juanatey, Jose R.; Lauwers, Catheline; Salvador, Antonio; Portolés, Manuel; Bertomeu, Vicente; Rivera, Miguel

2012-01-01

Background The variability of NT-proBNP levels has been studied in heart failure, yet no data exist on these changes over time in hypertensive patients. Furthermore, studies on the relationship between natriuretic peptides and inflammatory status are limited. Methodology/Principal Findings 220 clinically and functionally asymptomatic stable patients (age 59±13, 120 male) out of 252 patients with essential hypertension were followed up, and NT-proBNP was measured at baseline, 12 and 24 months. No differences in NT-proBNP were found with respect to the basal stage in the hypertrophic group, but significant changes were found in non-hypertrophic subjects. The reproducibility of NT-proBNP measurements was better in patients with hypertrophy than in the non-hypertrophic group for the three intervals (stage I-basal; stage II-stage I; stage II-basal) with a reference change value of 34%, 35% and 41%, respectively, in the hypertrophic group. A more elevated coefficient of correlation was obtained in the hypertrophic group than in patients without hypertrophy: basal versus stage I (r = 0.79, p<0.0001 and r = 0.59, p<0.0001) and stage I versus stage II (r = 0.86, p<0.0001 and r = 0.56, p<0.0001). Finally, levels of NT-proBNP significantly correlated with sTNF-R1 (p<0.0001) and IL-6 (p<0.01) during follow-up. A multivariate linear regression analysis showed that sTNF-R1 is an independent factor of NT-proBNP. Conclusions/Significance This work shows that there is good stability in NT-proBNP levels in a follow-up study of asymptomatic patients with stable hypertension and left ventricular hypertrophy. As a consequence, assessment of NT-proBNP concentrations may be a useful tool for monitoring the follow-up of hypertensive patients with hypertrophy. Measured variations in peptide levels, exceeding 35% in a 12-month follow-up and 41% in a 24-month follow-up, may indicate an increase in cardiovascular risk, and therefore implies adjustment in the medical treatment. In addition, this study shows a link between neurohormonal and inflammatory activation in these patients. PMID:22384001

Concentrations of Elements in Hellbender Blood and Fish Fillets from the Missouri Department of Conservation Monitoring Programs

USGS Publications Warehouse

May, Thomas W.; Walther, Mike J.; Brumbaugh, William G.

2007-01-01

This report presents the results of contaminant monitoring surveys conducted annually by the Missouri Department of Conservation to examine the levels of selected elemental contaminants in hellbender (Cryptobranchus alleganiensis) blood and fish. Catfish (Ictalurus furcatus, Ictalurus punctatus, Pylodictis olivaris), redhorse (Moxostoma anisorum, Moxostoma erythrurum), bass (Micropterus salmoides, Micropterus punctulatus, Micropterus Lacepede, Ambloplites rupestris), walleye (Sander vitreus), and sunfish (Lepomis megalotis) were collected from 17 sites as part of the Department's General Contaminant Monitoring Program. Bluegill (Lepomis macrochirus) and other sunfish (Lepomis megalotis, Lepomis cyanellus) were collected from 18 sites as part of the Department's Resource Assessment and Monitoring Program. Blood from hellbenders was collected from seven sites as part of the Department's Hellbender Monitoring Program.

A reconnaissance study of halogenated organic compounds in catfish from the lower Mississippi river and its major tributaries

USGS Publications Warehouse

Leiker, T.J.; Rostad, C.E.; Barnes, C.R.; Pereira, W.E.

1991-01-01

Blue catfish, (Ictarurus furcatus), black bullhead catfish, (Ictalurus melas), channel catfish (Ictalurus punctatus), and flathead catfish (Pylodictus olivaris), were collected along a 1200 mile river reach of the Mississippi River and its major tributaries. Tissue samples were extracted and analyzed by fused silica capillary gas chromatography/mass spectrometry (GC/MS) to determine the concentrations of hydrophobic organic halogenated contaminants that have bioconcentrated within the tissues. The compounds identified in the tissue include chlordane, polychlorinated biphenyls (PCBs), DDT and its metabolites along with several other chlorinated pesticides. The data indicates that the southern reach of the river system appears to be more contaminated than the middle and upper reaches of the study area.

X-82 to Treat Age-related Macular Degeneration

ClinicalTrials.gov

2018-05-30

Age-Related Macular Degeneration (AMD); Macular Degeneration; Exudative Age-related Macular Degeneration; AMD; Macular Degeneration, Age-related, 10; Eye Diseases; Retinal Degeneration; Retinal Diseases

Ehlers-Danlos Syndrome associated with cardiomyopathy hypertrophic obstructive*

PubMed Central

Pinto, Raimundo José Almeida de Oliveira; dos Santos, Adaílton Araújo; Azevedo, Mablo de Castro; Meira, Saulo Sacramento

2015-01-01

Ehlers-Danlos syndrome is a rare clinical condition caused by a genetic change that results in the formation of structurally or functionally altered collagen. The clinical manifestations are varied, being the most obvious skin hypermotility and increased joint flexibility, although other systems - such as cardiovascular, respiratory and neurological - may also be affected. This paper presents the report of a patient who sought medical attention with complaints of atypical chest pain. Clinical evaluation enabled hypothetical diagnosis of hypertrophic obstructive cardiomyopathy and Ehlers-Danlos syndrome. Initial electrocardiogram, echocardiogram and 24 hours holter allowed the confirmation of the first hypothesis. A skin biopsy performed later associated clinical data and confirmed the second hypothesis. PMID:26312722

Centella asiatica in cosmetology.

PubMed

Bylka, Wiesława; Znajdek-Awiżeń, Paulina; Studzińska-Sroka, Elżbieta; Brzezińska, Małgorzata

2013-02-01

Centella asiatica known as Gotu Kola is a medicinal plant that has been used in folk medicine for hundreds of years as well as in scientifically oriented medicine. The active compounds include pentacyclic triterpenes, mainly asiaticoside, madecassoside, asiatic and madecassic acids. Centella asiatica is effective in improving treatment of small wounds, hypertrophic wounds as well as burns, psoriasis and scleroderma. The mechanism of action involves promoting fibroblast proliferation and increasing the synthesis of collagen and intracellular fibronectin content and also improvement of the tensile strength of newly formed skin as well as inhibiting the inflammatory phase of hypertrophic scars and keloids. Research results indicate that it can be used in the treatment of photoaging skin, cellulite and striae.

Centella asiatica in cosmetology

PubMed Central

Znajdek-Awiżeń, Paulina; Studzińska-Sroka, Elżbieta; Brzezińska, Małgorzata

2013-01-01

Centella asiatica known as Gotu Kola is a medicinal plant that has been used in folk medicine for hundreds of years as well as in scientifically oriented medicine. The active compounds include pentacyclic triterpenes, mainly asiaticoside, madecassoside, asiatic and madecassic acids. Centella asiatica is effective in improving treatment of small wounds, hypertrophic wounds as well as burns, psoriasis and scleroderma. The mechanism of action involves promoting fibroblast proliferation and increasing the synthesis of collagen and intracellular fibronectin content and also improvement of the tensile strength of newly formed skin as well as inhibiting the inflammatory phase of hypertrophic scars and keloids. Research results indicate that it can be used in the treatment of photoaging skin, cellulite and striae. PMID:24278045

Lasers and ancillary treatments for scar management Part 2: Keloid, hypertrophic, pigmented and acne scars

PubMed Central

McGoldrick, Rory Boyd; Theodorakopoulou, Evgenia; Azzopardi, Ernest Anthony; Murison, Maxwell

2017-01-01

The formation of a wide range of excessive scars following various skin injuries is a natural consequence of healing. Scars resulting from surgery or trauma affect approximately 100 million people per annum in the developed world and can have profound physical, aesthetic, psychological and social consequences. Thus, scar treatment is a priority for patient and physician alike. Laser treatment plays an important role in scar management with additional support from ancillary modalities. Subsequent to part 1: Burns scars, part 2 focuses on our strategies and literature review of treatment of keloid, hypertrophic, pigmented and acne scars where lasers are used in conjunction with other measures, and illustrated with case studies. PMID:29799579

Successful catheter ablation of hemodynamically unstable monomorphic ventricular tachycardia in a patient with hypertrophic cardiomyopathy and apical aneurysm.

PubMed

Lim, Kiam-Khiang; Maron, Barry J; Knight, Bradley P

2009-04-01

Patients with hypertrophic cardiomyopathy (HCM) and left ventricular (LV) apical aneurysm represent a previously under-recognized but important subgroup within this heterogeneous disease spectrum. Apical aneurysms and the contiguous areas of myocardial fibrosis have been associated with monomorphic ventricular tachycardia (VT) and increased risk for adverse clinical events including sudden cardiac death, prioritizing the application of primary prevention implantable defibrillators. However, VT may be repetitive, thereby raising considerations for additional treatment strategies such as radiofrequency ablation. In this report, we describe such a patient with HCM and apical aneurysm in whom the mapping and ablation procedure was effective in identifying and abolishing the VT focus.

Cardiac Magnetic Resonance and Computed Tomography in Hypertrophic Cardiomyopathy: an Update

PubMed Central

de Oliveira, Diogo Costa Leandro; Assunção, Fernanda Boldrini; dos Santos, Alair Agusto Sarmet Moreira Damas; Nacif, Marcelo Souto

2016-01-01

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease and represents the main cause of sudden death in young patients. Cardiac magnetic resonance (CMR) and cardiac computed tomography (CCT) are noninvasive imaging methods with high sensitivity and specificity, useful for the establishment of diagnosis and prognosis of HCM, and for the screening of patients with subclinical phenotypes. The improvement of image analysis by CMR and CCT offers the potential to promote interventions aiming at stopping the natural course of the disease. This study aims to describe the role of RCM and CCT in the diagnosis and prognosis of HCM, and how these methods can be used in the management of these patients. PMID:27305111

A patient with mitochondrial disorder due to a novel mutation in MRPS22.

PubMed

Kılıç, Mustafa; Oğuz, Kader-Karli; Kılıç, Esra; Yüksel, Deniz; Demirci, Hüseyin; Sağıroğlu, Mahmut Şamil; Yücel-Yılmaz, Didem; Özgül, Rıza Köksal

2017-10-01

MRPS22 gene defect is a very rare newly discovered mitochondrial disorder. We report a 4-month-old severely affected male infant with MRPS22 mutation. Whole exome sequencing revealed a novel homozygous splicing mutation c.339 + 5 G > A in MRPS22 gene. He has mild dysmorphism, hypotonia, developmental delay but not hypertrophic cardiomyopathy and tubulopathy which differ from other majority of reported patients. Therefore, hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22. With this case report, we also present first symmetrical bilateral brainstem and medial thalamic lesions, and cerebellar and cerebral atrophy on a brain MR imaging follow-up of ten months.

Self-adhesive silicone gel sheet: a treatment for hypertrophic scars and keloids.

PubMed

Chuangsuwanich, A; Osathalert, V; Muangsombut, S

2000-04-01

An open clinical trial was conducted to assess the effect of self-adhesive silicone gel sheet (SASGS) for the treatment of hypertrophic scars and keloids in Thai people. Patients were instructed to apply the SASGS to the scars as long as possible, but not less than 12 hours per day for at least 8 weeks. The subjective results of the treatment were evaluated by the patients. The scars were evaluated for color, height, weight before and after treatment at 4 and 8 weeks. Eighteen patients with 18 hypertrophic scars or keloids were recruited into the study. Their ages ranged from 6 to 33 years (mean 21 years). The average duration of the scars was 5.7 years. Twelve patients (66.67%) stated good results. All of the 18 patients wanted to continue the treatment with SASGS. Heights of the scars were reduced in 12 lesions (66.67%) after treatment for 8 weeks (P = 0.058). Weights of the lesions were decreased in 10 lesions (55.55%) but were not statistically different (P = 0.090). Seven lesions (36.84%) were improved in color. Two patients (11.11%) developed erythematous rash around the lesions which subsided after withdrawal of the treatment. The long term follow-up for the recurrence and the mechanism of action of this treatment should be studied further.

Tissue Doppler imaging for detection of radial and longitudinal myocardial dysfunction in a family of cats affected by dystrophin-deficient hypertrophic muscular dystrophy.

PubMed

Chetboul, Valérie; Blot, Stephane; Sampedrano, Carolina Carlos; Thibaud, Jean-Laurent; Granger, Nicolas; Tissier, Renaud; Bruneval, Patrick; Gaschen, Frederic; Gouni, Vassiliki; Nicolle, Audrey P; Pouchelon, Jean-Louis

2006-01-01

Diagnosis of feline hypertrophic cardiomyopathy currently is based on the presence of myocardial hypertrophy detected using conventional echocardiography. The accuracy of tissue Doppler imaging (TDI) for earlier detection of the disease has never been described. The objective of this sudy was to quantify left ventricular free wall (LVFW) velocities in cats with hypertrophic muscular dystrophy (HFMD) during preclinical cardiomyopathy using TDI. The study animals included 22 healthy controls and 7 cats belonging to a family of cats with HFMD (2 affected adult males, 2 heterozygous adult females, one 2.5-month-old affected male kitten, and 2 phenotypically normal female kittens from the same litter). All cats were examined via conventional echocardiography and 2-dimensional color TDI. No LVFW hypertrophy was detected in the 2 carriers or in the affected kitten when using conventional echocardiography and histologic examination, respectively. The LVFW also was normal for 1 affected male and at the upper limit of normal for the 2nd male. Conversely, LVFW dysfunction was detected in all affected and carrier cats with HFMD when using TDI. TDI consistently detects LVFW dysfunction in cats with HFMD despite the absence of myocardial hypertrophy. Therefore, TDI appears more sensitive than conventional echocardiography in detecting regional myocardial abnormalities.

Sex dimorphisms of crossbridge cycling kinetics in transgenic hypertrophic cardiomyopathy mice.

PubMed

Birch, Camille L; Behunin, Samantha M; Lopez-Pier, Marissa A; Danilo, Christiane; Lipovka, Yulia; Saripalli, Chandra; Granzier, Henk; Konhilas, John P

2016-07-01

Familial hypertrophic cardiomyopathy (HCM) is a disease of the sarcomere and may lead to hypertrophic, dilated, restrictive, and/or arrhythmogenic cardiomyopathy, congestive heart failure, or sudden cardiac death. We hypothesized that hearts from transgenic HCM mice harboring a mutant myosin heavy chain increase the energetic cost of contraction in a sex-specific manner. To do this, we assessed Ca(2+) sensitivity of tension and crossbridge kinetics in demembranated cardiac trabeculas from male and female wild-type (WT) and HCM hearts at an early time point (2 mo of age). We found a significant effect of sex on Ca(2+) sensitivity such that male, but not female, HCM mice displayed a decrease in Ca(2+) sensitivity compared with WT counterparts. The HCM transgene and sex significantly impacted the rate of force redevelopment by a rapid release-restretch protocol and tension cost by the ATPase-tension relationship. In each of these measures, HCM male trabeculas displayed a gain-of-function when compared with WT counterparts. In addition, cardiac remodeling measured by echocardiography, histology, morphometry, and posttranslational modifications demonstrated sex- and HCM-specific effects. In conclusion, female and male HCM mice display sex dimorphic crossbridge kinetics accompanied by sex- and HCM-dependent cardiac remodeling at the morphometric, histological, and cellular level. Copyright © 2016 the American Physiological Society.

Activation of the hypoxia-inducible factor 1α promotes myogenesis through the noncanonical Wnt pathway, leading to hypertrophic myotubes.

PubMed

Cirillo, Federica; Resmini, Giulia; Ghiroldi, Andrea; Piccoli, Marco; Bergante, Sonia; Tettamanti, Guido; Anastasia, Luigi

2017-05-01

Regeneration of skeletal muscle is a complex process that requires the activation of quiescent adult stem cells, called satellite cells, which are resident in hypoxic niches in the tissue. Hypoxia has been recognized as a key factor to maintain stem cells in an undifferentiated state. Herein we report that hypoxia plays a fundamental role also in activating myogenesis. In particular, we found that the activation of the hypoxia-inducible factor (HIF)-1α under hypoxia, in murine skeletal myoblasts, leads to activation of MyoD through the noncanonical Wnt/β-catenin pathway. Moreover, chemical inhibition of HIF-1α activity significantly reduces differentiation, thus confirming its crucial role in the process. Furthermore, hypoxia-preconditioned myoblasts, once induced to differentiate under normoxic conditions, tend to form hypertrophic myotubes. These results support the notion that hypoxia plays a pivotal role in activating the regeneration process by directly inducing myogenesis through HIF-1α. Although preliminary, these findings may suggest new perspective for novel therapeutic targets in the treatment of several muscle diseases.-Cirillo, F., Resmini, G., Ghiroldi, A., Piccoli, M., Bergante, S., Tettamanti, G., Anastasia, L. Activation of the hypoxia-inducible factor 1α promotes myogenesis through the noncanonical Wnt pathway, leading to hypertrophic myotubes. © FASEB.

Rac1 Dosage Is Crucial for Normal Endochondral Bone Growth.

PubMed

Suzuki, Dai; Bush, Jason R; Bryce, Dawn-Marie; Kamijo, Ryutaro; Beier, Frank

2017-10-01

Rac1, a member of the small Rho GTPase family, plays multiple cellular roles. Studies of mice conditionally lacking Rac1 have revealed essential roles for Rac1 in various tissues, including cartilage and limb mesenchyme, where Rac1 loss produces dwarfism and long bone shortening. To gain further insight into the role of Rac1 in skeletal development, we have used transgenic mouse lines to express a constitutively active (ca) Rac1 mutant protein in a Cre recombinase-dependent manner. Overexpression of caRac1 in limb bud mesenchyme or chondrocytes leads to reduced body weight and shorter bones compared with control mice. Histological analysis of growth plates showed that caRac1;Col2-Cre mice displayed ectopic hypertrophic chondrocytes in the proliferative zone and enlarged hypertrophic zones. These mice also displayed a reduced proportion of proliferating cell nuclear antigen-positive cells in the proliferative zone and nuclear β-catenin localization in the ectopic hypertrophic chondrocytes. Importantly, overexpression of caRac1 partially rescued the phenotypes of Rac1fl/fl;Col2-Cre and Rac1fl/fl;Prx1-Cre conditional knockout mice, including body weight, bone length, and growth plate disorganization. These results suggest that tight regulation of Rac1 activity is necessary for normal cartilage development. Copyright © 2017 Endocrine Society.

Phytoplankton biodiversity changes in a shallow tropical reservoir during the hypertrophication process.

PubMed

Crossetti, L O; Bicudo, D C; Bicudo, C E M; Bini, L M

2008-11-01

Study aimed at evaluating phytoplankton biodiversity changes in a shallow tropical reservoir during its hypertrophication process. Samplings were carried out monthly during 8 consecutive years (1997-2004) in 5 depths. Conspicuous limnological changes in the reservoir derived from the presence and/or removal of the water hyacinth, characterized 3 different phases. Over the time series, reservoir changed from a typical polymictic eutrophic system to hypertrophic one, leading to a reduction of approximately 70 species (average 37%). Chlorophyceae accounted for the highest species richness (46%) among all algal classes and strictly followed total species richness variation. Internal feedback mechanisms intensification over phase III clearly promoted the sharp decrease in biodiversity. Highest decreases, mainly during springs, occurred simultaneously to the highest Cyanobacteria blooms. Increased turbidity due to heavy phytoplankton blooms suppressed all other algal groups, so that at the end of the present study even Cyanobacteria species richness decreased. Total dissolved phosphorous was included in most of the best selected models used to analyze the temporal patterns in species richness loss. Present data show that biodiversity loss following trophic change was not a single dimension of a single factor but, rather, a template of factors (e.g. light, stability) co-varying in consequence of the larger levels of biomass supported in the reservoir.

Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation

PubMed Central

Ishise, Hisako; Larson, Barrett; Hirata, Yutaka; Fujiwara, Toshihiro; Nishimoto, Soh; Kubo, Tateki; Matsuda, Ken; Kanazawa, Shigeyuki; Sotsuka, Yohei; Fujita, Kazutoshi; Kakibuchi, Masao; Kawai, Kenichiro

2015-01-01

Wound healing process is a complex and highly orchestrated process that ultimately results in the formation of scar tissue. Hypertrophic scar contracture is considered to be a pathologic and exaggerated wound healing response that is known to be triggered by repetitive mechanical forces. We now show that Transient Receptor Potential (TRP) C3 regulates the expression of fibronectin, a key regulatory molecule involved in the wound healing process, in response to mechanical strain via the NFkB pathway. TRPC3 is highly expressed in human hypertrophic scar tissue and mechanical stimuli are known to upregulate TRPC3 expression in human skin fibroblasts in vitro. TRPC3 overexpressing fibroblasts subjected to repetitive stretching forces showed robust expression levels of fibronectin. Furthermore, mechanical stretching of TRPC3 overexpressing fibroblasts induced the activation of nuclear factor-kappa B (NFκB), a regulator fibronectin expression, which was able to be attenuated by pharmacologic blockade of either TRPC3 or NFκB. Finally, transplantation of TRPC3 overexpressing fibroblasts into mice promoted wound contraction and increased fibronectin levels in vivo. These observations demonstrate that mechanical stretching drives fibronectin expression via the TRPC3-NFkB axis, leading to intractable wound contracture. This model explains how mechanical strain on cutaneous wounds might contribute to pathologic scarring. PMID:26108359

Syndecan-4 Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

PubMed Central

Xie, Jun; He, Guixin; Chen, Qinhua; Sun, Jiayin; Dai, Qin; Lu, Jianrong; Li, Guannan; Wu, Han; Li, Ran; Chen, Jianzhou; Xu, Wei; Xu, Biao

2016-01-01

Cardiac hypertrophy can be broadly classified as either physiological or pathological. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy and normal heart function. Pathological stimuli including hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Syndecan-4 (synd4) is a transmembrane proteoglycan identified as being involved in cardiac adaptation after injury, but whether it takes part in physiological cardiac hypertrophy is unclear. We observed upregulation of synd4 in exercise-induced hypertrophic myocardium. To evaluate the role of synd4 in the physiological form of cardiac hypertrophy, mice lacking synd4 (synd4–/–) were exercised by swimming for 4 wks. Ultrasonic cardiogram (UCG) and histological analysis revealed that swimming induced the hypertrophic phenotype but was blunted in synd4–/– compared with wild-type (WT) mice. The swimming-induced activation of Akt, a key molecule in physiological hypertrophy was also more decreased than in WT controls. In cultured cardiomyocytes, synd4 overexpression could induce cell enlargement, protein synthesis and distinct physiological molecular alternation. Akt activation also was observed in synd4-overexpressed cardiomyocytes. Furthermore, inhibition of protein kinase C (PKC) prevented the synd4-induced hypertrophic phenotype and Akt phosphorylation. This study identified an essential role of synd4 in mediation of physiological cardiac hypertrophy. PMID:26835698

IGF-1 Gene Transfer to Human Synovial MSCs Promotes Their Chondrogenic Differentiation Potential without Induction of the Hypertrophic Phenotype.

PubMed

Ikeda, Yasutoshi; Sakaue, Morito; Chijimatsu, Ryota; Hart, David A; Otsubo, Hidenori; Shimomura, Kazunori; Madry, Henning; Suzuki, Tomoyuki; Yoshikawa, Hideki; Yamashita, Toshihiko; Nakamura, Norimasa

2017-01-01

Mesenchymal stem cell- (MSC-) based therapy is a promising treatment for cartilage. However, repair tissue in general fails to regenerate an original hyaline-like tissue. In this study, we focused on increasing the expression levels for insulin-like growth factor-1 (IGF-1) to improve repair tissue quality. The IGF-1 gene was introduced into human synovial MSCs with a lentiviral vector and examined the levels of gene expression and morphological status of MSCs under chondrogenic differentiation condition using pellet cultures. The size of the pellets derived from IGF-1-MSCs were significantly larger than those of the control group. The abundance of glycosaminoglycan (GAG) was also significantly higher in the IGF-1-MSC group. The histology of the IGF-1-induced pellets demonstrated similarities to hyaline cartilage without exhibiting features of a hypertrophic chondrocyte phenotype. Expression levels for the Col2A1 gene and protein were significantly higher in the IGF-1 pellets than in the control pellets, but expression levels for Col10, MMP-13, ALP, and Osterix were not higher. Thus, IGF-1 gene transfer to human synovial MSCs led to an improved chondrogenic differentiation capacity without the detectable induction of a hypertrophic or osteogenic phenotype.

Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling.

PubMed

Li, Yulin; Li, Zhenya; Zhang, Congcong; Li, Ping; Wu, Yina; Wang, Chunxiao; Bond Lau, Wayne; Ma, Xin-Liang; Du, Jie

2017-05-23

Hypertensive ventricular remodeling is a common cause of heart failure. However, the molecular mechanisms regulating ventricular remodeling remain poorly understood. We used a discovery-driven/nonbiased approach to identify increased activating transcription factor 3 (ATF3) expression in hypertensive heart. We used loss/gain of function approaches to understand the role of ATF3 in heart failure. We also examined the mechanisms through transcriptome, chromatin immunoprecipitation sequencing analysis, and in vivo and in vitro experiments. ATF3 expression increased in murine hypertensive heart and human hypertrophic heart. Cardiac fibroblast cells are the primary cell type expressing high ATF3 levels in response to hypertensive stimuli. ATF3 knockout (ATF3KO) markedly exaggerated hypertensive ventricular remodeling, a state rescued by lentivirus-mediated/miRNA-aided cardiac fibroblast-selective ATF3 overexpression. Conversely, conditional cardiac fibroblast cell-specific ATF3 transgenic overexpression significantly ameliorated ventricular remodeling and heart failure. We identified Map2K3 as a novel ATF3 target. ATF3 binds with the Map2K3 promoter, recruiting HDAC1, resulting in Map2K3 gene-associated histone deacetylation, thereby inhibiting Map2K3 expression. Genetic Map2K3 knockdown rescued the profibrotic/hypertrophic phenotype in ATF3KO cells. Last, we demonstrated that p38 is the downstream molecule of Map2K3 mediating the profibrotic/hypertrophic effects in ATF3KO animals. Inhibition of p38 signaling reduced transforming growth factor-β signaling-related profibrotic and hypertrophic gene expression, and blocked exaggerated cardiac remodeling in ATF3KO cells. Our study provides the first evidence that ATF3 upregulation in cardiac fibroblasts in response to hypertensive stimuli protects the heart by suppressing Map2K3 expression and subsequent p38-transforming growth factor-β signaling. These results suggest that positive modulation of cardiac fibroblast ATF3 may represent a novel therapeutic approach against hypertensive cardiac remodeling. © 2017 American Heart Association, Inc.

Assessing blood flow, microvasculature, erythema and redness in hypertrophic scars: A cross sectional study showing different features that require precise definitions.

PubMed

Jaspers, M E H; Stekelenburg, C M; Simons, J M; Brouwer, K M; Vlig, M; van den Kerckhove, E; Middelkoop, E; van Zuijlen, P P M

2017-08-01

In hypertrophic scar assessment, laser Doppler imaging (LDI), colorimetry and subjective assessment (POSAS) can be used to evaluate blood flow, erythema and redness, respectively. In addition, the microvasculature (i.e. presence of microvessels) can be determined by immunohistochemistry. These measurement techniques are frequently used in clinical practice and/or in research to evaluate treatment response and monitor scar development. However, until now it has not been tested to what extent the outcomes of these techniques are associated, whilst the outcome terms are frequently used interchangeably or replaced by the umbrella term 'vascularization'. This is confusing, as every technique seems to measure a specific feature. Therefore, we evaluated the correlations of the four measurement techniques. We included 32 consecutive patients, aged ≥18 years, who underwent elective resection of a hypertrophic scar. Pre-operatively, we performed LDI (measuring blood flow), colorimetry (measuring erythema) and the POSAS (subjective redness) within the predefined scar area of interest (∼1.5cm). Subsequently, the scar was excised and the area of interest was sent for immunohistochemistry, to determine the presence of microvessels. Only a statistically significant correlation was found between erythema values (colorimetry) and subjective redness assessment (POSAS) (r=0.403, p=0.030). We found no correlations between the outcomes of LDI, immunohistochemistry and colorimetry. Blood flow, the presence of microvessels and erythema appear to be different hypertrophic scar features because they show an absence of correlation. Therefore, in the field of scar assessment, these outcome terms cannot be used interchangeably. In addition, we conclude that the term 'vascularization' does not seem appropriate to serve as an umbrella term. The use of precise definitions in research as well as in clinical practice is recommended. Copyright © 2017 Elsevier Ltd and ISBI. All rights reserved.

Liganded Peroxisome Proliferator-Activated Receptors (PPARs) Preserve Nuclear Histone Deacetylase 5 Levels in Endothelin-Treated Sprague-Dawley Rat Cardiac Myocytes

PubMed Central

Zhang, Haining; Shao, Zongjun; Alibin, Caroline P.; Acosta, Crystal; Anderson, Hope D.

2014-01-01

Ligand activation of peroxisome proliferator-activated receptors (PPARs) prevents cardiac myocyte hypertrophy, and we previously reported that diacylglycerol kinase zeta (DGKζ) is critically involved. DGKζ is an intracellular lipid kinase that catalyzes phosphorylation of diacylglycerol; by attenuating DAG signaling, DGKζ suppresses protein kinase C (PKC) and G-protein signaling. Here, we investigated how PPAR-DGKζ signaling blocks activation of the hypertrophic gene program. We focused on export of histone deacetylase 5 (HDAC5) from the nucleus, a key event during hypertrophy, since crosstalk occurs between PPARs and other members of the HDAC family. Using cardiac myocytes isolated from Sprague-Dawley rats, we determined that liganded PPARs disrupt endothelin-1 (ET1)-induced nuclear export of HDAC5 in a manner that is dependent on DGKζ. When DGKζ-mediated PKC inhibition was circumvented using a constitutively-active PKCε mutant, PPARs failed to block ET1-induced nuclear retention of HDAC5. Liganded PPARs also prevented (i) activation of protein kinase D (the downstream effector of PKC), (ii) HDAC5 phosphorylation at 14-3-3 protein chaperone binding sites (serines 259 and 498), and (iii) physical interaction between HDAC5 and 14-3-3, all of which are consistent with blockade of nucleo-cytoplasmic shuttling of HDAC5. Finally, the ability of PPARs to prevent neutralization of HDAC5 activity was associated with transcriptional repression of hypertrophic genes. This occurred by first, reduced MEF2 transcriptional activity and second, augmented deacetylation of histone H3 associated with hypertrophic genes expressing brain natriuretic peptide, β-myosin heavy chain, skeletal muscle α-actin, and cardiac muscle α-actin. Our findings identify spatial regulation of HDAC5 as a target for liganded PPARs, and to our knowledge, are the first to describe a mechanistic role for nuclear DGKζ in cardiac myocytes. In conclusion, these results implicate modulation of HDAC5 as a mechanism by which liganded PPARs suppress the hypertrophic gene program. PMID:25514029

Spatial regulation of bone morphogenetic proteins (BMPs) in postnatal articular and growth plate cartilage

PubMed Central

Garrison, Presley; Yue, Shanna; Hanson, Jeffrey; Baron, Jeffrey; Lui, Julian C.

2017-01-01

Articular and growth plate cartilage both arise from condensations of mesenchymal cells, but ultimately develop important histological and functional differences. Each is composed of three layers—the superficial, mid and deep zones of articular cartilage and the resting, proliferative and hypertrophic zones of growth plate cartilage. The bone morphogenetic protein (BMP) system plays an important role in cartilage development. A gradient in expression of BMP-related genes has been observed across growth plate cartilage, likely playing a role in zonal differentiation. To investigate the presence of a similar expression gradient in articular cartilage, we used laser capture microdissection (LCM) to separate murine growth plate and articular cartilage from the proximal tibia into their six constituent zones, and used a solution hybridization assay with color-coded probes (nCounter) to quantify mRNAs for 30 different BMP-related genes in each zone. In situ hybridization and immunohistochemistry were then used to confirm spatial expression patterns. Expression gradients for Bmp2 and 6 were observed across growth plate cartilage with highest expression in hypertrophic zone. However, intracellular BMP signaling, assessed by phospho-Smad1/5/8 immunohistochemical staining, appeared to be higher in the proliferative zone and prehypertrophic area than in hypertrophic zone, possibly due to high expression of Smad7, an inhibitory Smad, in the hypertrophic zone. We also found BMP expression gradients across the articular cartilage with BMP agonists primarily expressed in the superficial zone and BMP functional antagonists primarily expressed in the deep zone. Phospho-Smad1/5/8 immunohistochemical staining showed a similar gradient. In combination with previous evidence that BMPs regulate chondrocyte proliferation and differentiation, the current findings suggest that BMP signaling gradients exist across both growth plate and articular cartilage and that these gradients may contribute to the spatial differentiation of chondrocytes in the postnatal endochondral skeleton. PMID:28467498

Identifying unmet clinical need in hypertrophic cardiomyopathy using national electronic health records.

PubMed

Pujades-Rodriguez, Mar; Guttmann, Oliver P; Gonzalez-Izquierdo, Arturo; Duyx, Bram; O'Mahony, Constantinos; Elliott, Perry; Hemingway, Harry

2018-01-01

To evaluate unmet clinical need in unselected hypertrophic cardiomyopathy (HCM) patients to determine the risk of a wide range of subsequent cardiovascular disease endpoints and safety endpoints relevant for trial design. Population based cohort (CALIBER, linked primary care, hospital and mortality records in England, period 1997-2010), all people diagnosed with HCM were identified and matched by age, sex and general practice with ten randomly selected people without HCM. Random-effects Poisson models were used to assess the associations between HCM and cardiovascular diseases and bleeding. Among 3,290,455 eligible people a diagnosis of hypertrophic cardiomyopathy was found in 4 per 10,000. Forty-one percent of the 1,160 individuals with hypertrophic cardiomyopathy were women and the median age was 57 years. The median follow-up was 4.0 years. Compared to general population controls, people with HCM had higher risk of ventricular arrhythmia (incidence rate ratio = 23.53, [95% confidence interval 12.67-43.72]), cardiac arrest or sudden cardiac death (6.33 [3.69-10.85]), heart failure (4.31, [3.30-5.62]), and atrial fibrillation (3.80 [3.04-4.75]). HCM was also associated with a higher incidence of myocardial infarction ([MI] 1.90 [1.27-2.84]) and coronary revascularisation (2.32 [1.46-3.69]).The absolute Kaplan-Meier risks at 3 years were 8.8% for the composite endpoint of cardiovascular death or heart failure, 8.4% for the composite of cardiovascular death, stroke or myocardial infarction, and 1.5% for major bleeding. Our study identified major unmet need in HCM and highlighted the importance of implementing improved cardiovascular prevention strategies to increase life-expectancy of the contemporary HCM population. They also show that national electronic health records provide an effective method for identifying outcomes and clinically relevant estimates of composite efficacy and safety endpoints essential for trial design in rare diseases.

Microplasma radiofrequency technology combined with triamcinolone improved the therapeutic effect on Chinese patients with hypertrophic scar and reduced the risk of tissue atrophy.

PubMed

Yu, Shui; Li, Hengjin

2016-01-01

The current study aimed to assess the value of microplasma radiofrequency technology combined with triamcinolone for the therapy of Chinese patients with hypertrophic scar. A total of 120 participants with hypertrophic scars were enrolled in the current study. Participants were divided into two groups based on sex, and then randomly and evenly divided into four groups (Groups A, B, C, and D). Participants in Group A received microplasma radiofrequency technology combined with triamcinolone. Participants in Group B received microplasma radiofrequency technology combined with normal saline. Participants in Groups C and D received triamcinolone (40 and 10 mg/mL) injected directly into scar. Experienced physicians evaluated the condition of scars according to the Vancouver Scar Scale 1 month before and after the therapy. There was no difference in age, sex, area, height and location of scars, and Vancouver Scar Scale scores before the therapy between any groups (P>0.05 for all). Vancouver Scar Scale scores after the therapy were significantly lower than those before the therapy in all groups (P<0.05 for all). Vancouver Scar Scale scores after the therapy in Group A were significantly lower than those after the therapy in Groups B and C (P<0.05 for all). Vancouver Scar Scale scores after the therapy in Group B were significantly higher than those after the therapy in Group C (P<0.05 for all) and similar to those after the therapy in Group D (P>0.05 for all). Incidences of tissue atrophy after the therapy were significantly lower in Groups A and B than in Group C (P<0.05 for all) and similar among Groups A, B, and D (P>0.05 for all). Microplasma radiofrequency technology combined with triamcinolone improved the therapeutic effect on Chinese patients with hypertrophic scar and reduced the risk of tissue atrophy compared with the use of either microplasma radiofrequency technology or triamcinolone injection alone.

Identification of Fat Mass and Obesity Associated (FTO) Protein Expression in Cardiomyocytes: Regulation by Leptin and Its Contribution to Leptin-Induced Hypertrophy

PubMed Central

Gan, Xiaohong Tracey; Zhao, Ganjian; Huang, Cathy X.; Rowe, Adrianna C.; Purdham, Daniel M.; Karmazyn, Morris

2013-01-01

The recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation. Ubiquitously expressed, FTO was identified in heart homogenates although its function is unknown. We studied whether FTO is specifically expressed within the cardiac myocyte and its potential role pertaining to the hypertrophic effect of the adipokine leptin. Most experiments were performed using cultured neonatal rat cardiomyocytes which showed nuclei-specific FTO expression. Leptin significantly increased FTO expression which was associated with myocyte hypertrophy although both events were abrogated by FTO knockdown with siRNA. Administration of a leptin receptor antibody to either normal or obese rats significant reduced myocardial FTO protein expression. Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects. Expression of the cut-like homeobox 1(CUX1) transcriptional factor was significantly increased by leptin although this was restricted to the cathepsin L-dependent, proteolytically-derived shorter p110CUX1 isoform whereas the longer p200CUX1 protein was not significantly affected. Cathepsin L expression and activity were both significantly increased by leptin whereas a cathepsin L peptide inhibitor or siRNA specific for CUX1 completely prevented the leptin-induced increase in FTO expression. The cathepsin L peptide inhibitor or siRNA-induced knockdown of either CUX1 or FTO abrogated the hypertrophic response to leptin. Two other pro-hypertrophic factors, endothelin-1 or angiotensin II had no effect on FTO expression and FTO knockdown did not alter the hypertrophic response to either agent. This study demonstrates leptin-induced FTO upregulation in cardiomyocytes via JAK2/STAT3- dependent CUX1 upregulation and suggests an FTO regulatory function of leptin. It also demonstrates for the first time a functional role of FTO in the cardiomyocyte. PMID:24019958

Identification of fat mass and obesity associated (FTO) protein expression in cardiomyocytes: regulation by leptin and its contribution to leptin-induced hypertrophy.

PubMed

Gan, Xiaohong Tracey; Zhao, Ganjian; Huang, Cathy X; Rowe, Adrianna C; Purdham, Daniel M; Karmazyn, Morris

2013-01-01

The recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation. Ubiquitously expressed, FTO was identified in heart homogenates although its function is unknown. We studied whether FTO is specifically expressed within the cardiac myocyte and its potential role pertaining to the hypertrophic effect of the adipokine leptin. Most experiments were performed using cultured neonatal rat cardiomyocytes which showed nuclei-specific FTO expression. Leptin significantly increased FTO expression which was associated with myocyte hypertrophy although both events were abrogated by FTO knockdown with siRNA. Administration of a leptin receptor antibody to either normal or obese rats significant reduced myocardial FTO protein expression. Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects. Expression of the cut-like homeobox 1(CUX1) transcriptional factor was significantly increased by leptin although this was restricted to the cathepsin L-dependent, proteolytically-derived shorter p110CUX1 isoform whereas the longer p200CUX1 protein was not significantly affected. Cathepsin L expression and activity were both significantly increased by leptin whereas a cathepsin L peptide inhibitor or siRNA specific for CUX1 completely prevented the leptin-induced increase in FTO expression. The cathepsin L peptide inhibitor or siRNA-induced knockdown of either CUX1 or FTO abrogated the hypertrophic response to leptin. Two other pro-hypertrophic factors, endothelin-1 or angiotensin II had no effect on FTO expression and FTO knockdown did not alter the hypertrophic response to either agent. This study demonstrates leptin-induced FTO upregulation in cardiomyocytes via JAK2/STAT3- dependent CUX1 upregulation and suggests an FTO regulatory function of leptin. It also demonstrates for the first time a functional role of FTO in the cardiomyocyte.

AMPK regulates energy metabolism through the SIRT1 signaling pathway to improve myocardial hypertrophy.

PubMed

Dong, H-W; Zhang, L-F; Bao, S-L

2018-05-01

We investigated the correlations of adenosine monophosphate-activated protein kinase (AMPK), Silence information regulator 1 (SIRT1) and energy metabolism with myocardial hypertrophy. Myocardial hypertrophy experimental model was established via transverse aortic constriction (TAC)-induced myocardial hypertrophy and phenylephrine (PE)-induced hypertrophic myocardial cell culture. After activation of AMPK, the messenger ribonucleic acid (mRNA) expressions in myocardial tissue- and myocardial cell hypertrophy-related genes, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC), were detected. The production rate of 14C-labeled 14CO2 from palmitic acid was quantitatively determined to detect the fatty acid and glucose oxidation of hypertrophic myocardial tissues or cells, and the glucose uptake of myocardial cells was studied using [14C] glucose. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were performed to detect the changes in SIRT1 mRNA and protein expressions in hypertrophic myocardial tissues. Moreover, SIRT1 small interfering ribonucleic acid (siRNA) was used to interfere in SIRT1 expression to further investigate the role of SIRT1 in the effect of AMPK activation on myocardial hypertrophy. AMPK activation could significantly reduce the mRNA expressions of ANP and β-MHC in vitro and in vivo. AMPK could increase the ejection fraction (EF) and decrease the protein synthesis rate in myocardial cells in mice with myocardial hypertrophy. Besides, AMPK activation could increase the fatty acid oxidation, improve the glucose uptake and reduce the glucose oxidation. After AMPK activation, both SIRT1 mRNA and protein expressions in hypertrophic myocardial tissues and myocardial cells were increased. After SIRT1 siRNA was further used to interfere in SIRT1 expression in myocardial cells, it was found that mRNA expressions and protein synthesis rates of ANP and β-MHC were increased. The activation of AMPK can inhibit the myocardial hypertrophy, which may be realized through regulating the myocardial energy metabolism via SIRT1 signaling pathway.

Generation of a Bone Organ by Human Adipose-Derived Stromal Cells Through Endochondral Ossification.

PubMed

Osinga, Rik; Di Maggio, Nunzia; Todorov, Atanas; Allafi, Nima; Barbero, Andrea; Laurent, Frédéric; Schaefer, Dirk Johannes; Martin, Ivan; Scherberich, Arnaud

2016-08-01

: Recapitulation of endochondral ossification (ECO) (i.e., generation of marrow-containing ossicles through a cartilage intermediate) has relevance to develop human organotypic models for bone or hematopoietic cells and to engineer grafts for bone regeneration. Unlike bone marrow-derived stromal cells (also known as bone marrow-derived mesenchymal stromal/stem cells), adipose-derived stromal cells (ASC) have so far failed to form a bone organ by ECO. The goal of the present study was to assess whether priming human ASC to a defined stage of chondrogenesis in vitro allows their autonomous ECO upon ectopic implantation. ASC were cultured either as micromass pellets or into collagen sponges in chondrogenic medium containing transforming growth factor-β3 and bone morphogenetic protein-6 for 4 weeks (early hypertrophic templates) or for two additional weeks in medium supplemented with β-glycerophosphate, l-thyroxin, and interleukin1-β to induce hypertrophic maturation (late hypertrophic templates). Constructs were implanted in vivo and analyzed after 8 weeks. In vitro, ASC deposited cartilaginous matrix positive for glycosaminoglycans, type II collagen, and Indian hedgehog. Hypertrophic maturation induced upregulation of type X collagen, bone sialoprotein, and matrix metalloproteinase13 (MMP13). In vivo, both early and late hypertrophic templates underwent cartilage remodeling, as assessed by MMP13- and tartrate-resistant acid phosphatase-positive staining, and developed bone ossicles, including bone marrow elements, although to variable degrees of efficiency. In situ hybridization for human-specific sequences and staining with a human specific anti-CD146 antibody demonstrated the direct contribution of ASC to bone and stromal tissue formation. In conclusion, despite their debated skeletal progenitor nature, human ASC can generate bone organs through ECO when suitably primed in vitro. Recapitulation of endochondral ossification (ECO) (i.e., generation of marrow-containing ossicles through a cartilage intermediate) has relevance to develop human organotypic models for bone or hematopoietic cells and to engineer grafts for bone regeneration. This study demonstrated that expanded, human adult adipose-derived stromal cells can generate ectopic bone through ECO, as previously reported for bone marrow stromal cells. This system can be used as a model in a variety of settings for mimicking ECO during development, physiology, or pathology (e.g., to investigate the role of BMPs, their receptors, and signaling pathways). The findings have also translational relevance in the field of bone regeneration, which, despite several advances in the domains of materials and surgical techniques, still faces various limitations before being introduced in the routine clinical practice. ©AlphaMed Press.

Concentration of elements in whole-body fish, fish fillets, fish muscle plugs, and fish eggs from the 2008 Missouri Department of Conservation General Contaminant Monitoring Program

USGS Publications Warehouse

May, Thomas W.; Walther, Michael J.; Brumbaugh, William G.; McKee, Michael J.

2009-01-01

This report presents the results of a contaminant monitoring survey conducted annually by the Missouri Department of Conservation to examine the levels of selected elemental contaminants in whole-body fish, fish fillets, fish muscle plugs, and fish eggs. Whole-body, fillet, or egg samples of catfish (Ictalurus punctatus, Ictalurus furcatus, Pylodictis olivaris), largemouth bass (Micropterus salmoides), walleye (Sander vitreus), crappie (Pomoxis annularis, Pomoxis nigromaculatus), shovelnose sturgeon (Scaphirhynchus platorynchus), northern hog sucker (Hypentelium nigricans), and Missouri saddled darter (Etheostoma tetrazonum) were collected from 23 sites as part of the Missouri Department of Conservation's Fish Contaminant Monitoring Program. Fish dorsal muscle plugs also were collected from walleye (Sander vitreus) at one of the sites.

Differential expression of c-fos following administration of two tremorgenic agents: harmaline and oxotremorine.

PubMed

Miwa, H; Nishi, K; Fuwa, T; Mizuno, Y

2000-08-03

The regional distribution of c-Fos expression in the brain after the administration of two tremorgenic agents was studied. In both the harmaline- and oxotremorin-treated rats, c-Fos-positive neurons were extensively distributed in the basal ganglia nuclei and the cerebellum. Additionally, in the harmaline-treated rats, numerous c-Fos-positive neurons were also distributed throughout the inferior olivary nucleus. In the oxotremorine-treated rats, while the inferior olive was not involved, c-Fos was strongly expressed in the neurons of the reticular thalamic nucleus, possibly due to the muscarinic effects of oxotremorine. The present study revealed that the inferior olive is selectively activated in the harmaline-administered animals and that the basal ganglia are involved in both harmaline- and oxotremorine-induced tremors.

Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway

PubMed Central

Al-rasheed, Nouf M; Al-Oteibi, Maha M; Al-Manee, Reem Z; Al-shareef, Sarah A; Al-Rasheed, Nawal M; Hasan, Iman H; Mohamad, Raeesa A; Mahmoud, Ayman M

2015-01-01

Simvastatin (SIM) is a lipid-soluble inhibitor of hydroxy-3-methylglutaryl coenzyme A reductase with multiple reported therapeutic benefits. The present study was designed to investigate the effect of pretreatment with SIM on isoproterenol (ISO)-induced cardiac hypertrophy in rats. Twenty-four male albino Wistar rats weighing 180–200 g were divided into four groups. Groups I and III received normal saline while groups II and IV received SIM (10 mg/kg body weight) for 30 days per gavage. In the last 7 days, rats of groups III and IV were administered ISO (5 mg/kg) intraperitoneally to induce cardiac hypertrophy. Administration of ISO induced an increase in heart-to-body weight (HW/BW) ratio, an increase in serum interleukin-6, and elevated systolic and diastolic blood pressure. Serum levels of lipids, cardiovascular risk indices, and cardiac troponin I and creatine phosphokinase-MB showed significant increase in ISO-induced hypertrophic rats. Histopathological examination of heart tissue revealed focal areas of subendocardium degeneration, mononuclear cellular infiltrations, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. In addition, ISO-administered rats exhibited significant upregulation of cardiac Janus kinase, phosphorylated signal transducer and activator of transcription, and nuclear factor-kappa B. Pretreatment with SIM significantly prevented ISO-induced cardiac hypertrophy, alleviated the altered biochemical parameters, and improved the heart architecture. In conclusion, our study provides evidence that SIM prevented the development of cardiac hypertrophy via modulation of the Janus kinase/signal transducer and activator of transcription-signaling pathway in the heart of ISO-administered animals. PMID:26150695

Mechanobiological dysregulation of the epidermis and dermis in skin disorders and in degeneration

PubMed Central

Ogawa, Rei; Hsu, Chao-Kai

2013-01-01

During growth and development, the skin expands to cover the growing skeleton and soft tissues by constantly responding to the intrinsic forces of underlying skeletal growth as well as to the extrinsic mechanical forces from body movements and external supports. Mechanical forces can be perceived by two types of skin receptors: (1) cellular mechanoreceptors/mechanosensors, such as the cytoskeleton, cell adhesion molecules and mechanosensitive (MS) ion channels, and (2) sensory nerve fibres that produce the somatic sensation of mechanical force. Skin disorders in which there is an abnormality of collagen [e.g. Ehlers–Danlos syndrome (EDS)] or elastic (e.g. cutis laxa) fibres or a malfunction of cutaneous nerve fibres (e.g. neurofibroma, leprosy and diabetes mellitus) are also characterized to some extent by deficiencies in mechanobiological processes. Recent studies have shown that mechanotransduction is crucial for skin development, especially hemidesmosome maturation, which implies that the pathogenesis of skin disorders such as bullous pemphigoid is related to skin mechanobiology. Similarly, autoimmune diseases, including scleroderma and mixed connective tissue disease, and pathological scarring in the form of keloids and hypertrophic scars would seem to be clearly associated with the mechanobiological dysfunction of the skin. Finally, skin ageing can also be considered as a degenerative process associated with mechanobiological dysfunction. Clinically, a therapeutic strategy involving mechanoreceptors or MS nociceptor inhibition or acceleration together with a reduction or augmentation in the relevant mechanical forces is likely to be successful. The development of novel approaches such as these will allow the treatment of a broad range of cutaneous diseases. PMID:23672502

Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway.

PubMed

Al-Rasheed, Nouf M; Al-Oteibi, Maha M; Al-Manee, Reem Z; Al-Shareef, Sarah A; Al-Rasheed, Nawal M; Hasan, Iman H; Mohamad, Raeesa A; Mahmoud, Ayman M

2015-01-01

Simvastatin (SIM) is a lipid-soluble inhibitor of hydroxy-3-methylglutaryl coenzyme A reductase with multiple reported therapeutic benefits. The present study was designed to investigate the effect of pretreatment with SIM on isoproterenol (ISO)-induced cardiac hypertrophy in rats. Twenty-four male albino Wistar rats weighing 180-200 g were divided into four groups. Groups I and III received normal saline while groups II and IV received SIM (10 mg/kg body weight) for 30 days per gavage. In the last 7 days, rats of groups III and IV were administered ISO (5 mg/kg) intraperitoneally to induce cardiac hypertrophy. Administration of ISO induced an increase in heart-to-body weight (HW/BW) ratio, an increase in serum interleukin-6, and elevated systolic and diastolic blood pressure. Serum levels of lipids, cardiovascular risk indices, and cardiac troponin I and creatine phosphokinase-MB showed significant increase in ISO-induced hypertrophic rats. Histopathological examination of heart tissue revealed focal areas of subendocardium degeneration, mononuclear cellular infiltrations, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. In addition, ISO-administered rats exhibited significant upregulation of cardiac Janus kinase, phosphorylated signal transducer and activator of transcription, and nuclear factor-kappa B. Pretreatment with SIM significantly prevented ISO-induced cardiac hypertrophy, alleviated the altered biochemical parameters, and improved the heart architecture. In conclusion, our study provides evidence that SIM prevented the development of cardiac hypertrophy via modulation of the Janus kinase/signal transducer and activator of transcription-signaling pathway in the heart of ISO-administered animals.

Intraoperative Two- and Three-Dimensional Transesophageal Echocardiography in Combined Myectomy-Mitral Operations for Hypertrophic Cardiomyopathy.

PubMed

Nampiaparampil, Robert G; Swistel, Daniel G; Schlame, Michael; Saric, Muhamed; Sherrid, Mark V

2018-03-01

Transesophageal echocardiography is essential in guiding the surgical approach for patients with obstructive hypertrophic cardiomyopathy. Septal hypertrophy, elongated mitral valve leaflets, and abnormalities of the subvalvular apparatus are prominent features, all of which may contribute to left ventricular outflow tract obstruction. Surgery aims to alleviate the obstruction via an extended myectomy, often with an intervention on the mitral valve and subvalvular apparatus. The goal of intraoperative echocardiography is to assess the anatomic pathology and pathophysiology in order to achieve a safe intraoperative course and a successful repair. This guide summarizes the systematic evaluation of these patients to determine the best surgical plan. Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

Poly(A) tail length regulates PABPC1 expression to tune translation in the heart.

PubMed

Chorghade, Sandip; Seimetz, Joseph; Emmons, Russell; Yang, Jing; Bresson, Stefan M; Lisio, Michael De; Parise, Gianni; Conrad, Nicholas K; Kalsotra, Auinash

2017-06-27

The rate of protein synthesis in the adult heart is one of the lowest in mammalian tissues, but it increases substantially in response to stress and hypertrophic stimuli through largely obscure mechanisms. Here, we demonstrate that regulated expression of cytosolic poly(A)-binding protein 1 (PABPC1) modulates protein synthetic capacity of the mammalian heart. We uncover a poly(A) tail-based regulatory mechanism that dynamically controls PABPC1 protein synthesis in cardiomyocytes and thereby titrates cellular translation in response to developmental and hypertrophic cues. Our findings identify PABPC1 as a direct regulator of cardiac hypertrophy and define a new paradigm of gene regulation in the heart, where controlled changes in poly(A) tail length influence mRNA translation.

High left ventricular outflow tract gradient: Aortic stenosis, obstructive hypertrophic cardiomyopathy or both?

PubMed

Almeida, Inês; Caetano, Francisca; Trigo, Joana; Mota, Paula; Marques, António Leitão

2015-05-01

The authors report the case of a patient diagnosed with both hypertrophic cardiomyopathy and aortic stenosis. Due to clinical deterioration, additional investigation was performed, and a high left ventricular outflow tract gradient was identified. Correct identification of the condition causing the symptoms was challenging, and involved several imaging techniques, the contribution of transesophageal echocardiography being crucial. The final diagnosis of severe aortic stenosis led to successful valve replacement surgery. The presence of these two conditions in the same patient has been documented, although it is uncommon. This association poses particular diagnostic and therapeutic challenges, which are discussed in this paper. Copyright © 2015 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Cardiac auscultation in sports medicine: strategies to improve clinical care.

PubMed

Barrett, Michael J; Ayub, Bilal; Martinez, Matthew W

2012-01-01

Cardiac auscultation is an important part of the preparticipation physical examination of athletes. Sudden death remains a rare but tragic event among athletes. The most common cause of sudden death among young athletes in the United States continues to be hypertrophic cardiomyopathy, which may or may not present with a typical heart murmur. Many clinicians do not possess sufficient proficiency in recognizing abnormal heart murmurs. New insights in the field of auditory learning suggest that cardiac auscultation is more of a technical skill than an intellectual one. Intensive repetition of abnormal heart murmurs has been shown to improve proficiency in cardiac auscultation markedly. Sample audio files of two important murmurs, i.e., an innocent murmur and hypertrophic cardiomyopathy, are provided online with this review.

Silicones in the rehabilitation of burns: a review and overview.

PubMed

Van den Kerckhove, E; Stappaerts, K; Boeckx, W; Van den Hof, B; Monstrey, S; Van der Kelen, A; De Cubber, J

2001-05-01

This article gives an overview of the use of silicones in the treatment and prevention of hypertrophic (burn related) scars. Of all non-invasive treatment modalities the use of continuous pressure and occlusive contact media, e.g. silicones, seem to be generally accepted as the only ones that are able to manage hypertrophic scarring without significant side-effects. A summary of the current opinions of the assumed working mechanisms of pressure as well as silicones is given. The use of silicones, either alone or in combination with pressure, is discussed. The recent development of custom made silicone devices has led to combinations of both modalities. Some of these, including the inflatable silicone insert systems (ISIS), are shown and discussed.

Comparison of different laser systems in the treatment of hypertrophic and atrophic scars and keloids

NASA Astrophysics Data System (ADS)

Scharschmidt, D.; Algermissen, Bernd; Willms-Jones, J.-C.; Philipp, Carsten M.; Berlien, Hans-Peter

1997-12-01

Different laser systems and techniques are used for the treatment of hypertrophic scars, keloids and acne scars. Significant criteria in selecting a suitable laser system are the scar's vascularization, age and diameter. Flashlamp- pumped dye-lasers, CO2-lasers with scanner, Argon and Nd:YAG-lasers are used. Telangiectatic scars respond well to argon lasers, erythematous scars and keloids to dye-laser treatment. Using interstitial Nd:YAG-laser vaporization, scars with a cross-section over 1 cm can generally be reduced. For the treatment of atrophic and acne scars good cosmetic results are achieved with a CO2-laser/scanner system, which allows a precise ablation of the upper dermis with low risk of side-effects.

[Usefullness of Beta-blocker for Hemodynamic Changes Induced by Uterotonic Drug in a Patient with Hypertrophic Obstructive Cardiomyopathy Undergoing Elective Cesarean Section].

PubMed

Tsukano, Yuri; Sugita, Michiko; Ikuta, Yoshihiro; Yamamoto, Tatsuo

2015-06-01

Combined spinal-epidural anesthesia (CSEA) was given to a 27-year-old woman with hypertrophic obstructive cardiomyopathy (HOCM) for a selective cesarean section. After the injection of uterotonic drug via uterine muscle and a vein after delivery, the patient developed dyspnea, tachycardia, ST-change on elecrocardiogram and hypotension. It is important in HOCM patients to control heart rate and left ventricular contractile force. We started to infuse beta-blocker (landiolol, 10 μg x kg(-1) x min(-1)) and improved these symptoms of the patient. This case demonstrates that CSEA is safe for HOCM patients and beta-blocker is effective to improve hemodynamic changes induced by uterotonic drug in these patients.

Eccentric apical hypertrophic cardiomyopathy unmasked by multimodality imaging: an uncommon but missed cause of out of hospital cardiac arrest

PubMed Central

Towe, Eric; Sharma, Saurabh; Geske, Jeffrey; Ackerman, Michael J

2015-01-01

A woman in her late 50s experienced a witnessed, sudden out of hospital cardiac arrest. Initial workup included coronary angiography, transthoracic echocardiogram and a CT scan of the chest to rule out pulmonary embolus. She was subsequently discharged home without an implantable cardioverter defibrillator (ICD) or a life vest. On follow-up at another facility, an ICD was placed and a Holter monitor showed no ventricular ectopy. Further transthoracic echocardiographic images were obtained, which were suggestive of apical hypertrophic cardiomyopathy. A limited transthoracic echocardiogram with contrast was performed, which did not elucidate the hypertrophy. However, eccentric left ventricular apical wall hypertrophy was visualised by a coronary CT scan. PMID:26153133

Maternal hyperthyroidism after intrauterine insemination due to hypertrophic action of human chorionic gonadotropin: a case report.

PubMed

Bakas, P; Tzouma, C; Creatsa, M; Boutas, I; Hassiakos, D

2016-01-01

To report a rare case of maternal hyperthyroidism after intrauterine insemination due to hypertrophic action of hCG. A 36-year-old woman after successful intrauterine insemination and triplet pregnancy, developed hyperthyroidism with resistance to medical treatment. All signs of hyperthyroidism resolved and the results of thyroid function tests returned to normal without any medication after embryo meiosis. De novo maternal hyperthyroidism may develop during pregnancy as a result of pathological stimulation of the thyroid gland from the high levels of hCG hormone that can be seen in multiple pregnancies. The risk of hyperthyroidism is related to the number of fetuses. Reversibility of symptomatology can be seen after fetal reduction of multiple pregnancies.

Contrast‐enhanced computed tomography with myocardial three‐dimensional printing can guide treatment in symptomatic hypertrophic obstructive cardiomyopathy

PubMed Central

Hamatani, Yasuhiro; Amaki, Makoto; Kanzaki, Hideaki; Yamashita, Kizuku; Nakashima, Yasuteru; Shibata, Atsushi; Okada, Atsushi; Takahama, Hiroyuki; Hasegawa, Takuya; Shimahara, Yusuke; Sugano, Yasuo; Fujita, Tomoyuki; Shiraishi, Isao; Yasuda, Satoshi; Kobayashi, Junjiro

2017-01-01

Abstract Both surgical myectomy and percutaneous transluminal septal myocardial ablation are effective treatments for drug‐refractory symptomatic hypertrophic obstructive cardiomyopathy (HOCM). However, in some cases, it is not easy to elucidate the abnormal structure of left ventricular outflow obstruction to adopt these treatments. Here, we presented a young female patient with drug‐refractory symptomatic HOCM. In this case, contrast‐enhanced computed tomography enabled us to assess the suitability of percutaneous transluminal septal myocardial ablation. By creating three‐dimensional printed models using computed tomography data, we could also visualize intracardiac structure and simulate the surgical procedure. A multimodality assessment strategy is useful for evaluating patients complicated with drug‐refractory symptomatic HOCM. PMID:29154429

Indian hedgehog contributes to human cartilage endplate degeneration.

PubMed

Wang, Shaowei; Yang, Kun; Chen, Shuai; Wang, Jiying; Du, Guoqing; Fan, Shunwu; Wei, Lei

2015-08-01

To determine the role of Indian hedgehog (Ihh) signaling in human cartilage endplate (CEP) degeneration. CEP-degenerated tissues from patients with Modic I or II changes (n = 9 and 45, respectively) and normal tissues from vertebral burst fracture patients (n = 17) were collected. Specimens were either cut into slices for organ culture ex vivo or digested to isolate chondrocytes for cell culture in vitro. Ihh expression and the effect of Ihh on cartilage degeneration were determined by investigating degeneration markers in this study. Ihh expression and cartilage degeneration markers significantly increased in the Modic I and II groups. The expression of cartilage degeneration markers was positively correlated with degeneration severity. Gain-of-function for Ihh promoted expression of cartilage degeneration markers in vitro, while loss-of-function for Ihh inhibited their expression both in vitro and ex vivo. These findings demonstrated that Ihh promotes CEP degeneration. Blocking Ihh pathway has potential clinical usage for attenuating CEP degeneration.

Oocyte Degeneration Associated with Follicle Cells in Female Mactra chinensis (Bivalvia: Mactridae)

PubMed Central

Kim, Sung Han; Chung, Ee-Yung; Lee, Ki-Young

2014-01-01

Ultrastructural studies of oocyte degeneration in the oocyte, and the functions of follicle cells during oocyte degeneration are described to clarify the reproductive mechanism on oocyte degeneration of Mactra chinensis using cytological methods. Commonly, the follicle cells are attached to the oocyte. Follicle cells play an important role in oocyte degeneration. In particular, the functions of follicle cells during oocyte degeneration are associated with phagocytosis and the intracellular digestion of products. In this study, morphologically similar degenerated phagosomes (various lysosomes), which were observed in the degenerated oocytes, appeared in the follicle cells. After the spawning of the oocytes, the follicle cells were involved in oocyte degeneration through phagocytosis by phagolysosomes. Therefore, it can be assumed that follicle cells reabsorb phagosomes from degenerated oocytes. In this study, the presence of lipid granules, which occurred from degenerating yolk granules, gradually increased in degenerating oocytes. The function of follicle cells can accumulate reserves of lipid granules and glycogen in the cytoplasm, which can be employed by the vitellogenic oocyte. Based on observations of follicle cells attached to degenerating oocytes after spawning, the follicle cells of this species are involved in the lysosomal induction of oocyte degeneration for the reabsorption of phagosomes (phagolysosomes) in the cytoplasm for nutrient storage, as seen in other bivalves. PMID:25949203

Keloids and Hypertrophic Scars

MedlinePlus

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Keloids and Hypertrophic Scars

MedlinePlus

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Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentials

PubMed Central

Garden, Derek L. F.; Rinaldi, Arianna

2016-01-01

Key points We establish experimental preparations for optogenetic investigation of glutamatergic input to the inferior olive.Neurones in the principal olivary nucleus receive monosynaptic extra‐somatic glutamatergic input from the neocortex.Glutamatergic inputs to neurones in the inferior olive generate bidirectional postsynaptic potentials (PSPs), with a fast excitatory component followed by a slower inhibitory component.Small conductance calcium‐activated potassium (SK) channels are required for the slow inhibitory component of glutamatergic PSPs and oppose temporal summation of inputs at intervals ≤ 20 ms.Active integration of synaptic input within the inferior olive may play a central role in control of olivo‐cerebellar climbing fibre signals. Abstract The inferior olive plays a critical role in motor coordination and learning by integrating diverse afferent signals to generate climbing fibre inputs to the cerebellar cortex. While it is well established that climbing fibre signals are important for motor coordination, the mechanisms by which neurones in the inferior olive integrate synaptic inputs and the roles of particular ion channels are unclear. Here, we test the hypothesis that neurones in the inferior olive actively integrate glutamatergic synaptic inputs. We demonstrate that optogenetically activated long‐range synaptic inputs to the inferior olive, including projections from the motor cortex, generate rapid excitatory potentials followed by slower inhibitory potentials. Synaptic projections from the motor cortex preferentially target the principal olivary nucleus. We show that inhibitory and excitatory components of the bidirectional synaptic potentials are dependent upon AMPA (GluA) receptors, are GABAA independent, and originate from the same presynaptic axons. Consistent with models that predict active integration of synaptic inputs by inferior olive neurones, we find that the inhibitory component is reduced by blocking large conductance calcium‐activated potassium channels with iberiotoxin, and is abolished by blocking small conductance calcium‐activated potassium channels with apamin. Summation of excitatory components of synaptic responses to inputs at intervals ≤ 20 ms is increased by apamin, suggesting a role for the inhibitory component of glutamatergic responses in temporal integration. Our results indicate that neurones in the inferior olive implement novel rules for synaptic integration and suggest new principles for the contribution of inferior olive neurones to coordinated motor behaviours. PMID:27767209

Graded and discontinuous EphA-ephrinB expression patterns in the developing auditory brainstem

PubMed Central

Wallace, Matthew M.; Harris, J. Aaron; Brubaker, Donald Q.; Klotz, Caitlyn A.; Gabriele, Mark L.

2016-01-01

Eph-ephrin interactions guide topographic mapping and pattern formation in a variety of systems. In contrast to other sensory pathways, their precise role in the assembly of central auditory circuits remains poorly understood. The auditory midbrain, or inferior colliculus (IC) is an intriguing structure for exploring guidance of patterned projections as adjacent subdivisions exhibit distinct organizational features. The central nucleus of the IC (CNIC) and deep aspects of its neighboring lateral cortex (LCIC, Layer 3) are tonotopically-organized and receive layered inputs from primarily downstream auditory sources. While less is known about more superficial aspects of the LCIC, its inputs are multimodal, lack a clear tonotopic order, and appear discontinuous, terminating in modular, patch/matrix-like distributions. Here we utilize X-Gal staining approaches in lacZ mutant mice (ephrin-B2, -B3, and EphA4) to reveal EphA-ephrinB expression patterns in the nascent IC during the period of projection shaping that precedes hearing onset. We also report early postnatal protein expression in the cochlear nuclei, the superior olivary complex, the nuclei of the lateral lemniscus, and relevant midline structures. Continuous ephrin-B2 and EphA4 expression gradients exist along frequency axes of the CNIC and LCIC Layer 3. In contrast, more superficial LCIC localization is not graded, but confined to a series of discrete ephrin-B2 and EphA4-positive Layer 2 modules. While heavily expressed in the midline, much of the auditory brainstem is devoid of ephrin-B3, including the CNIC, LCIC Layer 2 modular fields, the dorsal nucleus of the lateral lemniscus (DNLL), as well as much of the superior olivary complex and cochlear nuclei. Ephrin-B3 LCIC expression appears complementary to that of ephrin-B2 and EphA4, with protein most concentrated in presumptive extramodular zones. Described tonotopic gradients and seemingly complementary modular/extramodular patterns suggest Eph-ephrin guidance in establishing juxtaposed continuous and discrete neural maps in the developing IC prior to experience. PMID:26906676

Activity-dependent formation of a vesicular inhibitory amino acid transporter gradient in the superior olivary complex of NMRI mice.

PubMed

Ebbers, Lena; Weber, Maren; Nothwang, Hans Gerd

2017-10-26

In the mammalian superior olivary complex (SOC), synaptic inhibition contributes to the processing of binaural sound cues important for sound localization. Previous analyses demonstrated a tonotopic gradient for postsynaptic proteins mediating inhibitory neurotransmission in the lateral superior olive (LSO), a major nucleus of the SOC. To probe, whether a presynaptic molecular gradient exists as well, we investigated immunoreactivity against the vesicular inhibitory amino acid transporter (VIAAT) in the mouse auditory brainstem. Immunoreactivity against VIAAT revealed a gradient in the LSO and the superior paraolivary nucleus (SPN) of NMRI mice, with high expression in the lateral, low frequency processing limb and low expression in the medial, high frequency processing limb of both nuclei. This orientation is opposite to the previously reported gradient of glycine receptors in the LSO. Other nuclei of the SOC showed a uniform distribution of VIAAT-immunoreactivity. No gradient was observed for the glycine transporter GlyT2 and the neuronal protein NeuN. Formation of the VIAAT gradient was developmentally regulated and occurred around hearing-onset between postnatal days 8 and 16. Congenital deaf Claudin14 -/- mice bred on an NMRI background showed a uniform VIAAT-immunoreactivity in the LSO, whereas cochlear ablation in NMRI mice after hearing-onset did not affect the gradient. Additional analysis of C57Bl6/J, 129/SvJ and CBA/J mice revealed a strain-specific formation of the gradient. Our results identify an activity-regulated gradient of VIAAT in the SOC of NRMI mice. Its absence in other mouse strains adds a novel layer of strain-specific features in the auditory system, i.e. tonotopic organization of molecular gradients. This calls for caution when comparing data from different mouse strains frequently used in studies involving transgenic animals. The presence of strain-specific differences offers the possibility of genetic mapping to identify molecular factors involved in activity-dependent developmental processes in the auditory system. This would provide an important step forward concerning improved auditory rehabilitation in cases of congenital deafness.

Graded and discontinuous EphA-ephrinB expression patterns in the developing auditory brainstem.

PubMed

Wallace, Matthew M; Harris, J Aaron; Brubaker, Donald Q; Klotz, Caitlyn A; Gabriele, Mark L

2016-05-01

Eph-ephrin interactions guide topographic mapping and pattern formation in a variety of systems. In contrast to other sensory pathways, their precise role in the assembly of central auditory circuits remains poorly understood. The auditory midbrain, or inferior colliculus (IC) is an intriguing structure for exploring guidance of patterned projections as adjacent subdivisions exhibit distinct organizational features. The central nucleus of the IC (CNIC) and deep aspects of its neighboring lateral cortex (LCIC, Layer 3) are tonotopically-organized and receive layered inputs from primarily downstream auditory sources. While less is known about more superficial aspects of the LCIC, its inputs are multimodal, lack a clear tonotopic order, and appear discontinuous, terminating in modular, patch/matrix-like distributions. Here we utilize X-Gal staining approaches in lacZ mutant mice (ephrin-B2, -B3, and EphA4) to reveal EphA-ephrinB expression patterns in the nascent IC during the period of projection shaping that precedes hearing onset. We also report early postnatal protein expression in the cochlear nuclei, the superior olivary complex, the nuclei of the lateral lemniscus, and relevant midline structures. Continuous ephrin-B2 and EphA4 expression gradients exist along frequency axes of the CNIC and LCIC Layer 3. In contrast, more superficial LCIC localization is not graded, but confined to a series of discrete ephrin-B2 and EphA4-positive Layer 2 modules. While heavily expressed in the midline, much of the auditory brainstem is devoid of ephrin-B3, including the CNIC, LCIC Layer 2 modular fields, the dorsal nucleus of the lateral lemniscus (DNLL), as well as much of the superior olivary complex and cochlear nuclei. Ephrin-B3 LCIC expression appears complementary to that of ephrin-B2 and EphA4, with protein most concentrated in presumptive extramodular zones. Described tonotopic gradients and seemingly complementary modular/extramodular patterns suggest Eph-ephrin guidance in establishing juxtaposed continuous and discrete neural maps in the developing IC prior to experience. Copyright © 2016 Elsevier B.V. All rights reserved.

Biocompatible 5-Aminolevulinic Acid/Au Nanoparticle-Loaded Ethosomal Vesicles for In Vitro Transdermal Synergistic Photodynamic/Photothermal Therapy of Hypertrophic Scars

NASA Astrophysics Data System (ADS)

Zhang, Zheng; Chen, Yunsheng; Ding, Jiayue; Zhang, Chunlei; Zhang, Amin; He, Dannong; Zhang, Yixin

2017-12-01

Biocompatible 5-aminolevulinic acid/Au nanoparticle-loaded ethosomal vesicle (A/A-ES) is prepared via ultrasonication for synergistic transdermal photodynamic/photothermal therapy (PDT/PTT) of hypertrophic scar (HS). Utilizing ultrasonication, Au nanoparticles (AuNPs) are synthesized and simultaneously loaded in ethosomal vesicles (ES) without any toxic agents, and 5-aminolevulinic acid (ALA) is also loaded in ES with 20% of the entrapment efficiency (EE). The prepared A/A-ES displays strong absorbance in 600-650 nm due to the plasmonic coupling effect between neighboring AuNPs in the same A/A-ES, which can simultaneously stimulate A/A-ES to produce heat and enhance quantum yields of reactive oxygen species (ROS) by using 632 nm laser. In vitro transdermal penetrability study demonstrates that A/A-ES acts as a highly efficient drug carrier to enhance both ALA and AuNPs penetration into HS tissue . Taking human hypertrophic scar fibroblasts (HSF) as therapeutic targets, synergistic PDT/PTT of HS indicates that A/A-ES could enhance quantum yields of ROS by photothermal effect and localized surface plasmon resonance (LSPR) of AuNPs, resulting in a high level of apoptosis or necrosis. In a word, the prepared A/A-ES shows a better synergistic PDT/PTT efficiency for HSF than the individual PDT and PTT, encouraging perspective for treatment of HS.

ClinGen--the Clinical Genome Resource.

PubMed

Rehm, Heidi L; Berg, Jonathan S; Brooks, Lisa D; Bustamante, Carlos D; Evans, James P; Landrum, Melissa J; Ledbetter, David H; Maglott, Donna R; Martin, Christa Lese; Nussbaum, Robert L; Plon, Sharon E; Ramos, Erin M; Sherry, Stephen T; Watson, Michael S

2015-06-04

On autopsy, a patient is found to have hypertrophic cardiomyopathy. The patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication. Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk. Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy on echocardiography. Five years later, during a routine clinic visit of one of the genotype-positive family members, the cardiologist queries a database for current knowledge on the genetic variant and discovers that the variant is now interpreted as “likely benign” by another laboratory that uses more recently derived population-frequency data. A newly available testing panel for additional genes that are implicated in hypertrophic cardiomyopathy is initiated on an affected family member, and a different variant is found that is determined to be pathogenic. Family members are retested, and one member who previously tested negative is now found to be positive for this new variant. An immediate clinical workup detects evidence of cardiomyopathy, and an intracardiac defibrillator is implanted to reduce the risk of sudden cardiac death.

Genome-Wide Gene Expression Analysis Shows AKAP13-Mediated PKD1 Signaling Regulates the Transcriptional Response to Cardiac Hypertrophy.

PubMed

Johnson, Keven R; Nicodemus-Johnson, Jessie; Spindler, Mathew J; Carnegie, Graeme K

2015-01-01

In the heart, scaffolding proteins such as A-Kinase Anchoring Proteins (AKAPs) play a crucial role in normal cellular function by serving as a signaling hub for multiple protein kinases including protein kinase D1 (PKD1). Under cardiac hypertrophic conditions AKAP13 anchored PKD1 activates the transcription factor MEF2 leading to subsequent fetal gene activation and hypertrophic response. We used an expression microarray to identify the global transcriptional response in the hearts of wild-type mice expressing the native form of AKAP13 compared to a gene-trap mouse model expressing a truncated form of AKAP13 that is unable to bind PKD1 (AKAP13-ΔPKD1). Microarray analysis showed that AKAP13-ΔPKD1 mice broadly failed to exhibit the transcriptional profile normally associated with compensatory cardiac hypertrophy following trans-aortic constriction (TAC). The identified differentially expressed genes in WT and AKAP13-ΔPKD1 hearts are vital for the compensatory hypertrophic response to pressure-overload and include myofilament, apoptotic, and cell growth/differentiation genes in addition to genes not previously identified as affected by AKAP13-anchored PKD1. Our results show that AKAP13-PKD1 signaling is critical for transcriptional regulation of key contractile, cell death, and metabolic pathways during the development of compensatory hypertrophy in vivo.

Src Homology 2 Domain-containing Phosphatase 2 (Shp2) Is a Component of the A-kinase-anchoring Protein (AKAP)-Lbc Complex and Is Inhibited by Protein Kinase A (PKA) under Pathological Hypertrophic Conditions in the Heart*

PubMed Central

Burmeister, Brian T.; Taglieri, Domenico M.; Wang, Li; Carnegie, Graeme K.

2012-01-01

Pathological cardiac hypertrophy (an increase in cardiac mass resulting from stress-induced cardiac myocyte growth) is a major factor underlying heart failure. Our results identify a novel mechanism of Shp2 inhibition that may promote cardiac hypertrophy. We demonstrate that the tyrosine phosphatase, Shp2, is a component of the A-kinase-anchoring protein (AKAP)-Lbc complex. AKAP-Lbc facilitates PKA phosphorylation of Shp2, which inhibits its protein-tyrosine phosphatase activity. Given the important cardiac roles of both AKAP-Lbc and Shp2, we investigated the AKAP-Lbc-Shp2 interaction in the heart. AKAP-Lbc-tethered PKA is implicated in cardiac hypertrophic signaling; however, mechanism of PKA action is unknown. Mutations resulting in loss of Shp2 catalytic activity are also associated with cardiac hypertrophy and congenital heart defects. Our data indicate that AKAP-Lbc integrates PKA and Shp2 signaling in the heart and that AKAP-Lbc-associated Shp2 activity is reduced in hypertrophic hearts in response to chronic β-adrenergic stimulation and PKA activation. Thus, while induction of cardiac hypertrophy is a multifaceted process, inhibition of Shp2 activity through AKAP-Lbc-anchored PKA is a previously unrecognized mechanism that may promote compensatory cardiac hypertrophy. PMID:23045525

Genome-Wide Gene Expression Analysis Shows AKAP13-Mediated PKD1 Signaling Regulates the Transcriptional Response to Cardiac Hypertrophy

PubMed Central

Johnson, Keven R.; Nicodemus-Johnson, Jessie; Spindler, Mathew J.

2015-01-01

In the heart, scaffolding proteins such as A-Kinase Anchoring Proteins (AKAPs) play a crucial role in normal cellular function by serving as a signaling hub for multiple protein kinases including protein kinase D1 (PKD1). Under cardiac hypertrophic conditions AKAP13 anchored PKD1 activates the transcription factor MEF2 leading to subsequent fetal gene activation and hypertrophic response. We used an expression microarray to identify the global transcriptional response in the hearts of wild-type mice expressing the native form of AKAP13 compared to a gene-trap mouse model expressing a truncated form of AKAP13 that is unable to bind PKD1 (AKAP13-ΔPKD1). Microarray analysis showed that AKAP13-ΔPKD1 mice broadly failed to exhibit the transcriptional profile normally associated with compensatory cardiac hypertrophy following trans-aortic constriction (TAC). The identified differentially expressed genes in WT and AKAP13-ΔPKD1 hearts are vital for the compensatory hypertrophic response to pressure-overload and include myofilament, apoptotic, and cell growth/differentiation genes in addition to genes not previously identified as affected by AKAP13-anchored PKD1. Our results show that AKAP13-PKD1 signaling is critical for transcriptional regulation of key contractile, cell death, and metabolic pathways during the development of compensatory hypertrophy in vivo. PMID:26192751

[Electrocardiographic differences between apical hypertrophic cardiomyopathy and apical non-ST segment myocardial infarction].

PubMed

Chillik, Iván; Gil Ramírez, Andreina; Ordóñez, Santiago; Tomás, Leandro; Parodi, Josefina; Costabel, Juan Pablo

2018-01-01

Apocal hypertrophic cardiomyopathy (AHCM) is a phenotypic variant within hypertrophic cardiomyopathies, in which ventricular repolarization alterations are present. These electrocardiographic disturbances can mimic an anterior infarction which triggers a series of studies and treatments that may be unnecessary. The aim of this study was to describe and compare electrocardiographic differences in a series of patients with AHCM and apical non-ST segment elevation myocardial infarction in patients (NSTEMI) with T-wave changes. We conducted an observational and retrospective study, including patients with diagnosed AHCM (N = 19) and apical NSTEMI (N = 19) with negative T waves in V1 and V6 lead of the EKG. Those with AHCM presented higher T-wave voltage (7 mV vs. 5 mV, p = 0.001) and peak voltage (29 mV vs. 17 mV, p = 0.003), higher R-waves (25 mV vs. 10 mV, p = 0.0001), and a maximum voltage of R and T sum (R + T) significantly higher (33 vs. 14, p = 0.00001). They also showed a greater T-wave asymmetry, with a TiTp / TpTf ratio > 1. At a cut-off value of 26.5 mV for the R + T variable, 68% sensitivity and 100% specificity were obtained to diagnose AHCM. This study shows the existence of major differences in electrocardiographic presentation of AHCM and apical NSTEMI.

Alteration in mitochondrial Ca(2+) uptake disrupts insulin signaling in hypertrophic cardiomyocytes.

PubMed

Gutiérrez, Tomás; Parra, Valentina; Troncoso, Rodrigo; Pennanen, Christian; Contreras-Ferrat, Ariel; Vasquez-Trincado, César; Morales, Pablo E; Lopez-Crisosto, Camila; Sotomayor-Flores, Cristian; Chiong, Mario; Rothermel, Beverly A; Lavandero, Sergio

2014-11-07

Cardiac hypertrophy is characterized by alterations in both cardiac bioenergetics and insulin sensitivity. Insulin promotes glucose uptake by cardiomyocytes and its use as a substrate for glycolysis and mitochondrial oxidation in order to maintain the high cardiac energy demands. Insulin stimulates Ca(2+) release from the endoplasmic reticulum, however, how this translates to changes in mitochondrial metabolism in either healthy or hypertrophic cardiomyocytes is not fully understood. In the present study we investigated insulin-dependent mitochondrial Ca(2+) signaling in normal and norepinephrine or insulin like growth factor-1-induced hypertrophic cardiomyocytes. Using mitochondrion-selective Ca(2+)-fluorescent probes we showed that insulin increases mitochondrial Ca(2+) levels. This signal was inhibited by the pharmacological blockade of either the inositol 1,4,5-triphosphate receptor or the mitochondrial Ca(2+) uniporter, as well as by siRNA-dependent mitochondrial Ca(2+) uniporter knockdown. Norepinephrine-stimulated cardiomyocytes showed a significant decrease in endoplasmic reticulum-mitochondrial contacts compared to either control or insulin like growth factor-1-stimulated cells. This resulted in a reduction in mitochondrial Ca(2+) uptake, Akt activation, glucose uptake and oxygen consumption in response to insulin. Blocking mitochondrial Ca(2+) uptake was sufficient to mimic the effect of norepinephrine-induced cardiomyocyte hypertrophy on insulin signaling. Mitochondrial Ca(2+) uptake is a key event in insulin signaling and metabolism in cardiomyocytes.

AMPK modulatory activity of olive-tree leaves phenolic compounds: Bioassay-guided isolation on adipocyte model and in silico approach.

PubMed

Jiménez-Sánchez, Cecilia; Olivares-Vicente, Mariló; Rodríguez-Pérez, Celia; Herranz-López, María; Lozano-Sánchez, Jesús; Segura-Carretero, Antonio; Fernández-Gutiérrez, Alberto; Encinar, José Antonio; Micol, Vicente

2017-01-01

Olive-tree polyphenols have demonstrated potential for the management of obesity-related pathologies. We aimed to explore the capacity of Olive-tree leaves extract to modulate triglyceride accumulation and AMP-activated protein kinase activity (AMPK) on a hypertrophic adipocyte model. Intracellular triglycerides and AMPK activity were measured on the hypertrophic 3T3-L1 adipocyte model by AdipoRed and immunofluorescence microscopy, respectively. Reverse phase high performance liquid chromatography coupled to time-of-flight mass detection with electrospray ionization (RP-HPLC-ESI-TOF/MS) was used for the fractionation of the extract and the identification of the compounds. In-silico molecular docking of the AMPK alpha-2, beta and gamma subunits with the identified compounds was performed. Olive-tree leaves extract decreased the intracellular lipid accumulation through AMPK-dependent mechanisms in hypertrophic adipocytes. Secoiridoids, cinnamic acids, phenylethanoids and phenylpropanoids, flavonoids and lignans were the candidates predicted to account for this effect. Molecular docking revealed that some compounds may be AMPK-gamma modulators. The modulatory effects of compounds over the alpha and beta AMPK subunits appear to be less probable. Olive-tree leaves polyphenols modulate AMPK activity, which may become a therapeutic aid in the management of obesity-associated disturbances. The natural occurrence of these compounds may have important nutritional implications for the design of functional ingredients.

A prospective randomized clinical trial to investigate the effect of silicone gel sheeting (Cica-Care) on post-traumatic hypertrophic scar among the Chinese population.

PubMed

Li-Tsang, Cecilia W P; Lau, Joy C M; Choi, Jenny; Chan, Chetwyn C C; Jianan, Li

2006-09-01

This study aimed to determine the efficacy of silicone gel (Cica-Care) on severe post-traumatic hypertophic scars among the Chinese population. A randomized clinical trial (RCT) was conducted on 45 Chinese patients with post-traumatic hypertrophic scars. Twenty-two subjects were placed in the experimental group with silicone gel sheeting (SGS) applied 24h per day for 6 months while all subjects were taught to massage the scar daily for 15 min serving as the control intervention. Scar assessments were conducted regularly to measure the changes in thickness, pigmentation, vascularity, pliability, itchiness and pain. Two-way repeated ANOVA showed a significant difference between MT group and SGS group on scar thickness. The post hoc comparison analysis showed that the difference was significant at the post-2-month (p=0.008) and post-6-month (p<0.001) intervention. The SGS group also showed changes in pigmentation which resembled normal skin but no statistical significance was found. Pain, itchiness and pliability were also improved after intervention. This study indicated that silicone gel sheeting (Cica-Care) was effective to reduce thickness, pain, itchiness and pliability of the severe hypertrophic scar among the Chinese population. The moisturization effect of the tough and hard scar might contribute to the reduction of the skin thickness after 6 month's intervention.

Sildenafil prevents the up-regulation of transient receptor potential canonical channels in the development of cardiomyocyte hypertrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiso, Hironori; Ohba, Takayoshi; Iino, Kenji

2013-07-05

Highlights: •Transient receptor potential canonical (TRPC1, 3 and 6) are up-regulated by ET-1. •Sildenafil inhibited hypertrophic responses (BNP, Ca entry, NFAT activation). •Sildenafil suppressed TRPC1, 3 and 6 expression. -- Abstract: Background: Transient receptor potential canonical (TRPCs) channels are up-regulated in the development of cardiac hypertrophy. Sildenafil inhibits TRPC6 activation and expression, leading to the prevention of cardiac hypertrophy. However, the effects of sildenafil on the expression of other TRPCs remain unknown. We hypothesized that in addition to its effects of TRPC6, sildenafil blocks the up-regulation of other TRPC channels to suppress cardiomyocyte hypertrophy. Methods and results: In cultured neonatalmore » rat cardiomyocytes, a 48 h treatment with 10 nM endothelin (ET)-1 induced hypertrophic responses characterized by nuclear factor of activated T cells activation and enhancement of brain natriuretic peptide expression and cell surface area. Co-treatment with sildenafil (1 μM, 48 h) inhibited these ET-1-induced hypertrophic responses. Although ET-1 enhanced the gene expression of TRPCs, sildenafil inhibited the enhanced gene expression of TRPC1, C3 and C6. Moreover, co-treatment with sildenafil abolished the augmentation of SOCE in the hypertrophied cardiomyocytes. Conclusions: These results suggest that sildenafil inhibits cardiomyocyte hypertrophy by suppressing the up-regulation of TRPC expression.« less

A case of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated hypertrophic pachymeningitis presenting with multiple cranial nerve palsies and diabetes insipidus.

PubMed

Yasuda, Ken; Sainouchi, Makoto; Goto, Masahiro; Murase, Nagako; Ohtani, Ryo; Nakamura, Michikazu

2016-05-31

A 61-year-old woman developed hearing difficulties and became thirsty after experiencing cold symptoms. A neurological examination revealed a loss of odor sensation, facial palsy, dysphasia, and dysarthria. Vocal cord palsy was observed during pharyngoscopy. Brain magnetic resonance imaging (MRI) showed a thickened pituitary stalk and swelling of the pituitary gland, but no high signal intensity regions were seen in the posterior portion of the pituitary gland. Gadolinium-enhanced MRI demonstrated a thickened dura mater over the anterior cranial fossa. A biopsy specimen of the thickened dura mater showed fibrosis, granulomatous inflammation, and necrotic foci. Blood tests detected myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA). The patient's urine osmolarity was low even though she exhibited hypernatremia. We diagnosed her with hypertrophic pachymeningitis associated with MPO-ANCA and diabetes insipidus. The patient received two courses of 5-day high-dose intravenous methylprednisolone (1.0 g/day), and was subsequently administered oral prednisolone, which gradually relieved her symptoms. However, the patient's symptoms recurred despite the high-dose prednisolone treatment. It was difficult to control the patient's symptoms in this case with oral prednisolone monotherapy, but combined treatment with cyclosporine resulted in sustained remission. It is considered that patients with MPO-ANCA-positive hypertrophic pachymeningitis require combination therapy with prednisolone and immunosuppressive agents at an early stage.

Quantitative analysis of hypertrophic myocardium using diffusion tensor magnetic resonance imaging

PubMed Central

Tran, Nicholas; Giannakidis, Archontis; Gullberg, Grant T.; Seo, Youngho

2016-01-01

Abstract. Systemic hypertension is a causative factor in left ventricular hypertrophy (LVH). This study is motivated by the potential to reverse or manage the dysfunction associated with structural remodeling of the myocardium in this pathology. Using diffusion tensor magnetic resonance imaging, we present an analysis of myocardial fiber and laminar sheet orientation in ex vivo hypertrophic (6 SHR) and normal (5 WKY) rat hearts using the covariance of the diffusion tensor. First, an atlas of normal cardiac microstructure was formed using the WKY b0 images. Then, the SHR and WKY b0 hearts were registered to the atlas. The acquired deformation fields were applied to the SHR and WKY heart tensor fields followed by the preservation of principal direction (PPD) reorientation strategy. A mean tensor field was then formed from the registered WKY tensor images. Calculating the covariance of the registered tensor images about this mean for each heart, the hypertrophic myocardium exhibited significantly increased myocardial fiber derangement (p=0.017) with a mean dispersion of 38.7 deg, and an increased dispersion of the laminar sheet normal (p=0.030) of 54.8 deg compared with 34.8 deg and 51.8 deg, respectively, in the normal hearts. Results demonstrate significantly altered myocardial fiber and laminar sheet structure in rats with hypertensive LVH. PMID:27872872

TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy.

PubMed

Sunggip, Caroline; Shimoda, Kakeru; Oda, Sayaka; Tanaka, Tomohiro; Nishiyama, Kazuhiro; Mangmool, Supachoke; Nishimura, Akiyuki; Numaga-Tomita, Takuro; Nishida, Motohiro

2018-01-01

Cardiac hypertrophy, induced by neurohumoral factors, including angiotensin II and endothelin-1, is a major predisposing factor for heart failure. These ligands can induce hypertrophic growth of neonatal rat cardiomyocytes (NRCMs) mainly through Ca 2+ -dependent calcineurin/nuclear factor of activated T cell (NFAT) signaling pathways activated by diacylglycerol-activated transient receptor potential canonical 3 and 6 (TRPC3/6) heteromultimer channels. Although extracellular nucleotide, adenosine 5'-triphosphate (ATP), is also known as most potent Ca 2+ -mobilizing ligand that acts on purinergic receptors, ATP never induces cardiomyocyte hypertrophy. Here we show that ATP-induced production of nitric oxide (NO) negatively regulates hypertrophic signaling mediated by TRPC3/6 channels in NRCMs. Pharmacological inhibition of NO synthase (NOS) potentiated ATP-induced increases in NFAT activity, protein synthesis, and transcriptional activity of brain natriuretic peptide. ATP significantly increased NO production and protein kinase G (PKG) activity compared to angiotensin II and endothelin-1. We found that ATP-induced Ca 2+ signaling requires inositol 1,4,5-trisphosphate (IP 3 ) receptor activation. Interestingly, inhibition of TRPC5, but not TRPC6 attenuated ATP-induced activation of Ca 2+ /NFAT-dependent signaling. As inhibition of TRPC5 attenuates ATP-stimulated NOS activation, these results suggest that NO-cGMP-PKG axis activated by IP 3 -mediated TRPC5 channels underlies negative regulation of TRPC3/6-dependent hypertrophic signaling induced by ATP stimulation.

AMPK modulatory activity of olive–tree leaves phenolic compounds: Bioassay-guided isolation on adipocyte model and in silico approach

PubMed Central

Jiménez-Sánchez, Cecilia; Olivares-Vicente, Mariló; Rodríguez-Pérez, Celia; Herranz-López, María; Lozano-Sánchez, Jesús; Segura-Carretero, Antonio; Fernández-Gutiérrez, Alberto; Encinar, José Antonio; Micol, Vicente

2017-01-01

Scope Olive-tree polyphenols have demonstrated potential for the management of obesity-related pathologies. We aimed to explore the capacity of Olive-tree leaves extract to modulate triglyceride accumulation and AMP-activated protein kinase activity (AMPK) on a hypertrophic adipocyte model. Methods Intracellular triglycerides and AMPK activity were measured on the hypertrophic 3T3-L1 adipocyte model by AdipoRed and immunofluorescence microscopy, respectively. Reverse phase high performance liquid chromatography coupled to time-of-flight mass detection with electrospray ionization (RP-HPLC-ESI-TOF/MS) was used for the fractionation of the extract and the identification of the compounds. In-silico molecular docking of the AMPK alpha-2, beta and gamma subunits with the identified compounds was performed. Results Olive-tree leaves extract decreased the intracellular lipid accumulation through AMPK-dependent mechanisms in hypertrophic adipocytes. Secoiridoids, cinnamic acids, phenylethanoids and phenylpropanoids, flavonoids and lignans were the candidates predicted to account for this effect. Molecular docking revealed that some compounds may be AMPK-gamma modulators. The modulatory effects of compounds over the alpha and beta AMPK subunits appear to be less probable. Conclusions Olive-tree leaves polyphenols modulate AMPK activity, which may become a therapeutic aid in the management of obesity-associated disturbances. The natural occurrence of these compounds may have important nutritional implications for the design of functional ingredients. PMID:28278224

Emerin plays a crucial role in nuclear invagination and in the nuclear calcium transient

PubMed Central

Shimojima, Masaya; Yuasa, Shinsuke; Motoda, Chikaaki; Yozu, Gakuto; Nagai, Toshihiro; Ito, Shogo; Lachmann, Mark; Kashimura, Shin; Takei, Makoto; Kusumoto, Dai; Kunitomi, Akira; Hayashiji, Nozomi; Seki, Tomohisa; Tohyama, Shugo; Hashimoto, Hisayuki; Kodaira, Masaki; Egashira, Toru; Hayashi, Kenshi; Nakanishi, Chiaki; Sakata, Kenji; Yamagishi, Masakazu; Fukuda, Keiichi

2017-01-01

Alteration of the nuclear Ca2+ transient is an early event in cardiac remodeling. Regulation of the nuclear Ca2+ transient is partly independent of the cytosolic Ca2+ transient in cardiomyocytes. One nuclear membrane protein, emerin, is encoded by EMD, and an EMD mutation causes Emery-Dreifuss muscular dystrophy (EDMD). It remains unclear whether emerin is involved in nuclear Ca2+ homeostasis. The aim of this study is to elucidate the role of emerin in rat cardiomyocytes by means of hypertrophic stimuli and in EDMD induced pluripotent stem (iPS) cell-derived cardiomyocytes in terms of nuclear structure and the Ca2+ transient. The cardiac hypertrophic stimuli increased the nuclear area, decreased nuclear invagination, and increased the half-decay time of the nuclear Ca2+ transient in cardiomyocytes. Emd knockdown cardiomyocytes showed similar properties after hypertrophic stimuli. The EDMD-iPS cell-derived cardiomyocytes showed increased nuclear area, decreased nuclear invagination, and increased half-decay time of the nuclear Ca2+ transient. An autopsied heart from a patient with EDMD also showed increased nuclear area and decreased nuclear invagination. These data suggest that Emerin plays a crucial role in nuclear structure and in the nuclear Ca2+ transient. Thus, emerin and the nuclear Ca2+ transient are possible therapeutic targets in heart failure and EDMD. PMID:28290476

MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.

PubMed

Baruffini, Enrico; Dallabona, Cristina; Invernizzi, Federica; Yarham, John W; Melchionda, Laura; Blakely, Emma L; Lamantea, Eleonora; Donnini, Claudia; Santra, Saikat; Vijayaraghavan, Suresh; Roper, Helen P; Burlina, Alberto; Kopajtich, Robert; Walther, Anett; Strom, Tim M; Haack, Tobias B; Prokisch, Holger; Taylor, Robert W; Ferrero, Ileana; Zeviani, Massimo; Ghezzi, Daniele

2013-11-01

We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype. © 2013 The Authors. *Human Mutation published by Wiley Periodicals, Inc.

Effect of different pressure magnitudes on hypertrophic scar in a Chinese population.

PubMed

Candy, Lai Hoi Yan; Cecilia, Li-Tsang Wai Ping; Ping, Zheng Yong

2010-12-01

This study aimed to investigate the effect of different pressure magnitudes on treatment outcomes of hypertrophic scars, and determine pressure loss over time. A randomized clinical trial was adopted. 53 hypertrophic scar samples from 17 Chinese participants were recruited and randomly assigned into a high pressure group (20-25 mmHg) and low pressure group (10-15 mmHg) for a five-month intervention program. The scars were assessed objectively before intervention and monthly after intervention for thickness, color (redness, yellowness and lightness) and scar pliability. Pressure magnitude at each assessment was also measured. Two-way repeated ANOVA was used to compare for differences between groups. The results showed that both levels of pressure produced reduction in scar thickness and redness, but the improvement in the high pressure group was statistically better than that of the counterpart (both p<0.05). Monthly pressure measurement revealed that pressure loss in the high pressure group was more severe. However, no major changes in other color parameters and pliability were observed for both the groups. High pressure was demonstrated to be more effective for scar management, but it was also more prone to higher pressure loss. Pressure therapy integrated with regular monitoring of the interface pressure is suggested to improve its therapeutic efficacy. Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.

Bromocriptine modulates the expression of PTHrP receptor, Indian hedgehog, and Runx2 proteins in the growth plate of lactating rats.

PubMed

Wongdee, Kannikar; Thonapan, Natchayaporn; Saengamnart, Wasana; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

2013-09-01

In lactating rats, the endochondral bone growth is markedly enhanced, leading to the lengthening of long bone. This lactation-induced bone elongation could be abolished by a dopaminergic D2 receptor agonist bromocriptine, but how bromocriptine altered the expression of major chondroregulatory proteins in the growth plate cartilage was elusive. Here, we performed a quantitative immunohistochemical analysis to determine the expression of various peptides and transcription factors known to control the growth plate chondrocyte proliferation and differentiation [i.e., parathyroid hormone-related protein (PTHrP), PTHrP receptor, Indian hedgehog (Ihh), and runt-related transcription factor 2 (Runx2)], in bromocriptine-treated lactating rats. The results showed that bromocriptine markedly increased Ihh expression in hypertrophic chondrocytes during early and mid-lactation, while the expression of PTHrP receptor, but not its ligand PTHrP, was upregulated in the proliferative and hypertrophic zones during mid and late lactation. In contrast, the expression of Runx2, an important transcription factor for chondrocyte differentiation, was suppressed in the hypertrophic chondrocytes of bromocriptine-treated rats. In conclusion, bromocriptine increased Ihh and PTHrP receptor expressions and decreased Runx2 expression, which might, in turn, enhance chondrocyte proliferation and delay chondrocyte hypertrophy, thereby slowing down endochondral bone growth. This finding could explain how bromocriptine compromised the lactation-induced bone elongation.

Adult idiopathic hypertrophic pyloric stenosis - a common presentation with an uncommon diagnosis

PubMed Central

Mubarik, Ateeq; Muddassir, Salman; Haq, Furqan

2018-01-01

ABSTRACT Background and Objectives: Adult Idiopathic hypertrophic pyloric stenosis (AIHPS) is a rare but well-defined entity in adults with only 200-300 cases reported so far in the literature.We describe a case of AIHPS and the relevant literature review. Methods and Results: The patient presented with acute onset upper abdominal pain associated with nausea, vomiting, foul-smelling black tarry stools, and anorexia. On the Esophagogastroduodenoscopy (EGD), pylorus demonstrated a unique “cervix sign.” The patient had multiple endoscopic dilations with minimal relief. She then underwent a distal partial gastrectomy with a Billroth 1 gastroduodenostomy with considerable  improvement in her symptoms on follow up. Conclusion: Adult Idiopathic hypertrophic pyloric stenosis (AIHPS) is a rare disease which is also underreported due to a difficulty in diagnosis. The most common symptoms of AIHPS are postprandial nausea, vomiting, early satiety, and epigastric pain as seen in our patient. Endoscopy usually shows ?Cervix sign? a unique sign showing a fixed, markedly narrowed pylorus with a smooth border. Multiple treatments have been proposed for AIHPS, including endoscopic dilation, pyloromyotomy with or without pyloroplasty, gastrectomy with a Billroth 1 gastroduodenostomy. Currently, there is no evidence of one surgical technique being superior to another. Further research needs to be done on AIHPS before one technique can be standardized as the standard of care. PMID:29686790

Assessment of Efficacy of the 595-nm Pulsed Dye Laser in the Treatment of Facial Port-Wine Stains in Indian Patients.

PubMed

Khandpur, Sujay; Sharma, Vinod K

2016-06-01

Pulsed dye lasers have revolutionized treatment of port-wine stains (PWS). The authors' previous study with a 585-nm/0.45-millisecond pulsed dye laser (PDL) showed 25% to 75% improvement in 60% of facial PWS. The authors analyzed data on facial PWS treated with a 595-nm tunable PDL in Indian patients. Response was assessed subjectively on a scale of -1 to 5 (Investigator Global Assessment) by comparing pretreatment and posttreatment photographs. Patients' perception of change in PWS was also noted on a visual analog scale from 0 to 10 (Patient Global Assessment). Side effects were recorded. A total of 74 flat and 24 hypertrophic PWS in skin Types IV and V with a median lesion size of 56 cm and 102 cm, respectively, and color ranging from pink to purple were treated. They underwent a mean of 7.3 and 8.5 sessions (range: 4-10 session), respectively. A mean lightening of 54% in flat and 40% in hypertrophic PWS was observed. After 10 treatments, 46.6% of flat PWS cases showed >75% lightening and an equal number had 25% to 75% improvement. A >75% improvement was observed in 12.5% of hypertrophic PWS with 75% of cases showing between 25% to 75% improvement. No significant side effects were noted. The 595-nm tunable PDL produced moderate response with no significant side effects.

[Right ventricular hypertrophic cardiomyopathy in the fetus --may it be caused by chronic oral tocolysis with fenoterol?].

PubMed

Hamela-Olkowska, Anita; Szymkiewicz-Dangel, Joanna; Własienko, Paweł; Majewska, Urszula; Bokiniec, Renata

2012-02-01

The use of fenoterol in the treatment of preterm labor is associated with the risk of many complications in the mother and the fetus. We present a case of a multipara treated with oral fenoterol due to threatening preterm labor 14 weeks. At 35 weeks of gestation the fetus was diagnosed with hypertrophic cardiomyopathy with severe impairment of the right ventricle. The only factor that might have caused such a state of the fetal circulatory system was fenoterol, used from 21 weeks of gestation. After the withdrawal of the fenoterol the fetal right ventricular function improved gradually. However fetal cardiac hypertrophy persisted until the birth at 39 weeks of gestation. Concentric hypertrophy of the right ventricular wall and interventricular septum were confirmed in the newborn.

Invasive alien species water hyacinth Eichhornia crassipes as abode for macroinvertebrates in hypertrophic Ramsar Site, Lake Xochimilco, Mexico.

PubMed

Rocha-Ramirez, A; Robles-Valderrama, E; Ramirez-Flores, E

2014-11-01

This paper presents information on the density, diversity and functional feeding groups of macroinvertebrate assemblages associated with water hyacinth in Antiguo Canal Cuemanco, part of Lake Xochimilco in Mexico City. Rare (low frequency and density) and dominant (high frequency and density) taxa prevailed in the assemblages, with the most predominant being Hyalella azteca, Chironomus plumosus and Ischnura denticollis. Nonmetric Multidimensional Scaling confirmed two climatic seasons: warm-rainy and cold-dry; the former with the highest diversity and density of taxa. Canonical Correspondence Analysis showed that conductivity, nitrates and turbidity explained the density variations of taxa. Antiguo Canal Cuemanco waters are spatially homogeneous with the characteristics of hypertrophic shallow lakes, inhabited by scrapers and gathering-collectors. The species found were tolerant to organic pollution.

A skeletal case of hypertrophic osteoarthropathy from the Canary Islands dating from 1000 BP.

PubMed

González-Reimers, Emilio; Trujillo-Mederos, Aioze; Machado-Calvo, Manuel; Castañeyra-Ruiz, María; Ordóñez, Alejandra C; Arnay-de-la-Rosa, Matilde

2015-12-01

A left tibia, the distal right tibia, and the proximal four fifths of the right ulna and radius, probably belonging to an adult prehispanic man (antiquity of ≈1000 years BP) were found among commingled bone remains in a collective burial cave of the island of El Hierro, in the Canary Archipelago. All four bones show an intense periosteal bone formation, encrusting the preserved cortical bone of the diaphyses. Differential diagnosis include melorheostosis, syphilis, and leprosy, although the most likely diagnosis is hypertrophic osteoarthropathy, which is usually associated with lung neoplasm or non-malignant diseases leading to chronic hypoxemia. The marked bone proliferation, possibly due to a chronic condition, suggests that possibly the underlying illness was a non-malignant one. Copyright © 2015 Elsevier Inc. All rights reserved.

Imaging and histology in the diagnosis of multiple papillary fibroelastomas in a patient with hypertrophic obstructive cardiomyopathy. Case report.

PubMed

Ionescu, Alin Alexandru; Radulescu, Bogdan; Herlea, Vlad; Miclea, Ioan; Parepa, Irinel; Bubenek, Serban; Popescu, Bogdan Alexandru; Ginghina, Carmen; Jurcut, Ruxandra

2017-11-29

Papillary fibroelastomas (PFEs) are one of the most frequent primary cardiac tumors and occur more often in patients with hypertrophic obstructive cardiomyopathy (HOCM). PFEs have been linked to an increased risk of neurological events. We report a case of a 59-year-old woman with HOCM in whom echocardiography (transthoracic and transesophageal, using 2D and 3D techniques) revealed multiple masses in various locations in the left cardiac chambers. Surgical excision of the cardiac tumors and aortic valve replacement was performed and the pathologic report confirmed the diagnosis of PFEs. Patient followup using ultrasonography is crucial since recurrence is a possibility. Current cardiac ultrasound techniques are essential for diagnosing and for guiding the management of these conditions.

[Hypertrophic cardiomyopathy showing no 123I-BMIPP myocardial accumulation with type I CD36 deficiency].

PubMed

Watanabe, K; Miyajima, S; Kusano, Y; Tanabe, N; Hirokawa, Y

1997-07-01

A 57 years old male consulted our hospital in complaining chest oppression and short of breath. Familial and dilated phase hypertrophic cardiomyopathy (HCM) was detected by ECG, echocardiography, left ventriculography and left ventricular endomyocardial biopsy. 201T1 SPECT showed regional increased accumulation in the ventricular septum, however, no myocardial accumulation of 123I-beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) was observed. We analyzed CD36 in this patient, and found he had type 1 CD36 deficiency. Myocardial uptake of long-chain fatty acids occurs via a specific transporter, which is homologous with human CD36. We hypothesize that CD36 deficiency, especially type 1 CD36 deficiency, might be one factor of no myocardial 123I-BMIPP uptake.

Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1β and TNFα expression profile

PubMed Central

Le Maitre, Christine Lyn; Hoyland, Judith Alison; Freemont, Anthony J

2007-01-01

Low back pain is a common and debilitating disorder. Current evidence implicates intervertebral disc (IVD) degeneration and herniation as major causes, although the pathogenesis is poorly understood. While several cytokines have been implicated in the process of IVD degeneration and herniation, investigations have predominately focused on Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFα). However, to date no studies have investigated the expression of these cytokines simultaneously in IVD degeneration or herniation, or determined which may be the predominant cytokine associated with these disease states. Using quantitative real time PCR and immunohistochemistry we investigated gene and protein expression for IL-1β, TNFα and their receptors in non-degenerate, degenerate and herniated human IVDs. IL-1β gene expression was observed in a greater proportion of IVDs than TNFα (79% versus 59%). Degenerate and herniated IVDs displayed higher levels of both cytokines than non-degenerate IVDs, although in degenerate IVDs higher levels of IL-1β gene expression (1,300 copies/100 ng cDNA) were observed compared to those of TNFα (250 copies of TNFα/100 ng cDNA). Degenerate IVDs showed ten-fold higher IL-1 receptor gene expression compared to non-degenerate IVDs. In addition, 80% of degenerate IVD cells displayed IL-1 receptor immunopositivity compared to only 30% of cells in non-degenerate IVDs. However, no increase in TNF receptor I gene or protein expression was observed in degenerate or herniated IVDs compared to non-degenerate IVDs. We have demonstrated that although both cytokines are produced by human IVD cells, IL-1β is expressed at higher levels and in more IVDs, particularly in more degenerate IVDs (grades 4 to 12). Importantly, this study has highlighted an increase in gene and protein production for the IL-1 receptor type I but not the TNF receptor type I in degenerate IVDs. The data thus suggest that although both cytokines may be involved in the pathogenesis of IVD degeneration, IL-1 may have a more significant role than TNFα, and thus may be a better target for therapeutic intervention. PMID:17688691

Keloids and Hypertrophic Scars

MedlinePlus

... to the skin both skin cells and connective tissue cells (fibroblasts) begin multiplying to repair the damage. A scar is made up of 'connective tissue', gristle-like fibers deposited in the skin by ...

Behaviors of southwestern native fishes in response to introduced catfish predators

USGS Publications Warehouse

Ward, David L.; Figiel, Chester R.

2013-01-01

Native fishes reared in hatcheries typically suffer high predation mortality when stocked into natural environments. We evaluated the behavior of juvenile bonytail Gila elegans, roundtail chub Gila robusta, razorback sucker Xyrauchen texanus, and Sonora sucker Catostomus insignis in response to introduced channel catfish Ictalurus punctatus and flathead catfish Pylodictis olivaris. Our laboratory tests indicate these species did not inherently recognize catfish as a threat, but they can quickly (within 12 h) change their behavior in response to a novel predator paired with the sight and scent of a dead conspecific. Chubs appear to avoid predation by swimming away from the threat, whereas suckers reduced movement. Effects of antipredator conditioning on survival of fish reared in hatcheries is unknown; however, our results suggest some native fish can be conditioned to recognize introduced predators, which could increase poststocking survival.

Possible conditioned stimulus pathway for classical eyelid conditioning in rabbits. I. Anatomical evidence for direct projections from the pontine nuclei to the cerebellar interpositus nucleus.

PubMed

Steinmetz, J E; Sengelaub, D R

1992-03-01

Wheat germ agglutinin and cholera toxin-conjugated horseradish peroxidase (HRP) were used to retrogradely and anterogradely trace connectivity between the lateral regions of the pontine nuclei and the anterior interpositus nucleus of the cerebellum in rabbits. Projections from the pontine nuclei were found to terminate in the anterior interpositus nucleus and the interpositus was found to send projections to the pontine nuclei. Projections from the nucleus reticularis tegmenti pontis, dorsal accessory inferior olive, and Larsell's lobule HVI of the cerebellum were also found to terminate in the interpositus nucleus and projections from the interpositus nucleus to the inferior olivary complex were observed. The projections from brain stem regions to the interpositus nucleus are discussed as possible pathways that are involved in classical eyelid conditioning.

Integrin – Dependent Mechanotransduction in Mechanically Stimulated Human Annulus Fibrosus Cells: Evidence for an Alternative Mechanotransduction Pathway Operating with Degeneration

PubMed Central

Gilbert, Hamish T. J.; Nagra, Navraj S.; Freemont, Anthony J.; Millward-Sadler, Sarah J.; Hoyland, Judith A.

2013-01-01

Intervertebral disc (IVD) cells derived from degenerate tissue respond aberrantly to mechanical stimuli, potentially due to altered mechanotransduction pathways. Elucidation of the altered, or alternative, mechanotransduction pathways operating with degeneration could yield novel targets for the treatment of IVD disease. Our aim here was to investigate the involvement of RGD-recognising integrins and associated signalling molecules in the response to cyclic tensile strain (CTS) of human annulus fibrosus (AF) cells derived from non-degenerate and degenerate IVDs. AF cells from non-degenerate and degenerate human IVDs were cyclically strained with and without function blocking RGD – peptides with 10% strain, 1.0 Hz for 20 minutes using a Flexercell® strain device. QRT-PCR and Western blotting were performed to analyse gene expression of type I collagen and ADAMTS -4, and phosphorylation of focal adhesion kinase (FAK), respectively. The response to 1.0 Hz CTS differed between the two groups of AF cells, with decreased ADAMTS -4 gene expression and decreased type I collagen gene expression post load in AF cells derived from non-degenerate and degenerate IVDs, respectively. Pre-treatment of non-degenerate AF cells with RGD peptides prevented the CTS-induced decrease in ADAMTS -4 gene expression, but caused an increase in expression at 24 hours, a response not observed in degenerate AF cells where RGD pre-treatment failed to inhibit the mechano-response. In addition, FAK phosphorylation increased in CTS stimulated AF cells derived from non-degenerate, but not degenerate IVDs, with RGD pre-treatment inhibiting the CTS – dependent increase in phosphorylated FAK. Our findings suggest that RGD -integrins are involved in the 1.0 Hz CTS – induced mechano-response observed in AF cells derived from non-degenerate, but not degenerate IVDs. This data supports our previous work, suggesting an alternative mechanotransduction pathway may be operating in degenerate AF cells. PMID:24039840

Hypertrophic cardiomyopathy

MedlinePlus

... heart, forcing the heart to work harder to pump blood. It also can make it harder for the heart to relax ... from defects in the genes that control heart muscle growth. Younger people are likely to ...

Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu

Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System weremore » used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. - Highlights: • Hypertrophy (H) and hypertrophic carcinogenesis (C) were studied by toxicogenomics. • Important genes for H and C were selected by logistic ridge regression analysis. • Amino acid biosynthesis and oxidative responses may be involved in C. • Predictive models for H and C provided 94.8% and 82.7% accuracy, respectively. • The identified genes could be useful for assessment of liver hypertrophy.« less

The structure of winter phytoplankton in Lake Nero, Russia, a hypertrophic lake dominated by Planktothrix-like Cyanobacteria

PubMed Central

2013-01-01

Background The permanent dominance of Planktothrix-like сyanobacteria has been often reported for shallow eutrophic\\hypertrophic lakes in central Europe in summer\\autumn. However studies on phytoplankton growth under ice cover in nutrient-rich lakes are very scarce. Lake Nero provides a good example of the contrasting seasonal extremes in environmental conditions. Moreover, the ecosystem underwent a catastrophic transition from eutrophic to hypertrophic 2003–05, with dominance of filamentous cyanobacteria in summer\\autumn. Towards the end of the period of ice cover, there is an almost complete lack of light and oxygen but abundance in nutrients, especially ammonium nitrogen, soluble reactive phosphorus and total phosphorus in lake Nero. The aim of the present study was to describe species composition and abundance of the phytoplankton, in relation to the abiotic properties of the habitat to the end of winters 1999–2010. We were interested if Planktothrix-like сyanobacteria kept their dominant role under the ice conditions or only survived, and how did the under-ice phytoplankton community differ from year to year. Results Samples collected contained 172 algal taxa of sub-generic rank. Abundance of phytoplankton varied widely from very low to the bloom level. Cyanobacteria (Limnothrix, Pseudanabaena, Planktothrix) were present in all winter samples but did not always dominate. Favourable conditions included low winter temperature, thicker ice, almost complete lack of oxygen and high ammonium concentration. Flagellates belonging to Euglenophyta and Cryptophyta dominated in warmer winters, when phosphorus concentrations increased. Conclusion A full picture of algal succession in the lake may be obtained only if systematic winter observations are taken into account. Nearly anoxic conditions, severe light deficiency and high concentration of biogenic elements present a highly selective environment for phytoplankton. Hypertrophic water bodies of moderate zone covered by ice in winter and dominated by Planktothrix - like сyanobacteria in summer/autumn may follow several scenarios in the end of winter. It may be intense proliferation сyanobacteria normally dominating in summer, or the switch to the other species like the euglenoids and cryptomonads flagellates, or almost total depletion of phytoplankton. PMID:24079446

Using Amniotic Membrane as a Novel Method to Reduce Post-burn Hypertrophic Scar Formation: A Prospective Follow-up Study

PubMed Central

Mohammadi, Ali Akbar; Eskandari, Shima; Johari, Hamed Ghoddusi; Rajabnejad, Ata'ollah

2017-01-01

Background: Several studies have shown that the application of amniotic membrane as a biological dressing in the management of burns is accompanied by rapid re-epithelialisation. In this follow-up study, we aimed to evaluate the possible role of amniotic membrane as an adjunct to split thickness skin grafting on reducing itching and severity of hypertrophic scar formation. Materials and Methods: From October 2013 to January 2015, in a prospective follow-up study, 54 patients (108 limbs) with second and third degree burns, covering 4%–15% of total body surface area (TBSA), were included in the study. All patients needed split-thickness skin grafts for burn-wound coverage. Selected patients had symmetric burns on two (upper or lower) extremities. Then, in every patient, the extremities were randomly divided into two groups: In one limb, the skin graft was traditionally fixed with skin staples (control group) and in the other limb, the skin graft was covered with an amniotic membrane (amnion group). Therefore, in every patient, the graft was covered with an amniotic membrane in one extremity and fixed with skin staples in the other extremity. Finally, after 6 months, the degree of itching and hypertrophic scar formation was compared between the two groups. Results: The study group was composed of 108 limbs in 54 patients (27 males and 27 females) with a mean age of 23.54 ± 4.9 years and burn 9.03 ± 2.69% TBSA. The patients were divided into two groups: 54 limbs in amnion group and 54 limbs in control group. In 59.25% of the cases, patient had less itching in the extremity covered with amniotic membrane. Furthermore, in 64.81% of the cases, patients had less hypertrophic scar formation in the extremity covered with amniotic membrane. These differences were statistically significant (P < 0.001). Conclusions: Amniotic membrane used as an adjunct in split thickness skin grafting is a novel modality which significantly reduces scar formation and itching that can be greatly distressing to burn patients. However, still more prospective well designed studies are needed to prove it. PMID:28529415

Regulated Production of Mineralization-competent Matrix Vesicles in Hypertrophic Chondrocytes

PubMed Central

Kirsch, Thorsten; Nah, Hyun-Duck; Shapiro, Irving M.; Pacifici, Maurizio

1997-01-01

Matrix vesicles have a critical role in the initiation of mineral deposition in skeletal tissues, but the ways in which they exert this key function remain poorly understood. This issue is made even more intriguing by the fact that matrix vesicles are also present in nonmineralizing tissues. Thus, we tested the novel hypothesis that matrix vesicles produced and released by mineralizing cells are structurally and functionally different from those released by nonmineralizing cells. To test this hypothesis, we made use of cultures of chick embryonic hypertrophic chondrocytes in which mineralization was triggered by treatment with vitamin C and phosphate. Ultrastructural analysis revealed that both control nonmineralizing and vitamin C/phosphatetreated mineralizing chondrocytes produced and released matrix vesicles that exhibited similar round shape, smooth contour, and average size. However, unlike control vesicles, those produced by mineralizing chondrocytes had very strong alkaline phosphatase activity and contained annexin V, a membrane-associated protein known to mediate Ca2+ influx into matrix vesicles. Strikingly, these vesicles also formed numerous apatite-like crystals upon incubation with synthetic cartilage lymph, while control vesicles failed to do so. Northern blot and immunohistochemical analyses showed that the production and release of annexin V-rich matrix vesicles by mineralizing chondrocytes were accompanied by a marked increase in annexin V expression and, interestingly, were followed by increased expression of type I collagen. Studies on embryonic cartilages demonstrated a similar sequence of phenotypic changes during the mineralization process in vivo. Thus, chondrocytes located in the hypertrophic zone of chick embryo tibial growth plate were characterized by strong annexin V expression, and those located at the chondro–osseous mineralizing border exhibited expression of both annexin V and type I collagen. These findings reveal that hypertrophic chondrocytes can qualitatively modulate their production of matrix vesicles and only when induced to initiate mineralization, will release mineralization-competent matrix vesicles rich in annexin V and alkaline phosphatase. The occurrence of type I collagen in concert with cartilage matrix calcification suggests that the protein may facilitate crystal growth after rupture of the matrix vesicle membrane; it may also offer a smooth transition from mineralized type II/type X collagen-rich cartilage matrix to type I collagen-rich bone matrix. PMID:9166414

Assessment of left ventricular mass in hypertrophic cardiomyopathy by real-time three-dimensional echocardiography using single-beat capture image.

PubMed

Chang, Sung-A; Kim, Hyung-Kwan; Lee, Sang-Chol; Kim, Eun-Young; Hahm, Seung-Hee; Kwon, Oh Min; Park, Seung Woo; Choe, Yeon Hyeon; Oh, Jae K

2013-04-01

Left ventricular (LV) mass is an important prognostic indicator in hypertrophic cardiomyopathy. Although LV mass can be easily calculated using conventional echocardiography, it is based on geometric assumptions and has inherent limitations in asymmetric left ventricles. Real-time three-dimensional echocardiographic (RT3DE) imaging with single-beat capture provides an opportunity for the accurate estimation of LV mass. The aim of this study was to validate this new technique for LV mass measurement in patients with hypertrophic cardiomyopathy. Sixty-nine patients with adequate two-dimensional (2D) and three-dimensional echocardiographic image quality underwent cardiac magnetic resonance (CMR) imaging and echocardiography on the same day. Real-time three-dimensional echocardiographic images were acquired using an Acuson SC2000 system, and CMR-determined LV mass was considered the reference standard. Left ventricular mass was derived using the formula of the American Society of Echocardiography (M-mode mass), the 2D-based truncated ellipsoid method (2D mass), and the RT3DE technique (RT3DE mass). The mean time for RT3DE analysis was 5.85 ± 1.81 min. Intraclass correlation analysis showed a close relationship between RT3DE and CMR LV mass (r = 0.86, P < .0001). However, LV mass by the M-mode or 2D technique showed a smaller intraclass correlation coefficient compared with CMR-determined mass (r = 0.48, P = .01, and r = 0.71, P < .001, respectively). Bland-Altman analysis showed reasonable limits of agreement between LV mass by RT3DE imaging and by CMR, with a smaller positive bias (19.5 g [9.1%]) compared with that by the M-mode and 2D methods (-35.1 g [-20.2%] and 30.6 g [17.6%], respectively). RT3DE measurement of LV mass using the single-beat capture technique is practical and more accurate than 2D or M-mode LV mass in patients with hypertrophic cardiomyopathy. Copyright © 2013 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

R-spondin 2 facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/β-catenin signaling in endochondral ossification

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takegami, Yasuhiko; Department of Orthopaedic Surgery, Nagoya University School of Medicine, Nagoya; Ohkawara, Bisei

Endochondral ossification is a crucial process for longitudinal growth of bones. Differentiating chondrocytes in growth cartilage form four sequential zones of proliferation, alignment into column, hypertrophy, and substitution of chondrocytes with osteoblasts. Wnt/β-catenin signaling is essential for differentiation of proliferating chondrocytes into hypertrophic chondrocytes in growth cartilage. R-spondin 2 (Rspo2), a member of R-spondin family, is an agonist for Wnt signaling, but its role in chondrocyte differentiation remains unknown. Here we report that growth cartilage of Rspo2-knockout mice shows a decreased amount of β-catenin and increased amounts collagen type II (CII) and Sox9 in the abnormally extended proliferating zone. Inmore » contrast, expression of collagen type X (CX) in the hypertrophic zone remains unchanged. Differentiating chondrogenic ATDC5 cells, mimicking proliferating chondrocytes, upregulate Rspo2 and its putative receptor, Lgr5, in parallel. Addition of recombinant human Rspo2 to differentiating ATDC5 cells decreases expressions of Col2a1, Sox9, and Acan, as well as production of proteoglycans. In contrast, lentivirus-mediated knockdown of Rspo2 has the opposite effect. The effect of Rspo2 on chondrogenic differentiation is mediated by Wnt/β-catenin signaling, and not by Wnt/PCP or Wnt/Ca{sup 2+} signaling. We propose that Rspo2 activates Wnt/β-catenin signaling to reduce Col2a1 and Sox9 and to facilitate differentiation of proliferating chondrocytes into hypertrophic chondrocytes in growth cartilage. - Highlights: • Rspo2 is a secreted activator of Wnt, and its knockout shows extended proliferating chondrocytes in endochondral ossification. • In proliferating chondrocytes of Rspo2-knockout mice, Sox9 and collagen type 2 are increased and β-catenin is decreased. • Rspo2 and its receptor Lgr5, as well as Sox9 and collagen type 2, are expressed in differentiating ATDC5 chondrogenic cells. • In ATDC5 cells, Rspo2 decreases expressions of Sox9, collagen type 2, and aggrecan through Wnt/β-catenin signaling. • We propose that Rspo2 activates Wnt/β-catenin to facilitate chondrocyte differentiation in endochondral ossification.« less

Induction of endoplasmic reticulum stress and changes in expression levels of Zn2+-transporters in hypertrophic rat heart.

PubMed

Olgar, Yusuf; Ozdemir, Semir; Turan, Belma

2018-03-01

Clinical and experimental studies have shown an association between intracellular free Zn 2+ ([Zn 2+ ] i )-dyshomeostasis and cardiac dysfunction besides [Ca 2+ ] i -dyshomeostasis. Since [Zn 2+ ] i -homeostasis is regulated through Zn 2+ -transporters depending on their subcellular distributions, one can hypothesize that any imbalance in Zn 2+ -homeostasis via alteration in Zn 2+ -transporters may be associated with the induction of ER stress and apoptosis in hypertrophic heart. We used a transverse aortic constriction (TAC) model to induce hypertrophy in young male rat heart. We confirmed the development of hypertrophy with a high ratio of heart to body weight and cardiomyocyte capacitance. The expression levels of ER stress markers GRP78, CHOP/Gadd153, and calnexin are significantly high in TAC-group in comparison to those of controls (SHAM-group). Additionally, we detected high expression levels of apoptotic status marker proteins such as the serine kinase GSK-3β, Bax-to-Bcl-2 ratio, and PUMA in TAC-group in comparison to SHAM-group. The ratios of phospho-Akt to Akt and phospho-NFκB to the NFκB are significantly higher in TAC-group than in SHAM-group. Furthermore, we observed markedly increased phospho-PKCα and PKCα levels in TAC-group. We, also for the first time, determined significantly increased ZIP7, ZIP14, and ZnT8 expressions along with decreased ZIP8 and ZnT7 levels in the heart tissue from TAC-group in comparison to SHAM-group. Furthermore, a roughly calculated total expression level of ZIPs responsible for Zn 2+ -influx into the cytosol (increased about twofold) can be also responsible for the markedly increased [Zn 2+ ] i detected in hypertrophic cardiomyocytes. Taking into consideration the role of increased [Zn 2+ ] i via decreased ER-[Zn 2+ ] in the induction of ER stress in cardiomyocytes, our present data suggest that differential changes in the expression levels of Zn 2+ -transporters can underlie mechanical dysfunction, in part due to the induction of ER stress and apoptosis in hypertrophic heart via increased [Zn 2+ ] i - besides [Ca 2+ ] i -dyshomeostasis.

C1QTNF1 attenuates angiotensin II-induced cardiac hypertrophy via activation of the AMPKa pathway.

PubMed

Wu, Leiming; Gao, Lu; Zhang, Dianhong; Yao, Rui; Huang, Zhen; Du, Binbin; Wang, Zheng; Xiao, Lili; Li, Pengcheng; Li, Yapeng; Liang, Cui; Zhang, Yanzhou

2018-06-01

Complement C1q tumor necrosis factor related proteins (C1QTNFs) have been reported to have diverse biological influence on the cardiovascular system. C1QTNF1 is a member of the CTRP superfamily. C1QTNF1 is expressed in the myocardium; however, its function in myocytes has not yet been investigated. To systematically investigate the roles of C1QTNF1 in angiotensin II (Ang II)-induced cardiac hypertrophy. C1QTNF1 knock-out mice were used with the aim of determining the role of C1QTNF1 in cardiac hypertrophy in the adult heart. Data from experiments showed that C1QTNF1 was up-regulated during cardiac hypertrophic processes, which were triggered by increased reactive oxygen species. C1QTNF1 deficiency accelerated cardiac hypertrophy, fibrosis, inflammation responses, and oxidative stress with deteriorating cardiac dysfunction in the Ang II-induced cardiac hypertrophy mouse model. We identified C1QTNF1 as a negative regulator of cardiomyocyte hypertrophy in Ang II-stimulated neonatal rat cardiomyocytes using the recombinant human globular domain of C1QTNF1 and C1QTNF1 siRNA. Injection of the recombinant human globular domain of C1QTNF1 also suppressed the Ang II-induced cardiac hypertrophic response in vivo. The anti-hypertrophic effects of C1QTNF1 rely on AMPKa activation, which inhibits mTOR P70S6K phosphorylation. An AMPKa inhibitor abrogated the anti-hypertrophic effects of the recombinant human globular domain of C1QTNF1 both in vivo and vitro. Moreover, C1QTNF1-mediated AMPKa activation was triggered by the inhibition of PDE1-4, which subsequently activated the cAMP/PKA/LKB1 pathway. Our results demonstrated that C1QTNF1 improves cardiac function and inhibits cardiac hypertrophy and fibrosis by increasing and activating AMPKa, suggesting that C1QTNF1 could be a therapeutic target for cardiac hypertrophy and heart failure. Copyright © 2018 Elsevier Inc. All rights reserved.

Relationship of Tear Size and Location to Fatty Degeneration of the Rotator Cuff

PubMed Central

Kim, H. Mike; Dahiya, Nirvikar; Teefey, Sharlene A.; Keener, Jay D.; Galatz, Leesa M.; Yamaguchi, Ken

2010-01-01

Background: Fatty degeneration of the rotator cuff muscles may have detrimental effects on both anatomical and functional outcomes following shoulder surgery. The purpose of this study was to investigate the relationship between tear geometry and muscle fatty degeneration in shoulders with a deficient rotator cuff. Methods: Ultrasonograms of both shoulders of 262 patients were reviewed to assess the type of rotator cuff tear and fatty degeneration in the supraspinatus and infraspinatus muscles. The 251 shoulders with a full-thickness tear underwent further evaluation for tear size and location. The relationship of tear size and location to fatty degeneration of the supraspinatus and infraspinatus muscles was investigated with use of statistical comparisons and regression models. Results: Fatty degeneration was found almost exclusively in shoulders with a full-thickness rotator cuff tear. Of the 251 shoulders with a full-thickness tear, eighty-seven (34.7%) had fatty degeneration in either the supraspinatus or infraspinatus, or both. Eighty-two (32.7%) of the 251 full-thickness tears had a distance of 0 mm between the biceps tendon and anterior margin of the tear. Ninety percent of the full-thickness tears with fatty degeneration in both muscles had a distance of 0 mm posterior from the biceps, whereas only 9% of those without fatty degeneration had a distance of 0 mm. Tears with fatty degeneration had significantly greater width and length than those without fatty degeneration (p < 0.0001). Tears with fatty degeneration had a significantly shorter distance posterior from the biceps than those without fatty degeneration (p < 0.0001). The distance posterior from the biceps was found to be the most important predictor for supraspinatus fatty degeneration, whereas tear width and length were found to be the most important predictors for infraspinatus fatty degeneration. Conclusions: Fatty degeneration of the rotator cuff muscles is closely associated with tear size and location. The finding of this study suggests that the integrity of the anterior supraspinatus tendon is important to the development of fatty degeneration. Patients with full-thickness tears that extend through this area may benefit from earlier surgical intervention if fatty degeneration has not already occurred. Additionally, the findings suggest the importance of secure fixation and healing of the anterior aspect of the supraspinatus with surgical repair. PMID:20360505

Effect of amiodarone-induced hyperthyroidism on left ventricular outflow obstruction after septal myectomy for hypertrophic cardiomyopathy.

PubMed

Pokorney, Sean D; Stone, Neil J; Passman, Rod; Oyer, David; Rigolin, Vera H; Bonow, Robert O

2010-12-01

Patients with obstructive hypertrophic cardiomyopathy who undergo septal myectomy are at risk for developing postoperative atrial fibrillation. Amiodarone is effective in treating this arrhythmia but is associated with multiple adverse effects, often with delayed onset. A novel case is described of a patient who developed type 2 amiodarone-induced hyperthyroidism that presented as recurrence of outflow obstruction after septal myectomy. The patient's symptoms and echocardiographic findings of outflow obstruction resolved substantially with the treatment of the amiodarone-induced hyperthyroidism. Amiodarone-induced hyperthyroidism of delayed onset can be a subtle diagnosis, requiring a high index of suspicion. In conclusion, recognition of this diagnosis in patients with recurrence of outflow obstruction by symptoms and cardiac imaging after septal myectomy may avoid unnecessary repeat surgical intervention. Copyright © 2010 Elsevier Inc. All rights reserved.

Clinical image and pathology of hypertrophic cranial pachymeningitis.

PubMed

Shi, C H; Niu, S T; Zhang, Z Q

2014-12-12

The objective of this study was to examine the clinical findings, magnetic resonance imaging (MRI), pathological features, and treatment experiments of patients with hypertrophic cranial pachymeningitis (HCP). The clinical findings, MRI, and pathological appearances of 9 patients with HCP were analyzed retrospectively. The thickened dura mater was markedly enhanced after contrast media injection. The lesion near the brain hemisphere presented long regions of T1- and T2-weighted abnormal signal intensities. The abnormal signal intensities of the brain tissue were decreased significantly. Pathological examination demonstrated chronic inflammation changes, with cerebral dura mater fibrous tissue showing obvious hyperplasia, and the periphery of the blood vessel showing a great quantity of infiltrating phlegmonosis cells. HCP mainly presents headache and paralysis of multiple cranial nerves. The distinctive signs on brain MRIs involve strengthening the signal in the cerebral dura.

Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes.

PubMed

Francisco, Ana Rita G; Santos Gonçalves, Inês; Veiga, Fátima; Mendes Pedro, Mónica; Pinto, Fausto J; Brito, Dulce

2017-09-01

The lamin A/C (LMNA) gene encodes lamins A and C, which have an important role in nuclear cohesion and chromatin organization. Mutations in this gene usually lead to the so-called laminopathies, the primary cardiac manifestations of which are dilated cardiomyopathy and intracardiac conduction defects. Some mutations, associated with lipodystrophy but not cardiomyopathy, have been linked to metabolic abnormalities such as diabetes and severe dyslipidemia. Herein we describe a new phenotype associated with a mutation in exon 11 of the LMNA gene: hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. A 64-year-old woman with hypertrophic cardiomyopathy and a point mutation in exon 11 of the LMNA gene (c.1718C>T, Ser573Leu) presented with severe symptomatic ventricular hypertrophy and left ventricular outflow tract obstruction. She underwent septal alcohol ablation, followed by Morrow myectomy. The patient was also diagnosed with severe dyslipidemia, diabetes and obesity, and fulfilled diagnostic criteria for metabolic syndrome. No other characteristics of LMNA mutation-related phenotypes were identified. The development of type III atrioventricular block with no apparent cause, and mildly depressed systolic function, prompted referral for cardiac resynchronization therapy. In conclusion, the association between LMNA mutations and different phenotypes is complex and not fully understood, and can present with a broad spectrum of severity. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

GLUT4 Is Not Necessary for Overload-Induced Glucose Uptake or Hypertrophic Growth in Mouse Skeletal Muscle

PubMed Central

McMillin, Shawna L.; Schmidt, Denise L.; Kahn, Barbara B.

2017-01-01

GLUT4 is necessary for acute insulin- and contraction-induced skeletal muscle glucose uptake, but its role in chronic muscle loading (overload)-induced glucose uptake is unknown. Our goal was to determine whether GLUT4 is required for overload-induced glucose uptake. Overload was induced in mouse plantaris muscle by unilateral synergist ablation. After 5 days, muscle weights and ex vivo [3H]-2-deoxy-d-glucose uptake were assessed. Overload-induced muscle glucose uptake and hypertrophic growth were not impaired in muscle-specific GLUT4 knockout mice, demonstrating that GLUT4 is not necessary for these processes. To assess which transporters mediate overload-induced glucose uptake, chemical inhibitors were used. The facilitative GLUT inhibitor cytochalasin B, but not the sodium-dependent glucose cotransport inhibitor phloridzin, prevented overload-induced uptake demonstrating that GLUTs mediate this effect. To assess which GLUT, hexose competition experiments were performed. Overload-induced [3H]-2-deoxy-d-glucose uptake was not inhibited by d-fructose, demonstrating that the fructose-transporting GLUT2, GLUT5, GLUT8, and GLUT12 do not mediate this effect. To assess additional GLUTs, immunoblots were performed. Overload increased GLUT1, GLUT3, GLUT6, and GLUT10 protein levels twofold to fivefold. Collectively, these results demonstrate that GLUT4 is not necessary for overload-induced muscle glucose uptake or hypertrophic growth and suggest that GLUT1, GLUT3, GLUT6, and/or GLUT10 mediate overload-induced glucose uptake. PMID:28279980

Alcohol septal ablation in obstructive hypertrophic cardiomyopathy: four years of experience at a reference center.

PubMed

Fiarresga, António; Cacela, Duarte; Galrinho, Ana; Ramos, Ruben; de Sousa, Lídia; Bernardes, Luís; Patrício, Lino; Cruz Ferreira, Rui

2014-01-01

We describe our center's initial experience with alcohol septal ablation (ASA) for the treatment of obstructive hypertrophic cardiomyopathy. The procedure, its indications, results and clinical outcomes will be addressed, as will its current position compared to surgical myectomy. To assess the results of ASA in all patients treated in the first four years of activity at our center. We retrospectively studied all consecutive and unselected patients treated by ASA between January 2009 and February 2013. In the first four years of experience 40 patients were treated in our center. In three patients (7.5%) the intervention was repeated. Procedural success was 84%. Minor complications occurred in 7.5%. Two patients received a permanent pacemaker for atrioventricular block (6% of those without previous pacemaker). The major complication rate was 5%. There were no in-hospital deaths; during clinical follow-up (22 ± 14 months) cardiovascular mortality was 2.5% and overall mortality was 5%. The results presented reflect the initial experience of our center with ASA. The success rate was high and in line with published results, but with room to improve with better patient selection. ASA was shown to be safe, with a low complication rate and no procedure-related mortality. Our experience confirms ASA as a percutaneous alternative to myectomy for the treatment of symptomatic patients with obstructive hypertrophic cardiomyopathy refractory to medical treatment. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Efficacy of a polyurethane dressing versus a soft silicone sheet on hypertrophic scars.

PubMed

Wigger-Albert, W; Kuhlmann, M; Wilhelm, D; Mrowietz, U; Eichhorn, K; Ortega, J; Bredehorst, A; Wilhelm, K-P

2009-05-01

To compare the efficacy and safety of a polyurethane dressing with a silicone sheet in the treatment of hypertrophic scars. Sixty patients participated in this intra-individual 12-week clinical trial. Each scar was divided into two areas, to which the polyurethane dressing and the silicone sheet were randomly allocated. The primary outcome measure was the percentage change in the overall scar index (SI) between baseline and week 12. Secondary outcome measures included changes in skin redness, objectively measured by chromametry, and patients views on the aesthetic outcome of treatment. Both therapies achieved favourable results for all of the above outcome measures. Results were comparable for the primary outcome measure: 29.4% versus 33.7% for the silicone sheet and polyurethane product respectively. The decrease in the overall SI was significantly more pronounced for the polyurethane product after week 4 (5.6% versus 15.8% for the silicone sheet; p<0.0001) and week 8 (20.2% versus 27.1%; p=0.012). Both regimens were associated with a significant reduction in the clinical signs of hypertrophic scars over 12 weeks of treatment. The polyurethane dressing demonstrated a significantly more pronounced reduction in severity of these clinical signs after four and eight weeks of treatment and was better tolerated than the silicone sheet. l This study was funded by Beiersdorf AG. proDERM is an independent research company, and none of the authors have an interest in the sponsors commercial activities.

Elastin Is Differentially Regulated by Pressure Therapy in a Porcine Model of Hypertrophic Scar.

PubMed

Carney, Bonnie C; Liu, Zekun; Alkhalil, Abdulnaser; Travis, Taryn E; Ramella-Roman, Jessica; Moffatt, Lauren T; Shupp, Jeffrey W

Beneficial effects of pressure therapy for hypertrophic scars have been reported, but the mechanisms of action are not fully understood. This study evaluated elastin and its contribution to scar pliability. The relationship between changes in Vancouver Scar Scale (VSS) scores of pressure-treated scars and differential regulation of elastin was assessed. Hypertrophic scars were created and assessed weekly using VSS and biopsy procurement. Pressure treatment began on day 70 postinjury. Treated scars were compared with untreated shams. Treatment lasted 2 weeks, through day 84, and scars were assessed weekly through day 126. Transcript and protein levels of elastin were quantified. Pressure treatment resulted in lower VSS scores compared with sham-treated scars. Pliability (VSSP) was a key contributor to this difference. At day 70 pretreatment, VSSP = 2. Without treatment, sham-treated scars became less pliable, while pressure-treated scars became more pliable. The percentage of elastin in scars at day 70 was higher than in uninjured skin. Following treatment, the percentage of elastin increased and continued to increase through day 126. Untreated sham scars did not show a similar increase. Quantification of Verhoeff-Van Gieson staining corroborated the findings and immunofluorescence revealed the alignment of elastin fibers. Pressure treatment results in increased protein level expression of elastin compared with sham-untreated scars. These findings further characterize the extracellular matrix's response to the application of pressure as a scar treatment, which will contribute to the refinement of rehabilitation practices and ultimately improvements in functional and psychosocial outcomes for patients.

Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity.

PubMed

Vinciguerra, Manlio; Santini, Maria Paola; Claycomb, William C; Ladurner, Andreas G; Rosenthal, Nadia

2009-12-10

Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulin-like growth factor-1 (IGF-1) is a peptide hormone with a complex post-transcriptional regulation, generating distinct isoforms. Locally acting IGF-1 isoform (mIGF-1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderate overexpression of the NAD(+)-dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known to promote lifespan extension and to protect from metabolic challenges. Circulating IGF-1 and SirT1 play antagonizing biological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, how different IGF-1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally acting mIGF-1 increases SirT1 expression/activity, whereas circulating IGF-1 isoform does not affect it, in cultured HL-1 and neonatal cardiomyocytes. mIGF-1-induced SirT1 activity exerts protection against angiotensin II (Ang II)-triggered hypertrophy and against paraquat (PQ) and Ang II-induced oxidative stress. Conversely, circulating IGF-1 triggered itself oxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardio-protective genes (adiponectin, UCP-1 and MT-2) were increased specifically in mIGF-1-overexpressing cardiomyocytes, in a SirT1-dependent fashion. Thus, mIGF-1 protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiac therapeutic.

Hypertrophic Cardiomyopathy from A to Z: Genetics, Pathophysiology, Imaging, and Management.

PubMed

Baxi, Ameya Jagdish; Restrepo, Carlos S; Vargas, Daniel; Marmol-Velez, Alejandro; Ocazionez, Daniel; Murillo, Horacio

2016-01-01

Hypertrophic cardiomyopathy (HCM) is a heterogeneous group of diseases related to sarcomere gene mutations exhibiting heterogeneous phenotypes with an autosomal dominant mendelian pattern of inheritance. The disorder is characterized by diverse phenotypic expressions and variable natural progression, which may range from dyspnea and/or syncope to sudden cardiac death. It is found across all racial groups and is associated with left ventricular hypertrophy in the absence of another systemic or cardiac disease. The management of HCM is based on a thorough understanding of the underlying morphology, pathophysiology, and clinical course. Imaging findings of HCM mirror the variable expressivity and penetrance heterogeneity, with the added advantage of diagnosis even in cases where a specific mutation may not yet be found. The diagnostic information obtained from imaging varies depending on the specific stage of HCM-phenotype manifestation, including the prehypertrophic, hypertrophic, and later stages of adverse remodeling into the burned-out phase of overt heart failure. However, subtle or obvious, these imaging findings become critical components in diagnosis, management, and follow-up of HCM patients. Although diagnosis of HCM traditionally relies on clinical assessment and transthoracic echocardiography, recent studies have demonstrated increased utility of multidetector computed tomography (CT) and particularly cardiac magnetic resonance (MR) imaging in diagnosis, phenotype differentiation, therapeutic planning, and prognostication. In this article, we provide an overview of the genetics, pathophysiology, and clinical manifestations of HCM, with the spectrum of imaging findings at MR imaging and CT and their contribution in diagnosis, risk stratification, and therapy. (©)RSNA, 2016.

Hypertrophic Osteoarthropathy: Clinical and Imaging Features.

PubMed

Yap, Felix Y; Skalski, Matthew R; Patel, Dakshesh B; Schein, Aaron J; White, Eric A; Tomasian, Anderanik; Masih, Sulabha; Matcuk, George R

2017-01-01

Hypertrophic osteoarthropathy (HOA) is a medical condition characterized by abnormal proliferation of skin and periosteal tissues involving the extremities and characterized by three clinical features: digital clubbing (also termed Hippocratic fingers), periostosis of tubular bones, and synovial effusions. HOA can be a primary entity, known as pachydermoperiostosis, or can be secondary to extraskeletal conditions, with different prognoses and management implications for each. There is a high association between secondary HOA and malignancy, especially non-small cell lung cancer. In such cases, it can be considered a form of paraneoplastic syndrome. The most prevalent secondary causes of HOA are pulmonary in origin, which is why this condition was formerly referred to as hypertrophic pulmonary osteoarthropathy. HOA can also be associated with pleural, mediastinal, and cardiovascular causes, as well as extrathoracic conditions such as gastrointestinal tumors and infections, cirrhosis, and inflammatory bowel disease. Although the skeletal manifestations of HOA are most commonly detected with radiography, abnormalities can also be identified with other modalities such as computed tomography, magnetic resonance imaging, and bone scintigraphy. The authors summarize the pathogenesis, classification, causes, and symptoms and signs of HOA, including the genetics underlying the primary form (pachydermoperiostosis); describe key findings of HOA found at various imaging modalities, with examples of underlying causative conditions; and discuss features differentiating HOA from other causes of multifocal periostitis, such as thyroid acropachy, hypervitaminosis A, chronic venous insufficiency, voriconazole-induced periostitis, progressive diaphyseal dysplasia, and neoplastic causes such as lymphoma. © RSNA, 2016.

Establishing a Reproducible Hypertrophic Scar following Thermal Injury: A Porcine Model

PubMed Central

Rapp, Scott J.; Rumberg, Aaron; Visscher, Marty; Billmire, David A.; Schwentker, Ann S.

2015-01-01

Background: Our complete understanding of hypertrophic scarring is still deficient, as portrayed by the poor clinical outcomes when treating them. To address the need for alternative treatment strategies, we assess the swine animal burn model as an initial approach for immature scar evaluation and therapeutic application. Methods: Thermal contact burns were created on the dorsum of 3 domestic swine with the use of a branding iron at 170°F for 20 seconds. Deep partial-thickness burns were cared for with absorptive dressings over 10 weeks and wounds evaluated with laser and negative pressure transduction, histology, photographic analysis, and RNA isolation. Results: Overall average stiffness (mm Hg/mm) increased and elasticity (mm) decreased in the scars from the initial burn injury to 8 weeks when compared with normal skin (P < 0.01). Scars were thicker, more erythematous, and uniform in the caudal dorsum. The percent change of erythema in wounds increased from weeks 6 to 10. Histology demonstrated loss of dermal papillae, increased myofibroblast presence, vertically oriented vessels, epidermal and dermal hypercellularity, and parallel-layered collagen deposition. Immature scars remained elevated at 10 weeks, and minimal RNA was able to be isolated from the tissue. Conclusions: Deep partial-thickness thermal injury to the back of domestic swine produces an immature hypertrophic scar by 10 weeks following burn with thickness appearing to coincide with the location along the dorsal axis. With minimal pig to pig variation, we describe our technique to provide a testable immature scar model. PMID:25750848

Profiling analysis of long non-coding RNAs in early postnatal mouse hearts

PubMed Central

Sun, Xiongshan; Han, Qi; Luo, Hongqin; Pan, Xiaodong; Ji, Yan; Yang, Yao; Chen, Hanying; Wang, Fangjie; Lai, Wenjing; Guan, Xiao; Zhang, Qi; Tang, Yuan; Chu, Jianhong; Yu, Jianhua; Shou, Weinian; Deng, Youcai; Li, Xiaohui

2017-01-01

Mammalian cardiomyocytes undergo a critical hyperplastic-to-hypertrophic growth transition at early postnatal age, which is important in establishing normal physiological function of postnatal hearts. In the current study, we intended to explore the role of long non-coding (lnc) RNAs in this transitional stage. We analyzed lncRNA expression profiles in mouse hearts at postnatal day (P) 1, P7 and P28 via microarray. We identified 1,146 differentially expressed lncRNAs with more than 2.0-fold change when compared the expression profiles of P1 to P7, P1 to P28, and P7 to P28. The neighboring genes of these differentially expressed lncRNAs were mainly involved in DNA replication-associated biological processes. We were particularly interested in one novel cardiac-enriched lncRNA, ENSMUST00000117266, whose expression was dramatically down-regulated from P1 to P28 and was also sensitive to hypoxia, paraquat, and myocardial infarction. Knockdown ENSMUST00000117266 led to a significant increase of neonatal mouse cardiomyocytes in G0/G1 phase and reduction in G2/M phase, suggesting that ENSMUST00000117266 is involved in regulating cardiomyocyte proliferative activity and is likely associated with hyperplastic-to-hypertrophic growth transition. In conclusion, our data have identified a large group of lncRNAs presented in the early postnatal mouse heart. Some of these lncRNAs may have important functions in cardiac hyperplastic-to-hypertrophic growth transition. PMID:28266538

The effect of shock wave therapy on gene expression in human osteoblasts isolated from hypertrophic fracture non-unions

NASA Astrophysics Data System (ADS)

Hofmann, A.; Ritz, U.; Rompe, J.-D.; Tresch, A.; Rommens, P. M.

2015-01-01

Shock wave therapy has been increasingly evaluated as a non-invasive alternative for the treatment of delayed fracture healing and non-unions. Although several clinical studies showed a beneficial effect especially for the hypertrophic type of non-union, little is known about the biological mechanism of its osteogenic effect. To identify the molecular background for the positive effect of shock waves on healing of fracture non-unions, we have analyzed the changes of the global gene expression in human osteoblasts after exposure to shock waves of different energy flux densities. Human osteoblasts were isolated from five patients at non-union sites, treated with 500 impulses of energy flux densities of 0.06 and , and cultured for 96 h. HG-U133A microarrays were used for the analysis of the shock wave-regulated mRNA-transcripts. Differential gene expression was verified by reverse transcriptase polymerase chain reactions. We identified 47 transcripts that showed differential expression after and 45 transcripts after energy treatment. Most intriguing was the up-regulation of neprilysin, calmegin, osteoglycin, asporin, and interleukin-13 receptor-. Eighteen identified genes were previously described to fulfill an important function in bone growth and metabolism. Our study provides the first molecular profile of shock wave-induced gene expression changes in human osteoblasts from patients with hypertrophic fracture non-unions, and it offers a possible molecular explanation for the positive effects of shock waves in patients ridden with this disease.

An Immunohistochemical Study of Matrix Proteins in the Craniofacial Cartilage in Midterm Human Fetuses

PubMed Central

Shibata, S.; Sakamoto, Y.; Baba, O.; Qin, C.; Murakami, G.; Cho, B.H.

2013-01-01

Immunohistochemical localization of collagen types I, II, and X, aggrecan, versican, dentin matrix protein (DMP)-1, martix extracellular phosphoprotein (MEPE) were performed for Meckel’s cartilage, cranial base cartilage, and mandibular condylar cartilage in human midterm fetuses; staining patterns within the condylar cartilage were compared to those within other cartilaginous structures. Mandibular condylar cartilage contained aggrecan; it also had more type I collagen and a thicker hypertrophic cell layer than the other two types of cartilage; these three characteristics are similar to those of the secondary cartilage of rodents. MEPE immunoreactivity was first evident in the cartilage matrix of all types of cartilage in the human fetuses and in Meckel’s cartilage of mice and rats. MEPE immunoreactivity was enhanced in the deep layer of the hypertrophic cell layer and in the cartilaginous core of the bone trabeculae in the primary spongiosa. These results indicated that MEPE is a component of cartilage matrix and may be involved in cartilage mineralization. DMP-1 immunoreactivity first became evident in human bone lacunae walls and canaliculi; this pattern of expression was comparable to the pattern seen in rodents. In addition, chondroid bone was evident in the mandibular (glenoid) fossa of the temporal bone, and it had aggrecan, collagen types I and X, MEPE, and DMP-1 immunoreactivity; these findings indicated that chondroid bone in this region has phenotypic expression indicative of both hypertrophic chondrocytes and osteocytes. PMID:24441192

Blunted angiogenesis and hypertrophy are associated with increased fatigue resistance and unchanged aerobic capacity in old overloaded mouse muscle.

PubMed

Ballak, Sam B; Busé-Pot, Tinelies; Harding, Peter J; Yap, Moi H; Deldicque, Louise; de Haan, Arnold; Jaspers, Richard T; Degens, Hans

2016-04-01

We hypothesize that the attenuated hypertrophic response in old mouse muscle is (1) partly due to a reduced capillarization and angiogenesis, which is (2) accompanied by a reduced oxidative capacity and fatigue resistance in old control and overloaded muscles, that (3) can be rescued by the antioxidant resveratrol. To investigate this, the hypertrophic response, capillarization, oxidative capacity, and fatigue resistance of m. plantaris were compared in 9- and 25-month-old non-treated and 25-month-old resveratrol-treated mice. Overload increased the local capillary-to-fiber ratio less in old (15 %) than in adult (59 %) muscle (P < 0.05). Although muscles of old mice had a higher succinate dehydrogenase (SDH) activity (P < 0.05) and a slower fiber type profile (P < 0.05), the isometric fatigue resistance was similar in 9- and 25-month-old mice. In both age groups, the fatigue resistance was increased to the same extent after overload (P < 0.01), without a significant change in SDH activity, but an increased capillary density (P < 0.05). Attenuated angiogenesis during overload may contribute to the attenuated hypertrophic response in old age. Neither was rescued by resveratrol supplementation. Changes in fatigue resistance with overload and aging were dissociated from changes in SDH activity, but paralleled those in capillarization. This suggests that capillarization plays a more important role in fatigue resistance than oxidative capacity.

Role of IGF-I in follistatin-induced skeletal muscle hypertrophy

PubMed Central

Kalista, Stéphanie; Loumaye, Audrey; Ritvos, Olli; Lause, Pascale; Ferracin, Benjamin; Thissen, Jean-Paul

2015-01-01

Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth. PMID:26219865

Role of IGF-I in follistatin-induced skeletal muscle hypertrophy.

PubMed

Barbé, Caroline; Kalista, Stéphanie; Loumaye, Audrey; Ritvos, Olli; Lause, Pascale; Ferracin, Benjamin; Thissen, Jean-Paul

2015-09-15

Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth. Copyright © 2015 the American Physiological Society.

Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity

PubMed Central

Vinciguerra, Manlio; Santini, Maria Paola; Claycomb, William C.; Ladurner, Andreas G.; Rosenthal, Nadia

2010-01-01

Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulin-like growth factor-1 (IGF-1) is a peptide hormone with a complex post-transcriptional regulation, generating distinct isoforms. Locally acting IGF-1 isoform (mIGF-1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderate overexpression of the NAD+-dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known to promote lifespan extension and to protect from metabolic challenges. Circulating IGF-1 and SirT1 play antagonizing biological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, how different IGF-1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally acting mIGF-1 increases SirT1 expression/activity, whereas circulating IGF-1 isoform does not affect it, in cultured HL-1 and neonatal cardiomyocytes. mIGF-1-induced SirT1 activity exerts protection against angiotensin II (Ang II)-triggered hypertrophy and against paraquat (PQ) and Ang II-induced oxidative stress. Conversely, circulating IGF-1 triggered itself oxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardio-protective genes (adiponectin, UCP-1 and MT-2) were increased specifically in mIGF-1-overexpressing cardiomyocytes, in a SirT1-dependent fashion. Thus, mIGF-1 protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiac therapeutic. PMID:20228935

Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy.

PubMed

Mahmoudabady, Maryam; Mathieu, Myrielle; Touihri, Karim; Hadad, Ielham; Da Costa, Agnes Mendes; Naeije, Robert; Mc Entee, Kathleen

2009-10-09

Insulin-like growth factor-1 (IGF-1), transforming growth factor beta (TGFbeta) and cyclins are thought to play a role in myocardial hypertrophic response to insults. We investigated these signaling pathways in canine models of ischemic or overpacing-induced cardiomyopathy. Echocardiographic recordings and myocardial sampling for measurements of gene expressions of IGF-1, its receptor (IGF-1R), TGFbeta and of cyclins A, B, D1, D2, D3 and E, were obtained in 8 dogs with a healed myocardial infarction, 8 dogs after 7 weeks of overpacing and in 7 healthy control dogs. Ischemic cardiomyopathy was characterized by moderate left ventricular systolic dysfunction and eccentric hypertrophy, with increased expressions of IGF-1, IGF-1R and cyclins B, D1, D3 and E. Tachycardiomyopathy was characterized by severe left ventricular systolic dysfunction and dilation with no identifiable hypertrophic response. In the latter model, only IGF-1 was overexpressed while IGF-1R, cyclins B, D1, D3 and E stayed unchanged as compared to controls. The expressions of TGFbeta, cyclins A and D2 were comparable in the 3 groups. The expression of IGF-1R was correlated with the thickness of the interventricular septum, in systole and diastole, and to cyclins B, D1, D3 and E expression. These results agree with the notion that IGF-1/IGF-1R and cyclins are involved in the hypertrophic response observed in cardiomyopathies.

Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy

PubMed Central

Mahmoudabady, Maryam; Mathieu, Myrielle; Touihri, Karim; Hadad, Ielham; Da Costa, Agnes Mendes; Naeije, Robert; Mc Entee, Kathleen

2009-01-01

Background Insulin-like growth factor-1 (IGF-1), transforming growth factor β (TGFβ) and cyclins are thought to play a role in myocardial hypertrophic response to insults. We investigated these signaling pathways in canine models of ischemic or overpacing-induced cardiomyopathy. Methods Echocardiographic recordings and myocardial sampling for measurements of gene expressions of IGF-1, its receptor (IGF-1R), TGFβ and of cyclins A, B, D1, D2, D3 and E, were obtained in 8 dogs with a healed myocardial infarction, 8 dogs after 7 weeks of overpacing and in 7 healthy control dogs. Results Ischemic cardiomyopathy was characterized by moderate left ventricular systolic dysfunction and eccentric hypertrophy, with increased expressions of IGF-1, IGF-1R and cyclins B, D1, D3 and E. Tachycardiomyopathy was characterized by severe left ventricular systolic dysfunction and dilation with no identifiable hypertrophic response. In the latter model, only IGF-1 was overexpressed while IGF-1R, cyclins B, D1, D3 and E stayed unchanged as compared to controls. The expressions of TGFβ, cyclins A and D2 were comparable in the 3 groups. The expression of IGF-1R was correlated with the thickness of the interventricular septum, in systole and diastole, and to cyclins B, D1, D3 and E expression. Conclusion These results agree with the notion that IGF-1/IGF-1R and cyclins are involved in the hypertrophic response observed in cardiomyopathies. PMID:19818143

DYRK1A is a novel negative regulator of cardiomyocyte hypertrophy.

PubMed

Kuhn, Christian; Frank, Derk; Will, Rainer; Jaschinski, Christoph; Frauen, Robert; Katus, Hugo A; Frey, Norbert

2009-06-19

Activation of the phosphatase calcineurin and its downstream targets, transcription factors of the NFAT family, results in cardiomyocyte hypertrophy. Recently, it has been shown that the dual specificity tyrosine (Y) phosphorylation-regulated kinase 1A (DYRK1A) is able to antagonize calcineurin signaling by directly phosphorylating NFATs. We thus hypothesized that DYRK1A might modulate the hypertrophic response of cardiomyocytes. In a model of phenylephrine-induced hypertrophy, adenovirus-mediated overexpression of DYKR1A completely abrogated the hypertrophic response and significantly reduced the expression of the natriuretic peptides ANF and BNP. Furthermore, DYRK1A blunted cardiomyocyte hypertrophy induced by overexpression of constitutively active calcineurin and attenuated the induction of the hypertrophic gene program. Conversely, knockdown of DYRK1A, utilizing adenoviruses encoding for a specific synthetic miRNA, resulted in an increase in cell surface area accompanied by up-regulation of ANF- mRNA. Similarly, treatment of cardiomyocytes with harmine, a specific inhibitor of DYRK1A, revealed cardiomyocyte hypertrophy on morphological and molecular level. Moreover, constitutively active calcineurin led to robust induction of an NFAT-dependent luciferase reporter, whereas DYRK1A attenuated calcineurin-induced reporter activation in cardiomyocytes. Conversely, both knockdown and pharmacological inhibition of DYRK1A significantly augmented the effect of calcineurin in this assay. In summary, we identified DYRK1A as a novel negative regulator of cardiomyocyte hypertrophy. Mechanistically, this effect appears to be mediated via inhibition of NFAT transcription factors.

DYRK1A Is a Novel Negative Regulator of Cardiomyocyte Hypertrophy*

PubMed Central

Kuhn, Christian; Frank, Derk; Will, Rainer; Jaschinski, Christoph; Frauen, Robert; Katus, Hugo A.; Frey, Norbert

2009-01-01

Activation of the phosphatase calcineurin and its downstream targets, transcription factors of the NFAT family, results in cardiomyocyte hypertrophy. Recently, it has been shown that the dual specificity tyrosine (Y) phosphorylation-regulated kinase 1A (DYRK1A) is able to antagonize calcineurin signaling by directly phosphorylating NFATs. We thus hypothesized that DYRK1A might modulate the hypertrophic response of cardiomyocytes. In a model of phenylephrine-induced hypertrophy, adenovirus-mediated overexpression of DYKR1A completely abrogated the hypertrophic response and significantly reduced the expression of the natriuretic peptides ANF and BNP. Furthermore, DYRK1A blunted cardiomyocyte hypertrophy induced by overexpression of constitutively active calcineurin and attenuated the induction of the hypertrophic gene program. Conversely, knockdown of DYRK1A, utilizing adenoviruses encoding for a specific synthetic miRNA, resulted in an increase in cell surface area accompanied by up-regulation of ANF- mRNA. Similarly, treatment of cardiomyocytes with harmine, a specific inhibitor of DYRK1A, revealed cardiomyocyte hypertrophy on morphological and molecular level. Moreover, constitutively active calcineurin led to robust induction of an NFAT-dependent luciferase reporter, whereas DYRK1A attenuated calcineurin-induced reporter activation in cardiomyocytes. Conversely, both knockdown and pharmacological inhibition of DYRK1A significantly augmented the effect of calcineurin in this assay. In summary, we identified DYRK1A as a novel negative regulator of cardiomyocyte hypertrophy. Mechanistically, this effect appears to be mediated via inhibition of NFAT transcription factors. PMID:19372220

GLUT4 Is Not Necessary for Overload-Induced Glucose Uptake or Hypertrophic Growth in Mouse Skeletal Muscle.

PubMed

McMillin, Shawna L; Schmidt, Denise L; Kahn, Barbara B; Witczak, Carol A

2017-06-01

GLUT4 is necessary for acute insulin- and contraction-induced skeletal muscle glucose uptake, but its role in chronic muscle loading (overload)-induced glucose uptake is unknown. Our goal was to determine whether GLUT4 is required for overload-induced glucose uptake. Overload was induced in mouse plantaris muscle by unilateral synergist ablation. After 5 days, muscle weights and ex vivo [ 3 H]-2-deoxy-d-glucose uptake were assessed. Overload-induced muscle glucose uptake and hypertrophic growth were not impaired in muscle-specific GLUT4 knockout mice, demonstrating that GLUT4 is not necessary for these processes. To assess which transporters mediate overload-induced glucose uptake, chemical inhibitors were used. The facilitative GLUT inhibitor cytochalasin B, but not the sodium-dependent glucose cotransport inhibitor phloridzin, prevented overload-induced uptake demonstrating that GLUTs mediate this effect. To assess which GLUT, hexose competition experiments were performed. Overload-induced [ 3 H]-2-deoxy-d-glucose uptake was not inhibited by d-fructose, demonstrating that the fructose-transporting GLUT2, GLUT5, GLUT8, and GLUT12 do not mediate this effect. To assess additional GLUTs, immunoblots were performed. Overload increased GLUT1, GLUT3, GLUT6, and GLUT10 protein levels twofold to fivefold. Collectively, these results demonstrate that GLUT4 is not necessary for overload-induced muscle glucose uptake or hypertrophic growth and suggest that GLUT1, GLUT3, GLUT6, and/or GLUT10 mediate overload-induced glucose uptake. © 2017 by the American Diabetes Association.

β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

PubMed

Blankenburg, Robert; Hackert, Katarzyna; Wurster, Sebastian; Deenen, René; Seidman, J G; Seidman, Christine E; Lohse, Martin J; Schmitt, Joachim P

2014-07-07

Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in β-cardiac myosin heavy chain (β-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family. To characterize disease caused by β-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice. Unlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC/+) or Arg719Trp (RW/+), VM/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM/VM mice were indistinguishable from wild-type animals, whereas RC/RC- and RW/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM/RC hearts was severely impaired already before the onset of cardiac remodeling. The VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations. © 2014 American Heart Association, Inc.

Minimally invasive plate augmentation in the treatment of long-bone non-unions.

PubMed

Park, Ki-Chul; Oh, Chang-Wug; Kim, Joon-Woo; Park, Kyeong-Hyeon; Oh, Jong-Keon; Park, Il-Hyung; Kyung, Hee-Soo; Heo, Jeong

2017-11-01

Exchange nailing is most acceptable for treating hypertrophic non-union of the long bones, requiring the removal of previously fixed implant. However, its main effect of mechanical stabilization is controversial in non-isthmal area. We hypothesized that minimally invasive plate augmentation over the non-union site may have a better option, without the need of bone grafting or removing pre-existing implants. Seventeen patients with hypertrophic non-union of the long bones between 2010 and 2014 on radiography who previously underwent intramedullary (IM) nailing or plate osteosynthesis for long-bone fractures were included. A locking compression plate was inserted with at least three mono- or bicortical screws at each proximal and distal segment. Broken or loosened interlocking screws of IM nail were simultaneously re-fixed. Fracture site exposure, pre-fixed implant removal, and bone grafting were not performed. We investigated whether union occurred and analyzed functional outcomes and complications. Eleven femoral and six tibial non-unions were prospectively included. In the pre-existing implants, 13 nails and 4 plates were found. All cases achieved union at a mean 22.7 weeks. One case of superficial infection was managed with oral antibiotics. Deep infection or implant failure did not occur. Minimally invasive plate augmentation can achieve additional stability and promote healing of hypertrophic non-union of the long bones. When indicated, this technique is the least invasive alternative to exchange nailing and reduces surgical risks in the treatment of diaphyseal non-union.

Degenerate Cauchy numbers of the third kind.

PubMed

Pyo, Sung-Soo; Kim, Taekyun; Rim, Seog-Hoon

2018-01-01

Since Cauchy numbers were introduced, various types of Cauchy numbers have been presented. In this paper, we define degenerate Cauchy numbers of the third kind and give some identities for the degenerate Cauchy numbers of the third kind. In addition, we give some relations between four kinds of the degenerate Cauchy numbers, the Daehee numbers and the degenerate Bernoulli numbers.

Macular degeneration (image)

MedlinePlus

Macular degeneration is a disease of the retina that affects the macula in the back of the eye. ... see fine details. There are two types of macular degeneration, dry and wet. Dry macular degeneration is more ...

[Lipomatosis of nerve: a clinicopathologic analysis of 15 cases].

PubMed

MAO, Rong-jun; YANG, Ke-fei; WANG, Jian

2011-03-01

To study the clinicopathologic features of lipomatosis of nerve (NLS). The clinical, radiologic and pathologic features were analyzed in 15 cases of NLS. There were a total of 10 males and 5 females. The age of patients ranged from 4 to 42 years (mean age = 22.4 years). Eleven cases were located in the upper limbs and 4 cases in the lower limbs. The median nerve was the most common involved nerve. The patients typically presented before 30 years of age (often at birth or in early childhood) with a soft and slowly enlarging mass in the limb, with or without accompanying motor and sensory deficits. Some cases also had macrodactyly and carpal tunnel syndrome. MRI showed the presence of fatty tissue between nerve fascicles, resembling coaxial cable in axial plane and assuming a spaghetti-like appearance in coronal plane. On gross examination, the affected nerve was markedly increased in length and diameter. It consisted of a diffusely enlarged greyish-yellow lobulated fusiform beaded mass within the epineural sheath. Histologically, the epineurium was infiltrated by fibrofatty tissue which separated, surrounded and compressed the usually normal-appearing nerve fascicles, resulting in perineural septation of nerve fascicles and microfascicle formation. The infiltration sometimes resulted in concentric arrangement of perineural cells and pseudo-onion bulb-like hypertrophic changes. The perineurial cells might proliferate, with thickening of collagen fibers, degeneration and atrophic changes of nerve bundles. Immunohistochemical study showed that the nerve fibers expressed S-100 protein, neurofilament and CD56 (weak). The endothelial cells and dendritic fibers were highlighted by CD34. The intravascular smooth muscle cells were positive for muscle-specific actin. NLS is a rare benign soft tissue tumor of peripheral nerve. The MRI findings are characteristic. A definitive diagnosis can be made with histologic examination of tissue biopsy.

The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway

PubMed Central

Calpena, Eduardo; López del Amo, Víctor; Chakraborty, Mouli

2018-01-01

ABSTRACT Members of the Junctophilin (JPH) protein family have emerged as key actors in all excitable cells, with crucial implications for human pathophysiology. In mammals, this family consists of four members (JPH1-JPH4) that are differentially expressed throughout excitable cells. The analysis of knockout mice lacking JPH subtypes has demonstrated their essential contribution to physiological functions in skeletal and cardiac muscles and in neurons. Moreover, mutations in the human JPH2 gene are associated with hypertrophic and dilated cardiomyopathies; mutations in JPH3 are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereas JPH1 acts as a genetic modifier in Charcot–Marie–Tooth 2K peripheral neuropathy. Drosophila melanogaster has a single junctophilin (jp) gene, as is the case in all invertebrates, which might retain equivalent functions of the four homologous JPH genes present in mammalian genomes. Therefore, owing to the lack of putatively redundant genes, a jp Drosophila model could provide an excellent platform to model the Junctophilin-related diseases, to discover the ancestral functions of the JPH proteins and to reveal new pathways. By up- and downregulation of Jp in a tissue-specific manner in Drosophila, we show that altering its levels of expression produces a phenotypic spectrum characterized by muscular deficits, dilated cardiomyopathy and neuronal alterations. Importantly, our study has demonstrated that Jp modifies the neuronal degeneration in a Drosophila model of Huntington's disease, and it has allowed us to uncover an unsuspected functional relationship with the Notch pathway. Therefore, this Drosophila model has revealed new aspects of Junctophilin function that can be relevant for the disease mechanisms of their human counterparts. PMID:29208631

Gene expression of fibrinolytic factors urokinase plasminogen activator and plasminogen activator inhibitor-1 in rabbit temporo-mandibular joint cartilage with disc displacement.

PubMed

Zhan, Jing; Gu, Zhi-yuan; Wu, Li-qun; Zhang, Yin-kai; Hu, Ji-an

2005-06-20

The urokinase plasminogen activator system is believed to play an important role in degradation of the extracellular matrix associated with cartilage and bone destruction; however its precise roles in temporomandibular disorders have not yet been clarified. The aims of this study were to investigate the gene expression of fibrinolytic factors urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in the articular cartilage of rabbit temporomandibular joint (TMJ) with disc displacement (DD) and to probe the relationship between fibrinolytic activity and cartilage remodeling. Disc displacement of right joints was performed in 36 of 78 rabbits under investigation. The animals were sacrificed at 4 days and 1, 2, 4, 8 and 12 weeks after surgery, respectively. The right joints of these animals were harvested and processed for the examination of mRNA expression of uPA and PAI-1 in articular cartilage using in situ hybridization techniques. The expression of uPA and PAI-1 was co-expressed weakly in the chondrocytes from transitive zone to hypertrophic zone and mineralized zone, while no hybridizing signals were shown in proliferative zone and superficial zone in control rabbits. The most striking was the up-regulation of uPA and PAI-1 mRNA in 4-day rabbits postoperatively at the onset of cartilage degeneration. The strongest hybridizing signals for uPA and PAI-1 were seen in 2-week rabbits postoperatively. After 2 weeks, the expression of uPA and PAI-1 began to decrease and reached nearly normal level at 12 weeks. The expression of the uPA/PAI-1 system coincides with the pathological changes in condylar cartilage after DD. The uPA/PAI-1 system may be one of the essential mediators in articular cartilage remodeling.

Fibrotic-like changes in degenerate human intervertebral discs revealed by quantitative proteomic analysis.

PubMed

Yee, A; Lam, M P Y; Tam, V; Chan, W C W; Chu, I K; Cheah, K S E; Cheung, K M C; Chan, D

2016-03-01

Intervertebral disc degeneration (IDD) can lead to symptomatic conditions including sciatica and back pain. The purpose of this study is to understand the extracellular matrix (ECM) changes in disc biology through comparative proteomic analysis of degenerated and non-degenerated human intervertebral disc (IVD) tissues of different ages. Seven non-degenerated (11-46 years of age) and seven degenerated (16-53 years of age) annulus fibrosus (AF) and nucleus pulposus (NP) samples were used. Proteins were extracted using guanidine hydrochloride, separated from large proteoglycans (PGs) by caesium chloride (CsCl) density gradient ultracentrifugation, and identified using liquid chromatography (LC) coupled with tandem mass spectrometry (MS/MS). For quantitative comparison, proteins were labeled with iTRAQ reagents. Collagen fibrils in the NP were assessed using scanning electron microscopy (SEM). In the AF, quantitative analysis revealed increased levels of HTRA1, COMP and CILP in degeneration when compared with samples from older individuals. Fibronectin showed increment with age and degeneration. In the NP, more CILP and CILP2 were present in degenerated samples of younger individuals. Reduced protein solubility was observed in degenerated and older non-degenerated samples correlated with an accumulation of type I collagen in the insoluble fibers. Characterization of collagen fibrils in the NP revealed smaller mean fibril diameters and decreased porosity in the degenerated samples. Our study identified distinct matrix changes associated with aging and degeneration in the intervertebral discs (IVDs). The nature of the ECM changes, together with observed decreased in solubility and changes in fibril diameter is consistent with a fibrotic-like environment. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc

PubMed Central

Richardson, Stephen M; Doyle, Paul; Minogue, Ben M; Gnanalingham, Kanna; Hoyland, Judith A

2009-01-01

Introduction Matrix metalloproteinases (MMPs) are known to be involved in the degradation of the nucleus pulposus (NP) during intervertebral disc (IVD) degeneration. This study investigated MMP-10 (stromelysin-2) expression in the NP during IVD degeneration and correlated its expression with pro-inflammatory cytokines and molecules involved in innervation and nociception during degeneration which results in low back pain (LBP). Methods Human NP tissue was obtained at postmortem (PM) from patients without a history of back pain and graded as histologically normal or degenerate. Symptomatic degenerate NP samples were also obtained at surgery for LBP. Expression of MMP-10 mRNA and protein was analysed using real-time polymerase chain reaction and immunohistochemistry. Gene expression for pro-inflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-α), nerve growth factor (NGF) and the pain-associated neuropeptide substance P were also analysed. Correlations between MMP-10 and IL-1, TNF-α and NGF were assessed along with NGF with substance P. Results MMP-10 mRNA was significantly increased in surgical degenerate NP when compared to PM normal and PM degenerate samples. MMP-10 protein was also significantly higher in degenerate surgical NP samples compared to PM normal. IL-1 and MMP-10 mRNA demonstrated a significant correlation in surgical degenerate samples, while TNF-α was not correlated with MMP-10 mRNA. NGF was significantly correlated with both MMP-10 and substance P mRNA in surgical degenerate NP samples. Conclusions MMP-10 expression is increased in the symptomatic degenerate IVD, where it may contribute to matrix degradation and initiation of nociception. Importantly, this study suggests differences in the pathways involved in matrix degradation between painful and pain-free IVD degeneration. PMID:19695094

Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc.

PubMed

Richardson, Stephen M; Doyle, Paul; Minogue, Ben M; Gnanalingham, Kanna; Hoyland, Judith A

2009-01-01

Matrix metalloproteinases (MMPs) are known to be involved in the degradation of the nucleus pulposus (NP) during intervertebral disc (IVD) degeneration. This study investigated MMP-10 (stromelysin-2) expression in the NP during IVD degeneration and correlated its expression with pro-inflammatory cytokines and molecules involved in innervation and nociception during degeneration which results in low back pain (LBP). Human NP tissue was obtained at postmortem (PM) from patients without a history of back pain and graded as histologically normal or degenerate. Symptomatic degenerate NP samples were also obtained at surgery for LBP. Expression of MMP-10 mRNA and protein was analysed using real-time polymerase chain reaction and immunohistochemistry. Gene expression for pro-inflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), nerve growth factor (NGF) and the pain-associated neuropeptide substance P were also analysed. Correlations between MMP-10 and IL-1, TNF-alpha and NGF were assessed along with NGF with substance P. MMP-10 mRNA was significantly increased in surgical degenerate NP when compared to PM normal and PM degenerate samples. MMP-10 protein was also significantly higher in degenerate surgical NP samples compared to PM normal. IL-1 and MMP-10 mRNA demonstrated a significant correlation in surgical degenerate samples, while TNF-alpha was not correlated with MMP-10 mRNA. NGF was significantly correlated with both MMP-10 and substance P mRNA in surgical degenerate NP samples. MMP-10 expression is increased in the symptomatic degenerate IVD, where it may contribute to matrix degradation and initiation of nociception. Importantly, this study suggests differences in the pathways involved in matrix degradation between painful and pain-free IVD degeneration.

Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration

PubMed Central

Le Maitre, Christine Lyn; Freemont, Anthony John; Hoyland, Judith Alison

2007-01-01

Current evidence implicates intervertebral disc degeneration as a major cause of low back pain, although its pathogenesis is poorly understood. Numerous characteristic features of disc degeneration mimic those seen during ageing but appear to occur at an accelerated rate. We hypothesised that this is due to accelerated cellular senescence, which causes fundamental changes in the ability of disc cells to maintain the intervertebral disc (IVD) matrix, thus leading to IVD degeneration. Cells isolated from non-degenerate and degenerate human tissue were assessed for mean telomere length, senescence-associated β-galactosidase (SA-β-gal), and replicative potential. Expression of P16INK4A (increased in cellular senescence) was also investigated in IVD tissue by means of immunohistochemistry. RNA from tissue and cultured cells was used for real-time polymerase chain reaction analysis for matrix metalloproteinase-13, ADAMTS 5 (a disintegrin and metalloprotease with thrombospondin motifs 5), and P16INK4A. Mean telomere length decreased with age in cells from non-degenerate tissue and also decreased with progressive stages of degeneration. In non-degenerate discs, there was an age-related increase in cellular expression of P16INK4A. Cells from degenerate discs (even from young patients) exhibited increased expression of P16INK4A, increased SA-β-gal staining, and a decrease in replicative potential. Importantly, there was a positive correlation between P16INK4A and matrix-degrading enzyme gene expression. Our findings indicate that disc cell senescence occurs in vivo and is accelerated in IVD degeneration. Furthermore, the senescent phenotype is associated with increased catabolism, implicating cellular senescence in the pathogenesis of IVD degeneration. PMID:17498290

Before and After Photos: Treatment of Hypertrophic Scars

MedlinePlus

... Injectable Poly-l-lactic Acid Injectable Polymethylmethacrylate + Bovine Collagen Filler Injectable Calcium Hydroxylapatite Back Laser/light Therapy ... attempts to repair these lesions by forming new collagen fibers. These repairs usually aren't as smooth ...

[Application of enzymes for treatment of patients with hypertrophic cicatrices].

PubMed

Paramonov, B A; Turkovskiĭ, I I; Bondarev, S V

2007-01-01

Treatment of 27 patients by electrophoresis with preparation "Polycollagenase K" was analyzed and it was shown that it gave positive results according to complex assessment by the scale developed by the authors.

21 CFR 522.62 - Aminopentamide hydrogen sulfate injection.

Code of Federal Regulations, 2011 CFR

2011-04-01

...) Conditions of use. (1) It is intended for use in dogs and cats only for the treatment of vomiting and/or diarrhea, nausea, acute abdominal visceral spasm, pylorospasm, or hypertrophic gastritis. Note: Not for use...

21 CFR 522.62 - Aminopentamide hydrogen sulfate injection.

Code of Federal Regulations, 2010 CFR

2010-04-01

...) Conditions of use. (1) It is intended for use in dogs and cats only for the treatment of vomiting and/or diarrhea, nausea, acute abdominal visceral spasm, pylorospasm, or hypertrophic gastritis. Note: Not for use...

21 CFR 522.62 - Aminopentamide hydrogen sulfate injection.

Code of Federal Regulations, 2012 CFR

2012-04-01

...) Conditions of use. (1) It is intended for use in dogs and cats only for the treatment of vomiting and/or diarrhea, nausea, acute abdominal visceral spasm, pylorospasm, or hypertrophic gastritis. Note: Not for use...

21 CFR 522.62 - Aminopentamide hydrogen sulfate injection.

Code of Federal Regulations, 2013 CFR

2013-04-01

...) Conditions of use. (1) It is intended for use in dogs and cats only for the treatment of vomiting and/or diarrhea, nausea, acute abdominal visceral spasm, pylorospasm, or hypertrophic gastritis. Note: Not for use...

Qualitative and quantitative assessment of degeneration of cervical intervertebral discs and facet joints.

PubMed

Walraevens, Joris; Liu, Baoge; Meersschaert, Joke; Demaerel, Philippe; Delye, Hans; Depreitere, Bart; Vander Sloten, Jos; Goffin, Jan

2009-03-01

Degeneration of intervertebral discs and facet joints is one of the most frequently encountered spinal disorders. In order to describe and quantify degeneration and evaluate a possible relationship between degeneration and biomechanical parameters, e.g., the intervertebral range of motion and intradiscal pressure, a scoring system for degeneration is mandatory. However, few scoring systems for the assessment of degeneration of the cervical spine exist. Therefore, two separate objective scoring systems to qualitatively and quantitatively assess the degree of cervical intervertebral disc and facet joint degeneration were developed and validated. The scoring system for cervical disc degeneration consists of three variables which are individually scored on neutral lateral radiographs: "height loss" (0-4 points), "anterior osteophytes" (0-3 points) and "endplate sclerosis" (0-2 points). The scoring system for facet joint degeneration consists of four variables which are individually scored on neutral computed tomography scans: "hypertrophy" (0-2 points), "osteophytes" (0-1 point), "irregularity" on the articular surface (0-1 point) and "joint space narrowing" (0-1 point). Each variable contributes with varying importance to the overall degeneration score (max 9 points for the scoring system of cervical disc degeneration and max 5 points for facet joint degeneration). Degeneration of 20 discs and facet joints of 20 patients was blindly assessed by four raters: two neurosurgeons (one senior and one junior) and two radiologists (one senior and one junior), firstly based on first subjective impression and secondly using the scoring systems. Measurement errors and inter- and intra-rater agreement were determined. The measurement error of the scoring system for cervical disc degeneration was 11.1 versus 17.9% of the subjective impression results. This scoring system showed excellent intra-rater agreement (ICC = 0.86, 0.75-0.93) and excellent inter-rater agreement (ICC = 0.78, 0.64-0.88). Surgeons as well as radiologists and seniors as well as juniors obtained excellent inter- and intra-rater agreement. The measurement error of the scoring system for cervical facet joint degeneration was 20.1 versus 24.2% of the subjective impression results. This scoring system showed good intra-rater agreement (ICC = 0.71, 0.42-0.89) and fair inter-rater agreement (ICC = 0.49, 0.26-0.74). Both scoring systems fulfilled the criteria for recommendation proposed by Kettler and Wilke. Our scoring systems can be reliable and objective tools for assessing cervical disc and facet joint degeneration. Moreover, the scoring system of cervical disc degeneration was shown to be experience- and discipline-independent.

[Thalamus and Attention].

PubMed

Tokoro, Kazuhiko; Sato, Hironobu; Yamamoto, Mayumi; Nagai, Yoshiko

2015-12-01

Attention is the process by which information and selection occurs, the thalamus plays an important role in the selective attention of visual and auditory information. Selective attention is a conscious effort; however, it occurs subconsciously, as well. The lateral geniculate body (LGB) filters visual information before it reaches the cortex (bottom-up attention). The thalamic reticular nucleus (TRN) provides a strong inhibitory input to both the LGB and pulvinar. This regulation involves focusing a spotlight on important information, as well as inhibiting unnecessary background information. Behavioral contexts more strongly modulate activity of the TRN and pulvinar influencing feedforward and feedback information transmission between the frontal, temporal, parietal and occipital cortical areas (top-down attention). The medial geniculate body (MGB) filters auditory information the TRN inhibits the MGB. Attentional modulation occurring in the auditory pathway among the cochlea, cochlear nucleus, superior olivary complex, and inferior colliculus is more important than that of the MGB and TRN. We also discuss the attentional consequence of thalamic hemorrhage.

Mechanism of auditory hypersensitivity in human autism using autism model rats.

PubMed

Ida-Eto, Michiru; Hara, Nao; Ohkawara, Takeshi; Narita, Masaaki

2017-04-01

Auditory hypersensitivity is one of the major complications in autism spectrum disorder. The aim of this study was to investigate whether the auditory brain center is affected in autism model rats. Autism model rats were prepared by prenatal exposure to thalidomide on embryonic day 9 and 10 in pregnant rats. The superior olivary complex (SOC), a complex of auditory nuclei, was immunostained with anti-calbindin d28k antibody at postnatal day 50. In autism model rats, SOC immunoreactivity was markedly decreased. Strength of immunostaining of SOC auditory fibers was also weak in autism model rats. Surprisingly, the size of the medial nucleus of trapezoid body, a nucleus exerting inhibitory function in SOC, was significantly decreased in autism model rats. Auditory hypersensitivity may be, in part, due to impairment of inhibitory processing by the auditory brain center. © 2016 Japan Pediatric Society.

Magnetic resonance characteristics and susceptibility weighted imaging of the brain in gadolinium encephalopathy.

PubMed

Samardzic, Dejan; Thamburaj, Krishnamoorthy

2015-01-01

To report the brain imaging features on magnetic resonance imaging (MRI) in inadvertent intrathecal gadolinium administration. A 67-year-old female with gadolinium encephalopathy from inadvertent high dose intrathecal gadolinium administration during an epidural steroid injection was studied with multisequence 3T MRI. T1-weighted imaging shows pseudo-T2 appearance with diffusion of gadolinium into the brain parenchyma, olivary bodies, and membranous labyrinth. Nulling of cerebrospinal fluid (CSF) signal is absent on fluid attenuation recovery (FLAIR). Susceptibility-weighted imaging (SWI) demonstrates features similar to subarachnoid hemorrhage. CT may demonstrate a pseudo-cerebral edema pattern given the high attenuation characteristics of gadolinium. Intrathecal gadolinium demonstrates characteristic imaging features on MRI of the brain and may mimic subarachnoid hemorrhage on susceptibility-weighted imaging. Identifying high dose gadolinium within the CSF spaces on MRI is essential to avoid diagnostic and therapeutic errors. Copyright © 2013 by the American Society of Neuroimaging.

Functional imaging and the cerebellum: recent developments and challenges. Editorial.

PubMed

Habas, Christophe

2012-06-01

Recent neuroimaging developments allow a better in vivo characterization of the structural and functional connectivity of the human cerebellum. Ultrahigh fields, which considerably increase spatial resolution, enable to visualize deep cerebellar nuclei and cerebello-cortical sublayers. Tractography reconstructs afferent and efferent pathway of the cerebellum. Resting-state functional connectivity individualizes the prewired, parallel close-looped sensorimotor, cognitive, and affective networks passing through the cerebellum. These results are un agreement with activation maps obtained during stimulation functional neuroimaging or inferred from neurological deficits due to cerebellar lesions. Therefore, neuroimaging supports the hypothesis that cerebellum constitutes a general modulator involved in optimizing mental performance and computing internal models. However, the great challenges will remain to unravel: (1) the functional role of red and bulbar olivary nuclei, (2) the information processing in the cerebellar microcircuitry, and (3) the abstract computation performed by the cerebellum and shared by sensorimotor, cognitive, and affective domains.

Pharmacological tests of hypotheses for acquired pendular nystagmus.

PubMed

Shaikh, Aasef G; Thurtell, Matthew J; Optican, Lance M; Leigh, R John

2011-09-01

Acquired pendular nystagmus (APN) occurs with multiple sclerosis (MS) and oculopalatal tremor (OPT); distinct features of the nystagmus have led to the development of separate models for their pathogenesis. APN in MS has been attributed to instability in the neural integrator, which normally ensures steady gaze. APN in OPT may result from electrotonic coupling between neurons in the hypertrophied inferior olivary nucleus, which induces maladaptive learning in cerebellar cortex. We tested these two hypotheses by analyzing the effects of gabapentin, memantine, and baclofen on both forms of nystagmus. No drug changed the dominant frequency of either form of APN, but the variability of frequency was affected with gabapentin and memantine in patients with OPT. The amplitude of APN in both MS and OPT was reduced with gabapentin and memantine, but not baclofen. Analyzing the effects of drug therapies on ocular oscillations provides a novel approach to test models of nystagmus. © 2011 New York Academy of Sciences.

Pharmacological tests of hypotheses for acquired pendular nystagmus

PubMed Central

Shaikh, Aasef G.; Thurtell, Matthew J.; Optican, Lance M.; Leigh, R. John

2011-01-01

Acquired pendular nystagmus (APN) occurs with multiple sclerosis (MS) and oculopalatal tremor (OPT); distinct features of the nystagmus have led to the development of separate models for the pathogenesis. APN in MS has been attributed to instability in the neural integrator, which normally ensures steady gaze. APN in OPT may result from electrotonic coupling between neurons in the hypertrophied inferior olivary nucleus, which induces maladaptive learning in cerebellar cortex. We tested these two hypotheses by analyzing the effects of gabapentin, memantine, and baclofen on both forms of nystagmus. No drug changed the dominant frequency of either form of APN, but the variability of frequency was affected with gabapentin and memantine in patients with OPT. The amplitude of APN in both MS and OPT was reduced with gabapentin and memantine, but not baclofen. Analyzing the effects of drug therapies on ocular oscillations provides a novel approach to test models of nystagmus. PMID:21951011

Understanding essential tremor: progress on the biological front.

PubMed

Louis, Elan D

2014-06-01

For many years, little was written about the underlying biology of ET, despite its high prevalence. Discussions of disease mechanisms were dominated by a focus on tremor physiology. The traditional model of ET, the olivary model, was proposed in the 1970s. The model suffers from several critical problems, and its relevance to ET has been questioned. Recent mechanistic research has focused on the cerebellum. Clinical and neuroimaging studies strongly implicate the importance of this brain region in ET. Recent mechanistic research has been grounded more in tissue-based changes (i.e., postmortem studies of the brain). These studies have collectively and systematically identified a sizable number of changes in the ET cerebellum, and have led to a new model of ET, referred to as the cerebellar degenerative model. Hence, there is a renewed interest in the science behind the biology of ET. How the new understanding of ET will translate into treatment changes is an open question.

A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain.

PubMed

Makino, Hiroto; Seki, Shoji; Yahara, Yasuhito; Shiozawa, Shunichi; Aikawa, Yukihiko; Motomura, Hiraku; Nogami, Makiko; Watanabe, Kenta; Sainoh, Takeshi; Ito, Hisakatsu; Tsumaki, Noriyuki; Kawaguchi, Yoshiharu; Yamazaki, Mitsuaki; Kimura, Tomoatsu

2017-12-05

Intervertebral disc (IVD) degeneration is a major cause of low back pain. The transcription factor c-Fos/Activator Protein-1 (AP-1) controls the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that contribute to the pathogenesis IVD degeneration. We investigated the effects of inhibition of c-Fos/AP-1 on IVD degeneration and associated pain. A selective inhibitor, T-5224, significantly suppressed the interleukin-1β-induced up-regulation of Mmp-3, Mmp-13 and Adamts-5 transcription in human nucleus pulposus cells and in a mouse explant culture model of IVD degeneration. We used a tail disc percutaneous needle puncture method to further assess the effects of oral administration of T-5224 on IVD degeneration. Analysis of disc height, T2-magnetic resonance imaging (MRI) findings, and histology revealed that IVD degeneration was significantly mitigated by T-5224. Further, oral administration of T-5224 ameliorated pain as indicated by the extended tail-flick latency in response to heat stimulation of rats with needle-puncture-induced IVD degeneration. These findings suggest that the inhibition of c-Fos/AP-1 prevents disc degeneration and its associated pain and that T-5224 may serve as a drug for the prevention of IVD degeneration.

Subretinally transplanted embryonic stem cells rescue photoreceptor cells from degeneration in the RCS rats.

PubMed

Schraermeyer, U; Thumann, G; Luther, T; Kociok, N; Armhold, S; Kruttwig, K; Andressen, C; Addicks, K; Bartz-Schmidt, K U

2001-01-01

The Royal College of Surgeons (RCS) rat is an animal model for retinal degeneration such as the age-related macular degeneration. The RCS rat undergoes a progressive retinal degeneration during the early postnatal period. A potential treatment to prevent this retinal degeneration is the transplantation into the subretinal space of cells that would replace functions of the degenerating retinal pigment epithelium (RPE) cells or may form neurotrophic factors. In this study we have investigated the potential of subretinally transplanted embryonic stem cells to prevent the genetically determined photoreceptor cell degeneration in the RCS rat. Embryonic stem cells from the inner cell mass of the mouse blastocyst were allowed to differentiate to neural precursor cells in vitro and were then transplanted into the subretinal space of 20-day-old RCS rats. Transplanted and sham-operated rats were sacrificed 2 months following cell transplantation. The eyes were enucleated and photoreceptor degeneration was quantified by analyzing and determining the thickness of the outer nuclear layer by light and electron microscopy. In the eyes transplanted with embryonic cells up to 8 rows of photoreceptor cell nuclei were observed, whereas in nontreated control eyes the outer nuclear layer had degenerated completely. Transplantation of embryonic stem cells appears to delay photoreceptor cell degeneration in RCS rats.

Living with hypertrophic cardiomyopathy and an implantable defibrillator.

PubMed

Magnusson, Peter; Jonsson, Jessica; Mörner, Stellan; Fredriksson, Lennart

2017-05-10

ICDs efficiently terminate life-threatening arrhythmias, but complications occur during long-term follow-up. Patients' own perspective is largely unknown. The aim of the study was to describe experiences of hypertrophic cardiomyopathy (HCM) patients with implantable defibrillators (ICDs). We analyzed 26 Swedish patient interviews using hermeneutics and latent content analysis. Patients (aged 27-76 years) were limited by HCM especially if it deteriorates into heart failure. The ICD implies safety, gratitude, and is accepted as a part of the body even when inappropriate ICD shocks are encountered. Nobody regretted the implant. Both the disease and the ICD affected professional life and leisure time activities, especially at younger ages. Family support was usually strong, but sometimes resulted in overprotection, whereas health care focused on medical issues. Despite limitations, patients adapted, accepted, and managed challenges. HCM patients with ICDs reported good spirit and hope even though they had to adapt and accept limitations over time.

Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM

PubMed Central

Freeman, Lisa M.; Rush, John E.; Stern, Joshua A.; Huggins, Gordon S.; Maron, Martin S.

2017-01-01

Hypertrophic cardiomyopathy (HCM) is a common disease in pet cats, affecting 10-15% of the pet cat population. The similarity to human HCM, the rapid progression of disease, and the defined and readily determined endpoints of feline HCM make it an excellent natural model that is genotypically and phenotypically similar to human HCM. The Maine Coon and Ragdoll cats are particularly valuable models of HCM because of myosin binding protein-C mutations and even higher disease incidence compared to the overall feline population. The cat overcomes many of the limitations of rodent HCM models, and can provide enhanced translation of information from in vitro and induced small animal models to human clinical trials. Physicians and veterinarians working together in a collaborative and interdisciplinary approach can accelerate the discovery of more effective treatments for this and other cardiovascular diseases affecting human and veterinary patients. PMID:28868097

Hypertrophic Cardiomyopathy: Clinical Update.

PubMed

Geske, Jeffrey B; Ommen, Steve R; Gersh, Bernard J

2018-05-01

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, manifesting as left ventricular hypertrophy in the absence of a secondary cause. The genetic underpinnings of HCM arise largely from mutations of sarcomeric proteins; however, the specific underlying mutation often remains undetermined. Patient presentation is phenotypically diverse, ranging from asymptomatic to heart failure or sudden cardiac death. Left ventricular hypertrophy and abnormal ventricular configuration result in dynamic left ventricular outflow obstruction in most patients. The goal of therapeutic interventions is largely to reduce dynamic obstruction, with treatment modalities spanning lifestyle modifications, pharmacotherapies, and septal reduction therapies. A small subset of patients with HCM will experience sudden cardiac death, and risk stratification remains a clinical challenge. This paper presents a clinical update for diagnosis, family screening, clinical imaging, risk stratification, and management of symptoms in patients with HCM. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Subaortic membrane mimicking hypertrophic cardiomyopathy.

PubMed

Anderson, Mark Joseph; Arruda-Olson, Adelaide; Gersh, Bernard; Geske, Jeffrey

2015-11-04

A 34-year-old man was referred for progressive angina and exertional dyspnoea refractory to medical therapy, with a presumptive diagnosis of hypertrophic cardiomyopathy (HCM). Transthoracic echocardiography (TTE) revealed asymmetric septal hypertrophy without systolic anterior motion of the mitral valve leaflet and with no dynamic left ventricular outflow tract (LVOT) obstruction. However, the LVOT velocity was elevated at rest as well as with provocation, without the characteristic late peaking obstruction seen in HCM. Focused TTE to evaluate for suspected fixed obstruction demonstrated a subaortic membrane 2.2 cm below the aortic valve. Coronary CT angiography confirmed the presence of the subaortic membrane and was negative for concomitant coronary artery disease. Surgical resection of the subaortic membrane and septal myectomy resulted in significant symptomatic relief and lower LVOT velocities on postoperative TTE. This case reminds the clinician to carefully evaluate for alternative causes of LVOT obstruction, especially subaortic membrane, as a cause of symptoms mimicking HCM. 2015 BMJ Publishing Group Ltd.

Subaortic membrane mimicking hypertrophic cardiomyopathy

PubMed Central

Anderson, Mark Joseph; Arruda-Olson, Adelaide; Gersh, Bernard; Geske, Jeffrey

2015-01-01

A 34-year-old man was referred for progressive angina and exertional dyspnoea refractory to medical therapy, with a presumptive diagnosis of hypertrophic cardiomyopathy (HCM). Transthoracic echocardiography (TTE) revealed asymmetric septal hypertrophy without systolic anterior motion of the mitral valve leaflet and with no dynamic left ventricular outflow tract (LVOT) obstruction. However, the LVOT velocity was elevated at rest as well as with provocation, without the characteristic late peaking obstruction seen in HCM. Focused TTE to evaluate for suspected fixed obstruction demonstrated a subaortic membrane 2.2 cm below the aortic valve. Coronary CT angiography confirmed the presence of the subaortic membrane and was negative for concomitant coronary artery disease. Surgical resection of the subaortic membrane and septal myectomy resulted in significant symptomatic relief and lower LVOT velocities on postoperative TTE. This case reminds the clinician to carefully evaluate for alternative causes of LVOT obstruction, especially subaortic membrane, as a cause of symptoms mimicking HCM. PMID:26538250

Isolated papillary muscle hypertrophy: A gap in our knowledge of hypertrophic cardiomyopathy?

PubMed

Ferreira, Catarina; Delgado, Carlos; Vázquez, María; Trinidad, Carmen; Vilar, Manuel

2014-06-01

Increased thickness of left ventricular walls is the predominant characteristic and one of the diagnostic criteria of hypertrophic cardiomyopathy (HCM). This case illustrates an uncommon but important finding of isolated hypertrophy of the papillary muscles (PMs), observed in a young woman in whom an abnormal electrocardiogram was initially detected. During the investigation isolated PM hypertrophy was identified. The structural characteristics of the PMs have received scant attention in this setting and there is little information in the literature on this entity, whose real prevalence and clinical significance remain to be determined. The available information relates solitary PM hypertrophy with an early form or a different pattern of HCM. In this case PM hypertrophy was only detected due to the finding of an abnormal electrocardiogram, which prompted further diagnostic tests and a search for possible etiologies. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

[Mutation analysis of beta myosin heavy chain gene in hypertrophic cardiomyopathy families].

PubMed

Fan, Xin-ping; Yang, Zhong-wei; Feng, Xiu-li; Yang, Fu-hui; Xiao, Bai; Liang, Yan

2011-08-01

To detect the gene mutations of beta-myosin heavy chain gene (MYH7) in Chinese pedigrees with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype. Exons 3, 5, 7-9, 11-16 and 18-23 of the MYH7 gene were amplified with PCR in three Chinese pedigrees with HCM. The products were sequenced. Sequence alignment between the detected and the standard sequences was performed. A missense mutation of Thr441Met in exon 14 was identified in a pedigree, which was not detected in the controls. Several synonymous mutations of MYH7 gene were detected in the three pedigrees. The mutation of Thr441Met, located in the actin binding domain of the globular head, was first identified in Chinese. It probably caused HCM. HCM is a heterogeneous disease. Many factors are involved in the process of its occurrence and development.

Human disc degeneration is associated with increased MMP 7 expression.

PubMed

Le Maitre, C L; Freemont, A J; Hoyland, J A

2006-01-01

During intervertebral disc (IVD) degeneration, normal matrix synthesis decreases and degradation of disc matrix increases. A number of proteases that are increased during disc degeneration are thought to be involved in its pathogenesis. Matrix metalloproteinase 7 (MMP 7) (Matrilysin, PUMP-1) is known to cleave the major matrix molecules found within the IVD, i.e., the proteoglycan aggrecan and collagen type II. To date, however, it is not known how its expression changes with degeneration or its exact location. We investigated the localization of MMP 7 in human, histologically graded, nondegenerate, degenerated and prolapsed discs to ascertain whether MMP 7 is up-regulated during disc degeneration. Samples of human IVD tissue were fixed in neutral buffered formalin, embedded in paraffin, and sections stained with hematoxylin and eosin to score the degree of morphological degeneration. Immunohistochemistry was performed to localize MMP 7 in 41 human IVDs with varying degrees of degeneration. We found that the chondrocyte-like cells of the nucleus pulposus and inner annulus fibrosus were MMP 7 immunopositive; little immunopositivity was observed in the outer annulus. Nondegenerate discs showed few immunopositive cells. A significant increase in the proportion of MMP 7 immunopositive cells was seen in the nucleus pulposus of discs classified as showing intermediate levels of degeneration and a further increase was seen in discs with severe degeneration. Prolapsed discs showed more MMP 7 immunopositive cells compared to nondegenerated discs, but fewer than those seen in cases of severe degeneration.

MRI evaluation of spontaneous intervertebral disc degeneration in the alpaca cervical spine.

PubMed

Stolworthy, Dean K; Bowden, Anton E; Roeder, Beverly L; Robinson, Todd F; Holland, Jacob G; Christensen, S Loyd; Beatty, Amanda M; Bridgewater, Laura C; Eggett, Dennis L; Wendel, John D; Stieger-Vanegas, Susanne M; Taylor, Meredith D

2015-12-01

Animal models have historically provided an appropriate benchmark for understanding human pathology, treatment, and healing, but few animals are known to naturally develop intervertebral disc degeneration. The study of degenerative disc disease and its treatment would greatly benefit from a more comprehensive, and comparable animal model. Alpacas have recently been presented as a potential large animal model of intervertebral disc degeneration due to similarities in spinal posture, disc size, biomechanical flexibility, and natural disc pathology. This research further investigated alpacas by determining the prevalence of intervertebral disc degeneration among an aging alpaca population. Twenty healthy female alpacas comprised two age subgroups (5 young: 2-6 years; and 15 older: 10+ years) and were rated according to the Pfirrmann-grade for degeneration of the cervical intervertebral discs. Incidence rates of degeneration showed strong correlations with age and spinal level: younger alpacas were nearly immune to developing disc degeneration, and in older animals, disc degeneration had an increased incidence rate and severity at lower cervical levels. Advanced disc degeneration was present in at least one of the cervical intervertebral discs of 47% of the older alpacas, and it was most common at the two lowest cervical intervertebral discs. The prevalence of intervertebral disc degeneration encourages further investigation and application of the lower cervical spine of alpacas and similar camelids as a large animal model of intervertebral disc degeneration. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Deletion of Sarm1 gene is neuroprotective in two models of peripheral neuropathy.

PubMed

Turkiew, Elliot; Falconer, Debbie; Reed, Nicole; Höke, Ahmet

2017-09-01

Distal axon degeneration seen in many peripheral neuropathies is likely to share common molecular mechanisms with Wallerian degeneration. Although several studies in mouse models of peripheral neuropathy showed prevention of axon degeneration in the slow Wallerian degeneration (Wlds) mouse, the role of a recently identified player in Wallerian degeneration, Sarm1, has not been explored extensively. In this study, we show that mice lacking the Sarm1 gene are resistant to distal axonal degeneration in a model of chemotherapy induced peripheral neuropathy caused by paclitaxel and a model of high fat diet induced putative metabolic neuropathy. This study extends the role of Sarm1 to axon degeneration seen in peripheral neuropathies and identifies it as a likely target for therapeutic development. © 2017 Peripheral Nerve Society.

Associations between Rs4244285 and Rs762551 gene polymorphisms and age-related macular degeneration.

PubMed

Stasiukonyte, Neringa; Liutkeviciene, Rasa; Vilkeviciute, Alvita; Banevicius, Mantas; Kriauciuniene, Loresa

2017-01-01

Age-related macular degeneration is the leading cause of blindness in elderly individuals in developed countries. The etiology and pathophysiology of age-related macular degeneration have not been elucidated yet. Knowing that the main pathological change of age-related macular degeneration is formation of drusen containing about 40% of lipids, there have been attempts to find associations between age-related macular degeneration and genes controlling lipid metabolism. To determine the frequency of CYP2C19 (G681A) Rs4244285 and CYP1A2 (-163C>A) Rs762551 genotypes in patients with age-related macular degeneration. The study enrolled 150 patients with early age-related macular degeneration and 296 age- and gender-matched healthy controls. The genotyping of Rs4244285 and Rs762551 was carried out by using the real-time polymerase chain reaction method. The CYP1A2 (-163C>A) Rs762551 C/C genotype was more frequently detected in patients with age-related macular degeneration than in the control group (32.7% vs. 21.6%, p = 0.011) and was associated with an increased risk of developing early age-related macular degeneration (OR = 1.759, 95% CI: 1.133-2.729; p = 0.012). The CYP1A2 (-163C>A) Rs762551 C/A genotype was more frequently documented in the control group compared with patients with age-related macular degeneration (46.3% vs. 30.7%, p = 0.002) and was associated with a decreased risk of having age-related macular degeneration (OR = 0.580. 95% CI: 0.362-0.929, p = 0.023) in the co-dominant model. The study showed that the CYP1A2 (-163C>A) Rs762551 C/C genotype was associated with an increased risk of age-related macular degeneration.

Qualitative grading of disc degeneration by magnetic resonance in the lumbar and cervical spine: lack of correlation with histology in surgical cases.

PubMed

Davies, B M; Atkinson, R A; Ludwinski, F; Freemont, A J; Hoyland, J A; Gnanalingham, K K

2016-08-01

Clinically, magnetic resonance (MR) imaging is the most effective non-invasive tool for assessing IVD degeneration. Histological examination of the IVD provides a more detailed assessment of the pathological changes at a tissue level. However, very few reports have studied the relationship between these techniques. Identifying a relationship may allow more detailed staging of IVD degeneration, of importance in targeting future regenerative therapies. To investigate the relationship between MR and histological grading of IVD degeneration in the cervical and lumbar spine in patients undergoing discectomy. Lumbar (N = 99) and cervical (N = 106) IVD samples were obtained from adult patients undergoing discectomy surgery for symptomatic IVD herniation and graded to ascertain a histological grade of degeneration. The pre-operative MR images from these patients were graded for the degree of IVD (MR grade) and vertebral end-plate degeneration (Modic Changes, MC). The relationship between histological and MR grades of degeneration were studied. In lumbar and cervical IVD the majority of samples (93%) exhibited moderate levels of degeneration (ie MR grades 3-4) on pre-operative MR scans. Histologically, most specimens displayed moderate to severe grades of degeneration in lumbar (99%) and cervical spine (93%). MR grade was weakly correlated with patient age in lumbar and cervical study groups. MR and histological grades of IVD degeneration did not correlate in lumbar or cervical study groups. MC were more common in the lumbar than cervical spine (e.g. 39 versus 20% grade 2 changes; p < 0.05), but failed to correlate with MR or histological grades for degeneration. In this surgical series, the resected IVD tissue displayed moderate to severe degeneration, but there is no correlation between MR and histological grades using a qualitative classification system. There remains a need for a quantitative, non-invasive, pre-clinical measure of IVD degeneration that correlates with histological changes seen in the IVD.

The role of interleukin-1 in the pathogenesis of human Intervertebral disc degeneration

PubMed Central

Le Maitre, Christine Lyn; Freemont, Anthony J; Hoyland, Judith Alison

2005-01-01

In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1α, IL-1β, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1β-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family. This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1β-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6). In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration. PMID:15987475

Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis.

PubMed

Singh, Shailender; Dallenga, Tobias; Winkler, Anne; Roemer, Shanu; Maruschak, Brigitte; Siebert, Heike; Brück, Wolfgang; Stadelmann, Christine

2017-03-17

Axonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis. Here, we assessed the amount of Wallerian degeneration in brain tissue of multiple sclerosis patients in relation to demyelinating lesion activity and asked whether a transient blockade of Wallerian degeneration decreases axonal loss and clinical disability in a mouse model of inflammatory demyelination. Wallerian degeneration and acute axonal damage were determined immunohistochemically in the periplaque white matter of multiple sclerosis patients with early actively demyelinating lesions, chronic active lesions, and inactive lesions. Furthermore, we studied the effects of Wallerian degeneration blockage on clinical severity, inflammatory pathology, acute axonal damage, and long-term axonal loss in experimental autoimmune encephalomyelitis using Wallerian degeneration slow (Wld S ) mutant mice. The highest numbers of axons undergoing Wallerian degeneration were found in the perilesional white matter of multiple sclerosis patients early in the disease course and with actively demyelinating lesions. Furthermore, Wallerian degeneration was more abundant in patients harboring chronic active as compared to chronic inactive lesions. No co-localization of neuropeptide Y-Y1 receptor, a bona fide immunohistochemical marker of Wallerian degeneration, with amyloid precursor protein, frequently used as an indicator of acute axonal transport disturbance, was observed in human and mouse tissue, indicating distinct axon-degenerative processes. Experimentally, a delay of Wallerian degeneration, as observed in Wld S mice, did not result in a reduction of clinical disability or acute axonal damage in experimental autoimmune encephalomyelitis, further supporting that acute axonal damage as reflected by axonal transport disturbances does not share common molecular mechanisms with Wallerian degeneration. Furthermore, delaying Wallerian degeneration did not result in a net rescue of axons in late lesion stages of experimental autoimmune encephalomyelitis. Our data indicate that in multiple sclerosis, ongoing demyelination in focal lesions is associated with axonal degeneration in the perilesional white matter, supporting a role for focal pathology in diffuse white matter damage. Also, our results suggest that interfering with Wallerian degeneration in inflammatory demyelination does not suffice to prevent acute axonal damage and finally axonal loss.

Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse.

PubMed

Cupesi, Mihaela; Yoshioka, Jun; Gannon, Joseph; Kudinova, Anastacia; Stewart, Colin L; Lammerding, Jan

2010-06-01

Inherited mutations cause approximately 30% of all dilated cardiomyopathy cases, with autosomal dominant mutations in the LMNA gene accounting for more than one third of these. The LMNA gene encodes the nuclear envelope proteins lamins A and C, which provide structural support to the nucleus and also play critical roles in transcriptional regulation. Functional deletion of a single allele is sufficient to trigger dilated cardiomyopathy in humans and mice. However, whereas Lmna(-/-) mice develop severe muscular dystrophy and dilated cardiomyopathy and die by 8 weeks of age, heterozygous Lmna(+/-) mice have a much milder phenotype, with changes in ventricular function and morphology only becoming apparent at 1 year of age. Here, we studied 8- to 20-week-old Lmna(+/-) mice and wild-type littermates in a pressure overload model to examine whether increased mechanical load can accelerate or exacerbate myocardial dysfunction in the heterozygotes. While overall survival was similar between genotypes, Lmna(+/-) animals had a significantly attenuated hypertrophic response to pressure overload as evidenced by reduced ventricular mass and myocyte size. Analysis of pressure overload-induced transcriptional changes suggested that the reduced hypertrophy in the Lmna(+/-) mice was accompanied by impaired activation of the mechanosensitive gene Egr-1. In conclusion, our findings provide further support for a critical role of lamins A and C in regulating the cellular response to mechanical stress in cardiomyocytes and demonstrate that haploinsufficiency of lamins A and C alone is sufficient to alter hypertrophic responses and cardiac function in the face of pressure overload in the heart. (c) 2009 Elsevier Ltd. All rights reserved.

Protein quality control in protection against systolic overload cardiomyopathy: the long term role of small heat shock proteins

PubMed Central

Kumarapeli, Asangi R K; Horak, Kathleen; Wang, Xuejun

2010-01-01

Molecular chaperones represent the first line of defense of intracellular protein quality control. As a major constituent of molecular chaperones, heat shock proteins (HSP) are known to confer cardiomyocyte short-term protection against various insults and injuries. Previously, we reported that the small HSP αB-crystallin (CryAB) attenuates cardiac hypertrophic response in mice subjected to 2 weeks of severe pressure overload. However, the long-term role of small HSPs in cardiac hypertrophy and failure has rarely been studied. The present study investigates the cardiac responses to chronic severe pressure overload in CryAB/HSPB2 germ line ablated (KO) and cardiac-specific CryAB overexpressingtransgenic (TG) mice. Pressure overload was induced by transverse aortic constriction in KO, TG, and non-transgenic wild type (NTG) control mice and 10 weeks later molecular, cellular, and whole organ level hypertrophic responses were analyzed. As we previously described, CryAB/HSPB2 KO mice showed abnormal baseline cardiac physiology that worsened into a restrictive cardiomyopathic phenotype with aging. Severe pressure overload in these mice led to rapid deterioration of heart function and development of congestive cardiac failure. Contrary to their short term protective phenotype, CryAB TG mice showed no significant effects on cardiac hypertrophic responses and very modest improvement of hemodynamics during chronic systolic overload. These findings indicate that small HSPs CryAB and/or HSPB2 are essential to maintain cardiac structure and function but overex-pression of CryAB is not sufficient to confer a sustained protection against chronic systolic overload. PMID:20733949

Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse

PubMed Central

Cupesi, Mihaela; Yoshioka, Jun; Gannon, Joseph; Kudinova, Anastacia; Stewart, Colin L.; Lammerding, Jan

2009-01-01

Inherited mutations cause approximately 30% of all dilated cardiomyopathy cases, with autosomal dominant mutations in the LMNA gene accounting for more than one third of these. The LMNA gene encodes the nuclear envelope proteins lamins A and C, which provide structural support to the nucleus and also play critical roles in transcriptional regulation. Functional deletion of a single allele is sufficient to trigger dilated cardiomyopathy in humans and mice. However, whereas Lmna−/− mice develop severe muscular dystrophy and dilated cardiomyopathy and die by 8 weeks of age, heterozygous Lmna+/− mice have a much milder phenotype, with changes in ventricular function and morphology only becoming apparent at one year of age. Here, we studied 8 to 20 week old Lmna+/− mice and wild-type littermates in a pressure overload model to examine whether increased mechanical load can accelerate or exacerbate myocardial dysfunction in the heterozygotes. While overall survival was similar between genotypes, Lmna+/− animals had a significantly attenuated hypertrophic response to pressure overload as evidenced by reduced ventricular mass and myocyte size. Analysis of pressure-overload induced transcriptional changes suggested that the reduced hypertrophy in the Lmna+/− mice was accompanied by impaired activation of the mechanosensitive gene Egr-1. In conclusion, our findings provide further support for a critical role of lamins A and C in regulating the cellular response to mechanical stress in cardiomyocytes and demonstrate that haploinsufficiency of lamins A and C alone is sufficient to alter hypertrophic responses and cardiac function in the face of pressure overload in the heart. PMID:19913544

Regional variations in growth plate chondrocyte deformation as predicted by three-dimensional multi-scale simulations.

PubMed

Gao, Jie; Roan, Esra; Williams, John L

2015-01-01

The physis, or growth plate, is a complex disc-shaped cartilage structure that is responsible for longitudinal bone growth. In this study, a multi-scale computational approach was undertaken to better understand how physiological loads are experienced by chondrocytes embedded inside chondrons when subjected to moderate strain under instantaneous compressive loading of the growth plate. Models of representative samples of compressed bone/growth-plate/bone from a 0.67 mm thick 4-month old bovine proximal tibial physis were subjected to a prescribed displacement equal to 20% of the growth plate thickness. At the macroscale level, the applied compressive deformation resulted in an overall compressive strain across the proliferative-hypertrophic zone of 17%. The microscale model predicted that chondrocytes sustained compressive height strains of 12% and 6% in the proliferative and hypertrophic zones, respectively, in the interior regions of the plate. This pattern was reversed within the outer 300 μm region at the free surface where cells were compressed by 10% in the proliferative and 26% in the hypertrophic zones, in agreement with experimental observations. This work provides a new approach to study growth plate behavior under compression and illustrates the need for combining computational and experimental methods to better understand the chondrocyte mechanics in the growth plate cartilage. While the current model is relevant to fast dynamic events, such as heel strike in walking, we believe this approach provides new insight into the mechanical factors that regulate bone growth at the cell level and provides a basis for developing models to help interpret experimental results at varying time scales.

Essential role of obscurin in cardiac myofibrillogenesis and hypertrophic response: evidence from small interfering RNA-mediated gene silencing.

PubMed

Borisov, Andrei B; Sutter, Sarah B; Kontrogianni-Konstantopoulos, Aikaterini; Bloch, Robert J; Westfall, Margaret V; Russell, Mark W

2006-03-01

Obscurin is a recently identified giant multidomain muscle protein (approximately 800 kDa) whose structural and regulatory functions remain to be defined. The goal of this study was to examine the effect of obscurin gene silencing induced by RNA interference on the dynamics of myofibrillogenesis and hypertrophic response to phenylephrine in cultured rat cardiomyocytes. We found that that the adenoviral transfection of short interfering RNA (siRNA) constructs targeting the first coding exon of obscurin sequence resulted in progressive depletion of cellular obscurin. Confocal microscopy demonstrated that downregulation of obscurin expression led to the impaired assembly of new myofibrillar clusters and considerable aberrations of the normal structure of the contractile apparatus. While the establishment of the initial periodic pattern of alpha-actinin localization remained mainly unaffected in siRNA-transfected cells, obscurin depletion did cause the defective lateral alignment of myofibrillar bundles, leading to their abnormal bifurcation, dispersal and multiple branching. Bending of immature myofibrils, apparently associated with the loss of their rigidity, a modified titin pattern, the absence of well-formed A-bands in newly formed contractile structures as documented by a diffuse localization of sarcomeric myosin labeling, and an occasional irregular periodicity of sarcomere spacing were typical of obscurin siRNA-treated cells. These results suggest that obscurin is indispensable for spatial positioning of contractile proteins and for the structural integration and stabilization of myofibrils, especially at the stage of myosin filament incorporation and A-band assembly. This demonstrates a vital role for obscurin in myofibrillogenesis and hypertrophic growth.

Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice.

PubMed

Clemente, Carolina F M Z; Tornatore, Thais F; Theizen, Thais H; Deckmann, Ana C; Pereira, Tiago C; Lopes-Cendes, Iscia; Souza, José Roberto M; Franchini, Kleber G

2007-12-07

Hypertrophy is a critical event in the onset of failure in chronically overloaded hearts. Focal adhesion kinase (FAK) has attracted particular attention as a mediator of hypertrophy induced by increased load. Here, we demonstrate increased expression and phosphorylation of FAK in the hypertrophic left ventricles (LVs) of aortic-banded mice. We used an RNA interference strategy to examine whether FAK signaling plays a role in the pathophysiology of load-induced LV hypertrophy and failure. Intrajugular delivery of specific small interfering RNA induced prolonged FAK silencing ( approximately 70%) in both normal and hypertrophic LVs. Myocardial FAK silencing was accompanied by prevention, as well as reversal, of load-induced left ventricular hypertrophy. The function of LVs was preserved and the survival rate was higher in banded mice treated with small interfering RNA targeted to FAK, despite the persistent pressure overload. Studies in cardiac myocytes and fibroblasts harvested from LVs confirmed the ability of the systemically administered specific small interfering RNA to silence FAK in both cell types. Further analysis indicated attenuation of cardiac myocyte hypertrophic growth and of the rise in the expression of beta-myosin heavy chain in overloaded LVs. Moreover, FAK silencing was demonstrated to attenuate the rise in the fibrosis, collagen content, and activity of matrix metalloproteinase-2 in overloaded LVs, as well as the rise of matrix metalloproteinase-2 protein expression in fibroblasts harvested from overloaded LVs. This study provides novel evidence that FAK may be involved in multiple aspects of the pathophysiology of cardiac hypertrophy and failure induced by pressure overload.

Cardiac-targeting magnetic lipoplex delivery of SH-IGF1R plasmid attenuate norepinephrine-induced cardiac hypertrophy in murine heart.

PubMed

Xu, Yiping; Li, Xuebiao; Kong, Minjian; Jiang, Daming; Dong, Aiqiang; Shen, Zhonghua; Duan, Qunjun

2014-10-02

Recent studies have demonstrated a number of molecular mechanisms contributing to the initiation of cardiac hypertrophy response to pressure overload. IGF1R (insulin-like growth factor-1 receptor), an important oncogene, is overexpressed in hypertrophic heart and mediates the hypertrophic pathology process. In this study, we applied with liposomal magnetofection that potentiated gene transfection by applying an external magnetic field to enhance its transfection efficiency. Liposomal magnetofection provided high efficiency in transgene expression in vivo. In vivo, IGF1R-specific-shRNA (small-hairpin RNA) by magnetofection inhibited IGF1R protein expression by 72.2 ± 6.8, 80.7 ± 9.6 and 84.5 ± 5.6%, at 24, 48 and 72 h, respectively, after pGFPshIGF1R injection, indicating that liposomal magnetofection is a promising method that allows the targeting of gene therapy for heart failure. Furthermore, we found that the treated animals (liposomal magnetofection with shIGF1R) showed reduced septal and posterior wall thickness, reduced HW:BWs (heart weight-to-body weights) compared with controls. Moreover, we also found that liposomal magnetofection-based shIGF1R transfection decreased the expression level of p-ERK (phosphorylated extracellular-signal-regulated kinase)1/2, p-AKT1 (phosphorylated protein kinase B1) compared with untreated hearts. These results suggested that liposomal magnetofection-mediated IGF1R-specific-shRNA may be a promising method, and suppression the IGF1R expression inhibited norepinephrine-induced cardiac hypertrophic process via inhibiting PI3K (phosphoinositide 3-kinase)/AKT pathway.

Combined 595-nm and 1,064-nm laser irradiation of recalcitrant and hypertrophic port-wine stains in children and adults.

PubMed

Alster, Tina S; Tanzi, Elizabeth L

2009-06-01

Although pulsed dye laser (PDL) treatment of port-wine stain (PWS) has long been proven safe and effective, incomplete clearance of these vascular malformations can be problematic. In addition, advanced PWS with deeper coloration and tissue hypertrophy can be particularly difficult to treat because of the superficial dermal penetration of 585- to 595-nm light. The purpose of this study was to evaluate the safety and efficacy of a novel device that delivers sequential pulses of 595- and 1,064-nm wavelengths in the treatment of recalcitrant and hypertrophic PWS. Twenty-five children and adults (skin phototypes I-III) with recalcitrant or hypertrophic PWS showing incomplete clearance after 10 prior PDL treatments were included in the study. Successive treatments using a 595-nm PDL and a 1,064-nm neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser were delivered at 6- to 8-week intervals. Two masked assessors determined clinical improvement of treatment areas using independent evaluation of comparative photographs at baseline and 3 months after treatment using a standard quartile grading scale. The use of dual 595-/1,064-nm wavelengths provided continued improvement of PWS that were previously recalcitrant to ongoing PDL therapy. Side effects were limited to transient erythema, edema, and mild purpura. Rare vesicle formation was observed, with no subsequent scarring or undesirable pigmentary changes. The novel dual 595-nm PDL and 1,064-nm Nd:YAG laser is an effective treatment for PWS that are recalcitrant to PDL therapy alone.

Release and skin distribution of silicone-related compound(s) from a silicone gel sheet in vitro.

PubMed

Shigeki, S; Nobuoka, N; Murakami, T; Ikuta, Y

1999-01-01

The efficacy of topical silicone gel sheeting in prevention and/or reduction of keloids and hypertrophic scars is well recognized. In the present study, we reexamined the possible release of silicone-related compound(s) from a commercially available silicone gel sheet (Cica-Care, Smith and Nephew, Hull, England) in aqueous media in vitro. The silicone gel sheet was also applied on the excised skin surface to examine the possible distribution of silicone-related compounds into the skin in vitro. Silicone-related compounds were measured as silicon by an inductively coupled plasma-atomic emission spectrophotometer. When a piece of silicone gel sheet was placed in phosphate buffer solution (pH 3-9) at 37 degrees C for 7 days, the concentration of silicon in the medium increased with time, depending on the pH of the medium. This indicates that the released silicone-related compounds are water-soluble. When Cica-Care was applied on the surface of excised rat skin, human axilla skin and hypertrophic scars under hydrated conditions in vitro, silicon was detected in all skin samples. Greater distribution was observed in rat skin than in human axilla skin and hypertrophic scars. The release of silicone-related compounds from a silicone gel sheet (Cica-Care) and their distribution into the skin were demonstrated in vitro. Silicone-related compounds distributed into the skin may have pharmacological effects on the skin. Further investigation will be necessary to investigate in detail the action of silicone-related compounds on the proliferation of fibroblasts and excessive production of collagen.

Topical Application of a Silicone Gel Sheet with Verapamil Microparticles in a Rabbit Model of Hypertrophic Scar.

PubMed

Rha, Eun Young; Kim, Yun Ho; Kim, Tae-Jung; Yoo, Gyeol; Rhie, Jong Won; Kim, Hyun-Jung; Park, Il-Kyu

2016-01-01

The authors developed a novel treatment based on the topical application of a silicone gel sheet containing verapamil microparticles. The ability of these silicone gel sheets to inhibit hypertrophic scar in a rabbit ear wound model was examined. Ten New Zealand White rabbits with a total of 80 wounds in both ears were used in this study. The rabbits were divided into five groups (control; silicone gel sheet; and silicone gel sheet plus 0.25, 2.5, and 25 mg of verapamil per gram). Histopathologic findings were quantified. The mean scar elevation index, fibroblast counts, and capillary counts differed significantly among the five groups (p < 0.05). The median scar elevation index was significantly lower in the silicone gel sheet plus 2.5 mg of verapamil per gram group than in the silicone gel sheet group (1.2 versus 2.2). The median number of fibroblasts was significantly lower in the silicone gel sheet plus 0.25 mg of verapamil per gram group than in the silicone gel sheet group (172.5 versus 243). In the median number of capillary lumina, there was no significant difference between the silicone gel sheet group and the silicone gel sheet plus 0.25, 2.5, and 25 mg of verapamil per gram groups (28.5, 18, 20, and 18, respectively). Topical application of a silicone gel sheet with verapamil microparticles may be a novel, effective treatment method for hypertrophic scar, but its safety and efficacy in humans must be tested in clinical trials.

S100A8 and S100A9 Are Induced by Decreased Hydration in the Epidermis and Promote Fibroblast Activation and Fibrosis in the Dermis.

PubMed

Zhong, Aimei; Xu, Wei; Zhao, Jingling; Xie, Ping; Jia, Shengxian; Sun, Jiaming; Galiano, Robert D; Mustoe, Thomas A; Hong, Seok J

2016-01-01

The most critical function of the epidermis is to prevent water loss and maintain skin homeostasis. Disruption of the functional skin barrier causes delayed wound healing, hypertrophic scarring, and many skin diseases. Herein, we show that reduced hydration increases the expression of S100 protein family members, S100A8/S100A9, in stratified keratinocyte culture and human ex vivo skin culture. Immunohistological analyses show that S100A8/A9 are highly expressed in the epidermis of human hypertrophic scar and keloid tissues. Reduced hydration demonstrates activation of fibroblasts in the keratinocyte-fibroblast co-culture. In contrast, knockdown of S100A8 or S100A9 by RNA interference in keratinocytes failed to activate fibroblasts. Pretreatment with pharmacological blockers of S100A8/A9 receptors, Toll-like receptor 4 and receptor for advanced glycation end products, inhibits fibroblast activation induced by recombinant S100A8/A9 proteins. Moreover, we observe that local delivery of S100A8 protein results in a marked increase in hypertrophic scarring in the in vivo rabbit ear scar model. Our results indicate that hydration status promotes fibroblast activation and fibrosis by directly affecting the expression of inflammatory signaling in keratinocytes, thereby strongly suggesting S100A8/A9 to be novel targets in preventing scarring. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Diagnosis of apical hypertrophic cardiomyopathy: T-wave inversion and relative but not absolute apical left ventricular hypertrophy☆

PubMed Central

Flett, Andrew S.; Maestrini, Viviana; Milliken, Don; Fontana, Mariana; Treibel, Thomas A.; Harb, Rami; Sado, Daniel M.; Quarta, Giovanni; Herrey, Anna; Sneddon, James; Elliott, Perry; McKenna, William; Moon, James C.

2015-01-01

Background Diagnosis of apical HCM utilizes conventional wall thickness criteria. The normal left ventricular wall thins towards the apex such that normal values are lower in the apical versus the basal segments. The impact of this on the diagnosis of apical hypertrophic cardiomyopathy has not been evaluated. Methods We performed a retrospective review of 2662 consecutive CMR referrals, of which 75 patients were identified in whom there was abnormal T-wave inversion on ECG and a clinical suspicion of hypertrophic cardiomyopathy. These were retrospectively analyzed for imaging features consistent with cardiomyopathy, specifically: relative apical hypertrophy, left atrial dilatation, scar, apical cavity obliteration or apical aneurysm. For comparison, the same evaluation was performed in 60 healthy volunteers and 50 hypertensive patients. Results Of the 75 patients, 48 met conventional HCM diagnostic criteria and went on to act as another comparator group. Twenty-seven did not meet criteria for HCM and of these 5 had no relative apical hypertrophy and were not analyzed further. The remaining 22 patients had relative apical thickening with an apical:basal wall thickness ratio > 1 and a higher prevalence of features consistent with a cardiomyopathy than in the control groups with 54% having 2 or more of the 4 features. No individual in the healthy volunteer group had more than one feature and no hypertension patient had more than 2. Conclusion A cohort of individuals exist with T wave inversion, relative apical hypertrophy and additional imaging features of HCM suggesting an apical HCM phenotype not captured by existing diagnostic criteria. PMID:25666123

Comparing Two Methods of Cryotherapy and Intense Pulsed Light with Triamcinolone Injection in the Treatment of Keloid and Hypertrophic Scars: A Clinical Trial.

PubMed

Meymandi, Simin Shamsi; Moosazadeh, Mahmood; Rezazadeh, Azadeh

2016-10-01

Keloid and hypertrophic scars are abnormal manifestations of wounds that occur following skin injuries in the form of local proliferation of fibroblasts and increased production of collagen. There are several ways to cure these scars; treatment must be selected based on the nature of the scars. In this clinical trial, two methods-cryotherapy and intense pulsed light (IPL)-are compared in the treatment of scars, and the results are presented in terms of improvement level, complications, and patient satisfaction. This clinical trial was conducted in southeastern Iran. The intervention group included scars that underwent the IPL method and the control group, which consisted of scars that were subjected to cryotherapy. In both methods, intralesional corticosteroid injection was administered. To select samples, the easy sampling method was used. To determine the expected outcomes, the criteria determined in the Vancouver scar scale were used. Data were analyzed using the Mix Model, chi-square test, and t test. In this study, 166 samples of keloid and hypertrophic scars were cured using two methods (Cryotherapy, 83; IPL, 83). The recovery rate was higher in the Cryotherapy group than in the IPL group ( p  > 0.05), and the incidence of complications was also higher in the Cryotherapy group (14.5% vs. 12%). Moreover, patients were more satisfied, although not significantly so, with the cryotherapy method ( p  = 0.09). Both methods were highly successful in curing scars; participants were totally satisfied with both methods.

Hypertrophic remodeling of subcutaneous small resistance arteries in patients with Cushing's syndrome.

PubMed

Rizzoni, Damiano; Porteri, Enzo; De Ciuceis, Carolina; Rodella, Luigi F; Paiardi, Silvia; Rizzardi, Nicola; Platto, Caterina; Boari, Gianluca E M; Pilu, Annamaria; Tiberio, Guido A M; Giulini, Stefano M; Favero, Gaia; Rezzani, Rita; Rosei, Claudia Agabiti; Bulgari, Giuseppe; Avanzi, Daniele; Rosei, Enrico Agabiti

2009-12-01

Structural alterations of small resistance arteries in essential hypertensive patients (EH) are mostly characterized by inward eutrophic remodeling. However, we observed hypertrophic remodeling in patients with renovascular hypertension, in those with acromegaly, as well as in patients with non-insulin-dependent diabetes mellitus, suggesting a relevant effect of humoral growth factors on vascular structure, even independent from the hemodynamic load. Cortisol may stimulate the renin-angiotensin system and may induce cardiac hypertrophy. However, presently no data are available about small artery structure in patients with Cushing's syndrome. We have investigated the structure of sc small resistance arteries in 12 normotensive subjects (NT), in 12 EH subjects, and in eight patients with Cushing's syndrome (CS). Small arteries from sc fat were dissected and mounted on a micromyograph. The normalized internal diameter, media thickness, media to lumen ratio, and the media cross-sectional area were measured, as well as indices of oxidative stress. Demographic variables were similar in the three groups, except for clinic blood pressure. The media to lumen ratio was significantly greater in EH and CS, compared with NT; no difference was observed between EH and CS. The media cross-sectional area was significantly greater in CS compared with EH and with NT. An increased vascular oxidative stress was present in CS, as demonstrated by increased levels of superoxide anions, cyclooxygenase-1 and endothelial nitric oxide synthase in the microvessels. Our results suggest the presence of hypertrophic remodeling in sc small resistance arteries of CS, probably as a consequence of growth-promoting properties of circulating cortisol and/or increased vascular oxidative stress.

Cyclic tensile strain and cyclic hydrostatic pressure differentially regulate expression of hypertrophic markers in primary chondrocytes.

PubMed

Wong, Marcy; Siegrist, Mark; Goodwin, Kelly

2003-10-01

Endochondral ossification is regulated by many factors, including mechanical stimuli, which can suppress or accelerate chondrocyte maturation. Mathematical models of endochondral ossification have suggested that tension (or shear stress) can accelerate the formation of endochondral bone, while hydrostatic stress preserves the cartilage phenotype. The goal of this study was to test this hypothesis by examining the expression of hypertrophic chondrocyte markers (transcription factor Cbfa1, MMP-13, type X collagen, VEGF, CTGF) and cartilage matrix proteins under cyclic tension and cyclic hydrostatic pressure. Chondrocyte-seeded alginate constructs were exposed to one of the two loading modes for a period of 3 h per day for 3 days. Gene expression was analyzed using real-time RT-PCR. Cyclic tension upregulated the expression of Cbfa1, MMP-13, CTGF, type X collagen and VEGF and downregulated the expression of TIMP-1. Cyclic tension also upregulated the expression of type 2 collagen, COMP and lubricin, but did not change the expression of SOX9 and aggrecan. Cyclic hydrostatic pressure downregulated the expression of MMP-13 and type I collagen and upregulated expression of TIMP-1 compared to the unloaded controls. Hydrostatic pressure may slow chondrocyte differentiation and have a chondroprotective, anti-angiogenic influence on cartilage tissue. Our results suggest that cyclic tension activates the Cbfa1/MMP-13 pathway and increases the expression of terminal differentiation hypertrophic markers. Mammalian chondrocytes appear to have evolved complex mechanoresponsive mechanisms, the effects of which can be observed in the histomorphologic establishment of the cartilaginous skeleton during development and maturation.

Mice Deficient in NF-κB p50 and p52 or RANK Have Defective Growth Plate Formation and Post-natal Dwarfism.

PubMed

Xing, Lianping; Chen, Di; Boyce, Brendan F

2013-12-01

NF-κBp50/p52 double knockout (dKO) and RANK KO mice have no osteoclasts and develop severe osteopetrosis associated with dwarfism. In contrast, Op/Op mice, which form few osteoclasts, and Src KO mice, which have osteoclasts with defective resorptive function, are osteopetrotic, but they are not dwarfed. Here, we compared the morphologic features of long bones from p50/p52 dKO, RANK KO, Op/Op and Src KO mice to attempt to explain the differences in their long bone lengths. We found that growth plates in p50/p52 dKO and RANK KO mice are significantly thicker than those in WT mice due to a 2-3-fold increase in the hypertrophic chondrocyte zone associated with normal a proliferative chondrocyte zone. This growth plate abnormality disappears when animals become older, but their dwarfism persists. Op/Op or Src KO mice have relatively normal growth plate morphology. In-situ hybridization study of long bones from p50/p52 dKO mice showed marked thickening of the growth plate region containing type 10 collagen-expressing chondrocytes. Treatment of micro-mass chondrocyte cultures with RANKL did not affect expression levels of type 2 collagen and Sox9, markers for proliferative chondrocytes, but RANKL reduced the number of type 10 collagen-expressing hypertrophic chondrocytes. Thus, RANK/NF-κB signaling plays a regulatory role in post-natal endochondral ossification that maintains hypertrophic conversion and prevents dwarfism in normal mice.

Conditional inactivation of Has2 reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb.

PubMed

Matsumoto, Kazu; Li, Yingcui; Jakuba, Caroline; Sugiyama, Yoshinori; Sayo, Tetsuya; Okuno, Misako; Dealy, Caroline N; Toole, Bryan P; Takeda, Junji; Yamaguchi, Yu; Kosher, Robert A

2009-08-01

The glycosaminoglycan hyaluronan (HA) is a structural component of extracellular matrices and also interacts with cell surface receptors to directly influence cell behavior. To explore functions of HA in limb skeletal development, we conditionally inactivated the gene for HA synthase 2, Has2, in limb bud mesoderm using mice that harbor a floxed allele of Has2 and mice carrying a limb mesoderm-specific Prx1-Cre transgene. The skeletal elements of Has2-deficient limbs are severely shortened, indicating that HA is essential for normal longitudinal growth of all limb skeletal elements. Proximal phalanges are duplicated in Has2 mutant limbs indicating an involvement of HA in patterning specific portions of the digits. The growth plates of Has2-deficient skeletal elements are severely abnormal and disorganized, with a decrease in the deposition of aggrecan in the matrix and a disruption in normal columnar cellular relationships. Furthermore, there is a striking reduction in the number of hypertrophic chondrocytes and in the expression domains of markers of hypertrophic differentiation in the mutant growth plates, indicating that HA is necessary for the normal progression of chondrocyte maturation. In addition, secondary ossification centers do not form in the central regions of Has2 mutant growth plates owing to a failure of hypertrophic differentiation. In addition to skeletal defects, the formation of synovial joint cavities is defective in Has2-deficient limbs. Taken together, our results demonstrate that HA has a crucial role in skeletal growth, patterning, chondrocyte maturation and synovial joint formation in the developing limb.

A novel spectral imaging system for quantitative analysis of hypertrophic scar

NASA Astrophysics Data System (ADS)

Ghassemi, Pejhman; Shupp, Jeffrey W.; Moffatt, Lauren T.; Ramella-Roman, Jessica C.

2013-03-01

Scarring can lead to significant cosmetic, psychosocial, and functional consequences in patients with hypertrophic scars from burn and trauma injuries. Therefore, quantitative assessment of scar is needed in clinical diagnosis and treatment. The Vancouver Scar Scale (VSS), the accepted clinical scar assessment tool, was introduced in the nineties and relies only on the physician subjective evaluation of skin pliability, height, vascularity, and pigmentation. To date, no entirely objective method has been available for scar assessment. So, there is a continued need for better techniques to monitor patients with scars. We introduce a new spectral imaging system combining out-of-plane Stokes polarimetry, Spatial Frequency Domain Imaging (SFDI), and three-dimensional (3D) reconstruction. The main idea behind this system is to estimate hemoglobin and melanin contents of scar using SFDI technique, roughness and directional anisotropy features with Stokes polarimetry, and height and general shape with 3D reconstruction. Our proposed tool has several advantages compared to current methodologies. First and foremost, it is non-contact and non-invasive and thus can be used at any stage in wound healing without causing harm to the patient. Secondarily, the height, pigmentation, and hemoglobin assessments are co-registered and are based on imaging and not point measurement, allowing for more meaningful interpretation of the data. Finally, the algorithms used in the data analysis are physics based which will be very beneficial in the standardization of the technique. A swine model has also been developed for hypertrophic scarring and an ongoing pre-clinical evaluation of the technique is being conducted.

Iloprost improves ventricular function in the hypertrophic and functionally impaired right heart by direct stimulation.

PubMed

Holmboe, Sarah; Andersen, Asger; Vildbrad, Mads D; Nielsen, Jan M; Ringgaard, Steffen; Nielsen-Kudsk, Jens E

2013-12-01

Right heart function is an important predictor of morbidity and mortality in patients suffering from pulmonary arterial hypertension and congenital heart diseases. We investigated whether the prostacyclin analog iloprost has a direct inotropic effect in the pressure-overloaded hypertrophic and dysfunctional right ventricle (RV). Rats were randomized to monocrotaline injection (60 mg/kg; [Formula: see text]), pulmonary trunk banding (PTB; [Formula: see text]), or a sham operation ([Formula: see text]). RV function was evaluated with magnetic resonance imaging, echocardiography, and invasive pressure measurements at baseline, after intravenous administration of placebo, iloprost 10 ng/kg/min, or iloprost 100 ng/kg/min (Ilo100). Infusion of Ilo100 induced a [Formula: see text] ([Formula: see text]) increase in stroke volume in the sham group and a [Formula: see text] ([Formula: see text]) increase in the PTB group. RV [Formula: see text] was elevated by [Formula: see text] ([Formula: see text]) in the sham group and by [Formula: see text] ([Formula: see text]) in the PTB group. An elevation in cardiac output of [Formula: see text] ([Formula: see text]) and an [Formula: see text] ([Formula: see text]) increase in RV systolic pressure were found in the PTB group. Iloprost caused a decrease in mean arterial blood pressure (MAP) in all groups of animals. An equal reduction in MAP induced by the arterial vasodilator nitroprusside did not improve any of the measured parameters of RV function. We conclude that iloprost has inotropic properties directly improving ventricular function in the hypertrophic and dysfunctional right heart of the rat.

Thyroid Hormone-Induced Hypertrophy in Mesenchymal Stem Cell Chondrogenesis Is Mediated by Bone Morphogenetic Protein-4

PubMed Central

Karl, Alexandra; Olbrich, Norman; Pfeifer, Christian; Berner, Arne; Zellner, Johannes; Kujat, Richard; Angele, Peter; Nerlich, Michael

2014-01-01

Chondrogenic differentiating mesenchymal stem cells (MSCs) express markers of hypertrophic growth plate chondrocytes. As hypertrophic cartilage undergoes ossification, this is a concern for the application of MSCs in articular cartilage tissue engineering. To identify mechanisms that elicit this phenomenon, we used an in vitro hypertrophy model of chondrifying MSCs for differential gene expression analysis and functional experiments with the focus on bone morphogenetic protein (BMP) signaling. Hypertrophy was induced in chondrogenic MSC pellet cultures by transforming growth factor β (TGFβ) and dexamethasone withdrawal and addition of triiodothyronine. Differential gene expression analysis of BMPs and their receptors was performed. Based on these results, the in vitro hypertrophy model was used to investigate the effect of recombinant BMP4 and the BMP inhibitor Noggin. The enhancement of hypertrophy could be shown clearly by an increased cell size, alkaline phosphatase activity, and collagen type X deposition. Upon induction of hypertrophy, BMP4 and the BMP receptor 1B were upregulated. Addition of BMP4 further enhanced hypertrophy in the absence, but not in the presence of TGFβ and dexamethasone. Thyroid hormone induced hypertrophy by upregulation of BMP4 and this induced enhancement of hypertrophy could be blocked by the BMP antagonist Noggin. BMP signaling is an important modulator of the late differentiation stages in MSC chondrogenesis and the thyroid hormone induces this pathway. As cartilage tissue engineering constructs will be exposed to this factor in vivo, this study provides important insight into the biology of MSC-based cartilage. Furthermore, the possibility to engineer hypertrophic cartilage may be helpful for critical bone defect repair. PMID:23937304

Nonlinear optics for the study of human scar tissue

NASA Astrophysics Data System (ADS)

Ferro, D. P.; Vieira-Damiani, G.; Adam, R. L.; Cesar, C. L.; Metze, Konradin

2012-03-01

Collagen fibers are an essential component of the dynamic process of scarring, which accompanies various diseases. Scar tissue may reveal different morphologic expressions, such as hypertrophic scars or keloids. Collagen fibers can be visualized by fluorescent light when stained with eosin. Second Harmonic Generation (SHG) creates a non linear signal that occurs only in molecules without inversion symmetry and is particularly strong in the collagen fibers arranged in triple helices. The aim of this study was to describe the methodology for the analysis of the density and texture of collagen in keloids, hypertrophic scars and conventional scars. Samples were examined in the National Institute of Science and Technology on Photonics Applied to Cell Biology (INFABIC) at the State University of Campinas. The images were acquired in a multiphoton microscopy LSM 780-NLO Zeiss 40X. Both signals, two-photon fluorescence (TPEF) and SHG, were excited by a Mai-Tai Ti:Sapphire laser at 940 nm. We used a LP490/SP485 NDD filter for SHG, and a BP565-610 NDD filter for fluorescence In each case, ten images were acquired serially (512×512 μm) in Z-stack and joined together to one patchwork-image . Image analysis was performed by a gliding-box-system with in-house made software. Keloids, hypertrophic scars and normal scar tissue show different collagen architecture. Inside an individual case differences of the scar process may be found between central and peripheral parts. In summary, the use of nonlinear optics is a helpful tool for the study of scars tissue.

A new era in clinical genetic testing for hypertrophic cardiomyopathy.

PubMed

Wheeler, Matthew; Pavlovic, Aleksandra; DeGoma, Emil; Salisbury, Heidi; Brown, Colleen; Ashley, Euan A

2009-12-01

Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

PKA catalytic subunit compartmentation regulates contractile and hypertrophic responses to β-adrenergic signaling

PubMed Central

Yang, Jason H.; Polanowska-Grabowska, Renata K.; Smith, Jeffrey S.; Shields, Charles W.; Saucerman, Jeffrey J.

2014-01-01

β-adrenergic signaling is spatiotemporally heterogeneous in the cardiac myocyte, conferring exquisite control to sympathetic stimulation. Such heterogeneity drives the formation of protein kinase A (PKA) signaling microdomains, which regulate Ca2+ handling and contractility. Here, we test the hypothesis that the nucleus independently comprises a PKA signaling microdomain regulating myocyte hypertrophy. Spatially-targeted FRET reporters for PKA activity identified slower PKA activation and lower isoproterenol sensitivity in the nucleus (t50 = 10.60±0.68 min; EC50 = 89.00 nmol/L) than in the cytosol (t50 = 3.71±0.25 min; EC50 = 1.22 nmol/L). These differences were not explained by cAMP or AKAP-based compartmentation. A computational model of cytosolic and nuclear PKA activity was developed and predicted that differences in nuclear PKA dynamics and magnitude are regulated by slow PKA catalytic subunit diffusion, while differences in isoproterenol sensitivity are regulated by nuclear expression of protein kinase inhibitor (PKI). These were validated by FRET and immunofluorescence. The model also predicted differential phosphorylation of PKA substrates regulating cell contractility and hypertrophy. Ca2+ and cell hypertrophy measurements validated these predictions and identified higher isoproterenol sensitivity for contractile enhancements (EC50 = 1.84 nmol/L) over cell hypertrophy (EC50 = 85.88 nmol/L). Over-expression of spatially targeted PKA catalytic subunit to the cytosol or nucleus enhanced contractile and hypertrophic responses, respectively. We conclude that restricted PKA catalytic subunit diffusion is an important PKA compartmentation mechanism and the nucleus comprises a novel PKA signaling microdomain, insulating hypertrophic from contractile β-adrenergic signaling responses. PMID:24225179

The influence of hyaluronic acid hydrogel crosslinking density and macromolecular diffusivity on human MSC chondrogenesis and hypertrophy.

PubMed

Bian, Liming; Hou, Chieh; Tous, Elena; Rai, Reena; Mauck, Robert L; Burdick, Jason A

2013-01-01

Hyaluronic acid (HA) hydrogels formed via photocrosslinking provide stable 3D hydrogel environments that support the chondrogenesis of mesenchymal stem cells (MSCs). Crosslinking density has a significant impact on the physical properties of hydrogels, including their mechanical stiffness and macromolecular diffusivity. Variations in the HA hydrogel crosslinking density can be obtained by either changes in the HA macromer concentration (1, 3, or 5% w/v at 15 min exposure) or the extent of reaction through light exposure time (5% w/v at 5, 10, or 15 min). In this work, increased crosslinking by either method resulted in an overall decrease in cartilage matrix content and more restricted matrix distribution. Increased crosslinking also promoted hypertrophic differentiation of the chondrogenically induced MSCs, resulting in more matrix calcification in vitro. For example, type X collagen expression in the high crosslinking density 5% 15 min group was ~156 and 285% higher when compared to the low crosslinking density 1% 15 min and 5% 5 min groups on day 42, respectively. Supplementation with inhibitors of the small GTPase pathway involved in cytoskeletal tension or myosin II had no effect on hypertrophic differentiation and matrix calcification, indicating that the differential response is unlikely to be related to force-sensing mechanotransduction mechanisms. When implanted subcutaneously in nude mice, higher crosslinking density again resulted in reduced cartilage matrix content, restricted matrix distribution, and increased matrix calcification. This study demonstrates that hydrogel properties mediated through alterations in crosslinking density must be considered in the context of the hypertrophic differentiation of chondrogenically induced MSCs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Protein quality control in protection against systolic overload cardiomyopathy: the long term role of small heat shock proteins.

PubMed

Kumarapeli, Asangi R K; Horak, Kathleen; Wang, Xuejun

2010-07-21

Molecular chaperones represent the first line of defense of intracellular protein quality control. As a major constituent of molecular chaperones, heat shock proteins (HSP) are known to confer cardiomyocyte short-term protection against various insults and injuries. Previously, we reported that the small HSP alphaB-crystallin (CryAB) attenuates cardiac hypertrophic response in mice subjected to 2 weeks of severe pressure overload. However, the long-term role of small HSPs in cardiac hypertrophy and failure has rarely been studied. The present study investigates the cardiac responses to chronic severe pressure overload in CryAB/HSPB2 germ line ablated (KO) and cardiac-specific CryAB overexpressingtransgenic (TG) mice. Pressure overload was induced by transverse aortic constriction in KO, TG, and non-transgenic wild type (NTG) control mice and 10 weeks later molecular, cellular, and whole organ level hypertrophic responses were analyzed. As we previously described, CryAB/HSPB2 KO mice showed abnormal baseline cardiac physiology that worsened into a restrictive cardiomyopathic phenotype with aging. Severe pressure overload in these mice led to rapid deterioration of heart function and development of congestive cardiac failure. Contrary to their short term protective phenotype, CryAB TG mice showed no significant effects on cardiac hypertrophic responses and very modest improvement of hemodynamics during chronic systolic overload. These findings indicate that small HSPs CryAB and/or HSPB2 are essential to maintain cardiac structure and function but overex-pression of CryAB is not sufficient to confer a sustained protection against chronic systolic overload.

RSK3 is required for concentric myocyte hypertrophy in an activated Raf1 model for Noonan syndrome.

PubMed

Passariello, Catherine L; Martinez, Eliana C; Thakur, Hrishikesh; Cesareo, Maria; Li, Jinliang; Kapiloff, Michael S

2016-04-01

Noonan syndrome (NS) is a congenital disorder resulting from mutations of the Ras-Raf signaling pathway. Hypertrophic cardiomyopathy associated with RAF1 "RASopathy" mutations is a major risk factor for heart failure and death in NS and has been attributed to activation of MEK1/2-ERK1/2 mitogen-activated protein kinases. We recently discovered that type 3 p90 ribosomal S6 kinase (RSK3) is an ERK effector that is required, like ERK1/2, for concentric myocyte hypertrophy in response to pathological stress such as pressure overload. In order to test whether RSK3 also contributes to NS-associated hypertrophic cardiomyopathy, RSK3 knock-out mice were crossed with mice bearing the Raf1(L613V) human NS mutation. We confirmed that Raf1(L613V) knock-in confers a NS-like phenotype, including cardiac hypertrophy. Active RSK3 was increased in Raf1(L613V) mice. Constitutive RSK3 gene deletion prevented the Raf1(L613V)-dependent concentric growth in width of the cardiac myocyte and attenuated cardiac hypertrophy in female mice. These results are consistent with RSK3 being an important mediator of ERK1/2-dependent growth in RASopathy. In conjunction with previously published data showing that RSK3 is important for pathological remodeling of the heart, these data suggest that targeting of this downstream MAP-kinase pathway effector should be considered in the treatment of RASopathy-associated hypertrophic cardiomyopathy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ultrasound imaging of the thenar motor branch of the median nerve: a cadaveric study.

PubMed

Petrover, David; Bellity, Jonathan; Vigan, Marie; Nizard, Remy; Hakime, Antoine

2017-11-01

Anatomic variations of the median nerve (MN) increase the risk of iatrogenic injury during carpal tunnel release surgery. We investigated whether high-frequency ultrasonography could identify anatomic variations of the MN and its thenar motor branch (MBMN) in the carpal tunnel. For each volar wrist of healthy non-embalmed cadavers, the type of MN variant (Lanz classification), course and orientation of the MBMN, and presence of hypertrophic muscles were scored by 18-MHz ultrasound and then by dissection. MBMN was identified by ultrasound in all 30 wrists (15 subjects). By dissection, type 1, 2 and 3 variants were found in 84%, 3%, and 13% of wrists, respectively. Ultrasound had good agreement with dissection in identifying the variant type (kappa =0.9). With both techniques, extra-, sub-, and transligamentous courses were recorded in 65%, 31%, and 4% of cases, respectively. With both techniques, the bifid nerve, hypertrophic muscles, and bilateral symmetry for variant type were identified in 13.3%, 13.3%, and 86.7% of wrists, respectively. Agreement between ultrasound and dissection was excellent for the MBMN course and orientation (kappa =1). Ultrasound can be used reliably to identify anatomic variations of the MN and MBMN. It could be a useful tool before carpal tunnel release surgery. • Ultrasound can identify variations of the motor branch of the median nerve. • Ultrasound mapping should be used prior to carpal tunnel release surgery. • All sub-, extra-, and transligamentous courses were accurately identified. • Type 3 variants (bifid nerve), hypertrophic muscles, and bilateral symmetry were accurately identified.

CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy.

PubMed

Mosqueira, Diogo; Mannhardt, Ingra; Bhagwan, Jamie R; Lis-Slimak, Katarzyna; Katili, Puspita; Scott, Elizabeth; Hassan, Mustafa; Prondzynski, Maksymilian; Harmer, Stephen C; Tinker, Andrew; Smith, James G W; Carrier, Lucie; Williams, Philip M; Gaffney, Daniel; Eschenhagen, Thomas; Hansen, Arne; Denning, Chris

2018-05-08

Sarcomeric gene mutations frequently underlie hypertrophic cardiomyopathy (HCM), a prevalent and complex condition leading to left ventricle thickening and heart dysfunction. We evaluated isogenic genome-edited human pluripotent stem cell-cardiomyocytes (hPSC-CM) for their validity to model, and add clarity to, HCM. CRISPR/Cas9 editing produced 11 variants of the HCM-causing mutation c.C9123T-MYH7 [(p.R453C-β-myosin heavy chain (MHC)] in 3 independent hPSC lines. Isogenic sets were differentiated to hPSC-CMs for high-throughput, non-subjective molecular and functional assessment using 12 approaches in 2D monolayers and/or 3D engineered heart tissues. Although immature, edited hPSC-CMs exhibited the main hallmarks of HCM (hypertrophy, multi-nucleation, hypertrophic marker expression, sarcomeric disarray). Functional evaluation supported the energy depletion model due to higher metabolic respiration activity, accompanied by abnormalities in calcium handling, arrhythmias, and contraction force. Partial phenotypic rescue was achieved with ranolazine but not omecamtiv mecarbil, while RNAseq highlighted potentially novel molecular targets. Our holistic and comprehensive approach showed that energy depletion affected core cardiomyocyte functionality. The engineered R453C-βMHC-mutation triggered compensatory responses in hPSC-CMs, causing increased ATP production and αMHC to energy-efficient βMHC switching. We showed that pharmacological rescue of arrhythmias was possible, while MHY7: MYH6 and mutant: wild-type MYH7 ratios may be diagnostic, and previously undescribed lncRNAs and gene modifiers are suggestive of new mechanisms.

Regional Variations in Growth Plate Chondrocyte Deformation as Predicted By Three-Dimensional Multi-Scale Simulations

PubMed Central

Gao, Jie; Roan, Esra; Williams, John L.

2015-01-01

The physis, or growth plate, is a complex disc-shaped cartilage structure that is responsible for longitudinal bone growth. In this study, a multi-scale computational approach was undertaken to better understand how physiological loads are experienced by chondrocytes embedded inside chondrons when subjected to moderate strain under instantaneous compressive loading of the growth plate. Models of representative samples of compressed bone/growth-plate/bone from a 0.67 mm thick 4-month old bovine proximal tibial physis were subjected to a prescribed displacement equal to 20% of the growth plate thickness. At the macroscale level, the applied compressive deformation resulted in an overall compressive strain across the proliferative-hypertrophic zone of 17%. The microscale model predicted that chondrocytes sustained compressive height strains of 12% and 6% in the proliferative and hypertrophic zones, respectively, in the interior regions of the plate. This pattern was reversed within the outer 300 μm region at the free surface where cells were compressed by 10% in the proliferative and 26% in the hypertrophic zones, in agreement with experimental observations. This work provides a new approach to study growth plate behavior under compression and illustrates the need for combining computational and experimental methods to better understand the chondrocyte mechanics in the growth plate cartilage. While the current model is relevant to fast dynamic events, such as heel strike in walking, we believe this approach provides new insight into the mechanical factors that regulate bone growth at the cell level and provides a basis for developing models to help interpret experimental results at varying time scales. PMID:25885547