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Sample records for acinar atrophy paa

  1. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy. Disuse atrophy occurs from a lack of physical activity. In most people, muscle atrophy is caused by not using the ...

  2. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy: disuse and neurogenic. Disuse atrophy is caused by not using the muscles enough . This type of atrophy can often be ...

  3. Pancreatic Acinar Cell Carcinoma

    PubMed Central

    Béchade, Dominique; Desjardin, Marie; Salmon, Emma; Désolneux, Grégoire; Bécouarn, Yves; Evrard, Serge; Fonck, Marianne

    2016-01-01

    Pancreatic acinar cell carcinoma (ACC) is a rare malignant neoplasm that accounts for 1–2% of all pancreatic neoplasms. Here we report two cases of ACC and describe their clinical features, the therapies used to treat them, and their prognosis. The first patient was a 65-year-old woman who had an abdominal CT scan for a urinary infection. Fortuitously, a rounded and well-delimited corporeal pancreatic tumor was discovered. An endoscopic ultrasound (EUS)-guided fine needle aspiration revealed an ACC. During the puncture, a hypoechoic cavity appeared inside the lesion, corresponding to a probable necrotic area. Treatment consisted of a distal splenopancreatectomy. The second patient was a 75-year-old man who complained of abdominal pain. An abdominal CT scan showed a cephalic pancreatic lesion and two hepatic metastases. An EUS-guided fine needle aspiration showed a pancreatic ACC. The patient received chemotherapy with gemcitabine plus oxaliplatin (GEMOX regimen), which enabled an objective response after 6 cycles.

  4. Allograft pancreas: pale acinar nodules.

    PubMed

    Troxell, Megan L; Drachenberg, Cinthia

    2016-08-01

    Microscopic pale-staining acinar nodules were characterized in native pancreas in the 1980s under a variety of names but have been infrequently reported since. We retrospectively studied the frequency and characteristics of pale acinar nodules in allograft pancreas biopsies, as compared to a sampling of native pancreas specimens at our center. Pale acinar nodules were present in 13% (9/69) of allograft biopsies from 22% (7/32) of transplant patients, and 23% (5/22) of native pancreas surgical specimens, although more nodules per pancreas area were present in allograft needle biopsies. Acinar nodules had size of 100 to 700 μm, were periodic acid-Schiff pale, were synaptophysin negative, stained more weakly with keratin CAM 5.2 compared to surrounding parenchyma, and had a low proliferative rate. Ultrastructural evaluation revealed paucity of zymogen granules with dilated cistern-like structures. In our experience, pale acinar nodules have similar features in allograft and native pancreas specimens, yet remain of uncertain etiology and significance. PMID:27063474

  5. Atrophy of submandibular gland by the duct ligation and a blockade of SP receptor in rats

    PubMed Central

    Hishida, Sumiyo; Ozaki, Noriyuki; Honda, Takashi; Shigetomi, Toshio; Ueda, Minoru; Hibi, Hideharu; Sugiura, Yasuo

    2016-01-01

    ABSTRACT To clarify the mechanisms underlying the submandibular gland atrophies associated with ptyalolithiasis, morphological changes were examined in the rat submandibular gland following either surgical intervention of the duct or functional blockade at substance P receptors (SPRs). Progressive acinar atrophy was observed after duct ligation or avulsion of periductal tissues. This suggested that damage to periductal tissue involving nerve fibers might contribute to ligation-associated acinar atrophy. Immunohistochemically labeled-substance P positive nerve fibers (SPFs) coursed in parallel with the main duct and were distributed around the interlobular, striated, granular and intercalated duct, and glandular acini. Strong SPR immunoreactivity was observed in the duct. Injection into the submandibular gland of a SPR antagonist induced marked acinar atrophy. The results revealed that disturbance of SPFs and SPRs might be involved in the atrophy of the submandibular gland associated with ptyalolithiasis. PMID:27303108

  6. Cerebral Atrophy

    MedlinePlus

    ... In brain tissue, atrophy describes a loss of neurons and the connections between them. Atrophy can be ... syndrome, which interfere with the basic functions of neurons multiple sclerosis , which causes inflammation, myelin damage, and ...

  7. Poly(aspartic acid) (PAA) hydrolases and PAA biodegradation: current knowledge and impact on applications.

    PubMed

    Hiraishi, Tomohiro

    2016-02-01

    Thermally synthesized poly(aspartic acid) (tPAA) is a bio-based, biocompatible, biodegradable, and water-soluble polymer that has a high proportion of β-Asp units and equivalent moles of D- and L-Asp units. Poly(aspartic acid) (PAA) hydrolase-1 and hydrolase-2 are tPAA biodegradation enzymes purified from Gram-negative bacteria. PAA hydrolase-1 selectively cleaves amide bonds between β-Asp units via an endo-type process, whereas PAA hydrolase-2 catalyzes the exo-type hydrolysis of the products of tPAA hydrolysis by PAA hydrolase-1. The novel reactivity of PAA hydrolase-1 makes it a good candidate for a biocatalyst in β-peptide synthesis. This mini-review gives an overview of PAA hydrolases with emphasis on their biochemical and functional properties, in particular, PAA hydrolase-1. Functionally related enzymes, such as poly(R-3-hydroxybutyrate) depolymerases and β-aminopeptidases, are compared to PAA hydrolases. This mini-review also provides findings that offer an insight into the catalytic mechanisms of PAA hydrolase-1 from Pedobacter sp. KP-2. PMID:26695157

  8. Multiple System Atrophy

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Multiple System Atrophy Information Page Condensed from Multiple System Atrophy ... Trials Organizations Publicaciones en Español What is Multiple System Atrophy? Multiple system atrophy (MSA) is a progressive ...

  9. RADIAL TRANSPORT ALONG THE HUMAN ACINAR TREE

    PubMed Central

    Henry, F.S.; Tsuda, A.

    2013-01-01

    A numerical model of an expanding asymmetric alveolated duct was developed and used to investigate lateral transport between the central acinar channel and the surrounding alveoli along the acinar tree. Our results indicate that some degree of recirculation occurs in all but the terminal generations. We found that the rate of diffusional transport of axial momentum, from the duct to the alveolus, was by far the largest contributor to the resulting momentum in the alveolar flow but that the magnitude of the axial momentum is critical in determining the nature of the flow in the alveolus. Further, we found that alveolar flow rotation, and by implication chaotic mixing, are strongest in the entrance generations. We also found that the expanding alveolus provides a pathway by which particles with little intrinsic motion can enter the alveoli. Thus, our results offer a possible explanation for why submicron particles deposit preferentially in acinar entrance region. PMID:20887011

  10. Sudeck atrophy.

    PubMed

    Staunton, H

    2006-01-01

    This paper reviews the contribution of Sudeck to the understanding of the condition commonly referred to as 'Sudeck's atrophy' and which is commonly used as a synonym for a condition variously called reflex sympathetic dystrophy, causalgia, algodystrophy and others. Sudeck came to show in his later papers that the so-called atrophy was, in the majority of cases, a normal inflammatory process of bone change in the course of healing after an inflammatory/infective or traumatic insult. Contrary to the views of much current literature, the vast majority of such cases had a good prognosis. In those cases which became pathological and had a correspondingly poorer prognosis, the characteristic clinical picture becomes associated with radiological and pathological changes, which, uniquely, are described by Sudeck. A knowledge of such radiological and pathological substrate for clinical symptomatology is important in the analysis of pain following trauma. PMID:17274178

  11. PD2/Paf1 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia

    PubMed Central

    Dey, Parama; Rachagani, Satyanarayana; Vaz, Arokia P.; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2014-01-01

    Pancreatic differentiation 2 (PD2), a PAF (RNA Polymerase II Associated Factor) complex subunit, is overexpressed in pancreatic cancer cells and has demonstrated potential oncogenic property. Here, we report that PD2/Paf1 expression was restricted to acinar cells in the normal murine pancreas, but its expression increased in the ductal cells of Pdx1Cre; KrasG12D (KC) mouse model of pancreatic cancer with increasing age, showing highest expression in neoplastic ductal cells of 50 weeks old mice. PD2/Paf1 was specifically expressed in amylase and CK19 double positive metaplastic ducts, representing intermediate structures during pancreatic acinar-to-ductal metaplasia (ADM). Similar PD2/Paf1 expression was observed in murine pancreas that exhibited ADM-like histology upon cerulein challenge. In normal mice, cerulein-mediated inflammation induced a decrease in PD2/Paf1 expression, which was later restored upon recovery of the pancreatic parenchyma. In KC mice, however, PD2/Paf1 mRNA level continued to decrease with progressive dysplasia and subsequent neoplastic transformation. Additionally, knockdown of PD2/Paf1 in pancreatic acinar cells resulted in the abrogation of Amylase, Elastase and Lipase (acinar marker) mRNA levels with simultaneous increase in CK19 and CAII (ductal marker) transcripts. In conclusion, our studies indicate loss of PD2/Paf1 expression during acinar transdifferentiation in pancreatic cancer initiation and PD2/Paf1 mediated regulation of lineage specific markers. PMID:24947474

  12. PD2/Paf1 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia.

    PubMed

    Dey, Parama; Rachagani, Satyanarayana; Vaz, Arokia P; Ponnusamy, Moorthy P; Batra, Surinder K

    2014-06-30

    Pancreatic differentiation 2 (PD2), a PAF (RNA Polymerase II Associated Factor) complex subunit, is overexpressed in pancreatic cancer cells and has demonstrated potential oncogenic property. Here, we report that PD2/Paf1 expression was restricted to acinar cells in the normal murine pancreas, but its expression increased in the ductal cells of KrasG12D/Pdx1Cre (KC) mouse model of pancreatic cancer with increasing age, showing highest expression in neoplastic ductal cells of 50 weeks old mice. PD2/Paf1 was specifically expressed in amylase and CK19 double positive metaplastic ducts, representing intermediate structures during pancreatic acinar-to-ductal metaplasia (ADM). Similar PD2/Paf1 expression was observed in murine pancreas that exhibited ADM-like histology upon cerulein challenge. In normal mice, cerulein-mediated inflammation induced a decrease in PD2/Paf1 expression, which was later restored upon recovery of the pancreatic parenchyma. In KC mice, however, PD2/Paf1 mRNA level continued to decrease with progressive dysplasia and subsequent neoplastic transformation. Additionally, knockdown of PD2/Paf1 in pancreatic acinar cells resulted in the abrogation of Amylase, Elastase and Lipase (acinar marker) mRNA levels with simultaneous increase in CK19 and CAII (ductal marker) transcripts. In conclusion, our studies indicate loss of PD2/Paf1 expression during acinar transdifferentiation in pancreatic cancer initiation and PD2/Paf1 mediated regulation of lineage specific markers. PMID:24947474

  13. Multifunctional ORMOSIL and PAA nanoparticles

    NASA Astrophysics Data System (ADS)

    Gupta, Anurag; Rao, K. V. R.; Pera, Paula; Wang, Shouyan J.; Missert, Joseph R.; Ohulchanskyy, Tymish; Roy, Indrajit; Morgan, Janet; Prasad, Paras N.; Kopelman, Raoul; Pandey, Ravindra K.

    2009-06-01

    Various problems arising during molecular imaging of different fluoroprobes and metabolites used in PDT can be circumvented by focusing on multifunctional therapy agents. Thus an effective photo sensitizer coupled with other useful roles to play in PDT treatment make nanoparticles as a good vehicle for different delivery assuming multifunctional roles not only in PDT but also as therapeutic agents for targeted delivery. A new approach is the involving use of 100 nm NPs as photo sensitizers and/or imaging agents. In our Lab., we employ two such NPs and are ORMOSIL (organically Modified Silica) and PAA (Polyacrylamide) which are found to be biologically very safe without disturbing the therapeutic value. The size of the nanoparticles determined by TEM and Dynamic Light Scattering are ~30 nm. These NPs are taken up in conjunction with cyanine dye at near infra red as it has been reported in literature that encapsulated NPs shows very low singlet oxygen production compared with the post-loaded NPs though the reasons are not yet clear. Therefore, we investigated the idea of post-loading or adsorbing vis-a-vis encapsulation.

  14. Geographic Atrophy

    PubMed Central

    Bird, Alan C.; Phillips, Rachel L.; Hageman, Gregory S.

    2014-01-01

    IMPORTANCE Geographic atrophy (GA) is the major cause of blind registration in Western communities, although, with few exceptions, it is less common than choroidal neovascular disease. The variation of phenotype implies that age-related macular degeneration (AMD) does not follow the same course from one case to another and that phenotyping may be important before initiating a therapeutic trial. OBJECTIVE To document photoreceptor and retinal pigment epithelium (RPE) cell loss and other changes at the RPE-choroid interface in donated human eyes in which visual loss was deemed to be due to GA. DESIGN, SETTING, AND PARTICIPANTS Histological study of a consecutive series of eyes donated by individuals previously diagnosed clinically as having GA. Donors were chosen on the basis of available clinical records (from MidAmerica Transplant Services, St Louis, Missouri; the Iowa Lions Eye Bank, Iowa City; and the Utah Lions Eye Bank, Salt Lake City) and selected were those considered to have GA due to AMD. Tissues in the regions of atrophy were examined with light, electron, and autofluorescence microscopy. RESULTS In most of the 37 donors examined, there was marked loss of photoreceptor cells for variable distances distal from the edge of the GA. Rod loss was greater than cone loss. An inverse relationship existed between the quantity of autofluorescent inclusions in the RPE and the thickness of sub-RPE basal laminar deposit. Integrity of the choroid varied from one eye to another and was not related strictly to photoreceptor survival. In some eyes, photoreceptor loss existed in the absence of obvious morphological changes in the Bruch membrane or RPE. CONCLUSIONS AND RELEVANCE The findings support the view that photoreceptor loss occurs early in AMD in a proportion of cases and imply that photoreceptor-cell loss may contribute to the functional loss recorded in early stages of AMD at least in part. The variation of changes from one eye to another implies that patients

  15. Activation of mTOR coincides with autophagy during ligation-induced atrophy in the rat submandibular gland

    PubMed Central

    Silver, N; Proctor, G B; Arno, M; Carpenter, G H

    2010-01-01

    Salivary gland atrophy is a common consequence of pathology, including Sjögren's syndrome, irradiation therapy and obstructive sialadenitis. During severe atrophy of the rat submandibular gland caused by excretory duct ligation, the majority of acinar cells disappear through apoptosis, whereas ductal cells proliferate and dedifferentiate; yet, the gland can survive in the atrophic state almost indefinitely, with an ability to fully recover if deligated. The control mechanisms governing these observations are not well understood. We report that ∼10% of acinar cells survive in ligation-induced atrophy. Microarray and quantitative real-time PCR analysis of ligated glands indicated sustained transcription of acinar cell-specific genes, whereas ductal-specific genes were reduced to background levels. After 3 days of ligation, activation of the mammalian target of rapamycin (mTOR) pathway and autophagy occurred as shown by phosphorylation of 4E-BP1 and expression of autophagy-related proteins. These results suggest that activation of mTOR and the autophagosomal pathway are important mechanisms that may help to preserve acinar cells during atrophy of salivary glands after injury. PMID:20890458

  16. Alveolar mechanics using realistic acinar models

    NASA Astrophysics Data System (ADS)

    Kumar, Haribalan; Lin, Ching-Long; Tawhai, Merryn H.; Hoffman, Eric A.

    2009-11-01

    Accurate modeling of the mechanics in terminal airspaces of the lung is desirable for study of particle transport and pathology. The flow in the acinar region is traditionally studied by employing prescribed boundary conditions to represent rhythmic breathing and volumetric expansion. Conventional models utilize simplified spherical or polygonal units to represent the alveolar duct and sac. Accurate prediction of flow and transport characteristics may require geometries reconstructed from CT-based images and serve to understand the importance of physiologically realistic representation of the acinus. In this effort, we present a stabilized finite element framework, supplemented with appropriate boundary conditions at the alveolar mouth and septal borders for simulation of the alveolar mechanics and the resulting airflow. Results of material advection based on Lagrangian tracking are presented to complete the study of transport and compare the results with simplified acinar models. The current formulation provides improved understanding and realization of a dynamic framework for parenchymal mechanics with incorporation of alveolar pressure and traction stresses.

  17. Optic nerve atrophy

    MedlinePlus

    Optic atrophy; Optic neuropathy ... There are many causes of optic atrophy. The most common is poor blood flow. This is called ischemic optic neuropathy. The problem most often affects older adults. ...

  18. Multiple system atrophy

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/000757.htm Multiple system atrophy To use the sharing features on this page, please enable JavaScript. Multiple system atrophy (MSA) is a rare condition that causes ...

  19. A Microfluidic Model of Biomimetically Breathing Pulmonary Acinar Airways.

    PubMed

    Fishler, Rami; Sznitman, Josué

    2016-01-01

    Quantifying respiratory flow characteristics in the pulmonary acinar depths and how they influence inhaled aerosol transport is critical towards optimizing drug inhalation techniques as well as predicting deposition patterns of potentially toxic airborne particles in the pulmonary alveoli. Here, soft-lithography techniques are used to fabricate complex acinar-like airway structures at the truthful anatomical length-scales that reproduce physiological acinar flow phenomena in an optically accessible system. The microfluidic device features 5 generations of bifurcating alveolated ducts with periodically expanding and contracting walls. Wall actuation is achieved by altering the pressure inside water-filled chambers surrounding the thin PDMS acinar channel walls both from the sides and the top of the device. In contrast to common multilayer microfluidic devices, where the stacking of several PDMS molds is required, a simple method is presented to fabricate the top chamber by embedding the barrel section of a syringe into the PDMS mold. This novel microfluidic setup delivers physiological breathing motions which in turn give rise to characteristic acinar air-flows. In the current study, micro particle image velocimetry (µPIV) with liquid suspended particles was used to quantify such air flows based on hydrodynamic similarity matching. The good agreement between µPIV results and expected acinar flow phenomena suggest that the microfluidic platform may serve in the near future as an attractive in vitro tool to investigate directly airborne representative particle transport and deposition in the acinar regions of the lungs. PMID:27214269

  20. Gabapentin-induced mitogenic activity in rat pancreatic acinar cells.

    PubMed

    Dethloff, L; Barr, B; Bestervelt, L; Bulera, S; Sigler, R; LaGattuta, M; de La Iglesia, F

    2000-05-01

    Gabapentin induces pancreatic acinar cell tumors in rats through unknown, yet apparently nongenotoxic mechanisms. The primary objective of this study was to determine whether gabapentin acts as a tumor promoter by stimulating acinar cell proliferation in rat pancreas. To this end, indices of pancreatic growth, including increased pancreatic weight, stimulation of acinar cell proliferation, and/or enhanced expression of immediate-early oncogenes were monitored in rats given gabapentin in the diet at 2 g/kg/day for up to 12 months. Rats fed raw soy flour (RSF), a known inducer of pancreatic acinar cell tumors through cholecystokinin-mediated mitogenic stimulation, were used throughout as positive controls. In addition, recent data suggests that gabapentin binds to the alpha(2)delta subunit of a voltage-gated, L-type calcium channel. Because signaling pathways for proliferative processes in pancreatic acinar cells involve intracellular calcium mobilization, the effects of gabapentin on intracellular calcium mobilization ([Ca(2+)](i)) and (3)H-thymidine incorporation were investigated in pancreatic acinar cells isolated from normal rat pancreas and in the AR42J rat pancreatic tumor cell line. As indicated by BrdU labeling indices, acinar cell proliferation increased 3-fold by Day 3 of RSF treatment and remained slightly greater than controls throughout the experiment. Pancreatic weights of RSF-fed rats were 32 to 56% greater than controls throughout the experiment. In contrast, gabapentin had no effect on pancreatic weight or acinar cell labeling index, and therefore had no apparent effect on pancreatic growth. In isolated pancreatic acinar cells, however, gabapentin induced mobilization of intracellular calcium and caused a slight increase in (3)H-thymidine incorporation. The data suggest that gabapentin may possess low level mitogenic activity, which is not easily detectable in in vivo assays. PMID:10788559

  1. TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells

    PubMed Central

    Liu, Jun; Akanuma, Naoki; Liu, Chengyang; Naji, Ali; Halff, Glenn A.; Washburn, William K.; Sun, Luzhe; Wang, Pei

    2016-01-01

    Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases. PMID:27485764

  2. TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells.

    PubMed

    Liu, Jun; Akanuma, Naoki; Liu, Chengyang; Naji, Ali; Halff, Glenn A; Washburn, William K; Sun, Luzhe; Wang, Pei

    2016-01-01

    Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases. PMID:27485764

  3. NGAP: A (Brief) Update PaaS, IaaS, Onbording, and the Future

    NASA Technical Reports Server (NTRS)

    McLaughlin, Brett; Pawloski, Andrew

    2016-01-01

    NASA ESDIS has charged the EED2 program with delivering a NASA-compliant, secure, cloud-based platform for application hosting. More than just a move to the cloud, this has forced us to examine all aspects of application hosting, from resource management to system administration, patching to monitoring, deployment to multiple environments. The result of this mandate is NGAP, the NASA General Application Platform. In this presentation, we will also discuss the various applications we are supporting and targeting, and their architectures including NGAPs move to support both PaaS and IaaS architectures.

  4. Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer

    PubMed Central

    Wong, Chi-Hin; Li, You-Jia; Chen, Yang-Chao

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRasG12D mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of PanIN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching PanIN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC. PMID:27610015

  5. Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer.

    PubMed

    Wong, Chi-Hin; Li, You-Jia; Chen, Yang-Chao

    2016-08-21

    Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of PanIN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching PanIN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC. PMID:27610015

  6. Dynamic peracetic acid (PAA) exposure, a treatment strategy against ectoparasites

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The search for alternative therapeutic agents is a difficult and laborious task. The use of peracetic acid (PAA) has recently been evaluated as an alternative compound for disinfection (Gustavino et al., 2005). In addition to having a broad antimicrobial spectrum, PAA does not contribute to the form...

  7. Optic nerve atrophy

    MedlinePlus

    Optic nerve atrophy is damage to the optic nerve. The optic nerve carries images of what the eye sees to ... problem most often affects older adults. The optic nerve can also be damaged by shock, toxins, radiation, ...

  8. Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice

    PubMed Central

    Li, Ning; Wu, Xuefeng; Holzer, Ryan G.; Lee, Jun-Hee; Todoric, Jelena; Park, Eek-Joong; Ogata, Hisanobu; Gukovskaya, Anna S.; Gukovsky, Ilya; Pizzo, Donald P.; VandenBerg, Scott; Tarin, David; Atay, Çiǧdem; Arkan, Melek C.; Deerinck, Thomas J.; Moscat, Jorge; Diaz-Meco, Maria; Dawson, David; Erkan, Mert; Kleeff, Jörg; Karin, Michael

    2013-01-01

    Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of IκB kinase α (IKKα) in pancreatic homeostasis. Pancreas-specific ablation of IKKα (IkkαΔpan) caused spontaneous and progressive acinar cell vacuolization and death, interstitial fibrosis, inflammation, and circulatory release of pancreatic enzymes, clinical signs resembling those of human chronic pancreatitis. Loss of pancreatic IKKα causes defective autophagic protein degradation, leading to accumulation of p62-mediated protein aggregates and enhanced oxidative and ER stress in acinar cells, but none of these effects is related to NF-κB. Pancreas-specific p62 ablation prevented ER and oxidative stresses and attenuated pancreatitis in IkkαΔpan mice, suggesting that cellular stress induced by p62 aggregates promotes development of pancreatitis. Importantly, downregulation of IKKα and accumulation of p62 aggregates were also observed in chronic human pancreatitis. Our studies demonstrate that IKKα, which may control autophagic protein degradation through its interaction with ATG16L2, plays a critical role in maintaining pancreatic acinar cell homeostasis, whose dysregulation promotes pancreatitis through p62 aggregate accumulation. PMID:23563314

  9. Effects of Benzodiazepines on Acinar and Myoepithelial Cells

    PubMed Central

    Mattioli, Tatiana M. F.; Alanis, Luciana R. A.; Sapelli, Silvana da Silva; de Lima, Antonio A. S.; de Noronha, Lucia; Rosa, Edvaldo A. R.; Althobaiti, Yusuf S.; Almalki, Atiah H.; Sari, Youssef; Ignacio, Sergio A.; Johann, Aline C. B. R.; Gregio, Ana M. T.

    2016-01-01

    Background: Benzodiazepines (BZDs), the most commonly prescribed psychotropic drugs with anxiolytic action, may cause hyposalivation. It has been previously shown that BZDs can cause hypertrophy and decrease the acini cell number. In this study, we investigated the effects of BZDs and pilocarpine on rat parotid glands, specifically on acinar, ductal, and myoepithelial cells. Methods: Ninety male Wistar rats were divided into nine groups. Control groups received a saline solution for 30 days (C30) and 60 days (C60), and pilocarpine (PILO) for 60 days. Experimental groups received lorazepam (L30) and midazolam (M30) for 30 days. Another group (LS60 or MS60) received lorazepam or midazolam for 30 days, respectively, and saline for additional 30 days. Finally, other groups (LP60 or MP60) received either lorazepam or midazolam for 30 days, respectively, and pilocarpine for additional 30 days. The expression of calponin in myoepithelial cells and the proliferating cell nuclear antigen (PCNA) in acinar and ductal cells were evaluated. Results: Animals treated with lorazepam showed an increase in the number of positive staining cells for calponin as compared to control animals (p < 0.05). Midazolam administered with pilocarpine (MP60) induced an increase in the proliferation of acinar and ductal cells and a decrease in the positive staining cells for calponin as compared to midazolam administered with saline (MS60). Conclusion: We found that myoepithelial cells might be more sensitive to the effects of BZD than acinar and ductal cells in rat parotid glands. PMID:27445812

  10. Bed Rest Muscular Atrophy

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.

    2000-01-01

    A major debilitating response from prolonged bed rest (BR) is muscle atrophy, defined as a "decrease in size of a part of tissue after full development has been attained: a wasting away of tissue as from disuse, old age, injury or disease". Part of the complicated mechanism for the dizziness, increased body instability, and exaggerated gait in patients who arise immediately after BR may be a result of not only foot pain, but also of muscular atrophy and associated reduction in lower limb strength. Also, there seems to be a close association between muscle atrophy and bone atrophy. A discussion of many facets of the total BR homeostatic syndrome has been published. The old adage that use determines form which promotes function of bone (Wolff's law) also applies to those people exposed to prolonged BR (without exercise training) in whom muscle atrophy is a consistent finding. An extreme case involved a 16-year-old boy who was ordered to bed by his mother in 1932: after 50 years in bed he had "a lily-white frame with limbs as thin as the legs of a ladder-back chair". These findings emphasize the close relationship between muscle atrophy and bone atrophy. In addition to loss of muscle mass during deconditioning, there is a significant loss of muscle strength and a decrease in protein synthesis. Because the decreases in force (strength) are proportionately greater than those in fiber size or muscle cross-sectional area, other contributory factors must be involved; muscle fiber dehydration may be important.

  11. Acinar Cell Carcinoma of the Pancreas: Clinical and Cytomorphologic Characteristics

    PubMed Central

    Toll, Adam D.; Hruban, Ralph H.

    2013-01-01

    Acinar cell carcinoma is a rare malignant epithelial neoplasm with predominantly exocrine acinar differentiation and is seen primarily in older men (mean age, 62 years). The presenting symptoms are usually non-specific, and jaundice is often not present. Symptoms relating to the overproduction and release of lipase into the circulation are present in 10-15% of patients. Characteristic cytomorphologic features include a population of cells with minimal pleomorphism, eccentrically placed nuclei with a single prominent nucleoli and moderate hyperchromasia. The cytoplasm is finely granular, and the background may contain granular debris secondary to cytolysis. A significant proportion of the cases also have a minor neuroendocrine component or scattered neuroendocrine cells. Approximately 50% of patients have metastatic disease at presentation, often restricted to the regional lymph nodes and liver. The prognosis is poor, only slightly better than that of pancreatic ductal adenocarcinoma. PMID:23667367

  12. Research opportunities in muscle atrophy

    NASA Technical Reports Server (NTRS)

    Herbison, G. J. (Editor); Talbot, J. M. (Editor)

    1984-01-01

    Muscle atrophy in a weightless environment is studied. Topics of investigation include physiological factors of muscle atrophy in space flight, biochemistry, countermeasures, modelling of atrophied muscle tissue, and various methods of measurement of muscle strength and endurance. A review of the current literature and suggestions for future research are included.

  13. Protein-protein interactions in the β-oxidation part of the phenylacetate utilization pathway: crystal structure of the PaaF-PaaG hydratase-isomerase complex.

    PubMed

    Grishin, Andrey M; Ajamian, Eunice; Zhang, Linhua; Rouiller, Isabelle; Bostina, Mihnea; Cygler, Miroslaw

    2012-11-01

    Microbial anaerobic and so-called hybrid pathways for degradation of aromatic compounds contain β-oxidation-like steps. These reactions convert the product of the opening of the aromatic ring to common metabolites. The hybrid phenylacetate degradation pathway is encoded in Escherichia coli by the paa operon containing genes for 10 enzymes. Previously, we have analyzed protein-protein interactions among the enzymes catalyzing the initial oxidation steps in the paa pathway (Grishin, A. M., Ajamian, E., Tao, L., Zhang, L., Menard, R., and Cygler, M. (2011) J. Biol. Chem. 286, 10735-10743). Here we report characterization of interactions between the remaining enzymes of this pathway and show another stable complex, PaaFG, an enoyl-CoA hydratase and enoyl-Coa isomerase, both belonging to the crotonase superfamily. These steps are biochemically similar to the well studied fatty acid β-oxidation, which can be catalyzed by individual monofunctional enzymes, multifunctional enzymes comprising several domains, or enzymatic complexes such as the bacterial fatty acid β-oxidation complex. We have determined the structure of the PaaFG complex and determined that although individually PaaF and PaaG are similar to enzymes from the fatty acid β-oxidation pathway, the structure of the complex is dissimilar from bacterial fatty acid β-oxidation complexes. The PaaFG complex has a four-layered structure composed of homotrimeric discs of PaaF and PaaG. The active sites of PaaF and PaaG are adapted to accept the intermediary components of the Paa pathway, different from those of the fatty acid β-oxidation. The association of PaaF and PaaG into a stable complex might serve to speed up the steps of the pathway following the conversion of phenylacetyl-CoA to a toxic and unstable epoxide-CoA by PaaABCE monooxygenase. PMID:22961985

  14. [Muscle fiber atrophy].

    PubMed

    Nonaka, Ikuya

    2012-01-01

    Muscle fibers have been classified into two major forms of red (slow twitch) and white (fast twitch) muscles. The red muscle utilizes lipid as energy source through mitochondrial metabolism and function to sustain the position against gravity (sometimes called as antigravity muscle). Under microgravity the red muscle is selectively involved. In our unloading study by hindlimb suspension experiment on rats, the one of the representative red muscle of soleus muscle underwent rapid atrophy; they reduced their weights about 50% after 2 week-unloading. In addition, myofibrils were occasionally markedly disorganized with selective thin filament loss. Mitochondria in the degenerated area were decreased in number. The white muscle fibers in the soleus muscle had mostly transformed to the red ones. It took about 1 month to recover morphologically. The satellite cell playing a major role in muscle regeneration was not activated. There still remained unsolved what are the mechanosensors to keep muscle function under normal gravity. Dr Nikawa's group proposed that one of ubiquitin ligases, Cbl-b is activated under microgravity and induces muscle fiber degeneration. There might be many factors to induce muscle atrophy and degeneration under microgravity. Further study is necessary to explore the pathomechanism of muscle atrophy in disused and under immobility conditions. PMID:23196603

  15. Serotonin promotes acinar dedifferentiation following pancreatitis-induced regeneration in the adult pancreas.

    PubMed

    Saponara, Enrica; Grabliauskaite, Kamile; Bombardo, Marta; Buzzi, Raphael; Silva, Alberto B; Malagola, Ermanno; Tian, Yinghua; Hehl, Adrian B; Schraner, Elisabeth M; Seleznik, Gitta M; Zabel, Anja; Reding, Theresia; Sonda, Sabrina; Graf, Rolf

    2015-12-01

    The exocrine pancreas exhibits a distinctive capacity for tissue regeneration and renewal following injury. This regenerative ability has important implications for a variety of disorders, including pancreatitis and pancreatic cancer, diseases associated with high morbidity and mortality. Thus, understanding its underlying mechanisms may help in developing therapeutic interventions. Serotonin has been recognized as a potent mitogen for a variety of cells and tissues. Here we investigated whether serotonin exerts a mitogenic effect in pancreatic acinar cells in three regenerative models, inflammatory tissue injury following pancreatitis, tissue loss following partial pancreatectomy, and thyroid hormone-stimulated acinar proliferation. Genetic and pharmacological techniques were used to modulate serotonin levels in vivo. Acinar dedifferentiation and cell cycle progression during the regenerative phase were investigated over the course of 2 weeks. By comparing acinar proliferation in the different murine models of regeneration, we found that serotonin did not affect the clonal regeneration of mature acinar cells. Serotonin was, however, required for acinar dedifferentiation following inflammation-mediated tissue injury. Specifically, lack of serotonin resulted in delayed up-regulation of progenitor genes and delayed the formation of acinar-to-ductal metaplasia and defective acinar cell proliferation. We identified serotonin-dependent acinar secretion as a key step in progenitor-based regeneration, as it promoted acinar cell dedifferentiation and the recruitment of type 2 macrophages. Finally, we identified a regulatory Hes1-Ptfa axis in the uninjured adult pancreas, activated by zymogen secretion. Our findings indicated that serotonin plays a critical role in the regeneration of the adult pancreas following pancreatitis by promoting the dedifferentiation of acinar cells. PMID:26235267

  16. Acute toxicity of peracetic acid (PAA) to Ichthyophthirius multifiliis theronts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peracetic acid (PAA) is an antimicrobial disinfectant used in agriculture, food processing and medical facilities. It has recently been suggested as a means to control infestations of Ichthyophthirius multifiliis. The purpose of this study was to determine the acute toxicity of two products contai...

  17. Acute toxicity of peracetic acid (PAA) to fish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peracetic acid (PAA; also called peroxyacetic acid) is a promising new aquatic disinfectant that has also been used to treat parasites and fungus. It is registered with the U.S. Environmental Protection Agency (EPA) as an antimicrobial compound approved for indoor use on hard, non-porous surfaces. T...

  18. Functional somatostatin receptors on a rat pancreatic acinar cell line

    SciTech Connect

    Viguerie, N.; Tahiri-Jouti, N.; Esteve, J.P.; Clerc, P.; Logsdon, C.; Svoboda, M.; Susini, C.; Vaysse, N.; Ribet, A. Mount Zion Hospital and Medical Center, San Francisco, CA Universite Libre de Bruxelles, Brussels )

    1988-07-01

    Somatostatin receptors from a rat pancreatic acinar cell line, AR4-2J, were characterized biochemically, structurally, and functionally. Binding of {sup 125}I-(Tyr{sup 11})Somatostatin to AR4-2J cells was saturable, exhibiting a single class of high-affinity binding sites with a maximal binding capacity of 258 {plus minus} 20 fmol/10{sup 6} cells. Somatostatin receptor structure was analyzed by covalently cross-linking {sup 125}I-(Tyr{sup 11})somatostatin to its plasma membrane receptors. Gel electrophoresis and autoradiography of cross-linked proteins revealed a peptide containing the somatostatin receptor. Somatostatin inhibited vasoactive intestinal peptide (VIP)-stimulated adenosine 3{prime},5{prime}-cyclic monophosphate (cAMP) formation in a dose-dependent manner. The concentration of somatostatin that caused half-maximal inhibition of cAMP formation was close to the receptor affinity for somatostatin. Pertussis toxin pretreatment of AR4-2J cells prevented somatostatin inhibition of VIP-stimulated cAMP formation as well as somatostatin binding. The authors conclude that AR4-2J cells exhibit functional somatostatin receptors that retain both specificity and affinity of the pancreatic acinar cell somatostatin receptors and act via the pertussis toxin-sensitive guanine nucleotide-binding protein N{sub i} to inhibit adenylate cyclase.

  19. Proteoglycans support proper granule formation in pancreatic acinar cells.

    PubMed

    Aroso, Miguel; Agricola, Brigitte; Hacker, Christian; Schrader, Michael

    2015-10-01

    Zymogen granules (ZG) are specialized organelles in the exocrine pancreas which allow digestive enzyme storage and regulated secretion. The molecular mechanisms of their biogenesis and the sorting of zymogens are still incompletely understood. Here, we investigated the role of proteoglycans in granule formation and secretion of zymogens in pancreatic AR42J cells, an acinar model system. Cupromeronic Blue cytochemistry and biochemical studies revealed an association of proteoglycans primarily with the granule membrane. Removal of proteoglycans by carbonate treatment led to a loss of membrane curvature indicating a supportive role in the maintenance of membrane shape and stability. Chemical inhibition of proteoglycan synthesis impaired the formation of normal electron-dense granules in AR42J cells and resulted in the formation of unusually small granule structures. These structures still contained the zymogen carboxypeptidase, a cargo molecule of secretory granules, but migrated to lighter fractions after density gradient centrifugation. Furthermore, the basal secretion of amylase was increased in AR42J cells after inhibitor treatment. In addition, irregular-shaped granules appeared in pancreatic lobules. We conclude that the assembly of a proteoglycan scaffold at the ZG membrane is supporting efficient packaging of zymogens and the proper formation of stimulus-competent storage granules in acinar cells of the pancreas. PMID:26105026

  20. PERI-ANESTHESIA ANAPHYLAXIS (PAA): WE STILL HAVE NOT STARTED POST-PAA TESTING FOR INCITING ANESTHESIA-RELATED ALLERGENS.

    PubMed

    Alshaeri, Taghreed; Gupta, Deepak; Nagabhushana, Ananthamurthy

    2016-02-01

    Anaphylaxis during anesthesia is uncommon. Diagnosis of peri-anesthesia anaphylaxis (PAA) requires anesthesia providers' vigilance for prompt diagnosis and treatment. In this case report, we present a challenging case with suspected PAA including its perioperative management, intensive care unit (ICU) course, and post-discharge follow-up. A 44-year-old female (body mass index = 26) presented for elective abdominal panniculectomy. Post-intubation, severe bronchospasm occurred that was non-responsive to nebulized albuterol and intravenous epinephrine. Continuous infusion of epinephrine was initiated. After aborting surgical procedure, the patient was transferred to ICU on continuous intravenous infusion of epinephrine. Venous blood sampling showed elevated troponin level. Echocardiography revealed ejection fraction of 25% suspicious of Takotsubo cardiomyopathy (mid cavitary variant). Tracheal extubation was only possible after three days. Subsequently, patient was discharged home with a cardiology follow-up appointment and a referral to an allergy specialist. Unfortunately at our institution (an academic university hospital in United States) along with neighboring institutions in near-by areas, the only allergy skin tests available are for local anesthetics and antibiotics, while neuromuscular blocking agents (NMBAs) cannot be tested (the suspected anaphylactic agent in our case was presumably rocuronium). In summary, PAA requires and responds to emergent diagnosis and immediate treatment; however there is still a long way to go to ensure post-PAA testing for inciting anesthesia-related allergens. PMID:27382817

  1. Posterior Cortical Atrophy

    PubMed Central

    Crutch, Sebastian J; Lehmann, Manja; Schott, Jonathan M; Rabinovici, Gil D; Rossor, Martin N; Fox, Nick C

    2013-01-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterized by a progressive decline in visuospatial, visuoperceptual, literacy and praxic skills. The progressive neurodegeneration affecting parietal, occipital and occipito-temporal cortices which underlies PCA is attributable to Alzheimer's disease (AD) in the majority of patients. However, alternative underlying aetiologies including Dementia with Lewy Bodies (DLB), corticobasal degeneration (CBD) and prion disease have also been identified, and not all PCA patients have atrophy on clinical imaging. This heterogeneity has led to diagnostic and terminological inconsistencies, caused difficulty comparing studies from different centres, and limited the generalizability of clinical trials and investigations of factors driving phenotypic variability. Significant challenges remain in identifying the factors associated with both the selective vulnerability of posterior cortical regions and the young age of onset seen in PCA. Greater awareness of the syndrome and agreement over the correspondence between syndrome-and disease-level classifications are required in order to improve diagnostic accuracy, research study design and clinical management. PMID:22265212

  2. Genetics Home Reference: optic atrophy type 1

    MedlinePlus

    ... Conditions optic atrophy type 1 optic atrophy type 1 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Optic atrophy type 1 is a condition that affects vision. Individuals with ...

  3. PNA lectin for purifying mouse acinar cells from the inflamed pancreas

    PubMed Central

    Xiao, Xiangwei; Fischbach, Shane; Fusco, Joseph; Zimmerman, Ray; Song, Zewen; Nebres, Philip; Ricks, David Matthew; Prasadan, Krishna; Shiota, Chiyo; Husain, Sohail Z.; Gittes, George K.

    2016-01-01

    Better methods for purifying human or mouse acinar cells without the need for genetic modification are needed. Such techniques would be advantageous for the specific study of certain mechanisms, such as acinar-to-beta-cell reprogramming and pancreatitis. Ulex Europaeus Agglutinin I (UEA-I) lectin has been used to label and isolate acinar cells from the pancreas. However, the purity of the UEA-I-positive cell fraction has not been fully evaluated. Here, we screened 20 widely used lectins for their binding specificity for major pancreatic cell types, and found that UEA-I and Peanut agglutinin (PNA) have a specific affinity for acinar cells in the mouse pancreas, with minimal affinity for other major pancreatic cell types including endocrine cells, duct cells and endothelial cells. Moreover, PNA-purified acinar cells were less contaminated with mesenchymal and inflammatory cells, compared to UEA-I purified acinar cells. Thus, UEA-I and PNA appear to be excellent lectins for pancreatic acinar cell purification. PNA may be a better choice in situations where mesenchymal cells or inflammatory cells are significantly increased in the pancreas, such as type 1 diabetes, pancreatitis and pancreatic cancer. PMID:26884345

  4. [Multiple system atrophy].

    PubMed

    Damon-Perrière, Nathalie; Tison, François; Meissner, Wassilios G

    2010-09-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder of unknown etiology. It is the most frequent disorder among atypical parkinsonism with an estimated prevalence of 2 to 5 per 100 000 inhabitants. The clinical symptoms are rapidly progressing with a mean survival ranging between 6 to 9 years. The diagnosis is based on consensus criteria that have been revised in 2008. The diagnostic criteria allow defining "possible", "probable" and "definite" MSA. The latter requires post mortem confirmation of striatonigral and olivopontocerebellar degeneration with alpha-synuclein containing glial cytoplasmic inclusions. The diagnosis of "possible" and "probable" MSA is based on the variable presence and severity of parkinsonism, cerebellar dysfunction, autonomic failure and pyramidal signs. According to the revised criteria, atrophy of putamen, pons, middle cerebellar peduncle (MCP) or cerebellum on brain magnetic resonance imaging are considered to be additional features for the diagnosis of "possible" MSA. T2-weighted brain imaging may further reveal a putaminal hypointensity, a hyperintense lateral putaminal rim, the so called "hot cross bun sign" and MCP hyperintensities. Cardiovascular examination, urodynamic testing and anal sphincter electromyography may be helpful for the diagnosis of autonomic failure. Some patients may respond to levodopa, but usually to a lesser extent than those suffering from Parkinson's disease, and high doses are already required in early disease stages. No specific therapy is available for cerebellar dysfunction, while effective treatments exist for urinary and cardiovascular autonomic failure. Physical therapy may help to improve the difficulties of gait and stance, and to prevent their complications. In later disease stages, speech therapy becomes necessary for the treatment of dysarthria and dysphagia. Percutaneous gastrostomy is sometimes necessary in patients with severe dysphagia. Beyond these strategies, psychological

  5. KRAS Mutations in Canine and Feline Pancreatic Acinar Cell Carcinoma.

    PubMed

    Crozier, C; Wood, G A; Foster, R A; Stasi, S; Liu, J H W; Bartlett, J M S; Coomber, B L; Sabine, V S

    2016-07-01

    Companion animals may serve as valuable models for studying human cancers. Although KRAS is the most commonly mutated gene in human ductal pancreatic cancers (57%), with mutations frequently occurring at codons 12, 13 and 61, human pancreatic acinar cell carcinomas (ACCs) lack activating KRAS mutations. In the present study, 32 pancreatic ACC samples obtained from 14 dogs and 18 cats, including seven metastases, were analyzed for six common activating KRAS mutations located in codons 12 (n = 5) and 13 (n = 1) using Sequenom MassARRAY. No KRAS mutations were found, suggesting that, similar to human pancreatic ACC, KRAS mutations do not play a critical role in feline or canine pancreatic ACC. Due to the similarity of the clinical disease in dogs and cats to that of man, this study confirms that companion animals offer potential as a suitable model for investigating this rare subtype of pancreatic carcinoma. PMID:27290644

  6. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice

    PubMed Central

    Baeyens, Luc; Lemper, Marie; Leuckx, Gunter; De Groef, Sofie; Bonfanti, Paola; Stangé, Geert; Shemer, Ruth; Nord, Christoffer; Scheel, David W.; Pan, Fong C.; Ahlgren, Ulf; Gu, Guoqiang; Stoffers, Doris A.; Dor, Yuval; Ferrer, Jorge; Gradwohl, Gerard; Wright, Christopher VE; Van de Casteele, Mark; German, Michael S.; Bouwens, Luc; Heimberg, Harry

    2014-01-01

    Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose-responsive, and reinstate normal glycemic control for up to 248 days. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3) expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta cell reprogramming through transient cytokine exposure rather than genetic modification. PMID:24240391

  7. Spinal muscular atrophy

    PubMed Central

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic

  8. Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium

    PubMed Central

    Mishra, Vivek; Cline, Rachel; Noel, Pawan; Karlsson, Jenny; Baty, Catherine J.; Orlichenko, Lidiya; Patel, Krutika; Trivedi, Ram Narayan; Husain, Sohail Z.; Acharya, Chathur; Durgampudi, Chandra; Stolz, Donna B.; Navina, Sarah; Singh, Vijay P.

    2013-01-01

    Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an

  9. Research opportunities in muscle atrophy

    NASA Technical Reports Server (NTRS)

    Herbison, G. J.; Talbot, J. M.

    1984-01-01

    A trophy of skeletal muscle; muscle a trophy associated with manned space flight; the nature, causes, and mechanisms of muscle atrophy associated with space flight, selected physiological factors, biochemical aspects, and countermeasures are addressed.

  10. Dentatorubral-pallidoluysian atrophy.

    PubMed

    Tsuji, Shoji

    2012-01-01

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder clinically characterized by various combinations of cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia, and psychiatric symptoms. The most striking clinical features of DRPLA are the considerable heterogeneity in clinical presentation, depending on the age of onset, and the prominent genetic anticipation. DRPLA is caused by unstable expansion of CAG repeats coding for polyglutamine stretches located in exon 5 of the DRPLA gene. DRPLA is characterized by prominent anticipation, with paternal transmission resulting in more prominent anticipation than does maternal transmission, which is now understood based on the intergenerational stability of the CAG repeats. DRPLA protein (also called atrophin-1) is localized in the nucleus and functions as a transcription co-regulator. Recent immunohistochemical studies on autopsied tissues of patients with DRPLA have demonstrated that diffuse accumulation of mutant DRPLA protein (atrophin-1) in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), is the predominant pathologic condition and involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. Thus, age-dependent and CAG repeat-dependent intranuclear accumulation of mutant DRPLA leading to nuclear dysfunctions are suggested to be the essential pathophysiologic mechanisms in DRPLA. PMID:21827919

  11. Unsteady diffusional screening in 3D pulmonary acinar structures: from infancy to adulthood.

    PubMed

    Hofemeier, Philipp; Shachar-Berman, Lihi; Tenenbaum-Katan, Janna; Filoche, Marcel; Sznitman, Josué

    2016-07-26

    Diffusional screening in the lungs is a physical phenomenon where the specific topological arrangement of alveolated airways of the respiratory region leads to a depletion, or 'screening', of oxygen molecules with increasing acinar generation. Here, we revisit diffusional screening phenomena in anatomically-inspired pulmonary acinar models under realistic breathing maneuvers. By modelling 3D bifurcating alveolated airways capturing both convection and diffusion, unsteady oxygen transport is investigated under cyclic breathing motion. To evaluate screening characteristics in the developing lungs during growth, four representative stages of lung development were chosen (i.e. 3 months, 1 year and 9 months, 3 years and adulthood) that capture distinct morphological acinar changes spanning alveolarization phases to isotropic alveolar growth. Numerical simulations unveil the dramatic changes in O2 transport occurring during lung development, where young infants exhibit highest acinar efficiencies that rapidly converge with age to predictions at adulthood. With increased ventilatory effort, transient dynamics of oxygen transport is fundamentally altered compared to tidal breathing and emphasizes the augmented role of convection. Resolving the complex convective acinar flow patterns in 3D acinar trees allows for the first time a spatially-localized and time-resolved characterization of oxygen transport in the pulmonary acinus, from infancy to adulthood. PMID:26699945

  12. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

    PubMed Central

    Antonucci, Laura; Fagman, Johan B.; Kim, Ju Youn; Todoric, Jelena; Gukovsky, Ilya; Mackey, Mason; Ellisman, Mark H.; Karin, Michael

    2015-01-01

    Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures. PMID:26512112

  13. Duct Cells Contribute to Regeneration of Endocrine and Acinar Cells Following Pancreatic Damage in Adult Mice

    PubMed Central

    CRISCIMANNA, ANGELA; SPEICHER, JULIE A.; HOUSHMAND, GOLBAHAR; SHIOTA, CHIYO; PRASADAN, KRISHNA; Ji, BAOAN; LOGSDON, CRAIG D.; GITTES, GEORGE K.; ESNI, FARZAD

    2015-01-01

    BACKGROUND & AIMS There have been conflicting results on a cell of origin in pancreatic regeneration. These discrepancies predominantly stem from lack of specific markers for the pancreatic precursors/stem cells, as well as differences in the targeted cells and severity of tissue injury in the experimental models so far proposed. We attempted to create a model that used diphtheria toxin receptor (DTR) to ablate specific cell populations, control the extent of injury, and avoid induction of the inflammatory response. METHODS To target specific types of pancreatic cells, we crossed R26DTR or R26dtR/lacZ mice with transgenic mice that express the Cre recombinase in the pancreas, under control of the Pdx1 (global pancreatic) or elastase (acinar-specific) promoters. RESULTS Exposure of PdxCre;R26DTR mice to diphtheria toxin resulted in extensive ablation of acinar and endocrine tissues but not ductal cells. Surviving cells within the ductal compartment contributed to regeneration of endocrine and acinar cells via recapitulation of the embryonic pancreatic developmental program. However, following selective ablation of acinar tissue in ElaCre-ERT2;R26DTR mice, regeneration likely occurred by reprogramming of ductal cells to acinar lineage. CONCLUSIONS In the pancreas of adult mice, epithelial cells within the ductal compartment contribute to regeneration of endocrine and acinar cells. The severity of injury determines the regenerative mechanisms and cell types that contribute to this process. PMID:21763240

  14. Acinar cell-specific knockout of the PTHrP gene decreases the proinflammatory and profibrotic responses in pancreatitis

    PubMed Central

    Bhatia, Vandanajay; Rastellini, Cristiana; Han, Song; Aronson, Judith F.; Greeley, George H.

    2014-01-01

    Pancreatitis is a necroinflammatory disease with acute and chronic manifestations. Accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic pancreatitis (CP). Pancreatic parathyroid hormone-related protein (PTHrP) levels are elevated in a mouse model of cerulein-induced AP. Here, we show elevated PTHrP levels in mouse models of pancreatitis induced by chronic cerulein administration and pancreatic duct ligation. Because acinar cells play a major role in the pathophysiology of pancreatitis, mice with acinar cell-specific targeted disruption of the Pthrp gene (PTHrPΔacinar) were generated to assess the role of acinar cell-secreted PTHrP in pancreatitis. These mice were generated using Cre-LoxP technology and the acinar cell-specific elastase promoter. PTHrPΔacinar exerted protective effects in cerulein and pancreatic duct ligation models, evident as decreased edema, histological damage, amylase secretion, pancreatic stellate cell (PSC) activation, and extracellular matrix deposition. Treating acinar cells in vitro with cerulein increased IL-6 expression and NF-κB activity; these effects were attenuated in PTHrPΔacinar cells, as were the cerulein- and carbachol-induced elevations in amylase secretion. The cerulein-induced upregulation of procollagen I expression was lost in PSCs from PTHrPΔacinar mice. PTHrP immunostaining was elevated in human CP sections. The cerulein-induced upregulation of IL-6 and ICAM-1 (human acinar cells) and procollagen I (human PSCs) was suppressed by pretreatment with the PTH1R antagonist, PTHrP (7–34). These findings establish PTHrP as a novel mediator of inflammation and fibrosis associated with CP. Acinar cell-secreted PTHrP modulates acinar cell function via its effects on proinflammatory cytokine release and functions via a paracrine pathway to activate PSCs. PMID:25035110

  15. Electrospinning of Bioactive Dex-PAA Hydrogel Fibers

    NASA Astrophysics Data System (ADS)

    Louie, Katherine Boyook

    In this work, a novel method is developed for making nano- and micro-fibrous hydrogels capable of preventing the rejection of implanted materials. This is achieved by either (1) mimicking the native cellular environment, to exert fine control over the cellular response or (2) acting as a protective barrier, to camouflage the foreign nature of a material and evade recognition by the immune system. Comprehensive characterization and in vitro studies described here provide a foundation for developing substrates for use in clinical applications. Hydrogel dextran and poly(acrylic acid) (PAA) fibers are formed via electrospinning, in sizes ranging from nanometers to microns in diameter. While "as-electrospun" fibers are continuous in length, sonication is used to fragment fibers into short fiber "bristles" and generate nano- and micro- fibrous surface coatings over a wide range of topographies. Dex-PAA fibrous surfaces are chemically modified, and then optimized and characterized for non-fouling and ECM-mimetic properties. The non-fouling nature of fibers is verified, and cell culture studies show differential responses dependent upon chemical, topographical and mechanical properties. Dex-PAA fibers are advantageously unique in that (1) a fine degree of control is possible over three significant parameters critical for modifying cellular response: topography, chemistry and mechanical properties, over a range emulating that of native cellular environments, (2) the innate nature of the material is non-fouling, providing an inert background for adding back specific bioactive functionality, and (3) the fibers can be applied as a surface coating or comprise the scaffold itself. This is the first reported work of dex-PAA hydrogel fibers formed via electrospinning and thermal cross-linking, and unique to this method, no toxic solvents or cross-linking agents are needed to create hydrogels or for surface attachment. This is also the first reported work of using sonication to

  16. PAA/PEO comb polymer effects on the rheological property evolution in concentrated cement suspensions

    NASA Astrophysics Data System (ADS)

    Kirby, Glen Harold

    We have studied the behavior of polyelectrolyte-based comb polymers in dilute solution and on the rheological property evolution of concentrated Portland cement suspensions. These species consisted of charge-neutral, poly(ethylene oxide) (PEO) "teeth" grafted onto a poly(acrylic acid) (PAA) "backbone" that contains one ionizable carboxylic acid group (COOH) per monomer unit. As a benchmark, our observations were compared to those obtained for pure cement pastes and systems containing pure polyelectrolyte species, i.e., sulfonated naphthalene formaldehyde (SNF) and poly(acrylic acid) (PAA). The behavior of PAA/PEO comb polymers, SNF, and PAA in dilute solution was studied as a function of pH in the absence and presence of mono-, di-, and trivalent counterions. Light scattering and turbidity measurements were carried out to assess their hydrodynamic radius and stability in aqueous solution, respectively. PAA experienced large conformational changes as a function of solution pH and ionic strength. Moreover, dilute solutions of ionized SNF and PAA species became unstable in the presence of multivalent counterions due to ion-bridging interactions. PAA/PEO solutions exhibited enhanced stability relative to pure polyelectrolytes under analogous conditions. The charge neutral PEO teeth shielded the underlying PAA backbone from ion-bridging interactions. In addition, such species hindered conformational changes in solution due to steric interactions between adjacent teeth. A new oscillatory shear technique was developed to probe the rheological property evolution of concentrated cement systems. The rheological property evolution of ordinary and white Portland cement systems were studied in the absence and presence of pure polyelectrolytes and PAA/PEO comb polymers with a wide range of PAA backbone molecular weight, PEO teeth molecular weight, and acid:imide ratio. Cement-PAA suspensions experienced rapid irreversible stiffening and set at 6 min due to ion

  17. High strain-rate response of injectable PAA hydrogel.

    PubMed

    Lin, Hong-Ru; Wang, Shih-Han; Chiang, Chia-Chin; Juang, Yun-Ching; Yu, Fu-Ann; Tsai, Liren

    2015-01-01

    Hydrogel materials have been widely considered as potential soft tissue replacements because of their high permeability, hydrophilicity, and biocompatibility, as well as their low coefficient of friction. Injectable (thermo-responsive) hydrogels can provide support and cushioning at irregularly shaped disease sites, and are thus suitable for use in treating osteoarthritis or degenerative disc disease. However, while some injectable hydrogels have been proven to sustain human body weight during daily activities, their mechanical properties under harsh dynamic conditions have not been well documented. A specified injectable polyacrylic acid (PAA) hydrogel was prepared for this study. To simulate sudden impacts or unexpected shocks to the PAA hydrogel, the split Hopkinson pressure bar technique was utilized. The dynamic responses of various hydrogels at confined high strain rates (100-2590 s(-1)) were presented. Hydrogel specimens with 3.37, 6.75, and 13.5% acrylic acid (AAc) concentrations were tested in the following three different material conditions: raw, phosphate-buffered saline (PBS) swollen, and PBS swollen with elevated temperature (37 °C). The dynamic bulk moduli of the hydrogels varied from 1.55 to 47.8 MPa depending on the given hydrogel's AAc concentration and swollen condition. PMID:25816201

  18. Loss of Periostin Results in Impaired Regeneration and Pancreatic Atrophy after Cerulein-Induced Pancreatitis.

    PubMed

    Hausmann, Simone; Regel, Ivonne; Steiger, Katja; Wagner, Nadine; Thorwirth, Manja; Schlitter, Anna M; Esposito, Irene; Michalski, Christoph W; Friess, Helmut; Kleeff, Jörg; Erkan, Mert

    2016-01-01

    The extracellular matrix molecule periostin (POSTN, encoded by POSTN), which is secreted by activated pancreatic stellate cells, has important functions in chronic pancreatitis and pancreatic cancer. However, the role of POSTN in acute pancreatitis and subsequent regeneration processes has not been addressed so far. We analyzed the function of POSTN in pancreatic exocrine regeneration after the induction of a severe acute pancreatitis. Postn-deficient mice and wild-type control animals received repetitive cerulein injections, and a detailed histologic analysis of pancreatic tissues was performed. Although there was no difference in pancreatitis severity in the acute inflammatory phase, the recovery of the exocrine pancreas was massively impaired in Postn-deficient mice. Loss of Postn expression was accompanied by strong pancreatic atrophy and acinar-to-adipocyte differentiation, which was also reflected in gene expression patterns. Our data suggest that POSTN is a crucial factor for proper exocrine lineage-specific regeneration after severe acute pancreatitis. PMID:26632158

  19. Investigations of PAA degradation in aqueous solutions: Impacts of water hardness, salinity and DOC

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peracetic acid (PAA) is used in aquaculture under various conditions for disinfection purposes. However, there is lack of information about its environmental fate. Therefore, the impact of water hardness, salinity, and dissolved organic carbon (DOC) on PAA-degradation within 5 hours was investigat...

  20. Disinfection of water in recirculating aquaculture systems with peracetic acid (PAA)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The disinfection behaviour of peracetic acid (PAA) in recirculating aquaculture systems (RAS) was investigated. Peracetic acid is a strong oxidizing agent found in various concentrations in different products. Three Wofasteril PAA products (E400 (c), Lspecical; AC 150) were tested in vitro for the...

  1. Sanitizing with peracetic acid (PAA)- An alternative treatment to use in aquaculture ...?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Because of the lack of approved treatments for fish disease, disinfectants were tested to treat fish pathogens. One of these substances is peracetic acid (PAA). PAA is an agent used for disinfection in aquaculture, but it must be investigated thoroughly in order to mitigate diseases without harmful ...

  2. Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia

    PubMed Central

    Ebine, Kazumi; Chow, Christina R.; DeCant, Brian T.; Hattaway, Holly Z.; Grippo, Paul J.; Kumar, Krishan; Munshi, Hidayatullah G.

    2016-01-01

    Cells in the pancreas that have undergone acinar-ductal metaplasia (ADM) can transform into premalignant cells that can eventually become cancerous. Although the epithelial-mesenchymal transition regulator Snail (Snai1) can cooperate with Kras in acinar cells to enhance ADM development, the contribution of Snail-related protein Slug (Snai2) to ADM development is not known. Thus, transgenic mice expressing Slug and Kras in acinar cells were generated. Surprisingly, Slug attenuated Kras-induced ADM development, ERK1/2 phosphorylation and proliferation. Co-expression of Slug with Kras also attenuated chronic pancreatitis-induced changes in ADM development and fibrosis. In addition, Slug attenuated TGF-α-induced acinar cell metaplasia to ductal structures and TGF-α-induced expression of ductal markers in ex vivo acinar explant cultures. Significantly, blocking the Rho-associated protein kinase ROCK1/2 in the ex vivo cultures induced expression of ductal markers and reversed the effects of Slug by inducing ductal structures. In addition, blocking ROCK1/2 activity in Slug-expressing Kras mice reversed the inhibitory effects of Slug on ADM, ERK1/2 phosphorylation, proliferation and fibrosis. Overall, these results increase our understanding of the role of Slug in ADM, an early event that can eventually lead to pancreatic cancer development. PMID:27364947

  3. The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

    PubMed Central

    Krah, Nathan M; De La O, Jean-Paul; Swift, Galvin H; Hoang, Chinh Q; Willet, Spencer G; Chen Pan, Fong; Cash, Gabriela M; Bronner, Mary P; Wright, Christopher VE; MacDonald, Raymond J; Murtaugh, L Charles

    2015-01-01

    Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas. DOI: http://dx.doi.org/10.7554/eLife.07125.001 PMID:26151762

  4. Exocyst subunits are involved in isoproterenol-induced amylase release from rat parotid acinar cells.

    PubMed

    Imai, Akane; Yoshie, Sumio; Haga-Tsujimura, Maiko; Nashida, Tomoko; Shimomura, Hiromi

    2012-04-01

    Exocytosis of secretory granules in parotid acinar cells requires multiple events: tethering, docking, priming, and fusion with a luminal plasma membrane. The exocyst complex, which is composed of eight subunits (Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84) that are conserved in yeast and mammalian cells, is thought to participate in the exocytotic pathway. However, to date, no exocyst subunit has been identified in salivary glands. In the present study, we investigated the expression and function of exocyst subunits in rat parotid acinar cells. The expression of mRNA for all eight exocyst subunits was detected in parotid acinar cells by RT-PCR, and Sec6 and Sec8 proteins were localized on the luminal plasma membrane. Sec6 interacted with Sec8 after 5 min of stimulation with isoproterenol. In addition, antibodies to-Sec6 and Sec8 inhibited isoproterenol-induced amylase release from streptolysin O-permeabilized parotid acinar cells. These results suggest that an exocyst complex of eight subunits is required for amylase release from parotid acinar cells. PMID:22409218

  5. Characterization of single potassium channels in mouse pancreatic acinar cells.

    PubMed Central

    Schmid, A; Schulz, I

    1995-01-01

    1. Single K(+)-selective channels with a conductance of about 48 pS (pipette, 145 mM KCl; bath, 140 mM NaCl + 4.7 mM KCl) were recorded in the patch-clamp whole-cell configuration in isolated mouse pancreatic acinar cells. 2. Neither application of the secretagogues acetylcholine (second messenger, inositol 1,4,5-trisphosphate) or secretin (second messenger, cAMP), nor addition of the catalytic subunit of protein kinase A to the pipette solution changed the activity of the 48 pS K+ channel. 3. Intracellular acidification with sodium propionate (20 mM) diminished activity of the 48 pS channel, whereas channel open probability was increased by cytosolic alkalization with 20 mM NH4Cl. 4. BaCl2 (5 mM), TEA (10 mM) or apamin (1 microM) added to the bath solution had no obvious effect on the kinetics of the 48 pS channel. Similarly, glibenclamide and diazoxide failed to influence the channel activity. 5. When extracellular NaCl was replaced by KCl, whole-cell recordings revealed an inwardly rectifying K+ current carried by a 17 pS K+ channel. 6. The inwardly rectifying K+ current was not pH dependent and could largely be blocked by Ba2+ but not by TEA. 7. Since the 48 pS K+ channel is neither Ca2+ nor cAMP regulated, we suggest that this channel could play a role in the maintenance of the negative cell resting potential. PMID:7623283

  6. Genetics Home Reference: multiple system atrophy

    MedlinePlus

    ... OPCA progressive autonomic failure with multiple system atrophy SDS Shy-Drager syndrome sporadic olivopontocerebellar atrophy Related Information ... A, Hulot JS, Morrison KE, Renton A, Sussmuth SD, Landwehrmeyer BG, Ludolph A, Agid Y, Brice A, ...

  7. Derivation of ductlike cell lines from a transplantable acinar cell carcinoma of the rat pancreas.

    PubMed Central

    Pettengill, O. S.; Faris, R. A.; Bell, R. H.; Kuhlmann, E. T.; Longnecker, D. S.

    1993-01-01

    Two cell lines were derived from a transplantable acinar cell carcinoma that had been established from a primary carcinoma of the pancreas in an azaserine-treated Lewis rat. The cultured tumor cells initially produced amylase, but production of exocrine enzymes ceased after 1-2 weeks in culture. The cultured cells were tumorigenic in Lewis rats, and one line produced solid tumors composed of ductlike structures surrounded by dense fibrous tissue. The second cell line produced partially solid and partially cystic tumors with a mixed phenotype of squamous, mucinous, and glandular areas when it grew in vivo following regrafting. Both cell lines lost structural and immunohistochemical acinar cell markers while acquiring duct cell markers during culture and regrafting. These studies provide strong support for the hypothesis that ductlike carcinomas can arise from neoplastic pancreatic acinar cells in rats. Images Figure 2 Figure 3 Figure 4 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 PMID:8391218

  8. Phenotypic expansion of TBX4 mutations to include acinar dysplasia of the lungs.

    PubMed

    Szafranski, Przemyslaw; Coban-Akdemir, Zeynep H; Rupps, Rosemarie; Grazioli, Serge; Wensley, David; Jhangiani, Shalini N; Popek, Edwina; Lee, Anna F; Lupski, James R; Boerkoel, Cornelius F; Stankiewicz, Paweł

    2016-09-01

    Mutations in the T-box transcription factor TBX4 gene have been reported in patients with Ischiocoxopodopatellar syndrome (MIM# 147891) and childhood-onset pulmonary arterial hypertension. Whole exome sequencing of DNA from a 1 day old deceased newborn, with severe diffuse developmental lung disorder exhibiting features of acinar dysplasia, and her unaffected parents identified a de novo TBX4 missense mutation p.E86Q (c.256G>C) in the DNA-binding T-box domain. We propose phenotypic expansion of the TBX4-related clinical disease spectrum to include acinar dysplasia of the lungs. The reported mutation is the first identified genetic variant causative for acinar dysplasia. © 2016 Wiley Periodicals, Inc. PMID:27374786

  9. Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia

    NASA Astrophysics Data System (ADS)

    Liou, Geou-Yarh; Döppler, Heike; Braun, Ursula B.; Panayiotou, Richard; Scotti Buzhardt, Michele; Radisky, Derek C.; Crawford, Howard C.; Fields, Alan P.; Murray, Nicole R.; Wang, Q. Jane; Leitges, Michael; Storz, Peter

    2015-02-01

    The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.

  10. Pancreatic acinar cells-derived cyclophilin A promotes pancreatic damage by activating NF-κB pathway in experimental pancreatitis

    SciTech Connect

    Yu, Ge; Wan, Rong; Hu, Yanling; Ni, Jianbo; Yin, Guojian; Xing, Miao; Shen, Jie; Tang, Maochun; Chen, Congying; Fan, Yuting; Xiao, Wenqin; Zhao, Yan; Wang, Xingpeng; and others

    2014-01-31

    Highlights: • CypA is upregulated in experimental pancreatitis. • CCK induces expression and release of CypA in acinar cell in vitro. • rCypA aggravates CCK-induced acinar cell death and inflammatory cytokine production. • rCypA activates the NF-κB pathway in acinar cells in vitro. - Abstract: Inflammation triggered by necrotic acinar cells contributes to the pathophysiology of acute pancreatitis (AP), but its precise mechanism remains unclear. Recent studies have shown that Cyclophilin A (CypA) released from necrotic cells is involved in the pathogenesis of several inflammatory diseases. We therefore investigated the role of CypA in experimental AP induced by administration of sodium taurocholate (STC). CypA was markedly upregulated and widely expressed in disrupted acinar cells, infiltrated inflammatory cells, and tubular complexes. In vitro, it was released from damaged acinar cells by cholecystokinin (CCK) induction. rCypA (recombinant CypA) aggravated CCK-induced acinar cell necrosis, promoted nuclear factor (NF)-κB p65 activation, and increased cytokine production. In conclusion, CypA promotes pancreatic damage by upregulating expression of inflammatory cytokines of acinar cells via the NF-κB pathway.

  11. Experimental evidence of age-related adaptive changes in human acinar airways.

    PubMed

    Quirk, James D; Sukstanskii, Alexander L; Woods, Jason C; Lutey, Barbara A; Conradi, Mark S; Gierada, David S; Yusen, Roger D; Castro, Mario; Yablonskiy, Dmitriy A

    2016-01-15

    The progressive decline of lung function with aging is associated with changes in lung structure at all levels, from conducting airways to acinar airways (alveolar ducts and sacs). While information on conducting airways is becoming available from computed tomography, in vivo information on the acinar airways is not conventionally available, even though acini occupy 95% of lung volume and serve as major gas exchange units of the lung. The objectives of this study are to measure morphometric parameters of lung acinar airways in living adult humans over a broad range of ages by using an innovative MRI-based technique, in vivo lung morphometry with hyperpolarized (3)He gas, and to determine the influence of age-related differences in acinar airway morphometry on lung function. Pulmonary function tests and MRI with hyperpolarized (3)He gas were performed on 24 healthy nonsmokers aged 19-71 years. The most significant age-related difference across this population was a 27% loss of alveolar depth, h, leading to a 46% increased acinar airway lumen radius, hence, decreased resistance to acinar air transport. Importantly, the data show a negative correlation between h and the pulmonary function measures forced expiratory volume in 1 s and forced vital capacity. In vivo lung morphometry provides unique information on age-related changes in lung microstructure and their influence on lung function. We hypothesize that the observed reduction of alveolar depth in subjects with advanced aging represents a remodeling process that might be a compensatory mechanism, without which the pulmonary functional decline due to other biological factors with advancing age would be significantly larger. PMID:26542518

  12. Human mesenchymal stem cell osteoblast differentiation, ECM deposition, and biomineralization on PAH/PAA polyelectrolyte multilayers.

    PubMed

    Pattabhi, Sudhakara Rao; Lehaf, Ali M; Schlenoff, Joseph B; Keller, Thomas C S

    2015-05-01

    Polyelectrolyte multilayer (PEMU) coatings built layer by layer with alternating pairs of polyelectrolytes can be tuned to improve cell interactions with surfaces and may be useful as biocompatible coatings to improve fixation between implants and tissues. Here, we show that human mesenchymal stromal cells (hMSCs) induced with bone differentiation medium (BDM) to become osteoblasts biomineralize crosslinked PEMUs built with the polycation poly(allylamine hydrochloride) (PAH) and the polyanion poly(acrylic acid) (PAA). Degrees of hMSC osteoblast differentiation and surface biomineralization on the smooth PAH-terminated PEMUs (PAH-PEMUs) and microstructured PAA-terminated PEMUs (PAA-PEMUs) reflect differences in cell-deposited extracellular matrix (ECM). BDM-induced hMSCs expressed higher levels of the early osteoblast differentiation marker alkaline phosphatase and collagen 1 (COL1) sooner on PAA-PEMUs than on PAH-PEMUs. Cells on both types of PEMUs proceeded to express the later stage osteoblast differentiation marker bone sialoprotein (BSP), but the BDM-induced cells organized a more amorphous Collagen I and denser BSP localization on PAA-PEMUs than on PAH-PEMUs. These ECM properties correlated with greater biomineralization on the PAA-PEMUs than on PAH-PEMUs. Together, these results confirm the suitability of PAH/PAA PEMUs as a substrate for hMSC osteogenesis and highlight the importance of substrate effects on ECM organization and BSP presentation on biomineralization. PMID:25203301

  13. Geometrical influence of pulmonary acinar models on respiratory flows and particle deposition

    NASA Astrophysics Data System (ADS)

    Hofemeier, Philipp; Sznitman, Josue

    2012-11-01

    Due to experimental challenges in assessing respiratory flows in the deep regions of the lungs, computational simulations are typically sought to quantify inhaled aerosol transport and deposition in the acinus. Most commonly, simulations are performed using generic geometries of alveoli, including spheres, toroids and polyhedra to mimic the acinar region. However, local respiratory flows and ensuing particle trajectories are anticipated to be highly influenced by the specific geometrical structures chosen. To date, geometrical influences have not yet been thoroughly quantified. Knowing beforehand how geometries affect acinar flows and particle transport is critical in translating simulated data to predictions of aerosol deposition in real lungs. Here, we conduct a systematic investigation on a number of generic acinar models. Simulations are conducted for simple alveolated airways featuring a selection of geometries. Deposition patterns and efficiencies are quantified both for massless particles, highlighting details of the local flow, and micron-scale aerosols. This latter group of particles represents an important class of inhaled aerosols known to reach and deposit in the acinus. Our work emphasizes the subtleties of acinar geometry in determining the fate of inhaled aerosols.

  14. Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing.

    PubMed

    Barnett, Christopher P; Nataren, Nathalie J; Klingler-Hoffmann, Manuela; Schwarz, Quenten; Chong, Chan-Eng; Lee, Young K; Bruno, Damien L; Lipsett, Jill; McPhee, Andrew J; Schreiber, Andreas W; Feng, Jinghua; Hahn, Christopher N; Scott, Hamish S

    2016-09-01

    Ectrodactyly/split hand-foot malformation is genetically heterogeneous with more than 100 syndromic associations. Acinar dysplasia is a rare congenital lung lesion of unknown etiology, which is frequently lethal postnatally. To date, there have been no reports of combinations of these two phenotypes. Here, we present an infant from a consanguineous union with both ectrodactyly and autopsy confirmed acinar dysplasia. SNP array and whole-exome sequencing analyses of the affected infant identified a novel homozygous Fibroblast Growth Factor Receptor 2 (FGFR2) missense mutation (p.R255Q) in the IgIII domain (D3). Expression studies of Fgfr2 in development show localization to the affected limbs and organs. Molecular modeling and genetic and functional assays support that this mutation is at least a partial loss-of-function mutation, and contributes to ectrodactyly and acinar dysplasia only in homozygosity, unlike previously reported heterozygous activating FGFR2 mutations that cause Crouzon, Apert, and Pfeiffer syndromes. This is the first report of mutations in a human disease with ectrodactyly with pulmonary acinar dysplasia and, as such, homozygous loss-of-function FGFR2 mutations represent a unique syndrome. PMID:27323706

  15. Mixed acinar-neuroendocrine carcinoma of the pancreas with neuroendocrine predominance.

    PubMed

    Ogbonna, Onyekachi Henry; Garcon, Marie Carmel; Syrigos, Kostas N; Saif, Muhammad Wasif

    2013-01-01

    Background. Pancreatic tumors are rare and could arise from either the exocrine (ductal and acinar cells) or the endocrine (neuroendocrine cells) components of the pancreas. In some instances, the occurrence of pancreatic tumors comprising both acinar cells and neuroendocrine cells, with neuroendocrine cells making up more than 30% of the tumor, has been identified. This unique entity has been referred to as mixed acinar-neuroendocrine carcinoma (MANEC). Only about 20 such cases have been reported in the literature. Case Report. We report an interesting case of MANEC with neuroendocrine cell predominance in a woman presenting with epigastric pain secondary to a pancreatic mass with acinar and endocrine differentiation. She underwent surgical resection of the tumor and was offered adjuvant treatment chemotherapy with carboplatin, etoposide, and radiotherapy for positive tumor resection margins. Conclusions. Given the paucity of the cases of MANEC, continuous reporting of these cases when identified should be encouraged to aid oncologists in understanding the disease and help establish standardized management. PMID:24348574

  16. Mixed Acinar-Neuroendocrine Carcinoma of the Pancreas with Neuroendocrine Predominance

    PubMed Central

    Ogbonna, Onyekachi Henry; Syrigos, Kostas N.; Saif, Muhammad Wasif

    2013-01-01

    Background. Pancreatic tumors are rare and could arise from either the exocrine (ductal and acinar cells) or the endocrine (neuroendocrine cells) components of the pancreas. In some instances, the occurrence of pancreatic tumors comprising both acinar cells and neuroendocrine cells, with neuroendocrine cells making up more than 30% of the tumor, has been identified. This unique entity has been referred to as mixed acinar-neuroendocrine carcinoma (MANEC). Only about 20 such cases have been reported in the literature. Case Report. We report an interesting case of MANEC with neuroendocrine cell predominance in a woman presenting with epigastric pain secondary to a pancreatic mass with acinar and endocrine differentiation. She underwent surgical resection of the tumor and was offered adjuvant treatment chemotherapy with carboplatin, etoposide, and radiotherapy for positive tumor resection margins. Conclusions. Given the paucity of the cases of MANEC, continuous reporting of these cases when identified should be encouraged to aid oncologists in understanding the disease and help establish standardized management. PMID:24348574

  17. Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo.

    PubMed

    Baumann, Bernd; Wagner, Martin; Aleksic, Tamara; von Wichert, Götz; Weber, Christoph K; Adler, Guido; Wirth, Thomas

    2007-06-01

    Activation of the inhibitor of NF-kappaB kinase/NF-kappaB (IKK/NF-kappaB) system and expression of proinflammatory mediators are major events in acute pancreatitis. However, the in vivo consequences of IKK activation on the onset and progression of acute pancreatitis remain unclear. Therefore, we modulated IKK activity conditionally in pancreatic acinar cells. Transgenic mice expressing the reverse tetracycline-responsive transactivator (rtTA) gene under the control of the rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated cerulein-induced pancreatitis but did not affect activation of trypsin, an initial event in experimental pancreatitis. Notably, expression of constitutively active IKK2 was sufficient to induce acute pancreatitis. This acinar cell-specific phenotype included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels as well as pancreatic fibrosis. IKK2 activation caused increased expression of known NF-kappaB target genes, including mediators of the inflammatory response such as TNF-alpha and ICAM-1. Indeed, inhibition of TNF-alpha activity identified this cytokine as an important effector of IKK2-induced pancreatitis. Our data identify the IKK/NF-kappaB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response typical of this disease. PMID:17525799

  18. Acinar autolysis and mucous extravasation in human sublingual glands: a microscopic postmortem study

    PubMed Central

    AZEVEDO-ALANIS, Luciana Reis; TOLENTINO, Elen de Souza; de ASSIS, Gerson Francisco; CESTARI, Tânia Mary; LARA, Vanessa Soares; DAMANTE, José Humberto

    2015-01-01

    Although some morphological investigations on aged human sublingual glands (HSG) found eventual phenomena identified as autolysis and mucous extravasation, the exact meaning of these findings has not been elucidated. Objective The aim of this work is to investigate whether acinar autolysis and mucous extravasation are related to the aging process in human sublingual glands. We also speculate if autolytic changes may assist forensic pathologists in determining time of death. Material and Methods 186 cadavers’ glands were allocated to age groups: I (0–30 years); II (31–60), and III (61–90). Time and mode of death were also recorded. Acinar autolysis and mucous extravasation were classified as present or absent. Ultrastructural analysis was performed using transmission electron microscopy (TEM). Data were compared using Mann-Whitney U, Spearman’s correlation coefficient, Kruskal-Wallis, and Dunn tests (p<0.05). Results There was correlation between age and acinar autolysis (r=0.38; p=0.0001). However, there was no correlation between autolysis and time of death. No differences were observed between genders. TEM showed mucous and serous cells presenting nuclear and membrane alterations and mucous cells were more susceptible to autolysis. Conclusion Acinar autolysis occurred in all age groups and increased with age while mucous extravasation was rarely found. Both findings are independent. Autolysis degrees in HSG could not be used to determine time of death. PMID:26537715

  19. Omental acinar cell carcinoma of pancreatic origin in a child: a clinicopathological rarity.

    PubMed

    Sharma, Shilpa; Agarwal, Shipra; Nagendla, Murali Krishna; Gupta, Devendra K

    2016-03-01

    A 6-year-old boy presented with a large subhepatic mass associated with pain abdomen. Exploration revealed a tumor in lesser omentum, completely separate from the normal pancreas that was excised completely. Histopathology suggested acinar cell carcinoma of pancreatic origin in an ectopic location. The child is well at 5 months follow-up. PMID:26694824

  20. Snail1 is required for the maintenance of the pancreatic acinar phenotype

    PubMed Central

    Loubat-Casanovas, Jordina; Peña, Raúl; Gonzàlez, Núria; Alba-Castellón, Lorena; Rosell, Santi; Francí, Clara; Navarro, Pilar; de Herreros, Antonio García

    2016-01-01

    The Snail1 transcriptional factor is required for correct embryonic development, yet its expression in adult animals is very limited and its functional roles are not evident. We have now conditionally inactivated Snail1 in adult mice and analyzed the phenotype of these animals. Snail1 ablation rapidly altered pancreas structure: one month after Snail1 depletion, acinar cells were markedly depleted, and pancreas accumulated adipose tissue. Snail1 expression was not detected in the epithelium but was in pancreatic mesenchymal cells (PMCs). Snail1 ablation in cultured PMCs downregulated the expression of several β-catenin/Tcf-4 target genes, modified the secretome of these cells and decreased their ability to maintain acinar markers in cultured pancreas cells. Finally, Snail1 deficiency modified the phenotype of pancreatic tumors generated in transgenic mice expressing c-myc under the control of the elastase promoter. Specifically, Snail1 depletion did not significantly alter the size of the tumors but accelerated acinar-ductal metaplasia. These results demonstrate that Snail1 is expressed in PMCs and plays a pivotal role in maintaining acinar cells within the pancreas in normal and pathological conditions. PMID:26735179

  1. Cell cycle control in isoproterenol-induced murine salivary acinar cell proliferation.

    PubMed

    Zeng, T; Yamamoto, H; Bowen, E; Broverman, R L; Nguyen, K H; Humphreys-Beher, M G

    1996-11-01

    The eukaryotic cell cycle is a summary of a complex network of signal transduction pathways resulting in both DNA replication and cell division. Cyclin-dependent kinases (CDKs) control the cell cycle in all eukaryotes, whereas other proteins, known as cyclins, act as their regulatory subunits. Chronic injection with isoproterenol (ISO) can induce acinar cell proliferation in rodent salivary glands. Cyclins and CDK proteins from control and ISO-treated murine parotid acinar cells were detected by using Western blotting techniques. By comparing the expression of these cell cycle regulatory kinases in the parotid acinar cell transition from a quiescent state to a hypertrophic state, we found rapid increases in the protein levels of all CDKs, cyclin D and proliferating cell nuclear antigen (PCNA). The highest protein levels for CDKs and cyclins appeared at about 72 hr of ISO stimulation and were coincident with the highest rate of increase in gland wet weight. After 72 hr, the increase of both cell cycle protein and gland wet weight began to subside. By using a co-immunoprecipitation method, the following cell cycle regulators (CDK-cyclin complexes) were detected, CDK4-cyclin D, CDK2-cyclin E, CDK2-cyclin A, and cdc2-cyclin B, along with an increase in kinase activity over control untreated animals. Additionally, we detected significant decreases in the newly isolated CDK inhibitor (CKI) p27kip but not Wee 1 kinase. The increased levels of CKI correlated with a decrease in kinase activity of CDK/cyclin complexes by 144 hr of chronic isoproterenol treatment. Our data suggest that the holoenzymes for cell cycle control (cyclin-CDK complexes) function as a final regulatory mechanism leading to salivary gland acinar cell proliferation. The gradual decline in protein levels of the CDKs and cyclins after 3 days of chronic treatment further indicates that ISO-induced proliferation of parotid acinar cells is self-limiting and non-tumorigenic. PMID:9375366

  2. Internalization and cellular processing of cholecystokinin in rat pancreatic acinar cells

    SciTech Connect

    Izzo, R.S.; Pellecchia, C.; Praissman, M. )

    1988-12-01

    To evaluate the internalization of cholecystokinin, monoiodinated imidoester of cholecystokinin octapeptide ({sup 125}I-(IE)-CCK-8) was bound to dispersed pancreatic acinar cells, and surface-bound and internalized radioligand were differentiated by treating with an acidified glycine buffer. The amount of internalized radioligand was four- and sevenfold greater at 24 and 37{degree}C than at 4{degree}C between 5 and 60 min of association. Specific binding of radioligand to cell surface receptors was not significantly different at these temperatures. Chloroquine, a lysosomotropic agent that blocks intracellular proteolysis, significantly increased the amount of CCK-8 internalized by 18 and 16% at 30 and 60 min of binding, respectively, compared with control. Dithiothreitol (DTT), a sulfhydryl reducing agent, also augmented the amount of CCK-8 radioligand internalized by 25 and 29% at 30 and 60 min, respectively. The effect of chloroquine and DTT on the processing of internalized radioligand was also considered after an initial 60 min of binding of radioligand to acinar cells. After 180 min of processing, the amount of radioligand internalized was significantly greater in the presence of chloroquine compared with controls, whereas the amount of radioligand declined in acinar cells treated with DTT. Internalized and released radioactivity from acinar cells was rebound to pancreatic membrane homogenates to determine the amount of intact radioligand during intracellular processing. Chloroquine significantly increased the amount of intact {sup 125}I-(IE)-CCK-8 radioligand in released and internalized radioactivity while DTT increased the amount of intact radioligand only in internalized samples. This study shows that pancreatic acinar cells rapidly internalize large amounts of CCK-8 and that chloroquine and DTT inhibit intracellular degradation.

  3. PAA: an R/bioconductor package for biomarker discovery with protein microarrays

    PubMed Central

    Turewicz, Michael; Ahrens, Maike; May, Caroline; Marcus, Katrin; Eisenacher, Martin

    2016-01-01

    Summary: The R/Bioconductor package Protein Array Analyzer (PAA) facilitates a flexible analysis of protein microarrays for biomarker discovery (esp., ProtoArrays). It provides a complete data analysis workflow including preprocessing and quality control, uni- and multivariate feature selection as well as several different plots and results tables to outline and evaluate the analysis results. As a main feature, PAA’s multivariate feature selection methods are based on recursive feature elimination (e.g. SVM-recursive feature elimination, SVM-RFE) with stability ensuring strategies such as ensemble feature selection. This enables PAA to detect stable and reliable biomarker candidate panels. Availability and implementation: PAA is freely available (BSD 3-clause license) from http://www.bioconductor.org/packages/PAA/. Contact: michael.turewicz@rub.de or martin.eisenacher@rub.de PMID:26803161

  4. Cloning and expression of the porcine attaching and effacing-associated (paa) gene of enteropathogenic Escherichia coli.

    PubMed

    Pereira, D A; Teixeira Florian, E C; Ono, M A; Rossi, C Nachi; Vidotto, O; Vidotto, M C

    2015-01-01

    Porcine enteropathogenic Escherichia coli (PEPEC) produce an outer membrane protein (intimin) called Paa (porcine attaching and effacing-associated), which is involved in the pathogenesis of E. coli in piglets with diarrhea. The paa gene of a PEPEC strain isolated in Paraná, Brazil, was amplified by polymerase chain reaction, sequenced, and cloned into the pTrcHisTOPO2 vector. The deduced amino acid sequence encoded by the paa gene of PEPEC from Paraná, Brazil, showed 99% homology to the sequences from other PEPEC strains. In this study, the overexpression of recombinant Paa (rPaa) using alternative induction strategies was attempted. The auto-induction protocol showed excellent results for rPaa protein production with 0.4% (w/v) lactose. The rPaa protein is insoluble and was purified with Triton X-100 wash as a total antigen. This method produced a relatively high yield of rPaa. rPaa was recognized by serum from pigs immunized with the PEPEC strain. These results suggest that rPaa could be included in the development of a vaccine against swine colibacillosis. PMID:26345788

  5. Vulvar Skin Atrophy Induced by Topical Glucocorticoids

    PubMed Central

    Johnson, Elisabeth; Groben, Pamela; Eanes, Alisa; Iyer, Priya; Ugoeke, Joseph; Zolnoun, Denniz

    2011-01-01

    Steroid induced skin atrophy is the most frequent and perhaps most important cutaneous side effect of topical glucocorticoid therapy. To date, it has not been described in vulvar skin. We describe a patient with significant vulvar skin atrophy following prolonged steroid application to treat vulvar dermatitis. The extensive atrophy in the perineum resulted in secondary ‘webbing’ and partial obstruction of genital hiatus and superimposed dyspareunia. Prolonged topical steroids may result in atrophic changes in vulvar skin. Therefore, further research in clinical correlates of steroid-induced atrophy in the vulvar region is warranted. PMID:22594868

  6. Identification of miRNAs Involved in Reprogramming Acinar Cells into Insulin Producing Cells

    PubMed Central

    Teichenne, Joan; Morró, Meritxell; Casellas, Alba; Jimenez, Veronica; Tellez, Noelia; Leger, Adrien; Bosch, Fatima; Ayuso, Eduard

    2015-01-01

    Reprogramming acinar cells into insulin producing cells using adenoviral (Ad)-mediated delivery of Pdx1, Ngn3 and MafA (PNM) is an innovative approach for the treatment of diabetes. Here, we aimed to investigate the molecular mechanisms involved in this process and in particular, the role of microRNAs. To this end, we performed a comparative study of acinar-to-β cell reprogramming efficiency in the rat acinar cell line AR42J and its subclone B13 after transduction with Ad-PNM. B13 cells were more efficiently reprogrammed than AR42J cells, which was demonstrated by a strong activation of β cell markers (Ins1, Ins2, IAPP, NeuroD1 and Pax4). miRNome panels were used to analyze differentially expressed miRNAs in acinar cells under four experimental conditions (i) non-transduced AR42J cells, (ii) non-transduced B13 cells, (iii) B13 cells transduced with Ad-GFP vectors and (iv) B13 cells transduced with Ad-PNM vectors. A total of 59 miRNAs were found to be differentially expressed between non-transduced AR42J and B13 cells. Specifically, the miR-200 family was completely repressed in B13 cells, suggesting that these cells exist in a less differentiated state than AR42J cells and as a consequence they present a greater plasticity. Adenoviral transduction per se induced dedifferentiation of acinar cells and 11 miRNAs were putatively involved in this process, whereas 8 miRNAs were found to be associated with PNM expression. Of note, Ad-PNM reprogrammed B13 cells presented the same levels of miR-137-3p, miR-135a-5p, miR-204-5p and miR-210-3p of those detected in islets, highlighting their role in the process. In conclusion, this study led to the identification of miRNAs that might be of compelling importance to improve acinar-to-β cell conversion for the future treatment of diabetes. PMID:26690959

  7. Acinar phenotype is preserved in human exocrine pancreas cells cultured at low temperature: implications for lineage-tracing of β-cell neogenesis.

    PubMed

    Mfopou, Josué K; Houbracken, Isabelle; Wauters, Elke; Mathijs, Iris; Song, Imane; Himpe, Eddy; Baldan, Jonathan; Heimberg, Harry; Bouwens, Luc

    2016-06-01

    The regenerative medicine field is expanding with great successes in laboratory and preclinical settings. Pancreatic acinar cells in diabetic mice were recently converted into β-cells by treatment with ciliary neurotrophic factor (CNTF) and epidermal growth factor (EGF). This suggests that human acinar cells might become a cornerstone for diabetes cell therapy in the future, if they can also be converted into glucose-responsive insulin-producing cells. Presently, studying pancreatic acinar cell biology in vitro is limited by their high plasticity, as they rapidly lose their phenotype and spontaneously transdifferentiate to a duct-like phenotype in culture. We questioned whether human pancreatic acinar cell phenotype could be preserved in vitro by physico-chemical manipulations and whether this could be valuable in the study of β-cell neogenesis. We found that culture at low temperature (4°C) resulted in the maintenance of morphological and molecular acinar cell characteristics. Specifically, chilled acinar cells did not form the spherical clusters observed in controls (culture at 37°C), and they maintained high levels of acinar-specific transcripts and proteins. Five-day chilled acinar cells still transdifferentiated into duct-like cells upon transfer to 37°C. Moreover, adenoviral-mediated gene transfer evidenced an active Amylase promoter in the 7-day chilled acinar cells, and transduction performed in chilled conditions improved acinar cell labelling. Together, our findings indicate the maintenance of human pancreatic acinar cell phenotype at low temperature and the possibility to efficiently label acinar cells, which opens new perspectives for the study of human acinar-to-β-cell transdifferentiation. PMID:26987985

  8. Acinar phenotype is preserved in human exocrine pancreas cells cultured at low temperature: implications for lineage-tracing of β-cell neogenesis

    PubMed Central

    Mfopou, Josué K.; Houbracken, Isabelle; Wauters, Elke; Mathijs, Iris; Song, Imane; Himpe, Eddy; Baldan, Jonathan; Heimberg, Harry; Bouwens, Luc

    2016-01-01

    The regenerative medicine field is expanding with great successes in laboratory and preclinical settings. Pancreatic acinar cells in diabetic mice were recently converted into β-cells by treatment with ciliary neurotrophic factor (CNTF) and epidermal growth factor (EGF). This suggests that human acinar cells might become a cornerstone for diabetes cell therapy in the future, if they can also be converted into glucose-responsive insulin-producing cells. Presently, studying pancreatic acinar cell biology in vitro is limited by their high plasticity, as they rapidly lose their phenotype and spontaneously transdifferentiate to a duct-like phenotype in culture. We questioned whether human pancreatic acinar cell phenotype could be preserved in vitro by physico-chemical manipulations and whether this could be valuable in the study of β-cell neogenesis. We found that culture at low temperature (4°C) resulted in the maintenance of morphological and molecular acinar cell characteristics. Specifically, chilled acinar cells did not form the spherical clusters observed in controls (culture at 37°C), and they maintained high levels of acinar-specific transcripts and proteins. Five-day chilled acinar cells still transdifferentiated into duct-like cells upon transfer to 37°C. Moreover, adenoviral-mediated gene transfer evidenced an active Amylase promoter in the 7-day chilled acinar cells, and transduction performed in chilled conditions improved acinar cell labelling. Together, our findings indicate the maintenance of human pancreatic acinar cell phenotype at low temperature and the possibility to efficiently label acinar cells, which opens new perspectives for the study of human acinar-to-β-cell transdifferentiation. PMID:26987985

  9. Neuronal involvement in muscular atrophy

    PubMed Central

    Cisterna, Bruno A.; Cardozo, Christopher; Sáez, Juan C.

    2014-01-01

    The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor-related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression. PMID:25540609

  10. Replacement of Rbpj with Rbpjl in the PTF1 complex controls the final maturation of pancreatic acinar cells

    PubMed Central

    Masui, Toshihiko; Swift, Galvin H.; Deering, Tye; Shen, Chengcheng; Coats, Ward S.; Long, Qiaoming; Elsässer, Hans-Peter; Magnuson, Mark A.; MacDonald, Raymond J.

    2010-01-01

    Background & Aims The mature pancreatic acinar cell is dedicated to the production of very large amounts of digestive enzymes. The early stages of pancreatic development require the Rbpj-form of the trimeric transcription factor complex PTF1 (PTF1-J). As acinar development commences, Rbpjl gradually replaces Rbpj; in the mature pancreas, PTF1 contains Rbpjl (PTF1-L). We investigated whether PTF1-L controls the expression of genes that complete the final stage of acinar differentiation. Methods We analyzed acinar development and transcription in mice with disrupted Rbpjl (Rbpjlko/ko mice). We performed comprehensive analyses of the mRNA population and PTF1 target genes in pancreatic acinar cells from these and wild-type mice. Results In Rbpjlko/ko mice, acinar differentiation was incomplete and characterized by decreased expression (as much as 99%) of genes that encode digestive enzymes or proteins of regulated exocytosis and mitochondrial metabolism. Whereas PTF1-L bound regulatory sites of genes in normal adult pancreatic cells, the embryonic form (PTF1-J) persisted in the absence of Rbpjl and replaced PTF1-L; the extent of replacement determined gene expression levels. Loss of PTF1-L reduced expression (>2-fold) of only about 50 genes, 90% of which were direct targets of PTF1-L. The magnitude of the effects on individual digestive enzyme genes correlated with the developmental timing of gene activation. Absence of Rbpjl increased pancreatic expression of liver-restricted mRNAs. Conclusions Replacement of Rbpj by Rbpjl in the PTF1 complex drives acinar differentiation by maximizing secretory protein synthesis, stimulating mitochondrial metabolism and cytoplasmic creatine-phosphate energy stores, completing the packaging and secretory apparatus, and maintaining acinar-cell homeostasis. PMID:20398665

  11. Multiple System Atrophy with Orthostatic Hypotension (Shy-Drager Syndrome)

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Multiple System Atrophy with Orthostatic Hypotension Information Page Synonym(s): Shy- ... being done? Clinical Trials Organizations What is Multiple System Atrophy with Orthostatic Hypotension? Multiple system atrophy with ...

  12. Salivary gland acinar cells regenerate functional glandular structures in modified hydrogels

    NASA Astrophysics Data System (ADS)

    Pradhan, Swati

    Xerostomia, a condition resulting from irradiation of the head and neck, affects over 40,000 cancer patients each year in the United States. Direct radiation damage of the acinar cells that secrete fluid and protein results in salivary gland hypofunction. Present medical management for xerostomia for patients treated for upper respiratory cancer is largely ineffective. Patients who have survived their terminal diagnosis are often left with a diminished quality of life and are unable to enjoy the simple pleasures of eating and drinking. This project aims to ultimately reduce human suffering by developing a functional implantable artificial salivary gland. The goal was to create an extracellular matrix (ECM) modified hyaluronic acid (HA) based hydrogel culture system that allows for the growth and differentiation of salivary acinar cells into functional acini-like structures capable of secreting large amounts of protein and fluid unidirectionally and to ultimately engineer a functional artificial salivary gland that can be implanted into an animal model. A tissue collection protocol was established and salivary gland tissue was obtained from patients undergoing head and neck surgery. The tissue specimen was assessed by histology and immunohistochemistry to establish the phenotype of normal salivary gland cells including the native basement membranes. Hematoxylin and eosin staining confirmed normal glandular tissue structures including intercalated ducts, striated ducts and acini. alpha-Amylase and periodic acid schiff stain, used for structures with a high proportion of carbohydrate macromolecules, preferentially stained acinar cells in the tissue. Intercalated and striated duct structures were identified using cytokeratins 19 and 7 staining. Myoepithelial cells positive for cytokeratin 14 were found wrapped around the serous and mucous acini. Tight junction components including ZO-1 and E-cadherin were present between both ductal and acinar cells. Ductal and acinar

  13. Crustacean muscles: atrophy and regeneration during molting

    SciTech Connect

    Mykles, D.L.; Skinner, D.M.

    1981-01-01

    The ultrastructural basis of atrophy of claw closer muscle of the land crab and the organization of myofibrils and sacroplasmic reticulum during the hydrolysis of protein that occurs during proecdysis was examined. The changes that occur in contractile proteins during claw muscle atrophy and the involvement of Ca/sup 2 +/-dependent proteinases (CDP) in myofilament degradation were investigated. (ACR)

  14. Aerosol deposition characteristics in distal acinar airways under cyclic breathing conditions

    PubMed Central

    Ma, Baoshun

    2011-01-01

    Although the major mechanisms of aerosol deposition in the lung are known, detailed quantitative data in anatomically realistic models are still lacking, especially in the acinar airways. In this study, an algorithm was developed to build multigenerational three-dimensional models of alveolated airways with arbitrary bifurcation angles and spherical alveolar shape. Using computational fluid dynamics, the deposition of 1- and 3-μm aerosol particles was predicted in models of human alveolar sac and terminal acinar bifurcation under rhythmic wall motion for two breathing conditions (functional residual capacity = 3 liter, tidal volume = 0.5 and 0.9 liter, breathing period = 4 s). Particles entering the model during one inspiration period were tracked for multiple breathing cycles until all particles deposited or escaped from the model. Flow recirculation inside alveoli occurred only during transition between inspiration and expiration and accounted for no more than 1% of the whole cycle. Weak flow irreversibility and convective transport were observed in both models. The average deposition efficiency was similar for both breathing conditions and for both models. Under normal gravity, total deposition was ∼33 and 75%, of which ∼67 and 96% occurred during the first cycle, for 1- and 3-μm particles, respectively. Under zero gravity, total deposition was ∼2–5% for both particle sizes. These results support previous findings that gravitational sedimentation is the dominant deposition mechanism for micrometer-sized aerosols in acinar airways. The results also showed that moving walls and multiple breathing cycles are needed for accurate estimation of aerosol deposition in acinar airways. PMID:21330617

  15. Acinar inflammatory response to lipid derivatives generated in necrotic fat during acute pancreatitis.

    PubMed

    Mateu, A; Ramudo, L; Manso, M A; Closa, D; De Dios, I

    2014-09-01

    Lipids play a role in acute pancreatitis (AP) progression. We investigate the ability of pancreatic acinar cells to trigger inflammatory response in the presence of lipid compounds generated in necrotic areas of peripancreatic adipose tissue (AT) during AP induced in rats by 5% sodium taurocholate. Lipid composition of AT was analyzed by HPLC-mass spectrometry. Acinar inflammatory response to total lipids as well as to either the free fatty acid (FFA) fraction or their chlorinated products (Cl-FFAs) was evaluated. For this, mRNA expression of chemokine (C-C motif) ligand 2 (CCL2) and P-selectin as well as the activation of MAPKs, NF-κB and STAT-3 were analyzed in pancreatic acini. Myeloperoxidase (MPO) activity, as an inducer of Cl-FFA generation, was also analyzed in AT. MPO activity significantly increased in necrotic (AT-N) induced changes in lipid composition of necrotic fat, such as increase in FFA and phospholipid (PL) content, generation of Cl-FFAs and increases in saturated FFAs and in the poly-:mono-unsaturated FFA ratio. Total lipids from AT-N induced overexpression of CCL2 and P-selectin in pancreatic acini as well as MAPKs phosphorylation and activation of NF-κB and STAT3. FFAs, but not Cl-FFAs, up-regulated CCL2 and P-selectin in acinar cells. We conclude that FFAs are capable of up-regulating inflammatory mediators in pancreatic acini and given that they are highly produced during AP, mainly may contribute to the inflammatory response triggered in acinar cells by fat necrosis. No role is played by Cl-FFAs generated as a result of neutrophil infiltration. PMID:24959971

  16. Rab27b regulates exocytosis of secretory vesicles in acinar epithelial cells from the lacrimal gland

    PubMed Central

    Chiang, Lilian; Ngo, Julie; Schechter, Joel E.; Karvar, Serhan; Tolmachova, Tanya; Seabra, Miguel C.; Hume, Alistair N.

    2011-01-01

    Tear proteins are supplied by the regulated fusion of secretory vesicles at the apical surface of lacrimal gland acinar cells, utilizing trafficking mechanisms largely yet uncharacterized. We investigated the role of Rab27b in the terminal release of these secretory vesicles. Confocal fluorescence microscopy analysis of primary cultured rabbit lacrimal gland acinar cells revealed that Rab27b was enriched on the membrane of large subapical vesicles that were significantly colocalized with Rab3D and Myosin 5C. Stimulation of cultured acinar cells with the secretagogue carbachol resulted in apical fusion of these secretory vesicles with the plasma membrane. Evaluation of morphological changes by transmission electron microscopy of lacrimal glands from Rab27b−/− and Rab27ash/ash/Rab27b−/− mice, but not ashen mice deficient in Rab27a, showed changes in abundance and organization of secretory vesicles, further confirming a role for this protein in secretory vesicle exocytosis. Glands lacking Rab27b also showed increased lysosomes, damaged mitochondria, and autophagosome-like organelles. In vitro, expression of constitutively active Rab27b increased the average size but retained the subapical distribution of Rab27b-enriched secretory vesicles, whereas dominant-negative Rab27b redistributed this protein from membrane to the cytoplasm. Functional studies measuring release of a cotransduced secretory protein, syncollin-GFP, showed that constitutively active Rab27b enhanced, whereas dominant-negative Rab27b suppressed, stimulated release. Disruption of actin filaments inhibited vesicle fusion to the apical membrane but did not disrupt homotypic fusion. These data show that Rab27b participates in aspects of lacrimal gland acinar cell secretory vesicle formation and release. PMID:21525430

  17. Functional differences in the acinar cells of the murine major salivary glands.

    PubMed

    Kondo, Y; Nakamoto, T; Jaramillo, Y; Choi, S; Catalan, M A; Melvin, J E

    2015-05-01

    In humans, approximately 90% of saliva is secreted by the 3 major salivary glands: the parotid (PG), the submandibular (SMG), and the sublingual glands (SLG). Even though it is known that all 3 major salivary glands secrete saliva by a Cl(-)-dependent mechanism, salivary secretion rates differ greatly among these glands. The goal of this study was to gain insight into the properties of the ion-transporting pathways in acinar cells that might account for the differences among the major salivary glands. Pilocarpine-induced saliva was simultaneously collected in vivo from the 3 major salivary glands of mice. When normalized by gland weight, the amount of saliva secreted by the PG was more than 2-fold larger than that obtained from the SMG and SLG. At the cellular level, carbachol induced an increase in the intracellular [Ca(2+)] that was more than 2-fold larger in PG and SMG than in SLG acinar cells. Carbachol-stimulated Cl(-) efflux and the protein levels of the Ca(2+)-activated Cl(-) channel TMEM16A, the major apical Cl(-) efflux pathway in salivary acinar cells, were significantly greater in PG compared with SMG and SLG. In addition, we evaluated the transporter activity of the Na(+)-K(+)-2Cl(-) cotransporters (NKCC1) and anion exchangers (AE), the 2 primary basolateral Cl(-) uptake mechanisms in acinar cells. The SMG NKCC1 activity was about twice that of the PG and more than 12-fold greater than that of the SLG. AE activity was similar in PG and SLG, and both PG and SLG AE activity was about 2-fold larger than that of SMG. In summary, the salivation kinetics of the 3 major glands are distinct, and these differences can be explained by the unique functional properties of each gland related to Cl(-) movement, including the transporter activities of the Cl(-) uptake and efflux pathways, and intracellular Ca(2+) mobilization. PMID:25680367

  18. Coupling of guanine nucleotide inhibitory protein to somatostatin receptors on pancreatic acinar membranes

    SciTech Connect

    Sakamoto, C.; Matozaki, T.; Nagao, M.; Baba, S.

    1987-09-01

    Guanine nucleotides and pertussis toxin were used to investigate whether somatostatin receptors interact with the guanine nucleotide inhibitory protein (NI) on pancreatic acinar membranes in the rat. Guanine nucleotides reduced /sup 125/I-(Tyr/sup 1/)somatostatin binding to acinar membranes up to 80%, with rank order of potency being 5'-guanylyl imidodiphosphate (Gpp(NH)p)>GTP>TDP>GMP. Scatchard analysis revealed that the decrease in somatostatin binding caused by Gpp(NH)p was due to the decrease in the maximum binding capacity without a significant change in the binding affinity. The inhibitory effect of Gpp(NH)p was partially abolished in the absence of Mg/sup 2 +/. When pancreatic acini were treated with 1 ..mu..g/ml pertussis toxin for 4 h, subsequent /sup 125/I-(Tyr/sup 1/)somatostatin binding to acinar membranes was reduced. Pertussis toxin treatment also abolished the inhibitory effect of somatostatin on vasoactive intestinal peptide-stimulated increase in cellular content of adenosine 3',5'-cyclic monophosphate (cAMP) in the acini. The present results suggest that 1) somatostatin probably functions in the pancreas to regulate adenylate cyclase enzyme system via Ni, 2) the extent of modification of Ni is correlated with the ability of somatostatin to inhibit cAMP accumulation in acini, and 3) guanine nucleotides also inhibit somatostatin binding to its receptor.

  19. Acinus-on-a-chip: a microfluidic platform for pulmonary acinar flows

    NASA Astrophysics Data System (ADS)

    Fishler, Rami; Mulligan, Molly; Sznitman, Josue; Sznitman Biofluids Team

    2013-11-01

    Convective respiratory flows in the pulmonary acinus and their influence on the fate of inhaled particles are typically studied using computational fluid dynamics (CFD) or scaled-up experimental models. However, current experiments generally capture only flow dynamics, without inhaled particle dynamics, due to difficulties in simultaneously matching flow and particle dynamics. In an effort to overcome these limitations, we have designed a novel microfluidic device mimicking acinar flow conditions directly at the physiological scale. The model features an anatomically-inspired acinar geometry with five dichotomously branching airway generations lined with periodically expanding and contracting alveoli. Using micro-particle image velocimetry (PIV), we reveal experimentally a gradual transition of alveolar flow patterns along the acinar tree from recirculating to radial streamlines, in support of previous predictions from CFD simulations. We demonstrate the applicability of the device for studying the mechanisms of particle deposition in the pulmonary acinus by mapping deposition sites of airborne fluorescent micro-particles (0.1-1 μm) and visualizing trajectories of airborne incense particles inside the system.

  20. Effect of ethanol on cholecystokinin-stimulated zymogen conversion in pancreatic acinar cells.

    PubMed

    Katz, M; Carangelo, R; Miller, L J; Gorelick, F

    1996-01-01

    Exocrine pancreatic zymogens are proteolytically processed to active forms after they are secreted into the small intestine. However, intracellular conversion of zymogens to active forms can be stimulated by treating pancreatic acinar cells with high doses of cholecystokinin (0.1 microM) or carbamylcholine (0.1 mM). The high doses of cholecystokinin are unlikely to be achieved physiologically. The ability of ethanol to sensitize the acinar cell to zymogen conversion Induced by cholecystokinin or carbamylcholine was examined. Ethanol (10-200 mM) had no effect alone or when combined with carbamylcholine. However, ethanol (25 mM) added with low-dose cholecystokinin (0.1 nM) generated zymogen conversion that was 1) sixfold higher than cholecystokinin alone and 2) equivalent to that generated by highdose cholecystokinin (10 microM). The ability of ethanol to enhance cholecystokinin-induced zymogen conversion was dependent on the dose of ethanol and the duration of ethanol treatment. The cholecystokinin receptor antagonist, L-364,718, blocked the conversion stimulated by the addition of ethanol with cholecystokinin. This effect of ethanol did not change the affinity or number of cholecystokinin receptors, suggesting an effect more distal in the stimulus-activation cascade. These findings demonstrate that ethanol selectively sensitizes the pancreatic acinar cell to cholecystokinin-stimulated zymogen proteolysis. PMID:8772515

  1. Particle dynamics and deposition in true-scale pulmonary acinar models

    PubMed Central

    Fishler, Rami; Hofemeier, Philipp; Etzion, Yael; Dubowski, Yael; Sznitman, Josué

    2015-01-01

    Particle transport phenomena in the deep alveolated airways of the lungs (i.e. pulmonary acinus) govern deposition outcomes following inhalation of hazardous or pharmaceutical aerosols. Yet, there is still a dearth of experimental tools for resolving acinar particle dynamics and validating numerical simulations. Here, we present a true-scale experimental model of acinar structures consisting of bifurcating alveolated ducts that capture breathing-like wall motion and ensuing respiratory acinar flows. We study experimentally captured trajectories of inhaled polydispersed smoke particles (0.2 to 1 μm in diameter), demonstrating how intrinsic particle motion, i.e. gravity and diffusion, is crucial in determining dispersion and deposition of aerosols through a streamline crossing mechanism, a phenomenon paramount during flow reversal and locally within alveolar cavities. A simple conceptual framework is constructed for predicting the fate of inhaled particles near an alveolus by identifying capture and escape zones and considering how streamline crossing may shift particles between them. In addition, we examine the effect of particle size on detailed deposition patterns of monodispersed microspheres between 0.1–2 μm. Our experiments underline local modifications in the deposition patterns due to gravity for particles ≥0.5 μm compared to smaller particles, and show good agreement with corresponding numerical simulations. PMID:26358580

  2. Steady streaming: A key mixing mechanism in low-Reynolds-number acinar flows

    PubMed Central

    Kumar, Haribalan; Tawhai, Merryn H.; Hoffman, Eric A.; Lin, Ching-Long

    2011-01-01

    Study of mixing is important in understanding transport of submicron sized particles in the acinar region of the lung. In this article, we investigate transport in view of advective mixing utilizing Lagrangian particle tracking techniques: tracer advection, stretch rate and dispersion analysis. The phenomenon of steady streaming in an oscillatory flow is found to hold the key to the origin of kinematic mixing in the alveolus, the alveolar mouth and the alveolated duct. This mechanism provides the common route to folding of material lines and surfaces in any region of the acinar flow, and has no bearing on whether the geometry is expanding or if flow separates within the cavity or not. All analyses consistently indicate a significant decrease in mixing with decreasing Reynolds number (Re). For a given Re, dispersion is found to increase with degree of alveolation, indicating that geometry effects are important. These effects of Re and geometry can also be explained by the streaming mechanism. Based on flow conditions and resultant convective mixing measures, we conclude that significant convective mixing in the duct and within an alveolus could originate only in the first few generations of the acinar tree as a result of nonzero inertia, flow asymmetry, and large Keulegan–Carpenter (KC) number. PMID:21580803

  3. Loss of Ifnar1 in Pancreatic Acinar Cells Ameliorates the Disease Course of Acute Pancreatitis.

    PubMed

    Miller, Katharina J; Raulefs, Susanne; Kong, Bo; Steiger, Katja; Regel, Ivonne; Gewies, Andreas; Kleeff, Jörg; Michalski, Christoph W

    2015-01-01

    Type I interferon constitutes an essential component of the combinational therapy against viral disease. Acute pancreatitis is one side effect of type I interferon-based therapy, implying that activation of type I interferon signaling affects the homeostasis and integrity of pancreatic acinar cells. Here, we investigated the role of type I interferon signaling in pancreatic acinar cells using a caerulein-induced murine model of acute pancreatitis. Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage. Profiling of infiltrating immune cells revealed that this dampened tissue damage response correlated with the number of macrophages in the pancreas. Pharmacologic depletion of macrophages reversed the protective effect of Ifnar1 deficiency. Furthermore, expression of chemokine (C-C motif) ligand 2 (Ccl2), a potent factor for macrophage recruitment, was significantly increased in the Ifnar1-deficient pancreas. Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas. PMID:26618925

  4. Steady streaming: A key mixing mechanism in low-Reynolds-number acinar flows.

    PubMed

    Kumar, Haribalan; Tawhai, Merryn H; Hoffman, Eric A; Lin, Ching-Long

    2011-04-01

    Study of mixing is important in understanding transport of submicron sized particles in the acinar region of the lung. In this article, we investigate transport in view of advective mixing utilizing Lagrangian particle tracking techniques: tracer advection, stretch rate and dispersion analysis. The phenomenon of steady streaming in an oscillatory flow is found to hold the key to the origin of kinematic mixing in the alveolus, the alveolar mouth and the alveolated duct. This mechanism provides the common route to folding of material lines and surfaces in any region of the acinar flow, and has no bearing on whether the geometry is expanding or if flow separates within the cavity or not. All analyses consistently indicate a significant decrease in mixing with decreasing Reynolds number (Re). For a given Re, dispersion is found to increase with degree of alveolation, indicating that geometry effects are important. These effects of Re and geometry can also be explained by the streaming mechanism. Based on flow conditions and resultant convective mixing measures, we conclude that significant convective mixing in the duct and within an alveolus could originate only in the first few generations of the acinar tree as a result of nonzero inertia, flow asymmetry, and large Keulegan-Carpenter (K(C)) number. PMID:21580803

  5. Chronic hypoxia does not cause wall thickening of intra-acinar pulmonary supernumerary arteries.

    PubMed

    Oshima, Kaori; McLendon, Jared M; Wagner, Wiltz W; McMurtry, Ivan F; Oka, Masahiko

    2016-02-01

    Chronic exposure to hypoxia causes pulmonary hypertension and pulmonary arterial remodeling. Although the exact mechanisms of this remodeling are unclear, there is evidence that it is dependent on hemodynamic stress, rather than on hypoxia alone. Pulmonary supernumerary arteries experience low hemodynamic stress as a consequence of reduced perfusion due to 90° branching angles, small diameters, and "valve-like" structures at their orifices. We investigated whether or not intra-acinar supernumerary arteries undergo structural remodeling during the moderate pulmonary hypertension induced by chronic hypoxia. Rats were exposed to either normoxia or hypoxia for 6 weeks. The chronically hypoxic rats developed pulmonary hypertension. For both groups, pulmonary arteries were selectively filled with barium-gelatin mixture, and the wall thickness of intra-acinar pulmonary arteries was measured in histological samples. Only thin-walled arteries were observed in normoxic lungs. In hypertensive lungs, we found both thin- and thick-walled pulmonary arteries with similar diameters. Disproportionate degrees of arterial wall thickening between parent and daughter branches were observed with supernumerary branching patterns. While parent arteries developed significant wall thickening, their supernumerary branches did not. Thus, chronic hypoxia-induced pulmonary hypertension did not cause wall thickening of intra-acinar pulmonary supernumerary arteries. These findings are consistent with the idea that hemodynamic stress, rather than hypoxia alone, is the cause of structural remodeling during chronic exposure to hypoxia. PMID:26811053

  6. Pre/post-strike atmospheric assessment system (PAAS)

    SciTech Connect

    Peglow, S. G., LLNL; Molitoris, J. D., LLNL

    1997-02-03

    The Pre/Post-Strike Atmospheric Assessment System was proposed to show the importance of local meteorological conditions in the vicinity of a site suspected of storing or producing toxic agents and demonstrate a technology to measure these conditions, specifically wind fields. The ability to predict the collateral effects resulting from an attack on a facility containing hazardous materials is crucial to conducting effective military operations. Our study approach utilized a combination of field measurements with dispersion modeling to better understand which variables in terrain and weather were most important to collateral damage predictions. To develop the PAAS wind-sensing technology, we utilized a combination of emergent and available technology from micro-Doppler and highly coherent laser systems. The method used for wind sensing is to probe the atmosphere with a highly coherent laser beam. As the beam probes, light is back-scattered from particles entrained in the air to the lidar transceiver and detected by the instrument. Any motion of the aerosols with a component along the beam axis leads to a Doppler shift of the received light. Scanning in a conical fashion about the zenith results in a more accurate and two-dimensional measurement of the wind velocity. The major milestones in the benchtop system development were to verify the design by demonstrating the technique in the laboratory, then scale the design down to a size consistent with a demonstrator unit which could be built to take data in the field. The micro-Doppler heterodyne system we developed determines absolute motion by optically mixing a reference beam with the return signal and has shown motion sensitivity to better than 1 cm/s. This report describes the rationale, technical approach and laboratory testing undertaken to demonstrate the feasibility and utility of a system to provide local meteorological data and predict atmospheric particulate motion. The work described herein was funded by

  7. Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice

    PubMed Central

    Miyazaki, Satsuki; Tashiro, Fumi; Miyazaki, Jun-ichi

    2016-01-01

    A promising approach to new diabetes therapies is to generate β cells from other differentiated pancreatic cells in vivo. Because the acinar cells represent the most abundant cell type in the pancreas, an attractive possibility is to reprogram acinar cells into β cells. The transcription factor Pdx1 (Pancreas/duodenum homeobox protein 1) is essential for pancreatic development and cell lineage determination. Our objective is to examine whether exogenous expression of Pdx1 in acinar cells of adult mice might induce reprogramming of acinar cells into β cells. We established a transgenic mouse line in which Pdx1 and EGFP (enhanced green fluorescent protein) could be inducibly expressed in the acinar cells. After induction of Pdx1, we followed the acinar cells for their expression of exocrine and endocrine markers using cell-lineage tracing with EGFP. The acinar cell-specific expression of Pdx1 in adult mice reprogrammed the acinar cells as endocrine precursor cells, which migrated into the pancreatic islets and differentiated into insulin-, somatostatin-, or PP (pancreatic polypeptide)-producing endocrine cells, but not into glucagon-producing cells. When the mice undergoing such pancreatic reprogramming were treated with streptozotocin (STZ), the newly generated insulin-producing cells were able to ameliorate STZ-induced diabetes. This paradigm of in vivo reprogramming indicates that acinar cells hold promise as a source for new islet cells in regenerative therapies for diabetes. PMID:27526291

  8. Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice.

    PubMed

    Miyazaki, Satsuki; Tashiro, Fumi; Miyazaki, Jun-Ichi

    2016-01-01

    A promising approach to new diabetes therapies is to generate β cells from other differentiated pancreatic cells in vivo. Because the acinar cells represent the most abundant cell type in the pancreas, an attractive possibility is to reprogram acinar cells into β cells. The transcription factor Pdx1 (Pancreas/duodenum homeobox protein 1) is essential for pancreatic development and cell lineage determination. Our objective is to examine whether exogenous expression of Pdx1 in acinar cells of adult mice might induce reprogramming of acinar cells into β cells. We established a transgenic mouse line in which Pdx1 and EGFP (enhanced green fluorescent protein) could be inducibly expressed in the acinar cells. After induction of Pdx1, we followed the acinar cells for their expression of exocrine and endocrine markers using cell-lineage tracing with EGFP. The acinar cell-specific expression of Pdx1 in adult mice reprogrammed the acinar cells as endocrine precursor cells, which migrated into the pancreatic islets and differentiated into insulin-, somatostatin-, or PP (pancreatic polypeptide)-producing endocrine cells, but not into glucagon-producing cells. When the mice undergoing such pancreatic reprogramming were treated with streptozotocin (STZ), the newly generated insulin-producing cells were able to ameliorate STZ-induced diabetes. This paradigm of in vivo reprogramming indicates that acinar cells hold promise as a source for new islet cells in regenerative therapies for diabetes. PMID:27526291

  9. Biomechanical simulation of atrophy in MR images

    NASA Astrophysics Data System (ADS)

    Castellano Smith, Andrew D.; Crum, William R.; Hill, Derek L. G.; Thacker, Neil A.; Bromiley, Paul A.

    2003-05-01

    Progressive cerebral atrophy is a physical component of the most common forms of dementia - Alzheimer's disease, vascular dementia, Lewy-Body disease and fronto-temporal dementia. We propose a phenomenological simulation of atrophy in MR images that provides gold-standard data; the origin and rate of progression of atrophy can be controlled and the resultant remodelling of brain structures is known. We simulate diffuse global atrophic change by generating global volumetric change in a physically realistic biomechanical model of the human brain. Thermal loads are applied to either single, or multiple, tissue types within the brain to drive tissue expansion or contraction. Mechanical readjustment is modelled using finite element methods (FEM). In this preliminary work we apply these techniques to the MNI brainweb phantom to produce new images exhibiting global diffuse atrophy. We compare the applied atrophy with that measured from the images using an established quantitative technique. Early results are encouraging and suggest that the model can be extended and used for validation of atrophy measurement techniques and non-rigid image registration, and for understanding the effect of atrophy on brain shape.

  10. Chronic spinal muscular atrophy of facioscapulohumeral type.

    PubMed Central

    Furukawa, T; Toyokura, Y

    1976-01-01

    Chronic spinal muscular atrophy of FSH type affecting a mother and her son and daughter is reported. The relevant literature is reviewed and the relation between this conditon and Kugelberg-Welander (K-W) disease is discussed. Chronic spinal muscular atrophy of FSH type is considered to be a different entity from the eponymous K-W disease. Each type of muscular dystrophy, e.g. limb-girdle, FSH, distal, ocular, or oculopharyngeal type, has its counterpart of nuclear origin. A classification of the chronic spinal muscular atrophies is suggested following the classification of muscular dystrophy. Images PMID:957378

  11. Genetics Home Reference: spinal muscular atrophy

    MedlinePlus

    ... a loss of specialized nerve cells, called motor neurons , in the spinal cord and the part of ... spinal cord ( the brainstem ). The loss of motor neurons leads to weakness and wasting ( atrophy ) of muscles ...

  12. Infraspinatus muscle atrophy from suprascapular nerve compression.

    PubMed

    Cordova, Christopher B; Owens, Brett D

    2014-02-01

    Muscle weakness without pain may signal a nerve compression injury. Because these injuries should be identified and treated early to prevent permanent muscle weakness and atrophy, providers should consider suprascapular nerve compression in patients with shoulder muscle weakness. PMID:24463748

  13. Genetic deletion of Rab27B in pancreatic acinar cells affects granules size and has inhibitory effects on amylase secretion.

    PubMed

    Hou, Yanan; Ernst, Stephen A; Lentz, Stephen I; Williams, John A

    2016-03-18

    Small G protein Rab27B is expressed in various secretory cell types and plays a role in mediating secretion. In pancreatic acinar cells, Rab27B was found to be expressed on the zymogen granule membrane and by overexpression to regulate the secretion of zymogen granules. However, the effect of Rab27B deletion on the physiology of pancreatic acinar cells is unknown. In the current study, we utilized the Rab27B KO mouse model to better understand the role of Rab27B in the secretion of pancreatic acinar cells. Our data show that Rab27B deficiency had no obvious effects on the expression of major digestive enzymes and other closely related proteins, e.g. similar small G proteins, such as Rab3D and Rab27A, and putative downstream effectors. The overall morphology of acinar cells was not changed in the knockout pancreas. However, the size of zymogen granules was decreased in KO acinar cells, suggesting a role of Rab27B in regulating the maturation of secretory granules. The secretion of digestive enzymes was moderately decreased in KO acini, compared with the WT control. These data indicate that Rab27B is involved at a different steps of zymogen granule maturation and secretion, which is distinct from that of Rab3D. PMID:26845357

  14. A comparative ultrastructural study of the parotid gland acinar cells of nine wild ruminant species (mammalia, artiodactyla).

    PubMed

    Stolte, M; Ito, S

    1996-01-01

    The ultrastructural similarities and differences of the parotid gland acinar cells of nine wild ruminants (roe deer, nyala, tahr, Eld's deer, red deer, Pere David's deer, European mouflon, African buffalo, sable antelope) representing three feeding types i.e. concentrate selectors (CS), grass and roughage eaters (GR) and intermediate feeders (IM) were compared. The parotid acinar cells of the CS contained more granular endoplasmic reticulum, Golgi-complexes and secretory granules than those of the GR. The acinar cells of the latter were characterized by numerous mitochondria, folded plasma membranes and intercellular secretory canaliculi. The ultrastructure of the secretory granules varied in different species but their morphology was not related to feeding type. An unusual feature of the parotid acinar cells of all feeding types was the evidence of an apocrine-like mode of secretion. A typical morphological change of some parotid acinar cells was the compression of the nucleus by large vacuoles. No distinctive differences were found in the ultrastructure of the parotid gland of wild and captive ruminants. PMID:9090994

  15. Inactivation of TGFβ receptor II signalling in pancreatic epithelial cells promotes acinar cell proliferation, acinar-to-ductal metaplasia and fibrosis during pancreatitis.

    PubMed

    Grabliauskaite, Kamile; Saponara, Enrica; Reding, Theresia; Bombardo, Marta; Seleznik, Gitta M; Malagola, Ermanno; Zabel, Anja; Faso, Carmen; Sonda, Sabrina; Graf, Rolf

    2016-02-01

    Determining signalling pathways that regulate pancreatic regeneration following pancreatitis is critical for implementing therapeutic interventions. In this study we elucidated the molecular mechanisms underlying the effects of transforming growth factor-β (TGFβ) in pancreatic epithelial cells during tissue regeneration. To this end, we conditionally inactivated TGFβ receptor II (TGFβ-RII) using a Cre-LoxP system under the control of pancreas transcription factor 1a (PTF1a) promoter, specific for the pancreatic epithelium, and evaluated the molecular and cellular changes in a mouse model of cerulein-induced pancreatitis. We show that TGFβ-RII signalling does not mediate the initial acinar cell damage observed at the onset of pancreatitis. However, TGFβ-RII signalling not only restricts acinar cell replication during the regenerative phase of the disease but also limits ADM formation in vivo and in vitro in a cell-autonomous manner. Analyses of molecular mechanisms underlying the observed phenotype revealed that TGFβ-RII signalling stimulates the expression of cyclin-dependent kinase inhibitors and intersects with the EGFR signalling axis. Finally, TGFβ-RII ablation in epithelial cells resulted in increased infiltration of inflammatory cells in the early phases of pancreatitis and increased activation of pancreatic stellate cells in the later stages of pancreatitis, thus highlighting a TGFβ-based crosstalk between epithelial and stromal cells regulating the development of pancreatic inflammation and fibrosis. Collectively, our data not only contribute to clarifying the cellular processes governing pancreatic tissue regeneration, but also emphasize the conserved role of TGFβ as a tumour suppressor, both in the regenerative process following pancreatitis and in the initial phases of pancreatic cancer. PMID:26510396

  16. On the estimation and correction of bias in local atrophy estimations using example atrophy simulations.

    PubMed

    Sharma, Swati; Rousseau, François; Heitz, Fabrice; Rumbach, Lucien; Armspach, Jean-Paul

    2013-01-01

    Brain atrophy is considered an important marker of disease progression in many chronic neuro-degenerative diseases such as multiple sclerosis (MS). A great deal of attention is being paid toward developing tools that manipulate magnetic resonance (MR) images for obtaining an accurate estimate of atrophy. Nevertheless, artifacts in MR images, inaccuracies of intermediate steps and inadequacies of the mathematical model representing the physical brain volume change, make it rather difficult to obtain a precise and unbiased estimate. This work revolves around the nature and magnitude of bias in atrophy estimations as well as a potential way of correcting them. First, we demonstrate that for different atrophy estimation methods, bias estimates exhibit varying relations to the expected atrophy and these bias estimates are of the order of the expected atrophies for standard algorithms, stressing the need for bias correction procedures. Next, a framework for estimating uncertainty in longitudinal brain atrophy by means of constructing confidence intervals is developed. Errors arising from MRI artifacts and bias in estimations are learned from example atrophy simulations and anatomies. Results are discussed for three popular non-rigid registration approaches with the help of simulated localized brain atrophy in real MR images. PMID:23988649

  17. Models of Multiple System Atrophy

    PubMed Central

    Fellner, Lisa; Wenning, Gregor K.; Stefanova, Nadia

    2016-01-01

    Multiple system atrophy (MSA) is a predominantly sporadic, adult-onset, fatal neurodegenerative disease of unknown etiology. MSA is characterized by autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs in any combination. MSA belongs to a group of neurodegenerative disorders termed α-synucleinopathies, which also include Parkinson’s disease and dementia with Lewy bodies. Their common pathological feature is the occurrence of abnormal α-synuclein positive inclusions in neurons or glial cells. In MSA, the main cell type presenting aggregates composed of α-synuclein are oligodendroglial cells. This pathological hallmark, also called glial cytoplasmic inclusions (GCIs), is associated with progressive and profound neuronal loss in various regions of the brain. The development of animal models of MSA is justified by the limited understanding of the mechanisms of neurodegeneration and GCIs formation, which is paralleled by a lack of therapeutic strategies. Two main types of rodent models have been generated to replicate different features of MSA neuropathology. On one hand, neurotoxin-based models have been produced to reproduce neuronal loss in substantia nigra pars compacta and striatum. On the other hand, transgenic mouse models with overexpression of α-synuclein in oligodendroglia have been used to reproduce GCIs-related pathology. This chapter gives an overview of the atypical Parkinson’s syndrome MSA and summarizes the currently available MSA animal models and their relevance for pre-clinical testing of disease-modifying therapies. PMID:24338664

  18. Amylase release from dissociated mouse pancreatic acinar cells stimulated by glucagon: effect of membrane stabilizers.

    PubMed Central

    Singh, M

    1980-01-01

    1. The effect of membrane stabilizers and cytochalasin-B on amylase secretion, basal and induced by ionophore A23187, CCK-PZ, bethanechol and glucagon, was studied in dissociated mouse pancreatic acinar cells. 2. Cytochalasin-B did not affect basal or secretagogue-stimulated amylase secretion. 3. Membrane stabilizers [thymol (10(-7)-10(-4) M), chlorpromazine (10(-7)-10(-4) M) and propranolol (10(-7)-10(-5) M) did not alter basal release of amylase. At higher concentrations of thymol (10(-3) M), chlorpromazine (10(-3) M) and propranolol (10(-4) M), dissociated acinar cells were lysed as indicated by an increase in release of lactic dehydrogenase (LDH). 4. Ionophore A23187, CCK-PZ (maximal effective concentrations, 0.01 u. ml.-1), bethanechol (maximal effective concentrations, 10(-4) M) and glucagon increased amylase secretion in a dose-dependent fashion. Concentrations of CCK-PZ and bethanechol beyond optimal levels decreased amylase secretion. Concentrations of ionophore A23187 and glucagon when tested beyond 10(-6) M and 10(-4) M respectively increased the release of LDH. In concentrations that were non-toxic, membrane stabilizers blocked the stimulating effect of cholecystokinin-pancreozymin and bethanechol on amylase secretion but did not alter the response to A23187 and glucagon. 5. Unlike bethanechol, glucagon neither increased the uptake of 45Ca nor did it alter the release of 45Ca from cells previously loaded with 45CaCl2. 6. These data provide evidence that stimulus-secretion coupling in dissociated pancreatic acinar cells is basically similar to cells in situ. The effect of glucagon is consistent with the model in which hormone-dependent mobilization of Ca2+ from intra- or extracellular sources is bypassed leading to digestive enzyme secretion. PMID:6166745

  19. Involvement of the TetR-Type Regulator PaaR in the Regulation of Pristinamycin I Biosynthesis through an Effect on Precursor Supply in Streptomyces pristinaespiralis

    PubMed Central

    Zhao, Yawei; Feng, Rongrong; Zheng, Guosong; Tian, Jinzhong; Ruan, Lijun; Ge, Mei; Jiang, Weihong

    2015-01-01

    ABSTRACT Pristinamycin I (PI), produced by Streptomyces pristinaespiralis, is a streptogramin type B antibiotic, which contains two proteinogenic and five aproteinogenic amino acid precursors. PI is coproduced with pristinamycin II (PII), a member of streptogramin type A antibiotics. The PI biosynthetic gene cluster has been cloned and characterized. However, thus far little is understood about the regulation of PI biosynthesis. In this study, a TetR family regulator (encoded by SSDG_03033) was identified as playing a positive role in PI biosynthesis. Its homologue, PaaR, from Corynebacterium glutamicum serves as a transcriptional repressor of the paa genes involved in phenylacetic acid (PAA) catabolism. Herein, we also designated the identified regulator as PaaR. Deletion of paaR led to an approximately 70% decrease in PI production but had little effect on PII biosynthesis. Identical to the function of its homologue from C. glutamicum, PaaR is also involved in the suppression of paa expression. Given that phenylacetyl coenzyme A (PA-CoA) is the common intermediate of the PAA catabolic pathway and the biosynthetic pathway of l-phenylglycine (l-Phg), the last amino acid precursor for PI biosynthesis, we proposed that derepression of the transcription of paa genes in a ΔpaaR mutant possibly diverts more PA-CoA to the PAA catabolic pathway, thereby with less PA-CoA metabolic flux toward l-Phg formation, thus resulting in lower PI titers. This hypothesis was verified by the observations that PI production of a ΔpaaR mutant was restored by l-Phg supplementation as well as by deletion of the paaABCDE operon in the ΔpaaR mutant. Altogether, this study provides new insights into the regulation of PI biosynthesis by S. pristinaespiralis. IMPORTANCE A better understanding of the regulation mechanisms for antibiotic biosynthesis will provide valuable clues for Streptomyces strain improvement. Herein, a TetR family regulator PaaR, which serves as the repressor of the

  20. Microbial reduction in wastewater treatment using Fe(3+) and Al(3+) coagulants and PAA disinfectant.

    PubMed

    Pradhan, Surendra K; Kauppinen, Ari; Martikainen, Kati; Pitkänen, Tarja; Kusnetsov, Jaana; Miettinen, Ilkka T; Pessi, Matti; Poutiainen, Hannu; Heinonen-Tanski, Helvi

    2013-12-01

    Wastewater is an important source of pathogenic enteric microorganisms in surface water and a major contaminating agent of drinking water. Although primary and secondary wastewater treatments reduce the numbers of microorganisms in wastewater, significant numbers of microbes can still be present in the effluent. The aim of this study was to test the feasibility of tertiary treatment for municipal wastewater treatment plants (WWTPs) using PIX (FeCl3) or PAX (AlCl3) coagulants and peracetic acid (PAA) the disinfectant to reduce microbial load in effluent. Our study showed that both PIX and PAX efficiently reduced microbial numbers. PAA disinfection greatly reduced the numbers of culturable indicator microorganisms (Escherichia coli, intestinal enterococci, F-specific RNA coliphages and somatic DNA coliphages). In addition, pathogenic microorganisms, thermotolerant Campylobacter, Salmonella and norovirus GI, were successfully reduced using the tertiary treatments. In contrast, clostridia, Legionella, rotavirus, norovirus GII and adenovirus showed better resistance against PAA compared to the other microorganisms. However, interpretation of polymerase chain reaction (PCR) analysis results will need further studies to clarify the infectivity of the pathogenic microbes. In conclusion, PIX and PAX flocculants followed by PAA disinfectant can be used as a tertiary treatment for municipal WWTP effluents to reduce the numbers of indicator and pathogenic microorganisms. PMID:24334832

  1. In vivo kinetic analysis of the penicillin biosynthesis pathway using PAA stimulus response experiments.

    PubMed

    Deshmukh, Amit T; Verheijen, Peter J T; Maleki Seifar, Reza; Heijnen, Joseph J; van Gulik, Walter M

    2015-11-01

    In this study we combined experimentation with mathematical modeling to unravel the in vivo kinetic properties of the enzymes and transporters of the penicillin biosynthesis pathway in a high yielding Penicillium chrysogenum strain. The experiment consisted of a step response experiment with the side chain precursor phenyl acetic acid (PAA) in a glucose-limited chemostat. The metabolite data showed that in the absence of PAA all penicillin pathway enzymes were expressed, leading to the production of a significant amount of 6-aminopenicillanic acid (6APA) as end product. After the stepwise perturbation with PAA, the pathway produced PenG within seconds. From the extra- and intracellular metabolite measurements, hypotheses for the secretion mechanisms of penicillin pathway metabolites were derived. A dynamic model of the penicillin biosynthesis pathway was then constructed that included the formation and transport over the cytoplasmic membrane of pathway intermediates, PAA and the product penicillin-G (PenG). The model parameters and changes in the enzyme levels of the penicillin biosynthesis pathway under in vivo conditions were simultaneously estimated using experimental data obtained at three different timescales (seconds, minutes, hours). The model was applied to determine changes in the penicillin pathway enzymes in time, calculate fluxes and analyze the flux control of the pathway. This led to a reassessment of the in vivo behavior of the pathway enzymes and in particular Acyl-CoA:Isopenicillin N Acyltransferase (AT). PMID:26476338

  2. Acute toxicity of peracetic acid (PAA) formulations to Ichthyophthirius multifiliis theronts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peracetic acid (PAA) is an antimicrobial disinfectant used in agriculture, food processing and medical facilities. It has recently been suggested as a means to control infestations of Ichthyophthirius multifiliis. The purpose of this study was to determine the acute toxicity of two products contai...

  3. [Vital fluorochrome staining of isolated pancreatic acinar cells for the characterization of cell-structural changes].

    PubMed

    Dietzmann, K; Letko, G; Spormann, H

    1986-01-01

    Rhodamine 6 G as a cationic fluorophore is demonstrated to be selectively accumulated by mitochondria of living pancreatic acinar cells (cell isolation see Spormann et al. [1986]. The accumulation of rhodamine was studied under using of electron transport inhibitors, ionophores and some hydrogen donors. The application of DNP as wellknown protonophore resulted in a rapid dissipation of any fluorescent signals, whereas application of sodium succinate, hyperosmolaric exhibited a remarkable increase of fluorescence intensity. Using this technique it is possible to estimate the energy state of living cells under various conditions of energy supply and demand. PMID:2426729

  4. Pancreatic acinar cells: effect of acetylcholine, pancreozymin, gastrin and secretin on membrane potential and resistance in vivo and in vitro.

    PubMed Central

    Petersen, O H; Ueda, N

    1975-01-01

    1. Intracellular recordings of membrane potential and input resistance have been made in vivo and in vitro from the exocrine acinar cells of rat pancreas using indwelling glass micro-electrodes. 2. The resting cell membrane potential and input resistance in the in vivo experiments were not markedly different from the values obtained in the in vitro experiments. The effect of both acetylcholine (ACh) and pancreozymin (CCK-Pz) on the pancreas in vivo as well as in vitro was to reduce both the acinar cell membrane potential and the input resistance narkedly. The amplitude of the evoked depolarization and the change in input resistance evoked by supramaximal stimuli were of the same magnitude in both types of preparations. 3. Gastrin had an effect on the acinar cell potential and resistance which was indistinguishable from that of CCK-Pz or ACh. The effect of gastrin or CCK-Pz was, in contrast to that of ACh, not influenced by the presence of atropine. The reversal potential for the gastrin evoked potential change was about -20 mV. 4. Secretin in doses producing maximal volume secretion in vivo had no effect on acinar cell membrane potential and input resistance. 5. Dibutyryl cyclic AMP (5mM) and cyclic GMP (1mM) had no effect on cell membrane potential or resistance. 6. It is concluded that the in vitro superfused pancreas segment preparation is a useful model system in electrophysiological studies since it functions essentially as the in vivo preparation. In contrast to both gastrin and CCK-Pz, secretin has no effect on the bioelectrical properties of the acinar cells, indicating that there are no physiologically important secretin receptors in rat acinar cells. PMID:168355

  5. Glycyrrhizin down-regulates CCL2 and CXCL2 expression in cerulein-stimulated pancreatic acinar cells

    PubMed Central

    Panahi, Yaser; Fakhari, Shohreh; Mohammadi, Mehdi; Rahmani, Mohammad Reza; Hakhamaneshi, Mohammad Saeid; Jalili, Ali

    2015-01-01

    Many inflammatory chemokines release from leukocytes and pancreatic acinar cells which play important roles in pathophysiology of acute pancreatitis (AP). Of interests, CXCL2 and CCL2 have been shown elevated in the plasma of patients with AP. We have recently found that Glycyrrhizin (GZ) attenuates AP in mice model. In this study, we aimed to investigate the direct effect of GZ on expression levels of CCL2 and CXCl2 in isolated pancreatic acinar cells. Isolated acinar cells were isolated from the pancreas of healthy C57BL/6 mice, stimulated with cerulein (10-7 M) and then treated with either PBS or different doses of GZ. The levels of CCL2 and CXCL2 expression at mRNA were assessed by qRT-PCR. Conditioned media from supernatants of each cells culture condition were collected for detection of CCL2 and CXCL2 levels by ELISA. First, we observed that cerulein significantly upregulates both cytokines expression in acinar cells. Moreover, we treated the acinar cells with GZ and found that GZ significantly downregulates CCL2 and CXCL2 expression at mRNA levels in a dose-dependent manner. Consistently, the conditioned media of GZ-treated cells contained a significant lower levels of CCL2 and CXCL2 (p<0.05). In conclusion, our data demonstrate for the first time that GZ directly downregulates CCL2 and CXCL2 levels in cerulein-stimulated acinar cells which may explain the mechanism of therapeutic effects of GZ in cerulein-induced AP in mice. PMID:26155433

  6. p21(WAF1) (/Cip1) limits senescence and acinar-to-ductal metaplasia formation during pancreatitis.

    PubMed

    Grabliauskaite, Kamile; Hehl, Adrian B; Seleznik, Gitta M; Saponara, Enrica; Schlesinger, Kathryn; Zuellig, Richard A; Dittmann, Anja; Bain, Martha; Reding, Theresia; Sonda, Sabrina; Graf, Rolf

    2015-02-01

    Trans-differentiation of pancreatic acinar cells into ductal-like lesions, a process defined as acinar-to-ductal metaplasia (ADM), is observed in the course of organ regeneration following pancreatitis. In addition, ADM is found in association with pre-malignant PanIN lesions and correlates with an increased risk of pancreatic adenocarcinoma (PDAC). Human PDAC samples show down-regulation of p21(WAF1) (/Cip1) , a key regulator of cell cycle and cell differentiation. Here we investigated whether p21 down-regulation is implicated in controlling the early events of acinar cell trans-differentiation and ADM formation. p21-mediated regulation of ADM formation and regression was analysed in vivo during the course of cerulein-induced pancreatitis, using wild-type (WT) and p21-deficient (p21(-/-) ) mice. Biochemical and immunohistochemical methods were used to evaluate disease progression over 2 weeks of the disease and during a recovery phase. We found that p21 was strongly up-regulated in WT acinar cells during pancreatitis, while it was absent in ADM areas, suggesting that p21 down-regulation is associated with ADM formation. In support of this hypothesis, p21(-/-) mice showed a significant increase in number and size of metaplasia. In addition, p21 over-expression in acinar cells reduced ADM formation in vitro, suggesting that the protein regulates the metaplastic transition in a cell-autonomous manner. p21(-/-) mice displayed increased expression and relocalization of β-catenin both during pancreatitis and in the subsequent recovery phase. Finally, loss of p21 was accompanied by increased DNA damage and development of senescence. Our findings are consistent with a gate-keeper role of p21 in acinar cells to limit senescence activation and ADM formation during pancreatic regeneration. PMID:25212177

  7. Crystal structure of phenylacetic acid degradation protein PaaG from Thermus thermophilus HB8.

    PubMed

    Kichise, Tomoyasu; Hisano, Tamao; Takeda, Kazuki; Miki, Kunio

    2009-09-01

    Microbial degradation of phenylacetic acid proceeds via the hybrid pathway that includes formation of a coenzyme A thioester, ring hydroxylation, non-oxygenolytic ring opening, and beta-oxidation-like reactions. A phenylacetic acid degradation protein PaaG is a member of the crotonase superfamily, and is a candidate non-oxygenolytic ring-opening enzyme. The crystal structure of PaaG from Thermus thermophilus HB8 was determined at a resolution of 1.85 A. PaaG consists of three identical subunits related by local three-fold symmetry. The monomer is comprised of a spiral and a helical domain with a fold characteristic of the crotonase superfamily. A putative active site residue, Asp136, is situated in an active site cavity and surrounded by several hydrophobic and hydrophilic residues. The active site cavity is sufficiently large to accommodate a ring substrate. Two conformations are observed for helix H2 located adjacent to the active site. Helix H2 is kinked at Asn81 in two subunits, whereas it is kinked at Leu77 in the other subunit, and the side chain of Tyr80 is closer to Asp136. This indicates that catalytic reaction of PaaG may proceed with large conformational changes at the active site. Asp136 is the only conserved polar residue in the active site. It is located at the same position as those of 4-chlorobenzoyl-CoA dehalogenase and peroxisomal Delta(3),Delta(2)-enoyl-CoA isomerase, indicating that PaaG may undergo isomerization or a ring-opening reaction via a Delta(3),Delta(2)-enoyl-CoA isomerase-like mechanism. PMID:19452559

  8. Can endoscopic atrophy predict histological atrophy? Historical study in United Kingdom and Japan

    PubMed Central

    Kono, Shin; Gotoda, Takuji; Yoshida, Shigeaki; Oda, Ichiro; Kondo, Hitoshi; Gatta, Luigi; Naylor, Greg; Dixon, Michael; Moriyasu, Fuminori; Axon, Anthony

    2015-01-01

    AIM: To assess the diagnostic concordance between endoscopic and histological atrophy in the United Kingdom and Japan. METHODS: Using published data, a total of 252 patients, 126 in the United Kingdom and 126 in Japan, aged 20 to 80 years, were evaluated. The extent of endoscopic atrophy was classified into five subgroups according to a modified Kimura-Takemoto classification system and was compared with histological findings of atrophy at five biopsy sites according to the updated Sydney system. RESULTS: The strength of agreement of the extent of atrophy between histology and visual endoscopic inspection showed good reproducibility, with a weighted kappa value of 0.76 (P < 0.001). Multivariate analysis showed that three factors were associated with decreased concordance: Japanese ethnicity [odds ratio (OR) 0.22, 95% confidence interval (CI) 0.11-0.43], older age (OR = 0.32, 95%CI: 0.16-0.66) and endoscopic atrophy (OR = 0.10, 95%CI: 0.03-0.36). The strength of agreement between endoscopic and histological atrophy, assessed by cancer risk-oriented grading, was reproducible, with a kappa value of 0.81 (95%CI: 0.75-0.87). Only nine patients (3.6%) were endoscopically underdiagnosed with antral predominant rather than extensive atrophy and were considered false negatives. CONCLUSION: Endoscopic grading can predict histological atrophy with few false negatives, indicating that precancerous conditions can be identified during screening endoscopy, particularly in patients in western countries. PMID:26673849

  9. Glucocorticoid-induced skeletal muscle atrophy.

    PubMed

    Schakman, O; Kalista, S; Barbé, C; Loumaye, A; Thissen, J P

    2013-10-01

    Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes ("genes involved in atrophy"), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23806868

  10. The econobiology of pancreatic acinar cells granule inventory and the stealthy nano-machine behind it.

    PubMed

    Hammel, Ilan; Meilijson, Isaac

    2016-03-01

    The pancreatic gland secretes most of the enzymes and many other macromolecules needed for food digestion in the gastrointestinal tract. These molecules play an important role in digestion, host defense and lubrication. The secretion of pancreatic proteins ensures the availability of the correct mix of proteins when needed. This review describes model systems available for the study of the econobiology of secretory granule content. The secretory pancreatic molecules are stored in large dense-core secretory granules that may undergo either constitutive or evoked secretion, and constitute the granule inventory of the cell. It is proposed that the Golgi complex functions as a distribution center for secretory proteins in pancreatic acinar cells, packing the newly formed secretory molecules into maturing secretory granules, also known functionally as condensing vacuoles. Mathematical modelling brings forward a process underlying granule inventory maintenance at various physiological states of condensation and aggregation by homotypic fusion. These models suggest unique but simple mechanisms accountable for inventory buildup and size, as well as for the distribution of secretory molecules into different secretory pathways in pancreatic acinar cells. PMID:26702787

  11. Restricted diffusion in a model acinar labyrinth by NMR: Theoretical and numerical results

    NASA Astrophysics Data System (ADS)

    Grebenkov, D. S.; Guillot, G.; Sapoval, B.

    2007-01-01

    A branched geometrical structure of the mammal lungs is known to be crucial for rapid access of oxygen to blood. But an important pulmonary disease like emphysema results in partial destruction of the alveolar tissue and enlargement of the distal airspaces, which may reduce the total oxygen transfer. This effect has been intensively studied during the last decade by MRI of hyperpolarized gases like helium-3. The relation between geometry and signal attenuation remained obscure due to a lack of realistic geometrical model of the acinar morphology. In this paper, we use Monte Carlo simulations of restricted diffusion in a realistic model acinus to compute the signal attenuation in a diffusion-weighted NMR experiment. We demonstrate that this technique should be sensitive to destruction of the branched structure: partial removal of the interalveolar tissue creates loops in the tree-like acinar architecture that enhance diffusive motion and the consequent signal attenuation. The role of the local geometry and related practical applications are discussed.

  12. Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs.

    PubMed

    Eisses, John F; Criscimanna, Angela; Dionise, Zachary R; Orabi, Abrahim I; Javed, Tanveer A; Sarwar, Sheharyar; Jin, Shunqian; Zhou, Lili; Singh, Sucha; Poddar, Minakshi; Davis, Amy W; Tosun, Akif Burak; Ozolek, John A; Lowe, Mark E; Monga, Satdarshan P; Rohde, Gustavo K; Esni, Farzad; Husain, Sohail Z

    2015-12-01

    The mechanisms by which drugs induce pancreatitis are unknown. A definite cause of pancreatitis is due to the antiepileptic drug valproic acid (VPA). On the basis of three crucial observations-that VPA inhibits histone deacetylases (HDACs), HDACs mediate pancreas development, and aspects of pancreas development are recapitulated during recovery of the pancreas after injury-we hypothesized that VPA does not cause injury on its own, but it predisposes patients to pancreatitis by inhibiting HDACs and provoking an imbalance in pancreatic recovery. In an experimental model of pancreatic injury, we found that VPA delayed recovery of the pancreas and reduced acinar cell proliferation. In addition, pancreatic expression of class I HDACs (which are the primary VPA targets) increased in the midphase of pancreatic recovery. VPA administration inhibited pancreatic HDAC activity and led to the persistence of acinar-to-ductal metaplastic complexes, with prolonged Sox9 expression and sustained β-catenin nuclear activation, findings that characterize a delay in regenerative reprogramming. These effects were not observed with valpromide, an analog of VPA that lacks HDAC inhibition. This is the first report, to our knowledge, that VPA shifts the balance toward pancreatic injury and pancreatitis through HDAC inhibition. The work also identifies a new paradigm for therapies that could exploit epigenetic reprogramming to enhance pancreatic recovery and disorders of pancreatic injury. PMID:26476347

  13. Kinetic Control of Multiple Forms of Ca2+ Spikes by Inositol Trisphosphate in Pancreatic Acinar Cells

    PubMed Central

    Ito, Koichi; Miyashita, Yasushi; Kasai, Haruo

    1999-01-01

    The mechanisms of agonist-induced Ca2+ spikes have been investigated using a caged inositol 1,4,5-trisphosphate (IP3) and a low-affinity Ca2+ indicator, BTC, in pancreatic acinar cells. Rapid photolysis of caged IP3 was able to reproduce acetylcholine (ACh)-induced three forms of Ca2+ spikes: local Ca2+ spikes and submicromolar (<1 μM) and micromolar (1–15 μM) global Ca2+ spikes (Ca2+ waves). These observations indicate that subcellular gradients of IP3 sensitivity underlie all forms of ACh-induced Ca2+ spikes, and that the amplitude and extent of Ca2+ spikes are determined by the concentration of IP3. IP3-induced local Ca2+ spikes exhibited similar time courses to those generated by ACh, supporting a role for Ca2+-induced Ca2+ release in local Ca2+ spikes. In contrast, IP3- induced global Ca2+ spikes were consistently faster than those evoked with ACh at all concentrations of IP3 and ACh, suggesting that production of IP3 via phospholipase C was slow and limited the spread of the Ca2+ spikes. Indeed, gradual photolysis of caged IP3 reproduced ACh-induced slow Ca2+ spikes. Thus, local and global Ca2+ spikes involve distinct mechanisms, and the kinetics of global Ca2+ spikes depends on that of IP3 production particularly in those cells such as acinar cells where heterogeneity in IP3 sensitivity plays critical role. PMID:10427093

  14. Acinar ventilation heterogeneity in COPD relates to diffusion capacity, resistance and reactance.

    PubMed

    Jarenbäck, Linnea; Ankerst, Jaro; Bjermer, Leif; Tufvesson, Ellen

    2016-01-01

    The aim of this study was to investigate heterogenic ventilation in the acinar (Sacin) and conductive (Scond) airways of patients with varying chronic obstructive pulmonary disease (COPD) severity and how these relates to advanced lung function parameters, primarily measured by impulse oscillometry (IOS). A secondary aim was to investigate the effects of a short acting beta2-agonist and a muscarinic antagonist on the heterogenic ventilation. Eleven never smoking controls, 12 smoking controls, and 57 COPD patients (7 GOLD 1, 25 GOLD 2, 14 GOLD 3 and 11 GOLD 4) performed flow-volume spirometry, IOS, body plethysmography, single breath carbon monoxide diffusion, and N2-multiple breath washout. Six smoking controls and 13 of the COPD patients also performed double reversibility test by using salbutamol and its combination with ipratropium. Sacin was significantly higher in GOLD 2-4 compared to never smoking controls and smoking controls, but showed similar levels in GOLD 3 and 4. A factor analysis identified 4 components consisting of; 1) IOS parameters, 2) volume parameters, 3) diffusion parameters, Sacin and some IOS parameters and 4) Scond with central obstruction/air trapping. Salbutamol and its combination with ipratropium had no effect on Sacin and Scond. Increased Sacin in COPD was strongly related to diffusion capacity and lung volumes, but also weakly to resistance and reactance, showing a link between ventilation heterogeneity in the acinar airways and parameters measured by IOS. PMID:26607879

  15. Salivary gland acinar cells regenerate functional glandular structures in modified hydrogels

    NASA Astrophysics Data System (ADS)

    Pradhan, Swati

    Xerostomia, a condition resulting from irradiation of the head and neck, affects over 40,000 cancer patients each year in the United States. Direct radiation damage of the acinar cells that secrete fluid and protein results in salivary gland hypofunction. Present medical management for xerostomia for patients treated for upper respiratory cancer is largely ineffective. Patients who have survived their terminal diagnosis are often left with a diminished quality of life and are unable to enjoy the simple pleasures of eating and drinking. This project aims to ultimately reduce human suffering by developing a functional implantable artificial salivary gland. The goal was to create an extracellular matrix (ECM) modified hyaluronic acid (HA) based hydrogel culture system that allows for the growth and differentiation of salivary acinar cells into functional acini-like structures capable of secreting large amounts of protein and fluid unidirectionally and to ultimately engineer a functional artificial salivary gland that can be implanted into an animal model. A tissue collection protocol was established and salivary gland tissue was obtained from patients undergoing head and neck surgery. The tissue specimen was assessed by histology and immunohistochemistry to establish the phenotype of normal salivary gland cells including the native basement membranes. Hematoxylin and eosin staining confirmed normal glandular tissue structures including intercalated ducts, striated ducts and acini. alpha-Amylase and periodic acid schiff stain, used for structures with a high proportion of carbohydrate macromolecules, preferentially stained acinar cells in the tissue. Intercalated and striated duct structures were identified using cytokeratins 19 and 7 staining. Myoepithelial cells positive for cytokeratin 14 were found wrapped around the serous and mucous acini. Tight junction components including ZO-1 and E-cadherin were present between both ductal and acinar cells. Ductal and acinar

  16. Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis.

    PubMed

    Sendler, Matthias; Maertin, Sandrina; John, Daniel; Persike, Maria; Weiss, F Ulrich; Krüger, Burkhard; Wartmann, Thomas; Wagh, Preshit; Halangk, Walter; Schaschke, Norbert; Mayerle, Julia; Lerch, Markus M

    2016-07-01

    Pancreatitis is associated with premature activation of digestive proteases in the pancreas. The lysosomal hydrolase cathepsin B (CTSB) is a known activator of trypsinogen, and its deletion reduces disease severity in experimental pancreatitis. Here we studied the activation mechanism and subcellular compartment in which CTSB regulates protease activation and cellular injury. Cholecystokinin (CCK) increased the activity of CTSB, cathepsin L, trypsin, chymotrypsin, and caspase 3 in vivo and in vitro and induced redistribution of CTSB to a secretory vesicle-enriched fraction. Neither CTSB protein nor activity redistributed to the cytosol, where the CTSB inhibitors cystatin-B/C were abundantly present. Deletion of CTSB reduced and deletion of cathepsin L increased intracellular trypsin activation. CTSB deletion also abolished CCK-induced caspase 3 activation, apoptosis-inducing factor, as well as X-linked inhibitor of apoptosis protein degradation, but these depended on trypsinogen activation via CTSB. Raising the vesicular pH, but not trypsin inhibition, reduced CTSB activity. Trypsin inhibition did not affect apoptosis in hepatocytes. Deletion of CTSB affected apoptotic but not necrotic acinar cell death. In summary, CTSB in pancreatitis undergoes activation in a secretory, vesicular, and acidic compartment where it activates trypsinogen. Its deletion or inhibition regulates acinar cell apoptosis but not necrosis in two models of pancreatitis. Caspase 3-mediated apoptosis depends on intravesicular trypsinogen activation induced by CTSB, not CTSB activity directly, and this mechanism is pancreas-specific. PMID:27226576

  17. Functional involvement of Noc2, a Rab27 effector, in rat parotid acinar cells.

    PubMed

    Imai, Akane; Yoshie, Sumio; Nashida, Tomoko; Shimomura, Hiromi; Fukuda, Mitsunori

    2006-11-15

    Noc2 has recently been proposed to regulate exocytosis in both endocrine and exocrine cells; however, protein expression, subcellular localization and function of Noc2 in exocrine cells have never been elucidated. In this study, we investigated whether Noc2, a Rab27 effector, is involved in isoproterenol (IPR)-stimulated amylase release from acinar cells. Rab27 was detected in the apical plasma membrane (APM) and secretory granule membrane (SGM) fractions, and was translocated to the APM after IPR stimulation for 5 min, but was detected at lower levels in the APM after 30 min. In contrast, although Noc2 was expressed in SGM bound to Rab27, Noc2 was not translocated to APM and the Noc2/Rab27 complex was disrupted after stimulation with IPR for short time. In addition, the anti-Noc2-Rab-binding-domain antibody inhibited IPR-stimulated amylase release from streptolysin O-permeabilized parotid acinar cells. Our results suggest that the Noc2/Rab27 complex is an important constituent of the early stages of IPR-stimulated amylase release. PMID:17067543

  18. Transdifferentiation of human amniotic epithelial cells into acinar cells using a double-chamber system.

    PubMed

    Huang, Gui-Lin; Zhang, Ni-Ni; Wang, Jun-Sheng; Yao, Li; Zhao, Yu-Jie; Wang, Yu-Ying

    2012-08-01

    This study investigated the transdifferentiation of stem cells from human amnion tissue into functional acinar cells (ACs) using a co-culture system. Human amniotic epithelial cells (hAECs) were isolated from amnion tissue by mechanical mincing and enzymatic digestion. After primary culture, the phenotype of the cells was identified by flow cytometry (FCM) and immunocytochemical staining. hAECs were co-cultured with submandibular gland acinar cells of SD rats using a double-chamber system. The expression of α-amylase was determined by immunocytochemical method and fluorescent real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) after induction for 1 and 2 weeks, respectively. Digestion with trypsin is an effective method for isolating hAECs from amnion tissue. These cells were positive for CD29 and CK19 and weakly positive for CD44 and α-amylase. Within 2 weeks, α-amylase in hAECs increased with induction time. The expression of α-amylase in hAECs was increased 3.38-fold after co-culturing for 1 week. This ratio increased to 6.6-fold, and these cells were positive for mucins, after co-culturing for 2 weeks. hAECs possess the potential to differentiate into ACs in vitro. They might be a stem cell resource for clinical applications of cell replacement therapy in salivary gland dysfunction diseases. PMID:22800093

  19. Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy

    PubMed Central

    Deguise, Marc-Olivier; Boyer, Justin G.; McFall, Emily R.; Yazdani, Armin; De Repentigny, Yves; Kothary, Rashmi

    2016-01-01

    Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths. Previous studies have focused on deciphering disease pathogenesis in motor neurons. However, a systematic evaluation of atrophy pathways in muscles is lacking. Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice. Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn2B/− mice but not in the more severe Smn−/−; SMN2 mice. Expression of FoxO transcription factors, which regulate both proteasomal and autophagosomal degradation, is elevated in Smn2B/− muscle. Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy. Cardiac muscle also exhibits differential induction of atrophy between Smn2B/− and Smn−/−; SMN2 mice, albeit in the opposite direction to that of skeletal muscle. Altogether, our work highlights the importance of cautious analysis of different mouse models of SMA as distinct patterns of atrophy induction are at play depending on disease severity. We also revealed that one of the beneficial impacts of trichostatin A on SMA model mice is via attenuation of muscle atrophy through reduction of FoxO expression to normal levels. PMID:27349908

  20. Glucagon-like peptide-1 receptor is present in pancreatic acinar cells and regulates amylase secretion through cAMP.

    PubMed

    Hou, Yanan; Ernst, Stephen A; Heidenreich, Kaeli; Williams, John A

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is a glucoincretin hormone that can act through its receptor (GLP-1R) on pancreatic β-cells and increase insulin secretion and production. GLP-1R agonists are used clinically to treat type 2 diabetes. GLP-1 may also regulate the exocrine pancreas at multiple levels, including inhibition through the central nervous system, stimulation indirectly through insulin, and stimulation directly on acinar cells. However, it has been unclear whether GLP-1R is present in pancreatic acini and what physiological functions these receptors regulate. In the current study we utilized GLP-1R knockout (KO) mice to study the role of GLP-1R in acinar cells. RNA expression of GLP-1R was detected in acutely isolated pancreatic acini. Acinar cell morphology and expression of digestive enzymes were not affected by loss of GLP-1R. GLP-1 induced amylase secretion in wild-type (WT) acini. In GLP-1R KO mice, this effect was abolished, whereas vasoactive intestinal peptide-induced amylase release in KO acini showed a pattern similar to that in WT acini. GLP-1 stimulated cAMP production and increased protein kinase A-mediated protein phosphorylation in WT acini, and these effects were absent in KO acini. These data show that GLP-1R is present in pancreatic acinar cells and that GLP-1 can regulate secretion through its receptor and cAMP signaling pathway. PMID:26542397

  1. Epiplakin Deficiency Aggravates Murine Caerulein-Induced Acute Pancreatitis and Favors the Formation of Acinar Keratin Granules

    PubMed Central

    Wögenstein, Karl L.; Szabo, Sandra; Lunova, Mariia; Wiche, Gerhard; Haybaeck, Johannes; Strnad, Pavel; Boor, Peter; Wagner, Martin; Fuchs, Peter

    2014-01-01

    Epiplakin, a member of the plakin protein family, is exclusively expressed in epithelial tissues and was shown to bind to keratins. Epiplakin-deficient (EPPK−/−) mice showed no obvious spontaneous phenotype, however, EPPK−/− keratinocytes displayed faster keratin network breakdown in response to stress. The role of epiplakin in pancreas, a tissue with abundant keratin expression, was not yet known. We analyzed epiplakin’s expression in healthy and inflamed pancreatic tissue and compared wild-type and EPPK−/− mice during caerulein-induced acute pancreatitis. We found that epiplakin was expressed primarily in ductal cells of the pancreas and colocalized with apicolateral keratin bundles in murine pancreatic acinar cells. Epiplakin’s diffuse subcellular localization in keratin filament-free acini of K8-deficient mice indicated that its filament-associated localization in acinar cells completely depends on its binding partner keratin. During acute pancreatitis, epiplakin was upregulated in acinar cells and its redistribution closely paralleled keratin reorganization. EPPK−/− mice suffered from aggravated pancreatitis but showed no obvious regeneration phenotype. At the most severe stage of the disease, EPPK−/− acinar cells displayed more keratin aggregates than those of wild-type mice. Our data propose epiplakin to be a protective protein during acute pancreatitis, and that its loss causes impaired disease-associated keratin reorganization. PMID:25232867

  2. Cannabinoid receptor subtype 2 (CB2R) agonist, GW405833 reduces agonist-induced Ca2+ oscillations in mouse pancreatic acinar cells

    PubMed Central

    Huang, Zebing; Wang, Haiyan; Wang, Jingke; Zhao, Mengqin; Sun, Nana; Sun, Fangfang; Shen, Jianxin; Zhang, Haiying; Xia, Kunkun; Chen, Dejie; Gao, Ming; Hammer, Ronald P.; Liu, Qingrong; Xi, Zhengxiong; Fan, Xuegong; Wu, Jie

    2016-01-01

    Emerging evidence demonstrates that the blockade of intracellular Ca2+ signals may protect pancreatic acinar cells against Ca2+ overload, intracellular protease activation, and necrosis. The activation of cannabinoid receptor subtype 2 (CB2R) prevents acinar cell pathogenesis in animal models of acute pancreatitis. However, whether CB2Rs modulate intracellular Ca2+ signals in pancreatic acinar cells is largely unknown. We evaluated the roles of CB2R agonist, GW405833 (GW) in agonist-induced Ca2+ oscillations in pancreatic acinar cells using multiple experimental approaches with acute dissociated pancreatic acinar cells prepared from wild type, CB1R-knockout (KO), and CB2R-KO mice. Immunohistochemical labeling revealed that CB2R protein was expressed in mouse pancreatic acinar cells. Electrophysiological experiments showed that activation of CB2Rs by GW reduced acetylcholine (ACh)-, but not cholecystokinin (CCK)-induced Ca2+ oscillations in a concentration-dependent manner; this inhibition was prevented by a selective CB2R antagonist, AM630, or was absent in CB2R-KO but not CB1R-KO mice. In addition, GW eliminated L-arginine-induced enhancement of Ca2+ oscillations, pancreatic amylase, and pulmonary myeloperoxidase. Collectively, we provide novel evidence that activation of CB2Rs eliminates ACh-induced Ca2+ oscillations and L-arginine-induced enhancement of Ca2+ signaling in mouse pancreatic acinar cells, which suggests a potential cellular mechanism of CB2R-mediated protection in acute pancreatitis. PMID:27432473

  3. Cannabinoid receptor subtype 2 (CB2R) agonist, GW405833 reduces agonist-induced Ca(2+) oscillations in mouse pancreatic acinar cells.

    PubMed

    Huang, Zebing; Wang, Haiyan; Wang, Jingke; Zhao, Mengqin; Sun, Nana; Sun, Fangfang; Shen, Jianxin; Zhang, Haiying; Xia, Kunkun; Chen, Dejie; Gao, Ming; Hammer, Ronald P; Liu, Qingrong; Xi, Zhengxiong; Fan, Xuegong; Wu, Jie

    2016-01-01

    Emerging evidence demonstrates that the blockade of intracellular Ca(2+) signals may protect pancreatic acinar cells against Ca(2+) overload, intracellular protease activation, and necrosis. The activation of cannabinoid receptor subtype 2 (CB2R) prevents acinar cell pathogenesis in animal models of acute pancreatitis. However, whether CB2Rs modulate intracellular Ca(2+) signals in pancreatic acinar cells is largely unknown. We evaluated the roles of CB2R agonist, GW405833 (GW) in agonist-induced Ca(2+) oscillations in pancreatic acinar cells using multiple experimental approaches with acute dissociated pancreatic acinar cells prepared from wild type, CB1R-knockout (KO), and CB2R-KO mice. Immunohistochemical labeling revealed that CB2R protein was expressed in mouse pancreatic acinar cells. Electrophysiological experiments showed that activation of CB2Rs by GW reduced acetylcholine (ACh)-, but not cholecystokinin (CCK)-induced Ca(2+) oscillations in a concentration-dependent manner; this inhibition was prevented by a selective CB2R antagonist, AM630, or was absent in CB2R-KO but not CB1R-KO mice. In addition, GW eliminated L-arginine-induced enhancement of Ca(2+) oscillations, pancreatic amylase, and pulmonary myeloperoxidase. Collectively, we provide novel evidence that activation of CB2Rs eliminates ACh-induced Ca(2+) oscillations and L-arginine-induced enhancement of Ca(2+) signaling in mouse pancreatic acinar cells, which suggests a potential cellular mechanism of CB2R-mediated protection in acute pancreatitis. PMID:27432473

  4. The monoclonal anti-BCL10 antibody (clone 331.1) is a sensitive and specific marker of pancreatic acinar cell carcinoma and pancreatic metaplasia.

    PubMed

    La Rosa, Stefano; Franzi, Francesca; Marchet, Silvia; Finzi, Giovanna; Clerici, Moira; Vigetti, Davide; Chiaravalli, Anna Maria; Sessa, Fausto; Capella, Carlo

    2009-02-01

    Acinar cell carcinoma (ACC) is a rare pancreatic cancer which may be difficult to distinguish from other solid nonadenocarcinoma tumors. The diagnosis depends on the demonstration of acinar differentiation, obtained with antibodies recognizing various pancreatic enzymes that, although specific, show different sensitivity. The C-terminal portion of the BCL10 protein shows homology with carboxyl ester hydrolase (CEH), an enzyme produced by pancreatic acinar cells. We investigated the usefulness of a C-terminal BCL10 monoclonal antibody in the diagnosis of ACCs. We examined normal pancreases and different pancreatic tumors including ACCs, mixed acinar-endocrine carcinomas, ductal adenocarcinomas, mucinous, serous, solid pseudopapillary, and endocrine neoplasms. In addition, various normal tissues and cases of pancreatic metaplasia of the gastroesophageal mucosa, cases of ectopic pancreas, gastrointestinal endocrine tumors, salivary and breast acinic cell carcinomas, gastric adenocarcinomas with and without acinar differentiation, and hepatocellular carcinomas were studied. BCL10 immunoreactivity paralleled that of CEH and was restricted to acinar cells of normal and ectopic pancreas, of pancreatic metaplasia, and of ACCs. The anti-BCL10 antibody was more sensitive in detecting ACCs and pancreatic metaplasia than antibodies directed against other pancreatic enzymes. We suggest using BCL10 antibody for diagnosing pancreatic tumors and whenever an acinar differentiation is suspected in gastrointestinal neoplastic and metaplastic lesions. PMID:19066953

  5. Effect of glucagon on digestive enzyme synthesis, transport and secretion in mouse pancreatic acinar cells.

    PubMed Central

    Singh, M

    1980-01-01

    1. Effect of glucagon on amylase secretion and lactic dehydrogenase (LDH) release from functionally intact dissociated pancreatic acinar cells and acini was studied. 2. In dissociated rat pancreatic acinar cells, the rate of amylase secretion was increased by 70% with bethanechol (maximally effective concentration, 10(-4) M) and 125% with A23187 (10(-5) M), but the response to cholecystokinin-pancreozymin (CCK-PZ) was inconsistent. In dissociated cells from mouse pancreas, the increases amounted to 78% with bethanechol (10(-4) M), 134% with A23187 (10(-5) M) and 82% with CCK-PZ (maximally effective concentration, 0 . 01 u. ml.-1). Glucagon in concentrations ranging from 10(-7) to 10(-4) M increased amylase secretion by 3, 26, 67 and 80%, whereas secretin (10(-8)--10(-5) M) increased amylase secretion by 8, 39, 88 and 138%. LDH release was increased with A23187 in concentrations greater than 10(-6) M. 3. CCK-PZ, bethanechol and A23187 used in maximal concentrations potentiated the effect of a submaximal dose of glucagon whereas secretin did not have an additive or a potentiating effect. 4. Pancreatic acini were approximately 3 times more responsive to secretagogues than cells. The dose--response curves to bethanechol, glucagon and CCK-PZ for increase in amylase secretion were similar. LDH release was not increased by these agents. Cytochalasin B (5 microgram ml.-1) which is known to disrupt the integrity of luminal membrane inhibited the amylase secretion stimulated by glucagon, bethanechol and CCK-PZ. 5. Glucagon inhibited incorporation of a mixture of fifteen 14C-labelled amino acids (algal profile, Schwarz Mann) into perchloric acid precipitable proteins in dissociated mouse pancreatic acini within 30 min. 6. In 'pulse-chase' experiments, glucagon decreased the specific activity of zymogen granules isolated by differential centrifugation, from pancreatic lobules (120 min) and increased the specific activity of radiolabelled proteins in the medium (60 and 120 min

  6. A Systems Biology Approach Identifies a Regulatory Network in Parotid Acinar Cell Terminal Differentiation

    PubMed Central

    Metzler, Melissa A.; Venkatesh, Srirangapatnam G.; Lakshmanan, Jaganathan; Carenbauer, Anne L.; Perez, Sara M.; Andres, Sarah A.; Appana, Savitri; Brock, Guy N.; Wittliff, James L.; Darling, Douglas S.

    2015-01-01

    Objective The transcription factor networks that drive parotid salivary gland progenitor cells to terminally differentiate, remain largely unknown and are vital to understanding the regeneration process. Methodology A systems biology approach was taken to measure mRNA and microRNA expression in vivo across acinar cell terminal differentiation in the rat parotid salivary gland. Laser capture microdissection (LCM) was used to specifically isolate acinar cell RNA at times spanning the month-long period of parotid differentiation. Results Clustering of microarray measurements suggests that expression occurs in four stages. mRNA expression patterns suggest a novel role for Pparg which is transiently increased during mid postnatal differentiation in concert with several target gene mRNAs. 79 microRNAs are significantly differentially expressed across time. Profiles of statistically significant changes of mRNA expression, combined with reciprocal correlations of microRNAs and their target mRNAs, suggest a putative network involving Klf4, a differentiation inhibiting transcription factor, which decreases as several targeting microRNAs increase late in differentiation. The network suggests a molecular switch (involving Prdm1, Sox11, Pax5, miR-200a, and miR-30a) progressively decreases repression of Xbp1 gene transcription, in concert with decreased translational repression by miR-214. The transcription factor Xbp1 mRNA is initially low, increases progressively, and may be maintained by a positive feedback loop with Atf6. Transfection studies show that Xbp1Mist1 promoter. In addition, Xbp1 and Mist1 each activate the parotid secretory protein (Psp) gene, which encodes an abundant salivary protein, and is a marker of terminal differentiation. Conclusion This study identifies novel expression patterns of Pparg, Klf4, and Sox11 during parotid acinar cell differentiation, as well as numerous differentially expressed microRNAs. Network analysis identifies a novel stemness arm, a

  7. Genetics Home Reference: spinal muscular atrophy with progressive myoclonic epilepsy

    MedlinePlus

    ... myoclonic epilepsy spinal muscular atrophy with progressive myoclonic epilepsy Enable Javascript to view the expand/collapse boxes. ... All Description Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes ...

  8. Activation of neurokinin-1 receptors up-regulates substance P and neurokinin-1 receptor expression in murine pancreatic acinar cells

    PubMed Central

    Koh, Yung-Hua; Moochhala, Shabbir; Bhatia, Madhav

    2012-01-01

    Abstract Acute pancreatitis (AP) has been associated with an up-regulation of substance P (SP) and neurokinin-1 receptor (NK1R) in the pancreas. Increased SP-NK1R interaction was suggested to be pro-inflammatory during AP. Previously, we showed that caerulein treatment increased SP/NK1R expression in mouse pancreatic acinar cells, but the effect of SP treatment was not evaluated. Pancreatic acinar cells were obtained from pancreas of male swiss mice (25–30 g). We measured mRNA expression of preprotachykinin-A (PPTA) and NK1R following treatment of SP (10−6M). SP treatment increased PPTA and NK1R expression in isolated pancreatic acinar cells, which was abolished by pretreatment of a selective NK1R antagonist, CP96,345. SP also time dependently increased protein expression of NK1R. Treatment of cells with a specific NK1R agonist, GR73,632, up-regulated SP protein levels in the cells. Using previously established concentrations, pre-treatment of pancreatic acinar cells with Gö6976 (10 nM), rottlerin (5 μM), PD98059 (30 μM), SP600125 (30 μM) or Bay11-7082 (30 μM) significantly inhibited up-regulation of SP and NK1R. These observations suggested that the PKC-ERK/JNK-NF-κB pathway is necessary for the modulation of expression levels. In comparison, pre-treatment of CP96,345 reversed gene expression in SP-induced cells, but not in caerulein-treated cells. Overall, the findings in this study suggested a possible auto-regulatory mechanism of SP/NK1R expression in mouse pancreatic acinar cells, via activation of NK1R. Elevated SP levels during AP might increase the occurrence of a positive feedback loop that contributes to abnormally high expression of SP and NK1R. PMID:22040127

  9. Tmem16A Encodes the Ca2+-activated Cl− Channel in Mouse Submandibular Salivary Gland Acinar Cells*

    PubMed Central

    Romanenko, Victor G.; Catalán, Marcelo A.; Brown, David A.; Putzier, Ilva; Hartzell, H. Criss; Marmorstein, Alan D.; Gonzalez-Begne, Mireya; Rock, Jason R.; Harfe, Brian D.; Melvin, James E.

    2010-01-01

    Activation of an apical Ca2+-dependent Cl− channel (CaCC) is the rate-limiting step for fluid secretion in many exocrine tissues. Here, we compared the properties of native CaCC in mouse submandibular salivary gland acinar cells to the Ca2+-gated Cl− currents generated by Tmem16A and Best2, members from two distinct families of Ca2+-activated Cl− channels found in salivary glands. Heterologous expression of Tmem16A and Best2 transcripts in HEK293 cells produced Ca2+-activated Cl− currents with time and voltage dependence and inhibitor sensitivity that resembled the Ca2+-activated Cl− current found in native salivary acinar cells. Best2−/− and Tmem16A−/− mice were used to further characterize the role of these channels in the exocrine salivary gland. The amplitude and the biophysical footprint of the Ca2+-activated Cl− current in submandibular gland acinar cells from Best2-deficient mice were the same as in wild type cells. Consistent with this observation, the fluid secretion rate in Best2 null mice was comparable with that in wild type mice. In contrast, submandibular gland acinar cells from Tmem16A−/− mice lacked a Ca2+-activated Cl− current and a Ca2+-mobilizing agonist failed to stimulate Cl− efflux, requirements for fluid secretion. Furthermore, saliva secretion was abolished by the CaCC inhibitor niflumic acid in wild type and Best2−/− mice. Our results demonstrate that both Tmem16A and Best2 generate Ca2+-activated Cl− current in vitro with similar properties to those expressed in native cells, yet only Tmem16A appears to be a critical component of the acinar Ca2+-activated Cl− channel complex that is essential for saliva production by the submandibular gland. PMID:20177062

  10. Bio-inspired self-cleaning PAAS hydrogel released coating for marine antifouling.

    PubMed

    Xue, Lili; Lu, Xili; Wei, Huan; Long, Ping; Xu, Jina; Zheng, Yufeng

    2014-05-01

    In this paper, an antifouling hydrogel coating of slippery hydrogel-released hydrous surface (SHRHS) with the self-cleaning ability of oil-resistance and self-regeneration characters was designed. A physical blending method of loading Sodium polyacrylate (PAAS) powder into the organic silicon resin was employed to prepare the SHRHS coating. The oil-resistance of the intact and scratch SHRHS coatings was performed by time-sequence images of washing dyed beef tallow stain away. The results showed that the SHRHS coating has the greater ability of stain removal. The concentration of Na+ ions released from PAAS hydrogel on the surface of the SHRHS coating was investigated by ion chromatograph (IC). The results revealed that the coating had the ability of self-regeneration by PAAS hydrogel continuously peeling. The biomass of two marine microalgae species, Nitzschia closterium f. minutissima and Navicula climacospheniae Booth attached on the SHRHS was investigated using UV-Visible Spectrophotometer (UV) and Scanning electron microscopy (SEM). The results showed that the microalgaes attached a significantly lower numbers on the SHRHS in comparison with the organic silicon coating. In order to confirm the antifouling ability of the SHRHS coating, the field trials were carried out for 12weeks. It showed that the SHRHS may provide an effective attachment resistance to reduce biofouling. PMID:24594048

  11. Redox control of skeletal muscle atrophy.

    PubMed

    Powers, Scott K; Morton, Aaron B; Ahn, Bumsoo; Smuder, Ashley J

    2016-09-01

    Skeletal muscles comprise the largest organ system in the body and play an essential role in body movement, breathing, and glucose homeostasis. Skeletal muscle is also an important endocrine organ that contributes to the health of numerous body organs. Therefore, maintaining healthy skeletal muscles is important to support overall health of the body. Prolonged periods of muscle inactivity (e.g., bed rest or limb immobilization) or chronic inflammatory diseases (i.e., cancer, kidney failure, etc.) result in skeletal muscle atrophy. An excessive loss of muscle mass is associated with a poor prognosis in several diseases and significant muscle weakness impairs the quality of life. The skeletal muscle atrophy that occurs in response to inflammatory diseases or prolonged inactivity is often associated with both oxidative and nitrosative stress. In this report, we critically review the experimental evidence that provides support for a causative link between oxidants and muscle atrophy. More specifically, this review will debate the sources of oxidant production in skeletal muscle undergoing atrophy as well as provide a detailed discussion on how reactive oxygen species and reactive nitrogen species modulate the signaling pathways that regulate both protein synthesis and protein breakdown. PMID:26912035

  12. Developing therapies for spinal muscular atrophy.

    PubMed

    Wertz, Mary H; Sahin, Mustafa

    2016-02-01

    Spinal muscular atrophy is an autosomal-recessive pediatric neurodegenerative disease characterized by loss of spinal motor neurons. It is caused by mutation in the gene survival of motor neuron 1 (SMN1), leading to loss of function of the full-length SMN protein. SMN has a number of functions in neurons, including RNA splicing and snRNP biogenesis in the nucleus, and RNA trafficking in neurites. The expression level of full-length SMN protein from the SMN2 locus modifies disease severity. Increasing full-length SMN protein by a small amount can lead to significant improvements in the neurological phenotype. Currently available interventions for spinal muscular atrophy patients are physical therapy and orthopedic, nutritional, and pulmonary interventions; these are palliative or supportive measures and do not address the etiology of the disease. In the past decade, there has been a push for developing therapeutics to improve motor phenotypes and increase life span of spinal muscular atrophy patients. These therapies are aimed primarily at restoration of full-length SMN protein levels, but other neuroprotective treatments have been investigated as well. Here, we discuss recent advances in basic and clinical studies toward finding safe and effective treatments of spinal muscular atrophy using gene therapy, antisense oligonucleotides, and other small molecule modulators of SMN expression. PMID:26173388

  13. Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology

    PubMed Central

    La Rosa, Stefano; Sessa, Fausto; Capella, Carlo

    2015-01-01

    Acinar cell carcinomas (ACCs) of the pancreas are rare pancreatic neoplasms accounting for about 1–2% of pancreatic tumors in adults and about 15% in pediatric subjects. They show different clinical symptoms at presentation, different morphological features, different outcomes, and different molecular alterations. This heterogeneous clinicopathological spectrum may give rise to difficulties in the clinical and pathological diagnosis with consequential therapeutic and prognostic implications. The molecular mechanisms involved in the onset and progression of ACCs are still not completely understood, although in recent years, several attempts have been made to clarify the molecular mechanisms involved in ACC biology. In this paper, we will review the main clinicopathological and molecular features of pancreatic ACCs of both adult and pediatric subjects to give the reader a comprehensive overview of this rare tumor type. PMID:26137463

  14. Prolonged Survival in a Patient with a Pancreatic Acinar Cell Carcinoma

    PubMed Central

    Ploquin, Anne; Baldini, Capucine; Vuagnat, Perrine; Makhloufi, Samira; Desauw, Christophe; Hebbar, Mohamed

    2015-01-01

    Pancreatic acinar cell carcinoma (ACC) is a rare entity. Herein we present the case of a 50-year-old male patient with an unlimited mass on the pancreatic corpus and tail with peripancreatic effusion and multiple metastases in the liver and spleen. A liver biopsy showed a pancreatic ACC. The patient received 9 cycles of gemcitabine plus oxaliplatin (GEMOX regimen), which had to be stopped because of a persistent grade 2 neuropathy. A CT scan showed complete response after 14 years. At the age of 61 years, a localized prostatic cancer was diagnosed, treated by prostatectomy. The patient carried a BRCA2 mutation. None of the precedent case reports describe a chemosensibility to the GEMOX regimen. In spite of the lack of study in these patients, chemotherapy with oxaliplatin seems to be the most effective. Long survival can be expected. PMID:26600777

  15. Polyethylenimine-mediated expression of transgenes in the acinar cells of rats salivary glands in vivo

    PubMed Central

    Sramkova, Monika; Parente, Laura; Wigand, Timothy; Aye, Myo-Pale'; Shitara, Akiko; Weigert, Roberto

    2015-01-01

    Non viral-mediated transfection of plasmid DNA provides a fast and reliable way to express various transgenes in selected cell populations in live animals. Here, we show an improvement of a previously published method that is based on injecting plasmid DNA into the ductal system of the salivary glands in live rats. Specifically, using complexes between plasmid DNA and polyethyleneimine (PEI) we show that the expression of the transgenes is directed selectively to the salivary acinar cells. PEI does not affect the ability of cells to undergo regulated exocytosis, which was one of the main drawbacks of the previous methods. Moreover PEI does not affect the proper localization and targeting of transfected proteins, as shown for the apical plasma membrane water channel aquaporin 5 (AQP5). Overall, this approach, coupled with the use of intravital microscopy, permits to conduct localization and functional studies under physiological conditions, in a rapid, reliable, and affordable fashion. PMID:25621283

  16. Prolonged Survival in a Patient with a Pancreatic Acinar Cell Carcinoma.

    PubMed

    Ploquin, Anne; Baldini, Capucine; Vuagnat, Perrine; Makhloufi, Samira; Desauw, Christophe; Hebbar, Mohamed

    2015-01-01

    Pancreatic acinar cell carcinoma (ACC) is a rare entity. Herein we present the case of a 50-year-old male patient with an unlimited mass on the pancreatic corpus and tail with peripancreatic effusion and multiple metastases in the liver and spleen. A liver biopsy showed a pancreatic ACC. The patient received 9 cycles of gemcitabine plus oxaliplatin (GEMOX regimen), which had to be stopped because of a persistent grade 2 neuropathy. A CT scan showed complete response after 14 years. At the age of 61 years, a localized prostatic cancer was diagnosed, treated by prostatectomy. The patient carried a BRCA2 mutation. None of the precedent case reports describe a chemosensibility to the GEMOX regimen. In spite of the lack of study in these patients, chemotherapy with oxaliplatin seems to be the most effective. Long survival can be expected. PMID:26600777

  17. The Acinar Cage: Basement Membranes Determine Molecule Exchange and Mechanical Stability of Human Breast Cell Acini

    PubMed Central

    Gaiko-Shcherbak, Aljona; Fabris, Gloria; Dreissen, Georg; Merkel, Rudolf; Hoffmann, Bernd; Noetzel, Erik

    2015-01-01

    The biophysical properties of the basement membrane that surrounds human breast glands are poorly understood, but are thought to be decisive for normal organ function and malignancy. Here, we characterize the breast gland basement membrane with a focus on molecule permeation and mechanical stability, both crucial for organ function. We used well-established and nature-mimicking MCF10A acini as 3D cell model for human breast glands, with ether low- or highly-developed basement membrane scaffolds. Semi-quantitative dextran tracer (3 to 40 kDa) experiments allowed us to investigate the basement membrane scaffold as a molecule diffusion barrier in human breast acini in vitro. We demonstrated that molecule permeation correlated positively with macromolecule size and intriguingly also with basement membrane development state, revealing a pore size of at least 9 nm. Notably, an intact collagen IV mesh proved to be essential for this permeation function. Furthermore, we performed ultra-sensitive atomic force microscopy to quantify the response of native breast acini and of decellularized basement membrane shells against mechanical indentation. We found a clear correlation between increasing acinar force resistance and basement membrane formation stage. Most important native acini with highly-developed basement membranes as well as cell-free basement membrane shells could both withstand physiologically relevant loads (≤ 20 nN) without loss of structural integrity. In contrast, low-developed basement membranes were significantly softer and more fragile. In conclusion, our study emphasizes the key role of the basement membrane as conductor of acinar molecule influx and mechanical stability of human breast glands, which are fundamental for normal organ function. PMID:26674091

  18. A resected case of symptomatic acinar cell cystadenoma of the pancreas displacing the main pancreatic duct.

    PubMed

    Tanaka, Haruyoshi; Hatsuno, Tsuyoshi; Kinoshita, Mitsuru; Hasegawa, Kazuya; Ishihara, Hiromasa; Takano, Nao; Shimoyama, Satofumi; Nakayama, Hiroshi; Kataoka, Masato; Ichihara, Shu; Kanda, Mitsuro; Kodera, Yasuhiro; Kondo, Ken

    2016-12-01

    Acinar cell cystadenoma (ACA) of the pancreas has been newly recognized as an entity by the World Health Organization (WHO) definition (2010), and its pathogenesis has not been known adequately because of the rarity. Here, we report a case of a 22-year-old female who had been followed up for a cystic lesion at the tail of the pancreas pointed out by a screening computed tomography (CT) scan 7 years ago. The tumor grew in size from 3.3 to 5.1 cm in diameter for 6 years (0.3 cm per year). Particularly, it rapidly grew up to 6.3 cm in the latest 3 months in concurrence with the emergence of epigastralgia. A contrasted CT scan revealed the irregularly formed, multilocular cystic tumor having thin septum and calcification. The intratumoral magnetic resonance imaging intensity in the T1 and T2 weighted images were low and high, respectively. No communications between the tumor and the main pancreatic duct (MPD) were found, but the tumor displaced the MPD. She underwent surgical resection because the tumor was growing, turned symptomatic, and it seemed difficult to be diagnosed correctly until totally biopsied. Spleen-preserved distal pancreatectomy was performed. It was pathologically diagnosed as ACA; the cyst was lined by cells with normal acinar differentiation; cuboidal cells with round, basally oriented nuclei and eosinophilic granules in its apical cytoplasm. The abdominal pain has disappeared, and no recurrences have been found during a 5-year follow-up. Clinicians are recommended to consider an ACA as one of differential diagnoses of cystic tumors of the pancreas to provide appropriate diagnostics and therapeutics. PMID:27108123

  19. Progressive hemifacial atrophy. A natural history study.

    PubMed Central

    Miller, M T; Spencer, M A

    1995-01-01

    PURPOSE: To describe two very different natural history courses in 2 patients with hemifacial atrophy. Progressive hemifacial atrophy (Parry-Romberg syndrome, Romberg syndrome, PHA) is characterized by slowly progressive atrophy, frequently involving only one side of the face, primarily affecting the subcutaneous tissue and fat. The onset usually occurs during the first 2 decades of life. The cause and pathophysiology are unknown. Ophthalmic involvement is common, with progressive enophthalmos a frequent finding. Pupillary disturbances, heterochromia, uveitis, pigmentary disturbances of the ocular fundus, and restrictive strabismus have also been reported. Neurologic findings may be present, but the natural history and progression of ocular findings are often not described in the literature. METHODS: We studied the records and present findings of 2 patients with progressive hemifacial atrophy who were observed in our institution over a 10-year period. RESULTS: Both patients showed progression of ophthalmic findings, primarily on the affected side. One patient has had chronic uveitis with secondary cataract and glaucoma, in addition to retinal pigmentary changes. She also had a third-nerve paresis of the contralateral eye and mild seizure activity. The other patient had mild uveitis, some progression of unilateral retinal pigmentary changes, and a significant increase in hyperopia in the affected eye, in addition to hypotony at age 19 without a clear cause, but with secondary retinal and refractive changes. CONCLUSION: Ocular manifestations of progressive hemifacial atrophy are varied, but can progress from mild visual impairment to blindness. Images FIGURE 1 FIGURE 2 FIGURE 3A FIGURE 3B FIGURE 4 FIGURE 5 FIGURE 6 PMID:8719679

  20. A Novel Function of Noc2 in Agonist-Induced Intracellular Ca2+ Increase during Zymogen-Granule Exocytosis in Pancreatic Acinar Cells

    PubMed Central

    Ogata, Sho; Miki, Takashi; Seino, Susumu; Tamai, Seiichi; Kasai, Haruo; Nemoto, Tomomi

    2012-01-01

    Noc2, a putative Rab effector, contributes to secretory-granule exocytosis in neuroendocrine and exocrine cells. Here, using two-photon excitation live-cell imaging, we investigated its role in Ca2+-dependent zymogen granule (ZG) exocytosis in pancreatic acinar cells from wild-type (WT) and Noc2-knockout (KO) mice. Imaging of a KO acinar cell revealed an expanded granular area, indicating ZG accumulation. In our spatiotemporal analysis of the ZG exocytosis induced by agonist (cholecystokinin or acetylcholine) stimulation, the location and rate of progress of ZG exocytosis did not differ significantly between the two strains. ZG exocytosis from KO acinar cells was seldom observed at physiological concentrations of agonists, but was normal (vs. WT) at high concentrations. Flash photolysis of a caged calcium compound confirmed the integrity of the fusion step of ZG exocytosis in KO acinar cells. The decreased ZG exocytosis present at physiological concentrations of agonists raised the possibility of impaired elicitation of calcium spikes. When calcium spikes were evoked in KO acinar cells by a high agonist concentration: (a) they always started at the apical portion and traveled to the basal portion, and (b) calcium oscillations over the 10 µM level were observed, as in WT acinar cells. At physiological concentrations of agonists, however, sufficient calcium spikes were not observed, suggesting an impaired [Ca2+]i-increase mechanism in KO acinar cells. We propose that in pancreatic acinar cells, Noc2 is not indispensable for the membrane fusion of ZG per se, but instead performs a novel function favoring agonist-induced physiological [Ca2+]i increases. PMID:22615885

  1. A novel function of Noc2 in agonist-induced intracellular Ca2+ increase during zymogen-granule exocytosis in pancreatic acinar cells.

    PubMed

    Ogata, Sho; Miki, Takashi; Seino, Susumu; Tamai, Seiichi; Kasai, Haruo; Nemoto, Tomomi

    2012-01-01

    Noc2, a putative Rab effector, contributes to secretory-granule exocytosis in neuroendocrine and exocrine cells. Here, using two-photon excitation live-cell imaging, we investigated its role in Ca(2+)-dependent zymogen granule (ZG) exocytosis in pancreatic acinar cells from wild-type (WT) and Noc2-knockout (KO) mice. Imaging of a KO acinar cell revealed an expanded granular area, indicating ZG accumulation. In our spatiotemporal analysis of the ZG exocytosis induced by agonist (cholecystokinin or acetylcholine) stimulation, the location and rate of progress of ZG exocytosis did not differ significantly between the two strains. ZG exocytosis from KO acinar cells was seldom observed at physiological concentrations of agonists, but was normal (vs. WT) at high concentrations. Flash photolysis of a caged calcium compound confirmed the integrity of the fusion step of ZG exocytosis in KO acinar cells. The decreased ZG exocytosis present at physiological concentrations of agonists raised the possibility of impaired elicitation of calcium spikes. When calcium spikes were evoked in KO acinar cells by a high agonist concentration: (a) they always started at the apical portion and traveled to the basal portion, and (b) calcium oscillations over the 10 µM level were observed, as in WT acinar cells. At physiological concentrations of agonists, however, sufficient calcium spikes were not observed, suggesting an impaired [Ca(2+)](i)-increase mechanism in KO acinar cells. We propose that in pancreatic acinar cells, Noc2 is not indispensable for the membrane fusion of ZG per se, but instead performs a novel function favoring agonist-induced physiological [Ca(2+)](i) increases. PMID:22615885

  2. Tracheobronchial smooth muscle atrophy and separation.

    PubMed

    Mehta, Atul C; Zaki, Khawaja Salman; Banga, Amit; Singh, Jarmanjeet; Gildea, Thomas R; Arrossi, Valeria

    2015-01-01

    We report a case series involving 4 patients with chronic obstructive pulmonary disease who were on an appropriate medical regimen including a high dose of inhaled corticosteroids (ICS). During bronchoscopy, patients were found to have an excessive dynamic collapse of the posterior wall and its separation from the ends of the adjacent cartilaginous rings. This was causing a near-total occlusion of the tracheal and bronchial lumen during exhalation, thereby presenting with an obstructive pattern on the pulmonary functions. We suspect that this was caused by the atrophy of the smooth muscles of the tracheobronchial wall. We reviewed the literature to explore the mechanisms causing atrophy of the bronchial smooth muscle, focusing on the potential role of long-term ICS use. PMID:26138002

  3. [Posterior cortical atrophy with progressive visual agnosia].

    PubMed

    Zarranz, J J; Lasa, A; Fernández, M; Lezcano, E; Pérez Bas, M; Varona, L; Ruiz, J; Beristain, X

    1995-03-01

    Interest in progressive focal cerebral syndromes associated with classical degenerative diseases has increased in recent years. Descriptions of posterior cortical atrophy with progressive visual agnosia are relatively rare. We present 5 patients (2 women) ranging in age between 57 and 72 years old. In all cases symptoms began and progressed with no known etiology. All cases were sporadic. The main clinical signs are difficulty in recognizing objects, colors, persons or places; topographical disorientation and visual memory alterations; alexia, simultagnosia, loss of ocular fixing and optic ataxia. Some patients presented other disturbances of praxis or memory and 2 progressed to global dementia. Language function was preserved and behavioral disturbances did not develop. The amplitude of the P100 visual evoked potential was low but latency was normal in 4 patients and prolonged in 1. Brain images showed atrophy and hypoperfusion in the parieto-occipital area. The neuropathology status of these patients is unknown. PMID:7756009

  4. The Basic Helix-Loop-Helix Transcription Factor E47 Reprograms Human Pancreatic Cancer Cells to a Quiescent Acinar State With Reduced Tumorigenic Potential

    PubMed Central

    Kim, SangWun; Lahmy, Reyhaneh; Riha, Chelsea; Yang, Challeng; Jakubison, Brad L.; van Niekerk, Jaco; Staub, Claudio; Wu, Yifan; Gates, Keith; Dong, Duc Si; Konieczny, Stephen F.; Itkin-Ansari, Pamela

    2015-01-01

    Objectives Pancreatic ductal adenocarcinoma (PDA) initiates from quiescent acinar cells that attain a Kras mutation, lose signaling from basic helix-loop-helix (bHLH) transcription factors, undergo acinar-ductal metaplasia, and rapidly acquire increased growth potential. We queried whether PDA cells can be reprogrammed to revert to their original quiescent acinar cell state by shifting key transcription programs. Methods Human PDA cell lines were engineered to express an inducible form of the bHLH protein E47. Gene expression, growth, and functional studies were investigated using microarray, quantitative polymerase chain reaction, immunoblots, immunohistochemistry, small interfering RNA, chromatin immunoprecipitation analyses, and cell transplantation into mice. Results In human PDA cells, E47 activity triggers stable G0/G1 arrest, which requires the cyclin-dependent kinase inhibitor p21 and the stress response protein TP53INP1. Concurrently, E47 induces high level expression of acinar digestive enzymes and feed forward activation of the acinar maturation network regulated by the bHLH factor MIST1. Moreover, induction of E47 in human PDA cells in vitro is sufficient to inhibit tumorigenesis. Conclusions Human PDA cells retain a high degree of plasticity, which can be exploited to induce a quiescent acinar cell state with reduced tumorigenic potential. Moreover, bHLH activity is a critical node coordinately regulating human PDA cell growth versus cell fate. PMID:25894862

  5. Space travel directly induces skeletal muscle atrophy

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H.; Chromiak, J.; Shansky, J.; Del Tatto, M.; Lemaire, J.

    1999-01-01

    Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.

  6. Synthesis and high-efficiency methylene blue adsorption of magnetic PAA/MnFe2O4 nanocomposites

    NASA Astrophysics Data System (ADS)

    Wang, Wei; Ding, Zui; Cai, Minhan; Jian, Haitao; Zeng, Zhiqiao; Li, Feng; Liu, J. Ping

    2015-08-01

    MnFe2O4 nanoparticles and polyacrylic acid PAA/MnFe2O4 nanocomposites were synthesized by a hydrothermal method and ultrasonic mixing process. The obtained materials were characterized by XRD, FTIR, SEM, TEM, and VSM. XRD patterns indicate that the synthesized MnFe2O4 nanoparticles have a single cubic spinel phase. SEM images confirm the existence of three types of basic morphology of MnFe2O4 nanoparticles: octahedral, flower-like, and plate-like particles. High saturation magnetization Ms (up to 74.6 emu/g) of the as-synthesized MnFe2O4 nanoparticles was obtained. Experiments demonstrate that the variation of the hydrothermal reaction time does not remarkably affect the magnetic properties of MnFe2O4 nanoparticles. In PAA/MnFe2O4 nanocomposites, the coating of PAA leads to a slight decrease in magnetization of MnFe2O4 nanoparticles. Additionally, PAA coating greatly enhances the adsorption properties of MnFe2O4 nanoparticles for Methylene Blue (MB) dye. Especially, the removal efficiency reaches 96.3%. This research indicates that the as-synthesized PAA/MnFe2O4 nanocomposites exhibit excellent magnetic properties and can be taken as a promising adsorbent for removal of MB dye in industrial scale.

  7. Coupling High-Energy Radiography And Photon Activation Analysis (PAA) To Optimize The Characterization Of Nuclear Waste Packages

    SciTech Connect

    Carrel, F.; Agelou, M.; Gmar, M.; Laine, F.; Lamotte, T.; Lazaro, D.; Poumarede, B.; Rattoni, B.

    2009-12-02

    Radiological characterization of nuclear waste packages is an industrial issue in order to select the best mode of storage. The alpha-activity, mainly due to the presence of actinides ({sup 235}U, {sup 238}U, {sup 239}Pu,...) inside the package, is one of the most important parameter to assess during the characterization. Photon Activation Analysis (PAA) is a non-destructive active method (NDA method) based on the photofission process and on the detection of delayed particles (neutrons and gammas). This technique is well-adapted to the characterization of large concrete waste packages. However, PAA methods often require a simulation step which is necessary to analyze experimental results and to quantify the global mass of actinides. The weak point of this approach is that characteristics of the package are often not well-known, these latter having a huge impact on the final simulation result. High-energy radiography, based on the use of a linear electron accelerator (LINAC), allows to visualize the content of the package and is also a performing way to tune simulation models and to optimize the characterization process by PAA. In this article, we present high-energy radiography results obtained for two different large concrete waste packages in the SAPHIR facility (Active Photon and Irradiation System). This facility is dedicated to PAA study and development and setup for a decade in CEA Saclay. We also discuss possibilities offered by the coupling between high-energy radiography and PAA techniques.

  8. Chemical Analysis and Aqueous Solution Properties of Charged Amphiphilic Block Copolymers PBA-b-PAA Synthesized by MADIX

    SciTech Connect

    Jacquin,M.; Muller, P.; Talingting-Pabalan, R.; Cottet, H.; Berret, J.; Futterer, T.; Theodoly, O.

    2007-01-01

    We have linked the structural and dynamic properties in aqueous solution of amphiphilic charged diblock copolymers poly(butyl acrylate)-b-poly(acrylic acid), PBA-b-PAA, synthesized by controlled radical polymerization, with the physico-chemical characteristics of the samples. Despite product imperfections, the samples self-assemble in melt and aqueous solutions as predicted by monodisperse microphase separation theory. However, the PBA core are abnormally large; the swelling of PBA cores is not due to AA (the Flory parameter ?PBA/PAA, determined at 0.25, means strong segregation), but to h-PBA homopolymers (content determined by liquid chromatography at the point of exclusion and adsorption transition, LC-PEAT). Beside the dominant population of micelles detected by scattering experiments, capillary electrophoresis CE analysis permitted detection of two other populations, one of h-PAA, and the other of free PBA-b-PAA chains, that have very short PBA blocks and never self-assemble. Despite the presence of these free unimers, the self-assembly in solution was found out of equilibrium: the aggregation state is history dependant and no unimer exchange between micelles occurs over months (time-evolution SANS). The high PBA/water interfacial tension, measured at 20 mN/m, prohibits unimer exchange between micelles. PBA-b-PAA solution systems are neither at thermal equilibrium nor completely frozen systems: internal fractionation of individual aggregates can occur.

  9. Ligand-bound Thyroid Hormone Receptor Contributes to Reprogramming of Pancreatic Acinar Cells into Insulin-producing Cells*

    PubMed Central

    Furuya, Fumihiko; Shimura, Hiroki; Asami, Keiichi; Ichijo, Sayaka; Takahashi, Kazuya; Kaneshige, Masahiro; Oikawa, Yoichi; Aida, Kaoru; Endo, Toyoshi; Kobayashi, Tetsuro

    2013-01-01

    One goal of diabetic regenerative medicine is to instructively convert mature pancreatic exocrine cells into insulin-producing cells. We recently reported that ligand-bound thyroid hormone receptor α (TRα) plays a critical role in expansion of the β-cell mass during postnatal development. Here, we used an adenovirus vector that expresses TRα driven by the amylase 2 promoter (AdAmy2TRα) to induce the reprogramming of pancreatic acinar cells into insulin-producing cells. Treatment with l-3,5,3-triiodothyronine increases the association of TRα with the p85α subunit of phosphatidylinositol 3-kinase (PI3K), leading to the phosphorylation and activation of Akt and the expression of Pdx1, Ngn3, and MafA in purified acinar cells. Analyses performed with the lectin-associated cell lineage tracing system and the Cre/loxP-based direct cell lineage tracing system indicate that newly synthesized insulin-producing cells originate from elastase-expressing pancreatic acinar cells. Insulin-containing secretory granules were identified in these cells by electron microscopy. The inhibition of p85α expression by siRNA or the inhibition of PI3K by LY294002 prevents the expression of Pdx1, Ngn3, and MafA and the reprogramming to insulin-producing cells. In immunodeficient mice with streptozotocin-induced hyperglycemia, treatment with AdAmy2TRα leads to the reprogramming of pancreatic acinar cells to insulin-producing cells in vivo. Our findings suggest that ligand-bound TRα plays a critical role in β-cell regeneration during postnatal development via activation of PI3K signaling. PMID:23595988

  10. Ligand-bound thyroid hormone receptor contributes to reprogramming of pancreatic acinar cells into insulin-producing cells.

    PubMed

    Furuya, Fumihiko; Shimura, Hiroki; Asami, Keiichi; Ichijo, Sayaka; Takahashi, Kazuya; Kaneshige, Masahiro; Oikawa, Yoichi; Aida, Kaoru; Endo, Toyoshi; Kobayashi, Tetsuro

    2013-05-31

    One goal of diabetic regenerative medicine is to instructively convert mature pancreatic exocrine cells into insulin-producing cells. We recently reported that ligand-bound thyroid hormone receptor α (TRα) plays a critical role in expansion of the β-cell mass during postnatal development. Here, we used an adenovirus vector that expresses TRα driven by the amylase 2 promoter (AdAmy2TRα) to induce the reprogramming of pancreatic acinar cells into insulin-producing cells. Treatment with l-3,5,3-triiodothyronine increases the association of TRα with the p85α subunit of phosphatidylinositol 3-kinase (PI3K), leading to the phosphorylation and activation of Akt and the expression of Pdx1, Ngn3, and MafA in purified acinar cells. Analyses performed with the lectin-associated cell lineage tracing system and the Cre/loxP-based direct cell lineage tracing system indicate that newly synthesized insulin-producing cells originate from elastase-expressing pancreatic acinar cells. Insulin-containing secretory granules were identified in these cells by electron microscopy. The inhibition of p85α expression by siRNA or the inhibition of PI3K by LY294002 prevents the expression of Pdx1, Ngn3, and MafA and the reprogramming to insulin-producing cells. In immunodeficient mice with streptozotocin-induced hyperglycemia, treatment with AdAmy2TRα leads to the reprogramming of pancreatic acinar cells to insulin-producing cells in vivo. Our findings suggest that ligand-bound TRα plays a critical role in β-cell regeneration during postnatal development via activation of PI3K signaling. PMID:23595988

  11. Human pulmonary acinar airspace segmentation from three-dimensional synchrotron radiation micro CT images of secondary pulmonary lobule

    NASA Astrophysics Data System (ADS)

    Kawata, Y.; Hosokawa, T.; Niki, N.; Umetani, K.; Nakano, Y.; Ohmatsu, H.; Moriyama, N.; Itoh, H.

    2011-03-01

    The recognition of abnormalities relative to the lobular anatomy has become increasingly important in the diagnosis and differential diagnosis of lung abnormalities at clinical routines of CT examinations. This paper aims for a 3-D microstructural analysis of the pulmonary acinus with isotropic spatial resolution in the range of several micrometers by using micro CT. Previously, we demonstrated the ability of synchrotron radiation micro CT (SRμCT) using offset scan mode in microstructural analysis of the whole part of the secondary pulmonary lobule. In this paper, we present a semi-automatic method to segment the acinar and subacinar airspaces from the secondary pulmonary lobule imaged by the SRμCT. The method began with a segmentation of the tissues such as pleural surface, interlobular septa, alveola wall, or vessel using threshold technique and 3-D connected component analysis. Follow-on stages then constructed 3-D air space separated by tissues and represented branching patterns of airways and airspaces distal to the terminal bronchiole. Finally, a graph-partitioning approach isolated acini whose stems were interactively defined as the terminal bronchiole in the secondary pulmonary lobule. Additionally, the isolated acinar airspace was segmented into subacini in which the airway was considered as the stem using the graph-partitioning approach. Results demonstrate that the proposed method can extract several acinar airspaces from the 3-D SRμCT image of secondary pulmonary lobule and that the extracted acinar airspace enable an accurate quantitative description of the anatomy of the human acinus for interpretation of the basic unit of pulmonary structure and function.

  12. Rab27A Is Present in Mouse Pancreatic Acinar Cells and Is Required for Digestive Enzyme Secretion

    PubMed Central

    Hou, Yanan; Ernst, Stephen A.; Stuenkel, Edward L.; Lentz, Stephen I.; Williams, John A.

    2015-01-01

    The small G-protein Rab27A has been shown to regulate the intracellular trafficking of secretory granules in various cell types. However, the presence, subcellular localization and functional impact of Rab27A on digestive enzyme secretion by mouse pancreatic acinar cells are poorly understood. Ashen mice, which lack the expression of Rab27A due to a spontaneous mutation, were used to investigate the function of Rab27A in pancreatic acinar cells. Isolated pancreatic acini were prepared from wild-type or ashen mouse pancreas by collagenase digestion, and CCK- or carbachol-induced amylase secretion was measured. Secretion occurring through the major-regulated secretory pathway, which is characterized by zymogen granules secretion, was visualized by Dextran-Texas Red labeling of exocytotic granules. The minor-regulated secretory pathway, which operates through the endosomal/lysosomal pathway, was characterized by luminal cell surface labeling of lysosomal associated membrane protein 1 (LAMP1). Compared to wild-type, expression of Rab27B was slightly increased in ashen mouse acini, while Rab3D and digestive enzymes (amylase, lipase, chymotrypsin and elastase) were not affected. Localization of Rab27B, Rab3D and amylase by immunofluorescence was similar in both wild-type and ashen acinar cells. The GTP-bound states of Rab27B and Rab3D in wild-type and ashen mouse acini also remained similar in amount. In contrast, acini from ashen mice showed decreased amylase release induced by CCK- or carbachol. Rab27A deficiency reduced the apical cell surface labeling of LAMP1, but did not affect that of Dextran-Texas Red incorporation into the fusion pockets at luminal surface. These results show that Rab27A is present in mouse pancreatic acinar cells and mainly regulates secretion through the minor-regulated pathway. PMID:25951179

  13. Liquid crystal-based glucose biosensor functionalized with mixed PAA and QP4VP brushes.

    PubMed

    Khan, Mashooq; Park, Soo-Young

    2015-06-15

    4-Cyano-4'-pentylbiphenyl (5CB) in a transmission electron microscopy (TEM) grid was developed for glucose detection by coating with a monolayer of mixed polymer brushes using poly(acrylicacid-b-4-cynobiphenyl-4'-oxyundecylacrylate) (PAA-b-LCP) and quaternized poly(4-vinylpyridine-b-4-cynobiphenyl-4'-oxyundecylacrylate) (QP4VP-b-LCP) (LCP stands for liquid crystal polymer) at the 5CB/aqueous interface. The resultant 5CB in TEM grid was functionalized with the PAA and QP4VP brushes, which were strongly anchored by the LCP block. The PAA brush rendered the 5CB/aqueous interface pH-responsive and the QP4VP brush immobilized glucose oxidase (GOx) through electrostatic interactions without the aid of coupling agents. The glucose was detected through a homeotropic-to-planar orientational transition of the 5CB observed through a polarized optical microscope (POM) under crossed polarizers. The optimum immobilization with a 0.78 µM GOx solution on the dual-brush-coated TEM grid enabled glucose detection at concentrations higher than 0.5 mM with response times shorter than 180 s. This TEM grid glucose sensor provided a linear response of birefringence of the 5CB to glucose concentrations ranging from 0.5 to 11 mM with a Michaelis-Menten constant (Km) of 1.67 mM. This new and sensitive glucose biosensor has the advantages of low production cost, simple enzyme immobilization, high enzyme sensitivity and stability, and easy detection with POM, and may be useful for prescreening the glucose level in the human body. PMID:25617751

  14. Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas

    PubMed Central

    Furukawa, Toru; Sakamoto, Hitomi; Takeuchi, Shoko; Ameri, Mitra; Kuboki, Yuko; Yamamoto, Toshiyuki; Hatori, Takashi; Yamamoto, Masakazu; Sugiyama, Masanori; Ohike, Nobuyuki; Yamaguchi, Hiroshi; Shimizu, Michio; Shibata, Noriyuki; Shimizu, Kyoko; Shiratori, Keiko

    2015-01-01

    Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild-type allele, we identified recurrent mutations of BRCA2 and FAT genes. BRCA2 showed somatic or germline premature termination mutations, with loss of the wild-type allele in 3 of 7 tumors. FAT1, FAT3, and FAT4 showed somatic or germline missense mutations in 4 of 7 tumors. The germline FAT mutations were with loss of the wild-type allele. Loss of BRCA2 expression was observed in 5 of 11 tumors. One patient with a BRCA2-mutated tumor experienced complete remission of liver metastasis following cisplatinum chemotherapy. In conclusion, acinar cell carcinomas show a distinct mutation pattern and often harbor somatic or germline mutations of BRCA2 and FAT genes. This result may warrant assessment of BRCA2 abrogation in patients with the carcinoma to determine their sensitivity to chemotherapy. PMID:25743105

  15. Effect of ionizing radiation on acinar morphogenesis of human prostatic epithelial cells under three-dimensional culture conditions.

    PubMed

    Wang, T; X, S Ma; Kong, D; Yi, H; Wang, X; Liang, B; Xu, H; He, M; Jia, L; Qased, A B; Yang, Y; Liu, X

    2012-01-01

    Homeostasis is maintained by the interplay of multiple factors that directly or indirectly regulate cell proliferation and cell death. Complex multiple interactions between cells and the extracellular matrix occur during acinar morphogenesis and changes in these might indicate carcinogenesis of cells from a normal to a malignant, invasive phenotype. In this study, the human prostatic epithelial cell line RWPE-1 was cultured under three-dimensional (3-D) culture conditions, and the effect of ionizing radiation on acinar morphogenesis and its association with autophagy were discussed. The results illustrated that formation of specific spheroid (acinar) structures was detectable under 3-D culture conditions. Radiation induced the disruption of acini in different cell models using either gene overexpression (Akt) or gene knock-down (Beclin 1 and ATG7). Introduction of Akt not only accelerated the growth of cells (i.e., caused the cells to manifest elongating and microspike-like structures that are obviously different from structures seen in wild-type RWPE-1 cells under two-dimensional conditions), but also changed their morphological characteristics under 3-D culture conditions. Knock-down of autophagy-related genes (Beclin 1 and ATG7) increased the radiosensitivity of cells under 3-D culture conditions, and cells died of non-apoptotic death after radiation. The results suggested that ionizing radiation may change the cell phenotype and the formation of acini. Additionally even the autophagy mechanism may play a role in these processes. PMID:22296497

  16. Aroclor 1254 causes atrophy of exocrine pancreas in mice and the mechanism involved.

    PubMed

    Lin, Moudan; Wu, Tian; Sun, Lingbin; Lin, Jackie Jin; Zuo, Zhenghong; Wang, Chonggang

    2016-06-01

    Polychlorinated biphenyls (PCBs) are a class of organic pollutants that have been linked to pancreatic disease. However, their role in affecting the exocrine function of pancreas and the underlying mechanism remains elusive. In the present study, male C57 mice were treated with Aroclor 1254, a commercially available PCBs mixture, at a dosage of 0.5, 5, 50, or 500 μg kg(-1) every 3 days by oral gavage. Decrease in pancreas/soma index and acinar atrophy were observed in the mice after exposure for 50 days. Aroclor 1254 exposure significantly decreased the PCNA-positive cells in the pancreatic acini in a dose-dependent manner. In addition, western blot analysis showed that PCNA expression was decreased in pancreas in the presence of Aroclor 1254, which suggests that Aroclor 1254 suppresses cell proliferation. TUNEL-positive apoptotic cells as well as the expression of Bcl2, BclXL, BAX, and Bad of exocrine pancreas did not show significant changes in the treated mice, indicating that Aroclor 1254 has no effect on apoptosis. We also found that phosphorylation of ERK1/2, P90RSK1 and Bad was increased in the treated groups; this compensatory activation of phosphorylation in ERK1/2-P90RSK1-Bad signaling cascade could protect cell from apoptosis to maintain the cell numbers and function of exocrine pancreas. Moreover, we found that the expression of Kras and TNFα was increased in the pancreas, indicating that Aroclor 1254 exposure could result in increased risk of inflammation and carcinoma. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 671-678, 2016. PMID:25409620

  17. Skeletal muscle atrophy: disease-induced mechanisms may mask disuse atrophy.

    PubMed

    Malavaki, C J; Sakkas, G K; Mitrou, G I; Kalyva, A; Stefanidis, I; Myburgh, K H; Karatzaferi, C

    2015-12-01

    Disuse atrophy is the loss of skeletal muscle mass due to inactivity or lower than 'normal' use. It is not only a furtive component of the 'modern' sedentary lifestyle but also a part of numerous pathologies, where muscle loss is linked to disease specific and/or other toxicity factors, eventually leading to wasting (cachexia). Whether disuse-or-disease induced, muscle loss leads to weakness and metabolic comorbidities with a high societal and financial cost. This review discusses the intricate network of interacting signalling pathways including Atrogin-1/MAFbx, IGF1-Akt, myostatin, glucocorticoids, NF-kB, MAPKs and caspases that seem to regulate disuse atrophy but also share common activation patterns in other states of muscle loss such as sarcopenia or cachexia. Reactive oxygen species are also important regulators of cell signalling pathways that can accelerate proteolysis and depress protein synthesis. Exercise is an effective countermeasure and antioxidants may show some benefit. We discuss how the experimental model used can crucially affect the outcome and hence our understanding of atrophy. Timing of sampling is crucial as some signalling mechanisms reach their peak early during the atrophy process to rapidly decline thereafter, while other present high levels even weeks and months after study initiation. The importance of such differences lays in future consideration of appropriate treatment targets. Apart from attempting to correct defective genes or negate their effects, technological advances in new rational ways should aim to regulate specific gene expression at precise time points for the treatment of muscle atrophy in therapeutic protocols depending on the origin of atrophy induction. PMID:26728748

  18. Aerosol bolus dispersion in acinar airways--influence of gravity and airway asymmetry.

    PubMed

    Ma, Baoshun; Darquenne, Chantal

    2012-08-01

    The aerosol bolus technique can be used to estimate the degree of convective mixing in the lung; however, contributions of different lung compartments to measured dispersion cannot be differentiated unambiguously. To estimate dispersion in the distal lung, we studied the effect of gravity and airway asymmetry on the dispersion of 1 μm-diameter particle boluses in three-dimensional computational models of the lung periphery, ranging from a single alveolar sac to four-generation (g4) structures of bifurcating airways that deformed homogeneously during breathing. Boluses were introduced at the beginning of a 2-s inhalation, immediately followed by a 3-s exhalation. Dispersion was estimated by the half-width of the exhaled bolus. Dispersion was significantly affected by the spatial orientation of the models in normal gravity and was less in zero gravity than in normal gravity. Dispersion was strongly correlated with model volume in both normal and zero gravity. Predicted pulmonary dispersion based on a symmetric g4 acinar model was 391 ml and 238 ml under normal and zero gravity, respectively. These results accounted for a significant amount of dispersion measured experimentally. In zero gravity, predicted dispersion in a highly asymmetric model accounted for ∼20% of that obtained in a symmetric model with comparable volume and number of alveolated branches, whereas normal gravity dispersions were comparable in both models. These results suggest that gravitational sedimentation and not geometrical asymmetry is the dominant factor in aerosol dispersion in the lung periphery. PMID:22678957

  19. Aerosol bolus dispersion in acinar airways—influence of gravity and airway asymmetry

    PubMed Central

    Ma, Baoshun

    2012-01-01

    The aerosol bolus technique can be used to estimate the degree of convective mixing in the lung; however, contributions of different lung compartments to measured dispersion cannot be differentiated unambiguously. To estimate dispersion in the distal lung, we studied the effect of gravity and airway asymmetry on the dispersion of 1 μm-diameter particle boluses in three-dimensional computational models of the lung periphery, ranging from a single alveolar sac to four-generation (g4) structures of bifurcating airways that deformed homogeneously during breathing. Boluses were introduced at the beginning of a 2-s inhalation, immediately followed by a 3-s exhalation. Dispersion was estimated by the half-width of the exhaled bolus. Dispersion was significantly affected by the spatial orientation of the models in normal gravity and was less in zero gravity than in normal gravity. Dispersion was strongly correlated with model volume in both normal and zero gravity. Predicted pulmonary dispersion based on a symmetric g4 acinar model was 391 ml and 238 ml under normal and zero gravity, respectively. These results accounted for a significant amount of dispersion measured experimentally. In zero gravity, predicted dispersion in a highly asymmetric model accounted for ∼20% of that obtained in a symmetric model with comparable volume and number of alveolated branches, whereas normal gravity dispersions were comparable in both models. These results suggest that gravitational sedimentation and not geometrical asymmetry is the dominant factor in aerosol dispersion in the lung periphery. PMID:22678957

  20. Effects of caerulein on the apical cytoskeleton of the pancreatic acinar cell.

    PubMed Central

    O'Konski, M S; Pandol, S J

    1990-01-01

    In this study experiments were performed to correlate the rate of digestive enzyme secretion to morphologic observations of the apical cytoskeleton using dispersed rat pancreatic acini with various concentrations of caerulein. Caerulein at concentrations of 10 pM to 0.1 nM stimulated increasing rates of secretion of amylase, a digestive enzyme. Greater concentrations of caerulein caused progressively less amylase secretion. Transmission electron microscopy demonstrated several characteristics of the apical cytoskeleton in untreated acini that were altered with the "inhibitory" concentrations of caerulein. In control acini and acini stimulated with concentrations of caerulein up to 0.1 nM, the micrographs reveal an apical actin network extending into microvilli, an intermediate filament band, and electron-dense structures contained in both the actin filament network and the intermediate filament band. With concentrations of caerulein greater than 0.1 nM, these structures were progressively ablated. The findings with respect to the actin filament network were confirmed with light microscopic observations of dispersed acini stained with rhodamine-phalloidin. These results indicate that caerulein has marked morphologic effects on the pancreatic acinar cell cytoskeleton and that the cytoskeletal changes may modulate the secretory response. Images PMID:1700797

  1. CCK independently activates intracellular trypsinogen and NF-kappaB in rat pancreatic acinar cells.

    PubMed

    Han, B; Ji, B; Logsdon, C D

    2001-03-01

    In the cholecystokinin (CCK) hyperstimulation model of acute pancreatitis, two early intracellular events, activation of trypsinogen and activation of nuclear factor-kappaB (NF-kappaB), are thought to be important in the development of the disease. In this study, the relationship between these two events was investigated. NF-kappaB activity was monitored by using a DNA binding assay and mob-1 chemokine gene expression. Intracellular trypsin activity was measured by using a fluorogenic substrate. Protease inhibitors including FUT-175, Pefabloc, and E-64d prevented CCK stimulation of intracellular trypsinogen and NF-kappaB activation. Likewise, the NF-kappaB inhibitors pyrrolidine dithiocarbamate and N-acetyl-L-cysteine inhibited CCK stimulation of NF-kappaB and intracellular trypsinogen activation. These results suggested a possible codependency of these two events. However, CCK stimulated NF-kappaB activation in Chinese hamster ovary-CCK(A) cells, which do not express trypsinogen, indicating that trypsin is not necessary for CCK activation of NF-kappaB. Furthermore, adenovirus-mediated expression in acinar cells of active p65 subunits to stimulate NF-kappaB, or of inhibitory kappaB-alpha molecules to inhibit NF-kappaB, did not affect either basal or CCK-mediated trypsinogen activation. Thus trypsinogen and NF-kappaB activation are independent events stimulated by CCK. PMID:11171565

  2. Characterization of receptors for VIP on pancreatic acinar cell plasma membranes using covalent cross-linking

    SciTech Connect

    McArthur, K.E.; Wood, C.L.; O'Dorisio, M.S.; Zhou, Z.C.; Gardner, J.D.; Jensen, R.T.

    1987-03-01

    Vasoactive intestinal peptide (VIP) receptors on guinea pig pancreatic acini differ from those on all other tissues in containing a high-affinity VIP receptor and a low-affinity VIP receptor that has a high affinity for secretin. To characterize the molecular components of these receptors, /sup 125/I-VIP was covalently cross-linked to these receptors by four different cross-linking agents: disuccinimidyl suberate, ethylene glycol bis (succinimidyl succinate), dithiobis (succinimidylpropionate), and m-maleimidobenzoyl N-hydroxysuccinimide ester. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated a single major polypeptide band of M/sub r/ 45,000 and a minor polypeptide band of M/sub r/ 30,000 were cross-linked to /sup 125/I-VIP. Covalent cross-linking only occurred when a cross-linking agent was added, was inhibited by GTP, was inhibited by VIP receptor agonist or antagonists that interact with VIP receptors, and not by other pancreatic secretagogues that interact with difference receptors. Thus the high-affinity VIP receptor on pancreatic acinar cell membranes consists of a single major polypeptide of M/sub r/ 45,000, and this polypeptide is not a subunit of a larger disulfide-linked structure. Furthermore, either the low-affinity VIP/secretin-preferring receptor was not covalently cross-linked under the experimental conditions or it consist of a major polypeptide with the same molecular weight as the high-affinity VIP receptor.

  3. Activation of Ca2+ entry into acinar cells by a non-phosphorylatable inositol trisphosphate

    NASA Astrophysics Data System (ADS)

    Bird, G. S. J.; Rossier, M. F.; Hughes, A. R.; Shears, S. B.; Armstrong, D. L.; , J. W. Putney, Jr.

    1991-07-01

    IN many cell types, receptor activation of phosphoinositidase C results in an initial release of intracellular Ca2+ stores followed by sustained Ca2+ entry across the plasma membrane. Inositol 1,4,5-trisphosphate is the mediator of the initial Ca2+ release1, although its role in the mechanism underlying Ca2+ entry remains controversial1-6. We have now used two techniques to introduce inositol phosphates into mouse lacrimal acinar cells and measure their effects on Ca2+ entry: microinjection into cells loaded with Fura-2, a fluorescent dye which allows the measurement of intra-cellular free calcium concentration by microspectrofluorimetry, and perfusion of patch clamp pipettes in the whole-cell configuration while monitoring the activity of Ca2+-activated K+ channels as an indicator of intracellular Ca2+. We report here that inositol 1,4,5-trisphosphate serves as a signal that is both necessary and sufficient for receptor activation of Ca2+ entry across the plasma membrane in these cells.

  4. Mixed acinar-neuroendocrine-ductal carcinoma of the pancreas: a tale of three lineages.

    PubMed

    Anderson, Mark J; Kwong, Christina A; Atieh, Mohammed; Pappas, Sam G

    2016-01-01

    Most pancreatic cancers arise from a single cell type, although mixed pancreatic carcinomas represent a rare exception. The rarity of these aggressive malignancies and the limitations of fine-needle aspiration (FNA) pose significant barriers to diagnosis and appropriate management. We report a case of a 54-year-old man presenting with abdominal pain, jaundice and a hypodense lesion within the uncinate process on CT. FNA suggested poorly differentiated adenocarcinoma, which was subsequently resected via pancreaticoduodenectomy. Pathological analysis yielded diagnosis of invasive mixed acinar-neuroendocrine-ductal pancreatic carcinoma. Given the rare and deadly nature of these tumours, clinicians must be aware of their pathophysiology and do practice with a high degree of clinical suspicion, when appropriate. Surgical resection and thorough pathological analysis with immunohistochemical staining and electron microscopy remain the standards of care for mixed pancreatic tumours without gross evidence of metastasis. Diligent characterisation of the presentation and histological findings associated with these neoplasms should continue in order to promote optimal diagnostic and therapeutic strategies. PMID:27257019

  5. Endogenous and monoclonal antibodies to the rat pancreatic acinar cell Golgi complex

    PubMed Central

    1984-01-01

    Normal, unimmunized mouse serum from several strains (BALB/c, C57/b, DBA/2, NZB, SJL, CD/1) contains an endogenous IgG antibody that localizes to the Golgi complex of rat pancreatic acinar cells. Treatment of pancreatic acini with 5 microM monensin resulted in the swelling and vacuolization of the Golgi cisternae, and in a corresponding annular staining by the mouse serum as observed by immunofluorescence, suggesting that the antigen recognized is on the Golgi complex cisternal membrane. The antiserum did not react with pancreatic secretory proteins, and its binding to smooth microsomal membranes was retained following sodium carbonate washing, supporting a Golgi membrane localization. Advantage was taken of the existence of the endogenous murine antibody for the isolation of monoclonal antibodies directed to the Golgi complex of the rat pancreas. Two antibodies, antiGolgi 1 and antiGolgi 2, are described. Both antibodies are IgMs that recognize integral membrane proteins of the trans-Golgi cisternae, with lighter and patchy staining of the pancreatic lumen membrane, as observed both by light and electron microscopy. AntiGolgi 1 recognizes predominately a protein of molecular weight 103,000- 108,000, whereas antiGolgi 2 shows a strong reaction to a 180-kd band as well as the 103-108-kd protein. PMID:6373788

  6. A model system for the study of stimulus - enzyme secretion coupling in rat pancreatic acinar cells.

    PubMed

    Guderley, H; Heisler, S

    1980-08-01

    A superfusion technique was developed as a model system for the study of stimulus-secretion coupling in collagenase-dispersed rat pancreatic acinar cells. Cells (10(7)) were combined with a slurry of Biogel P-4 beads and the mixture was decanted into a plastic column (1.5 cm X 8.5 cm) and perfused with Krebs-Ringer. Amylase activity was determined in sequentially collected effusate fractions and used to estimate the secretory rate. Carbachol, carbachol plus dibutyryl cyclic AMP, cholecystokinin-pancreozymin, and the ionophore A-23187 all stimulated a rapid increase in the rate of secretion. Cell integrity was unaffected by these stimulants as evidenced microscopically and by the lack of lactate dehydrogenase activity in the effusates. Enzymes secreted in response to secretagogues were collected, concentrated, and isoelectrofocused on polyacrylamide gels. A film detection technique was developed to localize amylase activity. The model system has the following advantages: (1) secreted proteolytic products are removed from the vicinity of cells, thereby preventing direct cellular damage and hydrolysis of peptide agonist; (2) the need to add trypsin inhibitors is eliminated and only a minimal addition of albumin (0.001%) is required, thus allowing the separation and distortion-free analysis of secreted proteins; (3) the perfusion conditions can be changed rapidly without disturbing the cells. The model described is therefore well suited to the study of both molecular and kinetic events involved in the enzyme secretory phenomenon in exocrine pancreas. PMID:6164455

  7. Grafting mechanism of electrochromic PAA-WO{sub 3} composite film

    SciTech Connect

    Choy, J.H.; Kim, Y.I.; Kim, B.W.; Campet, G.; Portier, J.; Huong, P.V.

    1999-02-01

    A micro-Raman spectroscopic study has been carried out to investigate the electrochromic process in a porous and nanocrystalline tungsten oxide film. The film was prepared by dipping the tin-doped indium oxide glass into an aqueous mixture solution of PAA (polyacrylic acid) and WO{sub 3}-NH{sub 4}OH. After heating at low temperature, around 100 C, the film was treated in 1 N HCl in order to achieve polycondensation, where the ammonium ion was replaced with a proton. In the micro-Raman spectra for the bleached and colored PAA-WO{sub 3} films, it was evident that the coloration accompanies a peak reduction at {approximately}960 cm{sup {minus}1} and a peak enhancement at {approximately}810 cm{sup {minus}1}. Based upon the present Raman observation, the authors can confirm that the electrochromism of the nanocrystalline tungsten oxide is dominated by the grafting process, i.e., the surface modification of {single_bond}W{sup VI}{double_bond}O bonds into {single_bond}W{sup V}{double_bond}O{sup (1{minus}{delta})+}{emdash}M{sup {delta}+} (M = H, Li) ones.

  8. Up-regulation of Store-operated Ca2+ Entry and Nuclear Factor of Activated T Cells Promote the Acinar Phenotype of the Primary Human Salivary Gland Cells.

    PubMed

    Jang, Shyh-Ing; Ong, Hwei Ling; Liu, Xibao; Alevizos, Ilias; Ambudkar, Indu S

    2016-04-15

    The signaling pathways involved in the generation and maintenance of exocrine gland acinar cells have not yet been established. Primary human salivary gland epithelial cells, derived from salivary gland biopsies, acquired an acinar-like phenotype when the [Ca(2+)] in the serum-free medium (keratinocyte growth medium, KGM) was increased from 0.05 mm (KGM-L) to 1.2 mm (KGM-H). Here we examined the mechanism underlying this Ca(2+)-dependent generation of the acinar cell phenotype. Compared with cells in KGM-L, those in KGM-H display enhancement of Orai1, STIM1, STIM2, and nuclear factor of activated T cells 1 (NFAT1) expression together with an increase in store-operated Ca(2+) entry (SOCE), SOCE-dependent nuclear translocation of pGFP-NFAT1, and NFAT-dependent but not NFκB-dependent gene expression. Importantly, AQP5, an acinar-specific protein critical for function, is up-regulated in KGM-H via SOCE/NFAT-dependent gene expression. We identified critical NFAT binding motifs in the AQP5 promoter that are involved in Ca(2+)-dependent up-regulation of AQP5. These important findings reveal that the Ca(2+)-induced switch of salivary epithelial cells to an acinar-like phenotype involves remodeling of SOCE and NFAT signaling, which together control the expression of proteins critically relevant for acinar cell function. Our data provide a novel strategy for generating and maintaining acinar cells in culture. PMID:26903518

  9. [Susceptibility gene in multiple system atrophy (MSA)].

    PubMed

    Tsuji, Shoji

    2014-01-01

    To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress. PMID:25672683

  10. Cardiac atrophy after bed rest and spaceflight

    NASA Technical Reports Server (NTRS)

    Perhonen, M. A.; Franco, F.; Lane, L. D.; Buckey, J. C.; Blomqvist, C. G.; Zerwekh, J. E.; Peshock, R. M.; Weatherall, P. T.; Levine, B. D.

    2001-01-01

    Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity

  11. A working group classification of focal prostate atrophy lesions.

    PubMed

    De Marzo, Angelo M; Platz, Elizabeth A; Epstein, Jonathan I; Ali, Tehmina; Billis, Anthanase; Chan, Teresa Y; Cheng, Liang; Datta, Milton; Egevad, Lars; Ertoy-Baydar, Dilek; Farre, Xavier; Farree, Xavier; Fine, Samson W; Iczkowski, Kenneth A; Ittmann, Michael; Knudsen, Beatrice S; Loda, Massimo; Lopez-Beltran, Antonio; Magi-Galluzzi, Cristina; Mikuz, Gregor; Montironi, Roldolfo; Pikarsky, Eli; Pizov, Galina; Rubin, Mark A; Samaratunga, Hema; Sebo, Thomas; Sesterhenn, Isabel A; Shah, Rajal B; Shah, Rajiv B; Signoretti, Sabina; Simko, Jeffery; Thomas, George; Troncoso, Patricia; Tsuzuki, Toyonori T; van Leenders, Geert J; Yang, Ximing J; Zhou, Ming; Figg, William D; Hoque, Ashraful; Hoque, Ashrafal; Lucia, M S

    2006-10-01

    Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability. This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy. In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of "training" images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct "test" images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of "standard" diagnoses and the kappa statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median kappa) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median kappa for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation. Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was

  12. Brain atrophy in Alzheimer's Disease and aging.

    PubMed

    Pini, Lorenzo; Pievani, Michela; Bocchetta, Martina; Altomare, Daniele; Bosco, Paolo; Cavedo, Enrica; Galluzzi, Samantha; Marizzoni, Moira; Frisoni, Giovanni B

    2016-09-01

    Thanks to its safety and accessibility, magnetic resonance imaging (MRI) is extensively used in clinical routine and research field, largely contributing to our understanding of the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). This review aims to provide a comprehensive overview of the main findings in AD and normal aging over the past twenty years, focusing on the patterns of gray and white matter changes assessed in vivo using MRI. Major progresses in the field concern the segmentation of the hippocampus with novel manual and automatic segmentation approaches, which might soon enable to assess also hippocampal subfields. Advancements in quantification of hippocampal volumetry might pave the way to its broader use as outcome marker in AD clinical trials. Patterns of cortical atrophy have been shown to accurately track disease progression and seem promising in distinguishing among AD subtypes. Disease progression has also been associated with changes in white matter tracts. Recent studies have investigated two areas often overlooked in AD, such as the striatum and basal forebrain, reporting significant atrophy, although the impact of these changes on cognition is still unclear. Future integration of different MRI modalities may further advance the field by providing more powerful biomarkers of disease onset and progression. PMID:26827786

  13. Effects of muscle atrophy on motor control

    NASA Technical Reports Server (NTRS)

    Stuart, D. G.

    1985-01-01

    As a biological tissue, muscle adapts to the demands of usage. One traditional way of assessing the extent of this adaptation has been to examine the effects of an altered-activity protocol on the physiological properties of muscles. However, in order to accurately interpret the changes associated with an activity pattern, it is necessary to employ an appropriate control model. A substantial literature exists which reports altered-use effects by comparing experimental observations with those from animals raised in small laboratory cages. Some evidence suggests that small-cage-reared animals actually represent a model of reduced use. For example, laboratory animals subjected to limited physical activity have shown resistance to insulin-induced glucose uptake which can be altered by exercise training. This project concerned itself with the basic mechanisms underlying muscle atrophy. Specifically, the project addressed the issue of the appropriateness of rats raised in conventional-sized cages as experimental models to examine this phenomenon. The project hypothesis was that rats raised in small cages are inappropriate models for the study of muscle atrophy. The experimental protocol involved: 1) raising two populations of rats, one group in conventional (small)-sized cages and the other group in a much larger (133x) cage, from weanling age (21 days) through to young adulthood (125 days); 2) comparison of size- and force-related characteristics of selected test muscles in an acute terminal paradigm.

  14. [Multiple system atrophy - synuclein and neuronal degeneration].

    PubMed

    Yoshida, Mari

    2011-11-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome (SDS). The histopathological hallmarks are α-synuclein (AS) positive glial cytoplasmic inclusions (GCIs) in oligodendroglias. AS aggregation is also found in glial nuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurties. Reviewing the pathological features of 102 MSA cases, OPCA-type was relatively more frequent and SND-type was less frequent in Japanese MSA cases, which suggested different phenotypic pattern of MSA might exist between races, compared to the relatively high frequency of SND-type in western countries. In early stage of MSA, NNIs, NCIs and diffuse homogenous stain of AS in neuronal nuclei and cytoplasm were observed in various vulnerable lesions including the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of thoracic cord, lower motor neurons and cortical pyramidal neurons, in additions to GCIs. These findings indicated that the primary nonfibrillar and fibrillar AS aggregation also occurred in neurons. Therefore both the direct involvement of neurons themselves and the oligodendroglia-myelin-axon mechanism may synergistically accelerate the degenerative process of MSA. PMID:22277386

  15. Proximal spinal muscular atrophy: current orthopedic perspective

    PubMed Central

    Haaker, Gerrit; Fujak, Albert

    2013-01-01

    Spinal muscular atrophy (SMA) is a hereditary neuromuscular disease of lower motor neurons that is caused by a defective “survival motor neuron” (SMN) protein that is mainly associated with proximal progressive muscle weakness and atrophy. Although SMA involves a wide range of disease severity and a high mortality and morbidity rate, recent advances in multidisciplinary supportive care have enhanced quality of life and life expectancy. Active research for possible treatment options has become possible since the disease-causing gene defect was identified in 1995. Nevertheless, a causal therapy is not available at present, and therapeutic management of SMA remains challenging; the prolonged survival is increasing, especially orthopedic, respiratory and nutritive problems. This review focuses on orthopedic management of the disease, with discussion of key aspects that include scoliosis, muscular contractures, hip joint disorders, fractures, technical devices, and a comparative approach of conservative and surgical treatment. Also emphasized are associated complications including respiratory involvement, perioperative care and anesthesia, nutrition problems, and rehabilitation. The SMA disease course can be greatly improved with adequate therapy with established orthopedic procedures in a multidisciplinary therapeutic approach. PMID:24399883

  16. G protein in stimulation of PI hydrolysis by CCK (cholecystokinin) in isolated rat pancreatic acinar cells

    SciTech Connect

    Matozaki, Takashi; Sakamoto, Choitsu; Nagao, Munehiko; Nishizaki, Hogara; Baba, Shigeaki )

    1988-11-01

    To clarify the possible role of a guanine nucleotide-binding protein (G protein) in the signal transducing system activated by cholecystokinin (CCK), actions of CCK on rat pancreatic acini were compared with those of fluoride, a well-known activator of stimulatory (G{sub s}) or inhibitory (G{sub i}) G protein. When acini were incubated with increasing concentrations of either CCK-octapeptide (CCK8) or NaF, a maximal stimulation of amylase release from acini occurred at 100 pM CCK8 or 10 mM NaF, respectively; this secretory rate decreased as CCK8 or NaF concentration was increased. NaF caused an increase in cytoplasmic Ca{sup 2+} concentration from the internal Ca{sup 2+} store and stimulated accumulation of inositol phosphates in acini, as observed with CCK. Guanylimidodiphosphate activated the generation of inositol phosphates in the ({sup 3}H)inositol-labeled pancreatic acinar cell membrane preparation, with half-maximal and maximal stimulation at 1 and 10 {mu}M, respectively. Furthermore, the effects of submaximal CCK concentrations on inositol phosphate accumulation in membranes were markedly potentiated in the presence of 100 {mu}M GTP, which alone was ineffective. Combined findings of the present study strongly suggest that pancreatic CCK receptors are probably coupled to the activation of polyphosphoinositide (PI) breakdown by a G protein, which appears to be fluoride sensitive but is other than G{sub s}- or G{sub i}-like protein.

  17. Mechanisms underlying InsP3-evoked global Ca2+ signals in mouse pancreatic acinar cells

    PubMed Central

    Fogarty, Kevin E; Kidd, Jackie F; Tuft, Dick A; Thorn, Peter

    2000-01-01

    In secretory epithelial cells, complex patterns of Ca2+ signals regulate physiological processes. How these patterns are generated is still not fully understood. In particular, the basis of global Ca2+ waves is not clear. We have studied regional differences in InsP3-evoked Ca2+ release in single mouse pancreatic acinar cells, using high-speed (∼90 frames s−1), high-sensitivity Ca2+ imaging combined with rapid (10 ms) spot photolysis (2 μm diameter) of caged InsP3. Within a single region we measured Ca2+ response latency and rate of rise to construct an InsP3 dose-response relationship. Spot InsP3 liberation in the secretory pole region consistently elicited a dose-dependent, rapid release of Ca2+. Spot InsP3 liberation in the basal pole region of ∼50 % of cells elicited a similar dose-response relationship but with a lower apparent InsP3 affinity than in the secretory pole. In the other cells, basal pole InsP3 liberation did not elicit active Ca2+ release, even at the highest stimulus intensities we employed, although these same cells did respond when the stimulus spot was moved to different regions. We conclude that in the basal pole active sites of rapid Ca2+ release have a lower functional affinity for InsP3 than those in the secretory pole and are spread out in discrete sites across the basal pole. These properties explain the propagation of Ca2+ waves across the basal pole that are only observed at higher stimulus levels. PMID:10922004

  18. Aerosols in healthy and emphysematous in silico pulmonary acinar rat models.

    PubMed

    Oakes, Jessica M; Hofemeier, Philipp; Vignon-Clementel, Irene E; Sznitman, Josué

    2016-07-26

    There has been relatively little attention given on predicting particle deposition in the respiratory zone of the diseased lungs despite the high prevalence of chronic obstructive pulmonary disease (COPD). Increased alveolar volume and deterioration of alveolar septum, characteristic of emphysema, may alter the amount and location of particle deposition compared to healthy lungs, which is particularly important for toxic or therapeutic aerosols. In an attempt to shed new light on aerosol transport and deposition in emphysematous lungs, we performed numerical simulations in models of healthy and emphysematous acini motivated by recent experimental lobar-level data in rats (Oakes et al., 2014a). Compared to healthy acinar structures, models of emphysematous subacini were created by removing inter-septal alveolar walls and enhancing the alveolar volume in either a homogeneous or heterogeneous fashion. Flow waveforms and particle properties were implemented to match the experimental data. The occurrence of flow separation and recirculation within alveolar cavities was found in proximal generations of the healthy zones, in contrast to the radial-like airflows observed in the diseased regions. In agreement with experimental data, simulations point to particle deposition concentrations that are more heterogeneously distributed in the diseased models compared with the healthy one. Yet, simulations predicted less deposition in the emphysematous models in contrast to some experimental studies, a likely consequence due to the shallower penetration depths and modified flow topologies in disease compared to health. These spatial-temporal particle transport simulations provide new insight on deposition in the emphysematous acini and shed light on experimental observations. PMID:26726781

  19. Apical Ca2+-activated potassium channels in mouse parotid acinar cells

    PubMed Central

    Almassy, Janos; Won, Jong Hak; Begenisich, Ted B.

    2012-01-01

    Ca2+ activation of Cl and K channels is a key event underlying stimulated fluid secretion from parotid salivary glands. Cl channels are exclusively present on the apical plasma membrane (PM), whereas the localization of K channels has not been established. Mathematical models have suggested that localization of some K channels to the apical PM is optimum for fluid secretion. A combination of whole cell electrophysiology and temporally resolved digital imaging with local manipulation of intracellular [Ca2+] was used to investigate if Ca2+-activated K channels are present in the apical PM of parotid acinar cells. Initial experiments established Ca2+-buffering conditions that produced brief, localized increases in [Ca2+] after focal laser photolysis of caged Ca2+. Conditions were used to isolate K+ and Cl− conductances. Photolysis at the apical PM resulted in a robust increase in K+ and Cl− currents. A localized reduction in [Ca2+] at the apical PM after photolysis of Diazo-2, a caged Ca2+ chelator, resulted in a decrease in both K+ and Cl− currents. The K+ currents evoked by apical photolysis were partially blocked by both paxilline and TRAM-34, specific blockers of large-conductance “maxi-K” (BK) and intermediate K (IK), respectively, and almost abolished by incubation with both antagonists. Apical TRAM-34–sensitive K+ currents were also observed in BK-null parotid acini. In contrast, when the [Ca2+] was increased at the basal or lateral PM, no increase in either K+ or Cl− currents was evoked. These data provide strong evidence that K and Cl channels are similarly distributed in the apical PM. Furthermore, both IK and BK channels are present in this domain, and the density of these channels appears higher in the apical versus basolateral PM. Collectively, this study provides support for a model in which fluid secretion is optimized after expression of K channels specifically in the apical PM. PMID:22291145

  20. Salinity, water hardness, and dissolved organic carbon modulate degradation of peracetic acid (PAA) compounds in aqueous solutions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peracetic acid (PAA) is used in aquaculture under different conditions for disinfection purposes. However, there is a lack of information about its environmental fate, particularly its persistence in aquatic systems with different chemistries. Therefore, the impact of water hardness, salinity, and d...

  1. Nanoparticle Loading Induced Morphological Transitions and Size Fractionation of Coassemblies from PS-b-PAA with Quantum Dots.

    PubMed

    Liu, Wei; Mao, Jun; Xue, Yanhu; Zhao, Ziliang; Zhang, Haishan; Ji, Xiangling

    2016-08-01

    Inorganic nanoparticles play a very important role in the fabrication and regulation of desirable hybrid structures with block copolymers. In this study, polystyrene-b-poly(acrylic acid) (PS48-b-PAA67) and oleic acid-capped CdSe/CdS core/shell quantum dots (QDs) are coassembled in tetrahydrofuran (THF) through gradual water addition. QDs are incorporated into the hydrophilic PAA blocks because of the strong coordination between PAA blocks and the surface of QDs. Increasing the weight fraction of QDs (ω = 0-0.44) leads to morphological transitions from hybrid spherical micelles to large compound micelles (LCMs) and then to bowl-shaped structures. The coassembly process is monitored using transmission electron microscopy (TEM). Formation mechanism of different morphologies is further proposed in which the PAA blocks bridging QDs manipulates the polymer chain mobility and the resulting morphology. Furthermore, the size and size distribution of assemblies serving as drug carriers will influence the circulation time, organ distribution and cell entry pathway of assemblies. Therefore, it is important to prepare or isolate assemblies with monodisperse or narrow size distribution for biomedical applications. Here, the centrifugation and membrane filtration techniques are applied to fractionate polydisperse coassemblies, and the results indicate that both techniques provide effective size fractionation. PMID:27447738

  2. Hygienisierung in der Fischzucht mittels Per-essigsäure (Disinfection of water with PAA: State of the investigations)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There are very few therapeutic agents against aquaculture ectoparasites in Germany. Peracetic Acid (PAA) has been referred to as the best disinfective agent in the world, but it has not been used much here in aquaculture. We currently use this compound in ‘treatment crisis’ situations because ther...

  3. Cerebellar atrophy and prognosis after temporal lobe resection.

    PubMed Central

    Specht, U; May, T; Schulz, R; Rohde, M; Ebner, A; Schmidt, R C; Schütz, M; Wolf, P

    1997-01-01

    OBJECTIVE: Experimental data indicate inhibitory effects of the cerebellum on seizure activity. Structural damage such as cerebellar atrophy, which is a common finding in patients with chronic epilepsy, may reduce these effects. METHODS: Outcome after temporal lobectomy was studied in 78 consecutive patients, with or without cerebellar atrophy diagnosed by MRI. RESULTS: Thirty five patients (45%) showed cerebellar atrophy. At a mean follow up of 14.6 (range, 6-40) months, 50 patients (64%) had no postoperative seizures. In these patients, the frequency of cerebellar atrophy was significantly lower (34%) than in patients who relapsed (64%, p < 0.01). Occurrence of generalised tonic-clonic seizures (GTCS) within two years before surgery, occurrence of GTCS at any time preoperatively, long duration of epilepsy, and older age at surgery were also associated with recurrence of seizures. Multiple logistic regression analysis suggested occurrence of GTCS within two years before surgery and cerebellar atrophy as the main predictive indicators. When both factors were present, the percentage of patients remaining seizure free since surgery fell to 30%, compared with 60% when only GTCS were present, 78.6% when only cerebellar atrophy was present, and 87.5% when both factors were absent. CONCLUSIONS: Cerebellar atrophy shown by MRI was a frequent finding in surgically treated patients with temporal lobe epilepsy. The presence of cerebellar atrophy seems to worsen the prognosis after temporal lobe resection. Images PMID:9153610

  4. Molecular events in skeletal muscle during disuse atrophy

    NASA Technical Reports Server (NTRS)

    Kandarian, Susan C.; Stevenson, Eric J.

    2002-01-01

    This review summarizes the current knowledge of the molecular processes underlying skeletal muscle atrophy due to disuse. Because the processes involved with muscle wasting due to illness are similar to disuse, this literature is used for comparison. Areas that are ripe for further study and that will advance our understanding of muscle atrophy are suggested.

  5. Functional role of an islet transcription factor, INSM1/IA-1, on pancreatic acinar cell trans-differentiation

    PubMed Central

    Zhang, Tao; Saunee, Nicolle A.; Breslin, Mary B.; Song, Kejing; Lan, Michael S.

    2011-01-01

    In this study, the functional role of INSM1 is examined with an AR42J acinar cell model for trans-differentiation into insulin-positive cells. Islet transcription factors (ITFs: INSM1, Pdx-1, and NeuroD1) are over-expressed in AR42J cells using adenoviral vectors. Addition of Ad-INSM1 alone or the combination of three ITFs to the AR42J cells triggers cellular trans-differentiation. Ectopic expression of INSM1 directly induces insulin, Pax6, and Nkx6.1 expression, whereas Pdx-1 and NeuroD1 were slightly suppressed by INSM1. Addition of Pdx-1 and NeuroD1 with INSM1 further enhances endocrine trans-differentiation by increasing both the numbers and intensity of the insulin positive cells with simultaneous activation of ITFs, Ngn3 and MafA. INSM1 expression alone partially inhibits dexamethasone-induced exocrine amylase expression. The combination of the three ITFs completely inhibits amylase expression and concomitantly induces greater acinar cell trans-differentiation into endocrine cells. Also, addition of the three ITFs promotes EGF and TGFβ receptors expression. Stimulation by the three ITFs along with the EGF/TGFβ growth factors strongly promotes insulin gene expression. The combination of the three ITFs and EGF/TGFβ growth factors with the primary cultured pancreatic acini also facilitates exocrine to endocrine cell differentiation. Taken together, both the AR42J cell line and the primary cultured mouse acinar cells support INSM1 induced acini trans-differentiation model. PMID:21830214

  6. Atp2c2 Is Transcribed From a Unique Transcriptional Start Site in Mouse Pancreatic Acinar Cells.

    PubMed

    Fenech, Melissa A; Sullivan, Caitlin M; Ferreira, Lucimar T; Mehmood, Rashid; MacDonald, William A; Stathopulos, Peter B; Pin, Christopher L

    2016-12-01

    Proper regulation of cytosolic Ca(2+) is critical for pancreatic acinar cell function. Disruptions in normal Ca(2+) concentrations affect numerous cellular functions and are associated with pancreatitis. Membrane pumps and channels regulate cytosolic Ca(2+) homeostasis by promoting rapid Ca(2+) movement. Determining how expression of Ca(2+) modulators is regulated and the cellular alterations that occur upon changes in expression can provide insight into initiating events of pancreatitis. The goal of this study was to delineate the gene structure and regulation of a novel pancreas-specific isoform for Secretory Pathway Ca(2+) ATPase 2 (termed SPCA2C), which is encoded from the Atp2c2 gene. Using Next Generation Sequencing of RNA (RNA-seq), chromatin immunoprecipitation for epigenetic modifications and promoter-reporter assays, a novel transcriptional start site was identified that promotes expression of a transcript containing the last four exons of the Atp2c2 gene (Atp2c2c). This region was enriched for epigenetic marks and pancreatic transcription factors that promote gene activation. Promoter activity for regions upstream of the ATG codon in Atp2c2's 24th exon was observed in vitro but not in in vivo. Translation from this ATG encodes a protein aligned with the carboxy terminal of SPCA2. Functional analysis in HEK 293A cells indicates a unique role for SPCA2C in increasing cytosolic Ca(2+) . RNA analysis indicates that the decreased Atp2c2c expression observed early in experimental pancreatitis reflects a global molecular response of acinar cells to reduce cytosolic Ca(2+) levels. Combined, these results suggest SPCA2C affects Ca(2+) homeostasis in pancreatic acinar cells in a unique fashion relative to other Ca(2+) ATPases. J. Cell. Physiol. 231: 2768-2778, 2016. © 2016 Wiley Periodicals, Inc. PMID:27017909

  7. Microfluidic formation of pH responsive 5CB droplets decorated with PAA-b-LCP.

    PubMed

    Khan, Waliullah; Choi, Jin Ho; Kim, Gyu Man; Park, Soo-Young

    2011-10-21

    We are reporting for the first time the pH responsiveness of liquid crystal (LC) microdroplets decorated with an amphiphilic block copolymer of PAA-b-LCP. We successfully demonstrated the adsorption of block copolymer on LC droplets by fluorescence microscopy and pH response to the radial-to-bipolar orientational change of the LC droplets by changing pH from 12 to 2 through the polarized optical microscope (POM). We believe that our results may pave the way for the generation of monodisperse droplets decorated by various amphiphilic block copolymers which respond to several kinds of the external stimuli. These developments may be important for potential applications of the LC droplets in sensing and encapsulation fields. PMID:21874196

  8. Synthesis and self-assembly of PAMAM/PAA Janus dendrimers

    NASA Astrophysics Data System (ADS)

    Gao, Chunmei; Liu, Mingzhu; Lü, Shaoyu; Zhang, Xinjie; Chen, Yuanmou

    2014-03-01

    Janus dendrimers have two differently functionalized segments which are located on opposite sides. They have many excellent properties and broad application prospects. In this study, poly(amido amine)/poly(acrylic acid) (PAMAM/PAA) Janus dendrimers were prepared by click chemistry. One of the first steps taken was the synthesis of N-Boc-G3.0 PAMAM dendrimers with primary amine groups at the periphery. Second, by amide coupling between propargylic acid and N-Boc-G3.0 PAMAM, PAMAM dendrimers with alkyne were successfully synthesized. After being dissolved in aqueous solutions with different pH, Janus dendrimers spontaneously form flowerlike micellar, Janus particles, and spherical micelles due to primary amino, tertiary amino, and carboxyl groups in the dendrimers. This self-assembly behavior depending on pH changes has a number of potential applications in the field of materials.

  9. Simulation of tissue atrophy using a topology preserving transformation model.

    PubMed

    Karaçali, Bilge; Davatzikos, Christos

    2006-05-01

    We propose a method to simulate atrophy and other similar volumetric change effects on medical images. Given a desired level of atrophy, we find a dense warping deformation that produces the corresponding levels of volumetric loss on the labeled tissue using an energy minimization strategy. Simulated results on a real brain image indicate that the method generates realistic images of tissue loss. The method does not make assumptions regarding the mechanics of tissue deformation, and provides a framework where a pre-specified pattern of atrophy can readily be simulated. Furthermore, it provides exact correspondences between images prior and posterior to the atrophy that can be used to evaluate provisional image registration and atrophy quantification algorithms. PMID:16689268

  10. Bone and muscle atrophy with suspension of the rat

    NASA Technical Reports Server (NTRS)

    Leblanc, A.; Marsh, C.; Evans, H.; Johnson, P.; Schneider, V.; Jhingran, S.

    1985-01-01

    In order to identify a suitable model for the study of muscle atrophy due to suspension in space, a modified version of the Morey tail suspension model was used to measure the atrophic responses of rat bone and muscle to 14-30 days of unloading of the hindlimbs. The progress of atrophy was measured by increases in methylene diphosphonate (MDP) uptake. It is found that bone uptake of methylene diphosphonate followed a phasic pattern similar to changes in the bone formation rate of immobilized dogs and cats. Increased MDP uptake after a period of 60 days indicated an accelerated bone metabolism. Maximum muscle atrophy in the suspended rats was distinctly different from immobilization atrophy. On the basis of the experimental results, it is concluded that the tail suspension model is an adequate simulation of bone atrophy due to suspension.

  11. Indices of Regional Brain Atrophy: Formulae and Nomenclature

    PubMed Central

    Arias-Carrión, Oscar

    2015-01-01

    The pattern of brain atrophy helps to discriminate normal age-related changes from neurodegenerative diseases. Albeit indices of regional brain atrophy have proven to be a parameter useful in the early diagnosis and differential diagnosis of some neurodegenerative diseases, indices of absolute regional atrophy still have some important limitations. We propose using indices of relative atrophy for representing how the volume of a given region of interest (ROI) changes over time in comparison to changes in global brain measures over the same time. A second problem in morphometric studies is terminology. There is a lack of systematization naming indices and the same measure can be named with different terms by different research groups or imaging softwares. This limits the understanding and discussion of studies. In this technological report, we provide a general description on how to compute indices of absolute and relative regional brain atrophy and propose a standardized nomenclature. PMID:26261753

  12. Covalently-layers of PVA and PAA and in situ formed Ag nanoparticles as versatile antimicrobial surfaces.

    PubMed

    Fragal, Vanessa H; Cellet, Thelma S P; Pereira, Guilherme M; Fragal, Elizângela H; Costa, Marco Antonio; Nakamura, Celso Vataru; Asefa, Tewodros; Rubira, Adley F; Silva, Rafael

    2016-10-01

    The in situ synthesis of silver nanoparticles (AgNPs) within covalently-modified poly(ethylene terephthalate) (PET) films possessing ultra-thin layer of poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA) is successfully demonstrated. The resulting polymeric films are shown to exhibit antimicrobial activities toward Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria and fungus (Candida albicans). To make the films, first PET surfaces were subject to photo-oxidation and subsequent solid-state grafting to attach a PVA layer, followed by a PAA layer. To synthesize the AgNPs inside the films, the PVA and PAA-modified PET was soaked in AgNO3 solution and the polymeric film was modified with the Ag(+) ions via Ag(+)-carboxylate interaction, and then the Ag(+) ions-containing polymer film was subject to either photo-reduction or thermal reduction processes. The PVA and PAA thin layers attached by covalent bonds to the PET surface uniquely promoted not only the in situ synthesis but also the stabilization of AgNPs. The formation of the AgNPs was confirmed by UV-vis spectroscopy or by monitoring the surface plasmon resonance (SPR) peak associated with AgNPs. The resulting PVA and PAA ultrathin layers modified and AgNPs containing PET served as bactericide and fungicide, inhibiting the growth of bacteria and fungi on the surfaces. Given PET's versatility and common use in many commercial processes, the method can be used for producing plastic surfaces with versatile antimicrobial and antibacterial properties. PMID:27196366

  13. DNA quantification as prognostic factor in a case of acinar cell carcinoma of the parotid gland, diagnosed by FNA.

    PubMed

    Azúa-Romeo, Javier; Sánchez-Garnica, Juan Carlos; Azúa-Blanco, Javier; Tovar-Lázaro, Mayte

    2005-01-01

    Hereby we present a case of a 43-years-old male who complained of a three years history preauricular painful mass. Fine needle aspiration cytology was performed, diagnosing of compatible with acinar cell carcinoma, thus DNA quantification by image cytometry was carried out. Biological parameters studied (ploidy, S-phase, 5-c exceeding rate) showed that it is a low grade of malignancy lesion. Total parotidectomy conservative of facial nerve was recommended, without regional lymphadenectomy. Patient remains, one year later, asymptomatic and free of disease. PMID:16056182

  14. Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge.

    PubMed

    Cash, David M; Frost, Chris; Iheme, Leonardo O; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B; Pennec, Xavier; Pierson, Ronald K; Gunter, Jeffrey L; Senjem, Matthew L; Jack, Clifford R; Guizard, Nicolas; Fonov, Vladimir S; Collins, D Louis; Modat, Marc; Cardoso, M Jorge; Leung, Kelvin K; Wang, Hongzhi; Das, Sandhitsu R; Yushkevich, Paul A; Malone, Ian B; Fox, Nick C; Schott, Jonathan M; Ourselin, Sebastien

    2015-12-01

    Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated "direct" measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the

  15. Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge

    PubMed Central

    Cash, David M.; Frost, Chris; Iheme, Leonardo O.; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B.; Pennec, Xavier; Pierson, Ronald K.; Gunter, Jeffrey L.; Senjem, Matthew L.; Jack, Clifford R.; Guizard, Nicolas; Fonov, Vladimir S.; Collins, D. Louis; Modat, Marc; Cardoso, M. Jorge; Leung, Kelvin K.; Wang, Hongzhi; Das, Sandhitsu R.; Yushkevich, Paul A.; Malone, Ian B.; Fox, Nick C.; Schott, Jonathan M.; Ourselin, Sebastien

    2015-01-01

    Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated “direct” measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the

  16. The neuropsychiatric profile of posterior cortical atrophy.

    PubMed

    Isella, Valeria; Villa, Giulia; Mapelli, Cristina; Ferri, Francesca; Appollonio, Ildebrando Marco; Ferrarese, Carlo

    2015-06-01

    We analyzed scores obtained at the Neuropsychiatric Inventory (NPI) by 20 patients with posterior cortical atrophy (PCA) and contrasted it with 20 patients having Alzheimer disease (AD). Patients with hallucinations and delusions were not included due to the high probability of a diagnosis of Lewy body disease. Prevalence of behavioral and psychological symptoms (BPSD) was 95% in the PCA group, the most frequent being apathy and anxiety. Cluster analysis on NPI subscales highlighted a behavioral subsyndrome characterized by agitated temper and irritability. Depression, anxiety, and apathy did not cluster with any other BPSD nor with each other. The PCA group showed a significantly higher proportion of anxious patients and worse anxiety score than patients with AD. No correlation was found between NPI data and demographic, clinical, or neuropsychological features nor were there significant differences for the same variables between anxious and nonanxious cases with PCA. In agreement with anecdotal reports, anxiety seems particularly relevant in PCA. PMID:25330926

  17. Cardiac atrophy in women following bed rest.

    PubMed

    Dorfman, Todd A; Levine, Benjamin D; Tillery, Tommy; Peshock, Ronald M; Hastings, Jeff L; Schneider, Suzanne M; Macias, Brandon R; Biolo, Gianni; Hargens, Alan R

    2007-07-01

    Both chronic microgravity exposure and long-duration bed rest induce cardiac atrophy, which leads to reduced standing stroke volume and orthostatic intolerance. However, despite the fact that women appear to be more susceptible to postspaceflight presyncope and orthostatic hypotension than male astronauts, most previous high-resolution studies of cardiac morphology following microgravity have been performed only in men. Because female athletes have less physiological hypertrophy than male athletes, we reasoned that they also might have altered physiological cardiac atrophy after bed rest. Magnetic resonance imaging was performed in 24 healthy young women (32.1 +/- 4 yr) to measure left ventricular (LV) and right ventricular (RV) mass, volumes, and morphology accurately before and after 60 days of 6 degrees head-down tilt (HDT) bed rest. Subjects were matched and then randomly assigned to sedentary bed rest (controls, n = 8) or two treatment groups consisting of 1) exercise training using supine treadmill running within lower body negative pressure plus resistive training (n = 8), or 2) protein (0.45 g x kg(-1) x day(-1) increase) plus branched-chain amino acid (BCAA) (7.2 g/day) supplementation (n = 8). After sedentary bed rest without nutritional supplementation, there were significant reductions in LV (96 +/- 26 to 77 +/- 25 ml; P = 0.03) and RV volumes (104 +/- 33 to 86 +/- 25 ml; P = 0.02), LV (2.2 +/- 0.2 to 2.0 +/- 0.2 g/kg; P = 0.003) and RV masses (0.8 +/- 0.1 to 0.6 +/- 0.1 g/kg; P < 0.001), and the length of the major axis of the LV (90 +/- 6 to 84 +/- 7 mm. P < 0.001), similar to what has been observed previously in men (8.0%; Perhonen MA, Franco F, Lane LD, Buckey JC, Blomqvist Zerwekh JE, Peshock RM, Weatherall PT, Levine BD. J Appl Physiol 91: 645-653, 2001). In contrast, there were no significant reductions in LV or RV volumes in the exercise-trained group, and the length of the major axis was preserved. Moreover, there were significant increases in

  18. Asymptomatic cerebellar atrophy after acute enteroviral encephalitis.

    PubMed

    Vitaszil, Edina; Kamondi, Anita; Csillik, Anita; Velkey, Imre; Szirmai, Imre

    2005-07-01

    We report on a 13-year-old male who had acute enteroviral encephalitis causing cerebellar symptoms at the age of 10 years. Magnetic resonance imaging (MRI) showed no abnormalities. Clinically he appeared to be recovered completely after 6 months. Twenty-three months after the recovery, MRI was performed because he presented with slight lower-limb and truncal ataxia experienced as lack of foot coordination while playing football or riding a bicycle. MRI demonstrated severe cerebellar atrophy. Clinically he recovered completely in 10 days. Only sophisticated electrophysiological methods revealed cerebellar dysfunction. The case provides evidence for the plasticity of cerebellar regulatory structures involved in the coordination of fine movements. It seems that in childhood the slow, isolated disintegration of cerebellar systems can be compensated for by upper thalamic or telencephalic connections, in a similar way to a congenital deficit of the cerebellum. PMID:15991870

  19. Cluster of Differentiation 38 (CD38) Mediates Bile Acid-induced Acinar Cell Injury and Pancreatitis through Cyclic ADP-ribose and Intracellular Calcium Release*

    PubMed Central

    Orabi, Abrahim I.; Muili, Kamaldeen A.; Javed, Tanveer A.; Jin, Shunqian; Jayaraman, Thottala; Lund, Frances E.; Husain, Sohail Z.

    2013-01-01

    Aberrant Ca2+ signals within pancreatic acinar cells are an early and critical feature in acute pancreatitis, yet it is unclear how these signals are generated. An important mediator of the aberrant Ca2+ signals due to bile acid exposure is the intracellular Ca2+ channel ryanodine receptor. One putative activator of the ryanodine receptor is the nucleotide second messenger cyclic ADP-ribose (cADPR), which is generated by an ectoenzyme ADP-ribosyl cyclase, CD38. In this study, we examined the role of CD38 and cADPR in acinar cell Ca2+ signals and acinar injury due to bile acids using pharmacologic inhibitors of CD38 and cADPR as well as mice deficient in Cd38 (Cd38−/−). Cytosolic Ca2+ signals were imaged using live time-lapse confocal microscopy in freshly isolated mouse acinar cells during perifusion with the bile acid taurolithocholic acid 3-sulfate (TLCS; 500 μm). To focus on intracellular Ca2+ release and to specifically exclude Ca2+ influx, cells were perifused in Ca2+-free medium. Cell injury was assessed by lactate dehydrogenase leakage and propidium iodide uptake. Pretreatment with either nicotinamide (20 mm) or the cADPR antagonist 8-Br-cADPR (30 μm) abrogated TLCS-induced Ca2+ signals and cell injury. TLCS-induced Ca2+ release and cell injury were reduced by 30 and 95%, respectively, in Cd38-deficient acinar cells compared with wild-type cells (p < 0.05). Cd38-deficient mice were protected against a model of bile acid infusion pancreatitis. In summary, these data indicate that CD38-cADPR mediates bile acid-induced pancreatitis and acinar cell injury through aberrant intracellular Ca2+ signaling. PMID:23940051

  20. Evidence that zymogen granules do not function as an intracellular Ca2+ store for the generation of the Ca2+ signal in rat parotid acinar cells.

    PubMed Central

    Nezu, Akihiro; Tanimura, Akihiko; Morita, Takao; Irie, Kazuharu; Yajima, Toshihiko; Tojyo, Yosuke

    2002-01-01

    Rat parotid acinar cells lacking zymogen granules were obtained by inducing granule discharge with the beta-adrenoceptor agonist isoproterenol. To assess whether zymogen granules are involved in the regulation of Ca(2+) signalling as intracellular Ca(2+) stores, changes in cytosolic free Ca(2+) ion concentration ([Ca(2+)](i)) were studied with imaging microscopy in fura-2-loaded parotid acinar cells lacking zymogen granules. The increase in [Ca(2+)](i) induced by muscarinic receptor stimulation was initiated at the apical pole of the acinar cells, and rapidly spread as a Ca(2+) wave towards the basolateral region. The magnitude of the [Ca(2+)](i) response and the speed of the Ca(2+) wave were essentially similar to those in control acinar cells containing zymogen granules. Western blot analysis of the inositol 1,4,5-trisphosphate receptor (IP(3)R) was performed on zymogen granule membranes and microsomes using anti-IP(3)R antibodies. The immunoreactivity of all three IP(3)Rs was clearly observed in the microsomal preparations. Although a weak band of IP(3)R type-2 was detected in the zymogen granule membranes, this band probably resulted from contamination by the endoplasmic reticulum (ER), because calnexin, a marker protein of the ER, was also detected in the same preparation. Furthermore, Western blotting and reverse transcriptase-PCR analysis failed to provide evidence for the expression of ryanodine receptors in rat parotid acinar cells, whereas expression was clearly detectable in rat skeletal muscle, heart and brain. These results suggest that zymogen granules do not have a critical role in Ca(2+) signalling in rat parotid acinar cells. PMID:11903047

  1. Crystallization and preliminary X-ray analysis of two variants of the Escherichia coli O157 ParE2-PaaA2 toxin-antitoxin complex.

    PubMed

    Sterckx, Yann G J; Haesaerts, Sarah; Van Melderen, Laurence; Loris, Remy

    2014-09-01

    The paaR2-paaA2-parE2 operon is a three-component toxin-antitoxin module encoded in the genome of the human pathogen Escherichia coli O157. The toxin (ParE2) and antitoxin (PaaA2) interact to form a nontoxic toxin-antitoxin complex. In this paper, the crystallization and preliminary characterization of two variants of the ParE2-PaaA2 toxin-antitoxin complex are described. Selenomethionine-derivative crystals of the full-length ParE2-PaaA2 toxin-antitoxin complex diffracted to 2.8 Å resolution and belonged to space group P41212 (or P43212), with unit-cell parameters a = b = 90.5, c = 412.3 Å. It was previously reported that the full-length ParE2-PaaA2 toxin-antitoxin complex forms a higher-order oligomer. In contrast, ParE2 and PaaA213-63, a truncated form of PaaA2 in which the first 12 N-terminal residues of the antitoxin have been deleted, form a heterodimer as shown by analytical gel filtration, dynamic light scattering and small-angle X-ray scattering. Crystals of the PaaA213-63-ParE2 complex diffracted to 2.7 Å resolution and belonged to space group P6122 (or P6522), with unit-cell parameters a = b = 91.6, c = 185.6 Å. PMID:25195911

  2. Transcriptional profile of a myotube starvation model of atrophy

    NASA Technical Reports Server (NTRS)

    Stevenson, Eric J.; Koncarevic, Alan; Giresi, Paul G.; Jackman, Robert W.; Kandarian, Susan C.

    2005-01-01

    Skeletal muscle wasting is a pervasive phenomenon that can result from a wide range of pathological conditions as well as from habitual muscular inactivity. The present work describes a cell-culture condition that induces significant atrophy in skeletal muscle C2C12 myotubes. The failure to replenish differentiation media in mature myotubes leads to rapid atrophy (53% in diameter), which is referred to here as starvation. Affymetrix microarrays were used to develop a transcriptional profile of control (fed) vs. atrophied (nonfed) myotubes. Myotube starvation was characterized by an upregulation of genes involved in translational inhibition, amino acid biosynthesis and transport, and cell cycle arrest/apoptosis, among others. Downregulated genes included several structural and regulatory elements of the extracellular matrix as well as several elements of Wnt/frizzled and TGF-beta signaling pathways. Interestingly, the characteristic transcriptional upregulation of the ubiquitin-proteasome system, calpains, and cathepsins known to occur in multiple in vivo models of atrophy were not seen during myotube starvation. With the exception of the downregulation of extracellular matrix genes, serine protease inhibitor genes, and the upregulation of the translation initiation factor PHAS-I, this model of atrophy in cell culture has a transcriptional profile quite distinct from any study published to date with atrophy in whole muscle. These data show that, although the gross morphology of atrophied muscle fibers may be similar in whole muscle vs. myotube culture, the processes by which this phenotype is achieved differ markedly.

  3. LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

    PubMed Central

    2013-01-01

    Introduction Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigated the effects of LOXL2 expression in normal mammary epithelial cells to gain insight into how LOXL2 mediates cancer progression. Methods LOXL2 was expressed in MCF10A normal human mammary epithelial cells. The 3D acinar morphogenesis of these cells was assessed, as well as the ability of the cells to form branching structures on extracellular matrix (ECM)-coated surfaces. Transwell-invasion assays were used to assess the invasive properties of the cells. Clinically relevant inhibitors of ErbB2, lapatinib and Herceptin (traztuzumab), were used to investigate the role of ErbB2 signaling in this model. A retrospective study on a previously published breast cancer patient dataset was carried out by using Disease Specific Genomic Analysis (DSGA) to investigate the correlation of LOXL2 mRNA expression level with metastasis and survival of ErbB2-positive breast cancer patients. Results Fluorescence staining of the acini revealed increased proliferation, decreased apoptosis, and disrupted polarity, leading to abnormal lumen formation in response to LOXL2 expression in MCF10A cells. When plated onto ECM, the LOXL2-expressing cells formed branching structures and displayed increased invasion. We noted that LOXL2 induced ErbB2 activation through reactive oxygen species (ROS) production, and ErbB2 inhibition by using Herceptin or lapatinib abrogated the effects of LOXL2 on MCF10A cells. Finally, we found LOXL2 expression to be correlated with decreased overall survival and metastasis-free survival in breast cancer patients with ErbB2-positive tumors. Conclusions These findings suggest that LOXL2 expression in normal epithelial cells can induce abnormal changes that resemble oncogenic transformation and cancer progression

  4. Delayed expression of large conductance K+ channels reshaping agonist-induced currents in mouse pancreatic acinar cells

    PubMed Central

    Oshiro, Takako; Takahashi, Hidenori; Ohsaga, Atsushi; Ebihara, Satoru; Sasaki, Hidetada; Maruyama, Yoshio

    2005-01-01

    Epithelial secretory cells display cell-specific mechanisms of fluid secretion and express large conductance voltage- and Ca2+-activated K+ (Maxi-K) channels that generate the membrane negativity for effective Cl− exit to the lumen. Rat and mouse pancreatic acinar cells had been thought to be peculiar in this sense because of the previously reported lack of Maxi-K channels. However, this view is not entirely correct as evidenced in the present paper. Searching for their presence in pancreatic acinar cells in mice from 5 to 84 weeks of age with patch-clamp current measurements, we demonstrated that the expression of Maxi-K channels is regulated in an age-associated manner after birth. The expression started at approximately 12 postnatal weeks and increased steadily up to 84 weeks. In support of this, RT-PCR could not detect mSlo mRNA, the Maxi-K gene, at either 7 or 8 weeks but could at 58 and 64 postnatal weeks. These results suggest that a key steering element for fluid secretion, the Maxi-K channel, is progressively re-organized in rodent pancreas. A pancreatic secretagogue, acetylcholine, evoked Maxi-K channel current overlapping to various degrees on the previously known current response. This suggests that the rise in internal Ca2+ activates Maxi-K channels which reshape the mode of secretagogue-evoked current response and contribute to Cl− driving in fluid secretion in an age-associated fashion. PMID:15611028

  5. Depletion of intracellular calcium stores activates a calcium conducting nonselective cation current in mouse pancreatic acinar cells.

    PubMed

    Krause, E; Pfeiffer, F; Schmid, A; Schulz, I

    1996-12-20

    Receptor-mediated Ca2+ release from inositol (1,4,5)-trisphosphate (IP3)-sensitive Ca2+ stores causes "capacitative calcium entry" in many cell types (Putney, J. W., Jr. (1986) Cell Calcium 7, 1-12; Putney, J. W., Jr. (1990) Cell Calcium 11, 611-624). We used patch-clamp and fluorescence techniques in isolated mouse pancreatic acinar cells to identify ion currents and cytosolic calcium concentrations under conditions in which intracellular Ca2+ stores were emptied. We found that depletion of Ca2+ stores activated a calcium-release-activated nonselective cation current (ICRANC) which did not discriminate between monovalent cations. ICRANC possessed a significant conductance for Ca2+ and Ba2+. It was not inhibited by La3+, Gd3+, Co2+, or Cd2+ but was completely abolished by flufenamic acid or genistein. In whole cell and cell-attached recordings, a 40-45 pS nonselective cation channel was identified which was activated by Ca2+ store depletion. Calcium entry as detected by single cell fluorescence measurements with fluo-3 or fura-2, showed the same pharmacological properties as ICRANC. We conclude that in mouse pancreatic acinar cells 40-45 pS nonselective cation channels serve as a pathway for capacitative Ca2+ entry. This entry pathway differs from the previously described ICRAC (Hoth, M., and Penner, R. (1992) Nature 355, 353-356) in its ion-selectivity, pharmacological profile, and single-channel conductance. PMID:8955076

  6. Quantitative description of the spatial arrangement of organelles in a polarised secretory epithelial cell: the salivary gland acinar cell

    PubMed Central

    MAYHEW, TERRY M.

    1999-01-01

    Previous quantitative descriptions of cellular ultrastructure have focused on spatial content (volume, surface area and number of organelles and membrane domains). It is possible to complement such descriptions by also quantifying spatial arrangements. Hitherto, applications of stereological methods for achieving this (notably, estimation of covariance and pair correlation functions) have been confined to organ and tissue levels. This study explores 3-dimensional subcellular arrangements of key organelles within acinar cells of rabbit parotid salivary glands, highly polarised epithelial cells specialised for exocrine secretion of α-amylase. It focuses on spatial arrangements of secretion product stores (zymogen granules), rough endoplasmic reticulum (RER) and mitochondria. Systematic random samples of electron microscopical fields of view from 3 rabbits were analysed using test grids bearing linear dipole probes of different sizes. Unbiased estimates of organelle volume densities were obtained by point counting and estimates of covariance and pair correlation functions by dipole counting. Plots of pair correlation functions against dipole length identified spatial arrangement differences between organelle types. Volumes within RER and mitochondrial compartments were positively correlated with themselves at distances below 4 μm and 2 μm respectively but were essentially randomly arranged at longer distances. In sharp contrast, zymogen granules were not randomly arranged. They were clustered at distances below 6–7 μm and more widely scattered at greater distances. These findings provide quantitative confirmation of the polarised arrangement of zymogen granules within acinar cells and further support for the relative invariance of biological organisation between subjects. PMID:10337960

  7. Botulinum Toxin and Muscle Atrophy: A Wanted or Unwanted Effect.

    PubMed

    Durand, Paul D; Couto, Rafael A; Isakov, Raymond; Yoo, Donald B; Azizzadeh, Babak; Guyuron, Bahman; Zins, James E

    2016-04-01

    While the facial rejuvenating effect of botulinum toxin type A is well known and widespread, its use in body and facial contouring is less common. We first describe its use for deliberate muscle volume reduction, and then document instances of unanticipated and undesirable muscle atrophy. Finally, we investigate the potential long-term adverse effects of botulinum toxin-induced muscle atrophy. Although the use of botulinum toxin type A in the cosmetic patient has been extensively studied, there are several questions yet to be addressed. Does prolonged botulinum toxin treatment increase its duration of action? What is the mechanism of muscle atrophy and what is the cause of its reversibility once treatment has stopped? We proceed to examine how prolonged chemodenervation with botulinum toxin can increase its duration of effect and potentially contribute to muscle atrophy. Instances of inadvertent botulinum toxin-induced atrophy are also described. These include the "hourglass deformity" secondary to botulinum toxin type A treatment for migraine headaches, and a patient with atrophy of multiple facial muscles from injections for hemifacial spasm. Numerous reports demonstrate that muscle atrophy after botulinum toxin type A treatment occurs and is both reversible and temporary, with current literature supporting the notion that repeated chemodenervation with botulinum toxin likely responsible for both therapeutic and incidental temporary muscle atrophy. Furthermore, duration of response may be increased with subsequent treatments, thus minimizing frequency of reinjection. Practitioners should be aware of the temporary and reversible effect of botulinum toxin-induced muscle atrophy and be prepared to reassure patients on this matter. PMID:26780946

  8. Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact.

    PubMed

    Rojas, Juan Ignacio; Patrucco, Liliana; Miguez, Jimena; Cristiano, Edgardo

    2016-03-01

    Multiple sclerosis (MS) was always considered as a white matter inflammatory disease. Today, there is an important body of evidence that supports the hypothesis that gray matter involvement and the neurodegenerative mechanism are at least partially independent from inflammation. Gray matter atrophy develops faster than white matter atrophy, and predominates in the initial stages of the disease. The neurodegenerative mechanism creates permanent damage and correlates with physical and cognitive disability. In this review we describe the current available evidence regarding brain atrophy and its consequence in MS patients. PMID:27050854

  9. Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy

    PubMed Central

    Iyer, Chitra C.; McGovern, Vicki L.; Wise, Dawnne O.; Glass, David J.; Burghes, Arthur H. M.

    2014-01-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx−/−–SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1. PMID:24656734

  10. Mechanisms of cisplatin-induced muscle atrophy

    SciTech Connect

    Sakai, Hiroyasu; Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara; Sato, Ken; Chiba, Yoshihiko; Yamazaki, Mitsuaki; Matoba, Motohiro; Narita, Minoru

    2014-07-15

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.

  11. Pervaporation separation of binary organic-aqueous liquid mixtures using crosslinked PVA membranes. I. Characterization of the reaction between PVA and PAA

    SciTech Connect

    Jiwon Rhim; Kewho Lee . Membranes and Separation Lab.); Minyoung Sohn; Hyeokjong Joo . Dept. of Polymer Science and Engineering)

    1993-10-20

    For the purpose of the water-selective membrane material development for pervaporation separation, poly(vinyl alcohol) (PVA) was crosslinked with a low molecular weight of poly(acrylic acid) (PAA). The crosslinking reactions between PVA and PAA were characterized through IR spectroscopy, differential scanning calorimetry (DSC), and tensile tests when varying the reaction conditions, that is, time, temperature, amounts of cross-linking agents, PAA. It was found that the crosslinking reaction was fast: in other words, that the reaction mainly occurred at the initial step of each reaction condition. The best reaction conditions for preparing the crosslinked PVA membranes were found to be: reaction time not over 1 h, reaction temperature in the range of 150-180 C. PAA contents of 15-20 wt% were found satisfactory with respect to the application areas.

  12. Abnormalities of fundus autofluorescence in pigmented paravenous chorioretinal atrophy.

    PubMed

    Hashimoto, Yuki; Kase, Satoru; Saito, Wataru; Ishida, Susumu

    2012-01-01

    The aim of this study is to investigate fundus autofluorescence (FAF) as well as fluorescein angiography (FA), indocyanine green angiography (IA), and optical coherence tomography (OCT) in a patient with pigmented paravenous chorioretinal atrophy (PPCRA). A funduscopic examination revealed chorioretinal atrophy along the paravenous area in both eyes. A marked bone spicule pigment clumping together with the atrophy was noted left eye. FA and IA showed a window defect and hypofluorescence, respectively, which exclusively corresponds to the atrophic area along the retinal vein area and the optic disc both eyes. FAF revealed geographic hypofluorescence along the paravenous and supranasal retinal areas. Hyperfluorescence was noted, which comparatively surrounded the hypofluorescence in the peripheral paravenous distribution. Hypofluorescence detected by FAF corresponded to the areas of retinal thinning and atrophy detected by OCT and FA. FAF is a useful examination in PPCRA, which can noninvasively demonstrate the distribution of deficit and dysfunction of retinal pigment epithelium. PMID:23264840

  13. Biochemical adaptations of antigravity muscle fibers to disuse atrophy

    NASA Technical Reports Server (NTRS)

    Booth, F. W.

    1978-01-01

    Studies are presented in four parts of this report. The four parts include; (1) studies to gain information on the molecular basis of atrophy by antigravity muscle; (2) studies on the work capacity of antigravity muscles during atrophy and during recovery from atrophy; (3) studies on recovery of degenerated antigravity fibers after removal of hind-limb casts; and (4) studies on the atrophy and recovery of bone. The philosophy of these studies was to identify the time sequence of events in the soleus muscle of the rat following immobilization of the hind limbs, so that the length of the soleus muscle within the fixed limb is less than its resting length. In two separate studies, no decline in the weight of the soleus muscle could be detected during the first 72 hours of limb immobilization.

  14. Circulating micrornas as potential biomarkers of muscle atrophy

    NASA Astrophysics Data System (ADS)

    Wang, Fei

    2016-07-01

    Noninvasive biomarkers with diagnostic value and prognostic applications have long been desired to replace muscle biopsy for muscle atrophy patients. Growing evidence indicates that circulating microRNAs are biomarkers to assess pathophysiological status. Here, we show that the medium levels of six muscle-specific miRNAs (miR-1/23a/206/133/499/208b, also known as myomiRs) were all elevated in the medium of starved C2C12 cell (P < 0.01). And, the level of miR-1 and miR-23a were all elevated in the serum of hindlimb unloaded mice (P < 0.01). miR-23a levels were negatively correlated with both muscle mass and muscle fiber cross section area in muscle atrophy patients, indicating that they might represent the degree of muscle atrophy. Collectively, our data indicated that circulating myomiRs could serve as promising biomarkers for muscle atrophy.

  15. Calculation of brain atrophy using computed tomography and a new atrophy measurement tool

    NASA Astrophysics Data System (ADS)

    Bin Zahid, Abdullah; Mikheev, Artem; Yang, Andrew Il; Samadani, Uzma; Rusinek, Henry

    2015-03-01

    Purpose: To determine if brain atrophy can be calculated by performing volumetric analysis on conventional computed tomography (CT) scans in spite of relatively low contrast for this modality. Materials & Method: CTs for 73 patients from the local Veteran Affairs database were selected. Exclusion criteria: AD, NPH, tumor, and alcohol abuse. Protocol: conventional clinical acquisition (Toshiba; helical, 120 kVp, X-ray tube current 300mA, slice thickness 3-5mm). Locally developed, automatic algorithm was used to segment intracranial cavity (ICC) using (a) white matter seed (b) constrained growth, limited by inner skull layer and (c) topological connectivity. ICC was further segmented into CSF and brain parenchyma using a threshold of 16 Hu. Results: Age distribution: 25-95yrs; (Mean 67+/-17.5yrs.). Significant correlation was found between age and CSF/ICC(r=0.695, p<0.01 2-tailed). A quadratic model (y=0.06-0.001x+2.56x10-5x2 ; where y=CSF/ICC and x=age) was a better fit to data (r=0.716, p < 0.01). This is in agreement with MRI literature. For example, Smith et al. found annual CSF/ICC increase in 58 - 94.5 y.o. individuals to be 0.2%/year, whereas our data, restricted to the same age group yield 0.3%/year(0.2-0.4%/yrs. 95%C.I.). Slightly increased atrophy among elderly VA patients is attributable to the presence of other comorbidities. Conclusion: Brain atrophy can be reliably calculated using automated software and conventional CT. Compared to MRI, CT is more widely available, cheaper, and less affected by head motion due to ~100 times shorter scan time. Work is in progress to improve the precision of the measurements, possibly leading to assessment of longitudinal changes within the patient.

  16. Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy.

    PubMed

    Shakespeare, Timothy J; Kaski, Diego; Yong, Keir X X; Paterson, Ross W; Slattery, Catherine F; Ryan, Natalie S; Schott, Jonathan M; Crutch, Sebastian J

    2015-07-01

    The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal 'visual dementia' and most common atypical Alzheimer's disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients' (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer's disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer's disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer's disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with 'sticky fixation'. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer's disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large saccadic intrusions

  17. Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy

    PubMed Central

    Kaski, Diego; Yong, Keir X. X.; Paterson, Ross W.; Slattery, Catherine F.; Ryan, Natalie S.; Schott, Jonathan M.; Crutch, Sebastian J.

    2015-01-01

    The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal ‘visual dementia’ and most common atypical Alzheimer’s disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients’ (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer’s disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer’s disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer’s disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with ‘sticky fixation’. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer’s disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large

  18. Novel therapeutic approaches in multiple system atrophy.

    PubMed

    Palma, Jose-Alberto; Kaufmann, Horacio

    2015-02-01

    Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein-containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprises cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflammatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchymal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review. PMID:24928797

  19. Spinal Muscular Atrophy: Current Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Kiselyov, Alex S.; Gurney, Mark E.

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord. SMA is caused by deletion and/or mutation of the survival motor neuron gene (SMN1) on chromosome 5q13. There are variable numbers of copies of a second, related gene named SMN2 located in the proximity to SMN1. Both genes encode the same protein (Smn). Loss of SMN1 and incorrect splicing of SMN2 affect cellular levels of Smn triggering death of motor neurons. The severity of SMA is directly related to the normal number of copies of SMN2 carried by the patient. A considerable effort has been dedicated to identifying modalities including both biological and small molecule agents that increase SMN2 promoter activity to upregulate gene transcription and produce increased quantities of full-length Smn protein. This review summarizes recent progress in the area and suggests potential target product profile for an SMA therapeutic.

  20. Prenatal prediction of spinal muscular atrophy.

    PubMed Central

    Daniels, R J; Suthers, G K; Morrison, K E; Thomas, N H; Francis, M J; Mathew, C G; Loughlin, S; Heiberg, A; Wood, D; Dubowitz, V

    1992-01-01

    Spinal muscular atrophy (SMA) is a common cause of inherited morbidity and mortality in childhood. The wide range of phenotypes in SMA, uncertainty regarding its mode of inheritance, and the suggestion of linkage heterogeneity have complicated the genetic counselling of parents of affected children. The locus responsible for autosomal recessive SMA has been mapped to 5q11.2-q13.3. The most likely order of loci is cen-D5S6-(SMA,D5S125)-(JK53CA1/2,D5S112)-D5S3 9-qter, with highly polymorphic loci being identified at JK53CA1/2 and D5S39. We describe linkage studies with another highly polymorphic locus, D5S127, that is closely linked to D5S39. This genetic map can be used as the basis for genetic counselling in families with autosomal recessive SMA. Appropriate allowance can be made for sporadic cases owing to non-inherited causes and for linkage heterogeneity or misdiagnoses. Images PMID:1348091

  1. Facilitating text reading in posterior cortical atrophy

    PubMed Central

    Rajdev, Kishan; Shakespeare, Timothy J.; Leff, Alexander P.; Crutch, Sebastian J.

    2015-01-01

    Objective: We report (1) the quantitative investigation of text reading in posterior cortical atrophy (PCA), and (2) the effects of 2 novel software-based reading aids that result in dramatic improvements in the reading ability of patients with PCA. Methods: Reading performance, eye movements, and fixations were assessed in patients with PCA and typical Alzheimer disease and in healthy controls (experiment 1). Two reading aids (single- and double-word) were evaluated based on the notion that reducing the spatial and oculomotor demands of text reading might support reading in PCA (experiment 2). Results: Mean reading accuracy in patients with PCA was significantly worse (57%) compared with both patients with typical Alzheimer disease (98%) and healthy controls (99%); spatial aspects of passages were the primary determinants of text reading ability in PCA. Both aids led to considerable gains in reading accuracy (PCA mean reading accuracy: single-word reading aid = 96%; individual patient improvement range: 6%–270%) and self-rated measures of reading. Data suggest a greater efficiency of fixations and eye movements under the single-word reading aid in patients with PCA. Conclusions: These findings demonstrate how neurologic characterization of a neurodegenerative syndrome (PCA) and detailed cognitive analysis of an important everyday skill (reading) can combine to yield aids capable of supporting important everyday functional abilities. Classification of evidence: This study provides Class III evidence that for patients with PCA, 2 software-based reading aids (single-word and double-word) improve reading accuracy. PMID:26138948

  2. Meibomian gland dysfunction: hyperkeratinization or atrophy?

    PubMed

    Jester, James V; Parfitt, Geraint J; Brown, Donald J

    2015-01-01

    Meibomian gland dysfunction (MGD) is the major cause of evaporative dry eye disease (EDED) and dysfunction is widely thought to mechanistically involve ductal hyperkeratinization, plugging and obstruction. This review re-evaluates the role of hyperkeratinization in MGD based on more recent findings from mouse models. In these studies, eyelids from normal young and old mice or mice exposed to desiccating stress were evaluated by immunofluorescent tomography and 3-dimensional reconstruction to evaluate gland volume, expression of hyperkeratinization markers and cell proliferation or stimulated Raman scattering (SRS) microscopy to assess lipid quality. Results indicate that aging mice show dropout of meibomian glands with loss of gland volume and a forward migration of the mucocutaneous junction anterior to the gland orifice; similar age-related changes that are detected in human subjects. Atrophic glands also showed evidence of epithelial plugging of the orifice without the presence of hyperkeratinization. Mice exposed to desiccating stress showed hyperproliferation of the meibomian gland and ductal dilation suggesting a marked increase in lipid synthesis. Lipid quality was also affected in EDED mice with an increase in the protein content of lipid within the duct of the gland. Overall, age-related changes in the mouse show similar structural and functional correlates with that observed in clinical MGD without evidence of hyperkeratinization suggesting that gland atrophy may be a major cause of EDED. The response of the meibomian gland to desiccating stress also suggest that environmental conditions may accelerate or potentiate age-related changes. PMID:26817690

  3. Preventable Sternocleidomastoid Muscular Atrophy after Neck Dissection

    PubMed Central

    Yamamoto, Nao; Sawai, Natsuko Yoshimura; Ishimoto, Shunsuke; Ogura, Hide; Aikawa, Tomonao; Kogo, Mikihiko

    2015-01-01

    Background: Modified radical neck dissection (mRND) [preserving the sternocleidomastoid muscle (SCM) and the spinal accessory nerve] and supraomohyoid neck dissection have become common surgical procedures for treating head and neck cancer. Postoperative severe asymmetry of the neck and severe atrophy of the SCM, however, have been demonstrated. Methods: Using computed tomographic images, cross-sectional areas of the SCMs were measured in 99 patients with carcinoma of the oral cavity who underwent unilateral mRND or supraomohyoid neck dissection. An asymmetry index was used. Results: Innervation to the SCM was preserved in 91 patients. The spinal accessory nerve and the innervation were sacrificed in 3 patients; the innervation was repaired in 5 patients. Sacrifice of innervation to the SCM resulted in extremely severe asymmetry. Repair of the innervation prevented severe asymmetry in 40%. Preservation of the innervation prevented severe asymmetry in 75% at the middle portion of the neck and in 56% at the lower portion after mRND. Conclusion: Preserving innervation to the SCM and gentle handling of the nerve during neck dissection could prevent severe asymmetry after neck dissection. PMID:26495217

  4. Multiple system atrophy: pathogenic mechanisms and biomarkers.

    PubMed

    Jellinger, Kurt A; Wenning, Gregor K

    2016-06-01

    Multiple system atrophy (MSA) is a unique proteinopathy that differs from other α-synucleinopathies since the pathological process resulting from accumulation of aberrant α-synuclein (αSyn) involves the oligodendroglia rather than neurons, although both pathologies affect multiple parts of the brain, spinal cord, autonomic and peripheral nervous system. Both the etiology and pathogenesis of MSA are unknown, although animal models have provided insight into the basic molecular changes of this disorder. Accumulation of aberrant αSyn in oligodendroglial cells and preceded by relocation of p25α protein from myelin to oligodendroglia results in the formation of insoluble glial cytoplasmic inclusions that cause cell dysfunction and demise. These changes are associated with proteasomal, mitochondrial and lipid transport dysfunction, oxidative stress, reduced trophic transport, neuroinflammation and other noxious factors. Their complex interaction induces dysfunction of the oligodendroglial-myelin-axon-neuron complex, resulting in the system-specific pattern of neurodegeneration characterizing MSA as a synucleinopathy with oligodendroglio-neuronopathy. Propagation of modified toxic αSyn species from neurons to oligodendroglia by "prion-like" transfer and its spreading associated with neuronal pathways result in a multi-system involvement. No reliable biomarkers are currently available for the clinical diagnosis and prognosis of MSA. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable diagnostic biomarkers and to deliver targets for effective treatment of this hitherto incurable disorder is urgently needed. PMID:27098666

  5. Novel Therapeutic Approaches in Multiple System Atrophy

    PubMed Central

    Palma, Jose-Alberto; Kaufmann, Horacio

    2014-01-01

    Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly, progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein–containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprise cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflamatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchimal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review. PMID:24928797

  6. Towards translational therapies for multiple system atrophy

    PubMed Central

    Kuzdas-Wood, Daniela; Stefanova, Nadia; Jellinger, Kurt A.; Seppi, Klaus; Schlossmacher, Michael G.; Poewe, Werner; Wenning, Gregor K.

    2014-01-01

    Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiopathogenesis manifesting with autonomic failure, parkinsonism, and ataxia in any combination. The underlying neuropathology affects central autonomic, striatonigral and olivopontocerebellar pathways and it is associated with distinctive glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) that contain aggregates of α-synuclein. Current treatment options are very limited and mainly focused on symptomatic relief, whereas disease modifying options are lacking. Despite extensive testing, no neuroprotective drug treatment has been identified up to now; however, a neurorestorative approach utilizing autologous mesenchymal stem cells has shown remarkable beneficial effects in the cerebellar variant of MSA. Here, we review the progress made over the last decade in defining pathogenic targets in MSA and summarize insights gained from candidate disease-modifying interventions that have utilized a variety of well-established preclinical MSA models. We also discuss the current limitations that our field faces and suggest solutions for possible approaches in cause-directed therapies of MSA. PMID:24598411

  7. Pancreatic atrophy and diabetes mellitus following blunt abdominal trauma.

    PubMed

    Edwards, Mary J; Crudo, David F; Carlson, Terri L; Pedersen, Anita M; Keller, Laura

    2013-02-01

    Following pancreatic trauma, loss of uninjured parenchyma as a result of surgical management is expected, and atrophy of parenchyma following nonoperative management has been described. While endocrine insufficiency as a sequela of pancreatic trauma has been reported in adults, it is not a described entity in children. We report a case of pancreatic atrophy following blunt injury in an 8 year old boy who presented 3 years later with diabetes mellitus. Further analysis revealed significant genetic predisposition to diabetes. PMID:23414880

  8. The ParE2–PaaA2 toxin–antitoxin complex from Escherichia coli O157 forms a heterodocecamer in solution and in the crystal

    PubMed Central

    Sterckx, Yann G. J.; Garcia-Pino, Abel; Haesaerts, Sarah; Jové, Thomas; Geerts, Lieselotte; Sakellaris, Viktor; Van Melderen, Laurence; Loris, Remy

    2012-01-01

    Escherichia coli O157 paaR2-paaA2-parE2 constitutes a unique three-component toxin–antitoxin (TA) module encoding a toxin (ParE2) related to the classic parDE family but with an unrelated antitoxin called PaaA2. The complex between PaaA2 and ParE2 was purified and characterized by analytical gel filtration, dynamic light scattering and small-angle X-ray scattering. It consists of a particle with a radius of gyration of 3.95 nm and is likely to form a heterododecamer. Crystals of the ParE2–PaaA2 complex diffract to 3.8 Å resolution and belong to space group P3121 or P3221, with unit-cell parameters a = b = 142.9, c = 87.5 Å. The asymmetric unit is consistent with a particle of around 125 kDa, which is compatible with the solution data. Therefore, the ParE2–PaaA2 complex is the largest toxin–antitoxin complex identified to date and its quaternary arrangement is likely to be of biological significance. PMID:22684081

  9. Kinetics of temperature response of PEO-b-PNIPAM-b-PAA triblock terpolymer aggregates and of their complexes with lysozyme

    DOE PAGESBeta

    Papagiannopoulos, Aristeidis; Meristoudi, Anastasia; Hong, Kunlun; Pispas, Stergios

    2015-12-18

    We present the kinetics of temperature response of a PEO-b-PNIPAM-b-PAA triblock terpolymer and of its complexes with lysozyme in aqueous solution. It is found that during the coil-to-globule transition of PNIPAM new bonds within the polymer aggregates are created, making the transition of the aggregates partially irreversible. This effect is also found for the protein loaded PEO-b-PNIPAM-b-PAA aggregates whereas in this case protein globules appear to enhance the formation of bonds, making the transition totally irreversible. The internal dynamics of both aggregates and complexes are “frozen” once the temperature is increased upon PINIPAM's LCST in water and remain so evenmore » when the temperature drops below LCST. As a result, we investigate the complexation kinetics of lysozyme and PEO-b-PNIPAM-b-PAA and observe that it occurs in two stages, one where protein globules adsorb on single pre-formed aggregates and one where protein globules cause inter-aggregate clustering.« less

  10. Kinetics of temperature response of PEO-b-PNIPAM-b-PAA triblock terpolymer aggregates and of their complexes with lysozyme

    SciTech Connect

    Papagiannopoulos, Aristeidis; Meristoudi, Anastasia; Hong, Kunlun; Pispas, Stergios

    2015-12-18

    We present the kinetics of temperature response of a PEO-b-PNIPAM-b-PAA triblock terpolymer and of its complexes with lysozyme in aqueous solution. It is found that during the coil-to-globule transition of PNIPAM new bonds within the polymer aggregates are created, making the transition of the aggregates partially irreversible. This effect is also found for the protein loaded PEO-b-PNIPAM-b-PAA aggregates whereas in this case protein globules appear to enhance the formation of bonds, making the transition totally irreversible. The internal dynamics of both aggregates and complexes are “frozen” once the temperature is increased upon PINIPAM's LCST in water and remain so even when the temperature drops below LCST. As a result, we investigate the complexation kinetics of lysozyme and PEO-b-PNIPAM-b-PAA and observe that it occurs in two stages, one where protein globules adsorb on single pre-formed aggregates and one where protein globules cause inter-aggregate clustering.

  11. Network structure of brain atrophy in de novo Parkinson's disease

    PubMed Central

    Zeighami, Yashar; Ulla, Miguel; Iturria-Medina, Yasser; Dadar, Mahsa; Zhang, Yu; Larcher, Kevin Michel-Herve; Fonov, Vladimir; Evans, Alan C; Collins, D Louis; Dagher, Alain

    2015-01-01

    We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation. DOI: http://dx.doi.org/10.7554/eLife.08440.001 PMID:26344547

  12. Rapamycin delays salivary gland atrophy following ductal ligation

    PubMed Central

    Bozorgi, S S; Proctor, G B; Carpenter, G H

    2014-01-01

    Salivary gland atrophy is a frequent consequence of head and neck cancer irradiation therapy but can potentially be regulated through the mammalian target of rapamycin (mTOR). Excretory duct ligation of the mouse submandibular gland provokes severe glandular atrophy causing activation of mTOR. This study aims to discover the effects of blocking mTOR signaling in ligation-induced atrophic salivary glands. Following 1 week of unilateral submandibular excretory duct ligation: gland weights were significantly reduced, 4E-BP1 and S6rp were activated, and tissue morphology revealed typical signs of atrophy. However, 3 days following ligation with rapamycin treatment, a selective mTOR inhibitor, gland weights were maintained, 4E-BP1 and S6rp phosphorylation was inhibited, and there were morphological signs of recovery from atrophy. However, following 5 and 7 days of ligation and rapamycin treatment, glands expressed active mTOR and showed signs of considerable atrophy. This evidence suggests that inhibition of mTOR by rapamycin delays ligation-induced atrophy of salivary glands. PMID:24675464

  13. FGFR1 inhibits skeletal muscle atrophy associated with hindlimb suspension

    PubMed Central

    Eash, John; Olsen, Aaron; Breur, Gert; Gerrard, Dave; Hannon, Kevin

    2007-01-01

    Background Skeletal muscle atrophy can occur under many different conditions, including prolonged disuse or immobilization, cachexia, cushingoid conditions, secondary to surgery, or with advanced age. The mechanisms by which unloading of muscle is sensed and translated into signals controlling tissue reduction remains a major question in the field of musculoskeletal research. While the fibroblast growth factors (FGFs) and their receptors are synthesized by, and intimately involved in, embryonic skeletal muscle growth and repair, their role maintaining adult muscle status has not been examined. Methods We examined the effects of ectopic expression of FGFR1 during disuse-mediated skeletal muscle atrophy, utilizing hindlimb suspension and DNA electroporation in mice. Results We found skeletal muscle FGF4 and FGFR1 mRNA expression to be modified by hind limb suspension,. In addition, we found FGFR1 protein localized in muscle fibers within atrophying mouse muscle which appeared to be resistant to atrophy. Electroporation and ectopic expression of FGFR1 significantly inhibited the decrease in muscle fiber area within skeletal muscles of mice undergoing suspension induced muscle atrophy. Ectopic FGFR1 expression in muscle also significantly stimulated protein synthesis in muscle fibers, and increased protein degradation in weight bearing muscle fibers. Conclusion These results support the theory that FGF signaling can play a role in regulation of postnatal skeletal muscle maintenance, and could offer potentially novel and efficient therapeutic options for attenuating muscle atrophy during aging, illness and spaceflight. PMID:17425786

  14. Insulation of a G protein-coupled receptor on the plasmalemmal surface of the pancreatic acinar cell

    PubMed Central

    1995-01-01

    Receptor desensitization is a key process for the protection of the cell from continuous or repeated exposure to high concentrations of an agonist. Well-established mechanisms for desensitization of guanine nucleotide-binding protein (G protein)-coupled receptors include phosphorylation, sequestration/internalization, and down-regulation. In this work, we have examined some mechanisms for desensitization of the cholecystokinin (CCK) receptor which is native to the pancreatic acinar cell, and have found the predominant mechanism to be distinct from these recognized processes. Upon fluorescent agonist occupancy of the native receptor, it becomes "insulated" from the effects of acid washing and becomes immobilized on the surface of the plasma membrane in a time- and temperature-dependent manner. This localization was assessed by ultrastructural studies using a colloidal gold conjugate of CCK, and lateral mobility of the receptor was assessed using fluorescence recovery after photobleaching. Of note, recent application of the same morphologic techniques to a CCK receptor-bearing Chinese hamster ovary cell line demonstrated prominent internalization via the clathrin-dependent endocytic pathway, as well as entry into caveolae (Roettger, B.F., R.U. Rentsch, D. Pinon, E. Holicky, E. Hadac, J.M. Larkin, and L.J. Miller, 1995, J. Cell Biol. 128: 1029-1041). These organelles are not observed to represent prominent compartments for the same receptor to traverse in the acinar cell, although fluorescent insulin is clearly internalized in these cells via receptor-mediated endocytosis. In this work, the rate of lateral mobility of the CCK receptor is observed to be similar in both cell types (1-3 x 10(-10) cm2/s), while the fate of the agonist-occupied receptor is quite distinct in each cell. This supports the unique nature of desensitization processes which occur in a cell-specific manner. A plasmalemmal site of insulation of this important receptor on the pancreatic acinar cell

  15. Chronic alcohol exposure exacerbates inflammation and triggers pancreatic acinar-to-ductal metaplasia through PI3K/Akt/IKK

    PubMed Central

    HUANG, XIN; LI, XUQI; MA, QINGYONG; XU, QINHONG; DUAN, WANXING; LEI, JIANJUN; ZHANG, LUN; WU, ZHENG

    2015-01-01

    Pancreatic acinar-to-ductal metaplasia (ADM) has been identified as an initiating event that can progress to pancreatic intraepithelial neoplasia (PanIN) or pancreatic ductal adenocarcinoma (PDAC). Acini transdifferentiation can be induced by persistent inflammation. Notably, compelling evidence has emerged that chronic alcohol exposure may trigger an inflammatory response of macrophages/monocytes stimulated by endotoxins. In the present study, we aimed to evaluate the role of inflammation induced by chronic alcohol and lipopolysaccharide (LPS) exposure in the progression of pancreatic ADM, as well as to elucidate the possible mechanisms involved. For this purpose, cultured macrophages were exposed to varying doses of alcohol for 1 week prior to stimulation with LPS. Tumor necrosis factor-α (TNF-α) and regulated upon activation, normal T cell expression and secreted (RANTES) expression were upregulated in the intoxicated macrophages with activated nuclear factor-κB (NF-κB). Following treatment with the supernatant of intoxicated macrophages, ADM of primary acinar cells was induced. Furthermore, the expression of TNF-α and RANTES, as well as the phosphatidylinositol-3-kinase (PI3K)/protein kinase B(Akt)/inhibitory κB kinase (IKK) signaling pathway have been proven to be involved in the ADM of acinar cells. Moreover, Sprague-Dawley (SD) rats were employed to further explore the induction of pancreatic ADM by chronic alcohol and LPS exposure in vivo. At the end of the treatment period, a number of physiological parameters, such as body weight, liver weight and pancreatic weight were reduced in the exposed rats. Plasma alcohol concentrations and oxidative stress levels in the serum, as well as TNF-α and RANTES expression in monocytes were also induced following chronic alcohol and LPS exposure. In addition, pancreatic ADM was induced through the PI3K/Akt/IKK signaling pathway by the augmented TNF-α and RANTES expression levels in the exposed rats. Overall, we

  16. Aqueous – Phase Synthesis of PAA in PVDF Membrane Pores for Nanoparticle Synthesis and Dichlorobiphenyl Degradation

    PubMed Central

    Smuleac, V.; Bachas, L.; Bhattacharyya, D.

    2009-01-01

    This paper deals with bimetallic (Fe/Pd) nanoparticle synthesis inside the membrane pores and application for catalytic dechlorination of toxic organic compounds form aqueous streams. Membranes have been used as platforms for nanoparticle synthesis in order to reduce the agglomeration, encountered in solution phase synthesis which leads to a dramatic loss of reactivity. The membrane support, polyvinylidene fluoride (PVDF) was modified by in situ polymerization of acrylic acid in aqueous phase. Subsequent steps included ion exchange with Fe2+, reduction to Fe0 with sodium borohydride and Pd deposition. Various techniques, such as STEM, EDX, FTIR and permeability measurements, were used for membrane characterization and showed that bimetallic (Fe/Pd) nanoparticles with an average size of 20-30 nm have been incorporated inside of the PAA-coated membrane pores. The Fe/Pd–modified membranes showed a high reactivity toward a model compound, 2, 2′-dichlorobyphenyl and a strong dependence of degradation on Pd (hydrogenation catalyst) content. The use of convective flow substantially reduces the degradation time: 43% conversion of dichlorobiphenyl to biphenyl can be achieved in less than 40 s residence time. Another important aspect is the ability to regenerate and reuse the Fe/Pd bimetallic systems by washing with a solution of sodium borohydride, because the iron becomes inactivated (corroded) as the dechlorination reaction proceeds. PMID:20161475

  17. Frequency-dependent magnetic susceptibility of magnetite and cobalt ferrite nanoparticles embedded in PAA hydrogel.

    PubMed

    van Berkum, Susanne; Dee, Joris T; Philipse, Albert P; Erné, Ben H

    2013-01-01

    Chemically responsive hydrogels with embedded magnetic nanoparticles are of interest for biosensors that magnetically detect chemical changes. A crucial point is the irreversible linkage of nanoparticles to the hydrogel network, preventing loss of nanoparticles upon repeated swelling and shrinking of the gel. Here, acrylic acid monomers are adsorbed onto ferrite nanoparticles, which subsequently participate in polymerization during synthesis of poly(acrylic acid)-based hydrogels (PAA). To demonstrate the fixation of the nanoparticles to the polymer, our original approach is to measure low-field AC magnetic susceptibility spectra in the 0.1 Hz to 1 MHz range. In the hydrogel, the magnetization dynamics of small iron oxide nanoparticles are comparable to those of the particles dispersed in a liquid, due to fast Néel relaxation inside the particles; this renders the ferrogel useful for chemical sensing at frequencies of several kHz. However, ferrogels holding thermally blocked iron oxide or cobalt ferrite nanoparticles show significant decrease of the magnetic susceptibility resulting from a frozen magnetic structure. This confirms that the nanoparticles are unable to rotate thermally inside the hydrogel, in agreement with their irreversible fixation to the polymer network. PMID:23673482

  18. Frequency-Dependent Magnetic Susceptibility of Magnetite and Cobalt Ferrite Nanoparticles Embedded in PAA Hydrogel

    PubMed Central

    van Berkum, Susanne; Dee, Joris T.; Philipse, Albert P.; Erné, Ben H.

    2013-01-01

    Chemically responsive hydrogels with embedded magnetic nanoparticles are of interest for biosensors that magnetically detect chemical changes. A crucial point is the irreversible linkage of nanoparticles to the hydrogel network, preventing loss of nanoparticles upon repeated swelling and shrinking of the gel. Here, acrylic acid monomers are adsorbed onto ferrite nanoparticles, which subsequently participate in polymerization during synthesis of poly(acrylic acid)-based hydrogels (PAA). To demonstrate the fixation of the nanoparticles to the polymer, our original approach is to measure low-field AC magnetic susceptibility spectra in the 0.1 Hz to 1 MHz range. In the hydrogel, the magnetization dynamics of small iron oxide nanoparticles are comparable to those of the particles dispersed in a liquid, due to fast Néel relaxation inside the particles; this renders the ferrogel useful for chemical sensing at frequencies of several kHz. However, ferrogels holding thermally blocked iron oxide or cobalt ferrite nanoparticles show significant decrease of the magnetic susceptibility resulting from a frozen magnetic structure. This confirms that the nanoparticles are unable to rotate thermally inside the hydrogel, in agreement with their irreversible fixation to the polymer network. PMID:23673482

  19. Short Stimulation of Electro-Responsive PAA/Fibrin Hydrogel Induces Collagen Production

    PubMed Central

    Rahimi, Nastaran; Swennen, Geertje; Verbruggen, Sanne; Scibiorek, Martyna; Molin, Daniel G.

    2014-01-01

    Acrylic acid/fibrin hydrogel can mechanically stimulate cells when an external electrical field is applied, enabling them to migrate and align throughout the depth of the gel. The ability of electro-responsive polyacrylic acid (PAA)/fibrin hydrogel to promote collagen production and remodeling has been investigated by three-dimensional (3D) culturing and conditioning of smooth muscle cells (SMCs). SMCs-seeded hydrogels were subjected to an alternating electrical field (0.06 V/mm) for 2 h for one, two, or three times per week during 4 weeks of culturing. Fluorescent images of collagen structure and accumulation, assessed by CNA-35 probe, showed increased collagen content (>100-fold at 1× stimulation/week) in the center of the hydrogels after 4 weeks of culture. The increase in collagen production correlated with increasing extracellular matrix gene expression and resulted in significantly improved mechanical properties of the stimulated hydrogels. Matrix metalloproteinase (MMP)-2 activity was also significantly enhanced by stimulation, which probably has a role in the reorganization of the collagen. Short stimulation (2 h) induced a favorable response in the cells and enhanced tissue formation and integrity of the scaffold by inducing collagen production. The presented set up could be used for conditioning and improving the functionality of current tissue-engineered vascular grafts. PMID:24341313

  20. Role of protein kinase C in caerulein induced expression of substance P and neurokinin-1-receptors in murine pancreatic acinar cells

    PubMed Central

    Koh, Yung-Hua; Tamizhselvi, Ramasamy; Moochhala, Shabbir; Bian, Jin-Song; Bhatia, Madhav

    2011-01-01

    Substance P (SP) is involved in the pathophysiology of acute pancreatitis (AP) via binding to its high-affinity receptor, neurokinin-1-receptor (NK1R). An up-regulation of SP and NK1R expression was observed in experimental AP and in caerulein-stimulated pancreatic acinar cells. However, the mechanisms that lead to this up-regulation are not fully understood. In this study, we showed the role of protein kinase C (PKC) in caerulein-induced SP and NK1R production in isolated mouse pancreatic acinar cells. Caerulein (10−7 M) stimulation rapidly activated the conventional PKC-α and novel PKC-δ as observed by the phosphorylation of these molecules. Pre-treatment of pancreatic acinar cells with Gö6976 (1–10 nM) and rottlerin (1–10 μM) inhibited PKC-α and PKC-δ phosphorylation, respectively, but not the other way round. At these concentrations used, PKC-α and PKC-δ inhibition reversed the caerulein-induced up-regulation of SP and NK1R, indicating an important role of PKCs in the modulation of SP and NK1R expression. Further experiments looking into signalling mechanisms showed that treatment of pancreatic acinar cells with both Gö6976 and rottlerin inhibited the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Inhibition of PKC-α or PKC-δ also affected caerulein-induced transcription factor activation, as represented by nuclear factor-κB and AP-1 DNA-binding activity. The findings in this study suggested that PKC is upstream of the mitogen-activated protein kinases and transcription factors, which then lead to the up-regulation of SP/NK1R expression in caerulein-treated mouse pancreatic acinar cells. PMID:20973912

  1. Ae4 (Slc4a9) Anion Exchanger Drives Cl- Uptake-dependent Fluid Secretion by Mouse Submandibular Gland Acinar Cells.

    PubMed

    Peña-Münzenmayer, Gaspar; Catalán, Marcelo A; Kondo, Yusuke; Jaramillo, Yasna; Liu, Frances; Shull, Gary E; Melvin, James E

    2015-04-24

    Transcellular Cl(-) movement across acinar cells is the rate-limiting step for salivary gland fluid secretion. Basolateral Nkcc1 Na(+)-K(+)-2Cl(-) cotransporters play a critical role in fluid secretion by promoting the intracellular accumulation of Cl(-) above its equilibrium potential. However, salivation is only partially abolished in the absence of Nkcc1 cotransporter activity, suggesting that another Cl(-) uptake pathway concentrates Cl(-) ions in acinar cells. To identify alternative molecular mechanisms, we studied mice lacking Ae2 and Ae4 Cl(-)/HCO3 (-) exchangers. We found that salivation stimulated by muscarinic and β-adrenergic receptor agonists was normal in the submandibular glands of Ae2(-/-) mice. In contrast, saliva secretion was reduced by 35% in Ae4(-/-) mice. The decrease in salivation was not related to loss of Na(+)-K(+)-2Cl(-) cotransporter or Na(+)/H(+) exchanger activity in Ae4(-/-) mice but correlated with reduced Cl(-) uptake during β-adrenergic receptor activation of cAMP signaling. Direct measurements of Cl(-)/HCO3 (-) exchanger activity revealed that HCO3 (-)-dependent Cl(-) uptake was reduced in the acinar cells of Ae2(-/-) and Ae4(-/-) mice. Moreover, Cl(-)/HCO3 (-) exchanger activity was nearly abolished in double Ae4/Ae2 knock-out mice, suggesting that most of the Cl(-)/HCO3 (-) exchanger activity in submandibular acinar cells depends on Ae2 and Ae4 expression. In conclusion, both Ae2 and Ae4 anion exchangers are functionally expressed in submandibular acinar cells; however, only Ae4 expression appears to be important for cAMP-dependent regulation of fluid secretion. PMID:25745107

  2. The language profile of Posterior Cortical Atrophy

    PubMed Central

    Crutch, Sebastian J.; Lehmann, Manja; Warren, Jason D.; Rohrer, Jonathan D.

    2015-01-01

    Background Posterior Cortical Atrophy (PCA) is typically considered to be a visual syndrome, primarily characterised by progressive impairment of visuoperceptual and visuospatial skills. However patients commonly describe early difficulties with word retrieval. This paper details the first systematic analysis of linguistic function in PCA. Characterising and quantifying the aphasia associated with PCA is important for clarifying diagnostic and selection criteria for clinical and research studies. Methods Fifteen patients with PCA, 7 patients with logopenic/phonological aphasia (LPA) and 18 age-matched healthy participants completed a detailed battery of linguistic tests evaluating auditory input processing, repetition and working memory, lexical and grammatical comprehension, single word retrieval and fluency, and spontaneous speech. Results Relative to healthy controls, PCA patients exhibited language impairments across all the domains examined, but with anomia, reduced phonemic fluency and slowed speech rate the most prominent deficits. PCA performance most closely resembled that of LPA patients on tests of auditory input processing, repetition and digit span, but was relatively stronger on tasks of comprehension and spontaneous speech. Conclusions The study demonstrates that in addition to the well-reported degradation of vision, literacy and numeracy, PCA is characterised by a progressive oral language dysfunction with prominent word retrieval difficulties. Overlap in the linguistic profiles of PCA and LPA, which are both most commonly caused by Alzheimer’s disease, further emphasises the notion of a phenotypic continuum between typical and atypical manifestations of the disease. Clarifying the boundaries between AD phenotypes has important implications for diagnosis, clinical trial recruitment and investigations into biological factors driving phenotypic heterogeneity in AD. Rehabilitation strategies to ameliorate the phonological deficit in PCA are required

  3. Morphometric studies of secretory granule formation in mouse pancreatic acinar cells. Dissecting the early structural changes following pilocarpine injection

    PubMed Central

    HAMMEL, ILAN; SHOR-HAZAN, OSNAT; ELDAR, TORA; AMIHAI, DINA; LEW, SYLVIA

    1999-01-01

    Secretory granule formation in pancreatic acinar cells is known to involve massive membrane flow. In previous studies we have undertaken morphometry of the regranulation mechanism in these cells and in mast cells as a model for cellular membrane movement. In our current work, electron micrographs of pancreatic acinar cells from ICR mice were taken at several time points after extensive degranulation induced by pilocarpine injection in order to investigate the volume changes of rough endoplasmic reticulum (RER), nucleus, mitochondria and autophagosomes. At 2–4 h after stimulation, when the pancreatic cells demonstrated a complete loss of granules, this was accompanied by an increased proportion of autophagosomal activity. This change primarily reflected a greatly increased proportion of profiles retaining autophagic vacuoles containing recognisable cytoplasmic structures such as mitochondria, granule profiles and fragments of RER. The mitochondrial structures reached a significant maximal size 4 h following injection (before degranulation 0.178±0.028 μm3; at 4 h peak value, 0.535±0.109 μm3). Nucleus size showed an early volume increase approaching a maximum value 2 h following degranulation. The regranulation span was thus divided into 3 stages. The first was the membrane remodelling stage (0–2 h). During this period the volume of the RER and secretory granules was greatly decreased. At the intermediate stage (2–4 h) a significant increase of the synthesis zone was observed within the nucleus. The volume of the mitochondria was increasing. At the last step, the major finding was a significant granule accumulation in parallel with an active Golgi zone. PMID:10227666

  4. Actin and non-muscle myosin II facilitate apical exocytosis of tear proteins in rabbit lacrimal acinar epithelial cells

    PubMed Central

    Jerdeva, Galina V.; Wu, Kaijin; Yarber, Francie A.; Rhodes, Christopher J.; Kalman, Daniel; Schechter, Joel E.; Hamm-Alvarez, Sarah F.

    2006-01-01

    Summary The acinar epithelial cells of the lacrimal gland exocytose the contents of mature secretory vesicles containing tear proteins at their apical membranes in response to secretagogues. Here we use time-lapse confocal fluorescence microscopy and fluorescence recovery after photobleaching to investigate the changes in actin filaments located beneath the apical membrane during exocytosis evoked by the muscarinic agonist, carbachol (100 μM). Time-lapse confocal fluorescence microscopy of apical actin filaments in reconstituted rabbit lacrimal acini transduced with replication-deficient adenovirus containing GFP-actin revealed a relatively quiescent apical actin array in resting acini. Carbachol markedly increased apical actin filament turnover and also promoted transient actin assembly around apparent fusion intermediates. Fluorescence recovery after photobleaching measurements revealed significant (p≤0.05) increases and decreases, respectively, in mobile fraction (Mf) and turnover times (t½) for apical actin filaments in carbachol-stimulated acini relative to untreated acini. The myosin inhibitors, 2,3-butanedione monoxime (BDM, 10 mM, 15 min) and ML-7 (40 μM, 15 min), significantly decreased carbachol-stimulated secretion of bulk protein and the exogenous secretory vesicle marker, syncollin-GFP; these agents also promoted accumulation of actin-coated structures which were enriched, in transduced acini, in syncollin-GFP, confirming their identity as fusion intermediates. Actin-coated fusion intermediates were sized consistent with incorporation of multiple rather than single secretory vesicles; moreover, BDM and ML-7 caused a shift towards formation of multiple secretory vesicle aggregates while significantly increasing the diameter of actin-coated fusion intermediates. Our findings suggest that the increased turnover of apical actin filaments and the interaction of actin with non-muscle myosin II assembled around aggregates of secretory vesicles facilitate

  5. Early and Degressive Putamen Atrophy in Multiple Sclerosis

    PubMed Central

    Krämer, Julia; Meuth, Sven G.; Tenberge, Jan-Gerd; Schiffler, Patrick; Wiendl, Heinz; Deppe, Michael

    2015-01-01

    Putamen atrophy and its long-term progress during disease course were recently shown in patients with multiple sclerosis (MS). Here we investigated retrospectively the time point of atrophy onset in patients with relapsing-remitting MS (RRMS). 68 patients with RRMS and 26 healthy controls (HC) were admitted to 3T MRI in a cross-sectional study. We quantitatively analyzed the putamen volume of individual patients in relation to disease duration by correcting for age and intracranial volume (ICV). Patient’s relative putamen volume (RPV), expressed in percent of ICV, was significantly reduced compared to HC. Based on the correlation between RPV and age, we computed the age-corrected RPV deviation (ΔRPV) from HC. Patients showed significantly negative ΔRPV. Interestingly, the age-corrected ΔRPV depended logarithmically on disease duration: Directly after first symptom manifestation, patients already showed a reduced RPV followed by a further degressive volumetric decline. This means that atrophy progression was stronger in the first than in later years of disease. Putamen atrophy starts directly after initial symptom manifestation or even years before, and progresses in a degressive manner. Due to its important role in neurological functions, early detection of putamen atrophy seems necessary. High-resolution structural MRI allows monitoring of disease course. PMID:26404239

  6. Intrathecal Injections in Children With Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Sethna, Navil; Farrow-Gillespie, Alan; Khandji, Alexander; Xia, Shuting; Bishop, Kathie M.

    2016-01-01

    Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post–lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture–related adverse event frequency was similar to that previously reported in children. PMID:26823478

  7. Astaxanthin intake attenuates muscle atrophy caused by immobilization in rats.

    PubMed

    Shibaguchi, Tsubasa; Yamaguchi, Yusuke; Miyaji, Nobuyuki; Yoshihara, Toshinori; Naito, Hisashi; Goto, Katsumasa; Ohmori, Daijiro; Yoshioka, Toshitada; Sugiura, Takao

    2016-08-01

    Astaxanthin is a carotenoid pigment and has been shown to be an effective inhibitor of oxidative damage. We tested the hypothesis that astaxanthin intake would attenuate immobilization-induced muscle atrophy in rats. Male Wistar rats (14-week old) were fed for 24 days with either astaxanthin or placebo diet. After 14 days of each experimental diet intake, the hindlimb muscles of one leg were immobilized in plantar flexion position using a plaster cast. Following 10 days of immobilization, both the atrophic and the contralateral plantaris muscles were removed and analyzed to determine the level of muscle atrophy along with measurement of the protein levels of CuZn-superoxide dismutase (CuZn-SOD) and selected proteases. Compared with placebo diet animals, the degree of muscle atrophy in response to immobilization was significantly reduced in astaxanthin diet animals. Further, astaxanthin supplementation significantly prevented the immobilization-induced increase in the expression of CuZn-SOD, cathepsin L, calpain, and ubiquitin in the atrophied muscle. These results support the postulate that dietary astaxanthin intake attenuates the rate of disuse muscle atrophy by inhibiting oxidative stress and proteolysis via three major proteolytic pathways. PMID:27482075

  8. Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations.

    PubMed

    Iwama, Kazuhiro; Sasaki, Masayuki; Hirabayashi, Shinichi; Ohba, Chihiro; Iwabuchi, Emi; Miyatake, Satoko; Nakashima, Mitsuko; Miyake, Noriko; Ito, Shuichi; Saitsu, Hirotomo; Matsumoto, Naomichi

    2016-06-01

    Cerebellar atrophy is recognized in various types of childhood neurological disorders with clinical and genetic heterogeneity. Genetic analyses such as whole exome sequencing are useful for elucidating the genetic basis of these conditions. Pathological recessive mutations in Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase (SEPSECS) have been reported in a total of 11 patients with pontocerebellar hypoplasia type 2, progressive cerebellocerebral atrophy or progressive encephalopathy, yet detailed clinical features are limited to only four patients. We identified two new families with progressive cerebellar atrophy, and by whole exome sequencing detected biallelic SEPSECS mutations: c.356A>G (p.Asn119Ser) and c.77delG (p.Arg26Profs*42) in family 1, and c.356A>G (p.Asn119Ser) and c.467G>A (p.Arg156Gln) in family 2. Their development was slightly delayed regardless of normal brain magnetic resonance imaging (MRI) in infancy. The progression of clinical symptoms in these families is evidently slower than in previously reported cases, and the cerebellar atrophy milder by brain MRI, indicating that SEPSECS mutations are also involved in milder late-onset cerebellar atrophy. PMID:26888482

  9. Predictive modeling of neuroanatomic structures for brain atrophy detection

    NASA Astrophysics Data System (ADS)

    Hu, Xintao; Guo, Lei; Nie, Jingxin; Li, Kaiming; Liu, Tianming

    2010-03-01

    In this paper, we present an approach of predictive modeling of neuroanatomic structures for the detection of brain atrophy based on cross-sectional MRI image. The underlying premise of applying predictive modeling for atrophy detection is that brain atrophy is defined as significant deviation of part of the anatomy from what the remaining normal anatomy predicts for that part. The steps of predictive modeling are as follows. The central cortical surface under consideration is reconstructed from brain tissue map and Regions of Interests (ROI) on it are predicted from other reliable anatomies. The vertex pair-wise distance between the predicted vertex and the true one within the abnormal region is expected to be larger than that of the vertex in normal brain region. Change of white matter/gray matter ratio within a spherical region is used to identify the direction of vertex displacement. In this way, the severity of brain atrophy can be defined quantitatively by the displacements of those vertices. The proposed predictive modeling method has been evaluated by using both simulated atrophies and MRI images of Alzheimer's disease.

  10. Adenovirus-mediated hAQP1 expression in irradiated mouse salivary glands causes recovery of saliva secretion by enhancing acinar cell volume decrease.

    PubMed

    Teos, L Y; Zheng, C-Y; Liu, X; Swaim, W D; Goldsmith, C M; Cotrim, A P; Baum, B J; Ambudkar, I S

    2016-07-01

    Head and neck irradiation (IR) during cancer treatment causes by-stander effects on the salivary glands leading to irreversible loss of saliva secretion. The mechanism underlying loss of fluid secretion is not understood and no adequate therapy is currently available. Delivery of an adenoviral vector encoding human aquaporin-1 (hAQP1) into the salivary glands of human subjects and animal models with radiation-induced salivary hypofunction leads to significant recovery of saliva secretion and symptomatic relief in subjects. To elucidate the mechanism underlying loss of salivary secretion and the basis for AdhAQP1-dependent recovery of salivary gland function we assessed submandibular gland function in control mice and mice 2 and 8 months after treatment with a single 15-Gy dose of IR (delivered to the salivary gland region). Salivary secretion and neurotransmitter-stimulated changes in acinar cell volume, an in vitro read-out for fluid secretion, were monitored. Consistent with the sustained 60% loss of fluid secretion following IR, a carbachol (CCh)-induced decrease in acinar cell volume from the glands of mice post IR was transient and attenuated as compared with that in cells from non-IR age-matched mice. The hAQP1 expression in non-IR mice induced no significant effect on salivary fluid secretion or CCh-stimulated cell volume changes, except in acinar cells from 8-month group where the initial rate of cell shrinkage was increased. Importantly, the expression of hAQP1 in the glands of mice post IR induced recovery of salivary fluid secretion and a volume decrease in acinar cells to levels similar to those in cells from non-IR mice. The initial rates of CCh-stimulated cell volume reduction in acinar cells from hAQP1-expressing glands post IR were similar to those from control cells. Altogether, the data suggest that expression of hAQP1 increases the water permeability of acinar cells, which underlies the recovery of fluid secretion in the salivary glands

  11. Whole-Brain Atrophy Rate in Idiopathic Parkinson's Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy

    PubMed Central

    Guevara, C.; Bulatova, K.; Barker, G. J.; Gonzalez, G.; Crossley, N.; Kempton, M. J.

    2016-01-01

    In multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), the absence of surrogate endpoints makes clinical trials long and expensive. We aim to determine annualized whole-brain atrophy rates (a-WBAR) in idiopathic Parkinson's disease (IPD), MSA, and PSP. Ten healthy controls, 20 IPD, 12 PSP, and 8 MSA patients were studied using a volumetric MRI technique (SIENA). In controls, the a-WBAR was 0.37% ± 0.28 (CI 95% 0.17–0.57), while in IPD a-WBAR was 0.54% ± 0.38 (CI 95% 0.32–0.68). The IPD patients did not differ from the controls. In PSP, the a-WBAR was 1.26% ± 0.51 (CI 95%: 0.95–1.58). In MSA, a-WBAR was 1.65% ± 1.12 (CI 95%: 0.71–2.59). MSA did not differ from PSP. The a-WBAR in PSP and MSA were significantly higher than in the IPD group (p = 0.004 and p < 0.001, resp.). In PSP, the use of a-WBAR required one-half of the patients needed for clinical scales to detect a 50% reduction in their progression. In MSA, one-quarter of the patients would be needed to detect the same effect. a-WBAR is a reasonable candidate to consider as a surrogate endpoint in short clinical trials using smaller sample sizes. The confidence intervals for a-WBAR may add a potential retrospective application for a-WBAR to improve the diagnostic accuracy of MSA and PSP versus IPD. PMID:27190673

  12. Argyrophilic ubiquitinated cytoplasmic inclusions of Leu-7-positive glial cells in olivopontocerebellar atrophy (multiple system atrophy).

    PubMed

    Kato, S; Nakamura, H; Hirano, A; Ito, H; Llena, J F; Yen, S H

    1991-01-01

    We described cytoplasmic inclusions in glial cells in 18 patients with olivopontocerebellar atrophy (OPCA) (multiple system atrophy, MSA). These glial inclusions showed intense argyrophilia with modified Bielschowsky's and Bodian's silver impregnation techniques, and were observed in the pons, cerebellar white matter, midbrain, medulla oblongata and basal ganglia, as well as cerebral white matter and spinal cord. None of the 54 control cases had glial argyrophilic inclusions. Immunohistochemically, these inclusions were intensely labeled by anti-ubiquitin antibody. Some of them reacted with an antibody to Rosenthal fiber (RF) protein. The cytoplasm of ubiquitinated inclusion-bearing glial cells was immunostained by anti-Leu-7 antibody, but not by anti-GFAP antibody. Ultrastructurally, the glial inclusions were composed primarily of approximately 24- to 40-nm fibrils, which were coated with osmiophilic granular material along their length in longitudinal section. These fibrils appeared as annuli in cross section. Often, a central granule approximately 5 nm in diameter was seen in the lucent lumen of a cross-sectioned fibril. The granule-coated fibrils were not seen in the glial filament-containing astrocytes. Electron microscopic examination of silver-impregnated specimens revealed that the granule-coated fibrils had strong affinity for silver. Immunoelectron microscopy using the indirect immunoperoxidase techniques with antibodies to ubiquitin and RF protein revealed that the electron-dense reaction products respective to both were located on constituents of glial inclusions. Our observation that Leu-7-positive glial cells, mainly oligodendroglial cells, had argyrophilic ubiquitinated inclusions may be of significance for the evaluation of the pathology of OPCA(MSA). PMID:1723828

  13. Tongue atrophy and fasciculations in transthyretin familial amyloid neuropathy

    PubMed Central

    Mozaffar, Tahseen

    2015-01-01

    Objective: Macroglossia is a well-known feature of amyloidosis; however, tongue atrophy and fasciculations are rarely seen and can lead to the misdiagnosis of amyotrophic lateral sclerosis (ALS). Methods: We identified 2 unrelated patients with atypical features of tongue atrophy and fasciculations in the setting of a severe neuropathy. Results: Both patients were confirmed to have transthyretin-related familial amyloid polyneuropathy (TTR-FAP) by genetic testing. Conclusions: TTR-FAP should be considered as a possible mimicker of ALS when tongue atrophy and fasciculations are seen in the setting of a severely progressive polyneuropathy. Other atypical mimickers of ALS include polyglucosan body disease, hexosaminidase A deficiency, multisystem proteinopathy, and Allgrove syndrome. PMID:27066555

  14. Pathomechanisms of atrophy in insular cortex in Alzheimer's disease.

    PubMed

    Moon, Yeonsil; Moon, Won-Jin; Han, Seol-Heui

    2015-08-01

    The insular cortex is associated with neuropsychiatric symptoms, changes in cardiovascular and autonomic control, and mortality in Alzheimer's dementia. However, the insular cortex does not provide information on the contribution of the other cortices to cognitive decline. We hypothesized that the factors that affect to atrophy in insular cortex are different from other cortical regions. A total of 42 patients with probable Alzheimer's dementia were included in the analyses. The manual drawing of regions of interest was used to detect insular cortex located in the deep gray matter and to avoid coatrophy. Covariates, which could affect to the atrophy of the cerebral cortex, were selected based on previous studies. Any of the demographic factors, vascular risk factors, and the severity scales of dementia was not associated with any insular volume ratio. We suggest that the pathomechanisms of atrophy in insular cortex are different from those of other cortex regions in Alzheimer's disease. PMID:25596207

  15. Progressive Hemifacial Atrophy With Contralateral Uveitis: A Case Report

    PubMed Central

    Ayyildiz, Onder; Ayyildiz, Simel; Durukan, Ali Hakan; Sobaci, Gungor

    2015-01-01

    Introduction: Progressive hemifacial atrophy, known as Parry-Romberg syndrome (PRS), was first described by Parry in 1825. There is a progressive atrophy of facial tissues including skin, bones and muscles. Ophthalmic disorders are common and include keratitis, uveitis, cataract, ipsilateral enophthalmos, optic neuritis, retinal vasculitis and scleral melting. Case Presentation: We describe a patient with progressive hemifacial atrophy at right facial side who developed granulomatous uveitis and periferic retinal vasculitis in his left eye. We started topical and systemic steroid therapy. Uveitic reaction had regressed almost entirely after a 3-month steroid treatment. Conclusions: The individuals should have multidisciplinary approach for the variety of disorders to maintain the appropriate treatment for a better appearance of the patients. PMID:26473067

  16. Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis.

    PubMed

    MacKenzie-Graham, Allan J; Rinek, Gilda A; Avedisian, Andrea; Morales, Laurie B; Umeda, Elizabeth; Boulat, Benoit; Jacobs, Russell E; Toga, Arthur W; Voskuhl, Rhonda R

    2012-07-01

    Gray matter atrophy is an important correlate to clinical disability in multiple sclerosis (MS), and many treatment trials include atrophy as an outcome measure. Atrophy has been shown to occur in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The clinical severity of EAE is reduced in estrogen-reated mice, but it remains unknown whether estrogen treatment can reduce gray matter atrophy in EAE. In this study, mice with EAE were treated with either estrogen receptor (ER)-α ligand or ER-β ligand, and diffusion tensor images (DTI) were collected and neuropathology was performed. DTI showed atrophy in the cerebellar gray matter of vehicle-treated EAE mice compared with healthy controls but not in ER-α or ER-β ligand-treated EAE mice. Neuropathology demonstrated that Purkinje cell numbers were decreased in vehicle-treated EAE mice, whereas neither ER ligand-treated EAE groups showed a decrease. This is the first report of a neuroprotective therapy in EAE that unambiguously prevents gray matter atrophy while sparing a major neuronal cell type. Fractional anisotropy (FA) in the cerebellar white matter was decreased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Inflammatory cell infiltration was increased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Myelin staining was decreased in vehicle-treated EAE mice and was spared in both ER ligand-treated groups. This is consistent with decreased FA as a potential biomarker for inflammation rather than myelination or axonal damage in the cerebellum in EAE. PMID:22411609

  17. Muscle ring finger 1 mediates cardiac atrophy in vivo.

    PubMed

    Willis, Monte S; Rojas, Mauricio; Li, Luge; Selzman, Craig H; Tang, Ru-Hang; Stansfield, William E; Rodriguez, Jessica E; Glass, David J; Patterson, Cam

    2009-04-01

    Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in two independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression after reversal of transaortic constriction (TAC) reversal and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analyses, we found that upon TAC release, cardiac mass and cardiomyocyte cross-sectional areas in MuRF1(-/-) mice decreased approximately 70% less than in wild type mice in the 4 wk after release. This was in striking contrast to wild-type mice, who returned to baseline cardiac mass and cardiomyocyte size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by beta-myosin heavy chain, smooth muscle actin, and brain natriuretic peptide was attenuated similarly in both MuRF1(-/-) and wild-type hearts after TAC release. In the second model, MuRF1(-/-) mice also displayed resistance to dexamethasone-induced cardiac atrophy, as determined by echocardiographic analysis. This study demonstrates, for the first time, that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic

  18. Olivopontocerebellar atrophy of neonatal onset and disialotransferrin developmental deficiency syndrome.

    PubMed Central

    Horslen, S P; Clayton, P T; Harding, B N; Hall, N A; Keir, G; Winchester, B

    1991-01-01

    Two brothers presented with olivopontocerebellar atrophy of neonatal onset. The clinical features (failure to thrive, hypotonia, liver disease, effusions, and visual inattention) were similar to those of the four cases already reported, as were the necropsy findings of olivopontocerebellar atrophy, hepatic steatosis and fibrosis, and microcystic renal changes. The clinical similarities between this and the disialotransferrin developmental deficiency syndrome were noted. The characteristic abnormality of serum transferrin found in the latter syndrome was also found in the two cases reported here. We suggest that both syndromes are caused by the same, or related, defects in glycoprotein metabolism. Images Figure 2 p1028-b Figure 3 p1029-b Figure 4 PMID:1929507

  19. [A Case of Musicophilia with Right Predominant Temporal Lobe Atrophy].

    PubMed

    Shinagawa, Shunichiro; Nakayama, Kazuhiko

    2015-11-01

    A 68-year-old woman exhibiting musicophilia with right predominant temporal lobe atrophy happened to visit our clinic. She had no musical background, but beginning two years ago, she acquired a strong preference for especially popular music and sometimes sang at home. She did not exhibit obvious semantic aphasia or facial agnosia, and showed only mild behavioral changes including apathy. Her musicophilia can be explained as an instance of stereotypical behavior. Her right temporal lobe atrophy may have caused changes in her emotional and reward systems, resulting in her music specific behaviors. PMID:26560960

  20. Respiratory management of spinal muscular atrophy type 2.

    PubMed

    Gormley, Maurade C

    2014-12-01

    Respiratory insufficiency is the primary cause of morbidity and mortality among patients with spinal muscular atrophy type 2. The primary complications include ineffective cough with decreased airway clearance, nocturnal hypoventilation, diminished lung and chest wall development, and increased risk for pulmonary infection. Respiratory devices including mechanical insufflator-exsufflator and bilevel positive airway pressure are the primary devices of respiratory maintenance and treatment and are associated with decreased morbidity and fewer hospital admissions. This article discusses the primary respiratory complications of spinal muscular atrophy type 2 and the role of respiratory interventions to promote growth and development, improve cough efficacy, reverse nocturnal hypoventilation, and prevent and treat pulmonary infection. PMID:25365058

  1. Late onset GM2 gangliosidosis mimicking spinal muscular atrophy.

    PubMed

    Jamrozik, Z; Lugowska, A; Gołębiowski, M; Królicki, L; Mączewska, J; Kuźma-Kozakiewicz, M

    2013-09-25

    A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally. PMID:23820084

  2. Vulvar and Vaginal Atrophy: Physiology, Clinical Presentation, and Treatment Considerations.

    PubMed

    Lev-Sagie, Ahinoam

    2015-09-01

    Vulvovaginal atrophy is a common condition associated with decreased estrogenization of the vaginal tissue. Symptoms include vaginal dryness, irritation, itching, soreness, burning, dyspareunia, discharge, urinary frequency, and urgency. It can occur at any time in a woman's life cycle, although more commonly in the postmenopausal phase, during which the prevalence is approximately 50%. Despite the high prevalence and the substantial effect on quality of life, vulvovaginal atrophy often remains underreported and undertreated. This article aims to review the physiology, clinical presentation, assessment, and current recommendations for treatment, including aspects of effectiveness and safety of local vaginal estrogen therapies. PMID:26125962

  3. Lactic acidosis associated with cerebellar vermal atrophy and cardiomyopathy.

    PubMed

    Challa, V R; Markesbery, W R; Baumann, R J; Noonan, J A

    1978-08-01

    The association of fluctuating neurological signs and congestive cardiomyopathy with chronic lactic acidosis is described in a 5 1/2 year-old-boy who ultimately succumbed to congestive heart failure. The autopsy findings included severe atrophy of the anterior cerebellar vermis and a hypertrophied heart with left sided endocardial fibroelastosis. Skeletal and cardial muscle calcification was prominent and probably due to the effect of intracellular metabolic alterations associated with lactic acidosis. A review of the literature shows that the combination of cardiomyopathy, isolated atrophy of cerebellar vermis and muscle fiber calcification have not been reported in association with idiopathic lactic acidosis previously. PMID:152418

  4. Differentially expressed microRNA identification and target gene function analysis in starvation-induced autophagy of AR42J pancreatic acinar cells.

    PubMed

    Gao, Bo; Wang, Duanping; Sun, Wang; Meng, Xianzhi; Zhang, Weihui; Xue, Dongbo

    2016-07-01

    Acute pancreatitis (AP) is a common acute digestive tract disease, with increased morbidity and mortality, and an unclear pathogenesis. Trypsinogen activation in pancreatic acinar cells may be the primary mechanism underlying the development of AP. Previous studies reported that autophagy participates in the formation of acinar cell vacuoles in AP and in the process of trypsinogen activation as an important cause of AP. Furthermore, microRNAs (miRNAs) maintain the autophagy process by regulating the expression of autophagy‑associated genes. In the present study, an in vitro pancreatic acinar cell autophagy model was established using the AR42J starvation‑induced pancreatic acinar cell line. Twenty differentially expressed microRNAs were identified using miRNA microarray. Bioinformatics analysis was used to predict the target genes of miRNAs and analyze the functions of differentially expressed miRNAs. The results demonstrated that only the downregulated miRNA rno‑miR‑148b‑3p predicted 593 target genes with a statistical significance (P<0.05), from which 10 genes were autophagy‑associated. The results of gene ontology and pathway analyses demonstrated that the target genes of miRNAs were enriched in the Response to insulin stimulus, Regulation of cell death and the Insulin signaling pathways (P<0.05, FDR<0.05). In addition, protein‑protein interaction network analysis demonstrated a widespread interaction among the 593 target genes. The results of the present study may provide novel targets for research on the mechanisms of autophagy-promoted AP and AP treatment. PMID:27175615

  5. Clinicopathologic study of 62 acinar cell carcinomas of the pancreas: insights into the morphology and immunophenotype and search for prognostic markers.

    PubMed

    La Rosa, Stefano; Adsay, Volkan; Albarello, Luca; Asioli, Sofia; Casnedi, Selenia; Franzi, Francesca; Marando, Alessandro; Notohara, Kenji; Sessa, Fausto; Vanoli, Alessandro; Zhang, Lizhi; Capella, Carlo

    2012-12-01

    Acinar cell carcinoma (ACC) of the pancreas is a very rare tumor that has various morphologic features, which may give rise to diagnostic difficulties. Because of its rarity, many clinicopathologic characteristics remain to be further elucidated, and prognostic factors are yet to be well established. With the aim of better characterizing this carcinoma and searching for prognostic indicators, we collected 62 ACCs and investigated the following parameters: site, size, local infiltration, node and distant metastases, architectural pattern, nuclear atypia, presence of necrosis, lymphovascular and perineural invasion, proliferation, BCL10, trypsin, carboxyl ester lipase, amylase, lipase, PDX1, cytokeratin 19 (CK19), CK7, p53, and β-catenin expression. Twelve cases showing >30% of endocrine cells were reclassified as mixed acinar-neuroendocrine carcinomas, whereas 1 tumor was reclassified as a mixed ductal-acinar carcinoma and was excluded from the statistical prognostic evaluations. BCL10 and trypsin were the most reliable immunohistochemical markers, whereas amylase and lipase were not. Surgery was statistically correlated with a better prognosis (P=0.0008). Among resected tumors there was no difference in survival between ACCs and mixed acinar-neuroendocrine carcinomas, and factors that significantly correlated with poor prognosis were size >6.5 cm (P=0.004), lymph node (P=0.0039) and distant (P=0.008) metastases, and UICC stage (P=0.009). Stage was the only independent prognostic factor at multivariable analysis, and the best prognostic discrimination was observed on grouping together stages I and II and grouping together stages III and IV, suggesting a simplification of the UICC staging for such cancers. In addition, vascular and perineural invasion and CK19 and p53 expression showed a trend for poor prognosis, not reaching statistical significance. PMID:23026929

  6. HCO3(-) secretion by murine nasal submucosal gland serous acinar cells during Ca2+-stimulated fluid secretion.

    PubMed

    Lee, Robert J; Harlow, Janice M; Limberis, Maria P; Wilson, James M; Foskett, J Kevin

    2008-07-01

    Airway submucosal glands contribute to airway surface liquid (ASL) composition and volume, both important for lung mucociliary clearance. Serous acini generate most of the fluid secreted by glands, but the molecular mechanisms remain poorly characterized. We previously described cholinergic-regulated fluid secretion driven by Ca(2+)-activated Cl(-) secretion in primary murine serous acinar cells revealed by simultaneous differential interference contrast (DIC) and fluorescence microscopy. Here, we evaluated whether Ca(2+)-activated Cl(-) secretion was accompanied by secretion of HCO(3)(-), possibly a critical ASL component, by simultaneous measurements of intracellular pH (pH(i)) and cell volume. Resting pH(i) was 7.17 +/- 0.01 in physiological medium (5% CO(2)-25 mM HCO(3)(-)). During carbachol (CCh) stimulation, pH(i) fell transiently by 0.08 +/- 0.01 U concomitantly with a fall in Cl(-) content revealed by cell shrinkage, reflecting Cl(-) secretion. A subsequent alkalinization elevated pH(i) to above resting levels until agonist removal, whereupon it returned to prestimulation values. In nominally CO(2)-HCO(3)(-)-free media, the CCh-induced acidification was reduced, whereas the alkalinization remained intact. Elimination of driving forces for conductive HCO(3)(-) efflux by ion substitution or exposure to the Cl(-) channel inhibitor niflumic acid (100 microM) strongly inhibited agonist-induced acidification by >80% and >70%, respectively. The Na(+)/H(+) exchanger (NHE) inhibitor dimethylamiloride (DMA) increased the magnitude (greater than twofold) and duration of the CCh-induced acidification. Gene expression profiling suggested that serous cells express NHE isoforms 1-4 and 6-9, but pharmacological sensitivities demonstrated that alkalinization observed during both CCh stimulation and pH(i) recovery from agonist-induced acidification was primarily due to NHE1, localized to the basolateral membrane. These results suggest that serous acinar cells secrete HCO(3

  7. Metastatic mixed acinar-neuroendocrine carcinoma of the pancreas to the liver: a cytopathology case report with review of the literature.

    PubMed

    Lee, Lili; Bajor-Dattilo, Ewa B; Das, Kasturi

    2013-02-01

    A case of metastatic mixed acinar-neuroendocrine carcinoma (MANEC) of the pancreas to the liver is reported. A diagnostic percutaneous US-guided FNA and core biopsy of a liver nodule was performed. The FNA smears were cellular and showed neoplastic cells in clusters with acinar formation, isolated single cells, and scattered naked nuclei. The cytoplasm was finely granular. The nuclei were relatively uniform, some with speckled chromatin and prominent nucleoli. The immunohistochemistry performed on the cell block showed strong positivity for cytokeratin AE1/AE3, chromogranin, and synaptophysin. Furthermore, the tumor cells were weakly positive for α1-antichymotrypsin. The Ki-67 mitotic index was up to 50%. Based on the morphology and supporting immunohistochemical stains, the final cytopathologic diagnosis rendered was "Positive for malignant cells. Carcinoma with mixed acinar and endocrine features." To our knowledge, this is the first report of a metastatic MANEC to the liver diagnosed based on cytology with confirmatory histology. The difficulties in the cytopathologic diagnosis and differential diagnosis of MANEC are discussed in this article. PMID:22903971

  8. Dual stimuli-responsive coating designed through layer-by-layer assembly of PAA-b-PNIPAM block copolymers for the control of protein adsorption.

    PubMed

    Osypova, A; Magnin, D; Sibret, P; Aqil, A; Jérôme, C; Dupont-Gillain, C; Pradier, C-M; Demoustier-Champagne, S; Landoulsi, J

    2015-11-01

    In this paper, we describe the successful construction, characteristics and interaction with proteins of stimuli-responsive thin nanostructured films prepared by layer-by-layer (LbL) sequential assembly of PNIPAM-containing polyelectrolytes and PAH. PAA-b-PNIPAM block copolymers were synthesized in order to benefit from (i) the ionizable properties of PAA, to be involved in the LbL assembly, and (ii) the sensitivity of PNIPAM to temperature stimulus. The impact of parameters related to the structure and size of the macromolecules (their molecular weight and the relative degree of polymerization of PAA and PNIPAM), and the interaction with proteins under physico-chemical stimuli, such as pH and temperature, are carefully investigated. The incorporation of PAA-b-PNIPAM into multilayered films is shown to be successful whatever the block copolymer used, resulting in slightly thicker films than the corresponding (PAA/PAH)n film. Importantly, the protein adsorption studies demonstrate that it is possible to alter the adsorption behavior of proteins on (PAA-b-PNIPAM/PAH)n surfaces by varying the temperature and/or the pH of the medium, which seems to be intimately related to two key factors: (i) the ability of PNIPAM units to undergo conformational changes and (ii) the structural changes of the film made of weak polyelectrolytes. The simplicity of construction of these PNIPAM block copolymer-based LbL coatings on a large range of substrates, combined with their highly tunable features, make them ideal candidates to be employed for various biomedical applications requiring the control of protein adsorption. PMID:26338028

  9. CS/PAA@TPGS/PLGA nanoparticles with intracellular pH-sensitive sequential release for delivering drug to the nucleus of MDR cells.

    PubMed

    Wang, Ying-Ying; Zhang, Dan-Dan; Kong, Yan-Yan; Shao, Luan-Luan; Zhang, Fen-Yi; Gao, Yu; Mu, Xu; Wang, Jie; Li, Hao-Fan; Yu, Shu-Qin; Xu, Qian

    2016-09-01

    Development of novel nano-drug delivery systems (NDDS) that can transport anticancer drugs into cell nuclei is still a highly desirable strategy for reversing multi-drug resistance (MDR) in cancer therapy. Herein, we designed and prepared a novel NDDS, designated S@L NPs, in which several smaller nanoparticles are contained within a larger nanoparticle. Our S@L NPs (CS/PAA/VP-16@TPGS/PLGA NPs) possess a structure in which smaller nanoparticles (Chitosan-Poly(acrylic acid) nanoparticles, CS/PAA NPs) containing the drug etoposide (VP-16) are loaded within a larger nanoparticle (Vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid) nanoparticles, TPGS/PLGA NPs). The system utilizes intracellular pH gradients to achieve pH-sensitive sequential release within different intracellular domains of MDR cells. S@L NPs could be triggered to degrade and release CS/PAA/VP-16 NPs in the acid environment of the cytosol, endosomes or lysosomes, and CS/PAA/VP-16 NPs were capable of entering the nucleus through nucleopores. It is significant that CS/PAA/VP-16 NPs exhibit disaggregation in the alkaline environment of the nucleus and thereby release the contained anticancer drug. Further mechanistic studies showed that CS/PAA/VP-16 NPs escaped retention and degradation within lysosomes and protected the drug from P-glycoprotein-induced efflux. Simultaneously, S@L NPs enhanced the anticancer effect of the loaded drug by inducing autophagy and apoptosis of MDR cells. This novel NDDS may provide a promising platform for nuclear drug delivery for reversing MDR. PMID:27289313

  10. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghreli...

  11. Episodic Memory and Regional Atrophy in Frontotemporal Lobar Degeneration

    PubMed Central

    Söderlund, Hedvig; Black, Sandra E.; Miller, Bruce L.; Freedman, Morris; Levine, Brian

    2008-01-01

    It has been unclear to what extent memory is affected in frontotemporal lobar degeneration (FTLD). Since patients usually have atrophy in regions implicated in memory function, the frontal and/or temporal lobes, one would expect some memory impairment, and that the degree of atrophy in these regions would be inversely related to memory function. The purposes of this study were 1) to assess episodic memory function in FTLD, and more specifically patients' ability to episodically re-experience an event, and determine its source; 2) to examine whether memory performance is related to quantified regional brain atrophy. FTLD patients (n=18) and healthy comparison subjects (n=14) were assessed with cued recall, recognition, “remember/know” (self-reported re-experiencing) and source recall, at 30 min and 24 hr after encoding. Regional gray matter volumes were assessed with high resolution structural MRI concurrently to testing. Patients performed worse than comparison subjects on all memory measures. Gray matter volume in the left medial temporal lobe was positively correlated with recognition, re-experiencing, and source recall. Gray matter volume in the left posterior temporal lobe correlated significantly with recognition, at 30 min and 24 hr, and with source recall at 30 min. Estimated familiarity at 30 min was positively correlated with gray matter volume in the left inferior parietal lobe. In summary, episodic memory deficits in FTLD may be more common than previously thought, particularly in patients with left medial and posterior temporal atrophy. PMID:17888461

  12. Frontal Cortical Atrophy as a Predictor of Poststroke Apathy.

    PubMed

    Mihalov, Ján; Mikula, Peter; Budiš, Jaroslav; Valkovič, Peter

    2016-07-01

    The aim of the study was to identify associations between the symptoms of poststroke apathy and sociodemographic, stroke-related (severity of stroke, degree of disability, and performance in activities of daily living), and radiological correlates. We determined the degree of cortical and subcortical brain atrophy, the severity of white matter and basal ganglia lesions on baseline computed tomography (CT) scans, and the localization of acute ischemia on control CT or magnetic resonance imaging scans in subacute stages of stroke. During follow-up examinations, in addition to the assessment of apathy symptoms using the Apathy Scale, we also evaluated symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale. The study included 47 consecutive patients with acute ischemic stroke. Correlates significantly associated with apathy, determined at baseline and during follow-up, were entered into the "predictive" and "associative" multiple regression models, respectively. Frontal cortical atrophy and symptoms of depression were most strongly associated with poststroke apathy symptoms. In order to model an interrelation between both cortical atrophy and white matter lesions and aging, we supplemented 2 additional "predictive" models using interaction variables, whereby we confirmed the role of frontal cortical atrophy as a predictor of poststroke apathy also as a function of the increasing age of patients. PMID:27056065

  13. Posterior Cortical Atrophy Presenting with Superior Arcuate Field Defect

    PubMed Central

    Wan, Sue Ling; Bukowska, Danuta M.; Ford, Stephen; Chen, Fred K.

    2015-01-01

    An 80-year-old female with reading difficulty presented with progressive arcuate field defect despite low intraocular pressure. Over a 5-year period, the field defect evolved into an incongruous homonymous hemianopia and the repeated neuroimaging revealed progressive posterior cortical atrophy. Further neuropsychiatric assessment demonstrated symptoms and signs consistent with Benson's syndrome. PMID:26417467

  14. Intravaginally applied oxytocin improves post-menopausal vaginal atrophy

    PubMed Central

    Uvnäs-Moberg, Kerstin; Jonasson, Aino F

    2015-01-01

    Objective To explore the efficacy of local oxytocin for the treatment of post-menopausal vaginal atrophy. Design Double-blinded randomised controlled trial. Setting Healthy post-menopausal women in Stockholm, Sweden. Participants Sixty four post-menopausal women between February and June 2012 at the Karolinska University Hospital Huddinge/Sweden. Main outcome measures The efficacy of oxytocin for treatment of vaginal atrophy after seven weeks and cytological evaluation. Results The percentage of superficial cells in the vaginal smears and the maturation values were significantly increased after seven weeks of treatment with vagitocin 400 IU (p = 0.0288 and p = 0.0002, respectively). The vaginal pH decreased significantly after seven weeks of treatment with vagitocin 100 IU (p = 0.02). The scores of vaginal atrophy, according to the histological evaluation, were significantly reduced after administration of vagitocin 100 IU (p = 0.03). The thickness of the endometrium did not differ between the treatment and placebo groups after seven weeks of treatment. The symptom experienced as the most bothersome was significantly reduced after seven weeks of treatment in the women receiving vagitocin 400 IU compared to women in the placebo group (p = 0.0089). Conclusions Treatment with intravaginally applied oxytocin could be an alternative to local estrogen treatment in women with post-menopausal vaginal atrophy. PMID:25995333

  15. Haptoglobin Is Required to Prevent Oxidative Stress and Muscle Atrophy

    PubMed Central

    Lo Verso, Francesca; Santini, Ferruccio; Vitti, Paolo; Chisari, Carmelo; Sandri, Marco; Maffei, Margherita

    2014-01-01

    Background Oxidative stress (OS) plays a major role on tissue function. Several catabolic or stress conditions exacerbate OS, inducing organ deterioration. Haptoglobin (Hp) is a circulating acute phase protein, produced by liver and adipose tissue, and has an important anti-oxidant function. Hp is induced in pro-oxidative conditions such as systemic inflammation or obesity. The role of systemic factors that modulate oxidative stress inside muscle cells is still poorly investigated. Results We used Hp knockout mice (Hp-/-) to determine the role of this protein and therefore, of systemic OS in maintenance of muscle mass and function. Absence of Hp caused muscle atrophy and weakness due to activation of an atrophy program. When animals were stressed by acute exercise or by high fat diet (HFD), OS, muscle atrophy and force drop were exacerbated in Hp-/-. Depending from the stress condition, autophagy-lysosome and ubiquitin-proteasome systems were differently induced. Conclusions Hp is required to prevent OS and the activation of pathways leading to muscle atrophy and weakness in normal condition and upon metabolic challenges. PMID:24959824

  16. Atrophy of the Parietal Lobe in Preclinical Dementia

    ERIC Educational Resources Information Center

    Jacobs, Heidi I. L.; Van Boxtel, Martin P. J.; Uylings, Harry B. M.; Gronenschild, Ed H. B. M.; Verhey, Frans R.; Jolles, Jelle

    2011-01-01

    Cortical grey matter atrophy patterns have been reported in healthy ageing and Alzheimer disease (AD), but less consistently in the parietal regions of the brain. We investigated cortical grey matter volume patterns in parietal areas. The grey matter of the somatosensory cortex, superior and inferior parietal lobule was measured in 75 older adults…

  17. Benefits of Laser Therapy in Postmenopausal Vaginal Atrophy

    NASA Astrophysics Data System (ADS)

    Brînzan, Daniela; Pǎiuşan, Lucian; Daşcǎu, Voicu; Furǎu, Gheorghe

    2011-08-01

    Maybe the worst aspect of menopause is the decline of the quality of the sexual life. The aim of the study is to demonstrate the beneficial effects of laser therapy in comparison with topical application of estrogen preparations, for the treatment of vaginal atrophy and sexual dysfunctions induced by menopause. A total of 50 menopausal patients were examined during a one year period. The methods used for objectifying vaginal atrophy and sexual dysfunctions were history taking, local clinical exam and PAP smear. From this group, 40 patients had vaginal atrophy with sexual dysfunctions. They have been treated differently, being included in four groups: patients treated with local estrogens, patients treated with intravaginal laser therapy, patients treated with both laser therapy and estrogens, patients treated with estrogens and placebo laser therapy. Therapeutic benefit, improvement of vaginal atrophy and quality of sexual life, were objectified by anamnesis (questionnaire), local and general clinical examination and PAP smear. The best results have been obtained, by far, in the 3rd group, followed by the women treated only with laser. In conclusion, we can say that laser therapy is the best way for solving the sexual inconveniences of menopause.

  18. Characterization of disuse skeletal muscle atrophy and the efficacy of a novel muscle atrophy countermeasure during spaceflight and simulated microgravity

    NASA Astrophysics Data System (ADS)

    Hanson, Andrea Marie

    Humans are an integral part of the engineered systems that will enable return to the Moon and eventually travel to Mars. Major advancements in countermeasure development addressing deleterious effects of microgravity and reduced gravity on the musculoskeletal system need to be made to ensure mission safety and success. The primary objectives of this dissertation are to advance the knowledge and understanding of skeletal muscle atrophy, and support development of novel countermeasures for disuse atrophy to enable healthy long-duration human spaceflight. Models simulating microgravity and actual spaceflight were used to examine the musculoskeletal adaptations during periods of unloading. Myostatin inhibition, a novel anti-atrophy drug therapy, and exercise were examined as a means of preventing and recovering from disuse atrophy. A combination of assays was used to quantify adaptation responses to unloading and examine efficacy of the countermeasures. Body and muscle masses were collected to analyze systemic changes due to treatments. Hindlimb strength and individual muscle forces were measured to demonstrate functional adaptations to treatments. Muscle fiber morphology and myosin heavy chain (MHC) expression was examined to identify adaptations at the cellular level. Protein synthesis signals insulin-like growth factor-1 (IGF-1), Akt, and p70s6 kinase; and the degradation signals Atrogin-1 and MuRF-1 were examined to identify adaptations at the molecular level that ultimately lead to muscle hypertrophy and atrophy. A time course study provided a thorough characterization of the adaptation of skeletal muscle during unloading in C57BL/6 mice, and baseline data for comparison to and evaluation of subsequent studies. Time points defining the on-set and endpoints of disuse muscle atrophy were identified to enable characterization of rapid vs. long-term responses of skeletal muscle to hindlimb suspension. Unloading-induced atrophy primarily resulted from increased protein

  19. Design of a novel crosslinked HEC-PAA porous hydrogel composite for dissolution rate and solubility enhancement of efavirenz.

    PubMed

    Mabrouk, M; Chejara, D R; Mulla, J A S; Badhe, R V; Choonara, Y E; Kumar, P; du Toit, L C; Pillay, V

    2015-07-25

    The purpose of this research was to synthesize, characterize and evaluate a Crosslinked Hydrogel Composite (CHC) as a new carrier for improving the solubility of the anti-HIV drug, efavirenz. The CHC was prepared by physical blending of hydroxyethylcellulose (HEC) with poly(acrylic acid) (PAA) (1:1) in the presence of poly(vinyl alcohol) (PVA) (as a crosslinker) (1:5) under lyophilization. Efavirenz was loaded in situ into the CHC in varying proportions (200-600 mg). The CHC demonstrated impressive rheological properties (dynamic viscosity=6053 mPa; 500 s(-1)) and tensile strength (2.5 mPa) compared with the native polymers (HEC and PAA). The physicochemical and thermal behavior also confirmed that the CHC was compatible with efavirenz. The incorporation of efavirenz in the CHC increased the surface area (4.4489-8.4948 m(2)/g) and pore volume (469.547-776.916Å) of the hydrogel system which was confirmed by SEM imagery and BET surface area measurements. The solubility of efavirenz was significantly enhanced (150 times) in a sustained release manner over 24h as affirmed by the in vitro drug release studies. The hydration medium provided by the CHC network played a pivotal role in improving the efavirenz solubility via increasing hydrogen bonding as proved by the zeta potential measurements (-18.0 to +0.10). The CHC may be a promising alternative as an oral formulation for the delivery of efavirenz with enhanced solubility. PMID:26047962

  20. Is the Supraspinatus Muscle Atrophy Truly Irreversible after Surgical Repair of Rotator Cuff Tears?

    PubMed Central

    Chung, Seok Won; Kim, Sae Hoon; Tae, Suk-Kee; Yoon, Jong Pil; Choi, Jung-Ah

    2013-01-01

    Background Atrophy of rotator cuff muscles has been considered an irreversible phenomenon. The purpose of this study is to evaluate whether atrophy is truly irreversible after rotator cuff repair. Methods We measured supraspinatus muscle atrophy of 191 patients with full-thickness rotator cuff tears on preoperative magnetic resonance imaging and postoperative multidetector computed tomography images, taken at least 1 year after operation. The occupation ratio was calculated using Photoshop CS3 software. We compared the change between pre- and postoperative occupation ratios after modifying the preoperative occupation ratio. In addition, possible relationship between various clinical factors and the change of atrophy, and between the change of atrophy and cuff integrity after surgical repair were evaluated. Results The mean occupation ratio was significantly increased postoperatively from 0.44 ± 0.17 to 0.52 ± 0.17 (p < 0.001). Among 191 patients, 81 (42.4%) showed improvement of atrophy (more than a 10% increase in occupation ratio) and 33 (17.3%) worsening (more than a 10% decrease). Various clinical factors such as age tear size, or initial degree of atrophy did not affect the change of atrophy. However, the change of atrophy was related to repair integrity: cuff healing failure rate of 48.5% (16 of 33) in worsened atrophy; and 22.2% (18 of 81) in improved atrophy (p = 0.007). Conclusions The supraspinatus muscle atrophy as measured by occupation ratio could be improved postoperatively in case of successful cuff repair. PMID:23467404

  1. [Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

    PubMed

    Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases. PMID:27431631

  2. Potential predictors of hippocampal atrophy in Alzheimer's disease.

    PubMed

    Dhikav, Vikas; Anand, Kuljeet

    2011-01-01

    The hippocampus is a vulnerable and plastic brain structure that is damaged by a variety of stimuli, e.g. hypoxia, hypoperfusion, hypoglycaemia, stress and seizures. Alzheimer's disease is a common and important disorder in which hippocampal atrophy is reported. Indeed, the available evidence suggests that hippocampal atrophy is the starting point of the pathogenesis of Alzheimer's disease and a significant number of patients with hippocampal atrophy will develop Alzheimer's disease. Studies indicate that hippocampal atrophy has functional consequences, e.g. cognitive impairment. Deposition of tau protein, formation of neurofibrillary tangles and accumulation of β-amyloid (Aβ) contributes to hippocampal atrophy together with damage caused by several other factors. Some of the factors associated with the development of hippocampal atrophy in Alzheimer's disease have been identified, e.g. hypertension, diabetes mellitus, hyperlipidaemia, seizures, affective disturbances and stress, and more is being learnt about other factors. Hypertension can potentially damage the hippocampus through ischaemia caused by atherosclerosis and cerebral amyloid angiopathy. Diabetes can produce hippocampal lesions via both vascular and non-vascular pathologies and can reduce the threshold for hippocampal damage. Carriers of the apolipoprotein E (ApoE)-ε4 genotype have been shown to have greater mesial temporal atrophy and poorer memory functions than non-carriers. In addition to giving rise to abnormal lipid metabolism, the ApoE-ε4 allele can affect the course of Alzheimer's disease via both Aβ-dependent and -independent pathways. Repetitive seizures can increase Aβ-peptide production and cause neurotransmission dysfunction and cytoskeletal abnormalities or a combination of these. Affective disturbances and stress are proposed to increase corticosteroid-induced hippocampal damage in many different ways. In the absence of any specific markers for predicting Alzheimer's disease

  3. Renal Atrophy Secondary to Chemoradiotherapy of Abdominal Malignancies

    SciTech Connect

    Yang, Gary Y.; May, Kilian Salerno; Iyer, Renuka V.; Chandrasekhar, Rameela M.A.; Wilding, Gregory E.; McCloskey, Susan A.; Khushalani, Nikhil I.; Yendamuri, Saikrishna S.; Gibbs, John F.; Fakih, Marwan; Thomas, Charles R.

    2010-10-01

    Purpose: To identify factors predictive of renal atrophy after chemoradiotherapy of gastrointestinal malignancies. Methods and Materials: Patients who received chemotherapy and abdominal radiotherapy (RT) between 2002 and 2008 were identified for this study evaluating change in kidney size and function after RT. Imaging and biochemical data were obtained before and after RT in 6-month intervals. Kidney size was defined by craniocaudal measurement on CT images. The primarily irradiated kidney (PK) was defined as the kidney that received the greater mean kidney dose. Receiver operating characteristic (ROC) curves were generated to predict risk for renal atrophy. Results: Of 130 patients, median age was 64 years, and 51.5% were male. Most primary disease sites were pancreas and periampullary tumors (77.7%). Median follow-up was 9.4 months. Creatinine clearance declined 20.89%, and size of the PK decreased 4.67% 1 year after completion of chemoradiation. Compensatory hypertrophy of the non-PK was not seen. Percentage volumes of the PK receiving {>=}10 Gy (V{sub 10}), 15 Gy (V{sub 15}), and 20 Gy (V{sub 20}) were significantly associated with renal atrophy 1 year after RT (p = 0.0030, 0.0029, and 0.0028, respectively). Areas under the ROC curves for V{sub 10}, V{sub 15}, and V{sub 20} to predict >5% decrease in PK size were 0.760, 0.760, and 0.762, respectively. Conclusions: Significant detriments in PK size and renal function were seen after abdominal RT. The V{sub 10}, V{sub 15}, and V{sub 20} were predictive of risk for PK atrophy 1 year after RT. Analyses suggest the association of lower-dose renal irradiation with subsequent development of renal atrophy.

  4. Exocytosis in the dissociated pancreatic acinar cells of the guinea pig directly visualized by VEC-DIC microscopy.

    PubMed

    Ishihara, Y; Sakurai, T; Habara, Y; Busik, J V; Kanno, T; Terakawa, S

    2000-10-14

    To elucidate the detailed process of exocytosis at the highest possible accuracy, we dissociated the pancreatic acinus of the guinea pig and observed zymogen granules under a video-enhanced contrast differential interference contrast (VEC-DIC) microscope. The preparation was thin enough to resolve each zymogen granule with the best clarity. When acinar cells were stimulated with ACh (20 microM), many zymogen granules near the lumen showed an abrupt light intensity change. For a period of 10 s immediately before exocytosis, zymogen granules neither shifted their position nor altered their shape within an accuracy of 38 nm. The time required for individual granules to change the light intensity (the releasing time) ranged from 0.15 to 0.70 s. After each response, the granule maintained its altered contrast for a few seconds until it was retrieved to a planar membrane. No compound exocytosis including granule-granule fusion was observed. We concluded that the exocytosis is not directly initiated by any supramolecular change but by a purely molecular event. PMID:11027653

  5. Platelet-activating factor promotes motility in breast cancer cells and disrupts non-transformed breast acinar structures.

    PubMed

    Anandi, V Libi; Ashiq, K A; Nitheesh, K; Lahiri, M

    2016-01-01

    A plethora of studies have demonstrated that chronic inflammatory microenvironment influences the genesis and progression of tumors. Such microenvironments are enriched with various lipid mediators. Platelet activating factor (PAF, 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is one such lipid mediator that is secreted by different immune cell types during inflammation and by breast cancer cells upon stimulation with growth factors. Overexpression of PAF-receptor has also been observed in many other cancers. Here we report the possible roles of PAF in tumor initiation and progression. MCF10A, a non-transformed and non-malignant mammary epithelial cell line, when grown as 3D 'on-top' cultures form spheroids that have a distinct hollow lumen surrounded by a monolayer of epithelial cells. Exposure of these spheroids to PAF resulted in the formation of large deformed acinar structures with disrupted lumen, implying transformation. We then examined the response of transformed cells such as MDA-MB 231 to stimulation with PAF. We observed collective cell migration as well as motility at the single cell level on PAF induction, suggesting its role during metastasis. This increase in collective cell migration is mediated via PI3-kinase and/or JNK pathway and is independent of the MAP-kinase pathway. Taken together this study signifies a novel role of PAF in inducing transformation of non-tumorigenic cells and the vital role in promotion of breast cancer cell migration. PMID:26531049

  6. E-cadherin-negative acinar cell carcinoma of the pancreas: report of a case showing a solid pseudopapillary growth pattern.

    PubMed

    Tajima, Shogo; Waki, Michihiko; Azuma, Masaki; Koda, Kenji; Ohata, Akihiko

    2016-09-01

    E-cadherin expression patterns in acinar cell carcinomas (ACCs) of the pancreas have not been well documented. Herein, we present a hitherto undescribed case of E-cadherin-negative ACC with a solid pseudopapillary growth pattern in a 65-year-old man. We used an antibody against the extracellular domain of E-cadherin. As a further unusual status in ACC, faint β-catenin expression was observed in the cytoplasm of carcinoma cells. Morphological distinction from a solid pseudopapillary neoplasm (SPN) of the pancreas might be problematic in such a case, because of their similarities concerned with the growth pattern and E-cadherin negativity. Without nuclear accumulation of β-catenin, a diagnosis of SPN was almost excluded. Immunoreactivity for trypsin and BCL10 made an accurate diagnosis of ACC to this case. The tumor recurred 10 months post-surgery as rapidly enlarging masses in the liver, presumably indicating the aggressiveness of the E-cadherin-negative phenotype among ACCs. PMID:25600280

  7. Factors Associated with Changes in Brain Atrophy during a Three-Year Observation in Elderly Diabetic Patients: Effect of Renal Impairment on Hippocampal Atrophy

    PubMed Central

    Kawamura, Takahiko; Umemura, Toshitaka; Umegaki, Hiroyuki; Imamine, Rui; Kawano, Naoko; Mase, Hajime; Mizoguchi, Asako; Minatoguchi, Makiko; Kusama, Minoru; Kouchi, Yu; Watarai, Atsuko; Kanai, Akio; Nakashima, Eitaro; Hotta, Nigishi

    2016-01-01

    Background/Aims We conducted a 3-year longitudinal study concerning factors associated with changes in brain atrophy in elderly diabetic patients. Methods We evaluated hippocampal and global brain atrophy using automatic voxel-based morphometry of structural magnetic resonance images, 4 cognitive function tests, and cerebral small vessel disease (SVD) in 66 diabetic patients. Results During the 3-year follow-up, hippocampal and global brain atrophy advanced, and cognitive functions worsened. For changes in hippocampal atrophy, changes in estimated glomerular filtration rate (eGFR), albuminuria, and being an ApoE ε4 carrier were independent factors; change in the number of silent brain infarctions was an independent factor for changes in global brain atrophy. A significant association of changes in eGFR and albuminuria with hippocampal atrophy remained after adjusting for confounders including SVD. Both types of brain atrophy at baseline were significantly correlated with cognitive impairment at baseline and especially associated with changes in delayed word recall during the follow-up after adjusting for confounders. Conclusion Changes in eGFR and albuminuria during follow-up were independent risk factors for hippocampal atrophy, which was associated with decline in delayed word recall, suggesting that management of chronic kidney disease may prevent the progression of hippocampal atrophy. PMID:27293417

  8. Pharmacological Inhibitors of the Proteosome in Atrophying Muscles

    NASA Technical Reports Server (NTRS)

    Goldberg, Alfred

    1999-01-01

    It is now clear that the marked loss of muscle mass that occurs with disuse, denervation or in many systemic diseases (cancer cachexia, sepsis, acidosis, various endocrine disorders) is due primarily to accelerated degradation of muscle proteins, especially myofibrillar components. Recent work primarily in Dr. Goldberg's laboratory had suggested that in these diverse conditions, the enhancement of muscle proteolysis results mainly from activation of the Ub-proteasome degradative pathway. In various experimental models of atrophy, rat muscles show a common series of changes indicative of activation of this pathway, including increases in MRNA for Ub and proteasome subunits, content of ubiquitinated proteins, and sensitivity to inhibitors of the proteasome. In order to understand the muscle atrophy seen in weightlessness, Dr. Goldberg's laboratory is collaborating with Dr. Baldwin in studies to define the changes in these parameters upon hind-limb suspension. Related experiments will explore the effects on this degradative system of exercise regimens and also of glucocorticoids, which are known to rise in space personnel and to promote muscle, especially in inactive muscles. The main goals will be: (A) to define the enzymatic changes leading to enhanced activity of the Ub-proteasome pathway in inactive muscles upon hind-limb suspension, and the effects on this system of exposure to glucocorticoids or exercise; and (B) to learn whether inhibitors of the Ub-proteasome pathway may be useful in retarding the excessive proteolysis in atrophying muscles. Using muscle extracts, Dr. Goldberg's group hopes to define the rate-limiting, enzymatic changes that lead to the accelerated Ub-conjugation and protein degradation. They have recently developed cell-free preparations from atrophying rat muscles, in which Ub-conjugation to muscle proteins is increased above control levels. Because these new preparations seem to reproduce the changes occurring in vivo, they will analyze in

  9. Expanding the spectrum of neuronal pathology in multiple system atrophy

    PubMed Central

    Cykowski, Matthew D.; Coon, Elizabeth A.; Powell, Suzanne Z.; Jenkins, Sarah M.; Benarroch, Eduardo E.; Low, Phillip A.; Schmeichel, Ann M.

    2015-01-01

    Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients

  10. Dynamic Foot Pressure as a Countermeasure to Muscle Atrophy

    NASA Astrophysics Data System (ADS)

    Kyparos, A.; Layne, C. S.; Martinez, D. A.; Clarke, M. S. F.; Feeback, D. L.

    2002-01-01

    Mechanical unloading of skeletal muscle (SKM) as a consequence of space flight or ground-based analogues, such as human bedrest and rodent hindlimb suspension (HLS) models, induces SKM atrophy particularly affecting the anti-gravity musculature of the lower limbs. In the context of manned space flight, the subsequent loss of muscle strength and functionality will pose operational implications jeopardizing mission success. Exercise, currently the primary muscle degradation countermeasure, has not proven completely effective in preventing muscle atrophy. It is therefore imperative that some other forms of in- flight countermeasure be also developed to supplement the prescribed exercise regimen the astronauts follow during spaceflight. Previous work in both humans and rats has shown that mechanical stimulation of the soles of the feet increases neuromuscular activation in the lower limb musculature and that such stimulation results in the limited prevention of atrophy in the soleus muscle of unloaded rats. This study was designed to investigate the effect of cutaneous mechanoreceptor stimulation on hindlimb unloading- induced SKM atrophy in rats. It was hypothesized that mechanical stimulation of the plantar surface of the rat foot during hindlimb suspension (HLS), utilizing a novel stimulation paradigm known as Dynamic Foot Pressure (DFP), would attenuate unloading-induced SKM atrophy. Mature adult male Wistar rats were randomly assigned to four groups of 10 rats each as follows: sedentary controls (Ctrl), hindlimb suspended only (HLS), hindlimb suspended wearing an inflatable boot (HLS-IFL) and hindlimb suspended rats wearing a non-inflatable boot (HLS-NIFL). The stimulation of mechanoreceptors was achieved by applying pressure to the plantar surface of the foot during the 10-day period of HLS using a custom-built boot. The anti-atrophic effects of DFP application was quantified directly by morphological (muscle wet weight, myofiber cross-sectional area

  11. Cognitive planning deficit in patients with cerebellar atrophy.

    PubMed

    Grafman, J; Litvan, I; Massaquoi, S; Stewart, M; Sirigu, A; Hallett, M

    1992-08-01

    We compared the performance of 12 patients with cerebellar atrophy (CA) and 12 normal controls matched for age and education on the Tower of Hanoi, a nine-problem task that requires cognitive planning. CA patients performed significantly worse than controls on this task despite no difference in planning and between-move pause times. A reanalysis of the data using just the subgroup of patients with pure cerebellar cortical atrophy (CCA) (N = 9) replicated the above results and also showed that CCA patients had significantly increased planning times compared with controls. Neither age, sex, education level, severity of dementia, word fluency, response time, memory, nor visuomotor procedural learning predicted CA or CCA performance. This deficit in cognitive planning suggests a functional link between the cerebellum, basal ganglia, and the frontal lobe concerning specific cognitive processes. However, the exact role of the cerebellum in cognitive planning remains undetermined. PMID:1641142

  12. Crustaceans as a model for microgravity-induced muscle atrophy

    NASA Astrophysics Data System (ADS)

    Mykles, D. L.

    Atrophy of skeletal muscles is a serious problem in a microgravity environment. It is hypothesized that the unloading of postural muscles, which no longer must resist gravity force, causes an accelerated breakdown of contractile proteins, resulting in a reduction in muscle mass and strength. A crustacean model using the land crab, Gecarcinus lateralis, to assess the effects of spaceflight on protein metabolism is presented. The model is compared to a developmentally-regulated atrophy in which a premolt reduction in muscle mass allows the withdrawal of the large claws at molt. The biochemical mechanisms underlying protein breakdown involves both Ca^2+-dependent and multicatalytic proteolytic enzymes. Crustacean claw muscle can be used to determine the interactions between shortening and unloading at the molecular level.

  13. Crustaceans as a model for microgravity-induced muscle atrophy

    NASA Technical Reports Server (NTRS)

    Mykles, D. L.

    1996-01-01

    Atrophy of skeletal muscles is a serious problem in a microgravity environment. It is hypothesized that the unloading of postural muscles, which no longer must resist gravity force, causes an accelerated breakdown of contractile proteins, resulting in reduction in muscle mass and strength. A crustacean model using the land crab, Gecarcinus lateralis, to assess the effects of spaceflight on protein meatabolism is presented. The model is compared to a developmentally-regulated atrophy in which a premolt reduction in muscle mass allows the withdrawal of the large claws at molt. The biochemical mechanisms underlying protein breakdown involves both Ca2(+) -dependent and multicatalytic proteolytic enzymes. Crustacean claw muscle can be used to determine the interactions between shortening and unloading at the molecular level.

  14. Cholecystokinin activates Gi1-, Gi2-, Gi3- and several Gs-proteins in rat pancreatic acinar cells.

    PubMed Central

    Schnefel, S; Pröfrock, A; Hinsch, K D; Schulz, I

    1990-01-01

    On separation of rat pancreatic plasma membrane proteins by two-dimensional gel electrophoresis, 15 GTP-binding protein (G-protein) alpha-subunits could be detected immunochemically using an alpha common antibody. These consisted of five 48 kDa proteins (pI 5.70, 5.80, 5.90, 6.10 and 6.25) and five 45 kDa proteins (pI 5.90, 6.05, 6.25, 6.30 and 6.70), presumably corresponding to low- and high-molecular mass forms of the Gs-protein, as well as three 40/41 kDa proteins (pI 5.50, 5.70 and 6.00) and two 39 kDa proteins (pI 5.50 and 6.00). All of these proteins except for the more acidic 39 kDa protein were ADP-ribosylated by cholera toxin (CT). In addition, the three 40/41 kDa proteins and the more alkaline 39 kDa protein were also ADP-ribosylated by pertussis toxin (PT). CT- and PT-induced ADP-ribosylation changed the pI values of G-protein alpha-subunits by 0.2 pI units to more acidic values. Preincubation of isolated pancreatic membranes with cholecystokinin octapeptide (CCK-OP), which stimulates phospholipase C in acinar cells, decreased CT-induced as well as PT-induced ADP-ribosylation of the three 40/41 kDa proteins, whereas CT-induced ADP-ribosylation of one 45 kDa (pI 5.80) and all 48 kDa proteins was enhanced in the presence of CCK. Carbachol, another stimulant of phospholipase C, had no effect. The three 40/41 kDa proteins and one 48 kDa protein could be labelled with the GTP analogue [alpha-32P]GTP-gamma-azidoanilide. CCK, but not carbachol, stimulated incorporation of the GTP analogue into all of these four proteins. Using different anti-peptide antisera specific for alpha-subunits of G-proteins we identified the three 40/41 kDa Gi-proteins as Gi1 (pI 6.00), Gi2 (pI 5.50) and Gi3 (pI 5.70). The Gi3-protein was found to be the major Gi-protein of pancreatic plasma membranes. One of the 39 kDa proteins (pI 6.0) was identified as Go. These results indicate that CCK receptors functionally interact with six Gs-proteins and with Gi1, Gi2 and Gi3-proteins. Since

  15. A Case of Solitary Kidney Atrophy Due to Primary Hyperparathyroidism

    PubMed Central

    Lin, Yu-Ting; Jiang, Jiunn-Song; Fang, Yu-Wei; Tsai, Ming-Hsien

    2016-01-01

    Abstract Although primary hyperparathyroidism (PHPT) is asymptomatic in most patients, its main clinical manifestation is nephrolithiasis. In general, hypercalcemia would lead to unilateral renal stones, which may become bilateral over time. We present a rare case of a large unilateral asymptomatic ureteral stone in a patient with hypercalcemia secondary to PHPT, which eventually led to renal atrophy. The diagnosis of PHPT should be considered in patients with hypercalcemia and renal stones, as asymptomatic PHPT may result in a devastating renal outcome. PMID:26765435

  16. Neonatal lupus erythematosus associated with unilateral pectoralis major atrophy.

    PubMed

    Mondal, Rakesh; Nandi, Madhumita; Sarkar, Sumantra; Mukherjee, Krishnendu

    2011-11-01

    Neonatal lupus erythematosus (NLE), in most cases, presents with cardiac and dermatological manifestation due to transferred IgG auto antibodies (anti Ro/SSA and anti La/SSB) from the mother. Some unusual associations with myelopathy, vasculopathy, transient myasthenia gravis, congenital nephrotic syndrome, chondrodysplasia punctata etc. are also reported. Here, the authors present a case of NLE with isolated left sided pectoralis major muscle atrophy, which has not been reported earlier. PMID:21553209

  17. Potential role of lampalizumab for treatment of geographic atrophy

    PubMed Central

    Rhoades, William; Dickson, Drew; Do, Diana V

    2015-01-01

    The purpose of this article is to review the pathways underlying age-related macular degeneration and potential therapeutic targets, focusing on the complement pathway and the recent MAHALO Phase II trial of the investigational drug lampalizumab. This trial was the first to have shown positive results for the treatment of geographic atrophy in age-related macular degeneration. It has potential as a future treatment, and is currently undergoing a Phase III trial. PMID:26089637

  18. Masticatory muscles of mouse do not undergo atrophy in space

    PubMed Central

    Philippou, Anastassios; Minozzo, Fabio C.; Spinazzola, Janelle M.; Smith, Lucas R.; Lei, Hanqin; Rassier, Dilson E.; Barton, Elisabeth R.

    2015-01-01

    Muscle loading is important for maintaining muscle mass; when load is removed, atrophy is inevitable. However, in clinical situations such as critical care myopathy, masticatory muscles do not lose mass. Thus, their properties may be harnessed to preserve mass. We compared masticatory and appendicular muscles responses to microgravity, using mice aboard the space shuttle Space Transportation System-135. Age- and sex-matched controls remained on the ground. After 13 days of space flight, 1 masseter (MA) and tibialis anterior (TA) were frozen rapidly for biochemical and functional measurements, and the contralateral MA was processed for morphologic measurements. Flight TA muscles exhibited 20 ± 3% decreased muscle mass, 2-fold decreased phosphorylated (P)-Akt, and 4- to 12-fold increased atrogene expression. In contrast, MAs had no significant change in mass but a 3-fold increase in P-focal adhesion kinase, 1.5-fold increase in P-Akt, and 50–90% lower atrogene expression compared with limb muscles, which were unaltered in microgravity. Myofibril force measurements revealed that microgravity caused a 3-fold decrease in specific force and maximal shortening velocity in TA muscles. It is surprising that myofibril-specific force from both control and flight MAs were similar to flight TA muscles, yet power was compromised by 40% following flight. Continued loading in microgravity prevents atrophy, but masticatory muscles have a different set point that mimics disuse atrophy in the appendicular muscle.—Philippou, A., Minozzo, F. C., Spinazzola, J. M., Smith, L. R., Lei, H., Rassier, D. E., Barton, E. R. Masticatory muscles of mouse do not undergo atrophy in space. PMID:25795455

  19. Chronic Nicotine Exposure In Vivo and In Vitro Inhibits Vitamin B1 (Thiamin) Uptake by Pancreatic Acinar Cells

    PubMed Central

    Srinivasan, Padmanabhan; Thrower, Edwin C.; Loganathan, Gopalakrishnan; Balamurugan, A. N.; Subramanian, Veedamali S.; Gorelick, Fred S.; Said, Hamid M.

    2015-01-01

    Thiamin (vitamin B1), a member of the water-soluble family of vitamins, is essential for normal cellular functions; its deficiency results in oxidative stress and mitochondrial dysfunction. Pancreatic acinar cells (PAC) obtain thiamin from the circulation using a specific carrier-mediated process mediated by both thiamin transporters -1 and -2 (THTR-1 and THTR-2; encoded by the SLC19A2 and SLC19A3 genes, respectively). The aim of the current study was to examine the effect of chronic exposure of mouse PAC in vivo and human PAC in vitro to nicotine (a major component of cigarette smoke that has been implicated in pancreatic diseases) on thiamin uptake and to delineate the mechanism involved. The results showed that chronic exposure of mice to nicotine significantly inhibits thiamin uptake in murine PAC, and that this inhibition is associated with a marked decrease in expression of THTR-1 and THTR-2 at the protein, mRNA and hnRNAs level. Furthermore, expression of the important thiamin-metabolizing enzyme, thiamin pyrophosphokinase (TPKase), was significantly reduced in PAC of mice exposed to nicotine. Similarly, chronic exposure of cultured human PAC to nicotine (0.5 μM, 48 h) significantly inhibited thiamin uptake, which was also associated with a decrease in expression of THTR-1 and THTR-2 proteins and mRNAs. This study demonstrates that chronic exposure of PAC to nicotine impairs the physiology and the molecular biology of the thiamin uptake process. Furthermore, the study suggests that the effect is, in part, mediated through transcriptional mechanism(s) affecting the SLC19A2 and SLC19A3 genes. PMID:26633299

  20. Chronic Nicotine Exposure In Vivo and In Vitro Inhibits Vitamin B1 (Thiamin) Uptake by Pancreatic Acinar Cells.

    PubMed

    Srinivasan, Padmanabhan; Thrower, Edwin C; Loganathan, Gopalakrishnan; Balamurugan, A N; Subramanian, Veedamali S; Gorelick, Fred S; Said, Hamid M

    2015-01-01

    Thiamin (vitamin B1), a member of the water-soluble family of vitamins, is essential for normal cellular functions; its deficiency results in oxidative stress and mitochondrial dysfunction. Pancreatic acinar cells (PAC) obtain thiamin from the circulation using a specific carrier-mediated process mediated by both thiamin transporters -1 and -2 (THTR-1 and THTR-2; encoded by the SLC19A2 and SLC19A3 genes, respectively). The aim of the current study was to examine the effect of chronic exposure of mouse PAC in vivo and human PAC in vitro to nicotine (a major component of cigarette smoke that has been implicated in pancreatic diseases) on thiamin uptake and to delineate the mechanism involved. The results showed that chronic exposure of mice to nicotine significantly inhibits thiamin uptake in murine PAC, and that this inhibition is associated with a marked decrease in expression of THTR-1 and THTR-2 at the protein, mRNA and hnRNAs level. Furthermore, expression of the important thiamin-metabolizing enzyme, thiamin pyrophosphokinase (TPKase), was significantly reduced in PAC of mice exposed to nicotine. Similarly, chronic exposure of cultured human PAC to nicotine (0.5 μM, 48 h) significantly inhibited thiamin uptake, which was also associated with a decrease in expression of THTR-1 and THTR-2 proteins and mRNAs. This study demonstrates that chronic exposure of PAC to nicotine impairs the physiology and the molecular biology of the thiamin uptake process. Furthermore, the study suggests that the effect is, in part, mediated through transcriptional mechanism(s) affecting the SLC19A2 and SLC19A3 genes. PMID:26633299

  1. Ionizing irradiation induces apoptotic damage of salivary gland acinar cells via NADPH oxidase 1-dependent superoxide generation

    SciTech Connect

    Tateishi, Yoshihisa Sasabe, Eri; Ueta, Eisaku; Yamamoto, Tetsuya

    2008-02-08

    Reactive oxygen species (ROS) have important roles in various physiological processes. Recently, several novel homologues of the phagocytic NADPH oxidase have been discovered and this protein family is now designated as the Nox family. We investigated the involvement of Nox family proteins in ionizing irradiation-induced ROS generation and impairment in immortalized salivary gland acinar cells (NS-SV-AC), which are radiosensitive, and immortalized ductal cells (NS-SV-DC), which are radioresistant. Nox1-mRNA was upregulated by {gamma}-ray irradiation in NS-SV-AC, and the ROS level in NS-SV-AC was increased to approximately threefold of the control level after 10 Gy irradiation. The increase of ROS level in NS-SV-AC was suppressed by Nox1-siRNA-transfection. In parallel with the suppression of ROS generation and Nox1-mRNA expression by Nox1-siRNA, ionizing irradiation-induced apoptosis was strongly decreased in Nox1-siRNA-transfected NS-SV-AC. There were no large differences in total SOD or catalase activities between NS-SV-AC and NS-SV-DC although the post-irradiation ROS level in NS-SV-AC was higher than that in NS-SV-DC. In conclusion, these results indicate that Nox1 plays a crucial role in irradiation-induced ROS generation and ROS-associated impairment of salivary gland cells and that Nox1 gene may be targeted for preservation of the salivary gland function from radiation-induced impairment.

  2. Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia.

    PubMed

    Fukawa, Tomoya; Yan-Jiang, Benjamin Chua; Min-Wen, Jason Chua; Jun-Hao, Elwin Tan; Huang, Dan; Qian, Chao-Nan; Ong, Pauline; Li, Zhimei; Chen, Shuwen; Mak, Shi Ya; Lim, Wan Jun; Kanayama, Hiro-Omi; Mohan, Rosmin Elsa; Wang, Ruiqi Rachel; Lai, Jiunn Herng; Chua, Clarinda; Ong, Hock Soo; Tan, Ker-Kan; Ho, Ying Swan; Tan, Iain Beehuat; Teh, Bin Tean; Shyh-Chang, Ng

    2016-06-01

    Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia. PMID:27135739

  3. Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance

    PubMed Central

    Troncoso, Rodrigo; Paredes, Felipe; Parra, Valentina; Gatica, Damián; Vásquez-Trincado, César; Quiroga, Clara; Bravo-Sagua, Roberto; López-Crisosto, Camila; Rodriguez, Andrea E; Oyarzún, Alejandra P; Kroemer, Guido; Lavandero, Sergio

    2014-01-01

    Glucocorticoids, such as dexamethasone, enhance protein breakdown via ubiquitin–proteasome system. However, the role of autophagy in organelle and protein turnover in the glucocorticoid-dependent atrophy program remains unknown. Here, we show that dexamethasone stimulates an early activation of autophagy in L6 myotubes depending on protein kinase, AMPK, and glucocorticoid receptor activity. Dexamethasone increases expression of several autophagy genes, including ATG5, LC3, BECN1, and SQSTM1 and triggers AMPK-dependent mitochondrial fragmentation associated with increased DNM1L protein levels. This process is required for mitophagy induced by dexamethasone. Inhibition of mitochondrial fragmentation by Mdivi-1 results in disrupted dexamethasone-induced autophagy/mitophagy. Furthermore, Mdivi-1 increases the expression of genes associated with the atrophy program, suggesting that mitophagy may serve as part of the quality control process in dexamethasone-treated L6 myotubes. Collectively, these data suggest a novel role for dexamethasone-induced autophagy/mitophagy in the regulation of the muscle atrophy program. PMID:24897381

  4. Counteracting Muscle Atrophy using Galvanic Stimulation of the Vestibular System

    NASA Technical Reports Server (NTRS)

    Fox, Robert A.; Polyakov, Igor

    1999-01-01

    The unloading of weight bearing from antigravity muscles during space flight produces significant muscle atrophy and is one of the most serious health problems facing the space program. Various exercise regimens have been developed and used either alone or in combination with pharmacological techniques to ameliorate this atrophy, but no effective countermeasure exists for this problem. The research in this project was conducted to evaluate the potential use of vestibular galvanic stimulation (VGS) to prevent muscle atrophy resulting from unloading of weight bearing from antigravity muscles. This approach was developed based on two concepts related to the process of maintaining the status of the anti-gravity neuromuscular system. These two premises are: (1) The "tone," or bias on spinal motorneurons is affected by vestibular projections that contribute importantly to maintaining muscle health and status. (2) VGS can be used to modify the excitability, or 'tone' of motorneuron of antigravity muscles. Thus, the strategy is to use VGS to modify the gain of vestibular projections to antigravity muscles and thereby change the general status of these muscles.

  5. A family with optic atrophy and congenital hearing loss.

    PubMed

    Amemiya, T; Honda, A

    1994-06-01

    A 37-year-old woman had optic atrophy in both eyes and low-tone hearing disturbance of both ears noted after 34 years of age. Her visual acuity was 0.5 in the right eye and 0.6 in the left. The visual fields of both eyes showed slight progressive concentric narrowing. Hearing loss was gradually progressive. Her 13-year-old daughter also had optic atrophy in both eyes and low-tone hearing loss in both ears after 11 years of age. Her visual acuity was 0.8 in the right eye and 1.0 in the left. Her visual fields showed slight concentric narrowing. She had enlarged blind spots in both eyes. The mother and her daughter had deuteranomaly. Family history showed that the father, one brother and three sisters of the mother had congenital hearing loss. No other cause for the optic nerve atrophy and hearing disturbance could be found except heredity. PMID:7850273

  6. Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy

    PubMed Central

    Calvani, Riccardo; Joseph, Anna-Maria; Adhihetty, Peter J.; Miccheli, Alfredo; Bossola, Maurizio; Leeuwenburgh, Christiaan; Bernabei, Roberto; Marzetti, Emanuele

    2014-01-01

    Muscle loss during aging and disuse is a highly prevalent and disabling condition, but knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and muscle atrophy. Damaged mitochondria are not only less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display a greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, which suggests that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such a network will likely provide clinicians with novel and highly effective therapeutics to counter the muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions. PMID:23154422

  7. Masticatory muscles of mouse do not undergo atrophy in space.

    PubMed

    Philippou, Anastassios; Minozzo, Fabio C; Spinazzola, Janelle M; Smith, Lucas R; Lei, Hanqin; Rassier, Dilson E; Barton, Elisabeth R

    2015-07-01

    Muscle loading is important for maintaining muscle mass; when load is removed, atrophy is inevitable. However, in clinical situations such as critical care myopathy, masticatory muscles do not lose mass. Thus, their properties may be harnessed to preserve mass. We compared masticatory and appendicular muscles responses to microgravity, using mice aboard the space shuttle Space Transportation System-135. Age- and sex-matched controls remained on the ground. After 13 days of space flight, 1 masseter (MA) and tibialis anterior (TA) were frozen rapidly for biochemical and functional measurements, and the contralateral MA was processed for morphologic measurements. Flight TA muscles exhibited 20 ± 3% decreased muscle mass, 2-fold decreased phosphorylated (P)-Akt, and 4- to 12-fold increased atrogene expression. In contrast, MAs had no significant change in mass but a 3-fold increase in P-focal adhesion kinase, 1.5-fold increase in P-Akt, and 50-90% lower atrogene expression compared with limb muscles, which were unaltered in microgravity. Myofibril force measurements revealed that microgravity caused a 3-fold decrease in specific force and maximal shortening velocity in TA muscles. It is surprising that myofibril-specific force from both control and flight MAs were similar to flight TA muscles, yet power was compromised by 40% following flight. Continued loading in microgravity prevents atrophy, but masticatory muscles have a different set point that mimics disuse atrophy in the appendicular muscle. PMID:25795455

  8. Atrophy of the parietal lobe in preclinical dementia.

    PubMed

    Jacobs, Heidi I L; Van Boxtel, Martin P J; Uylings, Harry B M; Gronenschild, Ed H B M; Verhey, Frans R; Jolles, Jelle

    2011-03-01

    Cortical grey matter atrophy patterns have been reported in healthy ageing and Alzheimer disease (AD), but less consistently in the parietal regions of the brain. We investigated cortical grey matter volume patterns in parietal areas. The grey matter of the somatosensory cortex, superior and inferior parietal lobule was measured in 75 older adults (38 cognitively stable and 37 individuals with cognitive decline after 3 years). Dementia screening 6 years after scanning resulted in nine AD cases from the cognitively stable (n=3) and cognitive decline group (n=6), who were assigned to a third group, the preclinical AD group. When regional differences in cortical volume in the parietal lobe areas were compared between groups, significant differences were found between either the cognitive decline or stable group on the one hand and preclinical AD individuals on the other hand in the inferior parietal lobule. Group membership was best predicted by the grey matter volume of the inferior parietal lobule, compared to the other parietal lobe areas. The parietal lobe was characterised by a differential atrophy pattern based on cognitive status, which is in agreement with the 'last-developed-first-atrophied' principle. Future studies should investigate the surplus value of the inferior parietal lobe as a potential marker for the diagnosis of AD compared to other brain regions, such as the medial temporal lobe and the prefrontal lobe. PMID:21130554

  9. Motor features in posterior cortical atrophy and their imaging correlates.

    PubMed

    Ryan, Natalie S; Shakespeare, Timothy J; Lehmann, Manja; Keihaninejad, Shiva; Nicholas, Jennifer M; Leung, Kelvin K; Fox, Nick C; Crutch, Sebastian J

    2014-12-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by impaired higher visual processing skills; however, motor features more commonly associated with corticobasal syndrome may also occur. We investigated the frequency and clinical characteristics of motor features in 44 PCA patients and, with 30 controls, conducted voxel-based morphometry, cortical thickness, and subcortical volumetric analyses of their magnetic resonance imaging. Prominent limb rigidity was used to define a PCA-motor subgroup. A total of 30% (13) had PCA-motor; all demonstrating asymmetrical left upper limb rigidity. Limb apraxia was more frequent and asymmetrical in PCA-motor, as was myoclonus. Tremor and alien limb phenomena only occurred in this subgroup. The subgroups did not differ in neuropsychological test performance or apolipoprotein E4 allele frequency. Greater asymmetry of atrophy occurred in PCA-motor, particularly involving right frontoparietal and peri-rolandic cortices, putamen, and thalamus. The 9 patients (including 4 PCA-motor) with pathology or cerebrospinal fluid all showed evidence of Alzheimer's disease. Our data suggest that PCA patients with motor features have greater atrophy of contralateral sensorimotor areas but are still likely to have underlying Alzheimer's disease. PMID:25086839

  10. The pathogenesis and treatment of cardiac atrophy in cancer cachexia.

    PubMed

    Murphy, Kate T

    2016-02-15

    Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. In addition to a loss of skeletal muscle mass and function, many patients with cancer cachexia also experience cardiac atrophy, remodeling, and dysfunction, which in the field of cancer cachexia is described as cardiac cachexia. The cardiac alterations may be due to underlying heart disease, the cancer itself, or problems initiated by the cancer treatment and, unfortunately, remains largely underappreciated by clinicians and basic scientists. Despite recent major advances in the treatment of cancer, little progress has been made in the treatment of cardiac cachexia in cancer, and much of this is due to lack of information regarding the mechanisms. This review focuses on the cardiac atrophy associated with cancer cachexia, describing some of the known mechanisms and discussing the current and future therapeutic strategies to treat this condition. Above all else, improved awareness of the condition and an increased focus on identification of mechanisms and therapeutic targets will facilitate the eventual development of an effective treatment for cardiac atrophy in cancer cachexia. PMID:26718971

  11. Autophagy in pancreatic acinar cells in caerulein-treated mice: immunolocalization of related proteins and their potential as markers of pancreatitis.

    PubMed

    Zhang, Leshuai; Zhang, Jun; Shea, Katherine; Xu, Lin; Tobin, Grainne; Knapton, Alan; Sharron, Stewart; Rouse, Rodney

    2014-01-01

    Drug-induced pancreatitis (DIP) is an underdiagnosed condition that lacks sensitive and specific biomarkers. To better understand the mechanisms of DIP and to identify potential tissue biomarkers, we studied experimental pancreatitis induced in male C57BL/6 mice by intraperitoneal injection of caerulein (10 or 50 μg/kg) at 1-hr intervals for a total of 7 injections. Pancreata from caerulein-treated mice exhibited consistent acinar cell autophagy and apoptosis with infrequent necrosis. Kinetic assays for serum amylase and lipase also showed a dose-dependent increase. Terminal deoxynucleotidyl transferase-mediated biotin-dNTP nick labeling (TUNEL) detected dose-dependent acinar cell apoptosis. By light microscopy, autophagy was characterized by the formation of autophagosomes and autolysosomes (ALs) within the cytoplasm of acinar cells. Immunohistochemical studies with specific antibodies for proteins related to autophagy and pancreatic stress were conducted to evaluate these proteins as potential biomarkers of pancreatitis. Western blots were used to confirm immunohistochemical results using pancreatic lysates from control and treated animals. Autophagy was identified as a contributing process in caerulein-induced pancreatitis and proteins previously associated with autophagy were upregulated following caerulein treatment. Autophagosomes and ALs were found to be a common pathway, in which cathepsins, lysosome-associated membrane protein 2, vacuole membrane protein 1, microtubule-associated protein 1 light chain 3 (LC3), autophagy-related protein 9, Beclin1, and pancreatitis-associated proteins were simultaneously involved in response to caerulein stimulus. Regenerating islet-derived 3 gamma (Reg3γ), a pancreatic acute response protein, was dose-dependently induced in caerulein-treated mice and colocalized with the autophagosomal marker, LC3. This finding supports Reg3γ as a candidate biomarker for pancreatic injury. PMID:23640381

  12. Damage to pancreatic acinar cells and preservation of islets of Langerhans in a rat model of acute pancreatitis induced by Karwinskia humboldtiana (buckthorn).

    PubMed

    Carcano-Diaz, Katya; Garcia-Garcia, Aracely; Segoviano-Ramirez, Juan Carlos; Rodriguez-Rocha, Humberto; Loera-Arias, Maria de Jesus; Garcia-Juarez, Jaime

    2016-09-01

    Karwinskia humboldtiana (Kh) is a poisonous plant that grows in some regions of the American continent. Consuming large amounts of Kh fruit results in acute intoxication leading to respiratory failure, culminating in death within days. There is evidence of histological damage to the lungs, liver, and kidneys following accidental and experimental Kh intoxication. To date, the microscopic effect of Kh consumption on the pancreas has not been described. We examined the early effects of Kh fruit on pancreatic tissue at different stages of acute intoxication in the Wistar rat. We found progressive damage confined to the exocrine pancreas, starting with a reduction in the number of zymogen granules, loss of acinar architecture, the presence of autophagy-like vesicles, apoptosis and inflammatory infiltrate. The pancreatic pathology culminated in damaged acini characterized by necrosis and edema, with a complete loss of lobular architecture. Interestingly, the morphology of the islets of Langerhans was conserved throughout our evaluations. Taken together, our results indicate the damage induced by a high dose of Kh fruit in the Wistar rat is consistent with an early acute necrotizing pancreatitis that exclusively affects the exocrine pancreas. Therefore, this system might be useful as an animal model to study the treatment of pancreatic diseases. More importantly, as the islets of Langerhans were preserved, the active compounds of Kh fruit could be utilized for the treatment of acinar pancreatic cancer. Further studies might provide insight into the severity of acute Kh intoxication in humans and influence the design of treatments for pancreatic diseases and acinar pancreatic cancer. PMID:26877198

  13. A skeleton-tree-based approach to acinar morphometric analysis using microcomputed tomography with comparison of acini in young and old C57BL/6 mice.

    PubMed

    Kizhakke Puliyakote, Abhilash S; Vasilescu, Dragoş M; Sen Sharma, Kriti; Wang, Ge; Hoffman, Eric A

    2016-06-15

    We seek to establish a method using interior tomographic techniques (Xradia MicroXCT-400) for acinar morphometric analysis using the pathway center lines from micro X-ray computed tomographic (Micro-CT) images as the road map. Through the application of these techniques, we present a method to extend the atlas of murine lungs to acinar levels and present a comparison between two age groups of the C57BL/6 strain. Lungs fixed via vascular perfusion were scanned using high-resolution Micro-CT protocols. Individual acini were segmented, and skeletonized paths to alveolar sacs from the entrance to the acinus were formed. Morphometric parameters, including branch lengths, diameters, and branching angles, were generated. Six mice each, at two age groups (∼20 and ∼90 wk of age), were studied. Additive Gaussian noise (0 mean and SD 1, 2, 5, and 10) was used to test the robustness of the analytical method. Noise-based variations were within ±6 μm for branch lengths and ±5 μm for diameters. At a noise level of 10, errors increased. Branch diameters were less susceptible to noise than lengths. There was >95% center line overlap across all noise levels. The measurements obtained using the center lines as a road map were not affected by added noise. Acini from younger mice had smaller branch diameters and lengths at all generations without significant differences in branching angles. The relative distribution of volume in the alveolar ducts was similar across both age groups. The method has been demonstrated to be repeatable and robust to image noise and provides a new, nondestructive technique to assess and compare acinar morphometry quantitatively. PMID:26940656

  14. Crystallization and preliminary X-ray analysis of two variants of the Escherichia coli O157 ParE2–PaaA2 toxin–antitoxin complex

    PubMed Central

    Sterckx, Yann G. J.; Haesaerts, Sarah; Van Melderen, Laurence; Loris, Remy

    2014-01-01

    The paaR2–paaA2–parE2 operon is a three-component toxin–antitoxin module encoded in the genome of the human pathogen Escherichia coli O157. The toxin (ParE2) and antitoxin (PaaA2) interact to form a nontoxic toxin–antitoxin complex. In this paper, the crystallization and preliminary characterization of two variants of the ParE2–PaaA2 toxin–antitoxin complex are described. Selenomethionine-derivative crystals of the full-length ParE2–PaaA2 toxin–antitoxin complex diffracted to 2.8 Å resolution and belonged to space group P41212 (or P43212), with unit-cell parameters a = b = 90.5, c = 412.3 Å. It was previously reported that the full-length ParE2–PaaA2 toxin–antitoxin complex forms a higher-order oligomer. In contrast, ParE2 and PaaA213–63, a truncated form of PaaA2 in which the first 12 N-terminal residues of the antitoxin have been deleted, form a heterodimer as shown by analytical gel filtration, dynamic light scattering and small-angle X-ray scattering. Crystals of the PaaA213–63–ParE2 complex diffracted to 2.7 Å resolution and belonged to space group P6122 (or P6522), with unit-cell parameters a = b = 91.6, c = 185.6 Å. PMID:25195911

  15. PI3 kinase regulation of skeletal muscle hypertrophy and atrophy.

    PubMed

    Glass, David J

    2010-01-01

    Activation of the PI3 kinase pathway can induce skeletal muscle hypertrophy, defined as an increase in skeletal muscle mass. In mammals, skeletal muscle hypertrophy occurs as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle fibers. This pathway's effects on skeletal muscle have been implicated most prominently downstream of Insulin-like growth factor 1 signaling. IGF-1's pro-hypertrophy activity comes predominantly through its ability to activate the Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Akt is a serine-threonine protein kinase that can induce protein synthesis and block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the E3 ubiquitin ligases MuRF1 and MAFbx (also called Atrogin-1), by phosphorylating and thereby inhibiting the nuclear translocation of the FOXO (also called "forkhead") family of transcription factors. Once phosphorylated by Akt, the FOXOs are excluded from the nucleus, and upregulation of MuRF1 and MAFbx is blocked. MuRF1 and MAFbx mediate atrophy by ubiquitinating particular protein substrates, causing them to undergo degradation by the proteasome. MuRF1's substrates include several components of the sarcomeric thick filament, including Myosin Heavy Chain (MyHC). Thus, by blocking MuRF1 activation, IGF-1 helps prevent the breakdown of the thick filament under atrophy conditions.IGF1/PI3K/Akt signaling also can dominantly inhibit the effects of a secreted protein called "myostatin," which is a member of the TGFβ family of proteins. Deletion or inhibition of myostatin causes an increase in skeletal muscle size, because myostatin acts both to inhibit myoblast differentiation and to block the Akt pathway. Thus by blocking myostatin, PI3K/Akt activation stimulates differentiation and protein synthesis by this distinct mechanism. Myostatin induces the phosphorylation and activation of the transcription factors of Smad2 and Smad3, downstream of the Act

  16. Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy.

    PubMed

    Dyle, Michael C; Ebert, Scott M; Cook, Daniel P; Kunkel, Steven D; Fox, Daniel K; Bongers, Kale S; Bullard, Steven A; Dierdorff, Jason M; Adams, Christopher M

    2014-05-23

    Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy. PMID:24719321

  17. Cerebral blood flow and brain atrophy correlated by xenon contrast CT scanning

    SciTech Connect

    Kitagawa, Y.; Meyer, J.S.; Tanahashi, N.; Rogers, R.L.; Tachibana, H.; Kandula, P.; Dowell, R.E.; Mortel, K.F.

    1985-11-01

    Correlations between cerebral blood flow (CBF) measured during stable xenon contrast CT scanning and standard CT indices of brain atrophy were investigated in the patients with senile dementia of Alzheimer type, multi-infarct dementia and idiopathic Parkinson's disease. Compared to age-matched normal volunteers, significant correlations were found in patients with idiopathic Parkinson's disease between cortical and subcortical gray matter blood flow and brain atrophy estimated by the ventricular body ratio, and mild to moderate brain atrophy were correlated with stepwise CBF reductions. However, in patients with senile dementia of Alzheimer type and multi-infarct dementia, brain atrophy was not associated with stepwise CBF reductions. Overall correlations between brain atrophy and reduced CBF were weak. Mild degrees of brain atrophy are not always associated with reduced CBF.

  18. Blockade of ATP binding site of P2 purinoceptors in rat parotid acinar cells by isothiocyanate compounds.

    PubMed

    Soltoff, S P; McMillian, M K; Talamo, B R; Cantley, L C

    1993-05-01

    Extracellular ATP activates a P2Z-type purinergic receptor (purinoceptor) in rat parotid acinar cells that increases the intracellular free Ca2+ concentration via the entry of extracellular Ca2+ through an ATP-sensitive cation channel (Soltoff et al., Am J Physiol 262: C934-C940, 1992). To learn more about the ATP binding site of the purinoceptor, we examined the effects of several stilbene isothiocyanate analogs of DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid), which block the binding of [32P]ATP to intact parotid cells (McMillian et al., Biochem J 255:291-300, 1988) and blocked the activation of the P2Z purinoceptor. The ATP-stimulated 45Ca2+ uptake was blocked by DIDS, H2DIDS (dihydro-DIDS; 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonic acid), and SITS (4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid), but not by DNDS (4,4'-dinitrostilbene-2,2'-disulfonic acid), a stilbene disulfonate compound lacking isothiocyanate (SCN-) groups, or by KSCN. The potency of the stilbene disulfonates was related to the number of isothiocyanate groups on each compound. Under the experimental conditions, the IC50 value of DIDS (approximately 35 microM), which has two SCN-groups, was much lower than that of SITS (approximately 125 microM), which has only one SCN-group. The inhibitory effects of DIDS appeared to be much more potent than those of SITS due to the kinetics of their binding to the purinoceptors. Eosin-5-isothiocyanate (EITC) and fluorescein-5-isothiocyanate (FITC), non-stilbene isothiocyanate compounds with single SCN-groups, also blocked the response to ATP and were less potent than DIDS. Trinitrophenyl-ATP (TNP-ATP), an ATP derivative that is not an effective agonist of the parotid P2Z receptor, blocked the covalent binding of DIDS to the plasma membrane, suggesting that ATP and DIDS bind to the same site. Reactive Blue 2 (Cibacron Blue 3GA), an anthraquinone-sulfonic acid derivative that is a noncovalent purinergic antagonist, also blocked

  19. Quantitative characterization of the protein contents of the exocrine pancreatic acinar cell by soft x-ray microscopy and advanced digital imaging methods

    SciTech Connect

    Loo Jr., Billy W.

    2000-06-09

    The study of the exocrine pancreatic acinar cell has been central to the development of models of many cellular processes, especially of protein transport and secretion. Traditional methods used to examine this system have provided a wealth of qualitative information from which mechanistic models have been inferred. However they have lacked the ability to make quantitative measurements, particularly of the distribution of protein in the cell, information critical for grounding of models in terms of magnitude and relative significance. This dissertation describes the development and application of new tools that were used to measure the protein content of the major intracellular compartments in the acinar cell, particularly the zymogen granule. Soft x-ray microscopy permits image formation with high resolution and contrast determined by the underlying protein content of tissue rather than staining avidity. A sample preparation method compatible with x-ray microscopy was developed and its properties evaluated. Automatic computerized methods were developed to acquire, calibrate, and analyze large volumes of x-ray microscopic images of exocrine pancreatic tissue sections. Statistics were compiled on the protein density of several organelles, and on the protein density, size, and spatial distribution of tens of thousands of zymogen granules. The results of these measurements, and how they compare to predictions of different models of protein transport, are discussed.

  20. Multiple system atrophy: alpha-synuclein and neuronal degeneration.

    PubMed

    Yoshida, Mari

    2007-10-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome (SDS). The histopathological hallmark is the formation of alpha-synuclein-positive glial cytoplasmic inclusions (GCIs) in oligodendroglia. alpha-synuclein aggregation is also found in glial nuclear inclusions, neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurites. We evaluated the pathological features of 102 MSA cases, and presented the pathological spectrum of MSA and initial features of alpha-synuclein accumulation. We found that 39% of the 102 cases showed equivalent SND and OPCA pathologies, 33% showed OPCA- and 22% showed SND-predominant pathology, whereas 6% showed extremely mild changes. Our pathological analysis indicated that OPCA-type was relatively more frequent and SND-type was less frequent in Japanese MSA cases, compared to the relatively high frequency of SND-type in Western countries, suggesting that different phenotypic patterns of MSA may exist between races. In the early stage, in addition to GCIs, NNIs and diffuse homogenous alpha-synuclein staining in neuronal nuclei and cytoplasm were observed in lesions in the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of thoracic spinal cord, lower motor neurons and cortical pyramidal neurons. A subgroup of MSA cases with severe temporal atrophy showed numerous NCIs, particularly in the limbic system. These findings suggest that primary non-fibrillar and fibrillar alpha-synuclein aggregation also occur in neurons. The oligo-myelin-axon-neuron complex mechanism, along with the direct involvement of neurons themselves, may synergistically accelerate the degenerative process of MSA. PMID:18018485

  1. Dominant spinal muscular atrophy with lower extremity predominance

    PubMed Central

    Harms, M.B.; Allred, P.; Gardner, R.; Fernandes Filho, J.A.; Florence, J.; Pestronk, A.; Al-Lozi, M.; Baloh, R.H.

    2010-01-01

    Objective: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA. Methods: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed. Results: Ten affected individuals (ages 7–58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 (θ = 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,765–106,368,585. No segregating copy number variations were found within the disease interval. Conclusions: We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy–lower extremity, dominant. GLOSSARY lod = logarithm of the odds; SMA = spinal muscular atrophy; SMA-LED = spinal muscular atrophy–lower extremity, dominant; SNP = single-nucleotide polymorphism. PMID:20697106

  2. Abdominal Obesity and Brain Atrophy in Type 2 Diabetes Mellitus

    PubMed Central

    Callisaya, Michele; Blizzard, Leigh; Sharman, James E.; Venn, Alison; Phan, Thanh G.; Beare, Richard; Forbes, Josephine; Blackburn, Nicholas B.; Srikanth, Velandai

    2015-01-01

    Aim Type 2 diabetes mellitus (T2D) is associated with gray matter atrophy. Adiposity and physical inactivity are risk factors for T2D and brain atrophy. We studied whether the associations of T2D with total gray matter volume (GMV) and hippocampal volume (HV) are dependent on obesity and physical activity. Materials and Methods In this cross-sectional study, we measured waist-hip ratio (WHR), body mass index (BMI), mean steps/day and brain volumes in a community dwelling cohort of people with and without T2D. Using multivariable linear regression, we examined whether WHR, BMI and physical activity mediated or modified the association between T2D, GMV and HV. Results There were 258 participants with (mean age 67±7 years) and 302 without (mean age 72±7 years) T2D. Adjusting for age, sex and intracranial volume, T2D was independently associated with lower total GMV (p = 0.001) and HV (p<0.001), greater WHR (p<0.001) and BMI (p<0.001), and lower mean steps/day (p = 0.002). After adjusting for covariates, the inclusion of BMI and mean steps/day did not significantly affect the T2D-GMV association, but WHR attenuated it by 32% while remaining independently associated with lower GMV (p<0.01). The T2D-HV association was minimally changed by the addition of BMI, steps/day or WHR in the model. No statistical interactions were observed between T2D and measures of obesity and physical activity in explaining brain volumes. Conclusions Abdominal obesity or its downstream effects may partially mediate the adverse effect of T2D on brain atrophy. This requires confirmation in longitudinal studies. PMID:26560876

  3. Fibrosis, adipogenesis, and muscle atrophy in congenital muscular torticollis.

    PubMed

    Chen, Huan-Xiong; Tang, Sheng-Ping; Gao, Fu-Tang; Xu, Jiang-Long; Jiang, Xian-Ping; Cao, Juan; Fu, Gui-Bing; Sun, Ke; Liu, Shi-Zhe; Shi, Wei

    2014-11-01

    In the traditional view, muscle atrophy and interstitial fibrosis were regarded as the basic pathological features of congenital muscular torticollis (CMT). But in the ultrastructure study, the mesenchyme-like cells, myoblasts, myofibroblasts, and fibroblasts were found in the proliferation of interstitium of CMT. To investigate the characteristics of pathological features and the mechanisms of muscle atrophy in CMT, we retrospectively reviewed the medical records of 185 CMT patients from July 2009 to July 2011 in Shenzhen Children's Hospital in China and performed pathological studies. According to age, the 185 CMT patients were divided into 4 groups. All resected surgical specimens were processed for hematoxylin and eosin staining and Masson trichromic staining. Sudan III staining was used for frozen sections, whereas immunohistochemical staining for S-100, calpain-1, ubiquitin, and 20S proteasome was carried out on 40 CMT specimens. Eight adductor muscle specimens from 8 patients with development dysplasia of the hip were taken as control group in the immunohistochemical staining. By Masson trichromic staining, the differences in the percent area of fibrous tissue in each CMT groups were significant. In Sudan III staining and immunostaining for S-100, adipocyte hyperplasia was the pathological feature of CMT. Moreover, compared with controls, most atrophic muscle fibers in CMT specimens were found to show strong immunoreactivity for calpain-1, ubiquitin, and 20S proteasome. With increasing age, fibrosis peaked at both sides and it was low in middle age group. Adipocytes increased with age. The characteristics of pathological features in CMT are changeable with age. The calpain and the ubiquitin-proteasome system may play a role in muscle atrophy of CMT. In the CMT, adipogenesis, fibrogenesis, and myogenesis may be the results of mesenchyme-like cells in SCM (sternocleidomastoid muscle). In conclusion, the present study furthermore supports maldevelopment of the

  4. Bone marrow atrophy induced by murine cytomegalovirus infection.

    PubMed Central

    Gibbons, A E; Price, P; Shellam, G R

    1994-01-01

    Acute, sublethal infection of mice with murine cytomegalovirus (MCMV) resulted in up to 80% decreases in the number of cells recoverable from the bone marrow, and a decrease in peripheral blood leucocyte counts during the first week of infection. Depopulation of the leucopoietic areas of the marrow was evident from examination of histological sections. The severity of bone marrow atrophy in MCMV-infected mice of different strains correlated with previously described genetically determined sensitivity to MCMV disease. Although the phenomenon only occurred when mice were inoculated with infectious virus preparations, fewer than one in 10(5) marrow cells were productively infected, suggesting that atrophy was not due to lytic infection of large numbers of bone marrow cells. Interestingly, increases in serum colony-stimulating activity were observed and these were proportional to the severity of bone marrow atrophy. After MCMV infection, we observed increases in the proportions of cells expressing some B-cell and myeloid cell markers and a decrease in the proportion of cells expressing an erythroid cell marker. There was no change in the frequency of marrow cells expressing mature T-cell markers. The numbers of myeloid lineage-committed progenitor cells (GM-CFU) in the marrow decreased 10- to 20-fold in BALB/c nu/+ mice, while there was a threefold decrease in their numbers in BALB/c nu/nu mice. In addition, increases in serum colony-stimulating activity were greater in BALB/c nu/+ mice than in BALB/c nu/nu mice. Our results suggest that growth factors produced after MCMV infection may accelerate the maturation and migration of cells from the marrow to sites of virus replication and inflammation, thus accounting for the depletion in numbers of marrow cells observed soon after MCMV infection. Images Figure 3 Figure 4 PMID:7959876

  5. Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy.

    PubMed

    Tando, Toshimi; Hirayama, Akiyoshi; Furukawa, Mitsuru; Sato, Yuiko; Kobayashi, Tami; Funayama, Atsushi; Kanaji, Arihiko; Hao, Wu; Watanabe, Ryuichi; Morita, Mayu; Oike, Takatsugu; Miyamoto, Kana; Soga, Tomoyoshi; Nomura, Masatoshi; Yoshimura, Akihiko; Tomita, Masaru; Matsumoto, Morio; Nakamura, Masaya; Toyama, Yoshiaki; Miyamoto, Takeshi

    2016-06-01

    Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes. PMID:27129272

  6. Mitochondrial Dysfunction Launches Dexamethasone-Induced Skeletal Muscle Atrophy via AMPK/FOXO3 Signaling.

    PubMed

    Liu, Jing; Peng, Yunhua; Wang, Xun; Fan, Yingying; Qin, Chuan; Shi, Le; Tang, Ying; Cao, Ke; Li, Hua; Long, Jiangang; Liu, Jiankang

    2016-01-01

    Muscle atrophy occurs in several pathologic conditions such as diabetes and chronic obstructive pulmonary disease (COPD), as well as after long-term clinical administration of synthesized glucocorticoid, where increased circulating glucocorticoid accounts for the pathogenesis of muscle atrophy. Others and we previously reported mitochondrial dysfunction in muscle atrophy-related conditions and that mitochondria-targeting nutrients efficiently prevent kinds of muscle atrophy. However, whether and how mitochondrial dysfunction involves glucocorticoid-induced muscle atrophy remains unclear. Therefore, in the present study, we measured mitochondrial function in dexamethasone-induced muscle atrophy in vivo and in vitro, and we found that mitochondrial respiration was compromised on the 3rd day following after dexamethasone administration, earlier than the increases of MuRF1 and Fbx32, and dexamethasone-induced loss of mitochondrial components and key mitochondrial dynamics proteins. Furthermore, dexamethasone treatment caused intracellular ATP deprivation and robust AMPK activation, which further activated the FOXO3/Atrogenes pathway. By directly impairing mitochondrial respiration, FCCP leads to similar readouts in C2C12 myotubes as dexamethasone does. On the contrary, resveratrol, a mitochondrial nutrient, efficiently reversed dexamethasone-induced mitochondrial dysfunction and muscle atrophy in both C2C12 myotubes and mice, by improving mitochondrial function and blocking AMPK/FOXO3 signaling. These results indicate that mitochondrial dysfunction acts as a central role in dexamethasone-induced skeletal muscle atrophy and that nutrients or drugs targeting mitochondria might be beneficial in preventing or curing muscle atrophy. PMID:26592738

  7. Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy.

    PubMed

    Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

    2015-01-01

    Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy. PMID:25945103

  8. Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy

    PubMed Central

    Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

    2015-01-01

    Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy. PMID:25945103

  9. A randomized clinical trial of lithium in multiple system atrophy.

    PubMed

    Saccà, Francesco; Marsili, Angela; Quarantelli, Mario; Brescia Morra, Vincenzo; Brunetti, Arturo; Carbone, Rosa; Pane, Chiara; Puorro, Giorgia; Russo, Cinzia Valeria; Salvatore, Elena; Tucci, Tecla; De Michele, Giuseppe; Filla, Alessandro

    2013-02-01

    The aim of our study was to test the safety and tolerability of lithium in multiple system atrophy (MSA). The study was randomized, placebo-controlled, and double-blind. The primary endpoint of the study was safety and tolerability. An interim analysis, performed 1 year after the first patient was randomized, showed a higher proportion of trial abandon (P < 0.01) and a higher number of adverse events (P < 0.02) in the lithium group. The trial was stopped by the Data Monitoring Committee. Overall, lithium was not well tolerated, and we do not encourage future studies with lithium in MSA patients. PMID:22932748

  10. Cerebellar atrophy in a patient with velocardiofacial syndrome.

    PubMed Central

    Lynch, D R; McDonald-McGinn, D M; Zackai, E H; Emanuel, B S; Driscoll, D A; Whitaker, L A; Fischbeck, K H

    1995-01-01

    Velocardiofacial syndrome and DiGeorge syndrome have not previously been associated with central nervous system degeneration. We report a 34 year old man who presented for neurological evaluation with cerebellar atrophy of unknown aetiology. On historical review, he had neonatal hypocalcaemia, an atrial septal defect, and a corrected cleft palate. His physical examination showed the characteristic facies of velocardiofacial syndrome as well as dysmetria and dysdiadocho-kinesia consistent with cerebellar degeneration. Molecular cytogenetic studies showed a deletion of 22q11.2. This man is the first reported patient with the association of a neurodegenerative disorder and 22q11.2 deletion syndrome. Images PMID:7562973

  11. Muscle spasms associated with Sudeck's atrophy after injury.

    PubMed Central

    Marsden, C D; Obeso, J A; Traub, M M; Rothwell, J C; Kranz, H; La Cruz, F

    1984-01-01

    Four patients developed abnormal involuntary movements of a limb after injury. All subsequently developed sympathetic algodystrophy with Sudeck's atrophy and then abnormal muscle spasms or jerks of the affected limb, lasting years. Sympathetic block in three patients did not relieve the abnormal movements. Two patients obtained partial recovery spontaneously, but the other two required surgery for relief. The pathophysiology of this condition remains to be determined but the evidence suggests that it is a distinct, disabling clinical syndrome. Images FIG 1 FIG 3 PMID:6198018

  12. Spinal cord atrophy in neuromyelitis optica spectrum disorders.

    PubMed

    Wang, Yanqiang; Wang, Yuge; Tan, Sa; Lu, Zhengqi

    2016-07-01

    Neuromyelitis optica spectrum disorders (NMOSDs) is an immune mediated inflammatory disease of the central nervous system (CNS) and often displays a monophasic or relapsing-remitting course. Spinal cord lesions is one of the predominant characteristics in NMOSD. Assessment of spinal cord atrophy (SCA) is of growing interest in monitoring disease progression in multiple sclerosis (MS), and correlates closely with the neurological disability. However, the studies of the SCA in NMOSD are still scarce. In this review, we describe the recent progress about the SCA in NMOSD, mainly the NMOSD with spinal cord lesions. PMID:27456868

  13. Evaluation of the endogenous glucocorticoid hypothesis of denervation atrophy

    NASA Technical Reports Server (NTRS)

    Konagaya, Masaaki; Konagaya, Yoko; Max, Stephen R.

    1988-01-01

    The effects are studied of the oral administration of RU38486, a potent selective glucocorticoid antagonist, on muscle weight, non-collagen protein content, and selected enzyme activities (choline acetyltransferase, glucose 6-phosphate dehydrogenase, and glutamine synthetase) following denervation of rat skeletal muscle. Neither decreases in muscle weight, protein content, and choline acetyltransferase activity, nor increases in the activities of glucose 6-phosphate dehydrogernase and glutamine synthetase were affected by RU38486. These data do not support the hypothesis that denervation atrophy results from enhanced sensitivity of muscle to endogenous glucocorticoids.

  14. Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy

    PubMed Central

    Mohseni, Jafar; Zabidi-Hussin, Z.A.M.H.; Sasongko, Teguh Haryo

    2013-01-01

    Histone acetylation plays an important role in regulation of transcription in eukaryotic cells by promoting a more relaxed chromatin structure necessary for transcriptional activation. Histone deacetylases (HDACs) remove acetyl groups and suppress gene expression. HDAC inhibitors (HDACIs) are a group of small molecules that promote gene transcription by chromatin remodeling and have been extensively studied as potential drugs for treating of spinal muscular atrophy. Various drugs in this class have been studied with regard to their efficacy in increasing the expression of survival of motor neuron (SMN) protein. In this review, we discuss the current literature on this topic and summarize the findings of the main studies in this field. PMID:24130434

  15. Protective variant for hippocampal atrophy identified by whole exome sequencing.

    PubMed

    Nho, Kwangsik; Kim, Sungeun; Risacher, Shannon L; Shen, Li; Corneveaux, Jason J; Swaminathan, Shanker; Lin, Hai; Ramanan, Vijay K; Liu, Yunlong; Foroud, Tatiana M; Inlow, Mark H; Siniard, Ashley L; Reiman, Rebecca A; Aisen, Paul S; Petersen, Ronald C; Green, Robert C; Jack, Clifford R; Weiner, Michael W; Baldwin, Clinton T; Lunetta, Kathryn L; Farrer, Lindsay A; Furney, Simon J; Lovestone, Simon; Simmons, Andrew; Mecocci, Patrizia; Vellas, Bruno; Tsolaki, Magda; Kloszewska, Iwona; Soininen, Hilkka; McDonald, Brenna C; Farlow, Martin R; Ghetti, Bernardino; Huentelman, Matthew J; Saykin, Andrew J

    2015-03-01

    We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. PMID:25559091

  16. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy

    PubMed Central

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term “minipolyfasciculations” may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  17. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy.

    PubMed

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term "minipolyfasciculations" may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  18. IPSCs, a Promising Tool to Restore Muscle Atrophy.

    PubMed

    Pareja-Galeano, Helios; Sanchis-Gomar, Fabian; Emanuele, Enzo; Gallardo, María Esther; Lucia, Alejandro

    2016-02-01

    Induced pluripotent stem cells (iPSCs) are a promising tool for regenerative medicine in chronic conditions associated with muscle atrophy since iPSCs are easier to obtain, pose less ethical limitations and can better capture human genetic diversity compared with human embryonic stem cells. We highlight the potentiality of iPSCs for treating muscle-affecting conditions for which no effective cure is yet available, notably aging sarcopenia and inherited neurometabolic conditions. J. Cell. Physiol. 231: 259-260, 2016. © 2015 Wiley Periodicals, Inc. PMID:26224204

  19. Study of the interaction between a diblock polyelectrolyte PDMA-b-PAA and a gemini surfactant 12-6-12 in basic media.

    PubMed

    Kang, Hongmei; Peng, Baoliang; Liang, Yanyan; Han, Xia; Liu, Honglai

    2009-05-01

    The interactions between negatively charged diblock polyelectrolyte PDMA(71)-b-PAA(59) and oppositely charged gemini surfactant hexylene-1,6-bis(dodecyldimethylammonium bromide) (12-6-12) in basic media were studied using dynamic light scattering, fluorescence spectroscopy, surface tension, and (1)H NMR. With increased addition of surfactant, the conformation of polyelectrolyte experienced changes from the initial unimer with open-extended PAA block, to the nano-scaled aggregates/complexes with a maximum hydrodynamic diameter (D(h)), and finally to the stable complexes with a smaller D(h). Accordingly, the value of D(h) during the whole process of increasing the surfactant concentration changed from 14-17 nm, to 184 nm, and to the final 70 nm, respectively. This transformation was driven by the electrostatic attractive/repulsive interactions, the hydrophobic interaction between hydrophobic surfactant tails, and the hydrophilicity of PDMA block. PMID:19217121

  20. Small-angle X-ray scattering- and nuclear magnetic resonance-derived conformational ensemble of the highly flexible antitoxin PaaA2.

    PubMed

    Sterckx, Yann G J; Volkov, Alexander N; Vranken, Wim F; Kragelj, Jaka; Jensen, Malene Ringkjøbing; Buts, Lieven; Garcia-Pino, Abel; Jové, Thomas; Van Melderen, Laurence; Blackledge, Martin; van Nuland, Nico A J; Loris, Remy

    2014-06-10

    Antitoxins from prokaryotic type II toxin-antitoxin modules are characterized by a high degree of intrinsic disorder. The description of such highly flexible proteins is challenging because they cannot be represented by a single structure. Here, we present a combination of SAXS and NMR data to describe the conformational ensemble of the PaaA2 antitoxin from the human pathogen E. coli O157. The method encompasses the use of SAXS data to filter ensembles out of a pool of conformers generated by a custom NMR structure calculation protocol and the subsequent refinement by a block jackknife procedure. The final ensemble obtained through the method is validated by an established residual dipolar coupling analysis. We show that the conformational ensemble of PaaA2 is highly compact and that the protein exists in solution as two preformed helices, connected by a flexible linker, that probably act as molecular recognition elements for toxin inhibition. PMID:24768114

  1. A unique hetero-hexadecameric architecture displayed by the Escherichia coli O157 PaaA2-ParE2 antitoxin-toxin complex.

    PubMed

    Sterckx, Yann G-J; Jové, Thomas; Shkumatov, Alexander V; Garcia-Pino, Abel; Geerts, Lieselotte; De Kerpel, Maia; Lah, Jurij; De Greve, Henri; Van Melderen, Laurence; Loris, Remy

    2016-04-24

    Many bacterial pathogens modulate their metabolic activity, virulence and pathogenicity through so-called "toxin-antitoxin" (TA) modules. The genome of the human pathogen Escherichia coli O157 contains two three-component TA modules related to the known parDE module. Here, we show that the toxin EcParE2 maps in a branch of the RelE/ParE toxin superfamily that is distinct from the branches that contain verified gyrase and ribosome inhibitors. The structure of EcParE2 closely resembles that of Caulobacter crescentus ParE but shows a distinct pattern of conserved surface residues, in agreement with its apparent inability to interact with GyrA. The antitoxin EcPaaA2 is characterized by two α-helices (H1 and H2) that serve as molecular recognition elements to wrap itself around EcParE2. Both EcPaaA2 H1 and H2 are required to sustain a high-affinity interaction with EcParE2 and for the inhibition of EcParE2-mediated killing in vivo. Furthermore, evidence demonstrates that EcPaaA2 H2, but not H1, determines specificity for EcParE2. The initially formed EcPaaA2-EcParE2 heterodimer then assembles into a hetero-hexadecamer, which is stable in solution and is formed in a highly cooperative manner. Together these findings provide novel data on quaternary structure, TA interactions and activity of a hitherto poorly characterized family of TA modules. PMID:26996937

  2. Feasibility of the Medial Temporal lobe Atrophy index (MTAi) and derived methods for measuring atrophy of the medial temporal lobe

    PubMed Central

    Conejo Bayón, Francisco; Maese, Jesús; Fernandez Oliveira, Aníbal; Mesas, Tamara; Herrera de la Llave, Estibaliz; Álvarez Avellón, Tania; Menéndez-González, Manuel

    2014-01-01

    Introduction: The Medial Temporal-lobe Atrophy index (MTAi), 2D-Medial Temporal Atrophy (2D-MTA), yearly rate of MTA (yrRMTA) and yearly rate of relative MTA (yrRMTA) are simple protocols for measuring the relative extent of atrophy in the medial temporal lobe (MTL) in relation to the global brain atrophy. Albeit preliminary studies showed interest of these methods in the diagnosis of Alzheimer’s disease (AD), frontotemporal lobe degeneration (FTLD) and correlation with cognitive impairment in Parkinson’s disease (PD), formal feasibility and validity studies remained pending. As a first step, we aimed to assess the feasibility. Mainly, we aimed to assess the reproducibility of measuring the areas needed to compute these indices. We also aimed to assess the efforts needed to start using these methods correctly. Methods: A series of 290 1.5T-MRI studies from 230 subjects ranging 65–85 years old who had been studied for cognitive impairment were used in this study. Six inexperienced tracers (IT) plus one experienced tracer (ET) traced the three areas needed to compute the indices. Finally, tracers underwent a short survey on their experience learning to compute the MTAi and experience of usage, including items relative to training time needed to understand and apply the MTAi, time to perform a study after training and overall satisfaction. Results: Learning to trace the areas needed to compute the MTAi and derived methods is quick and easy. Results indicate very good intrarater Intraclass Correlation Coefficient (ICC) for the MTAi, good intrarater ICC for the 2D-MTA, yrMTA and yrRMTA and also good interrater ICC for the MTAi, 2D-MTA, yrMTA and yrRMTA. Conclusion: Our data support that MTAi and derived methods (2D-MTA, yrMTA and yrRTMA) have good to very good intrarater and interrater reproducibility and may be easily implemented in clinical practice even if new users have no experience tracing the area of regions of interest. PMID:25414666

  3. Genetic inhibition of JNK3 ameliorates spinal muscular atrophy.

    PubMed

    Genabai, Naresh K; Ahmad, Saif; Zhang, Zhanying; Jiang, Xiaoting; Gabaldon, Cynthia A; Gangwani, Laxman

    2015-12-15

    Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecular mechanism underlying neurodegeneration in SMA is unknown. No treatment is available to prevent neurodegeneration and reduce the burden of illness in SMA. We report that the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required for neuron degeneration caused by SMN deficiency. JNK3 deficiency reduces degeneration of cultured neurons caused by low levels of SMN. Genetic inhibition of JNK pathway in vivo by Jnk3 knockout results in amelioration of SMA phenotype. JNK3 deficiency prevents the loss of spinal cord motor neurons, reduces muscle degeneration, improves muscle fiber thickness and muscle growth, improves motor function and overall growth and increases lifespan of mice with SMA that shows a systemic rescue of phenotype by a SMN-independent mechanism. JNK3 represents a potential (non-SMN) therapeutic target for the treatment of SMA. PMID:26423457

  4. Juvenile spinal muscular atrophy: a new hexosaminidase deficiency phenotype.

    PubMed

    Johnson, W G; Wigger, H J; Karp, H R; Glaubiger, L M; Rowland, L P

    1982-01-01

    A 24-year-old Ashkenazi Jewish man was evaluated for a nine-year history of progressive leg weakness with fasciculations. Electromyography, nerve conduction velocities, muscle biopsy, and serum creatine kinase were consistent with anterior horn cell disease. On rectal biopsy, ganglion cells were filled with membranous cytoplasmic bodies and an unusual submucosal layer of periodic acid-Schiff positive histiocytes filled with granules was seen. Hexosaminidase A in serum and leukocytes was severely decreased in the patient and partially decreased in parents and a brother. A paternal relative had classic infantile Tay-Sachs disease. Juvenile spinal muscular atrophy in this patient, closely resembling the Kugelberg-Welander phenotype, resulted from an alpha-locus hexosaminidase deficiency disorder, possibly a genetic compound of HEX alpha 2 and a milder hexosaminidase alpha-locus allele. Other cases of hexosaminidase deficiency have included anterior horn cell disease as part of a more complex disorder, but this is the first case, to our knowledge, of a hexosaminidase deficiency disorder presenting as spinal muscular atrophy. PMID:6460466

  5. Neuropsychiatric Symptoms in Posterior Cortical Atrophy and Alzheimer Disease

    PubMed Central

    Crutch, Sebastian J.; Franco-Macías, Emilio; Gil-Néciga, Eulogio

    2016-01-01

    Background: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by early progressive visual dysfunction in the context of relative preservation of memory and a pattern of atrophy mainly involving the posterior cortex. The aim of the present study is to characterize the neuropsychiatric profile of PCA. Methods: The Neuropsychiatric Inventory was used to assess 12 neuropsychiatric symptoms (NPS) in 28 patients with PCA and 34 patients with typical Alzheimer disease (AD) matched by age, disease duration, and illness severity. Results: The most commonly reported NPS in both groups were depression, anxiety, apathy, and irritability. However, aside from a trend toward lower rates of apathy in patients with PCA, there were no differences in the percentage of NPS presented in each group. All those patients presenting visual hallucinations in the PCA group also met diagnostic criteria for dementia with Lewy bodies (DLB). Auditory hallucinations were only present in patients meeting diagnosis criteria for DLB. Conclusion: Prevalence of the 12 NPS examined was similar between patients with PCA and AD. Hallucinations in PCA may be helpful in the differential diagnosis between PCA-AD and PCA-DLB. PMID:26404166

  6. Spinal muscular atrophy with respiratory distress type 1 (SMARD1)

    PubMed Central

    San Millan, Beatriz; Fernandez, Jose M.; Navarro, Carmen; Reparaz, Alfredo; Teijeira, Susana

    2016-01-01

    Background: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a clinically and genetically distinct and uncommon variant of SMA that results from irreversible degeneration of α-motor neurons in the anterior horns of the spinal cord and in ganglion cells on the spinal root ganglia. Aims: To describe the clinical, electrophysiological, neuropathological, and genetic findings, at different stages from birth to death, of a Spanish child diagnosed with SMARD1. Patient and methods: We report the case of a 3-month-old girl with severe respiratory insufficiency and, later, intense hypotonia. Paraclinical tests included biochemistry, chest X-ray, and electrophysiological studies, among others. Muscle and nerve biopsies were performed at 5 and 10 months and studied under light and electron microscopy. Post-mortem examination and genetic investigations were performed. Results: Pre- and post-mortem histopathological findings demonstrated the disease progression over time. Muscle biopsy at 5 months of age was normal, however a marked neurogenic atrophy was present in post-mortem samples. Peripheral motor and sensory nerves were severely involved likely due to a primary axonal disorder. Automatic sequencing of IGHMBP2 revealed a compound heterozygous mutation. Conclusions: The diagnosis of SMARD1 should be considered in children with early respiratory insufficiency or in cases of atypical SMA. Direct sequencing of the IGHMBP2 gene should be performed. PMID:26709713

  7. Clinical features of spinal and bulbar muscular atrophy

    PubMed Central

    Rhodes, Lindsay E.; Freeman, Brandi K.; Auh, Sungyoung; Kokkinis, Angela D.; La Pean, Alison; Chen, Cheunju; Lehky, Tanya J.; Shrader, Joseph A.; Levy, Ellen W.; Harris-Love, Michael; Di Prospero, Nicholas A.

    2009-01-01

    Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models. PMID:19846582

  8. [Mechanism of neuronal degeneration of multiple system atrophy].

    PubMed

    Yoshida, Mari; Sone, Mie

    2009-09-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome (SDS). The histopathological hallmarks are alpha-synuclein (AS) positive glial cytoplasmic inclusions (GCIs) in oligodendroglias. AS aggregation is also found in glial nuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurites. Reviewing the pathological features in 102 MSA cases revealed that the, OPCA-type was relatively more frequent and SND-type was less frequent in Japanese MSA cases. The frequency of the SND-type is relatively high in Western countries. This different in the dominant type suggests that the phenotypic patterns of MSA may vary with the race. In early stages of MSA, in addition to GCIs, NNIs, NCIs, and diffuse homogenous stain of AS in neuronal nuclei and cytoplasm were observed in various vulnerable lesions including the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of the thoracic cord, lower motor neurons, and cortical pyramidal neurons. These findings indicated that the primary nonfibrillar and fibrillar AS aggregation also occurred in neurons. Therefore, both the direct involvement of neurons themselves and the oligodendroglia-myelin-axon mechanism may synergistically accelerate the degenerative process of MSA. PMID:19803404

  9. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

    PubMed Central

    Tisdale, Sarah

    2015-01-01

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID:26063904

  10. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    PubMed Central

    Ahmad, Saif; Bhatia, Kanchan; Kannan, Annapoorna; Gangwani, Laxman

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA. PMID:27042141

  11. Nuclear Factor-kappa B Signaling in Skeletal Muscle Atrophy

    PubMed Central

    Li, Hong; Malhotra, Shweta; Kumar, Ashok

    2008-01-01

    Skeletal muscle atrophy/wasting is a serious complication of a wide range of diseases and conditions such as aging, disuse, AIDS, chronic obstructive pulmonary disease, space travel, muscular dystrophy, chronic heart failure, sepsis, and cancer. Emerging evidence suggests that nuclear factor-kappa B (NF-κB) is one of most important signaling pathways linked to the loss of skeletal muscle mass in various physiological and pathophysiological conditions. Activation of NF-κB in skeletal muscle leads to degradation of specific muscle proteins, induces inflammation and fibrosis, and blocks the regeneration of myofibers after injury/atrophy. Recent studies employing genetic mouse models have provided strong evidence that NF-κB can serve as an important molecular target for the prevention of skeletal muscle loss. In this article, we have outlined the current understanding regarding the role of NF-κB in skeletal muscle with particular reference to different models of muscle-wasting and the development of novel therapy. PMID:18574572

  12. Active immunization therapies for Parkinson's disease and multiple system atrophy.

    PubMed

    Schneeberger, Achim; Tierney, Lanay; Mandler, Markus

    2016-02-01

    Vaccination is increasingly being investigated as a potential treatment for synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies associated with α-synuclein pathology. All lack a causal therapy. Development of novel, disease-altering treatment strategies is urgently needed. Vaccination has positioned itself as a prime strategy for addressing these diseases because it is broadly applicable, requires infrequent administration, and maintains low production costs for treating a large population or as a preventive measure. Current evidence points to a causal role of misfolded α-synuclein in the development and progression of synucleinopathies. In the past decade, significant progress in active immunization against α-synuclein has been shown both in preclinical animal models and in early clinical development. In this review, we describe the state-of-the-art in active immunization approaches to synucleinopathies, with a focus on advances in Parkinson's disease (PD) and multiple-system atrophy (MSA). We first review preclinical animal models, highlighting their progress in translation to the clinical setting. We then discuss current clinical applications, stressing different approaches taken to address α-synuclein pathology. Finally, we address challenges, trends, and future perspectives of current vaccination programs. PMID:26260853

  13. The evolution of alexia and simultanagnosia in posterior cortical atrophy.

    PubMed

    Mendez, M F; Cherrier, M M

    1998-04-01

    Early alexia and higher visual impairments characterize Posterior cortical atrophy (PCA), a progressive dementing syndrome most often caused by Alzheimer disease. Posterior cortical atrophy is rare, and the nature of the visual impairments in PCA are unclear. The authors observed two patients who had an insidiously progressive reading difficulty characterized by letter-by-letter reading and otherwise intact cognitive functions. Over time, these patients developed "ventral simultanagnosia" with preserved detection of multiple stimuli but inability to interpret whole scenes. Subsequently, they progressed to Balint syndrome with "dorsal simultanagnosia," optic ataxia, and oculomotor apraxia. Structural imaging was normal, but functional imaging revealed posterior cortical dysfunction. On a letter reading task, both patients had a word superiority effect, and on a whole word reading task, they could not read most words with missing or crosshatched letters. An inability to assess whole scenes progressed to an inability to detect more than one stimulus in an array. These findings suggest an evolution of PCA with progressive difficulty in visual integration beginning with letters, progressing to whole scenes, and culminating in Balint syndrome. These changes may reflect an extension of the pathophysiology of PCA from the extrastriate visual cortex to its occipitotemporal and occipitoparietal connections. PMID:9652488

  14. Expression, purification, crystallization and preliminary X-ray analysis of the PaaI-like thioesterase SAV0944 from Staphylococcus aureus.

    PubMed

    Khandokar, Yogesh B; Roman, Noelia; Smith, Kate M; Srivastava, Parul; Forwood, Jade K

    2014-02-01

    Staphylococcus aureus is the causative agent of many diseases, including meningitis, bacteraemia, pneumonia, food poisoning and toxic shock syndrome. Structural characterization of the PaaI-like thioesterase SAV0944 (SaPaaI) from S. aureus subsp. aureus Mu50 will aid in understanding its potential as a new therapeutic target by knowledge of its molecular details and cellular functions. Here, the recombinant expression, purification and crystallization of SaPaaI thioesterase from S. aureus are reported. This protein initially crystallized with the ligand coenzyme A using the hanging-drop vapour-diffusion technique with condition No. 40 of Crystal Screen from Hampton Research at 296 K. Optimal final conditions consisting of 24% PEG 4000, 100 mM sodium citrate pH 6.5, 12% 2-propanol gave single diffraction-quality crystals. These crystals diffracted to beyond 2 Å resolution at the Australian Synchrotron and belonged to space group P12(1)1, with unit-cell parameters a = 44.05, b = 89.05, c = 60.74 Å, β = 100.5°. Initial structure determination and refinement gave an R factor and R(free) of 17.3 and 22.0%, respectively, confirming a positive solution in obtaining phases using molecular replacement. PMID:24637766

  15. RF beam transmission of x-band PAA system utilizing large-area, polymer-based true-time-delay module developed using imprinting and inkjet printing

    NASA Astrophysics Data System (ADS)

    Pan, Zeyu; Subbaraman, Harish; Zhang, Cheng; Li, Qiaochu; Xu, Xiaochuan; Chen, Xiangning; Zhang, Xingyu; Zou, Yi; Panday, Ashwin; Guo, L. Jay; Chen, Ray T.

    2016-02-01

    Phased-array antenna (PAA) technology plays a significant role in modern day radar and communication networks. Truetime- delay (TTD) enabled beam steering networks provide several advantages over their electronic counterparts, including squint-free beam steering, low RF loss, immunity to electromagnetic interference (EMI), and large bandwidth control of PAAs. Chip-scale and integrated TTD modules promise a miniaturized, light-weight system; however, the modules are still rigid and they require complex packaging solutions. Moreover, the total achievable time delay is still restricted by the wafer size. In this work, we propose a light-weight and large-area, true-time-delay beamforming network that can be fabricated on light-weight and flexible/rigid surfaces utilizing low-cost "printing" techniques. In order to prove the feasibility of the approach, a 2-bit thermo-optic polymer TTD network is developed using a combination of imprinting and ink-jet printing. RF beam steering of a 1×4 X-band PAA up to 60° is demonstrated. The development of such active components on large area, light-weight, and low-cost substrates promises significant improvement in size, weight, and power (SWaP) requirements over the state-of-the-art.

  16. The characterization of EIAV reverse transcriptase and its inhibition by 5'-triphosphates of 2'-deoxyuridine analogs, PFA and PAA.

    PubMed

    Tao, P; Zhang, X; Quan, K

    1990-01-01

    A characterization of equine infectious anemia virus reverse transcriptase (EIAV RT) and its inhibition by 5'-triphosphate analogs was undertaken to explore the possibility of using EIAV RT as an in vitro model for studying human immunodeficiency virus (HIV). EIAV RT activity was found to be dependent on the bivalent cations Mg++ and Mn++. The optimal pH for enzyme reaction was pH 8.2. EIAV RT preferred a 70 mmol/L concentration of monovalent salts. Phosphonoformic acid (PFA) was an active inhibitor of EIAV RT, but phosphonoacetic acid (PAA) and N-ethylmaleimide (NEM) were not. The inhibition of EIAV RT activity by 5'-triphosphates of nucleoside derivatives was in the following decreasing order: FLTTP greater than AZTTP greater than nPrearaUTP greater than nPredUTP = CEdUTP greater than EtdUTP greater than nPrdUTP greater than HMdUTP. nPrearaUTP was a linear competitive and PFA a linear noncompetitive inhibitor of EIAV RT with respect to dTTP. Apparent Kis and Kii were 1.5 and 2.2 mumol/L respectively. The susceptibility pattern of EIAV RT to inhibitors was similar to that of HIV RT. PMID:1711694

  17. DIGESTIVE TUBULE ATROPHY IN EASTERN OYSTERS, CRASSOSTREA VIRGINICA (GMELI, 1791), EXPOSED TO SALINITY AND STARVATION STRESS

    EPA Science Inventory

    Oysters sampled in February 1992, from a low salinity site (3 ppt) in Apalachicola Bay, Florida, showed digestive tubule atrophy when salinity site (18 ppt) 16 kilometers away. xperiments designed to induce tubule atrophy in the and two salinity stress tests. o quantify tubule co...

  18. The relationship of pineal calcification to cerebral atrophy on CT scan in multiple sclerosis.

    PubMed

    Sandyk, R; Awerbuch, G I

    1994-05-01

    Calcification is a known morphological feature of the pineal gland. The mechanisms underlying the development of pineal calcification (PC) are elusive although there is experimental evidence that calcification may be a marker of the past secretory activity of the gland and/or of degeneration. The increased incidence of PC with aging suggests that it may reflect cerebral degenerative changes as well. In a recent Editorial in this Journal it was proposed that the pineal gland is implicated in the pathogenesis of multiple sclerosis (MS). Cerebral atrophy, which can be demonstrated on CT scan, is a common feature of MS resulting from demyelination and gliosis. If PC is a marker of a cerebral degenerative process, then one would expect a higher incidence of calcification of the gland in patients with cerebral atrophy compared to those without cerebral atrophy. To test this hypothesis, we studied the incidence of PC on CT scan in a cohort of 48 MS patients, 21 of whom had cerebral atrophy. For the purpose of comparison, we also assessed the incidence of choroid plexus calcification (CPC) in relation to cerebral atrophy. PC was found in 42 patients (87.5%) and its incidence in patients with cerebral atrophy was significantly higher compared to the incidence in patients without cerebral atrophy (100% vs. 77.7%; p < .025). In contrast, CPC was unrelated to cerebral atrophy or to PC thus supporting the notion of a specific association between the pineal gland and the pathogenesis of MS.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7960471

  19. [The hemodynamic disorders in Sudeck's atrophy and the effect on them of interference therapy].

    PubMed

    Nikolova, L

    1992-01-01

    Interferential currents applied to the forearm fracture region of 80 patients with Sudeck atrophy eliminated hemodynamic changes in the affected limb as shown by capillaroscopy, rheovasography. The effect of the treatment is attributed to recovery of normal blood flow and microcirculation in the region of bone atrophy as well as analgetic action of pulse current. PMID:1384234

  20. Relating Cortical Atrophy in Temporal Lobe Epilepsy with Graph Diffusion-Based Network Models

    PubMed Central

    Abdelnour, Farras; Mueller, Susanne; Raj, Ashish

    2015-01-01

    Mesial temporal lobe epilepsy (TLE) is characterized by stereotyped origination and spread pattern of epileptogenic activity, which is reflected in stereotyped topographic distribution of neuronal atrophy on magnetic resonance imaging (MRI). Both epileptogenic activity and atrophy spread appear to follow white matter connections. We model the networked spread of activity and atrophy in TLE from first principles via two simple first order network diffusion models. Atrophy distribution is modeled as a simple consequence of the propagation of epileptogenic activity in one model, and as a progressive degenerative process in the other. We show that the network models closely reproduce the regional volumetric gray matter atrophy distribution of two epilepsy cohorts: 29 TLE subjects with medial temporal sclerosis (TLE-MTS), and 50 TLE subjects with normal appearance on MRI (TLE-no). Statistical validation at the group level suggests high correlation with measured atrophy (R = 0.586 for TLE-MTS, R = 0.283 for TLE-no). We conclude that atrophy spread model out-performs the hyperactivity spread model. These results pave the way for future clinical application of the proposed model on individual patients, including estimating future spread of atrophy, identification of seizure onset zones and surgical planning. PMID:26513579

  1. Maintenance electroconvulsive therapy in a patient with multiple system atrophy and bipolar disorder.

    PubMed

    Obiora, Onwuameze; McCormick, Laurie May; Karim, Yasser; Gonzales, Pedro; Beeghly, James

    2012-06-01

    Multiple system atrophy is a rapidly progressive neurodegenerative disorder with no known cure. It is a clinical diagnosis with no confirmation available other than brain biopsy after death. We report the successful treatment of multiple system atrophy co-occurring with bipolar disorder in a 62-year-old man using electroconvulsive therapy. PMID:22622294

  2. Parapapillary atrophy and optic disc region assessment (PANDORA): retinal imaging tool for assessment of the optic disc and parapapillary atrophy

    NASA Astrophysics Data System (ADS)

    Lu, Cheng-Kai; Tang, Tong Boon; Laude, Augustinus; Dhillon, Baljean; Murray, Alan F.

    2012-10-01

    We describe a computer-aided measuring tool, named parapapillary atrophy and optic disc region assessment (PANDORA), for automated detection and quantification of both the parapapillary atrophy (PPA) and the optic disc (OD) regions in two-dimensional color retinal fundus images. The OD region is segmented using a combination of edge detection and ellipse fitting methods. The PPA region is identified by the presence of bright pixels in the temporal zone of the OD, and it is segmented using a sequence of techniques, including a modified Chan-Vese approach, thresholding, scanning filter, and multiseed region growing. PANDORA has been tested with 133 color retinal images (82 with PPA; 51 without PPA) drawn randomly from the Lothian Birth Cohort (LBC) database, together with a "ground truth" estimate from an ophthalmologist. The PPA detection rate is 89.47% with a sensitivity of 0.83 and a specificity of 1. The mean accuracy in defining the OD region is 81.31% (SD=10.45) when PPA is present and 95.32% (SD=4.36) when PPA is absent. The mean accuracy in defining the PPA region is 73.57% (SD=11.62). PANDORA demonstrates for the first time how to quantify the OD and PPA regions using two-dimensional fundus images, enabling ophthalmologists to study ocular diseases related to PPA using a standard fundus camera.

  3. PKCαβγ- and PKCδ-dependent endocytosis of NBCe1-A and NBCe1-B in salivary parotid acinar cells

    PubMed Central

    Perry, Clint; Baker, Olga J.; Reyland, Mary E.

    2009-01-01

    We examined membrane trafficking of NBCe1-A and NBCe1-B variants of the electrogenic Na+-HCO3− cotransporter (NBCe1) encoded by the SLC4A4 gene, using confocal fluorescent microscopy in rat parotid acinar cells (ParC5 and ParC10). We showed that yellow fluorescent protein (YFP)-tagged NBCe1-A and green fluorescent protein (GFP)-tagged NBCe1-B are colocalized with E-cadherin in the basolateral membrane (BLM) but not with the apical membrane marker zona occludens 1 (ZO-1). We inhibited constitutive recycling with monensin and W13 and detected that NBCe1-A and NBCe1-B accumulated in vesicles marked with the early endosomal marker early endosome antigen-1 (EEA1), with a parallel loss from the BLM. We observed that NBCe1-A and NBCe1-B undergo massive carbachol (CCh)-stimulated redistribution from the BLM into early endosomes. We showed that internalization of NBCe1-A and NBCe1-B was prevented by the general PKC inhibitor GF-109203X, the PKCαβγ-specific inhibitor Gö-6976, and the PKCδ-specific inhibitor rottlerin. We verified the involvement of PKCδ by blocking CCh-induced internalization of NBCe1-A-cyan fluorescent protein (CFP) in cells transfected with dominant-negative kinase-dead (Lys376Arg) PKCδ-GFP. Our data suggest that NBCe1-A and NBCe1-B undergo constitutive and CCh-stimulated endocytosis regulated by conventional PKCs (PKCαβγ) and by novel PKCδ in rat epithelial cells. To help develop a more complete model of the role of NBCe1 in parotid acinar cells we also investigated the initial phase of the secretory response to cholinergic agonist. In an Ussing chamber study we showed that inhibition of basolateral NBCe1 with 5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H-indole-1-carboxamide (tenidap) significantly decreases an initial phase of luminal anion secretion measured as a transient short-circuit current (Isc) across ParC10 cell monolayers. Using trafficking and functional data we propose a model that describes a physiological role of

  4. Gelatinous marrow transformation and hematopoietic atrophy in a miniature horse stallion.

    PubMed

    Beeler-Marfisi, J; Gallastegui Menoyo, A; Beck, A; König, J; Hewson, J; Bienzle, D

    2011-03-01

    Gelatinous marrow transformation, or serous atrophy of bone marrow fat, has been noted in livestock, laboratory animals, and wildlife in association with an inadequate plane of nutrition, inanition, or intoxication. This is a report of gelatinous marrow transformation and hematopoietic marrow atrophy in a 5-year-old miniature horse stallion. The horse had oral malformations leading to poor food assimilation and emaciation. A bone marrow biopsy obtained to investigate persistent anemia and leukopenia showed hematopoietic atrophy and replacement of fat with a granular extracellular substance, which stained with alcian blue, consistent with acidic mucopolysaccharide content. Surgical correction of the dental abnormalities resulted in improved food assimilation, weight gain, and resolution of cytopenias. In humans, gelatinous bone marrow transformation and hematopoietic atrophy are commonly associated with malnutrition from anorexia nervosa and other causes. The cause of hematopoietic atrophy is unknown but may relate to a nonsupportive marrow microenvironment and inadequate hematopoietic substrate availability. Similar pathogenic mechanisms were suspected in this horse. PMID:20587692

  5. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies

    PubMed Central

    Jordanova, Albena

    2014-01-01

    Hereditary spinal muscular atrophy is a motor neuron disorder characterized by muscle weakness and atrophy due to degeneration of the anterior horn cells of the spinal cord. Initially, the disease was considered purely as an autosomal recessive condition caused by loss-of-function SMN1 mutations on 5q13. Recent developments in next generation sequencing technologies, however, have unveiled a growing number of clinical conditions designated as non-5q forms of spinal muscular atrophy. At present, 16 different genes and one unresolved locus are associated with proximal non-5q forms, having high phenotypic variability and diverse inheritance patterns. This review provides an overview of the current knowledge regarding the phenotypes, causative genes, and disease mechanisms associated with proximal SMN1-negative spinal muscular atrophies. We describe the molecular and cellular functions enriched among causative genes, and discuss the challenges in the post-genomics era of spinal muscular atrophy research. PMID:24970098

  6. Diagnostic Approach to Childhood-onset Cerebellar Atrophy: A 10-Year Retrospective Study of 300 Patients

    PubMed Central

    Al-Maawali, Almundher; Blaser, Susan; Yoon, Grace

    2013-01-01

    Hereditary ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. Selection of appropriate clinical and genetic tests for patients with cerebellar atrophy poses a diagnostic challenge. Neuroimaging is a crucial initial investigation in the diagnostic evaluation of ataxia in childhood, and the presence of cerebellar atrophy helps guide further investigations. We performed a detailed review of 300 patients with confirmed cerebellar atrophy on magnetic resonance imaging over a 10-year period. A diagnosis was established in 47% of patients: Mitochondrial disorders were most common, followed by the neuronal ceroid lipofuscinoses, ataxia telangectasia, and late GM2-gangliosidosis. We review the common causes of cerebellar atrophy in childhood and propose a diagnostic approach based on correlating specific neuroimaging patterns with clinical and genetic diagnoses. PMID:22764178

  7. A Patient with Posterior Cortical Atrophy Possesses a Novel Mutation in the Presenilin 1 Gene

    PubMed Central

    Sitek, Emilia J.; Narożańska, Ewa; Pepłońska, Beata; Filipek, Sławomir; Barczak, Anna; Styczyńska, Maria; Mlynarczyk, Krzysztof; Brockhuis, Bogna; Portelius, Erik; Religa, Dorota; Barcikowska, Maria

    2013-01-01

    Posterior cortical atrophy is a dementia syndrome with symptoms of cortical visual dysfunction, associated with amyloid plaques and neurofibrillary tangles predominantly affecting visual association cortex. Most patients diagnosed with posterior cortical atrophy will finally develop a typical Alzheimer's disease. However, there are a variety of neuropathological processes, which could lead towards a clinical presentation of posterior cortical atrophy. Mutations in the presenilin 1 gene, affecting the function of γ-secretase, are the most common genetic cause of familial, early-onset Alzheimer's disease. Here we present a patient with a clinical diagnosis of posterior cortical atrophy who harbors a novel Presenilin 1 mutation (I211M). In silico analysis predicts that the mutation could influence the interaction between presenilin 1 and presenilin1 enhancer-2 protein, a protein partner within the γ-secretase complex. These findings along with published literature support the inclusion of posterior cortical atrophy on the Alzheimer's disease spectrum. PMID:23593396

  8. MICROARRAY GENE EXPRESSION ANALYSIS IN ATROPHYING RAINBOW TROUT MUSCLE: AN UNIQUE NON-MAMMALIAN MUSCLE DEGRADATION MODEL

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Muscle atrophy is a physiological response to diverse physiological and pathological conditions that trigger muscle deterioration through distinct cellular stimuli. Despite different physiological signals, the resulting biochemical changes in atrophying muscle share many common cascades. Muscle dete...

  9. Regulatory Mechanism of Muscle Disuse Atrophy in Adult Rats

    NASA Technical Reports Server (NTRS)

    1993-01-01

    During the last phase of NAG 2-386 we completed three studies. The effects of 14 days of weightlessness; the vastus medialis (VM) from flight rats in COSMOS 2044 was compared with the VM from tail suspended rats and other controls. The type I and II fibers in the mixed fiber portion of the VM were significantly reduced in flight rats and capillary densities paralleled the fiber density changes. The results of this project compared favorably with those in the extensor digitorum longus following seven days of flight in SL 3. The cardiovascular projects focused on the blood pressure changes in head down tilted rats (HDT) and non-head down tilted (N-HDT) rats. Blood pressures (MAP, SP and DP) were significantly elevated through seven days of HDT and rapidly returned to control levels within one day after removal from the HDT position. The N-HDT showed some slight rise in blood pressure but these were not as great and they were not as rapid. The HDT rats were characterized as exhibiting transient hypertension. These results led to some of the microvascular and vascular graduate student projects of Dr. Bernhard Stepke. Also our results refute or, at least, do not agree with previous reports from other laboratories. Each animal, in our blood pressure projects, served as its own control thereby providing more accurate results. Also, our experiments focused on recovery studies which can, in and of themselves, provide guidelines for flight experiments concerned with blood pressure changes. Another experiment was conducted to examine the role of testicular atrophy in whole body suspended (WBS) and tail suspended (TS) rats. We worked in conjunction with Dr. D.R. Deaver's laboratory at Pennsylvania State University and Dr. R. P. Amann at Colorado State University. In the TS rats the testes are retracted into the abdominal cavity, unless a ligature is placed to maintain them in the external scrotal sac. The cryptorchid condition in TS rats results in atrophy of the testes and

  10. Regional brain atrophy development is related to specific aspects of clinical dysfunction in multiple sclerosis.

    PubMed

    Jasperse, Bas; Vrenken, Hugo; Sanz-Arigita, Ernesto; de Groot, Vincent; Smith, Stephen M; Polman, Chris H; Barkhof, Frederik

    2007-11-15

    Brain atrophy in multiple sclerosis (MS) is thought to reflect irreversible tissue damage leading to persistent clinical deficit. Little is known about the rate of atrophy in specific brain regions in relation to specific clinical deficits. We determined the displacement of the brain surface between two T1-weighted MRI images obtained at baseline and after a median follow-up time of 2.2 years for 79 recently diagnosed, mildly disabled MS patients. Voxel- and cluster-wise permutation-based statistics were used to identify brain regions in which atrophy development was significantly related to Expanded Disability Status Scale (EDSS), Timed Walk Test (TWT), Paced Auditory Serial Addition Test (PASAT) and 9-Hole Peg Test (HPT). Clusters were considered significant at a corrected cluster-wise p-value of 0.05. Worse EDSS change-score and worse follow-up EDSS were related to atrophy development of periventricular and brainstem regions and right-sided parietal, occipital and temporal regions. Worse PASAT at follow-up was significantly related to atrophy of the ventricles. A worse TWT change-score and worse follow-up TWT were exclusively related to atrophy around the ventricles and of the brainstem. Worse HPT change-score and worse follow-up HPT of either arm were significantly related to the atrophy of widely distributed peripheral regions, as well as atrophy of periventricular and brainstem regions. Our findings suggest that decline in ambulatory function is related to atrophy of central brain regions exclusively, whereas decline in neurologically more complex tasks for coordinated hand function is related to atrophy of both central and peripheral brain regions. PMID:17889567

  11. Induced pluripotent stem cells from a spinal muscular atrophy patient

    PubMed Central

    Ebert, Allison D.; Yu, Junying; Rose, Ferrill F.; Mattis, Virginia B.; Lorson, Christian L.; Thomson, James A.; Svendsen, Clive N.

    2009-01-01

    Spinal muscular atrophy (SMA) is one of the most common inherited forms of neurological disease leading to infant mortality. Patients exhibit selective loss of lower motor neurons resulting in muscle weakness, paralysis, and often death. Although patient fibroblasts have been used extensively to study SMA, motor neurons have a unique anatomy and physiology which may underlie their vulnerability to the disease process. Here we report the generation of induced pluripotent stem (iPS) cells from skin fibroblast samples taken from a child with SMA. These cells expanded robustly in culture, maintained the disease genotype, and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. This is the first study to show human iPS cells can be used to model the specific pathology seen in a genetically inherited disease. As such, it represents a promising resource to study disease mechanisms, screen novel drug compounds, and develop new therapies. PMID:19098894

  12. Multiple system atrophy: current and future approaches to management

    PubMed Central

    Flabeau, Olivier; Meissner, Wassilios G.; Tison, François

    2010-01-01

    Multiple system atrophy (MSA) is a rare neurodegenerative disorder without any effective treatment in slowing or stopping disease progression. It is characterized by poor levodopa responsive Parkinsonism, cerebellar ataxia, pyramidal signs and autonomic failure in any combination. Current therapeutic strategies are primarily based on dopamine replacement and improvement of autonomic failure. However, symptomatic management remains disappointing and no curative treatment is yet available. Recent experimental evidence has confirmed the key role of alpha-synuclein aggregation in the pathogenesis of MSA. Referring to this hypothesis, transgenic and toxic animal models have been developed to assess candidate drugs for MSA. The standardization of diagnosis criteria and assessment procedures will allow large multicentre clinical trials to be conducted. In this article we review the available symptomatic treatment, recent results of studies investigating potential neuroprotective drugs, and future approaches for the management in MSA. PMID:21179616

  13. RASCH ANALYSIS OF CLINICAL OUTCOME MEASURES IN SPINAL MUSCULAR ATROPHY

    PubMed Central

    CANO, STEFAN J.; MAYHEW, ANNA; GLANZMAN, ALLAN M.; KROSSCHELL, KRISTIN J.; SWOBODA, KATHRYN J.; MAIN, MARION; STEFFENSEN, BIRGIT F.; BÉRARD, CAROLE; GIRARDOT, FRANÇOISE; PAYAN, CHRISTINE A.M.; MERCURI, EUGENIO; MAZZONE, ELENA; ELSHEIKH, BAKRI; FLORENCE, JULAINE; HYNAN, LINDA S.; IANNACCONE, SUSAN T.; NELSON, LESLIE L.; PANDYA, SHREE; ROSE, MICHAEL; SCOTT, CHARLES; SADJADI, REZA; YORE, MACKENSIE A.; JOYCE, CYNTHIA; KISSEL, JOHN T.

    2015-01-01

    Introduction Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). Methods Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. Results Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. Conclusions The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges. PMID:23836324

  14. The nature of the autonomic dysfunction in multiple system atrophy

    NASA Technical Reports Server (NTRS)

    Parikh, Samir M.; Diedrich, Andre; Biaggioni, Italo; Robertson, David

    2002-01-01

    The concept that multiple system atrophy (MSA, Shy-Drager syndrome) is a disorder of the autonomic nervous system is several decades old. While there has been renewed interest in the movement disorder associated with MSA, two recent consensus statements confirm the centrality of the autonomic disorder to the diagnosis. Here, we reexamine the autonomic pathophysiology in MSA. Whereas MSA is often thought of as "autonomic failure", new evidence indicates substantial persistence of functioning sympathetic and parasympathetic nerves even in clinically advanced disease. These findings help explain some of the previously poorly understood features of MSA. Recognition that MSA entails persistent, constitutive autonomic tone requires a significant revision of our concepts of its diagnosis and therapy. We will review recent evidence bearing on autonomic tone in MSA and discuss their therapeutic implications, particularly in terms of the possible development of a bionic baroreflex for better control of blood pressure.

  15. Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability

    PubMed Central

    Liu, Huisheng; Lu, Jianfeng; Chen, Hong; Du, Zhongwei; Li, Xue-Jun; Zhang, Su-Chun

    2015-01-01

    Spinal muscular atrophy (SMA) presents severe muscle weakness with limited motor neuron (MN) loss at an early stage, suggesting potential functional alterations in MNs that contribute to SMA symptom presentation. Using SMA induced pluripotent stem cells (iPSCs), we found that SMA MNs displayed hyperexcitability with increased membrane input resistance, hyperpolarized threshold, and larger action potential amplitude, which was mimicked by knocking down full length survival motor neuron (SMN) in non-SMA MNs. We further discovered that SMA MNs exhibit enhanced sodium channel activities with increased current amplitude and facilitated recovery, which was corrected by restoration of SMN1 in SMA MNs. Together we propose that SMN reduction results in MN hyperexcitability and impaired neurotransmission, the latter of which exacerbate each other via a feedback loop, thus contributing to severe symptoms at an early stage of SMA. PMID:26190808

  16. Atrophy of rat skeletal muscles in simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Feller, D. D.; Ginoza, H. S.; Morey, E. R.

    1982-01-01

    A hypokinetic rat model was used for elucidation of the mechanism of skeletal muscle wasting which occurs in weightlessness. Rats were suspended from a back-harness with the head tilted downward and the hind limbs totally unloaded. A progressive decrease in the size of the soleus muscle from suspended rats was observed as a function of time. The rate of protein degradation of the homogenates from the soleus muscles of suspended and control animals was not significantly different. The rate of cell-free protein synthesis was severely repressed in the atrophied muscle. An initial rise in the levels of plasma glucose and corticosterone was observed on the second day of suspension, but they subsequently returned to normal values.

  17. Programmed cell death and the gene behind spinal muscular atrophy.

    PubMed Central

    Robinson, A

    1995-01-01

    A gene involved in the development of spinal muscular atrophy (SMA) has been found on human chromosome 5 after a 4-year search. Named the neuronal apoptosis inhibitor protein (NAIP) gene, it is believed to inhibit the normal process of apoptosis--the disintegration of single cells that results from programmed cell death--in motor neurons. The researchers who found the NAIP gene also discovered that healthy people carry one complete copy of the gene along with many other partial copies. Many children with SMA have the partial copies but not the complete gene. This discovery facilitates the accurate genetic diagnosis of SMA. But gene therapy for SMA will not be possible until researchers find a suitable vector to stably introduce activated and intact copies of the gene into the motor neurons of children with SMA in time to stop motor neuron loss. Images p1460-a PMID:7585374

  18. Helping Women Understand Treatment Options for Vulvar and Vaginal Atrophy.

    PubMed

    Parks, Diane M; Levine, Jeffrey

    2015-01-01

    Vulvar and vaginal atrophy (VVA) is a common and progressive medical condition in postmenopausal women. The REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs) survey assessed knowledge about VVA and its impact in 3,046 postmenopausal U.S. women, and recorded women's attitudes about their interactions with health care providers and about available treatments. REVIVE identified poor disease awareness and understanding among women, failure of health care professionals to evaluate women for VVA signs and symptoms, low treatment rates and concerns about the safety and efficacy of available therapies. Strategies to address these needs include proactive screening, education for women and clinicians about VVA and recommendations for treatment and follow-up. PMID:26264795

  19. Cytokine profiles in multifocal motor neuropathy and progressive muscular atrophy.

    PubMed

    Vlam, L; Stam, M; de Jager, W; Cats, E A; van den Berg, L H; van der Pol, W L

    2015-09-15

    Multifocal motor neuropathy (MMN) and progressive muscular atrophy (PMA) are associated with IgM monoclonal gammopathy or the presence IgM anti-GM1-antibodies. To further investigate the pathophysiology of MMN and PMA we determined concentrations of 16 mainly B-cell associated inflammatory markers in serum from 25 patients with MMN, 55 patients with PMA, 25 patients with amyotrophic lateral sclerosis (ALS) and 50 healthy controls. Median serum concentrations of the 16 tested cytokines and chemokines were not significantly increased in patients with MMN or patients with PMA, irrespective of the presence of IgM monoclonal gammopathy or high IgM anti-GM1 antibodies. These results argue against a systemic B-cell mediated immune response underlying the pathogenesis of MMN and PMA. PMID:26298317

  20. Newborn screening for spinal muscular atrophy: Anticipating an imminent need.

    PubMed

    Phan, Han C; Taylor, Jennifer L; Hannon, Harry; Howell, Rodney

    2015-04-01

    Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. Children with type I SMA typically die by the age of 2 years. Recent progress in gene modification and other innovative therapies suggest that improved outcomes may soon be forthcoming. In animal models, therapeutic intervention initiated before the loss of motor neurons alters SMA phenotype and increases lifespan. Presently, supportive care including respiratory, nutritional, physiatry, and orthopedic management can ameliorate clinical symptoms and improve survival rates if SMA is diagnosed early in life. Newborn screening could help optimize these potential benefits. A recent report demonstrated that SMA detection can be multiplexed at minimal additional cost with the assay for severe combined immunodeficiency, already implemented by many newborn screening programs. The public health community should remain alert to the rapidly changing developments in early detection and treatment of SMA. PMID:25979781

  1. Advances in therapeutic development for spinal muscular atrophy

    PubMed Central

    Howell, Matthew D; Singh, Natalia N; Singh, Ravindra N

    2015-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The disease originates from low levels of SMN protein due to deletion and/or mutations of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1. While SMN1 and SMN2 are nearly identical, SMN2 predominantly generates a truncated protein (SMNΔ7) due to skipping of exon 7, the last coding exon. Several avenues for SMA therapy are being explored, including means to enhance SMN2 transcription, correct SMN2 exon 7 splicing, stabilize SMN/SMNΔ7 protein, manipulate SMN-regulated pathways and SMN1 gene delivery by viral vectors. This review focuses on the aspects of target discovery, validations and outcome measures for a promising therapy of SMA. PMID:25068989

  2. Extent of hippocampal atrophy predicts degree of deficit in recall.

    PubMed

    Patai, Eva Zita; Gadian, David G; Cooper, Janine M; Dzieciol, Anna M; Mishkin, Mortimer; Vargha-Khadem, Faraneh

    2015-10-13

    Which specific memory functions are dependent on the hippocampus is still debated. The availability of a large cohort of patients who had sustained relatively selective hippocampal damage early in life enabled us to determine which type of mnemonic deficit showed a correlation with extent of hippocampal injury. We assessed our patient cohort on a test that provides measures of recognition and recall that are equated for difficulty and found that the patients' performance on the recall tests correlated significantly with their hippocampal volumes, whereas their performance on the equally difficult recognition tests did not and, indeed, was largely unaffected regardless of extent of hippocampal atrophy. The results provide new evidence in favor of the view that the hippocampus is essential for recall but not for recognition. PMID:26417089

  3. Extent of hippocampal atrophy predicts degree of deficit in recall

    PubMed Central

    Patai, Eva Zita; Gadian, David G.; Cooper, Janine M.; Dzieciol, Anna M.; Mishkin, Mortimer; Vargha-Khadem, Faraneh

    2015-01-01

    Which specific memory functions are dependent on the hippocampus is still debated. The availability of a large cohort of patients who had sustained relatively selective hippocampal damage early in life enabled us to determine which type of mnemonic deficit showed a correlation with extent of hippocampal injury. We assessed our patient cohort on a test that provides measures of recognition and recall that are equated for difficulty and found that the patients' performance on the recall tests correlated significantly with their hippocampal volumes, whereas their performance on the equally difficult recognition tests did not and, indeed, was largely unaffected regardless of extent of hippocampal atrophy. The results provide new evidence in favor of the view that the hippocampus is essential for recall but not for recognition. PMID:26417089

  4. Memory Impairment at Initial Clinical Presentation in Posterior Cortical Atrophy.

    PubMed

    Ahmed, Samrah; Baker, Ian; Husain, Masud; Thompson, Sian; Kipps, Christopher; Hornberger, Michael; Hodges, John R; Butler, Christopher R

    2016-04-23

    Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer's disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke's Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired compared to controls on the ACE total score (p < 0.001), visuospatial skills (p < 0.001), and memory (p < 0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p < 0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p < 0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation. The findings suggest that memory impairment must be considered in assessment and management of PCA. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment. PMID:27128371

  5. STARVATION INDUCED PROXIMAL GUT MUCOSAL ATROPHY DIMINISHED WITH AGING

    PubMed Central

    Song, Juquan; Wolf, Steven E.; Wu, Xiao-Wu; Finnerty, Celeste C.; Gauglitz, Gerd G.; Herndon, David N.; Jeschke, Marc G.

    2013-01-01

    Background Starvation induces small bowel atrophy with increased intestinal epithelial apoptosis and decreased proliferation. Here, we examined these parameters after starvation in aged animals. Methods Sixty-four 6 week-old and 26 month-old C57BL/6 mice were randomly assigned to either an ad libitum fed or fasted group. The small bowel was harvested at 12, 48, and 72 hours following starvation. Proximal gut mucosal height was measured and epithelial cells counted. Apoptosis was identified by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Proliferation was determined by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). Comparison of fed vs. fasted and adult vs. old groups was done by one-way ANOVA with Tukey’s test and unpaired t-test. Significance was accepted at p<0.05. Results Aged mice had higher proximal gut weights, mucosal heights and cell numbers at baseline compared with the adult group (p<0.05). The rate of apoptosis was lower in the aged (p<0.05) while proliferation was not different between groups before starvation. After starvation, proximal gut wet weight decreased only in adult mice (p<0.05); Gut mucosal height and mucosal cell number decreased greater in adult than in aged mice (p<0.05). This was related to decreased proliferation only in the adult group (p<0.05). The fold of epithelial apoptosis increased was higher in the aged group than in the adult after starvation (p<0.05). Conclusions Gut mucosal kinetics change with age had lower rates of apoptosis and greater mucosal mass; the character of starvation-induced atrophy is diminished with aging. PMID:19126762

  6. Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways.

    PubMed

    Rodriguez, J; Vernus, B; Chelh, I; Cassar-Malek, I; Gabillard, J C; Hadj Sassi, A; Seiliez, I; Picard, B; Bonnieu, A

    2014-11-01

    Myostatin, a member of the transforming growth factor-β superfamily, is a potent negative regulator of skeletal muscle growth and is conserved in many species, from rodents to humans. Myostatin inactivation can induce skeletal muscle hypertrophy, while its overexpression or systemic administration causes muscle atrophy. As it represents a potential target for stimulating muscle growth and/or preventing muscle wasting, myostatin regulation and functions in the control of muscle mass have been extensively studied. A wealth of data strongly suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression. Moreover, myostatin plays a central role in integrating/mediating anabolic and catabolic responses. Myostatin negatively regulates the activity of the Akt pathway, which promotes protein synthesis, and increases the activity of the ubiquitin-proteasome system to induce atrophy. Several new studies have brought new information on how myostatin may affect both ribosomal biogenesis and translation efficiency of specific mRNA subclasses. In addition, although myostatin has been identified as a modulator of the major catabolic pathways, including the ubiquitin-proteasome and the autophagy-lysosome systems, the underlying mechanisms are only partially understood. The goal of this review is to highlight outstanding questions about myostatin-mediated regulation of the anabolic and catabolic signaling pathways in skeletal muscle. Particular emphasis has been placed on (1) the cross-regulation between myostatin, the growth-promoting pathways and the proteolytic systems; (2) how myostatin inhibition leads to muscle hypertrophy; and (3) the regulation of translation by myostatin. PMID:25080109

  7. Transdifferentiation of mouse adipose-derived stromal cells into acinar cells of the submandibular gland using a co-culture system

    SciTech Connect

    Lee, Jingu; Park, Sangkyu; Roh, Sangho

    2015-05-15

    A loss of salivary gland function often occurs after radiation therapy in head and neck tumors, though secretion of saliva by the salivary glands is essential for the health and maintenance of the oral environment. Transplantation of salivary acinar cells (ACs), in part, may overcome the side effects of therapy. Here we directly differentiated mouse adipose-derived stromal cells (ADSCs) into ACs using a co-culture system. Multipotent ADSCs can be easily collected from stromal vascular fractions of adipose tissues. The isolated ADSCs showed positive expression of markers such as integrin beta-1 (CD29), cell surface glycoprotein (CD44), endoglin (CD105), and Nanog. The cells were able to differentiate into adipocytes, osteoblasts, and neural-like cells after 14 days in culture. ADSCs at passage 2 were co-cultured with mouse ACs in AC culture medium using the double-chamber (co-culture system) to avoid mixing the cell types. The ADSCs in this co-culture system expressed markers of ACs, such as α-amylases and aquaporin5, in both mRNA and protein. ADSCs cultured in AC-conditioned medium also expressed AC markers. Cellular proliferation and senescence analyses demonstrated that cells in the co-culture group showed lower senescence and a higher proliferation rate than the AC-conditioned medium group at Days 14 and 21. The results above imply direct conversion of ADSCs into ACs under the co-culture system; therefore, ADSCs may be a stem cell source for the therapy for salivary gland damage. - Highlights: • ADSCs could transdifferentiate into acinar cells (ACs) using ACs co-culture (CCA). • Transdifferentiated ADSCs expressed ACs markers such as α-amylase and aquaporin5. • High proliferation and low senescence were presented in CCA at Day 14. • Transdifferentiation of ADSCs into ACs using CCA may be an appropriate method for cell-based therapy.

  8. Inhibition of pancreatic acinar mitochondrial thiamin pyrophosphate uptake by the cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

    PubMed

    Srinivasan, Padmanabhan; Thrower, Edwin C; Gorelick, Fred S; Said, Hamid M

    2016-05-15

    Thiamin is essential for normal metabolism in pancreatic acinar cells (PAC) and is obtained from their microenvironment through specific plasma-membrane transporters, converted to thiamin pyrophosphate (TPP) in the cytoplasm, followed by uptake of TPP by mitochondria through the mitochondrial TPP (MTPP) transporter (MTPPT; product of SLC25A19 gene). TPP is essential for normal mitochondrial function. We examined the effect of long-term/chronic exposure of PAC in vitro (pancreatic acinar 266-6 cells) and in vivo (wild-type or transgenic mice carrying the SLC25A19 promoter) of the cigarette smoke toxin, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), on the MTPP uptake process. Our in vitro and in vivo findings demonstrate that NNK negatively affects MTPP uptake and reduced expression of MTPPT protein, MTPPT mRNA, and heterogenous nuclear RNA, as well as SLC25A19 promoter activity. The effect of NNK on Slc25a19 transcription was neither mediated by changes in expression of transcriptional factor NFY-1 (known to drive SLC25A19 transcription), nor due to changes in methylation profile of the Slc25a19 promoter. Rather, it appears to be due to changes in histone modifications that involve significant decreases in histone H3K4-trimethylation and H3K9-acetylation (activation markers). The effect of NNK on MTPPT function is mediated through the nonneuronal α7-nicotinic acetylcholine receptor (α7-nAChR), as indicated by both in vitro (using the nAChR antagonist mecamylamine) and in vivo (using an α7-nAchR(-/-) mouse model) studies. These findings demonstrate that chronic exposure of PAC to NNK negatively impacts PAC MTPP uptake. This effect appears to be exerted at the level of Slc25a19 transcription, involve epigenetic mechanism(s), and is mediated through the α7-nAchR. PMID:26999808

  9. Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease.

    PubMed

    Lambert, Christian; Benjamin, Philip; Zeestraten, Eva; Lawrence, Andrew J; Barrick, Thomas R; Markus, Hugh S

    2016-04-01

    Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson's R = -0.69, P < 1 × 10(-7)), and significant grey matter loss and whole brain atrophy occurs annually (P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity

  10. Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease

    PubMed Central

    Benjamin, Philip; Zeestraten, Eva; Lawrence, Andrew J.; Barrick, Thomas R.; Markus, Hugh S.

    2016-01-01

    Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson’s R = −0.69, P < 1 × 10−7), and significant grey matter loss and whole brain atrophy occurs annually (P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity

  11. Explicit memory in frontotemporal dementia: the role of medial temporal atrophy.

    PubMed

    Lavenu, I; Pasquier, F; Lebert, F; Pruvo, J P; Petit, H

    1998-01-01

    In our memory clinic experience, memory impairment differs widely in patients with frontotemporal dementia (FTD). We searched for a correlation between explicit memory disturbance assessed with the Grober and Buschke test and medial temporal atrophy on CT scan in 22 consecutive patients with FTD. Five of the 22 patients had a medial temporal lobe (MTL) atrophy. There was no significant difference between the two groups for the demographic characteristics. Free recall, cued recall and the learning curve were significantly better in patients without MTL atrophy. The patients with MTL atrophy made more intrusions. We found a positive correlation between total recall and cued recall and the mean of medial temporal lobe measurement. These results are in agreement with the role of the hippocampal formation in the memory process. In our group, the ratio of patients with MTL atrophy is similar to the ratio of Pick's disease in frontotemporal dementia. In histological series more severe hippocampal atrophy are reported in Pick's disease. Therefore MTL atrophy on CT scan could be a marker of Pick's disease in FTD. PMID:9524801

  12. Multidisciplinary Overview of Vaginal Atrophy and Associated Genitourinary Symptoms in Postmenopausal Women

    PubMed Central

    Goldstein, Irwin; Dicks, Brian; Kim, Noel N; Hartzell, Rose

    2013-01-01

    Introduction Vaginal atrophy, which may affect up to 45% of postmenopausal women, is often associated with one or more urinary symptoms, including urgency, increased frequency, nocturia, dysuria, incontinence, and recurrent urinary tract infection. Aims To provide an overview of the current literature regarding cellular and clinical aspects of vaginal atrophy and response to treatment with local vaginal estrogen therapy. Methods PubMed searches through February 2012 were conducted using the terms “vaginal atrophy,” “atrophic vaginitis,” and “vulvovaginal atrophy.” Expert opinion was based on review of the relevant scientific and medical literature. Main Outcome Measure Genitourinary symptoms and treatment of vaginal atrophy from peer-reviewed published literature. Results Typically, a diagnosis of vaginal atrophy is made based on patient-reported symptoms, including genitourinary symptoms, and an examination that reveals signs of the disorder; however, many women are hesitant to report vaginal-related symptoms, primarily because of embarrassment. Conclusions Physicians in various disciplines are encouraged to initiate open discussions about vulvovaginal health with postmenopausal women, including recommended treatment options. Goldstein I, Dicks B, Kim NN, and Hartzell R. Multidisciplinary overview of vaginal atrophy and associated genitourinary symptoms in postmenopausal women. Sex Med 2013;1:44–53. PMID:25356287

  13. Calpain-1 is required for hydrogen peroxide-induced myotube atrophy.

    PubMed

    McClung, J M; Judge, A R; Talbert, E E; Powers, S K

    2009-02-01

    Recent reports suggest numerous roles for cysteine proteases in the progression of skeletal muscle atrophy due to disuse or disease. Nonetheless, a specific requirement for these proteases in the progression of skeletal muscle atrophy has not been demonstrated. Therefore, this investigation determined whether calpains or caspase-3 is required for oxidant-induced C2C12 myotube atrophy. We demonstrate that exposure to hydrogen peroxide (25 microM H2O2) induces myotube oxidative damage and atrophy, with no evidence of cell death. Twenty-four hours of exposure to H2O2 significantly reduced both myotube diameter and the abundance of numerous proteins, including myosin (-81%), alpha-actinin (-40%), desmin (-79%), talin (-37%), and troponin I (-80%). Myotube atrophy was also characterized by increased cleavage of the cysteine protease substrate alphaII-spectrin following 4 h and 24 h of H2O2 treatment. This degradation was blocked by administration of the protease inhibitor leupeptin (10 microM). Using small interfering RNA transfection of mature myotubes against the specific proteases calpain-1, calpain-2, and caspase-3, we demonstrated that calpain-1 is required for H2O2-induced myotube atrophy. Collectively, our data provide the first evidence for an absolute requirement for calpain-1 in the development of skeletal muscle myotube atrophy in response to oxidant-induced cellular stress. PMID:19109522

  14. Distinct protein degradation profiles are induced by different disuse models of skeletal muscle atrophy

    PubMed Central

    Bialek, Peter; Morris, Carl; Parkington, Jascha; St. Andre, Michael; Owens, Jane; Yaworsky, Paul; Seeherman, Howard

    2011-01-01

    Skeletal muscle atrophy can be a consequence of many diseases, environmental insults, inactivity, age, and injury. Atrophy is characterized by active degradation, removal of contractile proteins, and a reduction in muscle fiber size. Animal models have been extensively used to identify pathways that lead to atrophic conditions. We used genome-wide expression profiling analyses and quantitative PCR to identify the molecular changes that occur in two clinically relevant mouse models of muscle atrophy: hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7, and 14 days after casting or injury. The total amount of muscle loss, as measured by wet weight and muscle fiber size, was equivalent between models on day 14, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tenotomy resulted in the regulation of significantly more mRNA transcripts then did casting. Analysis of the regulated genes and pathways suggest that the mechanisms of atrophy are distinct between these models. The degradation following casting was ubiquitin-proteasome mediated, while degradation following tenotomy was lysosomal and matrix-metalloproteinase mediated, suggesting a possible role for autophagy. These data suggest that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat atrophy resulting from different conditions. PMID:21791639

  15. MAPPING THE PROGRESSION OF ATROPHY IN EARLY AND LATE ONSET ALZHEIMER’S DISEASE

    PubMed Central

    Migliaccio, R; Agosta, F; Possin, KL; Canu, E; Filippi, M; Rabinovici, GD; Rosen, HJ; Miller, BL; Gorno-Tempini, ML

    2015-01-01

    The term early age-of-onset Alzheimer’s disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter (GM) atrophy in EOAD patients compared to late onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate. PMID:25737041

  16. The combined influence of stretch, mobility and electrical stimulation in the prevention of muscle fiber atrophy caused hypokinesia and hypodynamia

    NASA Technical Reports Server (NTRS)

    Goldspink, G.; Goldspink, D.; Loughna, P.

    1984-01-01

    The morphological and biochemical changes which occur in the hind limb muscles of the rat in response to hypokinesia and hypodynamia were investigated. Hind limb cast fixation and suspension techniques were employed to study the musclar atrophy after five days of hypokinesia and hypodynamia induced by suspension, appreciable muscular atrophy was apparent, particularly in the anti-gravity muscles. The effect of passive stretching and electrical stimulation on muscle atrophy was studied. Changes in muscle protein mass were assessed with spectrophotometric and radioactive techniques. Passive stretch is shown to counteract muscle disuse atrophy. The change in the numbers of specific muscle fibers in atrophied muscles is discussed.

  17. Restriction endonuclease analysis of leukocyte mitochondrial DNA in Leber's optic atrophy.

    PubMed Central

    Holt, I J; Miller, D H; Harding, A E

    1988-01-01

    In order to test the hypothesis that Leber's optic atrophy may be caused by mutation of the mitochondrial (mt) genome, restriction fragment length polymorphism in leukocyte mt DNA was studied in 16 patients with Leber's optic atrophy, 28 of their unaffected matrilineal relatives, and 35 normal control subjects. No differences in restriction fragment patterns were observed between affected and unaffected individuals in the same maternal line, and there was no evidence of major deletion of mt DNA in patients. This study provides no positive evidence of mitochondrial inheritance in Leber's optic atrophy but does not exclude it. PMID:2905730

  18. Combining the boundary shift integral and tensor-based morphometry for brain atrophy estimation

    NASA Astrophysics Data System (ADS)

    Michalkiewicz, Mateusz; Pai, Akshay; Leung, Kelvin K.; Sommer, Stefan; Darkner, Sune; Sørensen, Lauge; Sporring, Jon; Nielsen, Mads

    2016-03-01

    Brain atrophy from structural magnetic resonance images (MRIs) is widely used as an imaging surrogate marker for Alzheimers disease. Their utility has been limited due to the large degree of variance and subsequently high sample size estimates. The only consistent and reasonably powerful atrophy estimation methods has been the boundary shift integral (BSI). In this paper, we first propose a tensor-based morphometry (TBM) method to measure voxel-wise atrophy that we combine with BSI. The combined model decreases the sample size estimates significantly when compared to BSI and TBM alone.

  19. Pathology of iridectomy specimens in gyrate atrophy of the retina and choroid.

    PubMed

    Vannas-Sulonen, K; Vannas, A; O'Donnell, J J; Sipilä, I; Wood, I

    1983-02-01

    Gyrate atrophy of the retina and choroid is an autosomal recessive disease characterized by progressive retinal degeneration and ornithine aminotransferase deficiency. We report here the new histological findings and ultrastructural changes in 3 iridectomy specimens from 2 Finnish patients with gyrate atrophy. The iridectomy specimens were removed during routine cataract extraction and studied with a transmission electron microscope. The dilator muscle showed atrophy, abnormal mitochondria, and tubular aggregate type structures similar to those found in skeletal muscle. Degenerative changes such as extracted cellular matrix, dropout of cellular organelles, and dilated intercellular spaces were observed in the pigmented posterior epithelium and the anterior iris epithelium. PMID:6858648

  20. Controllable Cooperative Self-Assembly of PS-b-PAA/PS-b-P4VP Mixture by Tuning the Intercorona Interaction.

    PubMed

    Geng, Zhen; Cheng, Zhongkai; Zhu, Yutian; Jiang, Wei

    2016-06-23

    The cooperative self-assembly of amphiphilic polystyrene-block-poly(acrylic acid) (PS144-b-PAA22) and polystyrene-block-poly(4-vinylpyridine) (PS144-b-P4VP33) diblock copolymers in DMF/H2O mixtures has been investigated. Both copolymers self-assemble into small spherical micelles (SSMs) if used individually. However, the equimolar mixture of these two copolymers cooperatively self-assembles into vesicles. It is found that the formation of vesicles is attributed to the complex interactions between PAA and P4VP chains, including the hydrogen bonds between un-ionized acrylic acid units and pyridine units as well as the electronic attractions between ionized acrylic acid units and protonated pyridine units. Since these interactions between PAA and P4VP chains depend on pH value, the cooperatively self-assembled morphology can be easily tuned by the addition of HCl or NaOH. At high addition of H(+) or OH(-), the intercorona interaction is repulsive and the copolymer mixture tends to form SSMs (basic condition) or cylindrical micelles (acidic condition), whereas it prefers to aggregate into vesicles at low addition of H(+) or OH(-) because the intercorona interaction is attractive. Interestingly, the same morphology of the self-assembled aggregates can be obtained either at high H(+) addition or at low OH(-) addition, which results from the nonmonotonic variation of the intercorona interaction along with the addition of HCl or NaOH. The current study implies that it is the intercorona interaction rather than the chemical condition that dominates the cooperatively self-assembled morphology. PMID:27195581

  1. Gastric atrophy, metaplasia, and dysplasia: a clinical perspective.

    PubMed

    Kapadia, Cyrus R

    2003-01-01

    Gastric carcinoma of the intestinal type originates in dysplastic epithelium, which in turn develops in the milieu of atrophic gastritis and intestinal metaplasia. Cancers also may develop less often from gastric adenomatous polyps, which represent dysplastic epithelium arising in a raised lesion. The main causes of chronic atrophic gastritis and gastric atrophy are autoimmune due to pernicious anemia or chronic Helicobacter pylori infection. In the former condition, there is severe atrophy of the corpus (oxyntic mucosa), with the antrum being speared. In contrast, chronic atrophic gastritis consequent to H. pylori infection is a multifocal pangastritis, involving independent foci in the corpus and antrum of the stomach. For the most part, these clinical conditions are silent; the only manifestation of both these forms of chronic atrophic gastritis is cobalamin (vitamin B(12)) deficiency. In the case of the autoimmune gastritis of pernicious anemia, cobalamin deficiency results form the absence of intrinsic factor. When cobalamin deficiency occurs in patients with H. pylori-related gastritis, for the most part, it is because these patients have hypochlorhydria and are therefore unable to release cobalamin from its bound form in food. Patients may have advanced neuropsychiatric manifestations of cobalamin deficiency and yet not be anemic, have a normal blood smear, and even have serum cobalamin levels in the normal range. The condition may be identified by demonstrating elevated levels of homocysteine and methylmalonic acid. Intestinal metaplasia may be of the enteric (grade I), enterocolic (grade II), or colonic (grade III) type. Grade III intestinal metaplasia has traditionally been thought of as the most sinister variety, although the extent of atrophy and metaplasia may be a better marker for premalignancy than the mere identification of small areas of grade III intestinal metaplasia. Over the years, there has been much disagreement and a high degree of

  2. Isolated exon 8 deletion in type 1 spinal muscular atrophy with bilateral optic atrophy: unusual genetic mutation leading to unusual manifestation?

    PubMed

    Maiti, D; Bhattacharya, M; Yadav, S

    2012-01-01

    Proximal spinal muscular atrophy (SMA) or type 1 SMA is a fatal autosomal recessive disorder usually caused by homozygous deletion of exons 7 and 8 in the survivor motor neuron (SMN) gene. Additional deletion of the neuronal apotosis inhibitory protein (NAIP) gene exacerbates the clinical severity. Isolated exon 8 deletion has been reported in a single case series of SMA types 2 and 3 and never with SMA type 1. While extraocular muscles are typically spared, there are a few case reports documenting associated external ophthalmoplegia. Optic atrophy is a hitherto unreported association of SMA. We report a 10-month-old male infant with SMA type 1 with optic atrophy due to isolated deletion of exon 8 of the SMN gene with intact exon 7 and NAIP gene. PMID:23298926

  3. The yearly rate of Relative Thalamic Atrophy (yrRTA): a simple 2D/3D method for estimating deep gray matter atrophy in Multiple Sclerosis.

    PubMed

    Menéndez-González, Manuel; Salas-Pacheco, José M; Arias-Carrión, Oscar

    2014-01-01

    Despite a strong correlation to outcome, the measurement of gray matter (GM) atrophy is not being used in daily clinical practice as a prognostic factor and monitor the effect of treatments in Multiple Sclerosis (MS). This is mainly because the volumetric methods available to date are sophisticated and difficult to implement for routine use in most hospitals. In addition, the meanings of raw results from volumetric studies on regions of interest are not always easy to understand. Thus, there is a huge need of a methodology suitable to be applied in daily clinical practice in order to estimate GM atrophy in a convenient and comprehensive way. Given the thalamus is the brain structure found to be more consistently implied in MS both in terms of extent of atrophy and in terms of prognostic value, we propose a solution based in this structure. In particular, we propose to compare the extent of thalamus atrophy with the extent of unspecific, global brain atrophy, represented by ventricular enlargement. We name this ratio the "yearly rate of Relative Thalamic Atrophy" (yrRTA). In this report we aim to describe the concept of yrRTA and the guidelines for computing it under 2D and 3D approaches and explain the rationale behind this method. We have also conducted a very short crossectional retrospective study to proof the concept of yrRTA. However, we do not seek to describe here the validity of this parameter since these researches are being conducted currently and results will be addressed in future publications. PMID:25206331

  4. Iron may play a role in pancreatic atrophy in copper deficiency

    SciTech Connect

    Fields, M.; Lewis, C.G.; Lure, M.D. Dept. of Agriculture, Beltsville, MD Univ. of Maryland, College Park )

    1991-03-15

    The present study was undertaken to determine if pancreatic atrophy in copper deficient rats fed fructose is associated with excessive iron deposition. Weanling male and female rats were fed a copper deficient or copper adequate diet containing 62% carbohydrate as either fructose or starch. Another group of weanling rats consumed a copper deficient diet containing fructose that was low in iron. After consuming their respective diets for five weeks, the highest pancreatic iron concentration was seen in male rats consuming the copper deficient diet containing fructose. These animals also exhibited pancreatic atrophy. In contrast, neither copper deficient female rats fed fructose nor males fed starch exhibited pancreatic atrophy and their pancreata did not contain high levels of iron. In addition, reducing the availability of dietary iron in copper deficient rats fed fructose decreased pancreatic iron concentration and ameliorated the pathology. The data suggest that pancreatic atrophy in copper deficiency may be related to iron deposition in that tissue.

  5. Proteomic and bioinformatic analyses of spinal cord injury‑induced skeletal muscle atrophy in rats.

    PubMed

    Wei, Zhi-Jian; Zhou, Xian-Hu; Fan, Bao-You; Lin, Wei; Ren, Yi-Ming; Feng, Shi-Qing

    2016-07-01

    Spinal cord injury (SCI) may result in skeletal muscle atrophy. Identifying diagnostic biomarkers and effective targets for treatment is an important challenge in clinical work. The aim of the present study is to elucidate potential biomarkers and therapeutic targets for SCI‑induced muscle atrophy (SIMA) using proteomic and bioinformatic analyses. The protein samples from rat soleus muscle were collected at different time points following SCI injury and separated by two‑dimensional gel electrophoresis and compared with the sham group. The identities of these protein spots were analyzed by mass spectrometry (MS). MS demonstrated that 20 proteins associated with muscle atrophy were differentially expressed. Bioinformatic analyses indicated that SIMA changed the expression of proteins associated with cellular, developmental, immune system and metabolic processes, biological adhesion and localization. The results of the present study may be beneficial in understanding the molecular mechanisms of SIMA and elucidating potential biomarkers and targets for the treatment of muscle atrophy. PMID:27177391

  6. Atrophying Pityriasis Versicolor: Is This a New Variant of Pityriasis Versicolor?

    PubMed Central

    Yang, Yun-Seok; Shin, Min-Kyung

    2010-01-01

    An atypical clinical form of pityriasis versicolor has been infrequently reported, in which cutaneous atrophy is associated with individual pityriasis versicolor lesions. The pathogenesis of this atrophy remains unclear, but is believed to be a delayed-type hypersensitivity reaction to antigens derived from the Malassezia species. A 60-year-old man presented with multiple, slightly scaly, and depressed maculopatches or plaques on the trunk and extremities. Our microscopic examination of the skin scrapings on a KOH preparation revealed numerous short hyphae and spores. The patient was treated daily with 200 mg of itraconazole in combination with topical antifungals, achieving clinical improvement and mycological recovery, which was confirmed upon follow-up 1 month later. This is the first case report of atrophying pityriasis versicolor in Korea. It needs to be differentiated from other atrophying disorders of the skin. PMID:21165220

  7. Independent mobility after early introduction of a power wheelchair in spinal muscular atrophy.

    PubMed

    Dunaway, Sally; Montes, Jacqueline; O'Hagen, Jessica; Sproule, Douglas M; Vivo, Darryl C De; Kaufmann, Petra

    2013-05-01

    Weakness resulting from spinal muscular atrophy causes severe limitations in functional mobility. The early introduction of power mobility has potential to enhance development and mitigate disability. These outcomes are achieved by simulating normal skill acquisition and by promoting motor learning, visuospatial system development, self-exploration, cognition, and social development. There are few reports on early power mobility in spinal muscular atrophy, and it is typically not prescribed until school age. The authors evaluated 6 children under age 2 years with neuromuscular disease (5 spinal muscular atrophy, 1 congenital muscular dystrophy) for power mobility. Parents recorded the practice hours necessary to achieve independence using the Power Mobility Skills Checklist. Four children achieved independence in all items on the checklist by 7.9 months (range: 73-458 days). Introduction of early power mobility is feasible in spinal muscular atrophy patients under age 2 years and should be introduced in late infancy when children typically acquire locomotor skills. PMID:22772161

  8. Proteomic and bioinformatic analyses of spinal cord injury-induced skeletal muscle atrophy in rats

    PubMed Central

    WEI, ZHI-JIAN; ZHOU, XIAN-HU; FAN, BAO-YOU; LIN, WEI; REN, YI-MING; FENG, SHI-QING

    2016-01-01

    Spinal cord injury (SCI) may result in skeletal muscle atrophy. Identifying diagnostic biomarkers and effective targets for treatment is an important challenge in clinical work. The aim of the present study is to elucidate potential biomarkers and therapeutic targets for SCI-induced muscle atrophy (SIMA) using proteomic and bioinformatic analyses. The protein samples from rat soleus muscle were collected at different time points following SCI injury and separated by two-dimensional gel electrophoresis and compared with the sham group. The identities of these protein spots were analyzed by mass spectrometry (MS). MS demonstrated that 20 proteins associated with muscle atrophy were differentially expressed. Bioinformatic analyses indicated that SIMA changed the expression of proteins associated with cellular, developmental, immune system and metabolic processes, biological adhesion and localization. The results of the present study may be beneficial in understanding the molecular mechanisms of SIMA and elucidating potential biomarkers and targets for the treatment of muscle atrophy. PMID:27177391

  9. [Relationship between simulated weightlessness-induced muscle spindle change and muscle atrophy].

    PubMed

    Zhao, Xue-Hong; Fan, Xiao-Li

    2013-02-25

    One of the most important and urgent issues in the field of space medicine is to reveal the potential mechanism underlying the disused muscle atrophy during the weightlessness or microgravity environment. It will conduce to find out effective methods for the prevention and treatment of muscle atrophy during a long-term space flight. Increasing data show that muscle spindle discharges are significantly altered following the hindlimb unloading, suggesting a vital role in the progress of muscle atrophy. In the last decades, we have made a series of studies on changes in the morphological structure and function of muscle spindle following simulated weightlessness. This review will discuss our main results and related researches for understanding of muscle spindle activities during microgravity environment, which may provide a theoretic basis for effective prevention and treatment of muscle atrophy induced by weightlessness. PMID:23426520

  10. Ultrawide-field fundus photography of the first reported case of gyrate atrophy from Australia

    PubMed Central

    Moloney, Thomas P; O’Hagan, Stephen; Lee, Lawrence

    2014-01-01

    Gyrate atrophy of the choroid and retina is a rare chorioretinal dystrophy inherited in an autosomal recessive pattern. We describe the first documented case of gyrate atrophy from Australia in a 56-year-old woman with a history of previous diagnosis of retinitis pigmentosa and worsening night vision in her right eye over several years. She was myopic and bilaterally pseudophakic, and fundus examination revealed pale optic discs and extensive peripheral chorioretinal atrophy exposing bare sclera bilaterally with only small islands of normal-appearing retina at each posterior pole. Visual field testing showed grossly constricted fields, blood testing showed hyperornithinemia, and further questioning revealed consanguinity between the patient’s parents. We then used the patient’s typical retinal findings of gyrate atrophy to demonstrate the potential use of ultrawide-field fundus photography and angiography in diagnosis and monitoring response in future treatment. PMID:25187693

  11. Moving towards treatments for spinal muscular atrophy: hopes and limits.

    PubMed

    Wirth, Brunhilde; Barkats, Martine; Martinat, Cecile; Sendtner, Michael; Gillingwater, Thomas H

    2015-09-01

    Spinal muscular atrophy (SMA), one of the most frequent and devastating genetic disorders causing neuromuscular degeneration, has reached the forefront of clinical translation. The quite unique genetic situation of SMA patients, who lack functional SMN1 but carry the misspliced SMN2 copy gene, creates the possibility of correcting SMN2 splicing by antisense oligonucleotides or drugs. Both strategies showed impressive results in pre-clinical trials and are now in Phase II-III clinical trials. SMN gene therapy approaches using AAV9-SMN vectors are also highly promising and have entered a Phase I clinical trial. However, careful analysis of SMA animal models and patients has revealed some limitations that need to be taken very seriously, including: i) a limited time-window for successful therapy delivery, making neonatal screening of SMA mandatory; ii) multi-organ impairment, requiring systemic delivery of therapies; and iii) a potential need for combined therapies that both increase SMN levels and target pathways that preserve/rescue motor neuron function over the lifespan. Meeting these challenges will likely be crucial to cure SMA, instead of only ameliorating symptoms, particularly in its most severe form. This review discusses therapies currently in clinical trials, the hopes for SMA therapy, and the potential limitations of these new approaches. PMID:25920617

  12. Non-pharmacological intervention for posterior cortical atrophy.

    PubMed

    Weill-Chounlamountry, Agnès; Alves, Jorge; Pradat-Diehl, Pascale

    2016-08-16

    Posterior cortical atrophy (PCA) is a rare neurodegenerative condition characterized by progressive visual-perceptual deficits. Although the neurocognitive profile of PCA is a growing and relatively well-established field, non-pharmacological care remains understudied and to be widely established in clinical practice. In the present work we review the available literature on non-pharmacological approaches for PCA, such as cognitive rehabilitation including individual cognitive exercises and compensatory techniques to improve autonomy in daily life, and psycho-education aiming to inform people with PCA about the nature of their visual deficits and limits of cognitive rehabilitation. The reviewed studies represented a total of 7 patients. There is a scarcity of the number of studies, and mostly consisting of case studies. Results suggest non-pharmacological intervention to be a potentially beneficial approach for the partial compensation of deficits, improvement of daily functionality and improvement of quality of life. Clinical implications and future directions are also highlighted for the advancement of the field, in order to clarify the possible role of non-pharmacological interventions, and its extent, in PCA. PMID:27574605

  13. [A case of spinal muscular atrophy type 0 in Japan].

    PubMed

    Okamoto, Kentaro; Saito, Kayoko; Sato, Takatoshi; Ishigaki, Keiko; Funatsuka, Makoto; Osawa, Makiko

    2012-09-01

    The patient was a 2-month-old female infant born at 41 weeks and 2 days of gestation presenting multiple arthrogryposis, severe muscle hypotonia and respiratory distress with difficulty in feeding. She suffered from repeated complications with aspiration pneumonia. On admission to our hospital, she exhibited fasciculation and absence of deep tendon reflexes. Examination of the motor nerve conduction velocity (MCV) revealed no muscle contraction. Deletions of the SMN and NAIP genes were noted. Based on severe clinical course and disease development in utero, she was given a diagnosis of spinal muscular atrophy (SMA) type 0 (very severe type). Arthrogryposis and disappearance of MCV are exclusion criteria for SMA. However, the clinical course of the infant was very severe and included such exclusion items. Consequently, when an infant presents muscle hypotonia and respiratory distress, SMA must be considered as one of the differential diagnoses, even though arthrogryposis is an exclusion criterion for SMA. We discuss this case in relation to the few extant reports on SMA type 0 in Japanese infants in the literature. PMID:23012868

  14. Genetic findings of Cypriot spinal muscular atrophy patients.

    PubMed

    Theodorou, L; Nicolaou, P; Koutsou, P; Georghiou, A; Anastasiadou, V; Tanteles, G; Kyriakides, T; Zamba-Papanicolaou, E; Christodoulou, K

    2015-10-01

    Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disorder characterised commonly by proximal muscle weakness and wasting in the absence of sensory signs. Deletion or disruption of the SMN1 gene causes the disease. The SMN1 gene is located within an inverted duplication on chromosome 5q13 with the genes SMN2, NAIP and GTF2H2. MLPA analysis of 13 Cypriot SMA patients revealed that, 12 patients carried a homozygous SMN1 gene deletion and one patient carried two copies of the SMN1 gene. Two of 13 cases were a consequence of a paternally originating de novo mutation. Five genotypes were identified within the population, with the most frequent being a homozygous SMN1 and NAIP genes deletion. In conclusion, genotype-phenotype correlation revealed that SMN2 is inversely related to disease severity and that NAIP and GTF2H2 act as negative modifiers. This study provided, for the first time, a comprehensive overview of gene copy numbers and inheritance patterns within Cypriot SMA families. PMID:26017350

  15. Describing nutrition in spinal muscular atrophy: A systematic review.

    PubMed

    Moore, Georgia E; Lindenmayer, Amara W; McConchie, Grace A; Ryan, Monique M; Davidson, Zoe E

    2016-07-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease of variable severity. Progressive muscle wasting and impairment in functional ability in SMA have a profound influence on nutritional outcomes. This systematic review summarises the existing evidence on nutrition in SMA. The search strategy was conducted across five databases in August 2014, and updated in March 2016, using key terms relating to growth, nutrition requirements, dietary intake and nutrition management. Studies were selected for inclusion using a two pass method, and data systematically extracted using standardised forms. Thirty-nine studies met eligibility criteria. Body composition is abnormal in patients with SMA, and feeding and swallowing issues are prevalent among sufferers of SMA types I and II. Nutritional management practices vary internationally. There is a paucity of literature regarding nutrition requirements in SMA, although it appears that energy expenditure may be reduced. Children with SMA require individualised nutritional management in order to address their growth and nutrition requirements. There is an urgent need for larger, coordinated, prospective intervention studies of nutrition in SMA. PMID:27241822

  16. Subregional Basal Forebrain Atrophy in Alzheimer's Disease: A Multicenter Study

    PubMed Central

    Kilimann, Ingo; Grothe, Michel; Heinsen, Helmut; Alho, Eduardo Joaquim Lopez; Grinberg, Lea; Amaro, Edson; dos Santos, Gláucia Aparecida Bento; da Silva, Rafael Emídio; Mitchell, Alex J.; Frisoni, Giovanni B.; Bokde, Arun L.W.; Fellgiebel, Andreas; Filippi, Massimo; Hampel, Harald; Klöppel, Stefan; Teipel, Stefan J.

    2014-01-01

    Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD. PMID:24503619

  17. Personality of patients with Sudeck's atrophy following tibial fracture.

    PubMed

    De Vilder, J

    1992-01-01

    Patients with reflex sympathetic dystrophy are often considered by physicians and allied health personnel as having a peculiar personality. In medical literature they are frequently described as anxious and depressive, emotional, nervous and irritable patients with neurovegetative instability. A review of the literature on psychological research in this field is not always illuminating. Hypochondria and hysteria, whether or not accompanied by depression, are frequently reported to be typical traits, whereas other findings point more in the direction of psychosis. Increased anxiety, emotional lability and lowered self-esteem are psychological entities that are regularly encountered. The present study includes 42 cases of severe reflex sympathetic dystrophy. Except for the 7 cases of Sudeck atrophy of the hand and wrist, the localization was always in the foot or ankle. The majority of patients had a history of fractures or orthopedic procedures on the lower limbs as a causative factor. In addition to an interview, two questionnaires and a projective test (Rorschach) were used in the personality assessment. While the Rorschach test did not reveal any findings that could be considered as typical of our study population, we did observe different frequency distributions for the personality traits "self-satisfaction", "rigidity" and "somatization". PMID:1280898

  18. Optimization of Spinal Muscular Atrophy subject's muscle activity during gait

    NASA Astrophysics Data System (ADS)

    Umat, Gazlia; Rambely, Azmin Sham

    2014-06-01

    Spinal Muscular Atrophy (SMA) is a hereditary disease related muscle nerve disorder caused by degeneration of the anterior cells of the spinal cord. SMA is divided into four types according to the degree of seriousness. SMA patients show different gait with normal people. Therefore, this study focused on the effects of SMA patient muscle actions and the difference that exists between SMA subjects and normal subjects. Therefore, the electromyography (EMG) test will be used to track the behavior of muscle during walking and optimization methods are used to get the muscle stress that is capable of doing the work while walking. Involved objective function is non-linear function of the quadratic and cubic functions. The study concludes with a comparison of the objective function using the force that sought to use the moment of previous studies and the objective function using the data obtained from EMG. The results shows that the same muscles, peroneus longus and bisepsfemoris, were used during walking activity by SMA subjects and control subjects. Muscle stress force best solution achieved from part D in simulation carried out.

  19. Alexander disease with mild dorsal brainstem atrophy and infantile spasms.

    PubMed

    Torisu, Hiroyuki; Yoshikawa, Yoko; Yamaguchi-Takada, Yui; Yano, Tamami; Sanefuji, Masafumi; Ishizaki, Yoshito; Sawaishi, Yukio; Hara, Toshiro

    2013-05-01

    We present the case of a Japanese male infant with Alexander disease who developed infantile spasms at 8 months of age. The patient had a cluster of partial seizures at 4 months of age. He presented with mild general hypotonia and developmental delay. Macrocephaly was not observed. Brain magnetic resonance imaging (MRI) findings fulfilled all MRI-based criteria for the diagnosis of Alexander disease and revealed mild atrophy of the dorsal pons and medulla oblongata with abnormal intensities. DNA analysis disclosed a novel heterozygous missense mutation (c.1154 C>T, p.S385F) in the glial fibrillary acidic protein gene. At 8 months of age, tonic spasms occurred, and electroencephalography (EEG) revealed hypsarrhythmia. Lamotrigine effectively controlled the infantile spasms and improved the abnormal EEG findings. Although most patients with infantile Alexander disease have epilepsy, infantile spasms are rare. This comorbid condition may be associated with the distribution of the brain lesions and the age at onset of Alexander disease. PMID:22818990

  20. FBXO7 mutations in Parkinson's disease and multiple system atrophy.

    PubMed

    Conedera, Silvio; Apaydin, Hulya; Li, Yuanzhe; Yoshino, Hiroyo; Ikeda, Aya; Matsushima, Takashi; Funayama, Manabu; Nishioka, Kenya; Hattori, Nobutaka

    2016-04-01

    Mutations in the F-box only protein 7 (FBXO7) gene, located on chromosome 22q12-q13, have recently been identified as having distinct clinical features in patients with hereditary Parkinson's disease (PD). Pathologically, α-synuclein-positive inclusions have been identified using anti-FBXO7 antibody staining techniques. In the present study, we screened entire exons of FBXO7 from 271 patients (231 PD and 40 multiple system atrophy [MSA]), of which 221 samples were of Japanese origin. The PD patients (n = 231) comprised 31 autosomal dominant, 82 autosomal recessive, and 118 sporadic forms. The 40 cases of MSA consisted of 8 autosomal dominant, 2 autosomal recessive, and 30 sporadic forms. We detected a Turkish patient with autosomal recessive inheritance, harboring a homozygous truncating mutation, Arg498Stop (p.R498X), in the FBXO7 gene. Consequently, we evaluated her and assessed the correlation between her clinical manifestations and genotypic analysis, although the FBXO7 p.R498X gene has lower frequency than others. Her age at onset was 17 years, and she clinically manifested with progressive parkinsonism and cognitive decline. In contrast, no pathogenic mutations in FBXO7 among PD and MSA patients of Japanese or other ethnicities were observed. Based on recent literature, we reviewed and compared the clinical findings and population differences between documented FBXO7 cases. PMID:26882974

  1. Speech and oral motor learning in individuals with cerebellar atrophy.

    PubMed

    Schulz, G M; Dingwall, W O; Ludlow, C L

    1999-10-01

    The purpose of this study was to determine whether cerebellar pathology interferes with motor learning for either speech or novel tasks. Practice effects were contrasted between persons with cerebellar cortical atrophy (CCA) and control participants on previously learned real speech, nonsense speech, and novel nonspeech oral-movement tasks. Studies of limb motor learning suggested that control participants would evidence reduced variability, increased speed of movement, and reduced movement amplitude with practice as compared with the CCA group. No significant differences were found between the real- and nonsense-speech tasks. For both speech tasks, although neither group reduced their movement variability with practice, both groups significantly reduced jaw closing displacement and velocity with practice. For the novel nonspeech oral-movement task, no change with practice was observed in either group in terms of variability, amplitude, or peak velocity. No effects of cerebellar pathology were seen in either the speech- or oral-movement tasks. These results demonstrated that with practice of speech tasks, a previously learned motor skill, movement speed and displacement decreased in both groups. Therefore, the effects of practice differed between previously learned speech tasks and the novel oral-movement task regardless of cerebellar pathology. PMID:10515513

  2. Dyslexia susceptibility genes influence brain atrophy in frontotemporal dementia

    PubMed Central

    Paternicó, Donata; Premi, Enrico; Alberici, Antonella; Archetti, Silvana; Bonomi, Elisa; Gualeni, Vera; Gasparotti, Roberto; Padovani, Alessandro

    2015-01-01

    Objective: In this study, we evaluated whether variations within genes specifically associated with dyslexia, namely KIAA0319, DCDC2, and CNTNAP2, were associated with greater damage of language-related regions in patients with frontotemporal dementia (FTD) and primary progressive aphasia (PPA) in particular. Methods: A total of 118 patients with FTD, 84 with the behavioral variant of FTD (bvFTD) and 34 with PPA, underwent neuropsychological examination, genetic analyses, and brain MRI. KIAA0319 rs17243157 G/A, DCDC2 rs793842 A/G, and CNTNAP2 rs17236239 A/G genetic variations were assessed. Patients were grouped according to clinical phenotype and genotype status (GA/AA or GG). Gray matter (GM) and white matter (WM) differences were assessed by voxel-based morphometry and structural intercorrelation pattern analyses. Results: Patients carrying KIAA0319 A* (GA or AA) showed greater GM and WM atrophy in the left middle and inferior temporal gyri, as compared with KIAA0319 GG (p < 0.001). The effect of KIAA0319 polymorphism was mainly reported in patients with PPA. In patients with PPA carrying at-risk polymorphism, temporal damage led to loss of interhemispheric and intrahemispheric GM and WM structural association. No effect of DCDC2 and CNTNAP2 was found. Conclusions: Genes involved in dyslexia susceptibility, such as KIAA0319, result in language network vulnerability in FTD, and in PPA in particular. PMID:27066561

  3. Spinal muscular atrophy: An update on therapeutic progress

    PubMed Central

    Seo, Joonbae; Howell, Matthew D.; Singh, Natalia N.; Singh, Ravindra N.

    2013-01-01

    Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA. PMID:23994186

  4. Non-pharmacological intervention for posterior cortical atrophy

    PubMed Central

    Weill-Chounlamountry, Agnès; Alves, Jorge; Pradat-Diehl, Pascale

    2016-01-01

    Posterior cortical atrophy (PCA) is a rare neurodegenerative condition characterized by progressive visual-perceptual deficits. Although the neurocognitive profile of PCA is a growing and relatively well-established field, non-pharmacological care remains understudied and to be widely established in clinical practice. In the present work we review the available literature on non-pharmacological approaches for PCA, such as cognitive rehabilitation including individual cognitive exercises and compensatory techniques to improve autonomy in daily life, and psycho-education aiming to inform people with PCA about the nature of their visual deficits and limits of cognitive rehabilitation. The reviewed studies represented a total of 7 patients. There is a scarcity of the number of studies, and mostly consisting of case studies. Results suggest non-pharmacological intervention to be a potentially beneficial approach for the partial compensation of deficits, improvement of daily functionality and improvement of quality of life. Clinical implications and future directions are also highlighted for the advancement of the field, in order to clarify the possible role of non-pharmacological interventions, and its extent, in PCA. PMID:27574605

  5. Gastric atrophy: use of OLGA staging system in practice

    PubMed Central

    Molaei, Mahsa; Ehtiati, Ara; Mashayekhi, Reza; Rafizadeh, Mitra; Zojaji, Homayoun; Mirsattari, Dariush; Kishani Farahani, Roya

    2016-01-01

    Aim: This study used the OLGA system to characterize the histology pattern of gastritis in dyspeptic outpatients with a mean age of 45 years from regions with different gastric cancer risks. Background: Several classification systems have been purposed for understanding the status of the gastric mucosa. Currently, the Sydney system is the most widely employed. Nevertheless, the applicability of the Sydney system in therapeutic and prognostic areas is a matter of debate. Given this shortcoming an international group of gastroenterologists and pathologists developed a new system named Operative Link on Gastritis Assessment (OLGA). Patients and methods: In this cross-sectional comparative study the OLGA system was used to characterize the histology pattern of gastritis in 685 dyspeptic patients referring to the department of gastroenterology of a training hospital. Results: No significant correlation was found between active inflammation and total OLGA score (P > 0.05). Also, no statistically significant correlation was found between activity and intestinal metaplasia, dysplasia, atrophy, and cancer (P > 0.05). Even though, there is a positive correlation between mild chronic inflammation and total OLGA score, no correlation has been identified between chronicity and dysplasia or cancer (P > 0.05). Nearly, In all cases with no dysplasia OLGA score was zero but all patients with gastric cancer OLGA score was more than two. Conclusion: Generally, the activity is not a useful factor in predicting prognosis and its loss of relation with total OLGA score does not make OLGA score any less predictable. PMID:26744611

  6. Feeding problems and malnutrition in spinal muscular atrophy type II.

    PubMed

    Messina, Sonia; Pane, Marika; De Rose, Paola; Vasta, Isabella; Sorleti, Domenica; Aloysius, Annie; Sciarra, Federico; Mangiola, Fortunato; Kinali, Maria; Bertini, Enrico; Mercuri, Eugenio

    2008-05-01

    The aim of the study was to conduct a survey using a dedicated questionnaire to assess feeding difficulties and weight gain in a population of 122 Spinal Muscular Atrophy (SMA) type II patients, aged between 1 and 47 years. All the answers were entered in a database and were analysed subdividing the cohort into age groups (1-5, 6-10, 11-14, 15-19, 20-29, and 30-50 years). Six out of our 122 patients (5%), all younger than 11 years, had weights more than 2SD above the median for age matched controls, whilst 45 (37%) had weights less than 2SD below the median. Chewing difficulties were reported in 34 of the 122 patients (28%) and limitation in the ability to open the mouth in 36 (30%) and both were increasingly more frequent with age. Swallowing difficulties were reported in 30 patients (25%). The results of our survey suggest that a number of patients with SMA type II have limited jaw opening, and chewing and swallowing difficulties. Our findings raise a few issues concerning standards of care that should be implemented in the monitoring and management of feeding difficulties and weight gain. PMID:18420410

  7. Plastin 3 expression in discordant spinal muscular atrophy (SMA) siblings.

    PubMed

    Bernal, Sara; Also-Rallo, Eva; Martínez-Hernández, Rebeca; Alías, Laura; Rodríguez-Alvarez, Francisco Javier; Millán, José M; Hernández-Chico, Concepción; Baiget, Montserrat; Tizzano, Eduardo F

    2011-06-01

    Spinal muscular atrophy (SMA) is caused by loss or mutations of the survival motor neuron 1 gene (SMN1). Its highly homologous copy, SMN2, is present in all SMA cases and is a phenotypic modifier. There are cases where asymptomatic siblings of typical SMA patients possess a homozygous deletion of SMN1 just like their symptomatic brothers or sisters. Plastin 3 (PLS3) when over expressed in lymphoblasts from females has been suggested to act as a genetic modifier of SMA. We studied PLS3 expression in four Spanish SMA families with discordant siblings haploidentical for the SMA locus. We excluded PLS3 as a possible modifier in two of our families with female discordant siblings. In the remaining two, we observed small differences in PLS3 expression between male and female discordant siblings. Indeed, we found that values of PLS3 expression in lymphoblasts and peripheral blood ranged from 12 to 200-fold less than those in fibroblasts. These findings warrant further investigation in motor neurons derived from induced pluripotential stem cells of these patients. PMID:21546251

  8. Remobilization does not fully restore immobilization induced articular cartilage atrophy.

    PubMed

    Haapala, J; Arokoski, J P; Hyttinen, M M; Lammi, M; Tammi, M; Kovanen, V; Helminen, H J; Kiviranta, I

    1999-05-01

    The recovery of articular cartilage from immobilization induced atrophy was studied. The right hind limbs of 29-week-old beagle dogs were immobilized for 11 weeks and then remobilized for 50 weeks. Cartilage from the immobilized knee was compared with tissue from age matched control animals. After the immobilization period, uncalcified articular cartilage glycosaminoglycan concentration was reduced by 20% to 23%, the reduction being largest (44%) in the superficial zone. The collagen fibril network showed no significant changes, but the amount of collagen crosslinks was reduced (13.5%) during immobilization. After remobilization, glycosaminoglycan concentration was restored at most sites, except for in the upper parts of uncalcified cartilage in the medial femoral and tibial condyles (9% to 17% less glycosaminoglycans than in controls). The incorporation of 35SO4 was not changed, and remobilization also did not alter the birefringence of collagen fibrils. Remobilization restored the proportion of collagen crosslinks to the control level. The changes induced by joint unloading were reversible at most sites investigated, but full restoration of articular cartilage glycosaminoglycan concentration was not obtained in all sites, even after remobilization for 50 weeks. This suggests that lengthy immobilization of a joint can cause long lasting articular cartilage proteoglycan alterations at the same time as collagen organization remains largely unchanged. Because proteoglycans exert strong influence on the biomechanical properties of cartilage, lengthy immobilization may jeopardize the well being of articular cartilage. PMID:10335301

  9. Diffusion tensor imaging in the characterization of multiple system atrophy

    PubMed Central

    Rulseh, Aaron Michael; Keller, Jiri; Rusz, Jan; Syka, Michael; Brozova, Hana; Rusina, Robert; Havrankova, Petra; Zarubova, Katerina; Malikova, Hana; Jech, Robert; Vymazal, Josef

    2016-01-01

    Purpose Multiple system atrophy (MSA) is a rare neurodegenerative disease that remains poorly understood, and the diagnosis of MSA continues to be challenging. We endeavored to improve the diagnostic process and understanding of in vivo characteristics of MSA by diffusion tensor imaging (DTI). Materials and methods Twenty MSA subjects, ten parkinsonian dominant (MSA-P), ten cerebellar dominant (MSA-C), and 20 healthy volunteer subjects were recruited. Fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity maps were processed using tract-based spatial statistics. Diffusion data were additionally evaluated in the basal ganglia. A support vector machine was used to assess diagnostic utility, leave-one-out cross-validation in the evaluation of classification schemes, and receiver operating characteristic analyses to determine cutoff values. Results We detected widespread changes in the brain white matter of MSA subjects; however, no group-wise differences were found between MSA-C and MSA-P subgroups. Altered DTI metrics in the putamen and middle cerebellar peduncles were associated with a positive parkinsonian and cerebellar phenotype, respectively. Concerning clinical applicability, we achieved high classification performance on mean diffusivity data in the combined bilateral putamen and middle cerebellar peduncle (accuracy 90.3%±9%, sensitivity 86.5%±11%, and specificity 99.3%±4%). Conclusion DTI in the middle cerebellar peduncle and putamen may be used in the diagnosis of MSA with a high degree of accuracy. PMID:27616888

  10. Neuropsychological Investigation in Chinese Patients with Progressive Muscular Atrophy

    PubMed Central

    Cui, Bo; Cui, Liying; Liu, Mingsheng; Li, Xiaoguang; Ma, Junfang; Fang, Jia; Ding, Qingyun

    2015-01-01

    Background Progressive muscular atrophy (PMA) is a rare type of degenerative motor neuron disease (MND) of which the onset happens in adult period. Despite its well-defined clinical characteristics, its neuropsychological profile has remained poorly understood, considering the consensus of cognitive and behavioral impairment reached in amyotrophic lateral sclerosis (ALS). Methods We conducted a cross-sectional evaluation of Chinese PMA patients with a series of comprehensive batteries emphasizing the executive and attention function, and covering other domains of memory, language, visuospatial function, calculation and behavior as well. Their performances were compared with those of age- and education-matched ALS and healthy controls (HC). Results 21 patients newly diagnosed with PMA were consecutively enrolled into our ALS and other MND registry platform, accounting for 14.7% of all the incident MND cases registered during the same period. 20 patients who completed the neuropsychological batteries were included into analysis. Compared with HC, PMA performed significantly worse in maintenance function of attention, while they exhibited quantitative similarity to ALS in all behavioral inventories and neuropsychological tests except the time for Stroop interference effect. Conclusion PMA could display mild cognitive dysfunction in the same frontal-mediated territory of ALS but in a lesser degree, whereas they did not differ from ALS behaviorally. PMID:26042930

  11. Decreased Coenzyme Q10 Levels in Multiple System Atrophy Cerebellum.

    PubMed

    Barca, Emanuele; Kleiner, Giulio; Tang, Guomei; Ziosi, Marcello; Tadesse, Saba; Masliah, Eliezer; Louis, Elan D; Faust, Phyllis; Kang, Un J; Torres, Jose; Cortes, Etty P; Vonsattel, Jean-Paul G; Kuo, Sheng-Han; Quinzii, Catarina M

    2016-07-01

    In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients. PMID:27235405

  12. Unusual molecular findings in autosomal recessive spinal muscular atrophy.

    PubMed Central

    Matthijs, G; Schollen, E; Legius, E; Devriendt, K; Goemans, N; Kayserili, H; Apäk, M Y; Cassiman, J J

    1996-01-01

    All three types of autosomal recessive spinal muscular atrophy map to chromosome 5q11.2-q13.3 and are associated with deletions or mutations of the SMN (survival motor neurone) gene. The availability of a test to distinguish between the SMN gene and its nearly identical centromeric copy cBCD541 allows molecular diagnosis. We have analysed patients from 24 Belgian and 34 Turkish families for the presence or absence of a deletion in the SMN gene. A homozygous deletion in the SMN gene was seen in 90% of unrelated SMA patients. A non-radioactive SSCP assay allows for a semiquantitative analysis of the copy number of the centromeric and SMN genes. Hence, direct carrier detection has become feasible under certain conditions. We observed a phenotypically normal male, father of an SMA type I patient, presenting with only a single copy of the SMN gene and lacking both copies of the cBCD541 gene. This illustrates that a reduction of the total number of SMN and cBCD541 genes to a single SMN copy is compatible with normal life. In another SMA type I family, there is evidence for a de novo deletion of the centromeric gene in a normal sib. This observation illustrates the susceptibility of the SMA locus to de novo deletions and rearrangements. Images PMID:8782046

  13. Progressive Retinal Atrophy in the Border Collie: A new XLPRA

    PubMed Central

    Vilboux, Thierry; Chaudieu, Gilles; Jeannin, Patricia; Delattre, Delphine; Hedan, Benoit; Bourgain, Catherine; Queney, Guillaume; Galibert, Francis; Thomas, Anne; André, Catherine

    2008-01-01

    Background Several forms of progressive retinal atrophy (PRA) segregate in more than 100 breeds of dog with each PRA segregating in one or a few breeds. This breed specificity may be accounted for by founder effects and genetic drift, which have reduced the genetic heterogeneity of each breed, thereby facilitating the identification of causal mutations. We report here a new form of PRA segregating in the Border Collie breed. The clinical signs, including the loss of night vision and a progressive loss of day vision, resulting in complete blindness, occur at the age of three to four years and may be detected earlier through systematic ocular fundus examination and electroretinography (ERG). Results Ophthalmic examinations performed on 487 dogs showed that affected dogs present a classical form of PRA. Of those, 274 have been sampled for DNA extraction and 87 could be connected through a large pedigree. Segregation analysis suggested an X-linked mode of transmission; therefore both XLPRA1 and XLPRA2 mutations were excluded through the genetic tests. Conclusion Having excluded these mutations, we suggest that this PRA segregating in Border Collie is a new XLPRA (XLPRA3) and propose it as a potential model for the homologous human disease, X-Linked Retinitis Pigmentosa. PMID:18315866

  14. Multiple System Atrophy. Using Clinical Pharmacology to Reveal Pathophysiology

    PubMed Central

    Jordan, Jens; Shibao, Cyndya; Biaggioni, Italo

    2015-01-01

    Despite similarities in their clinical presentation, patients with multiple system atrophy (MSA) have residual sympathetic tone and intact post-ganglionic noradrenergic fibers, whereas patients with pure autonomic failure (PAF) and Parkinson’s disease (PD) have efferent post-ganglionic autonomic denervation. These differences are apparent biochemically, with near normal plasma norepinephrine in MSA but very low levels in PAF, and in neurophysiological testing. These differences are also reflected in the response patients have to drugs that interact with the autonomic nervous system. E.g., the ganglionic blocker trimethaphan reduce residual sympathetic tone and lower blood pressure in MSA but less so in PAF. Conversely, the α2-antagonist yohimbine produces a greater increase in blood pressure in MSA compared to PAF, although significant overlap exists. In normal subjects the norepinephrine reuptake (NET) inhibitor atomoxetine has little effect on blood pressure because the peripheral effects of NET inhibition that result in noradrenergic vasoconstriction, are counteracted by the increase in brain norepinephrine which reduces sympathetic outflow (a clonidine-like effect). In patients with autonomic failure and intact peripheral noradrenergic fibers only the peripheral vasoconstriction is apparent. This translates to a significant pressor effect of atomoxetine in MSA, but not in PAF patients. Thus, pharmacological probes can be used to understand the pathophysiology of the different forms of autonomic failure, assist in the diagnosis, and aid in the management of orthostatic hypotension. PMID:25757803

  15. GEMINs: potential therapeutic targets for spinal muscular atrophy?

    PubMed Central

    Borg, Rebecca; Cauchi, Ruben J.

    2014-01-01

    The motor neuron degenerative disease spinal muscular atrophy (SMA) remains one of the most frequently inherited causes of infant mortality. Afflicted patients loose the survival motor neuron 1 (SMN1) gene but retain one or more copies of SMN2, a homolog that is incorrectly spliced. Primary treatment strategies for SMA aim at boosting SMN protein levels, which are insufficient in patients. SMN is known to partner with a set of diverse proteins collectively known as GEMINs to form a macromolecular complex. The SMN-GEMINs complex is indispensible for chaperoning the assembly of small nuclear ribonucleoproteins (snRNPs), which are key for pre-mRNA splicing. Pharmaceutics that alleviate the neuromuscular phenotype by restoring the fundamental function of SMN without augmenting its levels are also crucial in the development of an effective treatment. Their use as an adjunct therapy is predicted to enhance benefit to patients. Inspired by the surprising discovery revealing a premier role for GEMINs in snRNP biogenesis together with in vivo studies documenting their requirement for the correct function of the motor system, this review speculates on whether GEMINs constitute valid targets for SMA therapeutic development. PMID:25360080

  16. Subacute brain atrophy after radiation therapy for malignant brain tumor

    SciTech Connect

    Asai, A.; Matsutani, M.; Kohno, T.; Nakamura, O.; Tanaka, H.; Fujimaki, T.; Funada, N.; Matsuda, T.; Nagata, K.; Takakura, K.

    1989-05-15

    Brain atrophy with mental and neurologic deterioration developing a few months after radiation therapy in patients without residual or recurrent brain tumors has been recognized. Two illustrative case reports of this pathologic entity are presented. Six autopsy cases with this entity including the two cases were reviewed neurologically, radiographically, and histopathologically. All patients presented progressive disturbances of mental status and consciousness, akinesia, and tremor-like involuntary movement. Computerized tomography (CT) demonstrated marked enlargement of the ventricles, moderate widening of the cortical sulci, and a moderately attenuated CT number for the white matter in all six patients. Four of the six patients had CSF drainage (ventriculoperitoneal shunt or continuous lumbar drainage), however, none of them improved. Histologic examination demonstrated swelling and loss of the myelin sheath in the white matter in all patients, and reactive astrocytosis in three of the six patients. Neither prominent neuronal loss in the cerebral cortex or basal ganglia, nor axonal loss in the white matter was generally identified. The blood vessels of the cerebral cortex and white matter were normal. Ependymal layer and the surrounding brain tissue were normal in all patients. These findings suggested that this pathologic condition results from demyelination secondary to direct neurotoxic effect of irradiation. The authors' previous report was reviewed and the differential diagnoses, the risk factors for this pathologic entity, and the indication for radiation therapy in aged patients with a malignant brain tumor are discussed.

  17. Quantitative pathological changes in the cerebellum of multiple system atrophy.

    PubMed

    Armstrong, Richard A

    2015-01-01

    Multiple system atrophy (MSA) is a rare neurodegenerative disorder associated with parkinsonism, ataxia, and autonomic dysfunction. Its pathology is primarily subcortical comprising vacuolation, neuronal loss, gliosis, and α-synucleinimmunoreactive glial cytoplasmic inclusions (GCI). To quantify cerebellar pathology in MSA, the density and spatial pattern of the pathological changes were studied in α-synuclein-immunolabelled sections of the cerebellar hemisphere in 10 MSA and 10 control cases. In MSA, densities of Purkinje cells (PC) were decreased and vacuoles in the granule cell layer (GL) increased compared with controls. In six MSA cases, GCI were present in cerebellar white matter. In the molecular layer (ML) and GL of MSA, vacuoles were clustered, the clusters exhibiting a regular distribution parallel to the edge of the folia. Purkinje cells were randomly or regularly distributed with large gaps between surviving cells. Densities of glial cells and surviving neurons in the ML and surviving cells and vacuoles in the GL were negatively correlated consistent with gliosis and vacuolation in response to neuronal loss. Principal components analysis (PCA) suggested vacuole densities in the ML and vacuole density and cell losses in the GL were the main source of neuropathological variation among cases. The data suggest that: (1) cell losses and vacuolation of the GCL and loss of PC were the most significant pathological changes in the cases studied, (2) pathological changes were topographically distributed, and (3) cerebellar pathology could influence cerebral function in MSA via the cerebello-dentato-thalamic tract. PMID:26443310

  18. Multiple system atrophy: using clinical pharmacology to reveal pathophysiology.

    PubMed

    Jordan, Jens; Shibao, Cyndya; Biaggioni, Italo

    2015-02-01

    Despite similarities in their clinical presentation, patients with multiple system atrophy (MSA) have residual sympathetic tone and intact post-ganglionic noradrenergic fibers, whereas patients with pure autonomic failure (PAF) and Parkinson disease have efferent post-ganglionic autonomic denervation. These differences are apparent biochemically, as well as in neurophysiological testing, with near normal plasma norephrine in MSA but very low levels in PAF. These differences are also reflected in the response patients have to drugs that interact with the autonomic nervous system. For example, the ganglionic blocker trimethaphan reduces residual sympathetic tone and lowers blood pressure in MSA, but less so in PAF. Conversely, the α2-antagonist yohimbine produces a greater increase in blood pressure in MSA compared to PAF, although significant overlap exists. In normal subjects, the norepinephrine reuptake (NET) inhibitor atomoxetine has little effect on blood pressure because the peripheral effects of NET inhibition that result in noradrenergic vasoconstriction are counteracted by the increase in brain norepinephrine, which reduces sympathetic outflow (a clonidine-like effect). In patients with autonomic failure and intact peripheral noradrenergic fibers, only the peripheral vasoconstriction is apparent. This translates to a significant pressor effect of atomoxetine in MSA, but not in PAF patients. Thus, pharmacological probes can be used to understand the pathophysiology of the different forms of autonomic failure, assist in the diagnosis, and aid in the management of orthostatic hypotension. PMID:25757803

  19. Hypospadias as a novel feature in spinal bulbar muscle atrophy.

    PubMed

    Nordenvall, Anna Skarin; Paucar, Martin; Almqvist, Catarina; Nordenström, Anna; Frisén, Louise; Nordenskjöld, Agneta

    2016-04-01

    Spinal and bulbar muscle atrophy (SBMA) is an X-linked neuromuscular disorder caused by CAG repeat expansions in the androgen receptor (AR) gene. The SBMA phenotype consists of slowly progressive neuromuscular symptoms and undermasculinization features as the result of malfunction of the AR. The latter mainly includes gynecomastia and infertility. Hypospadias is also a feature of undermasculinization with an underdeveloped urethra and penis; it has not been described as part of the SBMA phenotype but has been suggested to be associated with a prolonged CAG repeat in the AR gene. This study includes the first epidemiologic description of the co-occurrence of hypospadias and SBMA in subjects and their male relatives in Swedish population-based health registers, as well as an additional clinical case. One boy with severe hypospadias was screened for mutations in the AR gene and was found to have 42 CAG repeats in it, which is in the full range of mutations causing SBMA later in life. We also detected a maximum of four cases displaying the combination of SBMA and hypospadias in our national register databases. This is the third case report with hypospadias in association with CAG repeat expansions in the AR gene in the full range known to cause SBMA later in life. Our findings suggest that hypospadias may be an under diagnosed feature of the SBMA phenotype and we propose that neurologists working with SBMA further investigate and report the true prevalence of hypospadias among patients with SBMA. PMID:26872663

  20. Skeletal muscle calcineurin: influence of phenotype adaptation and atrophy

    NASA Technical Reports Server (NTRS)

    Spangenburg, E. E.; Williams, J. H.; Roy, R. R.; Talmadge, R. J.; Spangenberg, E. E. (Principal Investigator)

    2001-01-01

    Calcineurin (CaN) has been implicated as a signaling molecule that can transduce physiological stimuli (e.g., contractile activity) into molecular signals that initiate slow-fiber phenotypic gene expression and muscle growth. To determine the influence of muscle phenotype and atrophy on CaN levels in muscle, the levels of soluble CaN in rat muscles of varying phenotype, as assessed by myosin heavy chain (MHC)-isoform proportions, were determined by Western blotting. CaN levels were significantly greater in the plantaris muscle containing predominantly fast (IIx and IIb) MHC isoforms, compared with the soleus (predominantly type I MHC) or vastus intermedius (VI, contains all 4 adult MHC isoforms). Three months after a complete spinal cord transection (ST), the CaN levels in the VI muscle were significantly reduced, despite a significant increase in fast MHC isoforms. Surprisingly, the levels of CaN in the VI were highly correlated with muscle mass but not MHC isoform proportions in ST and control rats. These data demonstrate that CaN levels in skeletal muscle are highly correlated to muscle mass and that the normal relationship with phenotype is lost after ST.

  1. Spinal muscular atrophy in Holstein-Friesian calves.

    PubMed

    Pumarola, M; Añor, S; Majó, N; Borrás, D; Ferrer, I

    1997-02-01

    The clinical and neuropathological findings of spinal muscular atrophy (SMA) in Holstein-Friesian calves are described in four females and one male from a dairy farm composed of 150 cows and 2 breeding bulls. Locomotion difficulties started at the age of 15 days, and progressed to paraparesis and tetraparesis in 2 weeks. Signs consistent with denervation were revealed with electromyography. The neuropathological examination showed degeneration and loss of motor neurons in the spinal cord, together with astrocytosis. Among the remaining motor neurons were ghost cells and neurons filled with accumulations of straight filaments measuring 10-12 nm in diameter, which were strongly immunoreactive with antibodies produced against phosphorylated neurofilaments. Degenerating cells in SMA did not stain with the method of in situ labelling of nuclear DNA fragmentation and did not show c-Jun immunoreactivity. This feature contrasts with the in situ labelling of DNA breaks of apoptotic cells and with the strong c-Jun immunoreactivity restricted to dying cells during the whole process of naturally occurring cell death in the developing central nervous system. These features suggest that cell death in SMA differs from programmed cell death during normal development, and that pathological cell death in SMA should not be considered as a mere persistence or reactivation of normally occurring developmental cell death. PMID:9039466

  2. Towards identification of the gene for spinal muscular atrophy

    SciTech Connect

    Steege, G. van der; Cobben, J.M.; Draaijers, T.G.

    1994-09-01

    The proximal spinal muscular atrophies (SMAs) are irreversible lower motor neuron diseases of unknown primary cause. According to age of onset and severity of illness, this group of disorders can be classified into three types: SMA types I, II, and III. All three types of autosomal recessive SMA have been localized to chromosome 5 in bands of q11.2-q13 by genetic analysis. The gene resides in a small genetic interval flanked by the markers D5S435 and D5S557. From a hybrid cell line containing 5q11-q14 as its only human chromosome 5 material we constructed a cosmid library. A cosmid clone mapped by FISH between D5S125 and D5S112 was used to isolate some YACs, from which cosmid libraries were constructed. cDNA libraries are screened by hybridization directly with the YACs and with cosmids that give Northern signals. At present we are analysing 7 different cDNA clones mapping between D5S435 and D5S557.

  3. Transmission of multiple system atrophy prions to transgenic mice

    PubMed Central

    Watts, Joel C.; Giles, Kurt; Oehler, Abby; Middleton, Lefkos; Dexter, David T.; Gentleman, Steve M.; DeArmond, Stephen J.; Prusiner, Stanley B.

    2013-01-01

    Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson’s disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83+/+ mice homozygous for a mutant A53T α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83+/− mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-synuclein prions, we inoculated the TgM83+/− mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83+/− mice developed progressive signs of neurologic disease with an incubation period of ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83+/+ mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago. PMID:24218576

  4. MicroRNA in myogenesis and muscle atrophy

    PubMed Central

    Wang, Xiaonan H.

    2014-01-01

    Purpose of review To understand the impact of microRNA on myogenesis and muscle wasting in order to provide valuable information for clinical investigation. Recent findings Muscle wasting increases the risk of morbidity/mortality in primary muscle diseases, secondary muscle disorders and elderly population. Muscle mass is controlled by several different signalling pathways. Insulin-like growth factor/PI3K/Akt is a positive signalling pathway, as it increases muscle mass by increasing protein synthesis and decreasing protein degradation. This pathway is directly and/or indirectly downregulated by miR-1, miR-133, miR-206 or miR-125b, and upregulated by miR-23a or miR-486. Myostatin and the transforming growth factor-β signalling pathway are negative regulators that cause muscle wasting. An increase of miR-27 reduces myostatin and increases muscle cell proliferation. Muscle regeneration capacity also plays a significant role in the regulation of muscle mass. This review comprehensively describes the effect of microRNA on myoblasts proliferation and differentiation, and summarizes the varied influences of microRNA on different muscle atrophy. Summary Growing evidence indicates that microRNAs significantly impact muscle growth, regeneration and metabolism. MicroRNAs have a great potential to become diagnostic and/or prognostic markers, therapeutic agents and therapeutic targets. PMID:23449000

  5. Retinitis pigmentosa with concomitant essential iris atrophy and glaucoma – case report

    PubMed Central

    Meirelles, Sérgio Henrique Sampaio; Barreto, Aline Sá; Buscacio, Eduardo Scaldini; Shinzato, Elke; Patrão, Lia Florim; de Oliveira Silva, Mauro Sérgio

    2015-01-01

    Purpose To report a case of a young patient with retinitis pigmentosa (RP), essential iris atrophy, and glaucoma. Case report This report presents a case of a 22-year-old female patient with unilateral glaucoma, increased intraocular pressure, increased cup–disc ratio, iris atrophy, peripheral anterior synechiae, and bilateral RP. Discussion The patient presented glaucoma due to the iridocorneal endothelial syndrome, despite low age. RP is a bilateral disorder that may be associated with angle-closure glaucoma. PMID:26648683

  6. Dendritic atrophy constricts functional maps in resonance and impedance properties of hippocampal model neurons

    PubMed Central

    Dhupia, Neha; Rathour, Rahul K.; Narayanan, Rishikesh

    2015-01-01

    A gradient in the density of hyperpolarization-activated cyclic-nucleotide gated (HCN) channels is necessary for the emergence of several functional maps within hippocampal pyramidal neurons. Here, we systematically analyzed the impact of dendritic atrophy on nine such functional maps, related to input resistance and local/transfer impedance properties, using conductance-based models of hippocampal pyramidal neurons. We introduced progressive dendritic atrophy in a CA1 pyramidal neuron reconstruction through a pruning algorithm, measured all functional maps in each pruned reconstruction, and arrived at functional forms for the dependence of underlying measurements on dendritic length. We found that, across frequencies, atrophied neurons responded with higher efficiency to incoming inputs, and the transfer of signals across the dendritic tree was more effective in an atrophied reconstruction. Importantly, despite the presence of identical HCN-channel density gradients, spatial gradients in input resistance, local/transfer resonance frequencies and impedance profiles were significantly constricted in reconstructions with dendritic atrophy, where these physiological measurements across dendritic locations converged to similar values. These results revealed that, in atrophied dendritic structures, the presence of an ion channel density gradient alone was insufficient to sustain homologous functional maps along the same neuronal topograph. We assessed the biophysical basis for these conclusions and found that this atrophy-induced constriction of functional maps was mediated by an enhanced spatial spread of the influence of an HCN-channel cluster in atrophied trees. These results demonstrated that the influence fields of ion channel conductances need to be localized for channel gradients to express themselves as homologous functional maps, suggesting that ion channel gradients are necessary but not sufficient for the emergence of functional maps within single neurons

  7. Atrophy Patterns in Early Clinical Stages Across Distinct Phenotypes of Alzheimer’s Disease

    PubMed Central

    Ossenkoppele, Rik; Cohn-Sheehy, Brendan I.; La Joie, Renaud; Vogel, Jacob W.; Möller, Christiane; Lehmann, Manja; van Berckel, Bart N.M.; Seeley, William W.; Pijnenburg, Yolande A.; Gorno-Tempini, Maria L.; Kramer, Joel H.; Barkhof, Frederik; Rosen, Howard J.; van der Flier, Wiesje M.; Jagust, William J.; Miller, Bruce L.; Scheltens, Philip; Rabinovici, Gil D.

    2015-01-01

    Alzheimer’s disease (AD) can present with distinct clinical variants. Identifying the earliest neurodegenerative changes associated with each variant has implications for early diagnosis, and for understanding the mechanisms that underlie regional vulnerability and disease progression in AD. We performed voxel-based morphometry to detect atrophy patterns in early clinical stages of four AD phenotypes: Posterior cortical atrophy (PCA, “visual variant,” n = 93), logopenic variant primary progressive aphasia (lvPPA, “language variant,” n = 74), and memory-predominant AD categorized as early age-of-onset (EOAD, <65 years, n = 114) and late age-of-onset (LOAD, >65 years, n = 114). Patients with each syndrome were stratified based on: (1) degree of functional impairment, as measured by the clinical dementia rating (CDR) scale, and (2) overall extent of brain atrophy, as measured by a neuroimaging approach that sums the number of brain voxels showing significantly lower gray matter volume than cognitively normal controls (n = 80). Even at the earliest clinical stage (CDR =0.5 or bottom quartile of overall atrophy), patients with each syndrome showed both common and variant-specific atrophy. Common atrophy across variants was found in temporoparietal regions that comprise the posterior default mode network (DMN). Early syndrome-specific atrophy mirrored functional brain networks underlying functions that are uniquely affected in each variant: Language network in lvPPA, posterior cingulate cortex-hippocampal circuit in amnestic EOAD and LOAD, and visual networks in PCA. At more advanced stages, atrophy patterns largely converged across AD variants. These findings support a model in which neurodegeneration selectively targets both the DMN and syndrome-specific vulnerable networks at the earliest clinical stages of AD. PMID:26260856

  8. [On the Role of Titin Phosphorylation in Development of Muscular Atrophy].

    PubMed

    Salmov, N N; Gritsyna, Yu V; Ulanova, A D; Vikhlyantsev, I M; Podlubnaya, Z A

    2015-01-01

    From our earlier experiments on the study of changes in titin content and the level of its phosphorylation in skeletal muscles, atrophied during space flight, hibernation, and also because of the development of alcohol-induced lesions it has been suggested that an increase in the degree of titin phosphorylation results in increased proteolytic degradation of this protein, that contributes to the development of skeletal muscle atrophy. PMID:26394485

  9. Tourniquet Use During Knee Replacement Surgery May Contribute to Muscle Atrophy in Older Adults.

    PubMed

    Dreyer, Hans C

    2016-04-01

    Muscle atrophy after total knee arthroplasty (TKA) occurs at a rate of 1% per day for the first 2 wk. Our hypothesis is that tourniquet-induced ischemia-reperfusion injury occurring during TKA influences metabolism and may contribute to atrophy. Identifying pathways that are upregulated during this critical "14-d window" after surgery may help us delineate therapeutic approaches to avoid muscle loss. PMID:26829246

  10. Delphinidin prevents disuse muscle atrophy and reduces stress-related gene expression.

    PubMed

    Murata, Motoki; Kosaka, Reia; Kurihara, Kana; Yamashita, Shuya; Tachibana, Hirofumi

    2016-08-01

    Delphinidin is a member of the anthocyanidin class of plant pigments. We examined the effects of delphinidin on muscle atrophy. Oral administration of delphinidin suppressed the muscle weight loss induced by mechanical unloading. Microarray analysis showed that delphinidin suppresses the upregulation of oxidative stress-related gene expression, including the expression of Cbl-b. Thus, delphinidin may prevent unloading-mediated muscle atrophy. PMID:27180787

  11. Report from PAA.

    PubMed

    1995-06-01

    The Population Association of America Annual Meeting, held in San Francisco April 6-8, 1995, generated papers on the key demographic themes of marriage, birth, mortality, and migration. In the US 47% of people between the ages of 25 and 44 have lived with an unmarried partner for some period, up from 37% during 1987-1988. For teenagers, absence of contact with fathers is associated with symptoms of depression, becoming a teen parent, and delinquency. Single fathers in 1990 were younger and had lower incomes than in the past. About 40% of nonpaying fathers had children out of wedlock; 30% to 48% had low or no income. The tendency of Whites to leave or avoid minority neighborhoods is due to perceptions about crime, quality of the schools, neighborhood deterioration, and the socioeconomic level of neighbors. Although African-American death rates generally are higher than those of Whites, the pattern seems to reverse itself after age 85. Surprisingly, survival probability at ages 80-95 for US Whites is higher than that in Europe and Japan. When immigrants enter an area, there is not much evidence of low-skilled native-born people moving out. Families with undocumented heads received an average of $6,080 in welfare benefits, while refugees received $10,444. The Social Security system is shifting large amounts of money from regions of the country with younger age structures, such as California, to states with older age structures, such as Florida. Among other topics, the remarkably low total fertility rate of 3.4 in the Bangladesh 1993-1994 Demographic and Health Survey was questioned as biased; the infant mortality data for Tajikistan appeared to be suspect; the diffusion of information about family planning in Africa was mentioned; the significance of the 1994 International Conference on Population and Development regarding reproductive health services was hailed; and USAID's designing of indicators in safe pregnancy, breastfeeding, and women's nutrition was related. PMID:12289924

  12. Calcified neurocysticercosis associates with hippocampal atrophy: a population-based study.

    PubMed

    Del Brutto, Oscar H; Salgado, Perla; Lama, Julio; Del Brutto, Victor J; Campos, Xavier; Zambrano, Mauricio; García, Héctor H

    2015-01-01

    Calcified neurocysticercosis has been associated with hippocampal atrophy in patients with refractory epilepsy, but the relevance of this association in the population at large is unknown. We assessed calcified cysticerci and its association with hippocampal atrophy in elderly persons living in Atahualpa, an Ecuadorian village endemic for neurocysticercosis. All Atahualpa residents ≥ 60 years of age were invited to undergo computed tomography/magnetic resonance imaging for neurocysticercosis detection. Twenty-eight (11%) out of 248 enrolled persons had calcified cysticerci (case-patients) and were matched 1:1 by age, sex, and years of education to individuals without neurocysticercosis on computed tomography/magnetic resonance imaging (controls). Four case-patients and none of the controls had epilepsy (P = 0.134). Cognitive performance was similar across both groups. The Scheltens' medial temporal atrophy scale was used for hippocampal rating in case-patients and matched controls without neurocysticercosis. Mean score in the Scheltens' scale was higher in case-patients than in controls (P < 0.001). Atrophic hippocampi were noticed in 19 case-patients and five controls (P = 0.003). Atrophy was bilateral in 11 case-patients and unilateral in eight. All case-patients with unilateral hippocampal atrophy had at least one ipsilateral calcification. This study shows an association between calcified cysticerci and hippocampal atrophy and raises the possibility of an inflammation-mediated hippocampal damage as the responsible mechanism for these findings. PMID:25349375

  13. Calcified Neurocysticercosis Associates with Hippocampal Atrophy: A Population-Based Study

    PubMed Central

    Del Brutto, Oscar H.; Salgado, Perla; Lama, Julio; Del Brutto, Victor J.; Campos, Xavier; Zambrano, Mauricio; García, Héctor H.

    2015-01-01

    Calcified neurocysticercosis has been associated with hippocampal atrophy in patients with refractory epilepsy, but the relevance of this association in the population at large is unknown. We assessed calcified cysticerci and its association with hippocampal atrophy in elderly persons living in Atahualpa, an Ecuadorian village endemic for neurocysticercosis. All Atahualpa residents ≥ 60 years of age were invited to undergo computed tomography/magnetic resonance imaging for neurocysticercosis detection. Twenty-eight (11%) out of 248 enrolled persons had calcified cysticerci (case-patients) and were matched 1:1 by age, sex, and years of education to individuals without neurocysticercosis on computed tomography/magnetic resonance imaging (controls). Four case-patients and none of the controls had epilepsy (P = 0.134). Cognitive performance was similar across both groups. The Scheltens' medial temporal atrophy scale was used for hippocampal rating in case-patients and matched controls without neurocysticercosis. Mean score in the Scheltens' scale was higher in case-patients than in controls (P < 0.001). Atrophic hippocampi were noticed in 19 case-patients and five controls (P = 0.003). Atrophy was bilateral in 11 case-patients and unilateral in eight. All case-patients with unilateral hippocampal atrophy had at least one ipsilateral calcification. This study shows an association between calcified cysticerci and hippocampal atrophy and raises the possibility of an inflammation-mediated hippocampal damage as the responsible mechanism for these findings. PMID:25349375

  14. Molecular events underlying skeletal muscle atrophy and the development of effective countermeasures

    NASA Technical Reports Server (NTRS)

    Booth, F. W.; Criswell, D. S.

    1997-01-01

    Skeletal muscle adapts to loading; atrophying when exposed to unloading on Earth or in spaceflight. Significant atrophy (decreases in muscle fiber cross-section of 11-24%) in humans has been noted after only 5 days in space. Since muscle strength is determined both by muscle cross-section and synchronization of motor unit recruitment, a loss in muscle size weakens astronauts, which would increase risks to their safety if an emergency required maximal muscle force. Numerous countermeasures have been tested to prevent atrophy. Resistant exercise together with growth hormone and IGF-I are effective countermeasures to unloading as most atrophy is prevented in animal models. The loss of muscle protein is due to an early decrease in protein synthesis rate and a later increase in protein degradation. The initial decrease in protein synthesis is a result of decreased protein translation, caused by a prolongation in the elongation rate. A decrease in HSP70 by a sight increase in ATP may be the factors prolonging elongation rate. Increases in the activities of proteolytic enzymes and in ubiquitin contribute to the increased protein degradation rate in unloaded muscle. Numerous mRNA concentrations have been shown to be altered in unloaded muscles. Decreases in mRNAs for contractile proteins usually occur after the initial fall in protein synthesis rates. Much additional research is needed to determine the mechanism by which muscle senses the absence of gravity with an adaptive atrophy. The development of effective countermeasures to unloading atrophy will require more research.

  15. Muscle fatigue, nNOS and muscle fiber atrophy in limb girdle muscular dystrophy.

    PubMed

    Angelini, Corrado; Tasca, Elisabetta; Nascimbeni, Anna Chiara; Fanin, Marina

    2014-12-01

    Muscle fatigability and atrophy are frequent clinical signs in limb girdle muscular dystrophy (LGMD), but their pathogenetic mechanisms are still poorly understood. We review a series of different factors that may be connected in causing fatigue and atrophy, particularly considering the role of neuronal nitric oxide synthase (nNOS) and additional factors such as gender in different forms of LGMD (both recessive and dominant) underlying different pathogenetic mechanisms. In sarcoglycanopathies, the sarcolemmal nNOS reactivity varied from absent to reduced, depending on the residual level of sarcoglycan complex: in cases with complete sarcoglycan complex deficiency (mostly in beta-sarcoglycanopathy), the sarcolemmal nNOS reaction was absent and it was always associated with early severe clinical phenotype and cardiomyopathy. Calpainopathy, dysferlinopathy, and caveolinopathy present gradual onset of fatigability and had normal sarcolemmal nNOS reactivity. Notably, as compared with caveolinopathy and sarcoglycanopathies, calpainopathy and dysferlinopathy showed a higher degree of muscle fiber atrophy. Males with calpainopathy and dysferlinopathy showed significantly higher fiber atrophy than control males, whereas female patients have similar values than female controls, suggesting a gender difference in muscle fiber atrophy with a relative protection in females. In female patients, the smaller initial muscle fiber size associated to endocrine factors and less physical effort might attenuate gender-specific muscle loss and atrophy. PMID:25873780

  16. Thymic function is maintained during Salmonella-induced atrophy and recovery

    PubMed Central

    Ross, Ewan A.; Coughlan, Ruth E.; Flores-Langarica, Adriana; Lax, Sian; Nicholson, Julia; Desanti, Guillaume E.; Marshall, Jennifer L.; Bobat, Saeeda; Hitchcock, Jessica; White, Andrea; Jenkinson, William E.; Khan, Mahmood; Henderson, Ian R.; Lavery, Gareth G.; Buckley, Christopher D.; Anderson, Graham; Cunningham, Adam F.

    2014-01-01

    Thymic atrophy is a frequent consequence of infection with bacteria, viruses and parasites and is considered a common virulence trait between pathogens. Multiple reasons have been proposed to explain this atrophy, including premature egress of immature thymocytes, increased apoptosis or thymic shutdown to prevent tolerance to the pathogen from developing. The severe loss in thymic cell number can reflect an equally dramatic reduction in thymic output, potentially reducing peripheral T cell numbers. Here we examine the relationship between systemic Salmonella infection and thymic function. During infection, naive T cell numbers in peripheral lymphoid organs increase. Nevertheless, this occurs despite a pronounced thymic atrophy caused by viable bacteria, with a peak 50-fold reduction in thymocyte numbers. Thymic atrophy is not dependent upon homeostatic feedback from peripheral T cells or on regulation of endogenous glucocorticoids, as demonstrated by infection of genetically-altered mice. Once bacterial numbers fall, thymocyte numbers recover and this is associated with increases in the proportion and proliferation of early thymic progenitors. During atrophy, thymic T cell maturation is maintained and sjTREC analysis reveals there is only a modest fall in recent CD4+ thymic emigrants in secondary lymphoid tissues. Thus thymic atrophy does not necessarily result in a matching dysfunctional T cell output and thymic homeostasis can constantly adjust to systemic infection to ensure that naive T cell output is maintained. PMID:22993205

  17. Overlap in frontotemporal atrophy between normal aging and patients with frontotemporal dementias.

    PubMed

    Chow, Tiffany W; Binns, Malcolm A; Freedman, Morris; Stuss, Donald T; Ramirez, Joel; Scott, Chris J M; Black, Sandra

    2008-01-01

    Normal aging leads to frontocortical atrophy. The degree to which this complicates the use of frontotemporal atrophy as a diagnostic criterion for the frontotemporal dementias (FTDs) has not been reported. The present case-control study compared frontotemporal volumes delineated with semi-automatic brain region extraction [n=30 controls vs. 16 behavioral variant FTD (bvFTD) vs. 14 primary progressive aphasia]. Logistic regression identified those regions least helpful for distinguishing bvFTD and primary progressive aphasia from controls. Linear regression tested the correlation of duration of illness to atrophy severity. The control group showed high variance in volumes. Controls had right frontal lobe volumes that overlapped considerably with bvFTD volumes, but, as anticipated, the left anterior temporal volumes of interest showed 91% accuracy in distinguishing the aphasic subgroup from controls. Left-sided and not right-sided atrophy in the medial middle frontal region distinguished the bvFTD group from controls. The relegation of structural imaging to a supportive criterion for diagnosis is reasonable in the context of the range of atrophy due to normal aging. While volumetry identified left-sided atrophy as useful for identifying FTD cases, future studies should determine whether clinicians could make these distinctions on viewing routine diagnostic magnetic resonance imaging scans. PMID:18695590

  18. Crystallization and preliminary X-ray diffraction studies of the transcriptional repressor PaaX, the main regulator of the phenylacetic acid degradation pathway in Escherichia coli W

    PubMed Central

    Rojas-Altuve, Alzoray; Carrasco-López, César; Hernández-Rocamora, Víctor M.; Sanz, Jesús M.; Hermoso, Juan A.

    2011-01-01

    PaaX is the main regulator of the phenylacetic acid aerobic degradation pathway in bacteria and acts as a transcriptional repressor in the absence of its inducer phenylacetyl-coenzyme A. The natural presence and the recent accumulation of a variety of highly toxic aromatic compounds owing to human pollution has created considerable interest in the study of degradation pathways in bacteria, the most important microorganisms capable of recycling these compounds, in order to design and apply novel bioremediation strategies. PaaX from Escherichia coli W was cloned, overexpressed, purified and crystallized using the sitting-drop vapour-diffusion method at 291 K. Crystals grew from a mixture of 0.9 M Li2SO4 and 0.5 M sodium citrate pH 5.8. These crystals, which belonged to the monoclinic space group C2 with unit-cell parameters a = 167.88, b = 106.23, c = 85.87 Å, β = 108.33°, allowed the collection of an X-ray data set to 2.3 Å resolution. PMID:22102047

  19. NERVE LESIONS IN INDUSTRY—Atrophy of Disuse as a Confusing Element in Diagnosis; The Value of Electromyography

    PubMed Central

    Marinacci, A. A.; Rand, Carl W.

    1958-01-01

    Traumatic peripheral nerve lesions characteristically result in denervation muscular atrophy. Atrophy of disuse may take place concomitantly, either proximal, adjacent to or distal to the denervation muscular atrophy. The degree of atrophy of disuse depends upon the severity of the nerve lesion. Clinically, it is difficult to determine where true denervation muscular atrophy ends and accompanying atrophy of disuse begins. In such circumstances a clinician may be misled into belief that the cause of so apparently extensive a lesion is elsewhere. The patient then is often submitted to other complex diagnostic procedures and treatments. This difficulty can usually be dissipated by the use of electromyography, for each specific type of muscular atrophy produces its own characteristic electromyographic changes. Disuse atrophy produces no changes in electrical activity, whereas denervation atrophy manifests itself by typical denervation activity. Moreover it is possible to determine what part of muscular atrophy in a given area is owing to damage to a nerve and what part is owing only to disuse without denervation. PMID:13489511

  20. Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4.

    PubMed

    Bullard, Steven A; Seo, Seongjin; Schilling, Birgit; Dyle, Michael C; Dierdorff, Jason M; Ebert, Scott M; DeLau, Austin D; Gibson, Bradford W; Adams, Christopher M

    2016-08-19

    Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level. PMID:27358404

  1. Tremor in Multiple System Atrophy – a review

    PubMed Central

    Kaindlstorfer, Christine; Granata, Roberta; Wenning, Gregor Karl

    2013-01-01

    Background Multiple system atrophy (MSA) is a rare neurodegenerative movement disorder characterized by a rapidly progressive course. The clinical presentation can include autonomic failure, parkinsonism, and cerebellar signs. Differentiation from Parkinson’s disease (PD) is difficult if there is levodopa-responsive parkinsonism, rest tremor, lack of cerebellar ataxia, or mild/delayed autonomic failure. Little is known about tremor prevalence and features in MSA. Methods We performed a PubMed search to collect the literature on tremor in MSA and considered reports published between 1900 and 2013. Results Tremor is a common feature among MSA patients. Up to 80% of MSA patients show tremor, and patients with the parkinsonian variant of MSA are more commonly affected. Postural tremor has been documented in about half of the MSA population and is frequently referred to as jerky postural tremor with evidence of minipolymyoclonus on neurophysiological examination. Resting tremor has been reported in about one-third of patients but, in contrast to PD, only 10% show typical parkinsonian “pill-rolling” rest tremor. Some patients exhibit intention tremor associated with cerebellar dysmetria. In general, MSA patients can have more than one tremor type owing to a complex neuropathology that includes both the basal ganglia and pontocerebellar circuits. Discussion Tremor is not rare in MSA and might be underrecognized. Rest, postural, action and intention tremor can all be present, with jerky tremulous movements of the outstretched hands being the most characteristic. However, reviewing the data on tremor in MSA suggests that not every shaky movement satisfies tremor criteria; therefore, further studies are needed. PMID:24116345

  2. Patterns of regional cerebellar atrophy in genetic frontotemporal dementia

    PubMed Central

    Bocchetta, Martina; Cardoso, M. Jorge; Cash, David M.; Ourselin, Sebastien; Warren, Jason D.; Rohrer, Jonathan D.

    2016-01-01

    Background Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with a strong genetic component. The cerebellum has not traditionally been felt to be involved in FTD but recent research has suggested a potential role. Methods We investigated the volumetry of the cerebellum and its subregions in a cohort of 44 patients with genetic FTD (20 MAPT, 7 GRN, and 17 C9orf72 mutation carriers) compared with 18 cognitively normal controls. All groups were matched for age and gender. On volumetric T1-weighted magnetic resonance brain images we used an atlas propagation and label fusion strategy of the Diedrichsen cerebellar atlas to automatically extract subregions including the cerebellar lobules, the vermis and the deep nuclei. Results The global cerebellar volume was significantly smaller in C9orf72 carriers (mean (SD): 99989 (8939) mm3) compared with controls (108136 (7407) mm3). However, no significant differences were seen in the MAPT and GRN carriers compared with controls (104191 (6491) mm3 and 107883 (6205) mm3 respectively). Investigating the individual subregions, C9orf72 carriers had a significantly lower volume than controls in lobule VIIa-Crus I (15% smaller, p < 0.0005), whilst MAPT mutation carriers had a significantly lower vermal volume (10% smaller, p = 0.001) than controls. All cerebellar subregion volumes were preserved in GRN carriers compared with controls. Conclusion There appears to be a differential pattern of cerebellar atrophy in the major genetic forms of FTD, being relatively spared in GRN, localized to the lobule VIIa-Crus I in the superior-posterior region of the cerebellum in C9orf72, the area connected via the thalamus to the prefrontal cortex and involved in cognitive function, and localized to the vermis in MAPT, the ‘limbic cerebellum’ involved in emotional processing. PMID:26977398

  3. SHC2 gene copy number in multiple system atrophy (MSA)

    PubMed Central

    Ferguson, Marcus C.; Garland, Emily M.; Hedges, Lora; Womack-Nunley, Bethany; Hamid, Rizwan; Phillips, John A.; Shibao, Cyndya A.; Raj, Satish R.; Biaggioni, Italo; Robertson, David

    2013-01-01

    Purpose Multiple system atrophy (MSA) is a sporadic, late onset, rapidly-progressing neurodegenerative disorder, which is characterized by autonomic failure, together with parkinsonian, cerebellar, and pyramidal motor symptoms. The pathologic hallmark is the glial cytoplasmic inclusion with alpha-synuclein aggregates. MSA is thus an alpha synucleinopathy. Recently, Sasaki et al. reported that heterozygosity for copy number loss of Src homology 2 domain containing-transforming protein 2 (SHC2) genes (heterozygous SHC2 gene deletions) occurred in DNAs from many Japanese individuals with MSA. Because background copy number variation (CNV) can be distinct in different human populations, we assessed SHC2 allele copy number in DNAs from a US cohort of individuals with MSA, to determine the contribution of SHC2 gene copy number variation in an American cohort followed at a US referral center for MSA. Our cohort included 105 carefully phenotyped individuals with MSA. Methods We studied 105 well characterized patients with MSA and 5 control subjects with reduced SHC2 gene copy number. We used two TaqMan Gene Copy Number Assays, to determine the copy number of two segments of the SHC2 gene that are separated by 27 Kb. Results Assay results of DNAs from all of our 105 subjects with MSA showed two copies of both segments of their SHC2 genes. Conclusion Our results indicate that SHC2 gene deletions underlie few, if any, cases of well characterized MSA in the US population. This is in contrast to the Japanese experience reported by Sasaki et al., likely reflecting heterogeneity of the disease in different genetic backgrounds. PMID:24170347

  4. Growing up with bilateral hippocampal atrophy: from childhood to teenage.

    PubMed

    Bindschaedler, Claire; Peter-Favre, Claire; Maeder, Philippe; Hirsbrunner, Thérèse; Clarke, Stephanie

    2011-09-01

    The respective roles of the medial temporal lobe (MTL) structures in memory are controversial. Some authors put forward a modular account according to which episodic memory and recollection-based processes are crucially dependent on the hippocampal formation whereas semantic acquisition and familiarity-based processes rely on the adjacent parahippocampal gyri. Others defend a unitary view. We report the case of VJ, a boy with developmental amnesia of most likely perinatal onset diagnosed at the age of 8. Magnetic resonance imaging (MRI), including quantitative volumetric measurements of the hippocampal formation and of the entorhinal, perirhinal, and temporopolar cortices, showed severe, bilateral atrophy of the hippocampal formation, fornix and mammillary bodies; by contrast, the perirhinal cortex was within normal range and the entorhinal and temporopolar cortex remained within two standard deviations (SDs) from controls' mean. We examined the development of his semantic knowledge from childhood to teenage as well as his recognition and cued recall memory abilities. On tasks tapping semantic memory, VJ increased his raw scores across years at the same rate as children from large standardisation samples, except for one task; he achieved average performance, consistent with his socio-educational background. He performed within normal range on 74% of recognition tests and achieved average to above average scores on 42% of them despite very severe impairment on 82% of episodic recall tasks. Both faces and landscapes-scenes gave rise to above average scores when tested with coloured stimuli. Cued recall, although impaired, was largely superior to free recall. This case supports a modular account of the MTL with episodic, but not semantic memory depending on the hippocampal formation. Furthermore, the overall pattern of findings is consistent with evidence from both brain-damaged and neuroimaging studies indicating that recollection requires intact hippocampal

  5. Onset Manifestations of Spinal and Bulbar Muscular Atrophy (Kennedy's Disease).

    PubMed

    Finsterer, Josef; Soraru, Gianni

    2016-03-01

    Spinal and bulbar muscular atrophy (SBMA) is regarded as a disorder with adult onset between third and fifth decade of life. However, there is increasing evidence that SBMA may start already before adulthood. The present study investigated the following: (1) Which clinical manifestations have been described so far in the literature as initial manifestations? (2) Which was the age at onset of these manifestations? and (3) Is age at onset dependent on the CAG-repeat length if non-motor manifestations are additionally considered? Data for this review were identified by searches of MEDLINE using appropriate search terms. Onset manifestations in SBMA can be classified as frequent, rare, motor, non-motor, or questionable. Frequent are muscle weakness, cramps, fasciculations/twitching, tremor, dysarthria, dysphagia, or gynecomastia. Rare are myalgia, easy fatigability, exercise intolerance, polyneuropathy, hyper-CKemia, under-masculinized genitalia, scrotal hypospadias, microphallus, laryngospasm, or oligospermia. Questionable manifestations include sensory disturbances, cognitive impairment, increased pituitary volume, diabetes, reduced tongue pressure, elevated creatine-kinase, or low androgens/high estrogens. Age at onset is highly variable ranging from 4-76 years. Non-motor manifestations develop usually before motor manifestations. Age at onset depends on what is considered as an onset manifestation. Considering non-motor onset manifestations, age at onset is independent of the CAG-repeat size. In conclusion, age at onset of SBMA depends on what is regarded as onset manifestation. If non-motor manifestations are additionally considered, age at onset is independent of the CAG-repeat length. Since life expectancy is hardly reduced in SBMA, re-investigation of patients from published studies with regard to their initial disease profiles is recommended. PMID:26482145

  6. Acoustic Characteristics of Stridor in Multiple System Atrophy

    PubMed Central

    Lee, Jee Young; Joo, Eun Yeon; Nam, Hyunwoo

    2016-01-01

    Nocturnal stridor is a breathing disorder prevalent in patients with multiple system atrophy (MSA). An improved understanding of this breathing disorder is essential since nocturnal stridor carries a poor prognosis (an increased risk of sudden death). In this study, we aimed to classify types of stridor by sound analysis and to reveal their clinical significance. Patients who met the criteria for probable MSA and had undergone polysomnography (PSG) were recruited. Patients were then assessed clinically with sleep questionnaires, including the Pittsburgh Sleep Quality Index, and the Hoehn and Yahr scale. Nocturnal stridor and snoring were analyzed with the Multi-Dimensional Voice Program. Nocturnal stridor was recorded in 22 patients and snoring in 18 patients using the PSG. Waveforms of stridors were classified into rhythmic or semirhythmic after analysis of the oscillogram. Formants and harmonics were observed in both types of stridor, but not in snoring. Of the 22 patients diagnosed with stridor during the present study, fifteen have subsequently died, with the time to death after the PSG study being 1.9 ± 1.4 years (range 0.8 to 5.0 years). The rhythmic waveform group presented higher scores on the Hoehn and Yahr scale and the survival outcome of this group was lower compared to the semirhythmic waveform group (p = 0.030, p = 0.014). In the Kaplan Meier’s survival curve, the outcome of patients with rhythmic waveform was significantly less favorable than the outcome of patients with semirhythmic waveform (log-rank test, p < 0.001). Stridor in MSA can be classified into rhythmic and semirhythmic types and the rhythmic component signifies a poorer outcome. PMID:27093692

  7. Functional neural substrates of posterior cortical atrophy patients.

    PubMed

    Shames, H; Raz, N; Levin, Netta

    2015-07-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome in which the most pronounced pathologic involvement is in the occipito-parietal visual regions. Herein, we aimed to better define the cortical reflection of this unique syndrome using a thorough battery of behavioral and functional MRI (fMRI) tests. Eight PCA patients underwent extensive testing to map their visual deficits. Assessments included visual functions associated with lower and higher components of the cortical hierarchy, as well as dorsal- and ventral-related cortical functions. fMRI was performed on five patients to examine the neuronal substrate of their visual functions. The PCA patient cohort exhibited stereopsis, saccadic eye movements and higher dorsal stream-related functional impairments, including simultant perception, image orientation, figure-from-ground segregation, closure and spatial orientation. In accordance with the behavioral findings, fMRI revealed intact activation in the ventral visual regions of face and object perception while more dorsal aspects of perception, including motion and gestalt perception, revealed impaired patterns of activity. In most of the patients, there was a lack of activity in the word form area, which is known to be linked to reading disorders. Finally, there was evidence of reduced cortical representation of the peripheral visual field, corresponding to the behaviorally assessed peripheral visual deficit. The findings are discussed in the context of networks extending from parietal regions, which mediate navigationally related processing, visually guided actions, eye movement control and working memory, suggesting that damage to these networks might explain the wide range of deficits in PCA patients. PMID:25976028

  8. Comparison of Different Symptom Assessment Scales for Multiple System Atrophy.

    PubMed

    Matsushima, Masaaki; Yabe, Ichiro; Oba, Koji; Sakushima, Ken; Mito, Yasunori; Takei, Asako; Houzen, Hideki; Tsuzaka, Kazufumi; Yoshida, Kazuto; Maruo, Yasunori; Sasaki, Hidenao

    2016-04-01

    To identify the most sensitive scale for use in clinical trials on multiple system atrophy (MSA), a short and sensitive scale is needed for MSA clinical trials. Potential candidates are the Unified MSA Rating Scale (UMSARS), Scale for the Assessment and Rating of Ataxia (SARA), Berg Balance Scale (BBS), MSA Health-Related Quality of Life scale (MSA-QoL), and Scales for Outcomes in Parkinson's Disease-Autonomic questionnaire (SCOPA-AUT). We enrolled patients with MSA from eight hospitals in Hokkaido, Japan. Board-certified neurologists assessed each patient at 6-month intervals and scored them on the UMSARS, SARA, BBS, MSA-QoL, and SCOPA-AUT. Score changes were evaluated using the standardized response mean (SRM). The correlation between disease duration and each score was examined. The first evaluation was conducted on 85 patients (60 patients with MSA cerebellar ataxia dominant subtype [MSA-C] and 25 patients with MSA Parkinsonism-dominant subtype [MSA-P]). Sixty-nine patients were examined after 6 months and 63 patients after 12 months. The UMSARS Part 4 had the largest SRM after 6 months and the SARA after 12 months. SRMs for MSA-P, the shorter duration group, and the early-onset group were larger than were those for MSA-C, the longer duration group, and the late-onset group. SRMs for items regarding skilled hand activities, walking, and standing were relatively large. Our study indicates that the UMSARS (parts 2 and 4), SARA, and BBS are sensitive scales for evaluating MSA progression over 12 months. Items with large SRMs effectively evaluated short-term changes. PMID:26093615

  9. Pancreatic Acinar Cells Employ miRNAs as Mediators of Intercellular Communication to Participate in the Regulation of Pancreatitis-Associated Macrophage Activation

    PubMed Central

    Zhao, Yong; Wang, Hao; Qiao, Xin; Sun, Bei

    2016-01-01

    Macrophage activation plays an important role in the inflammatory response in acute pancreatitis. In the present study, the activation of AR42J pancreatic acinar cells was induced by taurolithocholate treatment. The results showed that the culture medium from the activated AR42J cells significantly enhanced NFκB activation in the macrophages compared to that without taurolithocholate treatment. Additionally, the precipitates obtained from ultracentrifugation of the culture media that were rich in exosomes were markedly more potent in activating macrophages compared with the supernatant fraction lacking exosomes. The results indicated that the mediators carried by the exosomes played important roles in macrophage activation. Exosomal miRNAs were extracted and examined using microarrays. A total of 115 differentially expressed miRNAs were identified, and 30 showed upregulated expression, while 85 displayed downregulated expression. Target genes of the differentially expressed miRNAs were predicted using TargetScan, MiRanda, and PicTar software programs. The putative target genes were subjected to KEGG functional analysis. The functions of the target genes were primarily enriched in MAPK pathways. Specifically, the target genes regulated macrophage activation through the TRAF6-TAB2-TAK1-NIK/IKK-NFκB pathway. As the mediators of signal transduction, miRNAs and their predicted target mRNAs regulate every step in the MAPK pathway. PMID:27546996

  10. APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation.

    PubMed

    Furlan, Daniela; Sahnane, Nora; Bernasconi, Barbara; Frattini, Milo; Tibiletti, Maria Grazia; Molinari, Francesca; Marando, Alessandro; Zhang, Lizhi; Vanoli, Alessandro; Casnedi, Selenia; Adsay, Volkan; Notohara, Kenji; Albarello, Luca; Asioli, Sofia; Sessa, Fausto; Capella, Carlo; La Rosa, Stefano

    2014-05-01

    Genetic and epigenetic alterations involved in the pathogenesis of pancreatic acinar cell carcinomas (ACCs) are poorly characterized, including the frequency and role of gene-specific hypermethylation, chromosome aberrations, and copy number alterations (CNAs). A subset of ACCs is known to show alterations in the APC/β-catenin pathway which includes mutations of APC gene. However, it is not known whether, in addition to mutation, loss of APC gene function can occur through alternative genetic and epigenetic mechanisms such as gene loss or promoter methylation. We investigated the global methylation profile of 34 tumor suppressor genes, CNAs of 52 chromosomal regions, and APC gene alterations (mutation, methylation, and loss) together with APC mRNA level in 45 ACCs and related peritumoral pancreatic tissues using methylation-specific multiplex ligation probe amplification (MS-MLPA), fluorescence in situ hybridization (FISH), mutation analysis, and reverse transcription-droplet digital PCR. ACCs did not show an extensive global gene hypermethylation profile. RASSF1 and APC were the only two genes frequently methylated. APC mutations were found in only 7 % of cases, while APC loss and methylation were more frequently observed (48 and 56 % of ACCs, respectively). APC mRNA low levels were found in 58 % of cases and correlated with CNAs. In conclusion, ACCs do not show extensive global gene hypermethylation. APC alterations are frequently involved in the pathogenesis of ACCs mainly through gene loss and promoter hypermethylation, along with reduction of APC mRNA levels. PMID:24590585

  11. The Distribution of Phosphatidylinositol 4,5-Bisphosphate in Acinar Cells of Rat Pancreas Revealed with the Freeze-Fracture Replica Labeling Method

    PubMed Central

    Fujimoto, Toyoshi

    2011-01-01

    Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is a phospholipid that has been implicated in multiple cellular activities. The distribution of PI(4,5)P2 has been analyzed extensively using live imaging of the GFP-coupled phospholipase C-δ1 pleckstrin homology domain in cultured cell lines. However, technical difficulties have prevented the study of PI(4,5)P2 in cells of in vivo tissues. We recently developed a method to analyze the nanoscale distribution of PI(4,5)P2 in cultured cells by using the quick-freezing and freeze-fracture replica labeling method. In principle, this method can be applied to any cell because it does not require the expression of artificial probes. In the present study, we modified the method to study cells of in vivo tissues and applied it to pancreatic exocrine acinar cells of the rat. We found that PI(4,5)P2 in the plasma membrane is distributed in an equivalent density in the apical and basolateral domains, but exists in a significantly higher concentration in the gap junction. The intracellular organelles did not show labeling for PI(4,5)P2. The results are novel or different from the reported distribution patterns in cell lines and highlight the importance of studying cells differentiated in vivo. PMID:21858170

  12. Pancreatic Acinar Cells Employ miRNAs as Mediators of Intercellular Communication to Participate in the Regulation of Pancreatitis-Associated Macrophage Activation.

    PubMed

    Z