Effect of restoration volume on stresses in a mandibular molar: a finite element study.

PubMed

Wayne, Jennifer S; Chande, Ruchi; Porter, H Christian; Janus, Charles

2014-10-01

There can be significant disagreement among dentists when planning treatment for a tooth with a failing medium-to-large--sized restoration. The clinician must determine whether the restoration should be replaced or treated with a crown, which covers and protects the remaining weakened tooth structure during function. The purpose of this study was to evaluate the stresses generated in different sized amalgam restorations via a computational modeling approach and reveal whether a predictable pattern emerges. A computer tomography scan was performed of an extracted mandibular first molar, and the resulting images were imported into a medical imaging software package for tissue segmentation. The software was used to separate the enamel, dentin, and pulp cavity through density thresholding and surface rendering. These tissue structures then were imported into 3-dimensional computer-aided design software in which material properties appropriate to the tissues in the model were assigned. A static finite element analysis was conducted to investigate the stresses that result from normal occlusal forces. Five models were analyzed, 1 with no restoration and 4 with increasingly larger restoration volume proportions: a normal-sized tooth, a small-sized restoration, 2 medium-sized restorations, and 1 large restoration as determined from bitewing radiographs and occlusal surface digital photographs. The resulting von Mises stresses for dentin-enamel of the loaded portion of the tooth grew progressively greater as the size of the restoration increased. The average stress in the normal, unrestored tooth was 4.13 MPa, whereas the smallest restoration size increased this stress to 5.52 MPa. The largest restoration had a dentin-enamel stress of 6.47 MPa. A linear correlation existed between restoration size and dentin-enamel stress, with an R(2) of 0.97. A larger restoration volume proportion resulted in higher dentin-enamel stresses under static loading. A comparison of the von Mises stresses to the yield strengths of the materials revealed a relationship between a tooth's restoration volume proportion and the potential for failure, although factors other than restoration volume proportion may also impact the stresses generated in moderate-sized restorations. Copyright © 2014 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Restoring tibiofemoral alignment during ACL reconstruction results in better knee biomechanics.

PubMed

Zampeli, Frantzeska; Terzidis, Ioannis; Espregueira-Mendes, João; Georgoulis, Jim-Dimitris; Bernard, Manfred; Pappas, Evangelos; Georgoulis, Anastasios D

2018-05-01

Anterior cruciate ligament (ACL) reconstruction (ACLR) aims to restore normal knee joint function, stability and biomechanics and in the long term avoid joint degeneration. The purpose of this study is to present the anatomic single bundle (SB) ACLR that emphasizes intraoperative correction of tibiofemoral subluxation that occurs after ACL injury. It was hypothesized that this technique leads to optimal outcomes and better restoration of pathological tibiofemoral joint movement that results from ACL deficiency (ACLD). Thirteen men with unilateral ACLD were prospectively evaluated before and at a mean follow-up of 14.9 (SD = 1.8) months after anatomic SB ACLR with bone patellar tendon bone autograft. The anatomic ACLR replicated the native ACL attachment site anatomy and graft orientation. Emphasis was placed on intraoperative correction of tibiofemoral subluxation by reducing anterior tibial translation (ATT) and internal tibial rotation. Function was measured with IKDC, Lysholm and the Tegner activity scale, ATT was measured with the KT-1000 arthrometer and tibial rotation (TR) kinematics were measured with 3Dmotion analysis during a high-demand pivoting task. The results showed significantly higher TR of the ACL-deficient knee when compared to the intact knee prior to surgery (12.2° ± 3.7° and 10.7° ± 2.6° respectively, P = 0.014). Postoperatively, the ACLR knee showed significantly lower TR as compared to the ACL-deficient knee (9.6°±3.1°, P = 0.001) but no difference as compared to the control knee (n.s.). All functional scores were significantly improved and ATT was restored within normal values (P < 0.001). Intraoperative correction of tibiofemoral subluxation that results after ACL injury is an important step during anatomic SB ACLR. The intraoperative correction of tibiofemoral subluxation along with the replication of native ACL anatomy results in restoration of rotational kinematics of ACLD patients to normal levels that are comparable to the control knee. These results indicate that the reestablishment of tibiofemoral alignment during ACLR may be an important step that facilitates normal knee kinematics postoperatively. Level II, prospective cohort study.

Surgical and conservative methods for restoring impaired motor function - facial nerve, spinal accessory nerve, hypoglossal nerve (not including vagal nerve or swallowing)

PubMed Central

Laskawi, R.; Rohrbach, S.

2005-01-01

The present review gives a survey of rehabilitative measures for disorders of the motor function of the mimetic muscles (facial nerve), and muscles innervated by the spinal accessory and hypoglossal nerves. The dysfunction can present either as paralysis or hyperkinesis (hyperkinesia). Conservative and surgical treatment options aimed at restoring normal motor function and correcting the movement disorders are described. Static reanimation techniques are not dealt with. The final section describes the use of botulinum toxin in the therapy of dysphagia. PMID:22073058

Effects of hyperthyroidism, hypothyroidism, and thyroid autoimmunity on female sexual function.

PubMed

Oppo, A; Franceschi, E; Atzeni, F; Taberlet, A; Mariotti, S

2011-06-01

Thyroid hormones affect male and female sexual functions, but data in hypo- and hyperthyroid women are scanty. To investigate sexual function in hypo- and hyperthyroid women before and immediately after restoration of euthyroidism and in women with euthyroid Hashimoto's thyroiditis (HT). Fifty-six women with thyroid diseases (age 19-50 yr; 22 with hyperthyroidism, 17 with hypothyroidism, and 17 with euthyroid HT) and 30 age-matched healthy women. Hypoactive sexual desire, disorders of sexual arousal, vaginal lubrication, orgasm, satisfaction, and sexual pain (SPD) were assessed by Female Sexual Function Index. Serum TSH, free T4 (FT4) and thyroid autoantibodies (anti-thyroglobulin, anti-thyroperoxidase, and TSH-receptor antibodies) were assessed at the diagnosis; FT4 and TSH were repeated after treatment to confirm normalization of thyroid function. All sexual domains scores were significantly reduced (p ranging <0.0001-<0.05) in both hypo- and hyperthyroid women. Correction of hypothyroidism was associated to normalization of desire, satisfaction, and pain, while arousal and orgasm remained unchanged. In hyperthyroid women therapy normalized sexual desire, arousal/lubrication, satisfaction, and pain, while orgasm remained significantly impaired. Interestingly, euthyroid HT women displayed a significant decrease in sexual desire (p<0.0005), with no changes in the other sexual domains. Both hypo- and hyperthyroidism markedly impair female sexual function. A rapid improvement is observed with the restoration of euthyroidism, although a longer period of time may be needed for full normalization. Preliminary data suggest that thyroid autoimmunity may selectively impair sexual desire, independently from thyroid function.

The Potential Transformation of Our Species by Neural Enhancement

PubMed Central

Zehr, E. Paul

2015-01-01

ABSTRACT. Neural enhancement represents recovery of function that has been lost due to injury or disease pathology. Restoration of functional ability is the objective. For example, a neuroprosthetic to replace a forearm and hand lost to the ravages of war or industrial accident. However, the same basic constructs used for neural enhancement after injury could amplify abilities that are already in the natural normal range. That is, neural enhancement technologies to restore function and improve daily abilities for independent living could be used to improve so-called normal function to ultimate function. Approaching that functional level by use and integration of technology takes us toward the concept of a new species. This new subspecies—homo sapiens technologicus—is one that uses technology not just to assist but to change its own inherent biological function. The author uses examples from prosthetics and neuroprosthetics to address the issue of the limitations of constructs on the accepted range of human performance ability and aims to provide a cautionary view toward reflection on where our science may take the entire species. PMID:25575224

Functional and Aesthetic Outcome Enhancement of Head and Neck Reconstruction through Secondary Procedures

PubMed Central

Hofer, Stefan O.P.; Payne, Caroline E.

2010-01-01

The foundation of head and neck reconstruction is based on two pillars: the restoration of function and the restoration of aesthetics. The objective of this article is to provide insight into how to prevent undesirable functional and aesthetic outcome after the initial procedure and also to provide solutions for enhancement of functional and aesthetic outcome with secondary procedures. Functional and aesthetic outcome enhancement is discussed in relation to the individual structures within the oral cavity, for the mandible, and for facial reconstruction. Normal prerequisites for all individual structures are described, and key points for restoration of these functional and aesthetic issues are proposed. In addition, further suggestions to improve suboptimal results after initial reconstructive surgery are presented. Understanding the function and aesthetics of the area to be reconstructed will allow appropriate planning and management of the initial reconstruction. Secondary enhancement should be attainable by minor procedures rather than a requirement to redo the initial reconstruction. PMID:22550452

Reverse Engineering Nature to Design Biomimetic Total Knee Implants.

PubMed

Varadarajan, Kartik Mangudi; Zumbrunn, Thomas; Rubash, Harry E; Malchau, Henrik; Muratoglu, Orhun K; Li, Guoan

2015-10-01

While contemporary total knee arthroplasty (TKA) provides tremendous clinical benefits, the normal feel and function of the knee is not fully restored. To address this, a novel design process was developed to reverse engineer "biomimetic" articular surfaces that are compatible with normal soft-tissue envelope and kinematics of the knee. The biomimetic articular surface is created by moving the TKA femoral component along in vivo kinematics of normal knees and carving out the tibial articular surface from a rectangular tibial block. Here, we describe the biomimetic design process. In addition, we utilize geometric comparisons and kinematic simulations to show that; (1) tibial articular surfaces of conventional implants are fundamentally incompatible with normal knee motion, and (2) the anatomic geometry of the biomimetic surface contributes directly to restoration of normal knee kinematics. Such biomimetic implants may enable us to achieve the long sought after goal of a "normal" knee post-TKA surgery. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment

PubMed Central

Hsu, Ying; Kim, Gunhee; Zhang, Qihong; Datta, Poppy; Seo, Seongjin

2017-01-01

Genetic mutations disrupting the structure and function of primary cilia cause various inherited retinal diseases in humans. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic ciliopathy characterized by retinal degeneration, obesity, postaxial polydactyly, intellectual disability, and genital and renal abnormalities. To gain insight into the mechanisms of retinal degeneration in BBS, we developed a congenital knockout mouse of Bbs8, as well as conditional mouse models in which function of the BBSome (a protein complex that mediates ciliary trafficking) can be temporally inactivated or restored. We demonstrate that BBS mutant mice have defects in retinal outer segment morphogenesis. We further demonstrate that removal of Bbs8 in adult mice affects photoreceptor function and disrupts the structural integrity of the outer segment. Notably, using a mouse model in which a gene trap inhibiting Bbs8 gene expression can be removed by an inducible FLP recombinase, we show that when BBS8 is restored in immature retinas with malformed outer segments, outer segment extension can resume normally and malformed outer segment discs are displaced distally by normal outer segment structures. Over time, the retinas of the rescued mice become morphologically and functionally normal, indicating that there is a window of plasticity when initial retinal outer segment morphogenesis defects can be ameliorated. PMID:29049287

Recycling energy to restore impaired ankle function during human walking.

PubMed

Collins, Steven H; Kuo, Arthur D

2010-02-17

Humans normally dissipate significant energy during walking, largely at the transitions between steps. The ankle then acts to restore energy during push-off, which may be the reason that ankle impairment nearly always leads to poorer walking economy. The replacement of lost energy is necessary for steady gait, in which mechanical energy is constant on average, external dissipation is negligible, and no net work is performed over a stride. However, dissipation and replacement by muscles might not be necessary if energy were instead captured and reused by an assistive device. We developed a microprocessor-controlled artificial foot that captures some of the energy that is normally dissipated by the leg and "recycles" it as positive ankle work. In tests on subjects walking with an artificially-impaired ankle, a conventional prosthesis reduced ankle push-off work and increased net metabolic energy expenditure by 23% compared to normal walking. Energy recycling restored ankle push-off to normal and reduced the net metabolic energy penalty to 14%. These results suggest that reduced ankle push-off contributes to the increased metabolic energy expenditure accompanying ankle impairments, and demonstrate that energy recycling can be used to reduce such cost.

Unusual presentation of hidradenitis suppurativa with massive enlargement of penis.

PubMed

Baughman, Steven M; Cespedes, R Duane

2004-08-01

Hidradenitis suppurativa is a chronic, recurrent inflammatory disease affecting the cutaneous apocrine glands and resulting in their obstruction. This enigmatic disease causes recurrent episodes of infection, edema, scarring, and fibrosis of surrounding tissues. We present the case of a 55-year-old man with two decades of inguinal hidradenitis suppurativa that resulted in extensive penile subcutaneous lymphedema and enlargement secondary to scarring and obstructive lymphadenopathy. Reconstructive phalloplasty to restore normal penile function was required. Minimal recurrent induration, normal cutaneous sensation, and normal voiding and erectile function were noted at 3 years of follow-up.

Differential effects of power training versus functional task practice on compensation and restoration of arm function after stroke.

PubMed

Corti, Manuela; McGuirk, Theresa E; Wu, Samuel S; Patten, Carolynn

2012-09-01

Improved upper-extremity (UE) movement with stroke rehabilitation may involve restoration of more normal or development of compensatory movement patterns. The authors investigated the differential effects of functional task practice (FTP) and dynamic resistance training (POWER) on clinical function and reaching kinematics in an effort to distinguish between mechanisms of gains. A total of 14 hemiparetic individuals were randomly assigned to 10 weeks of either FTP or POWER and then crossed over to 10 weeks of the alternate treatment. Treatment order A was FTP followed by POWER, whereas treatment order B was POWER followed by FTP. Evaluation before and after each treatment block included a battery of clinical evaluations and kinematics of paretic UE functional reach to grasp. Both FTP and POWER improved movement accuracy, as revealed by a shift toward normal, including fewer submovements and reduced reach-path ratio. However, active range of motion revealed differential treatment effects. Shoulder flexion and elbow extension decreased with FTP and were associated with increased trunk displacement. In contrast, shoulder flexion and elbow extension excursion increased with POWER and were associated with significantly reduced trunk displacement. Treatment order B (POWER followed by FTP) revealed greater overall improvements. FTP increases compensatory movement patterns to improve UE function. POWER leads to more normal movement patterns. POWER prior to FTP may enhance the benefits of repetitive task practice.

Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function.

PubMed

Kandasamy, Ram; Calsbeek, Jonas J; Morgan, Michael M

2017-01-15

Opioids are effective at inhibiting responses to noxious stimuli in rodents, but have limited efficacy and many side effects in chronic pain patients. One reason for this disconnect is that nociception is typically assessed using withdrawal from noxious stimuli in animals, whereas chronic pain patients suffer from abnormal pain that disrupts normal activity. We hypothesized that assessment of home cage wheel running in rats would provide a much more clinically relevant method to assess opioid efficacy to restore normal behavior. Intraplantar injection of Complete Freund's Adjuvant (CFA) into the right hindpaw depressed wheel running and caused mechanical allodynia measured with the von Frey test in both male and female rats. Administration of an ED 50 dose of morphine (3.2mg/kg) reversed mechanical allodynia, but did not reverse CFA-induced depression of wheel running. In contrast, administration of a low dose of morphine (1.0mg/kg) restored running for one hour in both sexes, but had no effect on mechanical allodynia. Administration of the atypical opioid buprenorphine had no effect on inflammation-induced depression of wheel running in male or female rats, but attenuated mechanical allodynia in male rats. Administration of buprenorphine and higher doses of morphine depressed wheel running in non-inflamed rats, suggesting that the side effects of opioids interfere with restoration of function. These data indicate that restoration of pain-depressed function requires antinociception in the absence of disruptive side effects. The disruptive side effects of opioids are consistent with the major limitation of opioid use in human pain patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Analysis of inflammation-induced depression of home cage wheel running in rats reveals the difference between opioid antinociception and restoration of function

PubMed Central

Kandasamy, Ram; Calsbeek, Jonas J.; Morgan, Michael M.

2016-01-01

Opioids are effective at inhibiting responses to noxious stimuli in rodents, but have limited efficacy and many side effects in chronic pain patients. One reason for this disconnect is that nociception is typically assessed using withdrawal from noxious stimuli in animals, whereas chronic pain patients suffer from abnormal pain that disrupts normal activity. We hypothesized that assessment of home cage wheel running in rats would provide a much more clinically relevant method to assess opioid efficacy to restore normal behavior. Intraplantar injection of Complete Freund’s Adjuvant (CFA) into the right hindpaw depressed wheel running and caused mechanical allodynia measured with the von Frey test in both male and female rats. Administration of an ED50 dose of morphine (3.2 mg/kg) reversed mechanical allodynia, but did not reverse CFA-induced depression of wheel running. In contrast, administration of a low dose of morphine (1.0 mg/kg) restored running for one hour in both sexes, but had no effect on mechanical allodynia. Administration of the atypical opioid buprenorphine had no effect on inflammation-induced depression of wheel running in male or female rats, but attenuated mechanical allodynia in male rats. Administration of buprenorphine and higher doses of morphine depressed wheel running in non-inflamed rats, suggesting that the side effects of opioids interfere with restoration of function. These data indicate that restoration of pain-depressed function requires antinociception in the absence of disruptive side effects. The disruptive side effects of opioids are consistent with the major limitation of opioid use in human pain patients. PMID:27746208

Contact with Nature and Children's Restorative Experiences: An Eye to the Future

PubMed Central

Collado, Silvia; Staats, Henk

2016-01-01

This article offers an overview of what has been done until now on restorative research with children and opens up new inquires for future research. Most of the work has studied children's exposure to nature and the restorative benefits this contact provides, focusing on the renewal of children's psychological resources. The paper begins with an introduction to children's current tendency toward an alienation from the natural world and sets out the objectives of the article. It is followed by four main sections. The first two sections report on what we already know in this research area, distinguishing between children with normal mental capabilities and those suffering from attention-deficit hyperactivity disorder (ADHD). The findings gathered in these sections suggest that children's contact with nature improves their mood and their cognitive functioning, increases their social interactions and reduces ADHD symptoms. The next section describes five suggestions for future research: (1) the need for considering the relational dynamics between the child and the environment in restoration research, and the concept of constrained restoration; (2) the possibility of restorative needs arising from understimulation; (3) the importance of considering children's social context for restoration; (4) the relationship between restoration and pro-social and pro-environmental behaviors; and (5) children's restorative environments other than nature. We close by making some final remarks about the importance of restoring daily depleted resources for children's healthy functioning. PMID:27965616

Clearwater Focus Watershed; Nez Perce Tribe, 2002-2003 Annual Report.

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

Jones, Ira

2004-01-01

The Nez Perce Tribe Department of Fisheries Resource Management, Watershed Division, approaches watershed restoration with a goal to protect, restore, and enhance a connected network of functioning habitat types capable of supporting all fish life stages. Its goal is also to re-establish normal patters of production, dispersal, and exchange of genetic information within the 1855 Treaty Area. The Nez Perce Tribe began watershed restoration projects within the Clearwater River Subbasin in 1996. Progress has been made in restoring the sub-basin by excluding cattle from critical riparian areas through fencing, stabilizing streambanks, decommissioning roads, and upgrading culverts. Coordination of these projectsmore » is critical to the success of the restoration of the sub-basin. Coordination includes: within department coordination, sub-basin assessment and planning, and treaty area coordination.« less

Structure and function of conjugative pili: monoclonal antibodies as probes for structural variants of F pili.

PubMed Central

Grossman, T H; Frost, L S; Silverman, P M

1990-01-01

The lac-tra operon fusion plasmid pTG801 contains the known F plasmid DNA transfer (tra) genes required by Escherichia coli to elaborate functional F pili (T. Grossman and P. M. Silverman, J. Bacteriol. 171:650-656, 1989). Here, we show that these pili are actually structural variants of normal F pili and that the F plasmid must contain additional genes that affect pilus structure and function. We confirmed a previous report that two monoclonal antibodies that recognize epitopes at and near the amino terminus of F pilin do not decorate the sides of normal F pili, as determined by immunogold electron microscopy. However, both antibodies laterally decorated pTG801 pili. The epitope for one of the antibodies has been shown to include the amino-terminal acetyl group of F pilin, which must therefore also be present on pTG801 pilin. Normal antibody staining was restored to pTG801 pili when cells contained, in addition to pTG801, the compatible plasmid pRS31, which must therefore include at least one gene affecting F-pilus structure. One candidate, traD, was excluded as the sole such gene, since traD+ derivatives of a pTG801 strain still elaborated pili that could be laterally decorated with antibody. Moreover, although traD alone restored RNA bacteriophage R17 infectivity to pTG801 cells, as expected, it did not mimic pRS31 in restoring to pTG801 pili other characteristics of normal F pili. We conclude that pRS31 contains as yet uncharacterized genes required for elaboration of structurally normal F pili. Finally, we identified vesicular material, especially abundant in cultures of pTG801 transformants, that stained heavily with the anti-F-pilin monoclonal antibodies. This material may reflect the inner membrane pool of F pilin. Images FIG. 3 FIG. 4 FIG. 5 PMID:1689713

Functional Tooth Restoration by Allogeneic Mesenchymal Stem Cell-Based Bio-Root Regeneration in Swine

PubMed Central

Wei, Fulan; Song, Tieli; Ding, Gang; Xu, Junji; Liu, Yi; Liu, Dayong; Fan, Zhipeng; Zhang, Chunmei

2013-01-01

Our previous proof-of-concept study showed the feasibility of regenerating the dental stem cell-based bioengineered tooth root (bio-root) structure in a large animal model. Here, we used allogeneic dental mesenchymal stem cells to regenerate bio-root, and then installed a crown on the bio-root to restore tooth function. A root shape hydroxyapatite tricalcium phosphate scaffold containing dental pulp stem cells was covered by a Vc-induced periodontal ligament stem cell sheet and implanted into a newly generated jaw bone implant socket. Six months after implantation, a prefabricated porcelain crown was cemented to the implant and subjected to tooth function. Clinical, radiological, histological, ultrastructural, systemic immunological evaluations and mechanical properties were analyzed for dynamic changes in the bio-root structure. The regenerated bio-root exhibited characteristics of a normal tooth after 6 months of use, including dentinal tubule-like and functional periodontal ligament-like structures. No immunological response to the bio-roots was observed. We developed a standard stem cell procedure for bio-root regeneration to restore adult tooth function. This study is the first to successfully regenerate a functional bio-root structure for artificial crown restoration by using allogeneic dental stem cells and Vc-induced cell sheet, and assess the recipient immune response in a preclinical model. PMID:23363023

Separable roles of UFO during floral development revealed by conditional restoration of gene function.

PubMed

Laufs, Patrick; Coen, Enrico; Kronenberger, Jocelyne; Traas, Jan; Doonan, John

2003-02-01

The UNUSUAL FLORAL ORGANS (UFO) gene is required for several aspects of floral development in Arabidopsis including specification of organ identity in the second and third whorls and the proper pattern of primordium initiation in the inner three whorls. UFO is expressed in a dynamic pattern during the early phases of flower development. Here we dissect the role of UFO by ubiquitously expressing it in ufo loss-of-function flowers at different developmental stages and for various durations using an ethanol-inducible expression system. The previously known functions of UFO could be separated and related to its expression at specific stages of development. We show that a 24- to 48-hour period of UFO expression from floral stage 2, before any floral organs are visible, is sufficient to restore normal petal and stamen development. The earliest requirement for UFO is during stage 2, when the endogenous UFO gene is transiently expressed in the centre of the wild-type flower and is required to specify the initiation patterns of petal, stamen and carpel primordia. Petal and stamen identity is determined during stages 2 or 3, when UFO is normally expressed in the presumptive second and third whorl. Although endogenous UFO expression is absent from the stamen whorl from stage 4 onwards, stamen identity can be restored by UFO activation up to stage 6. We also observed floral phenotypes not observed in loss-of-function or constitutive gain-of-function backgrounds, revealing additional roles of UFO in outgrowth of petal primordia.

Astressin B, a corticotropin-releasing hormone receptor antagonist, accelerates the return to normal luteal function after an inflammatory-like stress challenge in the rhesus monkey.

PubMed

Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas; Rivier, Jean; Ferin, Michel

2007-02-01

Endogenous release of CRH in stress has been associated with a dysfunctional reproductive endocrine axis. In the rhesus monkey, an inflammatory-like stress challenge in the luteal phase decreases luteal secretory function. Here, we tested the effectiveness of astressin B, a nonspecific CRH receptor antagonist, in constraining the deleterious impact of a 10-d lipopolysaccharide (LPS) challenge on the menstrual cycle. Two protocols were carried out in nine animals. In the first, the animals, after showing two normal consecutive control cycles, were injected daily for 10 days with LPS (75-125 mug/d) during the luteal phase of the cycle. The animals were followed through the two postchallenge cycles. The second protocol, carried out in the following year, was identical with protocol 1, except that the animals were treated with astressin B (0.45 mg/kg) 1 h before each daily LPS challenge during the luteal phase. Blood samples were obtained daily to document cyclic hormones levels. The LPS challenge significantly decreased luteal progesterone and LH release during the challenge cycle. Inhibition of luteal progesterone extended to the two successive postchallenge cycles. Astressin B treatment prevented luteal LH but not luteal progesterone decrease during the treatment cycle and restored normal progesterone secretion during the two posttreatment cycles. We conclude that the deleterious impact of a short-term inflammatory stress challenge on luteal function is far longer than the stress period itself. Systemic administration of astressin B accelerates the return to normal luteal function, presumably by restoring normal neuroendocrine regulation of gonadotropin secretion.

Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia.

PubMed

Cho, Jun-Ho; Kim, Goo-Young; Mansfield, Brian C; Chou, Janice Y

2018-05-08

Glycogen storage disease type Ia (GSD-Ia) deficient in glucose-6-phosphatase-α (G6Pase-α) is a metabolic disorder characterized by impaired glucose homeostasis and a long-term complication of hepatocellular adenoma/carcinoma (HCA/HCC). Mitochondrial dysfunction has been implicated in GSD-Ia but the underlying mechanism and its contribution to HCA/HCC development remain unclear. We have shown that hepatic G6Pase-α deficiency leads to downregulation of sirtuin 1 (SIRT1) signaling that underlies defective hepatic autophagy in GSD-Ia. SIRT1 is a NAD + -dependent deacetylase that can deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial integrity, biogenesis, and function. We hypothesized that downregulation of hepatic SIRT1 signaling in G6Pase-α-deficient livers impairs PGC-1α activity, leading to mitochondrial dysfunction. Here we show that the G6Pase-α-deficient livers display defective PGC-1α signaling, reduced numbers of functional mitochondria, and impaired oxidative phosphorylation. Overexpression of hepatic SIRT1 restores PGC-1α activity, normalizes the expression of electron transport chain components, and increases mitochondrial complex IV activity. We have previously shown that restoration of hepatic G6Pase-α expression normalized SIRT1 signaling. We now show that restoration of hepatic G6Pase-α expression also restores PGC-1α activity and mitochondrial function. Finally, we show that HCA/HCC lesions found in G6Pase-α-deficient livers contain marked mitochondrial and oxidative DNA damage. Taken together, our study shows that downregulation of hepatic SIRT1/PGC-1α signaling underlies mitochondrial dysfunction and that oxidative DNA damage incurred by damaged mitochondria may contribute to HCA/HCC development in GSD-Ia.

Lower extremity thrust and non-thrust joint mobilization for patellofemoral pain syndrome: a case report.

PubMed

Simpson, Brad G; Simon, Corey B

2014-05-01

A 40-year old female presented to physical therapy with a one-year history of insidious right anteromedial and anterolateral knee pain. Additionally, the patient had a history of multiple lateral ankle sprains bilaterally, the last sprain occurring on the right ankle 1 year prior to the onset of knee pain. The patient was evaluated and given a physical therapy diagnosis of patellofemoral pain syndrome (PFPS), with associated talocrural and tibiofemoral joint hypomobility limiting ankle dorsiflexion and knee extension, respectively. Treatment included a high-velocity low amplitude thrust manipulation to the talocrural joint, which helped restore normal ankle dorsiflexion range of motion. The patient also received tibiofemoral joint non-thrust manual therapy to regain normal knee extension mobility prior to implementing further functional progression exercises to her home program (HEP). This case report highlights the importance of a detailed evaluation of knee and ankle joint mobility in patients presenting with anterior knee pain. Further, manual physical therapy to the lower extremity was found to be successful in restoring normal movement patterns and pain-free function in a patient with chronic anterior knee pain.

Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function.

PubMed

Cardenas, Horacio; Arango, Daniel; Nicholas, Courtney; Duarte, Silvia; Nuovo, Gerard J; He, Wei; Voss, Oliver H; Gonzalez-Mejia, M Elba; Guttridge, Denis C; Grotewold, Erich; Doseff, Andrea I

2016-03-01

The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors' accumulation, re-establishing normal lung architecture. Using NF-κB luciferase transgenic mice, we found that apigenin effectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo.

Restoration of ovarian function and natural fertility following the cryopreservation and autotransplantation of whole adult sheep ovaries

PubMed Central

Campbell, B.K.; Hernandez-Medrano, J.; Onions, V.; Pincott-Allen, C.; Aljaser, F.; Fisher, J.; McNeilly, A.S.; Webb, R.; Picton, H.M.

2014-01-01

STUDY QUESTION Is it possible to restore ovarian function and natural fertility following the cryopreservation and autotransplantation of whole ovaries, complete with vascular pedicle, in adult females from a large monovulatory animal model species (i.e. sheep)? SUMMARY ANSWER Full (100%) restoration of acute ovarian function and high rates of natural fertility (pregnancy rate 64%; live birth rate 29%), with multiple live births, were obtained following whole ovary cryopreservation and autotransplantation (WOCP&TP) of adult sheep ovaries utilizing optimized cryopreservation and post-operative anti-coagulant regimes. WHAT IS KNOWN ALREADY Fertility preservation by WOCP&TP requires successful cryopreservation of both the ovary and its vascular supply. Previous work has indicated detrimental effects of WOCP&TP on the ovarian follicle population. Recent experiments suggest that these deleterious effects can be attributed to an acute loss of vascular patency due to clot formation induced by damage to ovarian arterial endothelial cells. STUDY DESIGN, SIZE, DURATION Study 1 (2010–2011; N = 16) examined the effect of post-thaw perfusion of survival factors (angiogenic, antioxidant, anti-apoptotic; n = 7–8) and treatment with aspirin (pre-operative versus pre- and post-operative (n = 7–9)) on the restoration of ovarian function for 3 months after WOCP&TP. Study 2 (2011–2012; N = 16) examined the effect of cryoprotectant (CPA) perfusion time (10 versus 60 min; n = 16) and pre- and post-operative treatment with aspirin in combination with enoxaparine (Clexane®; n = 8) or eptifibatide (Integrilin®; n = 8) on ovarian function and fertility 11–23 months after WOCP&TP. PARTICIPANTS/MATERIALS, SETTING, METHODS Both studies utilized mature, parous, Greyface ewes aged 3–6 years and weighing 50–75 kg. Restoration of ovarian function was monitored by bi-weekly blood sampling and display of behavioural oestrus. Blood samples were assayed for gonadotrophins, progesterone, anti-Müllerian Hormone and inhibin A. Fertility restoration in Study 2 was quantified by pregnancy rate after a 3 month fertile mating period and was confirmed by ultrasound, hormonal monitoring and live birth. Ovarian function was assessed at sacrifice by ovarian appearance and vascular patency (Doppler ultrasound) and by follicular histology. MAIN RESULTS AND THE ROLE OF CHANCE In Study 1, survival factors were found to have no benefit, but the inclusion of pre-operative aspirin resulted in four ewes showing acute restoration of ovarian function within 3 weeks and a further six ewes showing partial restoration. The addition of post-operative aspirin alone had no clear benefit. In Study 2, combination of aspirin with additional post-operative anti-coagulants resulted in total acute restoration of ovarian function in 14/14 ewes within 3 weeks of WOCP&TP, with 9/14 ewes becoming pregnant and 4/14 giving birth to a total of seven normal lambs. There was no difference between anti-coagulants in terms of restoration of reproductive function and fertility. In contrast, the duration of CPA perfusion was highly significant with a 60 min perfusion resulting in ovaries of normal appearance and function with high rates of primordial follicle survival (70%) and an abundant blood supply, whereas ovaries perfused for 10 min had either resorbed completely and were vestigial (7/14) or were markedly smaller (P < 0.01). It is concluded that both the degree of CPA penetration and the maintenance of post-operative vascular patency are critical determinants of the success of WOCP&TP. LIMITATIONS, REASONS FOR CAUTION Before application of this technology to fertility preservation patients, it will be critical to optimize the CPA perfusion time for different sized human ovaries, determine the optimum period and level of anti-coagulant therapy, and confirm the normality of offspring derived from this procedure. WIDER IMPLICATIONS OF THE FINDINGS This technology holds promise for the preservation of fertility in women. It could also potentially be applied to the cryopreservation of other reproductive or even major organs (kidneys) where there are considerable difficulties in storing donated tissue. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from the Medical Research Council, University of Nottingham. The authors confirm that they have no conflict of interest in relation to this work. PMID:24939954

Restoration of ovarian function and natural fertility following the cryopreservation and autotransplantation of whole adult sheep ovaries.

PubMed

Campbell, B K; Hernandez-Medrano, J; Onions, V; Pincott-Allen, C; Aljaser, F; Fisher, J; McNeilly, A S; Webb, R; Picton, H M

2014-08-01

Is it possible to restore ovarian function and natural fertility following the cryopreservation and autotransplantation of whole ovaries, complete with vascular pedicle, in adult females from a large monovulatory animal model species (i.e. sheep)? Full (100%) restoration of acute ovarian function and high rates of natural fertility (pregnancy rate 64%; live birth rate 29%), with multiple live births, were obtained following whole ovary cryopreservation and autotransplantation (WOCP&TP) of adult sheep ovaries utilizing optimized cryopreservation and post-operative anti-coagulant regimes. Fertility preservation by WOCP&TP requires successful cryopreservation of both the ovary and its vascular supply. Previous work has indicated detrimental effects of WOCP&TP on the ovarian follicle population. Recent experiments suggest that these deleterious effects can be attributed to an acute loss of vascular patency due to clot formation induced by damage to ovarian arterial endothelial cells. Study 1 (2010-2011; N = 16) examined the effect of post-thaw perfusion of survival factors (angiogenic, antioxidant, anti-apoptotic; n = 7-8) and treatment with aspirin (pre-operative versus pre- and post-operative (n = 7-9)) on the restoration of ovarian function for 3 months after WOCP&TP. Study 2 (2011-2012; N = 16) examined the effect of cryoprotectant (CPA) perfusion time (10 versus 60 min; n = 16) and pre- and post-operative treatment with aspirin in combination with enoxaparine (Clexane(®); n = 8) or eptifibatide (Integrilin(®); n = 8) on ovarian function and fertility 11-23 months after WOCP&TP. Both studies utilized mature, parous, Greyface ewes aged 3-6 years and weighing 50-75 kg. Restoration of ovarian function was monitored by bi-weekly blood sampling and display of behavioural oestrus. Blood samples were assayed for gonadotrophins, progesterone, anti-Müllerian Hormone and inhibin A. Fertility restoration in Study 2 was quantified by pregnancy rate after a 3 month fertile mating period and was confirmed by ultrasound, hormonal monitoring and live birth. Ovarian function was assessed at sacrifice by ovarian appearance and vascular patency (Doppler ultrasound) and by follicular histology. In Study 1, survival factors were found to have no benefit, but the inclusion of pre-operative aspirin resulted in four ewes showing acute restoration of ovarian function within 3 weeks and a further six ewes showing partial restoration. The addition of post-operative aspirin alone had no clear benefit. In Study 2, combination of aspirin with additional post-operative anti-coagulants resulted in total acute restoration of ovarian function in 14/14 ewes within 3 weeks of WOCP&TP, with 9/14 ewes becoming pregnant and 4/14 giving birth to a total of seven normal lambs. There was no difference between anti-coagulants in terms of restoration of reproductive function and fertility. In contrast, the duration of CPA perfusion was highly significant with a 60 min perfusion resulting in ovaries of normal appearance and function with high rates of primordial follicle survival (70%) and an abundant blood supply, whereas ovaries perfused for 10 min had either resorbed completely and were vestigial (7/14) or were markedly smaller (P < 0.01). It is concluded that both the degree of CPA penetration and the maintenance of post-operative vascular patency are critical determinants of the success of WOCP&TP. Before application of this technology to fertility preservation patients, it will be critical to optimize the CPA perfusion time for different sized human ovaries, determine the optimum period and level of anti-coagulant therapy, and confirm the normality of offspring derived from this procedure. This technology holds promise for the preservation of fertility in women. It could also potentially be applied to the cryopreservation of other reproductive or even major organs (kidneys) where there are considerable difficulties in storing donated tissue. Funding was received from the Medical Research Council, University of Nottingham. The authors confirm that they have no conflict of interest in relation to this work. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration

PubMed Central

Arnold, W. David; Duque, Sandra; Iyer, Chitra C.; Zaworski, Phillip; McGovern, Vicki L.; Taylor, Shannon J.; von Herrmann, Katharine M.; Kobayashi, Dione T.; Chen, Karen S.; Kolb, Stephen J.; Paushkin, Sergey V.; Burghes, Arthur H. M.

2016-01-01

Introduction and Objective Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function. The goal was to determine whether levels of plasma markers were altered in the SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers. Methods SMNΔ7 and control mice were treated with antisense oligonucleotides (ASO) targeting ISS-N1 to increase SMN protein from SMN2 or scramble ASO (sham treatment) via intracerebroventricular injection on postnatal day 1 (P1). Brain, spinal cord, quadriceps muscle, and liver were analyzed for SMN protein levels at P12 and P90. Ten plasma biomarkers (a subset of biomarkers in the SMA-MAP panel available for analysis in mice) were analyzed in plasma obtained at P12, P30, and P90. Results Of the eight plasma biomarkers assessed, 5 were significantly changed in sham treated SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 mice treated with ASO. Conclusion This study defines a subset of the SMA-MAP plasma biomarker panel that is abnormal in the most commonly used mouse model of SMA. Furthermore, some of these markers are responsive to postnatal SMN restoration. These findings support continued clinical development of these potential prognostic and pharmacodynamic biomarkers. PMID:27907033

Evaluation of Hi-Tec Implant Restoration in Mandibular First Molar Region- A Prospective Clinical Study.

PubMed

Sreeram, Roopa Rani S; Prasad, L Krishna; Chakravarthi, P Srinivas; Devi, Naga Neelima; Kattimani, Vivekanand S; Sreeram, Sanjay Krishna

2015-08-01

Missing teeth lead to loss of structural balance, inefficient function, poor aesthetics and psychological effects on human beings, which needs restoration for normal contour, function and aesthetics. Several natural or synthetic substitutes are being used for replacement of missing tooth since centuries. Implants are the latest modality of replacement. So, the study was aimed to assess clinical success rate of Hi-Tec implant; which is economical and new in market. Results of the study will help clinician for appropriate implant selection. The study included 10 patients from 19 to 31 years and needed restoration of missing mandibular first molar. Restoration had done using Hi Tec Single-tooth implants with metal-ceramic single crown prosthesis after three months of osseointegration. The implants were evaluated clinically (bleeding on probing, probing depth, implant mobility- periotest) and radiographically (marginal bone loss and peri-implant radiolucency) for six years. The observers were blinded for the duration of the study to prevent bias. All the patients had uneventful post-surgical healing. No bleeding on probing, Implant mobility, peri-implant radiolucency with minimal marginal bone loss and constant probing depths were observed well within the normal range during follow-up periods. Two stage single-tooth Hi Tec implant restoration can be used as a successful treatment modality for replacing mandibular first molar in an economic way. However, these results were obtained after 6 years of follow up with a smaller sample size, so long term multi center studies with a larger sample size is recommended for the predictability of success rate conclusively.

Exercise training preserves vagal preganglionic neurones and restores parasympathetic tonus in heart failure.

PubMed

Ichige, Marcelo H A; Santos, Carla R; Jordão, Camila P; Ceroni, Alexandre; Negrão, Carlos E; Michelini, Lisete C

2016-11-01

Heart Failure (HF) is accompanied by reduced ventricular function, activation of compensatory neurohormonal mechanisms and marked autonomic dysfunction characterized by exaggerated sympathoexcitation and reduced parasympathetic activity. With 6 weeks of exercise training, HF-related loss of choline acetyltransferase (ChAT)-positive vagal preganglionic neurones is avoided, restoring the parasympathetic tonus to the heart, and the immunoreactivity of dopamine β-hydroxylase-positive premotor neurones that drive sympathetic outflow to the heart is reduced. Training-induced correction of autonomic dysfunction occurs even with the persistence of abnormal ventricular function. Strong positive correlation between improved parasympathetic tonus to the heart and increased ChAT immunoreactivity in vagal preganglionic neurones after training indicates this is a crucial mechanism to restore autonomic function in heart failure. Exercise training is an efficient tool to attenuate sympathoexcitation, a hallmark of heart failure (HF). Although sympathetic modulation in HF is widely studied, information regarding parasympathetic control is lacking. We examined the combined effects of sympathetic and vagal tonus to the heart in sedentary (Sed) and exercise trained (ET) HF rats and the contribution of respective premotor and preganglionic neurones. Wistar rats submitted to coronary artery ligation or sham surgery were assigned to training or sedentary protocols for 6 weeks. After haemodynamic, autonomic tonus (atropine and atenolol i.v.) and ventricular function determinations, brains were collected for immunoreactivity assays (choline acetyltransferase, ChATir; dopamine β-hydroxylase, DBHir) and neuronal counting in the dorsal motor nucleus of vagus (DMV), nucleus ambiguus (NA) and rostroventrolateral medulla (RVLM). HF-Sed vs. SHAM-Sed exhibited decreased exercise capacity, reduced ejection fraction, increased left ventricle end diastolic pressure, smaller positive and negative dP/dt, decreased intrinsic heart rate (IHR), lower parasympathetic and higher sympathetic tonus, reduced preganglionic vagal neurones and ChATir in the DMV/NA, and increased RVLM DBHir. Training increased treadmill performance, normalized autonomic tonus and IHR, restored the number of DMV and NA neurones and corrected ChATir without affecting ventricular function. There were strong positive correlations between parasympathetic tonus and ChATir in NA and DMV. RVLM DBHir was also normalized by training, but there was no change in neurone number and no correlation with sympathetic tonus. Training-induced preservation of preganglionic vagal neurones is crucial to normalize parasympathetic activity and restore autonomic balance to the heart even in the persistence of cardiac dysfunction. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

BAAV mediated GJB2 gene transfer restores gap junction coupling in cochlear organotypic cultures from deaf Cx26Sox10Cre mice.

PubMed

Crispino, Giulia; Di Pasquale, Giovanni; Scimemi, Pietro; Rodriguez, Laura; Galindo Ramirez, Fabian; De Siati, Romolo Daniele; Santarelli, Rosa Maria; Arslan, Edoardo; Bortolozzi, Mario; Chiorini, John A; Mammano, Fabio

2011-01-01

The deafness locus DFNB1 contains GJB2, the gene encoding connexin26 and GJB6, encoding connexin30, which appear to be coordinately regulated in the inner ear. In this work, we investigated the expression and function of connexin26 and connexin30 from postnatal day 5 to adult age in double transgenic Cx26(Sox10Cre) mice, which we obtained by crossing connexin26 floxed mice with a deleter Sox10-Cre line. Cx26(Sox10Cre) mice presented with complete connexin26 ablation in the epithelial gap junction network of the cochlea, whereas connexin30 expression was developmentally delayed; immunolabeling patterns for both connexins were normal in the cochlear lateral wall. In vivo electrophysiological measurements in Cx26(Sox10Cre) mice revealed profound hearing loss accompanied by reduction of endocochlear potential, and functional experiments performed in postnatal cochlear organotypic cultures showed impaired gap junction coupling. Transduction of these cultures with a bovine adeno associated virus vector restored connexin26 protein expression and rescued gap junction coupling. These results suggest that restoration of normal connexin levels by gene delivery via recombinant adeno associated virus could be a way to rescue hearing function in DFNB1 mouse models and, in future, lead to the development of therapeutic interventions in humans.

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

PubMed

Wichmann, Thomas; DeLong, Mahlon R

2016-04-01

Deep brain stimulation (DBS) is highly effective for both hypo- and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson's disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal ganglia-thalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks.

Using motor behavior during an early critical period to restore skilled limb movement after damage to the corticospinal motor system during development

PubMed Central

Friel, KM; Chakrabarty, S; H-C, Kuo; Martin, JH

2012-01-01

This study investigated requirements for restoring motor function after corticospinal (CS) system damage during early postnatal development. Activity-dependent competition between the CS tracts (CST) of the two hemispheres is imperative for normal development. Blocking primary motor cortex (M1) activity unilaterally during a critical period (postnatal weeks-PW-5–7) produces permanent contralateral motor skill impairments, loss of M1 motor map, aberrant CS terminations, and decreases in CST presynaptic sites and spinal cholinergic interneuron numbers. To repair these motor systems impairments and restore function, we manipulated motor experience in three groups of cats after this CST injury produced by inactivation. One group wore a jacket restraining the limb ipsilateral to inactivation, forcing use of the contralateral, impaired, limb, for the month following M1 inactivation (PW8–13; “Restraint Alone”). A second group wore the restraint during PW8–13, and was also trained for 1 h/day in a reaching task with the contralateral forelimb (“Early Training”). To test the efficacy of intervention during adolescence, a third group wore the restraint and received reach training during PW20–24 (“Delayed Training”). Early training restored CST connections and the M1 motor map; increased cholinergic spinal interneurons numbers on the contralateral, relative to ipsilateral, side; and abrogated limb control impairments. Delayed training restored CST connectivity and the M1 motor map, but not contralateral spinal cholinergic cell counts or motor performance. Restraint alone only restored CST connectivity. Our findings stress the need to reestablish the integrated functions of the CS system at multiple hierarchical levels in restoring skilled motor function after developmental injury. PMID:22764234

The ability of multipotent mesenchymal stromal cells from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells.

PubMed

Sorokina, Tamara; Shipounova, Irina; Bigildeev, Alexey; Petinati, Nataliya; Drize, Nina; Turkina, Anna; Chelysheva, Ekaterina; Shukhov, Oleg; Kuzmina, Larisa; Parovichnikova, Elena; Savchenko, Valery

2016-09-01

The development of leukemia impairs normal hematopoiesis and marrow stromal microenvironment. The aim of the investigation was to study the ability of multipotent mesenchymal stromal cells (MSCs) derived from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells. MSCs were obtained from the bone marrow of 14 patients with acute lymphoblastic (ALL), 25 with myeloid (AML), and 15 with chronic myeloid (CML) leukemia. As a control, MSCs from 22 healthy donors were used. The incidence of cobblestone area forming cells (CAFC 7-8 d) in the bone marrow of healthy donor cultivated on the supportive layer of patients MSCs was measured. The ability of MSCs from AML and ALL patients at the moment of diagnosis to maintain normal CAFC was significantly decreased when compared to donors. After chemotherapy, the restoration of ALL patients' MSCs functions was slower than that of AML. CML MSCs maintained CAFC better than donors' at the moment of diagnosis and this ability increased with treatment. The ability of patients' MSCs to maintain normal hematopoietic progenitor cells was shown to change in comparison with MSCs from healthy donors and depended on nosology. During treatment, the functional capacity of patients' MSCs had been partially restored. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Simple Laparoscopic Procedure to Restore a Normal Vaginal Length After Colpohysterectomy With Large Upper Colpectomy for Cervical and/or Vaginal Neoplasia.

PubMed

Leblanc, Eric; Bresson, Lucie; Merlot, Benjamin; Puga, Marco; Kridelka, Frederic; Tsunoda, Audrey; Narducci, Fabrice

2016-01-01

Colpohysterectomy is sometimes associated with a large upper colpectomy resulting in a shortened vagina, potentially impacting sexual function. We report on a preliminary experience of a laparoscopic colpoplasty to restore a normal vaginal length. Patients with shortened vaginas after a laparoscopic colpohysterectomy were considered for a laparoscopic modified Davydov's procedure to create a new vaginal vault using the peritoneum of the rectum and bladder. From 2010 to 2014, 8 patients were offered this procedure, after informed preoperative consent. Indications were 2 extensive recurrent vaginal intraepithelial neoplasias grade 3 and 6 radical hysterectomies for cervical cancer. Mean vaginal length before surgery was 3.8 cm (standard deviation, 1.6). Median operative time was 50 minutes (range, 45-90). Blood loss was minimal (50-100 mL). No perioperative complications occurred. Median vaginal length at discharge was 11.3 cm (range, 9-13). Sexual intercourse could be resumed around 10 weeks after surgery. At a median follow-up of 33.8 months (range, 2.4-51.3), 6 patients remained sexually active but 2 had stopped. Although this experience is small, this laparoscopic modified Davydov's procedure seems to be an effective procedure, adaptable to each patient's anatomy. If the initial postoperative regular self-dilatation is carefully observed, vaginal patency is durably restored and enables normal sexual function. Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.

Estimation of the risk of failure for an endodontically treated maxillary premolar with MODP preparation and CAD/CAM ceramic restorations.

PubMed

Lin, Chun-Li; Chang, Yen-Hsiang; Pa, Che-An

2009-10-01

This study evaluated the risk of failure for an endodontically treated premolar with mesio occlusodistal palatal (MODP) preparation and 3 different computer-aided design/computer-aided manufacturing (CAD/CAM) ceramic restoration configurations. Three 3-dimensional finite element (FE) models designed with CAD/CAM ceramic onlay, endocrown, and conventional crown restorations were constructed to perform simulations. The Weibull function was incorporated with FE analysis to calculate the long-term failure probability relative to different load conditions. The results indicated that the stress values on the enamel, dentin, and luting cement for endocrown restoration were the lowest values relative to the other 2 restorations. Weibull analysis revealed that the individual failure probability in the endocrown enamel, dentin, and luting cement obviously diminished more than those for onlay and conventional crown restorations. The overall failure probabilities were 27.5%, 1%, and 1% for onlay, endocrown, and conventional crown restorations, respectively, in normal occlusal condition. This numeric investigation suggests that endocrown and conventional crown restorations for endodontically treated premolars with MODP preparation present similar longevity.

Clearwater Focus Watershed; Nez Perce Tribe, 2003-2004 Annual Report.

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

Jones, Ira

2004-06-01

The Nez Perce Tribe Department of Fisheries Resource Management, Watershed Division, approaches watershed restoration with a goal to protect, restore, and enhance a connected network of functioning habitat types capable of supporting all fish life stages. Its goal is also to re-establish normal patterns of production, dispersal, and exchange of genetic information within the 1855 Treaty Area. The Nez Perce Tribe began watershed restoration projects within the Clearwater River Subbasin in 1996. Progress has been made in restoring the sub-basin by excluding cattle from critical riparian areas through fencing, stabilizing stream banks, decommissioning roads, and upgrading culverts. Coordination of thesemore » projects is critical to the success of the restoration of the sub-basin. Coordination activities also includes: inter and intra-department coordination, sub-basin assessment and planning, involving government and private organizations, and treaty area coordination.« less

Endothelial insulin receptor restoration rescues vascular function in male insulin receptor haploinsufficient mice.

PubMed

Sengupta, Anshuman; Patel, Peysh A; Yuldasheva, Nadira Y; Mughal, Romana S; Galloway, Stacey; Viswambharan, Hema; Walker, Andrew M N; Aziz, Amir; Smith, Jessica; Ali, Noman; Mercer, Ben N; Imrie, Helen; Sukumar, Piruthivi; Wheatcroft, Stephen B; Kearney, Mark T; Cubbon, Richard M

2018-05-15

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We asked whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor haploinsufficient mice (IRKO) were crossed with mice expressing a human insulin receptor transgene in the endothelium (hIRECO), to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO in glucose- and insulin-tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild-type littermates. These phenotypic changes were associated with enhanced basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro, but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling.

The compensatory G88R change is essential in restoring the normal functions of influenza A/WSN/33 virus matrix protein 1 with a disrupted nuclear localization signal.

PubMed

Xie, Hang; Lin, Zhengshi; Mosier, Philip D; Desai, Umesh R; Gao, Yamei

2013-01-01

G88R emerged as a compensatory mutation in matrix protein 1 (M1) of influenza virus A/WSN/33 when its nuclear localization signal (NLS) was disrupted by R101S and R105S substitutions. The resultant M1 triple mutant M(NLS-88R) regained replication efficiency in vitro while remaining attenuated in vivo with the potential of being a live vaccine candidate. To understand why G88R was favored by the virus as a compensatory change for the NLS loss and resultant replication deficiency, three more M1 triple mutants with an alternative G88K, G88V, or G88E change in addition to R101S and R105S substitutions in the NLS were generated. Unlike the other M1 triple mutants, M(NLS-88R) replicated more efficiently in vitro and in vivo. The G88R compensatory mutation not only restored normal functions of M1 in the presence of a disrupted NLS but also resulted in a strong association of M1 with viral ribonucleoprotein. Under a transmission electron microscope, only the M1 layer of the M(NLS-88R) virion exhibited discontinuous fingerprint-like patterns with average thicknesses close to that of wild-type A/WSN/33. Computational modeling suggested that the compensatory G88R change could reestablish the integrity of the M1 layer through new salt bridges between adjacent M1 subunits when the original interactions were interrupted by simultaneous R101S and R105S replacements in the NLS. Our results suggested that restoring the normal functions of M1 was crucial for efficient virus replication.

Functional crown lengthening surgery in the aesthetic zone; periodontic and prosthodontic considerations.

PubMed

Patel, Rajiv M; Baker, Paul

2015-01-01

Crown lengthening surgery aims to increase the amount of supragingival tooth tissue by resection of the soft and/or hard tissues to enable otherwise unrestorable teeth to be restored by increasing the retention and resistance forms of the teeth. Restoration of the worn dentition may require significant prosthodontic knowledge and skill. A prosthodontist should be involved from the beginning of the management of the patient. A number of key stages should be considered for correct management. Although the periodontist may guide the prosthodontist with regards to what may or may not be possible surgically, the overall treatment plan should be prosthodontically driven. Clinical Relevance: Toothwear of the anterior dentition provides a unique challenge to restore not only function but also to manage the aesthetic demands of the patient. To ensure that the correct outcome is reached, clinicians should be familiar with the normal anatomical proportions and relationships to enable planning and treatment to take place.

Restoration of Full Shoulder Range of Motion After Application of the Fascial Distortion Model.

PubMed

Boucher, Joshua D; Figueroa, Jose

2018-05-01

Decreased active and passive range of motion (ROM) accompanied by pain in the shoulder is a common presentation for patients with frozen shoulder, and it can be difficult to restore normal function. Through the fascial distortion model, physicians can apply a manual technique to rapidly and effectively increase ROM and decrease pain. A 28-year-old man presented 18 months after sustaining a shoulder hyperextension injury. On active and passive ROM examination, he had approximately 90° of shoulder abduction and moderately reduced internal rotation associated with 8/10 pain. After 2 applications of the fascial distortion model, his shoulder restored to full abduction and internal rotation with no pain.

Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function

PubMed Central

Cardenas, Horacio; Arango, Daniel; Nicholas, Courtney; Duarte, Silvia; Nuovo, Gerard J.; He, Wei; Voss, Oliver H.; Gonzalez-Mejia, M. Elba; Guttridge, Denis C.; Grotewold, Erich; Doseff, Andrea I.

2016-01-01

The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors’ accumulation, re-establishing normal lung architecture. Using NF-κB luciferase transgenic mice, we found that apigenin effectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo. PMID:26938530

Lower extremity thrust and non-thrust joint mobilization for patellofemoral pain syndrome: a case report

PubMed Central

Simpson, Brad G; Simon, Corey B

2014-01-01

A 40-year old female presented to physical therapy with a one-year history of insidious right anteromedial and anterolateral knee pain. Additionally, the patient had a history of multiple lateral ankle sprains bilaterally, the last sprain occurring on the right ankle 1 year prior to the onset of knee pain. The patient was evaluated and given a physical therapy diagnosis of patellofemoral pain syndrome (PFPS), with associated talocrural and tibiofemoral joint hypomobility limiting ankle dorsiflexion and knee extension, respectively. Treatment included a high-velocity low amplitude thrust manipulation to the talocrural joint, which helped restore normal ankle dorsiflexion range of motion. The patient also received tibiofemoral joint non-thrust manual therapy to regain normal knee extension mobility prior to implementing further functional progression exercises to her home program (HEP). This case report highlights the importance of a detailed evaluation of knee and ankle joint mobility in patients presenting with anterior knee pain. Further, manual physical therapy to the lower extremity was found to be successful in restoring normal movement patterns and pain-free function in a patient with chronic anterior knee pain. PMID:24976753

Verification of watershed vegetation restoration policies, arid China

PubMed Central

Zhang, Chengqi; Li, Yu

2016-01-01

Verification of restoration policies that have been implemented is of significance to simultaneously reduce global environmental risks while also meeting economic development goals. This paper proposed a novel method according to the idea of multiple time scales to verify ecological restoration policies in the Shiyang River drainage basin, arid China. We integrated modern pollen transport characteristics of the entire basin and pollen records from 8 Holocene sedimentary sections, and quantitatively reconstructed the millennial-scale changes of watershed vegetation zones by defining a new pollen-precipitation index. Meanwhile, Empirical Orthogonal Function method was used to quantitatively analyze spatial and temporal variations of Normalized Difference Vegetation Index in summer (June to August) of 2000–2014. By contrasting the vegetation changes that mainly controlled by millennial-scale natural ecological evolution with that under conditions of modern ecological restoration measures, we found that vegetation changes of the entire Shiyang River drainage basin are synchronous in both two time scales, and the current ecological restoration policies met the requirements of long-term restoration objectives and showed promising early results on ecological environmental restoration. Our findings present an innovative method to verify river ecological restoration policies, and also provide the scientific basis to propose future emphasizes of ecological restoration strategies. PMID:27470948

Verification of watershed vegetation restoration policies, arid China

NASA Astrophysics Data System (ADS)

Zhang, Chengqi; Li, Yu

2016-07-01

Verification of restoration policies that have been implemented is of significance to simultaneously reduce global environmental risks while also meeting economic development goals. This paper proposed a novel method according to the idea of multiple time scales to verify ecological restoration policies in the Shiyang River drainage basin, arid China. We integrated modern pollen transport characteristics of the entire basin and pollen records from 8 Holocene sedimentary sections, and quantitatively reconstructed the millennial-scale changes of watershed vegetation zones by defining a new pollen-precipitation index. Meanwhile, Empirical Orthogonal Function method was used to quantitatively analyze spatial and temporal variations of Normalized Difference Vegetation Index in summer (June to August) of 2000-2014. By contrasting the vegetation changes that mainly controlled by millennial-scale natural ecological evolution with that under conditions of modern ecological restoration measures, we found that vegetation changes of the entire Shiyang River drainage basin are synchronous in both two time scales, and the current ecological restoration policies met the requirements of long-term restoration objectives and showed promising early results on ecological environmental restoration. Our findings present an innovative method to verify river ecological restoration policies, and also provide the scientific basis to propose future emphasizes of ecological restoration strategies.

Fault-Tolerant Algorithms for Connectivity Restoration in Wireless Sensor Networks.

PubMed

Zeng, Yali; Xu, Li; Chen, Zhide

2015-12-22

As wireless sensor network (WSN) is often deployed in a hostile environment, nodes in the networks are prone to large-scale failures, resulting in the network not working normally. In this case, an effective restoration scheme is needed to restore the faulty network timely. Most of existing restoration schemes consider more about the number of deployed nodes or fault tolerance alone, but fail to take into account the fact that network coverage and topology quality are also important to a network. To address this issue, we present two algorithms named Full 2-Connectivity Restoration Algorithm (F2CRA) and Partial 3-Connectivity Restoration Algorithm (P3CRA), which restore a faulty WSN in different aspects. F2CRA constructs the fan-shaped topology structure to reduce the number of deployed nodes, while P3CRA constructs the dual-ring topology structure to improve the fault tolerance of the network. F2CRA is suitable when the restoration cost is given the priority, and P3CRA is suitable when the network quality is considered first. Compared with other algorithms, these two algorithms ensure that the network has stronger fault-tolerant function, larger coverage area and better balanced load after the restoration.

Creep behaviour and creep mechanisms of normal and healing ligaments

NASA Astrophysics Data System (ADS)

Thornton, Gail Marilyn

Patients with knee ligament injuries often undergo ligament reconstructions to restore joint stability and, potentially, abate osteoarthritis. Careful literature review suggests that in 10% to 40% of these patients the graft tissue "stretches out". Some graft elongation is likely due to creep (increased elongation of tissue under repeated or sustained load). Quantifying creep behaviour and identifying creep mechanisms in both normal and healing ligaments is important for finding clinically relevant means to prevent creep. Ligament creep was accurately predicted using a novel yet simple structural model that incorporated both collagen fibre recruitment and fibre creep. Using the inverse stress relaxation function to model fibre creep in conjunction with fibre recruitment produced a superior prediction of ligament creep than that obtained from the inverse stress relaxation function alone. This implied mechanistic role of fibre recruitment during creep was supported using a new approach to quantify crimp patterns at stresses in the toe region (increasing stiffness) and linear region (constant stiffness) of the stress-strain curve. Ligament creep was relatively insensitive to increases in stress in the toe region; however, creep strain increased significantly when tested at the linear region stress. Concomitantly, fibre recruitment was evident at the toe region stresses; however, recruitment was limited at the linear region stress. Elevating the water content of normal ligament using phosphate buffered saline increased the creep response. Therefore, both water content and fibre recruitment are important mechanistic factors involved in creep of normal ligaments. Ligament scars had inferior creep behaviour compared to normal ligaments even after 14 weeks. In addition to inferior collagen properties affecting fibre recruitment and increased water content, increased glycosaminoglycan content and flaws in scar tissue were implicated as potential mechanisms of scar creep. Similarly, ligament autografts had persistently abnormal creep behaviour and creep recovery after 2 years likely due to infiltration by scar tissue. Short-term immobilization of autografts had long-term detrimental consequences perhaps due to re-injury of the graft at remobilization. Treatments that restore normal properties to these mechanistic factors in order to control creep would improve joint healing by restoring joint kinematics and maintaining normal joint loading.

Photovoltaic restoration of sight with high visual acuity

PubMed Central

Lorach, Henri; Goetz, Georges; Smith, Richard; Lei, Xin; Mandel, Yossi; Kamins, Theodore; Mathieson, Keith; Huie, Philip; Harris, James; Sher, Alexander; Palanker, Daniel

2015-01-01

Patients with retinal degeneration lose sight due to gradual demise of photoreceptors. Electrical stimulation of the surviving retinal neurons provides an alternative route for delivery of visual information. We demonstrate that subretinal arrays with 70 μm photovoltaic pixels provide highly localized stimulation, with electrical and visual receptive fields of comparable sizes in rat retinal ganglion cells. Similarly to normal vision, retinal response to prosthetic stimulation exhibits flicker fusion at high frequencies, adaptation to static images and non-linear spatial summation. In rats with retinal degeneration, these photovoltaic arrays provide spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in pigmented rats. Ease of implantation of these wireless and modular arrays, combined with their high resolution opens the door to functional restoration of sight. PMID:25915832

Effect of fluorocarbons on acetylcholinesterase activity and some counter measures

NASA Technical Reports Server (NTRS)

Young, W.; Parker, J. A.

1975-01-01

An isolated vagal sympathetic heart system has been successfully used for the study of the effect of fluorocarbons (FCs) on cardiac performance and in situ enzyme activity. Dichlorodifluoromethane sensitizes this preparation to sympathetic stimulation and to exogenous epinephrine challenge. Partial and complete A-V block and even cardiac arrest have been induced by epinephrine challenge in the FC sensitized heart. Potassium chloride alone restores the rhythmicity but not the normal contractility of the heart in such a situation. Addition of glucose will, however, completely restore the normal function of the heart which is sensitized by dichlorodifluoromethane. The ED 50 values of acetylcholinesterase activity which are used as a measure of relative effectiveness of fluorocarbons are compared with the maximum permissible concentration. Kinetic studies indicate that all the fluorocarbons tested so far are noncompetitive.

Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study.

PubMed

Le Page, Lydia M; Rider, Oliver J; Lewis, Andrew J; Ball, Vicky; Clarke, Kieran; Johansson, Edvin; Carr, Carolyn A; Heather, Lisa C; Tyler, Damian J

2015-08-01

Although diabetic cardiomyopathy is widely recognized, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1-(13)C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 ± 0.7 vs. 8.4 ± 0.5 mmol/L), lower PDH flux (0.005 ± 0.001 vs. 0.017 ± 0.002 s(-1)), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E'] 12.2 ± 0.8 vs. 20 ± 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 ± 0.002 s(-1)), reversed diastolic dysfunction (E/E' 14 ± 1), and normalized blood glucose levels (7.5 ± 0.7 mmol/L). The treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction, and normalized blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Migration, Integration and Maturation of Photoreceptor Precursors Following Transplantation in the Mouse Retina

PubMed Central

Warre-Cornish, Katherine; Barber, Amanda C.; Sowden, Jane C.; Ali, Robin R.

2014-01-01

Retinal degeneration leading to loss of photoreceptors is a major cause of untreatable blindness. Recent research has yielded definitive evidence for restoration of vision following the transplantation of rod photoreceptors in murine models of blindness, while advances in stem cell biology have enabled the generation of transplantable photoreceptors from embryonic stem cells. Importantly, the amount of visual function restored is dependent upon the number of photoreceptors that migrate correctly into the recipient retina. The developmental stage of the donor cells is important for their ability to migrate; they must be immature photoreceptor precursors. Little is known about how and when donor cell migration, integration, and maturation occurs. Here, we have performed a comprehensive histological analysis of the 6-week period following rod transplantation in mice. Donor cells migrate predominately as single entities during the first week undergoing a stereotyped sequence of morphological changes in their translocation from the site of transplantation, through the interphotoreceptor matrix and into the recipient retina. This includes initial polarization toward the outer nuclear layer (ONL), followed by formation of an apical attachment and rudimentary segment during migration into the ONL. Strikingly, acquisition of a nuclear architecture typical of mature rods was accelerated compared with normal development and a feature of migrating cells. Once within the ONL, precursors formed synaptic-like structures and outer segments in accordance with normal maturation. The restoration of visual function mediated by transplanted photoreceptors correlated with the later expression of rod α-transducin, achieving maximal function by 5 weeks. PMID:24328605

Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression.

PubMed

Byrne, Nikole J; Levasseur, Jody; Sung, Miranda M; Masson, Grant; Boisvenue, Jamie; Young, Martin E; Dyck, Jason R B

2016-05-15

Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes. Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction < 30) underwent a second surgery to remove the aortic constriction (debanding, DB). Three weeks following DB, there was a near complete recovery of systolic and diastolic function, and gene expression of several markers for hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1-week post-DB, which preceded functional recovery. The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Feasibility of Repairing Glomerular Basement Membrane Defects in Alport Syndrome

PubMed Central

Lin, Xiaobo; Suh, Jung Hee; Go, Gloriosa

2014-01-01

Alport syndrome is a hereditary glomerular disease that leads to kidney failure. It is caused by mutations affecting one of three chains of the collagen α3α4α5(IV) heterotrimer, which forms the major collagen IV network of the glomerular basement membrane (GBM). In the absence of the α3α4α5(IV) network, the α1α1α2(IV) network substitutes, but it is insufficient to maintain normal kidney function. Inhibition of angiotensin-converting enzyme slows progression to kidney failure in patients with Alport syndrome but is not a cure. Restoration of the normal collagen α3α4α5(IV) network in the GBM, by either cell- or gene-based therapy, is an attractive and logical approach toward a cure, but whether or not the abnormal GBM can be repaired once it has formed and is functioning is unknown. Using a mouse model of Alport syndrome and an inducible transgene system, we found that secretion of α3α4α5(IV) heterotrimers by podocytes into a preformed, abnormal, filtering Alport GBM is effective at restoring the missing collagen IV network, slowing kidney disease progression, and extending life span. This proof-of-principle study demonstrates the plasticity of the mature GBM and validates the pursuit of therapeutic approaches aimed at normalizing the GBM to prolong kidney function. PMID:24262794

Feasibility of repairing glomerular basement membrane defects in Alport syndrome.

PubMed

Lin, Xiaobo; Suh, Jung Hee; Go, Gloriosa; Miner, Jeffrey H

2014-04-01

Alport syndrome is a hereditary glomerular disease that leads to kidney failure. It is caused by mutations affecting one of three chains of the collagen α3α4α5(IV) heterotrimer, which forms the major collagen IV network of the glomerular basement membrane (GBM). In the absence of the α3α4α5(IV) network, the α1α1α2(IV) network substitutes, but it is insufficient to maintain normal kidney function. Inhibition of angiotensin-converting enzyme slows progression to kidney failure in patients with Alport syndrome but is not a cure. Restoration of the normal collagen α3α4α5(IV) network in the GBM, by either cell- or gene-based therapy, is an attractive and logical approach toward a cure, but whether or not the abnormal GBM can be repaired once it has formed and is functioning is unknown. Using a mouse model of Alport syndrome and an inducible transgene system, we found that secretion of α3α4α5(IV) heterotrimers by podocytes into a preformed, abnormal, filtering Alport GBM is effective at restoring the missing collagen IV network, slowing kidney disease progression, and extending life span. This proof-of-principle study demonstrates the plasticity of the mature GBM and validates the pursuit of therapeutic approaches aimed at normalizing the GBM to prolong kidney function.

Orthotopic Transplantation of Cryopreserved Mouse Ovaries and Gonadotrophin Releasing Hormone Analogues in the Restoration of Function following Chemotherapy-Induced Ovarian Damage

PubMed Central

Li, Qing; Szatmary, Peter; Liu, Yanyang; Ding, Zhenyu; Zhou, Jin; Sun, Yi; Luo, Feng

2015-01-01

Therapy advances are constantly improving survival rates of cancer patients, however the toxic effects of chemotherapy drugs can seriously affect patients’ quality of life. In women, fertility and premature ovarian endocrine dysfunction are of particular concern. It is urgently we find methods to preserve or reconstruct ovarian function for these women. This study compares GnRHa treatment with ovarian tissue cryopreservation and orthotopic transplantation in a chemotherapy-induced ovarian damage murine model. 56 inbred Lewis rats were divided into 4 treatment groups: Saline control (group I); cyclophosphamide only (group II); cyclophosphamide plus GnRHa (group III); cyclophosphamide and grafting of thawed cryopreserved ovaries (group IV). Body weight, estrous cycle recovery time, ovarian weight, morphology and follicle count, as well as breeding and fertility were compared among groups. Only group IV was able to restore to normal body weight by the end of the observation period and resumed normal estrous cycles in a shorter time compared to other treatment groups. There was a decrease in primordial follicles in all treatment groups, but group III had the greatest reduction. Although, there was no difference in pregnancy, only one animal littered normal pups in group II, none littered in group III and four littered in group IV. Thus, cryopreservation and orthotopic transplantation of ovarian tissue can restore the fertility of rats subjected to chemotherapy in a manner that is superior to GnRHa treatment. We also observed increased rates of hepatic, splenic and pulmonary haemorrhage in group III, suggesting there may be synergistic toxicity of GnRHa and cyclophosphamide. PMID:25811681

Adenosine A2A receptor inhibition restores the normal transport of endothelial glutamate transporters in the brain.

PubMed

Bai, Wei; Li, Ping; Ning, Ya-Lei; Peng, Yan; Xiong, Ren-Ping; Yang, Nan; Chen, Xing; Zhou, Yuan-Guo

2018-04-15

Excitatory amino acid transporters (EAATs) on cerebral vascular endothelial cells play an important role in maintaining glutamate homeostasis in the brain. The dysfunction of endothelial EAATs is an important reason for the dramatically elevated brain glutamate levels after brain injury, such as traumatic brain injury (TBI). The adenosine A 2A receptor (A 2A R) plays an important role in regulating the brain glutamate level after brain injury; however, researchers have not clearly determined whether this role was related to its ability to regulate endothelial EAATs. Activation of A 2A R in vitro not only decreased the PKA- and glutamate level-dependent strengthening of the interaction between NKA-α1 and the FXYD1 subunit and the subsequent decrease in the activity of Na + /K + -ATPases (NKAs) but also enhanced its interaction with EAATs and ultimately aggravated the reverse transport function of endothelial EAATs under oxygen-glucose deprivation (OGD) conditions. Conversely, inhibition of A 2A R restored the normal transport of EAAT. Moreover, A 2A R inhibition increased NKA activity and decreased its interaction with EAATs in isolated brain capillaries after TBI, further confirming its role in endothelial EAATs in vivo. Based on our results, A 2A R played an important role in regulating endothelial EAAT function, and strategies that restore the normal transport of endothelial EAATs through the inhibition of A 2A R might serve as an effective treatment for brain injury. Copyright © 2018 Elsevier Inc. All rights reserved.

Restoration of normal phenotype in cancer cells

DOEpatents

Bissell, M.J.; Weaver, V.M.

1998-12-08

A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying {beta}{sub 1} integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive. 14 figs.

Method for restoration of normal phenotype in cancer cells

DOEpatents

Bissell, Mina J.; Weaver, Valerie M.

2000-01-01

A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

Restoration of normal phenotype in cancer cells

DOEpatents

Bissell, Mina J.; Weaver, Valerie M.

1998-01-01

A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

49 CFR 236.746 - Feature, restoring.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Feature, restoring. An arrangement on an electro-pneumatic switch by means of which power is applied to restore the switch movement to full normal or to full reverse position, before the driving bar creeps sufficiently to unlock the switch, with control level in normal or reverse position. [49 FR 3388, Jan. 26, 1984] ...

A real-time MTFC algorithm of space remote-sensing camera based on FPGA

NASA Astrophysics Data System (ADS)

Zhao, Liting; Huang, Gang; Lin, Zhe

2018-01-01

A real-time MTFC algorithm of space remote-sensing camera based on FPGA was designed. The algorithm can provide real-time image processing to enhance image clarity when the remote-sensing camera running on-orbit. The image restoration algorithm adopted modular design. The MTF measurement calculation module on-orbit had the function of calculating the edge extension function, line extension function, ESF difference operation, normalization MTF and MTFC parameters. The MTFC image filtering and noise suppression had the function of filtering algorithm and effectively suppressing the noise. The algorithm used System Generator to design the image processing algorithms to simplify the design structure of system and the process redesign. The image gray gradient dot sharpness edge contrast and median-high frequency were enhanced. The image SNR after recovery reduced less than 1 dB compared to the original image. The image restoration system can be widely used in various fields.

Cloned cows with short telomeres deliver healthy offspring with normal-length telomeres.

PubMed

Miyashita, Norikazu; Kubo, Yasuaki; Yonai, Miharu; Kaneyama, Kanako; Saito, Norio; Sawai, Ken; Minamihashi, Akira; Suzuki, Toshiyuki; Kojima, Toshiyuki; Nagai, Takashi

2011-10-01

Dolly, the first mammal cloned from a somatic cell, had shorter telomeres than age-matched controls and died at an early age because of disease. To investigate longevity and lifetime performance in cloned animals, we produced cloned cows with short telomeres using oviductal epithelial cells as donor cells. At 5 years of age, despite the presence of short telomeres, all cloned cows delivered multiple healthy offspring following artificial insemination with conventionally processed spermatozoa from noncloned bulls, and their milk production was comparable to that of donor cows. Moreover, this study revealed that the offspring had normal-length telomeres in their leukocytes and major organs. Thus, cloned animals have normal functional germ lines, and therefore germ line function can completely restore telomere lengths in clone gametes by telomerase activity, resulting in healthy offspring with normal-length telomeres.

Central memory CD4 T cells are associated with incomplete restoration of the CD4 T cell pool after treatment-induced long-term undetectable HIV viraemia.

PubMed

Rallón, Norma; Sempere-Ortells, José M; Soriano, Vincent; Benito, José M

2013-11-01

It is unclear to what extent T cell reconstitution may be possible in HIV-1-infected individuals on continuous successful highly active antiretroviral therapy (HAART). Herein, we analysed distinct phenotypic markers of immune recovery in patients with undetectable viraemia for 8 years, taking as reference untreated patients and healthy controls. Seventy-two subjects were examined: 28 HIV-1+ patients on successful long-term HAART, 24 HIV-1+ untreated viraemic patients and 20 age-matched healthy controls. Analysis of naive and memory CD4 and CD8 T cells was combined with measurements of activation status (expression of CD38) and with thymic function (expression of CD31). Statistical significance was determined by non-parametric tests. After long-term HAART, the majority of parameters were normalized compared with age-matched control values, including T cell activation and thymic function. However, absolute counts of naive and central memory CD4 T cells remained below normal levels. The only parameters significantly associated with CD4 counts at the end of follow-up were the pre-HAART CD4 count ( β ± SD = 0.54 ± 0.16, P = 0.003) and the level of CD4 central memory cells at the end of follow-up (β ± SD = 1.18 ± 0.23, P < 0.0001). Only patients starting HAART with CD4 counts >350 cells/mm(3) reached a complete normalization of CD4 counts. Even after long-term successful HAART, complete CD4 restoration may be attainable only in patients starting therapy with moderately high CD4 counts, prompting early initiation of antiretroviral therapy. Incomplete CD4 restoration may be associated with a defective restoration of central memory CD4 T cells, a cell subset with a pivotal role in T cell homeostasis.

Planning strategies for development of effective exercise and nutrition countermeasures for long-duration space flight

NASA Technical Reports Server (NTRS)

Convertino, Victor A.

2002-01-01

Exercise and nutrition represent primary countermeasures used during space flight to maintain or restore maximal aerobic capacity, musculoskeletal structure, and orthostatic function. However, no single exercise, dietary regimen, or combination of prescriptions has proven entirely effective in maintaining or restoring cardiovascular and musculoskeletal functions to preflight levels after prolonged space flight. As human space flight exposures increase in duration, identification, assessment, and development of various effective exercise- and nutrition-based protective procedures will become paramount. The application of adequate dietary intake in combination with effective exercise prescription will be based on identification of basic physiologic stimuli that maintain normal function in terrestrial gravity, and understanding how specific combinations of exercise characteristics (e.g., duration, frequency, intensity, and mode) can be combined with minimal nutritional requirements that mimic the stimuli normally produced by living in Earth's gravity environment. This can be accomplished only with greater emphasis of research on ground-based experiments targeted at understanding the interactions between caloric intake and expenditure during space flight. Future strategies for application of nutrition and exercise countermeasures for long-duration space missions must be directed to minimizing crew time and the impact on life-support resources.

Planning strategies for development of effective exercise and nutrition countermeasures for long-duration space flight.

PubMed

Convertino, Victor A

2002-10-01

Exercise and nutrition represent primary countermeasures used during space flight to maintain or restore maximal aerobic capacity, musculoskeletal structure, and orthostatic function. However, no single exercise, dietary regimen, or combination of prescriptions has proven entirely effective in maintaining or restoring cardiovascular and musculoskeletal functions to preflight levels after prolonged space flight. As human space flight exposures increase in duration, identification, assessment, and development of various effective exercise- and nutrition-based protective procedures will become paramount. The application of adequate dietary intake in combination with effective exercise prescription will be based on identification of basic physiologic stimuli that maintain normal function in terrestrial gravity, and understanding how specific combinations of exercise characteristics (e.g., duration, frequency, intensity, and mode) can be combined with minimal nutritional requirements that mimic the stimuli normally produced by living in Earth's gravity environment. This can be accomplished only with greater emphasis of research on ground-based experiments targeted at understanding the interactions between caloric intake and expenditure during space flight. Future strategies for application of nutrition and exercise countermeasures for long-duration space missions must be directed to minimizing crew time and the impact on life-support resources.

Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly.

PubMed

Cunard, Robyn

2015-04-20

Diabetic kidney disease is the leading worldwide cause of end stage kidney disease and a growing public health challenge. The diabetic kidney is exposed to many environmental stressors and each cell type has developed intricate signaling systems designed to restore optimal cellular function. The unfolded protein response (UPR) is a homeostatic pathway that regulates endoplasmic reticulum (ER) membrane structure and secretory function. Studies suggest that the UPR is activated in the diabetic kidney to restore normal ER function and viability. However, when the cell is continuously stressed in an environment that lies outside of its normal physiological range, then the UPR is known as the ER stress response. The UPR reduces protein synthesis, augments the ER folding capacity and downregulates mRNA expression of genes by multiple pathways. Aberrant activation of ER stress can also induce inflammation and cellular apoptosis, and modify signaling of protective processes such as autophagy and mTORC activation. The following review will discuss our current understanding of ER stress in the diabetic kidney and explore novel means of modulating ER stress and its interacting signaling cascades with the overall goal of identifying therapeutic strategies that will improve outcomes in diabetic nephropathy.

Retinoic acid reverses the airway hyperresponsiveness but not the parenchymal defect that is associated with vitamin A deficiency.

PubMed

McGowan, Stephen E; Holmes, Amey Jo; Smith, Jennifer

2004-02-01

Airway hyperresponsiveness (AHR) is influenced by structural components of the bronchial wall, including the smooth muscle and connective tissue elements and the neuromuscular function. AHR is also influenced by parenchymally derived tethering forces on the bronchial wall, which maintain airway caliber by producing outward radial traction. Our previous work has shown that vitamin A-deficient (VAD) rats exhibit cholinergic hyperresponsiveness and a decrease in the expression and function of the muscarinic-2 receptors (M2R). We hypothesized that if decreases in radial traction from airway or parenchymal structures contributed to the VAD-related increase in AHR, then the radial traction would normalize more slowly than VAD-related alterations in neurotransmitter signaling. Rats remained vitamin A sufficient (VAS) or were rendered VAD and then maintained on the VAD diet in the presence or absence of supplementation with all-trans retinoic acid (RA). VAD was associated with an approximately twofold increase in respiratory resistance and elastance compared with VAS rats. Exposure to RA for 12 days but not 4 days restored resistance and elastance to control (VAS) levels. In VAD rats, AHR was accompanied by decreases in bronchial M2R gene expression and function, which were restored after 12 days of RA supplementation. Subepithelial bronchial elastic fibers were decreased by approximately 50% in VAD rats and were significantly restored by RA. The increase in AHR that is associated with VAD is accompanied by decreases in M2R expression and function that can be restored by RA and a reduction in airway elastic fibers that can be partially restored by RA.

Glial-derived neurotrophic factor is essential for blood-nerve barrier functional recovery in an experimental murine model of traumatic peripheral neuropathy.

PubMed

Dong, Chaoling; Helton, E Scott; Zhou, Ping; Ouyang, Xuan; d'Anglemont de Tassigny, Xavier; Pascual, Alberto; López-Barneo, José; Ubogu, Eroboghene E

2018-06-18

There is emerging evidence that glial-derived neurotrophic factor (GDNF) is a potent inducer of restrictive barrier function in tight junction-forming microvascular endothelium and epithelium, including the human blood-nerve barrier (BNB) in vitro. We sought to determine the role of GDNF in restoring BNB function in vivo by evaluating sciatic nerve horseradish peroxidase (HRP) permeability in tamoxifen-inducible GDNF conditional knockout (CKO) adult mice following non-transecting crush injury via electron microscopy, with appropriate wildtype (WT) and heterozygous (HET) littermate controls. A total of 24 age-, genotype- and sex-matched mice >12 weeks of age were injected with 30 mg/kg HRP via tail vein injection 7 or 14 days following unilateral sciatic nerve crush, and both sciatic nerves were harvested 30 minutes later for morphometric assessment by light and electron microscopy. The number and percentage of HRP-permeable endoneurial microvessels were ascertained to determine the effect of GDNF in restoring barrier function in vivo. Following sciatic nerve crush, there was significant upregulation in GDNF protein expression in WT and HET mice that was abrogated in CKO mice. GDNF significantly restored sciatic nerve BNB HRP impermeability to near normal levels by day 7, with complete restoration seen by day 14 in WT and HET mice. A significant recovery lag was observed in CKO mice. This effect was independent on VE-Cadherin or claudin-5 expression on endoneurial microvessels. These results imply an important role of GDNF in restoring restrictive BNB function in vivo, suggesting a potential strategy to re-establish the restrictive endoneurial microenvironment following traumatic peripheral neuropathies.

Afforestation or intense pasturing improve the ecological and economic value of abandoned tropical farmlands.

PubMed

Knoke, Thomas; Bendix, Jörg; Pohle, Perdita; Hamer, Ute; Hildebrandt, Patrick; Roos, Kristin; Gerique, Andrés; Sandoval, María L; Breuer, Lutz; Tischer, Alexander; Silva, Brenner; Calvas, Baltazar; Aguirre, Nikolay; Castro, Luz M; Windhorst, David; Weber, Michael; Stimm, Bernd; Günter, Sven; Palomeque, Ximena; Mora, Julio; Mosandl, Reinhard; Beck, Erwin

2014-11-26

Increasing demands for livelihood resources in tropical rural areas have led to progressive clearing of biodiverse natural forests. Restoration of abandoned farmlands could counter this process. However, as aims and modes of restoration differ in their ecological and socio-economic value, the assessment of achievable ecosystem functions and benefits requires holistic investigation. Here we combine the results from multidisciplinary research for a unique assessment based on a normalization of 23 ecological, economic and social indicators for four restoration options in the tropical Andes of Ecuador. A comparison of the outcomes among afforestation with native alder or exotic pine, pasture restoration with either low-input or intense management and the abandoned status quo shows that both variants of afforestation and intense pasture use improve the ecological value, but low-input pasture does not. Economic indicators favour either afforestation or intense pasturing. Both Mestizo and indigenous Saraguro settlers are more inclined to opt for afforestation.

Effect of Endocrown Restorations with Different CAD/CAM Materials: 3D Finite Element and Weibull Analyses

PubMed Central

Ulusoy, Nuran

2017-01-01

The aim of this study was to evaluate the effects of two endocrown designs and computer aided design/manufacturing (CAD/CAM) materials on stress distribution and failure probability of restorations applied to severely damaged endodontically treated maxillary first premolar tooth (MFP). Two types of designs without and with 3 mm intraradicular extensions, endocrown (E) and modified endocrown (ME), were modeled on a 3D Finite element (FE) model of the MFP. Vitablocks Mark II (VMII), Vita Enamic (VE), and Lava Ultimate (LU) CAD/CAM materials were used for each type of design. von Mises and maximum principle values were evaluated and the Weibull function was incorporated with FE analysis to calculate the long term failure probability. Regarding the stresses that occurred in enamel, for each group of material, ME restoration design transmitted less stress than endocrown. During normal occlusal function, the overall failure probability was minimum for ME with VMII. ME restoration design with VE was the best restorative option for premolar teeth with extensive loss of coronal structure under high occlusal loads. Therefore, ME design could be a favorable treatment option for MFPs with missing palatal cusp. Among the CAD/CAM materials tested, VMII and VE were found to be more tooth-friendly than LU. PMID:29119108

Adrenomedullin and angiopoietin-1 additively restore erectile function in diabetic rats: comparison with the combination therapy of vascular endothelial growth factor and angiopoietin-1.

PubMed

Nishimatsu, Hiroaki; Suzuki, Etsu; Nomiya, Akira; Niimi, Aya; Suzuki, Motofumi; Fujimura, Tetsuya; Fukuhara, Hiroshi; Homma, Yukio

2013-07-01

Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats. The aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin-1 (Ang-1) was more effective to treat ED than treatment with AM alone or Ang-1 alone. We also compared the effect of the combination therapy with that of treatment with vascular endothelial growth factor-A (VEGF-A). Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expressing AM (AdAM), Ang-1 (AdAng-1), and VEGF-A (AdVEGF-A) were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology, and protein expression were analyzed 4 weeks after the injection of the adenoviruses. Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of α-smooth muscle actin (SMA), VE-cadherin and type I collagen was assessed by Western blot analysis. Infection with AdAM plus AdAng-1 more effectively restored erectile function than infection with AdAM alone or AdAng-1 alone. This combination therapy restored erectile function to a level similar to that observed in the age-matched Wistar rats. Expression of SMA and VE-cadherin increased more significantly in the AdAM plus AdAng-1-treated group than in the AdAM- or AdAng-1-treated group. Although AdVEGF-A infection restored erectile function significantly, it also caused enlargement of the trabeculae of the cavernous body, aberrant angiogenesis, and overproduction of type I collagen. These results suggested that combination therapy with AM and Ang-1 potently restored erectile function and normal morphology of the cavernous body compared with VEGF-A administration. This combination therapy will be useful to treat ED patients with a severely damaged cavernous body. © 2013 International Society for Sexual Medicine.

Appearance is a function of the face.

PubMed

Borah, Gregory L; Rankin, Marlene K

2010-03-01

Increasingly, third-party insurers deny coverage to patients with posttraumatic and congenital facial deformities because these are not seen as "functional." Recent facial transplants have demonstrated that severely deformed patients are willing to undergo potentially life-threatening surgery in search of a normal physiognomy. Scant quantitative research exists that objectively documents appearance as a primary "function" of the face. This study was designed to establish a population-based definition of the functions of the human face, rank importance of the face among various anatomical areas, and determine the risk value the average person places on a normal appearance. Voluntary adult subjects (n = 210) in three states aged 18 to 75 years were recruited using a quota sampling technique. Subjects completed study questionnaires of demography and bias using the Gamble Chance of Death Questionnaire and the Rosenberg Self-Esteem Scale. The face ranked as the most important anatomical area for functional reconstruction. Appearance was the fifth most important function of the face, after breathing, sight, speech, and eating. Normal facial appearance was rated as very important for one to be a functioning member of American society (p = 0.01) by 49 percent. One in seven subjects (13 percent) would accept a 30 to 45 percent risk of death to obtain a "normal" face. Normal appearance is a primary function of the face, based on a large, culturally diverse population sample across the lifespan. Normal appearance ranks above smell and expression as a function. Restoration of facial appearance is ranked the most important anatomical area for repair. Normal facial appearance is very important for one to be a functional member of American society.

Fructo-oligosaccharides and intestinal barrier function in a methionine-choline-deficient mouse model of nonalcoholic steatohepatitis.

PubMed

Matsumoto, Kotaro; Ichimura, Mayuko; Tsuneyama, Koichi; Moritoki, Yuki; Tsunashima, Hiromichi; Omagari, Katsuhisa; Hara, Masumi; Yasuda, Ichiro; Miyakawa, Hiroshi; Kikuchi, Kentaro

2017-01-01

Impairments in intestinal barrier function, epithelial mucins, and tight junction proteins have been reported to be associated with nonalcoholic steatohepatitis. Prebiotic fructo-oligosaccharides restore balance in the gastrointestinal microbiome. This study was conducted to determine the effects of dietary fructo-oligosaccharides on intestinal barrier function and steatohepatitis in methionine-choline-deficient mice. Three groups of 12-week-old male C57BL/6J mice were studied for 3 weeks; specifically, mice were fed a methionine-choline-deficient diet, a methionine-choline-deficient diet plus 5% fructo-oligosaccharides in water, or a normal control diet. Fecal bacteria, short-chain fatty acids, and immunoglobulin A (IgA) levels were investigated. Histological and immunohistochemical examinations were performed using mice livers for CD14 and Toll-like receptor-4 (TLR4) expression and intestinal tissue samples for IgA and zonula occludens-1 expression in epithelial tight junctions. The methionine-choline-deficient mice administered 5% fructo-oligosaccharides maintained a normal gastrointestinal microbiome, whereas methionine-choline-deficient mice without prebiotic supplementation displayed increases in Clostridium cluster XI and subcluster XIVa populations and a reduction in Lactobacillales spp. counts. Methionine-choline-deficient mice given 5% fructo-oligosaccharides exhibited significantly decreased hepatic steatosis (p = 0.003), decreased liver inflammation (p = 0.005), a decreased proportion of CD14-positive Kupffer cells (p = 0.01), decreased expression of TLR4 (p = 0.04), and increases in fecal short-chain fatty acid and IgA concentrations (p < 0.04) compared with the findings in methionine-choline-deficient mice that were not administered this prebiotic. This study illustrated that in the methionine-choline-deficient mouse model, dietary fructo-oligosaccharides can restore normal gastrointestinal microflora and normal intestinal epithelial barrier function, and decrease steatohepatitis. The findings support the role of prebiotics, such as fructo-oligosaccharides, in maintaining a normal gastrointestinal microbiome; they also support the need for further studies on preventing or treating nonalcoholic steatohepatitis using dietary fructo-oligosaccharides.

Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice.

PubMed

Ohlmann, Andreas; Scholz, Michael; Goldwich, Andreas; Chauhan, Bharesh K; Hudl, Kristiane; Ohlmann, Anne V; Zrenner, Eberhart; Berger, Wolfgang; Cvekl, Ales; Seeliger, Mathias W; Tamm, Ernst R

2005-02-16

Norrie disease is an X-linked retinal dysplasia that presents with congenital blindness, sensorineural deafness, and mental retardation. Norrin, the protein product of the Norrie disease gene (NDP), is a secreted protein of unknown biochemical function. Norrie disease (Ndp(y/-)) mutant mice that are deficient in norrin develop blindness, show a distinct failure in retinal angiogenesis, and completely lack the deep capillary layers of the retina. We show here that the transgenic expression of ectopic norrin under control of a lens-specific promoter restores the formation of a normal retinal vascular network in Ndp(y/-) mutant mice. The improvement in structure correlates with restoration of neuronal function in the retina. In addition, lenses of transgenic mice with ectopic expression of norrin show significantly more capillaries in the hyaloid vasculature that surrounds the lens during development. In vitro, lenses of transgenic mice in coculture with microvascular endothelial cells induce proliferation of the cells. Transgenic mice with ectopic expression of norrin show more bromodeoxyuridine-labeled retinal progenitor cells at embryonic day 14.5 and thicker retinas at postnatal life than wild-type littermates, indicating a putative direct neurotrophic effect of norrin. These data provide direct evidence that norrin induces growth of ocular capillaries and that pharmacologic modulation of norrin might be used for treatment of the vascular abnormalities associated with Norrie disease or other vascular disorders of the retina.

Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy.

PubMed

Shchors, Ksenya; Persson, Anders I; Rostker, Fanya; Tihan, Tarik; Lyubynska, Natalya; Li, Nan; Swigart, Lamorna Brown; Berger, Mitchel S; Hanahan, Douglas; Weiss, William A; Evan, Gerard I

2013-04-16

Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific mechanisms. To model human gliomagenesis, we used a GFAP-HRas(V12) mouse model crossed into the p53ER(TAM) background, such that either one or both copies of endogenous p53 is replaced by a conditional p53ER(TAM) allele. The p53ER(TAM) protein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop in GFAP-HRas(V12);p53(+/KI) mice abrogate the p53 pathway by mutating p19(ARF)/MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of their p53ER(TAM) allele. By contrast, gliomas arising in GFAP-HRas(V12);p53(KI/KI) mice develop in the absence of functional p53. Such tumors retain a functional p19(ARF)/MDM2-signaling pathway, and restoration of p53ER(TAM) allele triggers p53-tumor-suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14(ARF)/MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearing GFAP-HRas(V12);p53(KI/KI) animals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ER(TAM) activity mitigated the selective pressure to inactivate the p19(ARF)/MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumor-suppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance.

Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy

PubMed Central

Shchors, Ksenya; Persson, Anders I.; Rostker, Fanya; Tihan, Tarik; Lyubynska, Natalya; Li, Nan; Swigart, Lamorna Brown; Berger, Mitchel S.; Hanahan, Douglas; Weiss, William A.; Evan, Gerard I.

2013-01-01

Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific mechanisms. To model human gliomagenesis, we used a GFAP-HRasV12 mouse model crossed into the p53ERTAM background, such that either one or both copies of endogenous p53 is replaced by a conditional p53ERTAM allele. The p53ERTAM protein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop in GFAP-HRasV12;p53+/KI mice abrogate the p53 pathway by mutating p19ARF/MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of their p53ERTAM allele. By contrast, gliomas arising in GFAP-HRasV12;p53KI/KI mice develop in the absence of functional p53. Such tumors retain a functional p19ARF/MDM2-signaling pathway, and restoration of p53ERTAM allele triggers p53-tumor–suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14ARF/MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearing GFAP-HRasV12;p53KI/KI animals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ERTAM activity mitigated the selective pressure to inactivate the p19ARF/MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumor-suppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance. PMID:23542378

Experience-Dependent Color Constancy in Guppies (Poecilia reticulata)

PubMed Central

Intskirveli, I. E.; Roinishvili, M. O.; Kezeli, A. R.

2002-01-01

We investigated the ability to recognize the color of surfaces in fish (Poecilia reticulata), bred from birth in conditions of artificial light with constant spectral content. The capacity for color constancy significantly deteriorated when compared that to the control group. Further alteration of lighting conditions and transfer into natural daylight conditions restored the suppressed function to its normal level. We suggest that the color constancy function belongs in the visual system-response functions, the full development of which requires the accumulation of individual visual experience. PMID:12757371

Experience-dependent color constancy in guppies (Poecilia reticulata).

PubMed

Intskirveli, I E; Roinishvili, M O; Kezeli, A R

2002-01-01

We investigated the ability to recognize the color of surfaces in fish (Poecilia reticulata), bred from birth in conditions of artificial light with constant spectral content. The capacity for color constancy significantly deteriorated when compared that to the control group. Further alteration of lighting conditions and transfer into natural daylight conditions restored the suppressed function to its normal level. We suggest that the color constancy function belongs in the visual system-response functions, the full development of which requires the accumulation of individual visual experience.

Clustered Regularly Interspaced Short Palindromic Repeats: Challenges in Treating Retinal Disease.

PubMed

Chrenek, Micah A; Nickerson, John M; Boatright, Jeffrey H

2016-01-01

Ophthalmic researchers and clinicians arguably have led the way for safe, effective gene therapy, most notably with adeno-associated viral gene supplementation in the treatment for patients with Leber congenital amaurosis type 2 with mutations in the RPE65 gene. These successes notwithstanding, most other genetic retinal disease will be refractory to supplementation. The ideal gene therapy approach would correct gene mutations to restore normal function in the affected cells. Gene editing in which a mutant allele is inactivated or converted to sequence that restores normal function is hypothetically one such approach. Such editing involves site-specific digestion of mutant genomic DNA followed by repair. Previous experimental approaches were hampered by inaccurate and high rates of off-site lesioning and by overall low digestion rates. A new tool, clustered regularly interspaced short palindromic repeats coupled with the nuclease Cas9, may address both shortcomings. Some of the many challenges that must be addressed in moving clustered regularly interspaced short palindromic repeats coupled with the nuclease Cas9 therapies to the ophthalmic clinic are discussed here.

Cardiomyocyte-specific desmin rescue of desmin null cardiomyopathy excludes vascular involvement.

PubMed

Weisleder, Noah; Soumaka, Elisavet; Abbasi, Shahrzad; Taegtmeyer, Heinrich; Capetanaki, Yassemi

2004-01-01

Mice deficient in desmin, the muscle-specific member of the intermediate filament gene family, display defects in all muscle types and particularly in the myocardium. Desmin null hearts develop cardiomyocyte hypertrophy and dilated cardiomyopathy (DCM) characterized by extensive myocyte cell death, calcific fibrosis and multiple ultrastructural defects. Several lines of evidence suggest impaired vascular function in desmin null animals. To determine whether altered capillary function or an intrinsic cardiomyocyte defect is responsible for desmin null DCM, transgenic mice were generated to rescue desmin expression specifically to cardiomyocytes. Desmin rescue mice display a wild-type cardiac phenotype with no fibrosis or calcification in the myocardium and normalization of coronary flow. Cardiomyocyte ultrastructure is also restored to normal. Markers of hypertrophy upregulated in desmin null hearts return to wild-type levels in desmin rescue mice. Working hearts were perfused to assess coronary flow and cardiac power. Restoration of a wild-type cardiac phenotype in a desmin null background by expression of desmin specifically within cardiomyocyte indicates that defects in the desmin null heart are due to an intrinsic cardiomyocytes defect rather than compromised coronary circulation.

Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations.

PubMed

Perry, Matthew D; Ng, Chai Ann; Phan, Kevin; David, Erikka; Steer, Kieran; Hunter, Mark J; Mann, Stefan A; Imtiaz, Mohammad; Hill, Adam P; Ke, Ying; Vandenberg, Jamie I

2016-07-15

Most missense long QT syndrome type 2 (LQTS2) mutations result in Kv11.1 channels that show reduced levels of membrane expression. Pharmacological chaperones that rescue mutant channel expression could have therapeutic potential to reduce the risk of LQTS2-associated arrhythmias and sudden cardiac death, but only if the mutant Kv11.1 channels function normally (i.e. like WT channels) after membrane expression is restored. Fewer than half of mutant channels exhibit relatively normal function after rescue by low temperature. The remaining rescued missense mutant Kv11.1 channels have perturbed gating and/or ion selectivity characteristics. Co-expression of WT subunits with gating defective missense mutations ameliorates but does not eliminate the functional abnormalities observed for most mutant channels. For patients with mutations that affect gating in addition to expression, it may be necessary to use a combination therapy to restore both normal function and normal expression of the channel protein. In the heart, Kv11.1 channels pass the rapid delayed rectifier current (IKr ) which plays critical roles in repolarization of the cardiac action potential and in the suppression of arrhythmias caused by premature stimuli. Over 500 inherited mutations in Kv11.1 are known to cause long QT syndrome type 2 (LQTS2), a cardiac electrical disorder associated with an increased risk of life threatening arrhythmias. Most missense mutations in Kv11.1 reduce the amount of channel protein expressed at the membrane and, as a consequence, there has been considerable interest in developing pharmacological agents to rescue the expression of these channels. However, pharmacological chaperones will only have clinical utility if the mutant Kv11.1 channels function normally after membrane expression is restored. The aim of this study was to characterize the gating phenotype for a subset of LQTS2 mutations to assess what proportion of mutations may be suitable for rescue. As an initial screen we used reduced temperature to rescue expression defects of mutant channels expressed in Xenopus laevis oocytes. Over half (∼56%) of Kv11.1 mutants exhibited functional gating defects that either dramatically reduced the amount of current contributing to cardiac action potential repolarization and/or reduced the amount of protective current elicited in response to premature depolarizations. Our data demonstrate that if pharmacological rescue of protein expression defects is going to have clinical utility in the treatment of LQTS2 then it will be important to assess the gating phenotype of LQTS2 mutations before attempting rescue. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Central and peripheral effects of chronic food restriction and weight restoration in the rat.

PubMed

Kinzig, Kimberly P; Hargrave, Sara L; Tao, Erin E

2009-02-01

Previous studies have demonstrated that some endocrine consequences of long-term caloric restriction persist after weight restoration in human subjects. Here we evaluate effects of chronic food restriction in rats that were restricted to 70% of control kcal for 4 wk and subsequently weight restored. Measures were taken from rats at 80% (chronically restricted; CR), 90% (partially weight restored; PR), 100% (fully weight restored; FR), and after 4 wk at 100% body weight of controls (extended weight restored; ER). Plasma insulin and leptin were decreased, and ghrelin was increased in CR compared with controls. Leptin and ghrelin normalized with weight restoration at PR, FR, and ER; however, baseline insulin was not normalized until the ER state. Hypothalamic mRNA expression levels for proopiomelanocortin (POMC), agouti-related protein (AgRP), and neuropeptide Y (NPY) revealed significantly less POMC mRNA expression in CR and PR rats, and significantly less arcuate NPY mRNA in PR and FR. In the dorsomedial hypothalamus, CR, PR, and FR rats had significantly increased NPY expression that was not normalized until the ER state. In response to a test meal, insulin and ghrelin release patterns were altered through the FR stage, and ghrelin remained affected at ER. Collectively, these data demonstrate that mere weight restoration is not sufficient to normalize hypothalamic gene expression levels and endocrine responses to a meal, and that meal-related ghrelin responses persist despite weight restoration for up to 4 wk.

Taste Changes in Vitamin A Deficiency

PubMed Central

Bernard, Rudy A.; Halpern, Bruce P.

1968-01-01

Taste preferences were studied in two groups of rats depleted of vitamin A by dietary restriction. One group received sufficient vitamin A acid supplement to maintain normal growth. The other group was repleted with vitamin A alcohol after the classical deficiency symptoms had appeared; this group gradually lost normal preferences for NaCl and aversion to quinine solutions during depletion. Vitamin A alcohol repletion tended to restore taste preferences to normal. In contrast, the group receiving vitamin A acid showed normal taste preferences throughout the depletion period. When the vitamin A acid supplement was removed taste preferences became abnormal and returned to normal when vitamin A acid was restored. Peripheral gustatory neural activity of depleted rats without any form of vitamin A was less than normal both at rest and when the tongue was stimulated with NaCl solutions. Histological examination showed keratin infiltrating the pores of the taste buds. Accessory glandular tissues were atrophied and debris filled the trenches of the papillae. It is concluded that vitamin A acid can provide the vitamin A required for normal taste, as contrasted with its inability to maintain visual function. It is suggested that the effect of vitamin A is exerted at the receptor level, as a result of its role in the biosynthesis of mucopolysaccharides, which have been recently identified in the pore area of taste buds, as well as being present in the various secretions of the oral cavity. PMID:4299794

Successful haploidentical donor hematopoietic stem cell transplant and restoration of STAT3 function in an adolescent with autosomal dominant hyper-IgE syndrome.

PubMed

Patel, N C; Gallagher, J L; Torgerson, T R; Gilman, A L

2015-07-01

Autosomal dominant hyper-IgE syndrome (AD-HIES), caused by mutations in Signal Transducer and Activator of Transcription 3 (STAT3) is associated with defective STAT3 signaling and Th17 differentiation and recurrent bacterial and fungal infections. Most patients suffer significant morbidity and premature mortality. Hematopoietic stem cell transplantation (HSCT) has been reported in a small number of cases, with mixed outcomes. We report successful haploidentical donor HSCT in a patient with AD-HIES. Evaluation of lymphocyte subsets, STAT3 signaling, and Th17 cells was performed pre- and post-HSCT. A 14-year old female with AD-HIES developed recurrent methicillin-resistant Staphylococcus aureus (MRSA) abscesses. Immunologic analysis showed elevated IgE (4331 kU/L), absent Th17 cells, and markedly decreased STAT3 phosphorylation in cytokine stimulated peripheral blood mononuclear cells. She had breakthrough abscesses despite clindamycin and trimethoprim-sulfamethoxazole prophylaxis, and developed steroid refractory autoimmune hemolytic anemia. She underwent T-cell depleted haploidentical HSCT from her father following reduced intensity conditioning. She developed one MRSA hand abscess after transplant. Twenty-four months post transplant, she had complete donor chimerism (>95 % donor), normal absolute T cell numbers, and a normal percentage of Th17 cells. IgE was normal at 25 kU/L. She remains well 42 months after transplantation off all antibacterial prophylaxis. Haploidentical HSCT led to successful bone marrow engraftment, normalization of STAT3 signaling in hematopoietic cells, normalization of IgE, and restoration of immune function in this patient with AD-HIES.

Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus

PubMed Central

Sobrevia, Luis; Salsoso, Rocío; Fuenzalida, Bárbara; Barros, Eric; Toledo, Lilian; Silva, Luis; Pizarro, Carolina; Subiabre, Mario; Villalobos, Roberto; Araos, Joaquín; Toledo, Fernando; González, Marcelo; Gutiérrez, Jaime; Farías, Marcelo; Chiarello, Delia I.; Pardo, Fabián; Leiva, Andrea

2016-01-01

Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies. PMID:27065887

Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke.

PubMed

Khodaparast, N; Hays, S A; Sloan, A M; Hulsey, D R; Ruiz, A; Pantoja, M; Rennaker, R L; Kilgard, M P

2013-12-01

Upper limb impairment is a common debilitating consequence of ischemic stroke. Physical rehabilitation after stroke enhances neuroplasticity and improves limb function, but does not typically restore normal movement. We have recently developed a novel method that uses vagus nerve stimulation (VNS) paired with forelimb movements to drive specific, long-lasting map plasticity in rat primary motor cortex. Here we report that VNS paired with rehabilitative training can enhance recovery of forelimb force generation following infarction of primary motor cortex in rats. Quantitative measures of forelimb function returned to pre-lesion levels when VNS was delivered during rehab training. Intensive rehab training without VNS failed to restore function back to pre-lesion levels. Animals that received VNS during rehab improved twice as much as rats that received the same rehabilitation without VNS. VNS delivered during physical rehabilitation represents a novel method that may provide long-lasting benefits towards stroke recovery. © 2013.

Repair of traumatized mammalian hair cells via sea anemone repair proteins.

PubMed

Tang, Pei-Ciao; Smith, Karen Müller; Watson, Glen M

2016-08-01

Mammalian hair cells possess only a limited ability to repair damage after trauma. In contrast, sea anemones show a marked capability to repair damaged hair bundles by means of secreted repair proteins (RPs). Previously, it was found that recovery of traumatized hair cells in blind cavefish was enhanced by anemone-derived RPs; therefore, the ability of anemone RPs to assist recovery of damaged hair cells in mammals was tested here. After a 1 h incubation in RP-enriched culture media, uptake of FM1-43 by experimentally traumatized murine cochlear hair cells was restored to levels comparable to those exhibited by healthy controls. In addition, RP-treated explants had significantly more normally structured hair bundles than time-matched traumatized control explants. Collectively, these results indicate that anemone-derived RPs assist in restoring normal function and structure of experimentally traumatized hair cells of the mouse cochlea. © 2016. Published by The Company of Biologists Ltd.

Consequences of inhibiting amyloid precursor protein processing enzymes on synaptic function and plasticity.

PubMed

Wang, Hui; Megill, Andrea; He, Kaiwen; Kirkwood, Alfredo; Lee, Hey-Kyoung

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregated β-amyloid (Aβ) peptides. It is now recognized that soluble Aβ oligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. Aβ is produced by a sequential cleavage of amyloid precursor protein (APP) by the activity of β- and γ-secretases, which have been identified as major candidate therapeutic targets of AD. This paper focuses on how Aβ alters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for Aβ generation. Abnormalities in synaptic function resulting from the absence or inhibition of the Aβ-producing enzymes suggest that Aβ itself may have normal physiological functions which are disrupted by abnormal accumulation of Aβ during AD pathology. This interpretation suggests that AD therapeutics targeting the β- and γ-secretases should be developed to restore normal levels of Aβ or combined with measures to circumvent the associated synaptic dysfunction(s) in order to have minimal impact on normal synaptic function.

Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration.

PubMed

Yang, Sujeong; Hilton, Sam; Alves, João Nuno; Saksida, Lisa M; Bussey, Timothy; Matthews, Russell T; Kitagawa, Hiroshi; Spillantini, Maria Grazia; Kwok, Jessica C F; Fawcett, James W

2017-11-01

Chondroitin sulfate proteoglycans (CSPGs) are the main active component of perineuronal nets (PNNs). Digestion of the glycosaminoglycan chains of CSPGs with chondroitinase ABC or transgenic attenuation of PNNs leads to prolongation of object recognition memory and activation of various forms of plasticity in the adult central nervous system. The inhibitory properties of the CSPGs depend on the pattern of sulfation of their glycosaminoglycans, with chondroitin 4-sulfate (C4S) being the most inhibitory form. In this study, we tested a number of candidates for functional blocking of C4S, leading to selection of an antibody, Cat316, which specifically recognizes C4S and blocks its inhibitory effects on axon growth. It also partly blocks binding of semaphorin 3A to PNNs and attenuates PNN formation. We asked whether injection of Cat316 into the perirhinal cortex would have the same effects on memory as chondroitinase ABC treatment. We found that masking C4S with the Cat316 antibody extended long-term object recognition memory in normal wild-type mice to 24 hours, similarly to chondroitinase or transgenic PNN attenuation. We then tested Cat316 for restoration of memory in a neurodegeneration model. Mice expressing tau with the P301S mutation showed profound loss of object recognition memory at 4 months of age. Injection of Cat316 into the perirhinal cortex normalized object recognition at 3 hours in P301S mice. These data indicate that Cat316 binding to C4S in the extracellular matrix can restore plasticity and memory in the same way as chondroitinase ABC digestion. Our results suggest that antibodies to C4S could be a useful therapeutic to restore memory function in neurodegenerative disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Revisiting the physiological effects of exercise training on autonomic regulation and chemoreflex control in heart failure: does ejection fraction matter?

PubMed

Andrade, David C; Arce-Alvarez, Alexis; Toledo, Camilo; Díaz, Hugo S; Lucero, Claudia; Quintanilla, Rodrigo A; Schultz, Harold D; Marcus, Noah J; Amann, Markus; Del Rio, Rodrigo

2018-03-01

Heart failure (HF) is a global public health problem that, independent of its etiology [reduced (HFrEF) or preserved ejection fraction (HFpEF)], is characterized by functional impairments of cardiac function, chemoreflex hypersensitivity, baroreflex sensitivity (BRS) impairment, and abnormal autonomic regulation, all of which contribute to increased morbidity and mortality. Exercise training (ExT) has been identified as a nonpharmacological therapy capable of restoring normal autonomic function and improving survival in patients with HFrEF. Improvements in autonomic function after ExT are correlated with restoration of normal peripheral chemoreflex sensitivity and BRS in HFrEF. To date, few studies have addressed the effects of ExT on chemoreflex control, BRS, and cardiac autonomic control in HFpEF; however, there are some studies that have suggested that ExT has a beneficial effect on cardiac autonomic control. The beneficial effects of ExT on cardiac function and autonomic control in HF may have important implications for functional capacity in addition to their obvious importance to survival. Recent studies have suggested that the peripheral chemoreflex may also play an important role in attenuating exercise intolerance in HFrEF patients. The role of the central/peripheral chemoreflex, if any, in mediating exercise intolerance in HFpEF has not been investigated. The present review focuses on recent studies that address primary pathophysiological mechanisms of HF (HFrEF and HFpEF) and the potential avenues by which ExT exerts its beneficial effects.

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine

PubMed Central

Wongjaikam, Suwakon; Kumfu, Sirinart; Khamseekaew, Juthamas; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

2017-01-01

Intracellular calcium [Ca2+]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca2+]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca2+]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca2+]i homeostasis, only DFP + NAC restored cardiac [Ca2+]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca2+]i homeostasis, leading to restored myocardial contractility in iron-overloaded rats. PMID:28287621

Pulp-dentin biology in restorative dentistry. Part 1: normal structure and physiology.

PubMed

Mjör, I A; Sveen, O B; Heyeraas, K J

2001-06-01

Considerable knowledge has accumulated over the years on the structure and function of the dental pulp and dentin. Some of this knowledge has important clinical implications. This review, which is the first of seven articles, will be limited to those parts of the normal structure and physiology of the pulp and dentin that have been shown to result in, or are likely lead to, tissue reactions associated with the clinical treatment of these tissues. Although certain normal structures will be highlighted in some detail, a basic knowledge of pulpal and dentinal development and structure is a prerequisite for an understanding of this text.

The usage of image trigonometry in bone measurements.

PubMed

Dymond, Ian W; Ashforth, James A; Dymond, Graeme F; Spirakis, Thanos; Learmonth, Ian D

2013-01-01

The entire musculo-skeletal system responds dynamically to stresses and strains applied to it. Restoring normal biomechanics contributes to the normal function that ensures that physiological stresses and strains are preserved. Appropriate preoperative planning is mandatory to restore normal biomechanics at reconstructive surgery. Effective preoperative planning depends on the ability to reproducibly make accurate measurements of lengths and angles from plain radiographs. Measurement has become an integral part of orthopaedics to define morphological abnormality, to plan for reconstruction and for comparative research. The most prevalent method of measurement is usually based on lines drawn on radiographs with no accurate reference to the actual geometry of the structures. This two-dimensional projection of an asymmetrical three-dimensional structure leads to inaccuracy and consequently to a compromise in the overall precision of many procedures. In addition it is also difficult to monitor the progression of disease as the exact relationship of the bones and joints to each other, and to prosthetics, cannot be accurately recorded. This paper presents a method of digitally measuring relevant bone parameters in a geometric manner in order to achieve accurate, repeatable measurements.

Neurologic manifestations of major electrolyte abnormalities.

PubMed

Diringer, M

2017-01-01

The brain operates in an extraordinarily intricate environment which demands precise regulation of electrolytes. Tight control over their concentrations and gradients across cellular compartments is essential and when these relationships are disturbed neurologic manifestations may develop. Perturbations of sodium are the electrolyte disturbances that most often lead to neurologic manifestations. Alterations in extracellular fluid sodium concentrations produce water shifts that lead to brain swelling or shrinkage. If marked or rapid they can result in profound changes in brain function which are proportional to the degree of cerebral edema or contraction. Adaptive mechanisms quickly respond to changes in cell size by either increasing or decreasing intracellular osmoles in order to restore size to normal. Unless cerebral edema has been severe or prolonged, correction of sodium disturbances usually restores function to normal. If the rate of correction is too rapid or overcorrection occurs, however, new neurologic manifestations may appear as a result of osmotic demyelination syndrome. Disturbances of magnesium, phosphate and calcium all may contribute to alterations in sensorium. Hypomagnesemia and hypocalcemia can lead to weakness, muscle spasms, and tetany; the weakness from hypophosphatemia and hypomagnesemia can impair respiratory function. Seizures can be seen in cases with very low concentrations of sodium, magnesium, calcium, and phosphate. © 2017 Elsevier B.V. All rights reserved.

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

PubMed Central

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J.; Isenberg, David A.; Magee, Anthony I.; Butters, Terry; Jury, Elizabeth C.

2014-01-01

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft–associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE. PMID:24463447

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients.

PubMed

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J; Isenberg, David A; Magee, Anthony I; Butters, Terry; Jury, Elizabeth C

2014-02-01

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

Diagnosis and management of urinary incontinence and functional fecal incontinence (encopresis) in children.

PubMed

Nijman, Rien J M

2008-09-01

The ability to maintain normal continence for urine and stools is not achievable in all children by a certain age. Gaining control of urinary and fecal continence is a complex process, and not all steps and factors involved are fully understood. While normal development of anatomy and physiology are prerequisites to becoming fully continent, anatomic abnormalities, such as bladder exstrophy, epispadias, ectopic ureters, and neurogenic disturbances that can usually be recognized at birth and cause incontinence, will require specialist treatment, not only to restore continence but also to preserve renal function. Most forms of urinary incontinence are not caused by an anatomic or physiologic abnormality and, hence, are more difficult to diagnose and their management requires a sound knowledge of bladder and bowel function.

Anorexia Nervosa and its Associated Endocrinopathy in Young People

PubMed Central

Misra, Madhusmita; Klibanski, Anne

2016-01-01

Anorexia nervosa (AN) is a condition of severe undernutrition associated with adaptive changes in many endocrine axes. These changes include hypogonadotropic hypogonadism, acquired growth hormone resistance with low insulin like growth factor-1 (IGF-1) levels, hypercortisolemia, altered secretion of adipokines and appetite regulating hormones, and low bone mineral density (BMD). Bone health is impaired subsequent to low BMI, decreased lean mass, and the endocrine changes described above. In addition to low areal BMD, AN is characterized by a decrease in volumetric BMD, changes in bone geometry, and reductions in strength estimates, leading to an increased risk for fracture. Weight restoration is essential for restoration of normal endocrine function; however, hypercortisolemia, high PYY levels, and ghrelin dynamics may not completely normalize. In some patients, hypogonadotropic hypogonadism persists despite weight restoration. Weight gain and menstrual recovery are critical for improving bone health in AN, however, residual deficits may persist. Physiologic estrogen replacement using transdermal, but not oral, estrogen increases bone accrual in adolescents with AN, while bisphosphonates improve BMD in adults. Recombinant human IGF-1 and teriparatide have been used in a few studies as bone anabolic therapies. More data are necessary to determine the optimal therapeutic strategies for low BMD in AN. PMID:26863308

[The features in preventing recurrent lower urinary tract infection].

PubMed

Gadzhieva, Z K; Kazilov, Yu B

2016-08-01

This review outlines characteristics of medications most commonly used for preventing recurrent lower urinary tract infection (UTI). It shows that the treatment and prophylaxis of UTI should be comprehensive and include the restoration of the normal urogenital tract anatomy and use in addition to antibacterial and anti-inflammatory drugs, agents, normalizing the function of the lower urinary tract, as well as drugs for local and systemic immunoprophylaxis, protection of the urothelium from recurrent infection, local hormone replacement therapy in menopause, and dietary supplements to acidify the urine.

Association between neuroendocrinological parameters and learning and memory functions in adolescent anorexia nervosa before and after weight recovery.

PubMed

Buehren, Katharina; Konrad, Kerstin; Schaefer, Kerstin; Kratzsch, Juergen; Kahraman-Lanzerath, Berak; Lente, Christina; Herpertz-Dahlmann, Beate

2011-06-01

A growing body of evidence indicates that hormones play an important role in learning and memory functions as well as in mood modulation. During the acute stage of anorexia nervosa (AN), weight loss has a significant effect on serum levels of estrogen, thyroid hormones, and cortisol. Furthermore deficits in learning and memory functions are evident in patients with eating disorders during emaciation. Hormonal and neuropsychological alterations at least partly remit during weight restoration. We investigated the association between learning and memory functions as well as mood and neuroendocrinological parameters before and after weight gain in adolescent AN. Twenty-eight female subjects with AN, diagnosed according to DSM-IV, were examined before and after weight recovery. Both investigations took place while the patients were receiving hospital treatment, and the results were compared to a control group consisting of 18 age- and IQ-matched normal-weight female adolescents also tested twice within 4 months. Verbal memory and learning were assessed by a German paper-pencil-test (LGT). We performed correlation calculations between neuropsychological functions and depressive symptoms and estrogen, cortisol and free triiodothyronine (fT₃) in the plasma at both time points. Compared to normal controls adolescents with AN performed worse in one subtest of the LGT which requires the verbal reproduction of figural material across both time points. Verbal learning was positively correlated with estrogen levels after weight recovery. Depressive symptoms of AN patients significantly decreased during weight rehabilitation and correlated negatively with fT₃ at T₁. We did not find a relationship between cortisol levels and neuropsychological functions. We observed subtle memory impairments and depressive symptoms in subjects with adolescent AN associated with starvation-induced estrogen and triiodothyronine deficits, respectively. Normalization of body weight and resuming of menses is needed to restore learning and memory functions as well as to alleviate depressive symptoms.

Afforestation or intense pasturing improve the ecological and economic value of abandoned tropical farmlands

PubMed Central

Knoke, Thomas; Bendix, Jörg; Pohle, Perdita; Hamer, Ute; Hildebrandt, Patrick; Roos, Kristin; Gerique, Andrés; Sandoval, María L.; Breuer, Lutz; Tischer, Alexander; Silva, Brenner; Calvas, Baltazar; Aguirre, Nikolay; Castro, Luz M.; Windhorst, David; Weber, Michael; Stimm, Bernd; Günter, Sven; Palomeque, Ximena; Mora, Julio; Mosandl, Reinhard; Beck, Erwin

2014-01-01

Increasing demands for livelihood resources in tropical rural areas have led to progressive clearing of biodiverse natural forests. Restoration of abandoned farmlands could counter this process. However, as aims and modes of restoration differ in their ecological and socio-economic value, the assessment of achievable ecosystem functions and benefits requires holistic investigation. Here we combine the results from multidisciplinary research for a unique assessment based on a normalization of 23 ecological, economic and social indicators for four restoration options in the tropical Andes of Ecuador. A comparison of the outcomes among afforestation with native alder or exotic pine, pasture restoration with either low-input or intense management and the abandoned status quo shows that both variants of afforestation and intense pasture use improve the ecological value, but low-input pasture does not. Economic indicators favour either afforestation or intense pasturing. Both Mestizo and indigenous Saraguro settlers are more inclined to opt for afforestation. PMID:25425182

The role of muscle spindles in the development of the monosynaptic stretch reflex

PubMed Central

Wang, Zhi; Li, LingYing

2012-01-01

Muscle sensory axons induce the development of specialized intrafusal muscle fibers in muscle spindles during development, but the role that the intrafusal fibers may play in the development of the central projections of these Ia sensory axons is unclear. In the present study, we assessed the influence of intrafusal fibers in muscle spindles on the formation of monosynaptic connections between Ia (muscle spindle) sensory axons and motoneurons (MNs) using two transgenic strains of mice. Deletion of the ErbB2 receptor from developing myotubes disrupts the formation of intrafusal muscle fibers and causes a nearly complete absence of functional synaptic connections between Ia axons and MNs. Monosynaptic connectivity can be fully restored by postnatal administration of neurotrophin-3 (NT-3), and the synaptic connections in NT-3-treated mice are as specific as in wild-type mice. Deletion of the Egr3 transcription factor also impairs the development of intrafusal muscle fibers and disrupts synaptic connectivity between Ia axons and MNs. Postnatal injections of NT-3 restore the normal strengths and specificity of Ia–motoneuronal connections in these mice as well. Severe deficits in intrafusal fiber development, therefore, do not disrupt the establishment of normal, selective patterns of connections between Ia axons and MNs, although these connections require the presence of NT-3, normally supplied by intrafusal fibers, to be functional. PMID:22490553

Complications in implant dentistry

PubMed Central

Hanif, Ayesha; Qureshi, Saima; Sheikh, Zeeshan; Rashid, Haroon

2017-01-01

After tooth loss, an individual may seek tooth replacement so that his/her function and esthetics could be restored. Clinical prosthodontics, during the past decade, has significantly improved and developed according to the advancements in the science and patient's demands and needs. Conventional options in prosthodontics for substituting a missing single tooth include the removable partial denture, partial and full coverage bridgework, and resin-bonded bridgework. Dental implants have gained increasing popularity over the years as they are capable of restoring the function to near normal in both partial and completely edentulous arches. With substantial evidence available, fixed implant-supported prosthesis are fully acknowledged as a reliable treatment option for the replacement of single or multiple missing teeth nowadays. While dental implants are increasingly becoming the choice of replacement for missing teeth, the impediments associated with them are progressively emerging too. PMID:28435381

Carbon nanotubes functionalized with sodium hyaluronate restore bone repair in diabetic rat sockets.

PubMed

Sá, M A; Andrade, V B; Mendes, R M; Caliari, M V; Ladeira, L O; Silva, E E; Silva, G A B; Corrêa-Júnior, J D; Ferreira, A J

2013-07-01

We evaluated the effects of sodium hyaluronate (HY) and carbon nanotubes functionalized with HY (HY-CNT) on bone repair in the tooth sockets of diabetic rats. Diabetes was induced by streptozotocin (50 mg kg(-1) i.v.), and the sockets were divided into normal control, diabetic control, diabetic treated with HY (1%), and diabetic treated with HY-CNT (100 μg ml(-1)) groups. The sockets were analyzed according to the percentage of bone formation and the number of cell nuclei. The percentage of bone trabeculae was lower in diabetic control animals (11.16 ± 5.10% vs 41.92 ± 6.34% in normal animals) after 14 days. Treating diabetic animals with HY or HY-CNT significantly increased the percentage of neoformed trabeculae (HY: 29.43 ± 3.29%; HY-CNT: 36.90 ± 3.07%). Moreover, the sockets of diabetic animals had an increased number of cell nuclei and HY or HY-CNT reduced this parameter. Our results indicate that HY and HY-CNT restore bone repair in the tooth sockets of diabetic rats, suggesting that these biomaterials are potential adjuvant therapies for the management of diabetes. © 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Achilles Tendon Rupture: Avoiding Tendon Lengthening during Surgical Repair and Rehabilitation

PubMed Central

Maquirriain, Javier

2011-01-01

Achilles tendon rupture is a serious injury for which the best treatment is still controversial. Its primary goal should be to restore normal length and tension, thus obtaining an optimal function. Tendon elongation correlates significantly with clinical outcome; lengthening is an important cause of morbidity and may produce permanent functional impairment. In this article, we review all factors that may influence the repair, including the type of surgical technique, suture material, and rehabilitation program, among many others. PMID:21966048

Robust low-dose dynamic cerebral perfusion CT image restoration via coupled dictionary learning scheme.

PubMed

Tian, Xiumei; Zeng, Dong; Zhang, Shanli; Huang, Jing; Zhang, Hua; He, Ji; Lu, Lijun; Xi, Weiwen; Ma, Jianhua; Bian, Zhaoying

2016-11-22

Dynamic cerebral perfusion x-ray computed tomography (PCT) imaging has been advocated to quantitatively and qualitatively assess hemodynamic parameters in the diagnosis of acute stroke or chronic cerebrovascular diseases. However, the associated radiation dose is a significant concern to patients due to its dynamic scan protocol. To address this issue, in this paper we propose an image restoration method by utilizing coupled dictionary learning (CDL) scheme to yield clinically acceptable PCT images with low-dose data acquisition. Specifically, in the present CDL scheme, the 2D background information from the average of the baseline time frames of low-dose unenhanced CT images and the 3D enhancement information from normal-dose sequential cerebral PCT images are exploited to train the dictionary atoms respectively. After getting the two trained dictionaries, we couple them to represent the desired PCT images as spatio-temporal prior in objective function construction. Finally, the low-dose dynamic cerebral PCT images are restored by using a general DL image processing. To get a robust solution, the objective function is solved by using a modified dictionary learning based image restoration algorithm. The experimental results on clinical data show that the present method can yield more accurate kinetic enhanced details and diagnostic hemodynamic parameter maps than the state-of-the-art methods.

Optimizing Functional Outcomes in Mandibular Condyle Reconstruction With the Free Fibula Flap Using Computer-Aided Design and Manufacturing Technology.

PubMed

Lee, Z-Hye; Avraham, Tomer; Monaco, Casian; Patel, Ashish A; Hirsch, David L; Levine, Jamie P

2018-05-01

Mandibular defects involving the condyle represent a complex reconstructive challenge for restoring proper function of the temporomandibular joint (TMJ) because it requires precise bone graft alignment for full restoration of joint function. The use of computer-aided design and manufacturing (CAD/CAM) technology can aid in accurate reconstruction of mandibular condyle defects with a vascularized free fibula flap without the need for additional adjuncts. The purpose of this study was to analyze clinical and functional outcomes after reconstruction of mandibular condyle defects using only a free fibula graft with the help of virtual surgery techniques. A retrospective review was performed to identify all patients who underwent mandibular reconstruction with only a free fibula flap without any TMJ adjuncts after a total condylectomy. Three-dimensional modeling software was used to plan and execute reconstruction for all patients. From 2009 through 2014, 14 patients underwent reconstruction of mandibular defects involving the condyle with the aid of virtual surgery technology. The average age was 38.7 years (range, 11 to 77 yr). The average follow-up period was 2.6 years (range, 0.8 to 4.2 yr). Flap survival was 100% (N = 14). All patients reported improved facial symmetry, adequate jaw opening, and normal dental occlusion. In addition, they achieved good functional outcomes, including normal intelligible speech and the tolerance of a regular diet with solid foods. Maximal interincisal opening range for all patients was 25 to 38 mm with no lateral deviation or subjective joint pain. No patient had progressive joint hypomobility or condylar migration. One patient had ankylosis, which required release. TMJ reconstruction poses considerable challenges in bone graft alignment for full restoration of joint function. The use of CAD/CAM technology can aid in accurate reconstruction of mandibular condyle defects with a vascularized free fibula flap through precise planning and intraoperative manipulation with optimal functional outcomes. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Chronic suppression of testicular function by constant infusion of gonadotropin-releasing hormone agonist and testosterone supplementation in the bonnet monkey (Macaca radiata).

PubMed

Ravindranath, N; Ramesh, V; Krishnamurthy, H N; Rao, A J; Moudgal, R N

1992-03-01

To study the efficacy of long-term buserelin acetate infusion to desensitize pituitary and block testicular function in adult male monkeys (Macaca radiata). Proven fertile male monkeys exhibiting normal testicular function. Each of the control (n = 5) and experimental monkeys (n = 10) received a fresh miniosmotic pump every 21 days, whereas pumps in controls delivered vehicle of experimentals released 50 micrograms buserelin acetate every 24 hours. On day 170 (renewed every 60 days) a silastic capsule containing crystalline testosterone (T) was implanted in the experimental monkeys. At the end of 3 years, treatment was stopped, and recovery of testicular function and fertility monitored. (1) Treatment resulted in marked reduction of nocturnal but not basal serum T; (2) the pituitary remained desensitized to buserelin acetate throughout the 3-year period; (3) animals were largely azoospermic with occasional oligospermia exhibited by two monkeys; and (4) withdrawal of treatment restored testicular function, with 70% of animals regaining fertility. Long-term infertility (but restorable) can be induced in male monkeys by constant infusion of buserelin acetate and T.

Examination of ceramic restoration adhesive coverage in cusp-replacement premolar using acoustic emission under fatigue testing.

PubMed

Chang, Yen-Hsiang; Yu, Jin-Jie; Lin, Chun-Li

2014-12-13

This study investigates CAD/CAM ceramic cusp-replacing restoration resistance with and without buccal cusp replacement under static and dynamic cyclic loads, monitored using the acoustic emission (AE) technique. The cavity was designed in a typical MODP (mesial-occlusal-distal-palatal) restoration failure shape when the palatal cusp has been lost. Two ceramic restorations [without coverage (WOC) and with (WC) buccal cuspal coverage with 2.0 mm reduction in cuspal height] were prepared to perform the fracture and fatigue tests with normal (200 N) and high (600 N) occlusal forces. The load versus AE signals in the fracture and fatigue tests were recorded to evaluate the restored tooth failure resistance. The results showed that non-significant differences in load value in the fracture test and the accumulated number of AE signals under normal occlusal force (200 N) in the fatigue test were found between with and without buccal cuspal coverage restorations. The first AE activity occurring for the WOC restoration was lower than that for the WC restoration in the fracture test. The number of AE signals increased with the cyclic load number. The accumulated number of AE signals for the WOC restoration was 187, higher than that (85) for the WC restoration under 600 N in the fatigue test. The AE technique and fatigue tests employed in this study were used as an assessment tool to evaluate the resistances in large CAD/CAM ceramic restorations. Non-significant differences in the tested fracture loads and accumulated number of AE signals under normal occlusal force (200 N) between different restorations indicated that aggressive treatment (with coverage preparation) in palatal cusp-replacing ceramic premolars require more attention for preserving and protecting the remaining tooth.

Biomechanical Assessment of Restored Mandibular Molar by Endocrown in Comparison to a Glass Fiber Post-Retained Conventional Crown: 3D Finite Element Analysis.

PubMed

Helal, Mohammed Abu; Wang, Zhigang

2017-10-25

To compare equivalent and contact stresses in a mandibular molar restored by all-ceramic crowns through two methods: ceramic endocrowns and ceramic crowns supported by fiber-reinforced composite (FRC) posts and core, by using 3D finite element analysis during normal masticatory load. Three 3D models of a mandibular first molar were made and labeled as such: intact molar with no restoration (A); ceramic endocrown-restored molar (B); ceramic crown supported by FRC posts and core restored molar (C). By using 3D FE analysis with contact components, normal masticatory load was simulated. The mvM stresses in all models were calculated. Maximal mvM stresses in the ceramic of restorations, dentin, and luting cement were contrasted among models and to values of materials' strength. Contact shear and tensile stresses in the restoration/tooth interface around restorations were also calculated. The highest mvM stress levels in the enamel and dentin for the tooth restored by ceramic endocrown were lower in the crown ceramic than in tooth restored with FRC posts and all-ceramic crowns; however, in the resin adhesive cement interface it was lower for ceramic crown supported by FRC posts than the in ceramic endocrown restoration. The maximum contact shear and tensile stress values along the restoration/tooth interface of ceramic endocrowns were lower than those with ceramic crowns supported by FRC posts. Ceramic endocrown restorations presented a lower mvM stress level in dentin than the conventional ceramic crowns supported by FRC posts and core. Ceramic endocrown restorations in molars are less susceptible to damage than those with conventional ceramic crowns retained by FRC posts. Ceramic endocrowns properly cemented in molars must not be fractured or loosen during normal masticatory load. Therefore, ceramic endocrowns are advised as practicable, minimally invasive, and esthetic restorations for root canal treated mandibular molars. © 2017 by the American College of Prosthodontists.

Giant mitochondria do not fuse and exchange their contents with normal mitochondria

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

Navratil, Marian; Terman, Alexei; Arriaga, Edgar A.

2008-01-01

Giant mitochondria accumulate within aged or diseased postmitotic cells as a consequence of insufficient autophagy, which is normally responsible for mitochondrial degradation. We report that giant mitochondria accumulating in cultured rat myoblasts due to inhibition of autophagy have low inner membrane potential and do not fuse with each other or with normal mitochondria. In addition to the low inner mitochondrial membrane potential in giant mitochondria, the quantity of the OPA1 mitochondrial fusion protein in these mitochondria was low, but the abundance of mitofusin-2 (Mfn2) remained unchanged. The combination of these factors may explain the lack of mitochondrial fusion in giantmore » mitochondria and imply that the dysfunctional giant mitochondria cannot restore their function by fusing and exchanging their contents with fully functional mitochondria. These findings have important implications for understanding the mechanisms of accumulation of age-related mitochondrial damage in postmitotic cells.« less

Improvement of Insulin Secretion and Pancreatic β-cell Function in Streptozotocin-induced Diabetic Rats Treated with Aloe vera Extract

PubMed Central

Noor, Ayesha; Gunasekaran, S.; Vijayalakshmi, M. A.

2017-01-01

Background: Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia. Plant extracts and their products are being used as an alternative system of medicine for the treatment of diabetes. Aloe vera has been traditionally used to treat several diseases and it exhibits antioxidant, anti-inflammatory, and wound-healing effects. Streptozotocin (STZ)-induced Wistar diabetic rats were used in this study to understand the potential protective effect of A. vera extract on the pancreatic islets. Objective: The aim of the present study was to evaluate the A. vera extract on improvement of insulin secretion and pancreatic β-cell function by morphometric analysis of pancreatic islets in STZ-induced diabetic Wistar rats. Materials and Methods: After acclimatization, male Wistar rats, maintained as per the Committee for the Purpose of Control and Supervision of Experiments on Animals guidelines, were randomly divided into four groups of six rats each. Fasting plasma glucose and insulin levels were assessed. The effect of A. vera extract in STZ-induced diabetic rats on the pancreatic islets by morphometric analysis was evaluated. Results: Oral administration of A. vera extract (300 mg/kg) daily to diabetic rats for 3 weeks showed restoration of blood glucose levels to normal levels with a concomitant increase in insulin levels upon feeding with A. vera extract in STZ-induced diabetic rats. Morphometric analysis of pancreatic sections revealed quantitative and qualitative gain in terms of number, diameter, volume, and area of the pancreatic islets of diabetic rats treated with A. vera extract when compared to the untreated diabetic rats. Conclusion: A. vera extract exerts antidiabetic effects by improving insulin secretion and pancreatic β-cell function by restoring pancreatic islet mass in STZ-induced diabetic Wistar rats. SUMMARY Fasting plasma glucose (FPG) and insulin levels were restored to normal levels in diabetic rats treated with Aloe vera extractIslets of pancreas were qualitatively and quantitatively restored to normalcy leading to restoration of FPG and insulin levels of diabetic rats treated with Aloe vera extractMorphometric analysis of pancreatic sections revealed quantitative and qualitative gain in terms of number, diameter, volume, and area of the pancreatic islets of diabetic rats treated with Aloe vera extract when compared to the untreated diabetic rats. Abbreviations Used: A. vera, FPG: Fasting plasma glucose, STZ: Streptozotocin, BW: Body weight PMID:29333050

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

46 CFR 112.30-10 - Restoration of normal source potential.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Section 112.30-10 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) ELECTRICAL ENGINEERING EMERGENCY LIGHTING AND POWER SYSTEMS Emergency Systems Having an Automatically Connected Storage Battery as the Sole Emergency Power Source § 112.30-10 Restoration of normal source potential. When the potential...

Restoring normal eating behaviour in adolescents with anorexia nervosa: A video analysis of nursing interventions.

PubMed

Beukers, Laura; Berends, Tamara; de Man-van Ginkel, Janneke M; van Elburg, Annemarie A; van Meijel, Berno

2015-12-01

An important part of inpatient treatment for adolescents with anorexia nervosa is to restore normal eating behaviour. Health-care professionals play a significant role in this process, but little is known about their interventions during patients' meals. The purpose of the present study was to describe nursing interventions aimed at restoring normal eating behaviour in patients with anorexia nervosa. The main research question was: 'Which interventions aimed at restoring normal eating behaviour do health-care professionals in a specialist eating disorder centre use during meal times for adolescents diagnosed with anorexia nervosa? The present study was a qualitative, descriptive study that used video recordings made during mealtimes. Thematic data analysis was applied. Four categories of interventions emerged from the data: (i) monitoring and instructing; (ii) encouraging and motivating; (iii) supporting and understanding; and (iv) educating. The data revealed a directive attitude aimed at promoting behavioural change, but always in combination with empathy and understanding. In the first stage of clinical treatment, health-care professionals focus primarily on changing patients' eating behaviour. However, they also address the psychosocial needs that become visible in patients as they struggle to restore normal eating behaviour. The findings of the present study can be used to assist health-care professionals, and improve multidisciplinary guidelines and health-care professionals' training programmes. © 2015 Australian College of Mental Health Nurses Inc.

Management of Amelogenesis Imperfecta: A 15-Year Case History of Two Siblings.

PubMed

Dursun, E; Savard, E; Vargas, C; Loison-Robert, L; Cherifi, H; Bdeoui, F; Landru, M-M

Amelogenesis imperfecta (AI) is a heterogenous genetic disorder that interferes with normal enamel formation in the absence of systemic disorders. The patients' main concerns are caries susceptibility, poor esthetics, and generalized sensitivity. There is a broad clinical spectrum, from discolorations to consequent enamel alterations. This case report describes the 15-year case study and the full-mouth rehabilitation of two siblings affected by a hypocalcified AI. Clinical Considerations: In these two patients, conservative care with stainless steel crowns and direct composite restorations was undertaken to restore function and esthetics and to reduce sensitivities in primary and mixed dentitions. The difficulties in monitoring resulted in severe infectious complications (dental abscess with cutaneous fistula), important dental defects, and loss of spaces with subsequent malocclusion. In the young adult dentition, they were treated by extractions, root canal therapies, and new restorations: stainless steel crowns for permanent molars, direct composite restorations (with strip crowns) for incisors and maxillary canines (to improve the crown morphology as well as to mask the discolorations and the malpositions), and adjusted composite crown molds using a thermoforming procedure for premolars and the mandibular canines. The main difficulties were rapid tooth surface loss, bonding to atypical enamel, developing dentition, long-term follow-up. Restoring function and esthetics in AI-affected patients is a challenge from primary to adult dentition. Early corrections are essential to avoid dental damage and for psychological benefits. This clinical report highlights the adhesive rehabilitation for anterior and premolar areas and the difficulty of patient follow-up.

Two non-allelic nuclear genes restore fertility in a gametophytic pattern and enhance abiotic stress tolerance in the hybrid rice plant.

PubMed

Huang, Wenchao; Hu, Jun; Yu, Changchun; Huang, Qi; Wan, Lei; Wang, Lili; Qin, Xiaojian; Ji, Yanxiao; Zhu, Renshan; Li, Shaoqing; Zhu, Yingguo

2012-03-01

In indica rice, the HongLian (HL)-type combination of cytoplasmic male sterility (CMS) and fertility restoration (Rf) is widely used for the production of commercial hybrid seeds in China, Laos, Vietnam and other Southeast Asian countries. Generally, any member of the gametophytic fertility restoration system, 50% of the pollen in hybrid F(1) plants displays recovered sterility. In this study, however, a HL-type hybrid variety named HongLian You6 had approximately 75% normal (viable) pollen rather than the expected 50%. To resolve this discrepancy, several fertility segregation populations, including F(2) and BC(1)F(1) derived from the HL-CMS line Yuetai A crossed with the restorer line 9311, were constructed and subjected to genetic analysis. A gametophytic restoration model was discovered to involve two non-allelic nuclear restorer genes, Rf5 and Rf6. The Rf5 had been previously identified using a positional clone strategy. The Rf6 gene represents a new restorer gene locus, which was mapped to the short arm of chromosome 8. The hybrid F(1) plants containing one restorer gene, either Rf5 or Rf6, displayed 50% normal pollen grains with I(2)-KI solution; however, those with both Rf5 and Rf6 displayed 75% normal pollens. We also established that the hybrid F(1) plants including both non-allelic restorer genes exhibited an increased stable seed setting when subjected to stress versus the F(1) plants with only one restorer gene. Finally, we discuss the breeding scheme for the plant gametophytic CMS/Rf system.

Interdisciplinary Trauma Management in an Elderly Patient, A Case Report

PubMed Central

Felt, George T; Soolari, Ahmad

2014-01-01

The current report reviews a case of mixed dental trauma consequent to a fall by an older patient. The patient’s teeth were forced out of alignment by the trauma and suffered pulpal necrosis. Treatment involved not only healing the acute injuries, but also attending to some subtle delayed problems that became apparent during treatment. Treatments involving endodontics, periodontics, orthodontics, and restorative dentistry were used to address all of the patient’s concerns. This insured that the traumatic occlusion was corrected, appropriate esthetics was restored and normal speech and function was regained. All signs of trauma were recognized, every treatment step was documented, and appropriate follow-up was provided throughout the recovery period. PMID:25419251

Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization

PubMed Central

Loges, Sonja; Schmidt, Thomas; Jonckx, Bart; Tian, Ya-Min; Lanahan, Anthony A.; Pollard, Patrick; de Almodovar, Carmen Ruiz; De Smet, Frederik; Vinckier, Stefan; Aragonés, Julián; Debackere, Koen; Luttun, Aernout; Wyns, Sabine; Jordan, Benedicte; Pisacane, Alberto; Gallez, Bernard; Lampugnani, Maria Grazia; Dejana, Elisabetta; Simons, Michael; Ratcliffe, Peter; Maxwell, Patrick; Carmeliet, Peter

2014-01-01

SUMMARY A key function of blood vessels, to supply oxygen, is impaired in tumors because of abnormalities in their endothelial lining. PHD proteins serve as oxygen sensors and may regulate oxygen delivery. We therefore studied the role of endothelial PHD2 in vessel shaping by implanting tumors in PHD2+/− mice. Haplodeficiency of PHD2 did not affect tumor vessel density or lumen size, but normalized the endothelial lining and vessel maturation. This resulted in improved tumor perfusion and oxygenation and inhibited tumor cell invasion, intravasation, and metastasis. Haplodeficiency of PHD2 redirected the specification of endothelial tip cells to a more quiescent cell type, lacking filopodia and arrayed in a phalanx formation. This transition relied on HIF-driven upregulation of (soluble) VEGFR-1 and VE-cadherin. Thus, decreased activity of an oxygen sensor in hypoxic conditions prompts endothelial cells to readjust their shape and phenotype to restore oxygen supply. Inhibition of PHD2 may offer alternative therapeutic opportunities for anticancer therapy. PMID:19217150

14 CFR 171.271 - Installation requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... generated. Adequate power capacity must be provided for the operation of test and working equipment of the... restoration of power, the batteries must be restored to full charge within 24 hours. When primary power is... battery must permit continuation of normal operation for at least two hours under the normal operating...

Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors.

PubMed

Fraites, Thomas J; Schleissing, Mary R; Shanely, R Andrew; Walter, Glenn A; Cloutier, Denise A; Zolotukhin, Irene; Pauly, Daniel F; Raben, Nina; Plotz, Paul H; Powers, Scott K; Kessler, Paul D; Byrne, Barry J

2002-05-01

Pompe disease is a lysosomal storage disease caused by the absence of acid alpha-1,4 glucosidase (GAA). The pathophysiology of Pompe disease includes generalized myopathy of both cardiac and skeletal muscle. We sought to use recombinant adeno-associated virus (rAAV) vectors to deliver functional GAA genes in vitro and in vivo. Myotubes and fibroblasts from Pompe patients were transduced in vitro with rAAV2-GAA. At 14 days postinfection, GAA activities were at least fourfold higher than in their respective untransduced controls, with a 10-fold increase observed in GAA-deficient myotubes. BALB/c and Gaa(-/-) mice were also treated with rAAV vectors. Persistent expression of vector-derived human GAA was observed in BALB/c mice up to 6 months after treatment. In Gaa(-/-) mice, intramuscular and intramyocardial delivery of rAAV2-Gaa (carrying the mouse Gaa cDNA) resulted in near-normal enzyme activities. Skeletal muscle contractility was partially restored in the soleus muscles of treated Gaa(-/-) mice, indicating the potential for vector-mediated restoration of both enzymatic activity and muscle function. Furthermore, intramuscular treatment with a recombinant AAV serotype 1 vector (rAAV1-Gaa) led to nearly eight times normal enzymatic activity in Gaa(-/-) mice, with concomitant glycogen clearance as assessed in vitro and by proton magnetic resonance spectroscopy.

Dilysine motifs in exon 2b of SMN protein mediate binding to the COPI vesicle protein α-COP and neurite outgrowth in a cell culture model of spinal muscular atrophy.

PubMed

Custer, Sara K; Todd, Adrian G; Singh, Natalia N; Androphy, Elliot J

2013-10-15

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder that stems from low levels of survival of motor neuron (SMN) protein. The processes that cause motor neurons and muscle cells to become dysfunctional are incompletely understood. We are interested in neuromuscular homeostasis and the stresses put upon that system by loss of SMN. We recently reported that α-COP, a member of the coatomer complex of coat protein I (COPI) vesicles, is an SMN-binding partner, implicating this protein complex in normal SMN function. To investigate the functional significance of the interaction between α-COP and SMN, we constructed an inducible NSC-34 cell culture system to model the consequences of SMN depletion and find that depletion of SMN protein results in shortened neurites. Heterologous expression of human SMN, and interestingly over-expression of α-COP, restores normal neurite length and morphology. Mutagenesis of the canonical COPI dilysine motifs in exon 2b results in failure to bind to α-COP and abrogates the ability of human SMN to restore neurite outgrowth in SMN-depleted motor neuron-like NSC-34 cells. We conclude that the interaction between SMN and α-COP serves an important function in the growth and maintenance of motor neuron processes and may play a significant role in the pathogenesis of SMA.

Estimation of the failure risk of a maxillary premolar with different crack depths with endodontic treatment by computer-aided design/computer-aided manufacturing ceramic restorations.

PubMed

Lin, Chun-Li; Chang, Yen-Hsiang; Hsieh, Shih-Kai; Chang, Wen-Jen

2013-03-01

This study evaluated the risk of failure for an endodontically treated premolar with different crack depths, which was shearing toward the pulp chamber and was restored by using 3 different computer-aided design/computer-aided manufacturing ceramic restoration configurations. Three 3-dimensional finite element models designed with computer-aided design/computer-aided manufacturing ceramic onlay, endocrown, and conventional crown restorations were constructed to perform simulations. The Weibull function was incorporated with finite element analysis to calculate the long-term failure probability relative to different load conditions. The results indicated that the stress values on the enamel, dentin, and luting cement for endocrown restorations exhibited the lowest values relative to the other 2 restoration methods. Weibull analysis revealed that the overall failure probabilities in a shallow cracked premolar were 27%, 2%, and 1% for the onlay, endocrown, and conventional crown restorations, respectively, in the normal occlusal condition. The corresponding values were 70%, 10%, and 2% for the depth cracked premolar. This numeric investigation suggests that the endocrown provides sufficient fracture resistance only in a shallow cracked premolar with endodontic treatment. The conventional crown treatment can immobilize the premolar for different cracked depths with lower failure risk. Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy

PubMed Central

Watkins, Crystal C.; Sawa, Akira; Jaffrey, Samie; Blackshaw, Seth; Barrow, Roxanne K.; Snyder, Solomon H.; Ferris, Christopher D.

2000-01-01

Gastrointestinal dysfunction is common in diabetic patients. In genetic (nonobese diabetic) and toxin-elicited (streptozotocin) models of diabetes in mice, we demonstrate defects in gastric emptying and nonadrenergic, noncholinergic relaxation of pyloric muscle, which resemble defects in mice harboring a deletion of the neuronal nitric oxide synthase gene (nNOS). The diabetic mice manifest pronounced reduction in pyloric nNOS protein and mRNA. The decline of nNOS in diabetic mice does not result from loss of myenteric neurons. nNOS expression and pyloric function are restored to normal levels by insulin treatment. Thus diabetic gastropathy in mice reflects an insulin-sensitive reversible loss of nNOS. In diabetic animals, delayed gastric emptying can be reversed with a phosphodiesterase inhibitor, sildenafil. These findings have implications for novel therapeutic approaches and may clarify the etiology of diabetic gastropathy. PMID:10930440

Epigenetics in prostate cancer.

PubMed

Albany, Costantine; Alva, Ajjai S; Aparicio, Ana M; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M

2011-01-01

Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a "normal" epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability

PubMed Central

Dell'Orco, James M.; Wasserman, Aaron H.; Chopra, Ravi; Ingram, Melissa A. C.; Hu, Yuan-Shih; Singh, Vikrant; Wulff, Heike; Opal, Puneet; Orr, Harry T.

2015-01-01

Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. SIGNIFICANCE STATEMENT In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated compensatory role for neuronal shrinkage. Purkinje neuron firing in these mice is initially normal, but is followed by abnormal membrane depolarization resulting from a reduction in potassium channels. Subsequently, these electrophysiological effects are counteracted by cell atrophy, which by restoring normal potassium channel membrane density, re-establishes pacemaker firing. Reversing the initial membrane depolarization improved motor function and Purkinje neuron morphology in the SCA1 mice. These results suggest that Purkinje neuron remodeling in ataxia is an active compensatory response that serves to normalize intrinsic membrane excitability. PMID:26269637

Cu isotopic signature in blood serum of liver transplant patients: a follow-up study

NASA Astrophysics Data System (ADS)

Lauwens, Sara; Costas-Rodríguez, Marta; van Vlierberghe, Hans; Vanhaecke, Frank

2016-07-01

End-stage liver disease (ESLD) is life-threatening and liver transplantation (LTx) is the definitive treatment with good outcomes. Given the essential role of hepatocytes in Cu homeostasis, the potential of the serum Cu isotopic composition for monitoring a patient’s condition post-LTx was evaluated. For this purpose, high-precision Cu isotopic analysis of blood serum of ESLD patients pre- and post-LTx was accomplished via multi-collector ICP-mass spectrometry (MC-ICP-MS). The Cu isotopic composition of the ESLD patients was fractionated in favour of the lighter isotope (by about -0.50‰). Post-LTx, a generalized normalization of the Cu isotopic composition was observed for the patients with normal liver function, while it remained light when this condition was not reached. A strong decrease in the δ65Cu value a longer term post-LTx seems to indicate the recurrence of liver failure or cancer. The observed trend in favour of the heavier Cu isotopic composition post-LTx seems to be related with the restored biosynthetic capacity of the liver, the restored hepatic metabolism and/or the restored biliary secretion pathways. Thus, Cu isotopic analysis could be a valuable tool for the follow-up of liver transplant patients and for establishing the potential recurrence of liver failure.

Short time effects of radiotherapy on lymphatic vessels and restorative lymphatic pathways: experimental approaches ina mouse model.

PubMed

Pastouret, F; Lievens, P; Leduc, O; Bourgeois, P; Tournel, K; Lamote, J; Zirak, C; Leduc, A

2014-06-01

Radiotherapy (RT) is an important component in the therapeutic approach to oncologic conditions. This study presents the investigative results on the impact of RT on lymphatic vessels and on the regenerative response of the lymphatic system in a mouse model. We first irradiated 3 groups of ten mice using brachytherapy in a single treatment of 20 Gy. We then performed morphological examination of the irradiated lymphatic vessels using an in vivo microscopic transillumination technique at 2, 4, and 6 weeks. Next we evaluated lymphatic flow using lymphoscintigraphy and in vivo microscopy at 6 to 11 weeks in: 10 additional mice following irradiation as above (IR), in 10 mice following incision of a lymphatic vessel (I), and in a non-treated control group of 10 mice (N). Intact lymphatic vessels were observed in all mice at 2, 4, and 8 weeks following the single dose of radiotherapy in the first group of mice and normal lymphatic flow was fully restored in the irradiated (IR) and incised (I) mice indicating that the reparative substitution lymphatic pathways are functioning normally. We found that following irradiation with one dose of 20 Gy, lymphatic vessels were not visibly damaged and also that lymphatic flow was consistently restored and substitutive lymphatic pathways formed.

Cu isotopic signature in blood serum of liver transplant patients: a follow-up study

PubMed Central

Lauwens, Sara; Costas-Rodríguez, Marta; Van Vlierberghe, Hans; Vanhaecke, Frank

2016-01-01

End-stage liver disease (ESLD) is life-threatening and liver transplantation (LTx) is the definitive treatment with good outcomes. Given the essential role of hepatocytes in Cu homeostasis, the potential of the serum Cu isotopic composition for monitoring a patient’s condition post-LTx was evaluated. For this purpose, high-precision Cu isotopic analysis of blood serum of ESLD patients pre- and post-LTx was accomplished via multi-collector ICP-mass spectrometry (MC-ICP-MS). The Cu isotopic composition of the ESLD patients was fractionated in favour of the lighter isotope (by about −0.50‰). Post-LTx, a generalized normalization of the Cu isotopic composition was observed for the patients with normal liver function, while it remained light when this condition was not reached. A strong decrease in the δ65Cu value a longer term post-LTx seems to indicate the recurrence of liver failure or cancer. The observed trend in favour of the heavier Cu isotopic composition post-LTx seems to be related with the restored biosynthetic capacity of the liver, the restored hepatic metabolism and/or the restored biliary secretion pathways. Thus, Cu isotopic analysis could be a valuable tool for the follow-up of liver transplant patients and for establishing the potential recurrence of liver failure. PMID:27468898

Cu isotopic signature in blood serum of liver transplant patients: a follow-up study.

PubMed

Lauwens, Sara; Costas-Rodríguez, Marta; Van Vlierberghe, Hans; Vanhaecke, Frank

2016-07-29

End-stage liver disease (ESLD) is life-threatening and liver transplantation (LTx) is the definitive treatment with good outcomes. Given the essential role of hepatocytes in Cu homeostasis, the potential of the serum Cu isotopic composition for monitoring a patient's condition post-LTx was evaluated. For this purpose, high-precision Cu isotopic analysis of blood serum of ESLD patients pre- and post-LTx was accomplished via multi-collector ICP-mass spectrometry (MC-ICP-MS). The Cu isotopic composition of the ESLD patients was fractionated in favour of the lighter isotope (by about -0.50‰). Post-LTx, a generalized normalization of the Cu isotopic composition was observed for the patients with normal liver function, while it remained light when this condition was not reached. A strong decrease in the δ(65)Cu value a longer term post-LTx seems to indicate the recurrence of liver failure or cancer. The observed trend in favour of the heavier Cu isotopic composition post-LTx seems to be related with the restored biosynthetic capacity of the liver, the restored hepatic metabolism and/or the restored biliary secretion pathways. Thus, Cu isotopic analysis could be a valuable tool for the follow-up of liver transplant patients and for establishing the potential recurrence of liver failure.

Apoptosis-Inducing-Factor-Dependent Mitochondrial Function Is Required for T Cell but Not B Cell Function.

PubMed

Milasta, Sandra; Dillon, Christopher P; Sturm, Oliver E; Verbist, Katherine C; Brewer, Taylor L; Quarato, Giovanni; Brown, Scott A; Frase, Sharon; Janke, Laura J; Perry, S Scott; Thomas, Paul G; Green, Douglas R

2016-01-19

The role of apoptosis inducing factor (AIF) in promoting cell death versus survival remains controversial. We report that the loss of AIF in fibroblasts led to mitochondrial electron transport chain defects and loss of proliferation that could be restored by ectopic expression of the yeast NADH dehydrogenase Ndi1. Aif-deficiency in T cells led to decreased peripheral T cell numbers and defective homeostatic proliferation, but thymic T cell development was unaffected. In contrast, Aif-deficient B cells developed and functioned normally. The difference in the dependency of T cells versus B cells on AIF for function and survival correlated with their metabolic requirements. Ectopic Ndi1 expression rescued homeostatic proliferation of Aif-deficient T cells. Despite its reported roles in cell death, fibroblasts, thymocytes and B cells lacking AIF underwent normal death. These studies suggest that the primary role of AIF relates to complex I function, with differential effects on T and B cells. Copyright © 2016 Elsevier Inc. All rights reserved.

Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice

PubMed Central

Wong, Wen Mai; Durakoglugil, Murat S.; Wasser, Catherine R.; Jiang, Shan; Xian, Xunde

2016-01-01

Alzheimer's disease (AD) is the most common form of dementia in individuals over the age of 65 years. The most prevalent genetic risk factor for AD is the ε4 allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are being considered. One unresolved question in ApoE biology is whether ApoE is necessary for healthy brain function. ApoE knock-out (KO) mice have synaptic loss and cognitive dysfunction; however, these findings are complicated by the fact that ApoE knock-out mice have highly elevated plasma lipid levels, which may independently affect brain function. To bypass the effect of ApoE loss on plasma lipids, we generated a novel mouse model that expresses ApoE normally in peripheral tissues, but has severely reduced ApoE in the brain, allowing us to study brain ApoE loss in the context of a normal plasma lipid profile. We found that these brain ApoE knock-out (bEKO) mice had synaptic loss and dysfunction similar to that of ApoE KO mice; however, the bEKO mice did not have the learning and memory impairment observed in ApoE KO mice. Moreover, we found that the memory deficit in the ApoE KO mice was specific to female mice and was fully rescued in female bEKO mice. Furthermore, while the AMPA/NMDA ratio was reduced in ApoE KO mice, it was unchanged in bEKO mice compared with controls. These findings suggest that plasma lipid levels can influence cognition and synaptic function independent of ApoE expression in the brain. SIGNIFICANCE STATEMENT One proposed treatment strategy for Alzheimer's disease (AD) is the reduction of ApoE, whose ε4 isoform is the most common genetic risk factor for the disease. A major concern of this strategy is that an animal model of ApoE deficiency, the ApoE knock-out (KO) mouse, has reduced synapses and cognitive impairment; however, these mice also develop dyslipidemia and severe atherosclerosis. Here, we have shown that genetic restoration of plasma ApoE to wild-type levels normalizes plasma lipids in ApoE KO mice. While this does not rescue synaptic loss, it does completely restore learning and memory in the mice, suggesting that both CNS and plasma ApoE are independent parameters that affect brain health. PMID:27683909

Galactose-depleted xyloglucan is dysfunctional and leads to dwarfism in Arabidopsis.

PubMed

Kong, Yingzhen; Peña, Maria J; Renna, Luciana; Avci, Utku; Pattathil, Sivakumar; Tuomivaara, Sami T; Li, Xuemei; Reiter, Wolf-Dieter; Brandizzi, Federica; Hahn, Michael G; Darvill, Alan G; York, William S; O'Neill, Malcolm A

2015-04-01

Xyloglucan is a polysaccharide that has important roles in the formation and function of the walls that surround growing land plant cells. Many of these plants synthesize xyloglucan that contains galactose in two different side chains (L and F), which exist in distinct molecular environments. However, little is known about the contribution of these side chains to xyloglucan function. Here, we show that Arabidopsis (Arabidopsis thaliana) mutants devoid of the F side chain galactosyltransferase MURUS3 (MUR3) form xyloglucan that lacks F side chains and contains much less galactosylated xylose than its wild-type counterpart. The galactose-depleted xyloglucan is dysfunctional, as it leads to mutants that are dwarfed with curled rosette leaves, short petioles, and short inflorescence stems. Moreover, cell wall matrix polysaccharides, including xyloglucan and pectin, are not properly secreted and instead accumulate within intracellular aggregates. Near-normal growth is restored by generating mur3 mutants that produce no detectable amounts of xyloglucan. Thus, cellular processes are affected more by the presence of the dysfunctional xyloglucan than by eliminating xyloglucan altogether. To identify structural features responsible for xyloglucan dysfunction, xyloglucan structure was modified in situ by generating mur3 mutants that lack specific xyloglucan xylosyltransferases (XXTs) or that overexpress the XYLOGLUCAN L-SIDE CHAIN GALACTOSYLTRANSFERASE2 (XLT2) gene. Normal growth was restored in the mur3-3 mutant overexpressing XLT2 and in mur3-3 xxt double mutants when the dysfunctional xyloglucan was modified by doubling the amounts of galactosylated side chains. Our study assigns a role for galactosylation in normal xyloglucan function and demonstrates that altering xyloglucan side chain structure disturbs diverse cellular and physiological processes. © 2015 American Society of Plant Biologists. All Rights Reserved.

Mechano-electrical feedback explains T-wave morphology and optimizes cardiac pump function: insight from a multi-scale model.

PubMed

Hermeling, Evelien; Delhaas, Tammo; Prinzen, Frits W; Kuijpers, Nico H L

2012-01-01

In the ECG, T- and R-wave are concordant during normal sinus rhythm (SR), but discordant after a period of ventricular pacing (VP). Experiments showed that the latter phenomenon, called T-wave memory, is mediated by a mechanical stimulus. By means of a mathematical model, we investigated the hypothesis that slow acting mechano-electrical feedback (MEF) explains T-wave memory. In our model, electromechanical behavior of the left ventricle (LV) was simulated using a series of mechanically and electrically coupled segments. Each segment comprised ionic membrane currents, calcium handling, and excitation-contraction coupling. MEF was incorporated by locally adjusting conductivity of L-type calcium current (g(CaL)) to local external work. In our set-up, g(CaL) could vary up to 25%, 50%, 100% or unlimited amount around its default value. Four consecutive simulations were performed: normal SR (with MEF), acute VP, sustained VP (with MEF), and acutely restored SR. MEF led to T-wave concordance in normal SR and to discordant T-waves acutely after restoring SR. Simulated ECGs with a maximum of 25-50% adaptation closely resembled those during T-wave memory experiments in vivo and also provided the best compromise between optimal systolic and diastolic function. In conclusion, these simulation results indicate that slow acting MEF in the LV can explain a) the relatively small differences in systolic shortening and mechanical work during SR, b) the small dispersion in repolarization time, c) the concordant T-wave during SR, and d) T-wave memory. The physiological distribution in electrophysiological properties, reflected by the concordant T-wave, may serve to optimize cardiac pump function. Copyright © 2012 Elsevier Ltd. All rights reserved.

Zebrafish msxB, msxC and msxE function together to refine the neural-nonneural border and regulate cranial placodes and neural crest development.

PubMed

Phillips, Bryan T; Kwon, Hye-Joo; Melton, Colt; Houghtaling, Paul; Fritz, Andreas; Riley, Bruce B

2006-06-15

The zebrafish muscle segment homeobox genes msxB, msxC and msxE are expressed in partially overlapping domains in the neural crest and preplacodal ectoderm. We examined the roles of these msx genes in early development. Disrupting individual msx genes causes modest variable defects, whereas disrupting all three produces a reproducible severe phenotype, suggesting functional redundancy. Neural crest differentiation is blocked at an early stage. Preplacodal development begins normally, but placodes arising from the msx expression domain later show elevated apoptosis and are reduced in size. Cell proliferation is normal in these tissues. Unexpectedly, Msx-deficient embryos become ventralized by late gastrulation whereas misexpression of msxB dorsalizes the embryo. These effects appear to involve Distal-less (Dlx) protein activity, as loss of dlx3b and dlx4b suppresses ventralization in Msx-depleted embryos. At the same time, Msx-depletion restores normal preplacodal gene expression to dlx3b-dlx4b mutants. These data suggest that mutual antagonism between Msx and Dlx proteins achieves a balance of function required for normal preplacodal differentiation and placement of the neural-nonneural border.

Fray, a Drosophila serine/threonine kinase homologous to mammalian PASK, is required for axonal ensheathment

NASA Technical Reports Server (NTRS)

Leiserson, W. M.; Harkins, E. W.; Keshishian, H.

2000-01-01

Fray is a serine/threonine kinase expressed by the peripheral glia of Drosophila, whose function is required for normal axonal ensheathment. Null fray mutants die early in larval development and have nerves with severe swelling and axonal defasciculation. The phenotype is associated with a failure of the ensheathing glia to correctly wrap peripheral axons. When the fray cDNA is expressed in the ensheathing glia of fray mutants, normal nerve morphology is restored. Fray belongs to a novel family of Ser/Thr kinases, the PF kinases, whose closest relatives are the PAK kinases. Rescue of the Drosophila mutant phenotype with PASK, the rat homolog of Fray, demonstrates a functional homology among these proteins and suggests that the Fray signaling pathway is widely conserved.

Developmental Programming: Insulin Sensitizer Prevents the GnRH-Stimulated LH Hypersecretion in a Sheep Model of PCOS

PubMed Central

Cardoso, Rodolfo C.; Burns, Ashleigh; Moeller, Jacob; Skinner, Donal C.

2016-01-01

Prenatal testosterone (T) treatment recapitulates the reproductive and metabolic phenotypes of polycystic ovary syndrome in female sheep. At the neuroendocrine level, prenatal T treatment results in disrupted steroid feedback on gonadotropin release, increased pituitary sensitivity to GnRH, and subsequent LH hypersecretion. Because prenatal T-treated sheep manifest functional hyperandrogenism and hyperinsulinemia, gonadal steroids and/or insulin may play a role in programming and/or maintaining these neuroendocrine defects. Here, we investigated the effects of prenatal and postnatal treatments with an androgen antagonist (flutamide [F]) or an insulin sensitizer (rosiglitazone [R]) on GnRH-stimulated LH secretion in prenatal T-treated sheep. As expected, prenatal T treatment increased the pituitary responsiveness to GnRH leading to LH hypersecretion. Neither prenatal interventions nor postnatal F treatment normalized the GnRH-stimulated LH secretion. Conversely, postnatal R treatment completely normalized the GnRH-stimulated LH secretion. At the tissue level, gestational T increased pituitary LHβ, androgen receptor, and insulin receptor-β, whereas it reduced estrogen receptor (ER)α protein levels. Although postnatal F normalized pituitary androgen receptor and insulin receptor-β, it failed to prevent an increase in LHβ expression. Contrarily, postnatal R treatment restored ERα and partially normalized LHβ pituitary levels. Immunohistochemical findings confirmed changes in pituitary ERα expression to be specific to gonadotropes. In conclusion, these findings indicate that increased pituitary responsiveness to GnRH in prenatal T-treated sheep is likely a function of reduced peripheral insulin sensitivity. Moreover, results suggest that restoration of ERα levels in the pituitary may be one mechanism by which R prevents GnRH-stimulated LH hypersecretion in this sheep model of polycystic ovary syndrome-like phenotype. PMID:27792406

Developmental Programming: Insulin Sensitizer Prevents the GnRH-Stimulated LH Hypersecretion in a Sheep Model of PCOS.

PubMed

Cardoso, Rodolfo C; Burns, Ashleigh; Moeller, Jacob; Skinner, Donal C; Padmanabhan, Vasantha

2016-12-01

Prenatal testosterone (T) treatment recapitulates the reproductive and metabolic phenotypes of polycystic ovary syndrome in female sheep. At the neuroendocrine level, prenatal T treatment results in disrupted steroid feedback on gonadotropin release, increased pituitary sensitivity to GnRH, and subsequent LH hypersecretion. Because prenatal T-treated sheep manifest functional hyperandrogenism and hyperinsulinemia, gonadal steroids and/or insulin may play a role in programming and/or maintaining these neuroendocrine defects. Here, we investigated the effects of prenatal and postnatal treatments with an androgen antagonist (flutamide [F]) or an insulin sensitizer (rosiglitazone [R]) on GnRH-stimulated LH secretion in prenatal T-treated sheep. As expected, prenatal T treatment increased the pituitary responsiveness to GnRH leading to LH hypersecretion. Neither prenatal interventions nor postnatal F treatment normalized the GnRH-stimulated LH secretion. Conversely, postnatal R treatment completely normalized the GnRH-stimulated LH secretion. At the tissue level, gestational T increased pituitary LHβ, androgen receptor, and insulin receptor-β, whereas it reduced estrogen receptor (ER)α protein levels. Although postnatal F normalized pituitary androgen receptor and insulin receptor-β, it failed to prevent an increase in LHβ expression. Contrarily, postnatal R treatment restored ERα and partially normalized LHβ pituitary levels. Immunohistochemical findings confirmed changes in pituitary ERα expression to be specific to gonadotropes. In conclusion, these findings indicate that increased pituitary responsiveness to GnRH in prenatal T-treated sheep is likely a function of reduced peripheral insulin sensitivity. Moreover, results suggest that restoration of ERα levels in the pituitary may be one mechanism by which R prevents GnRH-stimulated LH hypersecretion in this sheep model of polycystic ovary syndrome-like phenotype.

Biomechanical Evaluation of Knee Joint Laxities and Graft Forces After Anterior Cruciate Ligament Reconstruction by Anteromedial Portal, Outside-In, and Transtibial Techniques

PubMed Central

Sim, Jae Ang; Gadikota, Hemanth R.; Li, Jing-Sheng; Li, Guoan; Gill, Thomas J.

2013-01-01

Background Recently, anatomic anterior cruciate ligament (ACL) reconstruction is emphasized to improve joint laxity and to potentially avert initiation of cartilage degeneration. There is a paucity of information on the efficacy of ACL reconstructions by currently practiced tunnel creation techniques in restoring normal joint laxity. Study Design Controlled laboratory study. Hypothesis Anterior cruciate ligament reconstruction by the anteromedial (AM) portal technique, outside-in (OI) technique, and modified transtibial (TT) technique can equally restore the normal knee joint laxity and ACL forces. Methods Eight fresh-frozen human cadaveric knee specimens were tested using a robotic testing system under an anterior tibial load (134 N) at 0°, 30°, 60°, and 90° of flexion and combined torques (10-N·m valgus and 5-N·m internal tibial torques) at 0° and 30° of flexion. Knee joint kinematics, ACL, and ACL graft forces were measured in each knee specimen under 5 different conditions (ACL-intact knee, ACL-deficient knee, ACL-reconstructed knee by AM portal technique, ACL-reconstructed knee by OI technique, and ACL-reconstructed knee by TT technique). Results Under anterior tibial load, no significant difference was observed between the 3 reconstructions in terms of restoring anterior tibial translation (P > .05). However, none of the 3 ACL reconstruction techniques could completely restore the normal anterior tibial translations (P <.05). Under combined tibial torques, both AM portal and OI techniques closely restored the normal knee anterior tibial translation (P > .05) at 0° of flexion but could not do so at 30° of flexion (P <.05). The ACL reconstruction by the TT technique was unable to restore normal anterior tibial translations at both 0° and 30° of flexion under combined tibial torques (P <.05). Forces experienced by the ACL grafts in the 3 reconstruction techniques were lower than those experienced by normal ACL under both the loading conditions. Conclusion Anterior cruciate ligament reconstructions by AM portal, OI, and modified TT techniques are biomechanically comparable with each other in restoring normal knee joint laxity and in situ ACL forces. Clinical Relevance Anterior cruciate ligament reconstructions by AM portal, OI, and modified TT techniques result in similar knee joint laxities. Technical perils and pearls should be carefully considered before choosing a tunnel creating technique. PMID:21908717

Functional dilatation and medial remodeling of the renal artery in response to chronic increased blood flow.

PubMed

Roan, Jun-Neng; Yeh, Chin-Yi; Chiu, Wen-Cheng; Lee, Chou-Hwei; Chang, Shih-Wei; Jiangshieh, Ya-Fen; Tsai, Yu-Chuan; Lam, Chen-Fuh

2011-01-01

Renal blood flow (RBF) is tightly regulated by several intrinsic pathways in maintaining optimal kidney blood supply. Using a rat model of aortocaval (AC) fistula, we investigated remodeling of the renal artery following prolonged increased blood flow. An AC fistula was created in the infrarenal aorta of anesthetized rats, and changes of blood flow in the renal artery were assessed using an ultrasonic flow probe. Morphological changes and expression of endothelial nitric oxide synthase and matrix metalloproteinase-2 in the remodeled renal artery were analyzed. Blood flow in the renal artery increased immediately after creation of AC fistula, but normal RBF was restored 8 weeks later. The renal artery dilated significantly 8 weeks after operation. Expression of endothelial nitric oxide synthase and matrix metalloproteinase-2 was upregulated shortly after blood flow increase, and returned to baseline levels after 3 weeks. Histological sections showed luminal dilatation with medial thickening and endothelial cell-to-smooth muscle cell attachments in the remodeled renal artery. Increased RBF was accommodated by functional dilatation and remodeling in the medial layer of the renal artery in order to restore normal blood flow. Our results provide important mechanistic insight into the intrinsic regulation of the renal artery in response to increased RBF. Copyright © 2011 S. Karger AG, Basel.

Astrocytes influence the severity of spinal muscular atrophy

PubMed Central

Rindt, Hansjörg; Feng, Zhihua; Mazzasette, Chiara; Glascock, Jacqueline J.; Valdivia, David; Pyles, Noah; Crawford, Thomas O.; Swoboda, Kathryn J.; Patitucci, Teresa N.; Ebert, Allison D.; Sumner, Charlotte J.; Ko, Chien-Ping; Lorson, Christian L.

2015-01-01

Systemically low levels of survival motor neuron-1 (SMN1) protein cause spinal muscular atrophy (SMA). α-Motor neurons of the spinal cord are considered particularly vulnerable in this genetic disorder and their dysfunction and loss cause progressive muscle weakness, paralysis and eventually premature death of afflicted individuals. Historically, SMA was therefore considered a motor neuron-autonomous disease. However, depletion of SMN in motor neurons of normal mice elicited only a very mild phenotype. Conversely, restoration of SMN to motor neurons in an SMA mouse model had only modest effects on the SMA phenotype and survival. Collectively, these results suggested that additional cell types contribute to the pathogenesis of SMA, and understanding the non-autonomous requirements is crucial for developing effective therapies. Astrocytes are critical for regulating synapse formation and function as well as metabolic support for neurons. We hypothesized that astrocyte functions are disrupted in SMA, exacerbating disease progression. Using viral-based restoration of SMN specifically to astrocytes, survival in severe and intermediate SMA mice was observed. In addition, neuromuscular circuitry was improved. Astrogliosis was prominent in end-stage SMA mice and in post-mortem patient spinal cords. Increased expression of proinflammatory cytokines was partially normalized in treated mice, suggesting that astrocytes contribute to the pathogenesis of SMA. PMID:25911676

Modification of high saturated fat diet with n-3 polyunsaturated fat improves glucose intolerance and vascular dysfunction

PubMed Central

Lamping, KL; Nuno, DW; Coppey, LJ; Holmes, AJ; Hu, S; Oltman, CL; Norris, AW; Yorek, MA

2013-01-01

Aims The ability of dietary enrichment with monounsaturated (MUFA), n-3, or n-6 polyunsaturated fatty acids (PUFA) to reverse glucose intolerance and vascular dysfunction resulting from excessive dietary saturated fatty acids is not resolved. We hypothesized that partial replacement of dietary saturated fats with n-3 PUFA enriched menhaden oil (MO) would provide greater improvement in glucose tolerance and vascular function compared to n-6 enriched safflower oil (SO) or MUFA-enriched olive oil (OO). Material and Methods We fed mice a high saturated fat diet (60% kcal from lard) for 12 weeks before substituting half the lard with MO, SO or OO for an additional 4 weeks. At the end of 4 weeks, we assessed glucose tolerance, insulin signaling and reactivity of isolated pressurized gracilis arteries. Results After 12 weeks of saturated fat diet, body weights were elevated and glucose tolerance abnormal compared to mice on control diet (13% kcal lard). Diet substituted with MO restored basal glucose levels, glucose tolerance, and indices of insulin signaling (phosphorylated Akt) to normal whereas restoration was limited for SO and OO substitutions. Although dilation to acetylcholine was reduced in arteries from mice on HF, OO and SO diets compared to normal diet, dilation to acetylcholine was fully restored and constriction to phenylephrine reduced in MO fed mice compared to normal. Conclusion We conclude that short term enrichment of an ongoing high fat diet with n-3 PUFA rich MO but not MUFA rich OO or n-6 PUFA rich SO reverses glucose tolerance, insulin signaling, and vascular dysfunction. PMID:22950668

Prosthetic Rehabilitation of Mandibular Defects with Fixed-removable Partial Denture Prosthesis Using Precision Attachment: A Twin Case Report.

PubMed

Munot, Vimal Kantilal; Nayakar, Ramesh P; Patil, Raghunath

2017-01-01

The restoration of normal function and esthetic appearance with a dental prosthesis is a major challenge in the rehabilitation of patients who have lost their teeth and surrounding bone because of surgery for oral cyst or tumor. Rehabilitation with fixed or removable prosthesis is even more challenging when the edentulous span is long and the ridge is defective. Anatomic deformities and unfavorable biomechanics encountered in the region of resection add to the misery. In such situation, a fixed-removable prosthesis allows favorable biomechanical stress distribution along with restoration of esthetics, phonetics, comfort, hygiene, and better postoperative care and maintenance. This article describes rehabilitation of two cases with mandibular defects with an attachment-retained fixed-removable hybrid prosthesis.

The vestibulo-ocular reflex and its possible roles in space motion sickness

NASA Technical Reports Server (NTRS)

Watt, Douglas G. D.

1987-01-01

Prolonged exposure to an inappropriate vestibulo-ocular reflex (VOR) will usually lead to motion sickness, and it has been predicted on theoretical grounds that VOR gain may be decreased in weightlessness. While experiments during parabolic flight in aircraft tend to confirm this prediction, experiments during orbital spaceflight have led to apparently contradictory results. It is suggested that VOR gain is reduced initially, but that rapid compensatory mechanisms restore it to normal within minutes of reaching weightlessness. However, even though this process may lead to the rapid return of functionally normal gaze stability, it may not protect against the development of motion sickness.

The investigation of CD4+T-cell functions in primary HIV infection with antiretroviral therapy

PubMed Central

Sun, Yu; Fu, Yajing; Zhang, Zining; Tang, Tian; Liu, Jing; Ding, Haibo; Han, Xiaoxu; Xu, Junjie; Chu, Zhenxing; Shang, Hong; Jiang, Yongjun

2017-01-01

Abstract Human immunodeficiency virus (HIV) infection leads to reduced CD4+T-cell counts and immune dysfunction. Initiation of antiretroviral therapy (ART) in HIV primary infection has been recommended to achieve an optimal clinical outcome, but a comprehensive study on restoration of CD4+T-cell function in primary HIV-infected individuals with ART still needs to be eluciated. We investigated longitudinal changes in the CD4+T-cell counts, phenotypes, and functions in HIV-infected individuals with early ART (initiated within 6 months after HIV infection) or later ART (initiated more than 12 months after HIV infection). Patients from early ART and later ART groups had received ART for at least 1 year. Individuals with early ART had more CD4+T cells, a faster rate of CD4+T-cell recovery than those receiving later ART; the levels of CD4+T-cell activation and senescence were lower in early ART compared to those with later ART (P = .031; P = .016), but the activation was higher than normal controls (NC) (P = .001); thymic emigrant function was more upregulated in early ART than in later ART (P = .015), but still lower than NC (P = .027); proliferative capacity and interferon-γ secretion of CD4+T cells were significantly decreased in primary infection (P < .001; P = .029), and early ART restored these CD4+T-cell functions, there is no difference with NC, later ART could partially restore the functions of CD4+T cells, but it remained lower than that of NC (P = .005; P = .019). Early ART could better improve CD4+T-cell function. PMID:28700479

Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy.

PubMed

Ribera, Albert; Haurigot, Virginia; Garcia, Miguel; Marcó, Sara; Motas, Sandra; Villacampa, Pilar; Maggioni, Luca; León, Xavier; Molas, Maria; Sánchez, Víctor; Muñoz, Sergio; Leborgne, Christian; Moll, Xavier; Pumarola, Martí; Mingozzi, Federico; Ruberte, Jesús; Añor, Sònia; Bosch, Fatima

2015-04-01

Gene therapy is an attractive tool for the treatment of monogenic disorders, in particular for lysosomal storage diseases (LSD) caused by deficiencies in secretable lysosomal enzymes in which neither full restoration of normal enzymatic activity nor transduction of all affected cells are necessary. However, some LSD such as Mucopolysaccharidosis Type IIIB (MPSIIIB) are challenging because the disease's main target organ is the brain and enzymes do not efficiently cross the blood-brain barrier even if present at very high concentration in circulation. To overcome these limitations, we delivered AAV9 vectors encoding for α-N-acetylglucosaminidase (NAGLU) to the Cerebrospinal Fluid (CSF) of MPSIIIB mice with the disease already detectable at biochemical, histological and functional level. Restoration of enzymatic activity in Central Nervous System (CNS) resulted in normalization of glycosaminoglycan content and lysosomal physiology, resolved neuroinflammation and restored the pattern of gene expression in brain similar to that of healthy animals. Additionally, transduction of the liver due to passage of vectors to the circulation led to whole-body disease correction. Treated animals also showed reversal of behavioural deficits and extended lifespan. Importantly, when the levels of enzymatic activity were monitored in the CSF of dogs following administration of canine NAGLU-coding vectors to animals that were either naïve or had pre-existing immunity against AAV9, similar levels of activity were achieved, suggesting that CNS efficacy would not be compromised in patients seropositive for AAV9. Our studies provide a strong rationale for the clinical development of this novel therapeutic approach as the treatment for MPSIIIB. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Oral administration of soybean peptide Vglycin normalizes fasting glucose and restores impaired pancreatic function in Type 2 diabetic Wistar rats.

PubMed

Jiang, Hua; Feng, Jueping; Du, Zhongxia; Zhen, Hui; Lin, Mei; Jia, Shaohui; Li, Tao; Huang, Xinyuan; Ostenson, Claes-Goran; Chen, Zhengwang

2014-09-01

Vglycin, a natural 37-residue polypeptide isolated from pea seeds in which six half-cysteine residues are embedded in three pairs of disulfide bonds, is resistant to digestive enzymes and has antidiabetic potential. To investigate the pharmacological activity of Vglycin in vivo and to examine the mechanisms involved, the therapeutic effect of Vglycin in diabetic rats was examined. Diabetes was induced in Wistar rats by high-fat diet and multiple streptozotocin intraperitoneal injections. Diabetic rats were treated daily with Vglycin for 4 weeks. Body weight, food intake, fasting plasma glucose and insulin levels were assayed weekly. Glucose and insulin tolerance tests were conducted on Day 29. Subsequently, levels of p-Akt in the liver and pancreas and cleaved PARP, Pdx-1 and insulin in the pancreas were detected by immunoblotting. The morphology of the pancreas and the insulin expression in the pancreas were analyzed by hematoxylin-eosin staining and immunohistochemistry, respectively. Furthermore, human liver-derived cell lines were used to explore the in vitro effects of Vglycin on insulin sensitivity and glucose uptake. Chronic treatment with Vglycin normalized fasting glucose levels in diabetic rats. The improvement in glucose homeostasis and the increased insulin sensitivity mediated by restored insulin signaling likely contributed to decreased food intake and reduced body weight. Vglycin protected pancreatic cells from damage by streptozotocin. Although insulin synthesis and secretion in impaired β-cell were not significantly elevated, islets morphology was improved in the Vglycin-treated groups. These results suggest that Vglycin could be useful in Type 2 diabetes for restoring impaired insulin signaling, glucose tolerance and pancreatic function. Copyright © 2014 Elsevier Inc. All rights reserved.

Regulation of Synaptic Structure by the Ubiquitin C-terminal Hydrolase UCH-L1

PubMed Central

Cartier, Anna E.; Djakovic, Stevan N.; Salehi, Afshin; Wilson, Scott M.; Masliah, Eliezer; Patrick, Gentry N.

2009-01-01

UCH-L1 is a de-ubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We have found that UCH-L1 activity is rapidly up-regulated by NMDA receptor activation which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of pre and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1 inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner. PMID:19535597

Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1.

PubMed

Cartier, Anna E; Djakovic, Stevan N; Salehi, Afshin; Wilson, Scott M; Masliah, Eliezer; Patrick, Gentry N

2009-06-17

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We found that UCH-L1 activity is rapidly upregulated by NMDA receptor activation, which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of presynaptic and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1-inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling, most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner.

SLEEPLESS is a bi-functional regulator of excitability and cholinergic synaptic transmission

PubMed Central

Wu, Meilin; Robinson, James E.; Joiner, William J.

2014-01-01

Summary Background Although sleep is conserved throughout evolution, the molecular basis of its control is still largely a mystery. We previously showed that the quiver/sleepless (qvr/sss) gene encodes a membrane-tethered protein that is required for normal sleep in Drosophila. SLEEPLESS (SSS) protein functions, at least in part, by upregulating the levels and open probability of Shaker (Sh) potassium channels to suppress neuronal excitability and enable sleep. Consistent with this proposed mechanism, loss-of-function mutations in Sh phenocopy qvr/sss null mutants. However, sleep is more genetically modifiable in Sh than in qvr/sss mutants, suggesting that sss may regulate additional molecules to influence sleep. Results Here we show that SSS also antagonizes nicotinic acetylcholine receptors (nAChRs) to reduce synaptic transmission and promote sleep. Mimicking this antagonism with the nAChR inhibitor mecamylamine or by RNAi knockdown of specific nAChR subunits is sufficient to restore sleep to qvr/sss mutants. Regulation of nAChR activity by SSS occurs post-transcriptionally since the levels of nAChR mRNAs are unchanged in qvr/sss mutants. Regulation of nAChR activity by SSS may in fact be direct, since SSS forms a stable complex with and antagonizes fly nAChR function in transfected cells. Intriguingly, lynx1, a mammalian homolog of SSS, can partially restore normal sleep to qvr/sss mutants, and lynx1 can form stable complexes with Shaker-type channels and nAChRs. Conclusions Together, our data point to an evolutionarily conserved, bi-functional role for SSS and its homologs in controlling excitability and synaptic transmission in fundamental processes of the nervous system such as sleep. PMID:24613312

Neuroprosthetics and Solutions for Restoring Sensorimotor Functions

DTIC Science & Technology

2009-01-01

in the stab wound control (A, C) and the 1-week implantation of the electrode (B, D). Striking neurofilament loss occurred surrounding both the stab...force. (Like in heel strike and toe of in normal gait cycle). (B) The Proof Test is a static test for foot ankle unit in which maximum load is...applied on heel and forefoot in one single time successively. Project 1. Develop a somatosensory neural interface (SSNI) -Completed pilot testing of

Exercise as a countermeasure for physiological adaptation to prolonged spaceflight

NASA Technical Reports Server (NTRS)

Convertino, V. A.

1996-01-01

Exercise represents the primary countermeasure used during spaceflight to maintain or restore maximal aerobic capacity (VO2max), musculoskeletal structure, and orthostatic function. However, no single exercise or combination of prescriptions has proven entirely effective in restoring cardiovascular and musculoskeletal functions to preflight levels following prolonged spaceflight. As human spaceflight exposures increase in duration, assessment and development of various effective exercise-based protective procedures become paramount. This must involve improvement in specific countermeasure prescription as well as development of additional approaches that will allow space travelers greater flexibility and medical safety during long flights. Effective exercise prescription will be based on identification of basic physiological stimuli that maintain normal function in terrestrial gravity and understanding of how specific combinations of exercise characteristics e.g., duration, frequency, intensity, mode) can mimic these stimuli and affect the overall process of adaptation to microgravity. This can be accomplished only with greater emphasis of research on ground-based experiments. Future attention must be directed to improving exercise compliance while minimizing both crew time and the impact of the exercise on life-support resources.

Cellular apoptosis and cardiac dysfunction in STZ-induced diabetic rats attenuated by anthocyanins via activation of IGFI-R/PI3K/Akt survival signaling.

PubMed

Huang, Pei-Chen; Wang, Guei-Jane; Fan, Ming-Jen; Asokan Shibu, Marthandam; Liu, Yin-Tso; Padma Viswanadha, Vijaya; Lin, Yi-Lin; Lai, Chao-Hung; Chen, Yu-Feng; Liao, Hung-En; Huang, Chih-Yang

2017-12-01

Anthocyanins are known cyto-protective agents against various stress conditions. In this study cardio-protective effect of anthocyanins from black rice against diabetic mellitus (DM) was evaluated using a streptozotocin (STZ)-induced DM rat model. Five-week-old male Wistar rats were administered with STZ (55 mg kg -1 , IP) to induce DM; rats in the treatment group received 250 mg oral anthocyanin/kg/day during the 4-week treatment period. DM and the control rats received normal saline through oral gavage. The results reveal that STZ-induced DM elevates myocardial apoptosis and associated proapoptotic proteins but down-regulates the proteins of IGF1R mediated survival signaling mechanism. Furthermore, the functional parameters such as the ejection-fraction and fraction-shortening in the DM rat hearts declined considerably. However, the rats treated with anthocyanins significantly reduced apoptosis and the associated proapoptotic proteins and further increased the survival signals to restore the cardiac functions in DM rats. Anthocyanin supplementation enhances cardiomyocyte survival and restores cardiac function. © 2017 Wiley Periodicals, Inc.

Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy.

PubMed Central

Vachon, P H; Xu, H; Liu, L; Loechel, F; Hayashi, Y; Arahata, K; Reed, J C; Wewer, U M; Engvall, E

1997-01-01

Mutations in genes coding for dystrophin, for alpha, beta, gamma, and delta-sarcoglycans, or for the alpha2 chain of the basement membrane component merosin (laminin-2/4) cause various forms of muscular dystrophy. Analyses of integrins showed an abnormal expression and localization of alpha7beta1 isoforms in myofibers of merosin-deficient human patients and mice, but not in dystrophin-deficient or sarcoglycan-deficient humans and animals. It was shown previously that skeletal muscle fibers require merosin for survival and function (Vachon, P.H., F. Loechel, H. Xu, U.M. Wewer, and E. Engvall. 1996. J. Cell Biol. 134:1483-1497). Correction of merosin deficiency in vitro through cell transfection with the merosin alpha2 chain restored the normal localization of alpha7beta1D integrins as well as myotube survival. Overexpression of the apoptosis-suppressing molecule Bcl-2 also promoted the survival of merosin-deficient myotubes, but did not restore a normal expression of alpha7beta1D integrins. Blocking of beta1 integrins in normal myotubes induced apoptosis and severely reduced their survival. These findings (a) identify alpha7beta1D integrins as the de facto receptors for merosin in skeletal muscle; (b) indicate a merosin dependence for the accurate expression and membrane localization of alpha7beta1D integrins in myofibers; (c) provide a molecular basis for the critical role of merosin in myofiber survival; and (d) add new insights to the pathogenesis of neuromuscular disorders. PMID:9312189

A Multi-channel Semicircular Canal Neural Prosthesis Using Electrical Stimulation to Restore 3D Vestibular Sensation

PubMed Central

Della Santina, Charles C.; Migliaccio, Americo A.; Patel, Amit H.

2009-01-01

Bilateral loss of vestibular sensation can be disabling. Those afflicted suffer illusory visual field movement during head movements, chronic disequilibrium and postural instability due to failure of vestibulo-ocular and vestibulo-spinal reflexes. A neural prosthesis that emulates the normal transduction of head rotation by semicircular canals could significantly improve quality of life for these patients. Like the 3 semicircular canals in a normal ear, such a device should at least transduce 3 orthogonal (or linearly separable) components of head rotation into activity on corresponding ampullary branches of the vestibular nerve. We describe the design, circuit performance and in vivo application of a head-mounted, semi-implantable multi-channel vestibular prosthesis that encodes head movement in 3 dimensions as pulse-frequency-modulated electrical stimulation of 3 or more ampullary nerves. In chinchillas treated with intratympanic gentamicin to ablate vestibular sensation bilaterally, prosthetic stimuli elicited a partly compensatory angular vestibulo-ocular reflex in multiple planes. Minimizing misalignment between the axis of eye and head rotation, apparently caused by current spread beyond each electrode’s targeted nerve branch, emerged as a key challenge. Increasing stimulation selectivity via improvements in electrode design, surgical technique and stimulus protocol will likely be required to restore AVOR function over the full range of normal behavior. PMID:17554821

[Radiation-induced genomic instability: phenomenon, molecular mechanisms, pathogenetic significance].

PubMed

Mazurik, V K; Mikhaĭlov, V F

2001-01-01

The recent data on the radiation-induced genome instability as a special state of progeny of cells irradiated in vitro as well as after a whole body exposure to ionizing radiation, that make these cells considerably different from normal, unirradiated cells, were considered. This state presents a number of cytogenetical, molecular-biological, cytological and biochemical manifestations untypical for normal cells. The state is controlled by the mechanisms of regulation of checkpoints of cell cycle, and apoptosis, that is under gene p53 control. The proof has been found that this state transfers from irradiated maternal cells to their surviving progeny by the epigenetical mechanisms and would exist until the cells restore the original state of response on the DNA damage. From the point of view of the genome instability conception, that considers the chromatine rearrangement as the adaptive-evolution mechanism of adaptation of the species to changeable environmental conditions, the radiation-induced genome instability may be considered as transition of irradiated progeny to the state of read these to adaptation changes with two alternative pathways. The first leads to adaptation to enviromental conditions and restoring of normal cell functions. The second presents the cell transition into the transformed state with remain genome instability and with increase of tumour growth probability.

The Normalized Failure Index: a method for summarizing the results of studies on restoration longevity?

PubMed

Burke, F J T; Singh, V; Wilson, N H F

2013-01-01

Satisfactory restoration longevity is central to operative dentistry and is the subject of a wide variety of publications. However, combining the results of a number of studies to provide an overview, for example, for a meta-analysis may be problematic because of the heterogeneity of the data, and a high proportion of studies may therefore not be included. It is the purpose of this study to present a means whereby the data from cohort studies may be combined to present a representation of restoration longevity, termed the "Normalized Failure Index."

Nuclear-encoded mitochondrial complex I gene expression is restored to normal levels by inhibition of unedited ATP9 transgene expression in Arabidopsis thaliana.

PubMed

Busi, María V; Gómez-Casati, Diego F; Perales, Mariano; Araya, Alejandro; Zabaleta, Eduardo

2006-01-01

Mitochondria play an important role during sporogenesis in plants. The steady state levels of the nuclear-encoded mitochondrial complex I (nCI), PSST, TYKY and NADHBP transcripts increase in flowers of male-sterile plants with impairment of mitochondrial function generated by the expression of the unedited version of ATP9 (u-ATP9). This suggests a nuclear control of nCI genes in response to the mitochondrial flaw. To evaluate this hypothesis, transgenic plants carrying the GUS reporter gene, under the control of the PSST, TYKY and NADHBP promoters, were constructed. We present evidence that suppression by antisense strategy of the expression of u-ATP9 restores the normal levels of three nCI transcripts, indicating that the increase in PSST, TYKY and NADHBP in plants with a mitochondrial flaw occurs at the transcriptional level. The data presented here support the hypothesis that a mitochondrial dysfunction triggers a retrograde signaling which induce some nuclear-encoded mitochondrial genes. Moreover, these results demonstrate that this is a valuable experimental model for studying nucleus-mitochondria cross-talk events.

Osteogenic and chondrogenic master genes expression is dependent on the Kir2.1 potassium channel through the bone morphogenetic protein pathway.

PubMed

Pini, Jonathan; Giuliano, Serena; Matonti, Julia; Simkin, Dina; Rouleau, Matthieu; Bendahhou, Saïd

2018-05-29

Andersen's syndrome is a rare disorder affecting muscle, heart, and bone, that is associated with mutations leading to a loss of function of the inwardly rectifying K + channel Kir2.1. While the Kir2.1 function can be anticipated in excitable cells by controlling the electrical activity, its role in non-excitable cells remains to be investigated. Using Andersen's syndrome induced Pluripotent Stem cells, we investigated the cellular and molecular events during the osteoblastic and chondrogenic differentiation that are affected by the loss of the Ik1 current. We show that loss of Kir2.1 channel function impairs both osteoblastic and chondrogenic processes through the down regulation master gene expression. This down regulation is due to an impairment of the bone morphogenetic proteins signaling pathway through de-phosphorylation of the Smad proteins. Restoring Kir2.1 channel function in Andersen's syndrome cells rescued master genes expression, and restored normal osteoblasts and chondrocytes behavior. Our results show that Kir2.1-mediated activity controls endochondral and intramembranous ossification signaling pathways. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Intraovarian Transplantation of Female Germline Stem Cells Rescue Ovarian Function in Chemotherapy-Injured Ovaries.

PubMed

Xiong, Jiaqiang; Lu, Zhiyong; Wu, Meng; Zhang, Jinjin; Cheng, Jing; Luo, Aiyue; Shen, Wei; Fang, Li; Zhou, Su; Wang, Shixuan

2015-01-01

Early menopause and infertility often occur in female cancer patients after chemotherapy (CTx). For these patients, oocyte/embryo cryopreservation or ovarian tissue cryopreservation is the current modality for fertility preservation. However, the above methods are limited in the long-term protection of ovarian function, especially for fertility preservation (very few females with cancer have achieved pregnancy with cryopreserved ovarian tissue or eggs until now). In addition, the above methods are subject to their scope (females with no husband or prepubertal females with no mature oocytes). Thus, many females who suffer from cancers would not adopt the above methods pre- and post-CTx due to their uncertainty, safety and cost-effectiveness. Therefore, millions of women have achieved long-term survival after thorough CTx treatment and have desired to rescue their ovarian function and fertility with economic, durable and reliable methods. Recently, some studies showed that mice with infertility caused by CTx can produce normal offspring through intraovarian injection of exogenous female germline stem cells (FGSCs). Though exogenous FGSC can be derived from mice without immune rejection in the same strain, it is difficult to obtain human female germline stem cells (hFGSCs), and immune rejection could occur between different individuals. In this study, infertility in mice was caused by CTx, and the ability of FGSCs to restore ovarian function or even produce offspring was assessed. We had successfully isolated and purified the FGSCs from adult female mice two weeks after CTx. After infection with GFP-carrying virus, the FGSCs were transplanted into ovaries of mice with infertility caused by CTx. Finally, ovarian function was restored and the recipients produced offspring long-term. These findings showed that mice with CTx possessed FGSCs, restoring ovarian function and avoiding immune rejection from exogenous germline stem cells.

GSTP1 Loss results in accumulation of oxidative DNA base damage and promotes prostate cancer cell survival following exposure to protracted oxidative stress.

PubMed

Mian, Omar Y; Khattab, Mohamed H; Hedayati, Mohammad; Coulter, Jonathan; Abubaker-Sharif, Budri; Schwaninger, Julie M; Veeraswamy, Ravi K; Brooks, James D; Hopkins, Lisa; Shinohara, Debika Biswal; Cornblatt, Brian; Nelson, William G; Yegnasubramanian, Srinivasan; DeWeese, Theodore L

2016-02-01

Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1- transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. © 2015 Wiley Periodicals, Inc.

GSTP1 Loss Results in Accumulation of Oxidative DNA Base Damage and Promotes Prostate Cancer Cell Survival Following Exposure to Protracted Oxidative Stress

PubMed Central

Mian, Omar Y.; Khattab, Mohamed H.; Hedayati, Mohammad; Coulter, Jonathan; Abubaker-Sharif, Budri; Schwaninger, Julie M.; Veeraswamy, Ravi K.; Brooks, James D.; Hopkins, Lisa; Shinohara, Debika Biswal; Cornblatt, Brian; Nelson, William G.; Yegnasubramanian, Srinivasan; DeWeese, Theodore L.

2016-01-01

BACKGROUND Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). METHODS GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1-transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. RESULTS GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. CONCLUSIONS The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. PMID:26447830

Quantitative analysis of protein and gene expression in salivary glands of Sjogren's-like disease NOD mice treated by bone marrow soup.

PubMed

Misuno, Kaori; Tran, Simon D; Khalili, Saeed; Huang, Junwei; Liu, Younan; Hu, Shen

2014-01-01

Bone marrow cell extract (termed as BM Soup) has been demonstrated to repair irradiated salivary glands (SGs) and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD) mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment. Whole BM cells were lysed and soluble intracellular contents ("BM Soup") were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs) between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice. restored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice. BM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment.

Quantitative Analysis of Protein and Gene Expression in Salivary Glands of Sjogren’s-Like Disease NOD Mice Treated by Bone Marrow Soup

PubMed Central

Misuno, Kaori; Khalili, Saeed; Huang, Junwei; Liu, Younan

2014-01-01

Background Bone marrow cell extract (termed as BM Soup) has been demonstrated to repair irradiated salivary glands (SGs) and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD) mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment. Methods Whole BM cells were lysed and soluble intracellular contents (“BM Soup”) were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs) between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice. Results BM Soup restored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice. Conclusion BM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment. PMID:24489858

Current state of cartilage tissue engineering

PubMed Central

Tuli, Richard; Li, Wan-Ju; Tuan, Rocky S

2003-01-01

Damage to cartilage is of great clinical consequence given the tissue's limited intrinsic potential for healing. Current treatments for cartilage repair are less than satisfactory, and rarely restore full function or return the tissue to its native normal state. The rapidly emerging field of tissue engineering holds great promise for the generation of functional cartilage tissue substitutes. The general approach involves a biocompatible, structurally and mechanically sound scaffold, with an appropriate cell source, which is loaded with bioactive molecules that promote cellular differentiation and/or maturation. This review highlights aspects of current progress in cartilage tissue engineering. PMID:12932283

[Treatment of cognitive and psychoemotional disorders in poststroke patients].

PubMed

Kovalchuk, V V

2014-01-01

To evaluate the efficacy of the drug sermion (nicergoline) in poststroke patients with cognitive and psychoemotional disorders. The study included 880 patients, including 440 patients with depression and 440 with cognitive impairment, mean age of patients was 69,6 years. The restoration of cognitive functions was followed up using MMSE scales, psychoemotional condition was assessed with the Beck Depression Questionnaire and the Wakefield Depression Scale. The efficacy of sermion has been demonstrated. Application of this drug in the rehabilitation of stroke patients significantly contributes to the improvement of cognitive functions and normalization of mental and emotional state of patients.

Nutrition beyond nutrition: plausibility of immunotrophic nutrition for space travel.

PubMed

Kulkarni, A D; Yamauchi, K; Hales, N W; Ramesh, V; Ramesh, G T; Sundaresan, A; Andrassy, R J; Pellis, N R

2002-06-01

Microgravity has adverse effects on the immune system. We examined the effects of supplemental dietary nucleotides on immune function in ground-based in vivo anti-orthostatic tail-suspended (AOS) mice and in vitro (bioreactor-BIO) analogs of microgravity. BALB/c mice were divided into the following three groups: group housed, single isolation, and AOS. Mice were fed either control chow or chow supplemented with RNA or uracil. Immune function was assessed by in vivo popliteal lymph node proliferation (PLN), in vitro PHA-stimulated proliferation of splenocytes and cytokine production. BIO splenocytes were cultured in vitro with/without PHA, a nucleoside-nucleotide mixture (NS/NT) or uridine. The cell proliferation and scanning electron microscopic examination for cells were carried out. PLN response was significantly suppressed in AOS mice (P<0.05) and was restored by RNA and uracil diets. Splenocytes from AOS mice had decreased phytohemagglutinin (PHA)-stimulated proliferation, decreased IL-2 and IFN-gamma cytokine levels (P<0.05). These responses were restored by RNA and uracil diets. In BIO cultures, PHA response was suppressed significantly, and uridine and NS/NT restored the proliferative responses. Scanning electron microscopic analysis of cells cultured in BIO revealed cells with pinched, distorted and eroded membranes. Nucleotide supplementation especially uridine restored normal activated cell surface appearance and ruffling. In the microgravity analog environment of AOS and BIO, supplemental nucleotides and especially uracil/uridine have up-regulating and immunoprotective effects with potential as a countermeasure to the observed immune dysfunction in true microgravity.

Tissue-specific expression of transgenic secreted ACE in vasculature can restore normal kidney functions, but not blood pressure, of Ace-/- mice.

PubMed

Chattopadhyay, Saurabh; Kessler, Sean P; Colucci, Juliana Almada; Yamashita, Michifumi; Senanayake, Preenie deS; Sen, Ganes C

2014-01-01

Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE.

Tissue-Specific Expression of Transgenic Secreted ACE in Vasculature Can Restore Normal Kidney Functions, but Not Blood Pressure, of Ace-/- Mice

PubMed Central

Chattopadhyay, Saurabh; Kessler, Sean P.; Colucci, Juliana Almada; Yamashita, Michifumi; Senanayake, Preenie deS; Sen, Ganes C.

2014-01-01

Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE. PMID:24475296

Effects of Vernonia cinerea on reproductive performance in streptozotocin-induced diabetic rats.

PubMed

Pomjunya, Atchariya; Ratthanophart, Jasada; Fungfuang, Wirasak

2017-03-23

The present study investigated the effects of Vernonia cinerea (VC) on the reproductive function in streptozotocin (STZ)-induced diabetic male rats. Six-week-old male Sprague-Dawley rats were randomly divided into four groups: group 1, normal control rats; group 2, diabetic untreated rats; group 3, diabetic rats treated with VC (10 mg/kg); and group 4, diabetic rats treated with VC (40 mg/kg). Diabetes mellitus (DM) was induced by intraperitoneal injection of STZ (60 mg/kg). All animals were treated for 30 consecutive days. Body weight, blood glucose, food intake, epididymal sperm parameters, testicular microstructure and serum testosterone levels were evaluated. VC treatment significantly restored the sperm motility and testosterone concentration, and decreased the testicular histopathological changes in DM rats. Moreover, high-dose VC exhibited an antidibetic activity and significantly improved the sperm count. In conclusion, we found, for the first time, that administration of VC significantly restored the testicular function and testosterone concentration in diabetic male rats.

Effects of Vernonia cinerea on reproductive performance in streptozotocin-induced diabetic rats

PubMed Central

POMJUNYA, Atchariya; RATTHANOPHART, Jasada; FUNGFUANG, Wirasak

2017-01-01

The present study investigated the effects of Vernonia cinerea (VC) on the reproductive function in streptozotocin (STZ)-induced diabetic male rats. Six-week-old male Sprague-Dawley rats were randomly divided into four groups: group 1, normal control rats; group 2, diabetic untreated rats; group 3, diabetic rats treated with VC (10 mg/kg); and group 4, diabetic rats treated with VC (40 mg/kg). Diabetes mellitus (DM) was induced by intraperitoneal injection of STZ (60 mg/kg). All animals were treated for 30 consecutive days. Body weight, blood glucose, food intake, epididymal sperm parameters, testicular microstructure and serum testosterone levels were evaluated. VC treatment significantly restored the sperm motility and testosterone concentration, and decreased the testicular histopathological changes in DM rats. Moreover, high-dose VC exhibited an antidibetic activity and significantly improved the sperm count. In conclusion, we found, for the first time, that administration of VC significantly restored the testicular function and testosterone concentration in diabetic male rats. PMID:28190818

Promising Gene Therapeutics for Salivary Gland Radiotoxicity

PubMed Central

Nair, Renjith Parameswaran; Sunavala-Dossabhoy, Gulshan

2017-01-01

More than 0.5 million new cases of head and neck cancer are diagnosed worldwide each year, and approximately 75% of them are treated with radiation alone or in combination with other cancer treatments. A majority of patients treated with radiotherapy develop significant oral off-target effects because of the unavoidable irradiation of normal tissues. Salivary glands that lie within treatment fields are often irreparably damaged and a decline in function manifests as dry mouth or xerostomia. Limited ability of the salivary glands to regenerate lost acinar cells makes radiation-induced loss of function a chronic problem that affects the quality of life of the patients well beyond the completion of radiotherapy. The restoration of saliva production after irradiation has been a daunting challenge, and this review provides an overview of promising gene therapeutics that either improve the gland’s ability to survive radiation insult, or alternately, restore fluid flow after radiation. The salient features and shortcomings of each approach are discussed. PMID:28286865

Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging.

PubMed

Smith, Roy G; Sun, Yuxiang; Jiang, Hong; Albarran-Zeckler, Rosie; Timchenko, Nikolai

2007-11-01

Administration of an orally active agonist (MK-0677) of the growth hormone secretagogue receptor (GHS-R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS-R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase-2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS-R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS-R1a and dopamine receptor subtype-1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS-R and D1R form heterodimers, which modified G-protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS-R1a agonists to improve quality of life and maintain independence.

Analysis of vegetation recovery surrounding a restored wetland using the normalized difference infrared index (NDII) and normalized difference vegetation index (NDVI)

USGS Publications Warehouse

Wilson, Natalie R.; Norman, Laura

2018-01-01

Watershed restoration efforts seek to rejuvenate vegetation, biological diversity, and land productivity at Cienega San Bernardino, an important wetland in southeastern Arizona and northern Sonora, Mexico. Rock detention and earthen berm structures were built on the Cienega San Bernardino over the course of four decades, beginning in 1984 and continuing to the present. Previous research findings show that restoration supports and even increases vegetation health despite ongoing drought conditions in this arid watershed. However, the extent of restoration impacts is still unknown despite qualitative observations of improvement in surrounding vegetation amount and vigor. We analyzed spatial and temporal trends in vegetation greenness and soil moisture by applying the normalized difference vegetation index (NDVI) and normalized difference infrared index (NDII) to one dry summer season Landsat path/row from 1984 to 2016. The study area was divided into zones and spectral data for each zone was analyzed and compared with precipitation record using statistical measures including linear regression, Mann– Kendall test, and linear correlation. NDVI and NDII performed differently due to the presence of continued grazing and the effects of grazing on canopy cover; NDVI was better able to track changes in vegetation in areas without grazing while NDII was better at tracking changes in areas with continued grazing. Restoration impacts display higher greenness and vegetation water content levels, greater increases in greenness and water content through time, and a decoupling of vegetation greenness and water content from spring precipitation when compared to control sites in nearby tributary and upland areas. Our results confirm the potential of erosion control structures to affect areas up to 5 km downstream of restoration sites over time and to affect 1 km upstream of the sites.

Vision restoration after brain and retina damage: the "residual vision activation theory".

PubMed

Sabel, Bernhard A; Henrich-Noack, Petra; Fedorov, Anton; Gall, Carolin

2011-01-01

Vision loss after retinal or cerebral visual injury (CVI) was long considered to be irreversible. However, there is considerable potential for vision restoration and recovery even in adulthood. Here, we propose the "residual vision activation theory" of how visual functions can be reactivated and restored. CVI is usually not complete, but some structures are typically spared by the damage. They include (i) areas of partial damage at the visual field border, (ii) "islands" of surviving tissue inside the blind field, (iii) extrastriate pathways unaffected by the damage, and (iv) downstream, higher-level neuronal networks. However, residual structures have a triple handicap to be fully functional: (i) fewer neurons, (ii) lack of sufficient attentional resources because of the dominant intact hemisphere caused by excitation/inhibition dysbalance, and (iii) disturbance in their temporal processing. Because of this resulting activation loss, residual structures are unable to contribute much to everyday vision, and their "non-use" further impairs synaptic strength. However, residual structures can be reactivated by engaging them in repetitive stimulation by different means: (i) visual experience, (ii) visual training, or (iii) noninvasive electrical brain current stimulation. These methods lead to strengthening of synaptic transmission and synchronization of partially damaged structures (within-systems plasticity) and downstream neuronal networks (network plasticity). Just as in normal perceptual learning, synaptic plasticity can improve vision and lead to vision restoration. This can be induced at any time after the lesion, at all ages and in all types of visual field impairments after retinal or brain damage (stroke, neurotrauma, glaucoma, amblyopia, age-related macular degeneration). If and to what extent vision restoration can be achieved is a function of the amount of residual tissue and its activation state. However, sustained improvements require repetitive stimulation which, depending on the method, may take days (noninvasive brain stimulation) or months (behavioral training). By becoming again engaged in everyday vision, (re)activation of areas of residual vision outlasts the stimulation period, thus contributing to lasting vision restoration and improvements in quality of life. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of Mesalamine Treatment on Gut Barrier Integrity Following Burn Injury

PubMed Central

Cannon, Abigail R.; Akhtar, Suhail; Hammer, Adam M.; Morris, Niya L.; Javorski, Mike J.; Li, Xiaoling; Kennedy, Richard H.; Gamelli, Richard L.; Choudhry, Mashkoor A.

2016-01-01

Gut barrier disruption is often implicated in pathogenesis associated with burn and other traumatic injuries. In this study, we examined whether therapeutic intervention with mesalamine (5-ASA), a common anti-inflammatory treatment for patients with inflammatory bowel disease, reduces intestinal inflammation and maintains normal barrier integrity after burn injury. Male C57BL/6 mice were administered an ~20% total body surface area dorsal scald burn and resuscitated with either 1mL normal saline or 100mg/kg of 5-ASA dissolved in saline. We examined intestinal transit and permeability along with levels of small intestine epithelial cell pro-inflammatory cytokines and tight junction protein expression one day after burn injury in the presence or absence of 5-ASA. A significant decrease in intestinal transit was observed one day after burn injury, which accompanied a significant increase in gut permeability. We found a substantial increase in the levels of IL-6 (by ~1.5 fold) and IL-18 (by ~2.5 fold) in small intestine epithelial cells one day after injury. Furthermore, burn injury decreases expression of the tight junction proteins claudin-4, claudin-8, and occludin. Treatment with 5-ASA after burn injury prevented the burn induced increase in permeability, partially restored normal intestinal transit, normalized levels of the pro-inflammatory cytokines IL-6 and IL-18, and restored tight junction protein expression of claudin-4 and occludin to that of sham levels. Together these findings suggest that 5-ASA can potentially be used as treatment to decrease intestinal inflammation and normalize intestinal function after burn injury. PMID:27388883

Effects of Mesalamine Treatment on Gut Barrier Integrity After Burn Injury.

PubMed

Cannon, Abigail R; Akhtar, Suhail; Hammer, Adam M; Morris, Niya L; Javorski, Michael J; Li, Xiaoling; Kennedy, Richard H; Gamelli, Richard L; Choudhry, Mashkoor A

2016-01-01

Gut barrier disruption is often implicated in pathogenesis associated with burn and other traumatic injuries. In this study, the authors examined whether therapeutic intervention with mesalamine (5-aminosalicylic acid [5-ASA]), a common anti-inflammatory treatment for patients with inflammatory bowel disease, reduces intestinal inflammation and maintains normal barrier integrity after burn injury. Male C57BL/6 mice were administered an approximately 20% TBSA dorsal scald burn and resuscitated with either 1 ml normal saline or 100 mg/kg of 5-ASA dissolved in saline. The authors examined intestinal transit and permeability along with the levels of small intestine epithelial cell proinflammatory cytokines and tight junction protein expression 1 day after burn injury in the presence or absence of 5-ASA. A significant decrease in intestinal transit was observed 1 day after burn injury, which accompanied a significant increase in gut permeability. The authors found a substantial increase in the levels of interleukin (IL)-6 (by ~1.5-fold) and IL-18 (by ~2.5-fold) in the small intestine epithelial cells 1 day after injury. Furthermore, burn injury decreases the expression of the tight junction proteins claudin-4, claudin-8, and occludin. Treatment with 5-ASA after burn injury prevented the burn-induced increase in permeability, partially restored normal intestinal transit, normalized the levels of the proinflammatory cytokines IL-6 and IL-18, and restored tight junction protein expression of claudin-4 and occludin compared with that of sham levels. Together these findings suggest that 5-ASA can potentially be used as treatment to decrease intestinal inflammation and normalize intestinal function after burn injury.

Prosthetic Rehabilitation of Mandibular Defects with Fixed-removable Partial Denture Prosthesis Using Precision Attachment: A Twin Case Report

PubMed Central

Munot, Vimal Kantilal; Nayakar, Ramesh P.; Patil, Raghunath

2017-01-01

The restoration of normal function and esthetic appearance with a dental prosthesis is a major challenge in the rehabilitation of patients who have lost their teeth and surrounding bone because of surgery for oral cyst or tumor. Rehabilitation with fixed or removable prosthesis is even more challenging when the edentulous span is long and the ridge is defective. Anatomic deformities and unfavorable biomechanics encountered in the region of resection add to the misery. In such situation, a fixed-removable prosthesis allows favorable biomechanical stress distribution along with restoration of esthetics, phonetics, comfort, hygiene, and better postoperative care and maintenance. This article describes rehabilitation of two cases with mandibular defects with an attachment-retained fixed-removable hybrid prosthesis. PMID:29042738

Cytotoxic evaluation of hydroxyapatite-filled and silica/hydroxyapatite-filled acrylate-based restorative composite resins: An in vitro study.

PubMed

Chadda, Harshita; Naveen, Sangeetha Vasudevaraj; Mohan, Saktiswaren; Satapathy, Bhabani K; Ray, Alok R; Kamarul, Tunku

2016-07-01

Although the physical and mechanical properties of hydroxyapatite-filled dental restorative composite resins have been examined, the biocompatibility of these materials has not been studied in detail. The purpose of this in vitro study was to analyze the toxicity of acrylate-based restorative composite resins filled with hydroxyapatite and a silica/hydroxyapatite combination. Five different restorative materials based on bisphenol A-glycidyl methacrylate (bis-GMA) and tri-ethylene glycol dimethacrylate (TEGDMA) were developed: unfilled (H0), hydroxyapatite-filled (H30, H50), and silica/hydroxyapatite-filled (SH30, SH50) composite resins. These were tested for in vitro cytotoxicity by using human bone marrow mesenchymal stromal cells. Surface morphology, elemental composition, and functional groups were determined by scanning electron microscopy (SEM), energy-dispersive x-ray spectroscopy (EDX), and Fourier-transformed infrared spectroscopy (FTIR). The spectra normalization, baseline corrections, and peak integration were carried out by OPUS v4.0 software. Both in vitro cytotoxicity results and SEM analysis indicated that the composite resins developed were nontoxic and supported cell adherence. Elemental analysis with EDX revealed the presence of carbon, oxygen, calcium, silicon, and gold, while the presence of methacrylate, hydroxyl, and methylene functional groups was confirmed through FTIR analysis. The characterization and compatibility studies showed that these hydroxyapatite-filled and silica/hydroxyapatite-filled bis-GMA/TEGDMA-based restorative composite resins are nontoxic to human bone marrow mesenchymal stromal cells and show a favorable biologic response, making them potential biomaterials. Copyright © 2016 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Substance P restores normal skin architecture and reduces epidermal infiltration of sensory nerve fiber in TNCB-induced atopic dermatitis-like lesions in NC/Nga mice.

PubMed

Choi, Hyeongwon; Kim, Dong-Jin; Nam, Seungwoo; Lim, Sunki; Hwang, Jae-Sung; Park, Ki Sook; Hong, Hyun Sook; Won, Younsun; Shin, Min Kyung; Chung, Eunkyung; Son, Youngsook

2018-03-01

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense pruritus and eczematous lesion. Substance P (SP) is an 11-amino-acid endogenous neuropeptide that belongs to the tachykinin family and several reports recently have supported the anti-inflammatory and tissue repairing roles of SP. In this study, we investigated whether SP can improve AD symptoms, especially the impaired skin barrier function, in 2, 4, 6-trinitrochlorobenzene (TNCB)-induced chronic dermatitis of NC/Nga mice or not. AD-like dermatitis was induced in NC/Nga mice by repeated sensitization with TNCB for 5 weeks. The experimental group designations and topical treatments were as follows: vehicle group (AD-VE); SP group (AD-SP); and SP with NK1R antagonist CP99994 (AD-SP-A) group. Histological analysis was performed to evaluate epidermal differentiation, dermal integrity, and epidermal nerve innervation in AD-like lesions. The skin barrier functions and pruritus of NC/Nga mice were evaluated by measuring transepidermal water loss (TEWL) and scratching behavior, respectively. Topical SP treatment resulted in significant down-regulation of Ki67 and the abnormal-type keratins (K) K6, K16, and K17, restoration of filaggrin and claudin-1, marked reduction of TEWL, and restoration of basement membrane and dermal collagen deposition, even under continuous sensitization of low dose TNCB. In addition, SP significantly reduced innervation of itch-evoking nerve fibers, gelatinase activity and nerve growth factor (NGF) expression in the epidermis but upregulated semaphorin-3A (Sema3A) expression in the epidermis, along with reduced scratching behavior in TNCB-treated NC/Nga mice. All of these effects were completely reversed by co-treatment with the NK1R antagonist CP99994. In cultured human keratinocytes, SP treatment reduced expression of TGF-α, but upregulated TGF-β and Sema3A. Topically administered SP can restore normal skin barrier function, reduce epidermal infiltration of itch-evoking nerve fibers in the AD-like skin lesions, and alleviate scratching behavior. Thus, SP may be proposed as a potential medication for chronic dermatitis and AD. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1α activation following ischemia–reperfusion injury

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

Funk, Jason A., E-mail: funkj@musc.edu; Schnellmann, Rick G., E-mail: schnell@musc.edu; Ralph H. Johnson VA Medical Center, Charleston, SC 29401

Kidney ischemia–reperfusion (I/R) injury elicits cellular injury in the proximal tubule, and mitochondrial dysfunction is a pathological consequence of I/R. Promoting mitochondrial biogenesis (MB) as a repair mechanism after injury may offer a unique strategy to restore both mitochondrial and organ function. Rats subjected to bilateral renal pedicle ligation for 22 min were treated once daily with the SIRT1 activator SRT1720 (5 mg/kg) starting 24 h after reperfusion until 72 h–144 h. SIRT1 expression was elevated in the renal cortex of rats after I/R + vehicle treatment (IRV), but was associated with less nuclear localization. SIRT1 expression was even furthermore » augmented and nuclear localization was restored in the kidneys of rats after I/R + SRT1720 treatment (IRS). PGC-1α was elevated at 72 h–144 h in IRV and IRS kidneys; however, SRT1720 treatment induced deacetylation of PGC-1α, a marker of activation. Mitochondrial proteins ATP synthase β, COX I, and NDUFB8, as well as mitochondrial respiration, were diminished 24 h–144 h in IRV rats, but were partially or fully restored in IRS rats. Urinary kidney injury molecule-1 (KIM-1) was persistently elevated in both IRV and IRS rats; however, KIM-1 tissue expression was attenuated in IRS rats. Additionally, sustained loss of Na{sup +},K{sup +}–ATPase expression and basolateral localization and elevated vimentin in IRV rats was normalized in IRS rats, suggesting restoration of a differentiated, polarized tubule epithelium. The results suggest that SRT1720 treatment expedited recovery of mitochondrial protein expression and function by enhancing MB, which was associated with faster proximal tubule repair. Targeting MB may offer unique therapeutic strategy following ischemic injury. - Highlights: • We examined recovery of mitochondrial and renal function after ischemia–reperfusion. • SRT1720 treatment after I/R induced mitochondrial biogenesis via SIRT1/PGC-1α. • Recovery of mitochondrial function was expedited with SRT1720 treatment. • Restoration of tubule homeostasis was expedited with SRT1720 treatment. • Activators of SIRT1 and PGC-1α may offer new therapeutic targets for AKI.« less

Pediatric jaw fractures: indications for open reduction.

PubMed

Krausen, A S; Samuel, M

1979-01-01

Jaw fractures in children are generally managed without major surgical intervention. Closed reduction usually is sufficient to restore normal anatomy and function. The one inviolate principle is early treatment. During the past three years, four pediatric jaw fractures that required open reduction were treated. This mode of treatment was necessitated by the limitations imposed by pediatric dental anatomy and by the type of fractures encountered. In at least 24 months of follow-up, no dental problems have been seen.

Neurotrophin expression and laryngeal muscle pathophysiology following recurrent laryngeal nerve transection

PubMed Central

WANG, BAOXIN; YUAN, JUNJIE; XU, JIAFENG; XIE, JIN; WANG, GUOLIANG; DONG, PIN

2016-01-01

Laryngeal palsy often occurs as a result of recurrent laryngeal or vagal nerve injury during oncological surgery of the head and neck, affecting quality of life and increasing economic burden. Reinnervation following recurrent laryngeal nerve (RLN) injury is difficult despite development of techniques, such as neural anastomosis, nerve grafting and creation of a laryngeal muscle pedicle. In the present study, due to the limited availability of human nerve tissue for research, a rat model was used to investigate neurotrophin expression and laryngeal muscle pathophysiology in RLN injury. Twenty-five male Sprague-Dawley rats underwent right RLN transection with the excision of a 5-mm segment. Vocal fold movements, vocalization, histology and immunostaining were evaluated at different time-points (3, 6, 10 and 16 weeks). Although vocalization was restored, movement of the vocal fold failed to return to normal levels following RLN injury. The expression of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor differed in the thyroarytenoid (TA) and posterior cricoarytenoid muscles. The number of axons did not increase to baseline levels over time. Furthermore, normal muscle function was unlikely with spontaneous reinnervation. During regeneration following RLN injury, differences in the expression levels of neurotrophic factors may have resulted in preferential reinnervation of the TA muscles. Data from the present study indicated that neurotrophic factors may be applied for restoring the function of the laryngeal nerve following recurrent injury. PMID:26677138

Neurotrophin expression and laryngeal muscle pathophysiology following recurrent laryngeal nerve transection.

PubMed

Wang, Baoxin; Yuan, Junjie; Xu, Jiafeng; Xie, Jin; Wang, Guoliang; Dong, Pin

2016-02-01

Laryngeal palsy often occurs as a result of recurrent laryngeal or vagal nerve injury during oncological surgery of the head and neck, affecting quality of life and increasing economic burden. Reinnervation following recurrent laryngeal nerve (RLN) injury is difficult despite development of techniques, such as neural anastomosis, nerve grafting and creation of a laryngeal muscle pedicle. In the present study, due to the limited availability of human nerve tissue for research, a rat model was used to investigate neurotrophin expression and laryngeal muscle pathophysiology in RLN injury. Twenty-five male Sprague-Dawley rats underwent right RLN transection with the excision of a 5-mm segment. Vocal fold movements, vocalization, histology and immunostaining were evaluated at different time-points (3, 6, 10 and 16 weeks). Although vocalization was restored, movement of the vocal fold failed to return to normal levels following RLN injury. The expression of brain‑derived neurotrophic factor and glial cell line-derived neurotrophic factor differed in the thyroarytenoid (TA) and posterior cricoarytenoid muscles. The number of axons did not increase to baseline levels over time. Furthermore, normal muscle function was unlikely with spontaneous reinnervation. During regeneration following RLN injury, differences in the expression levels of neurotrophic factors may have resulted in preferential reinnervation of the TA muscles. Data from the present study indicated that neurotrophic factors may be applied for restoring the function of the laryngeal nerve following recurrent injury.

The Effect of Early Visual Deprivation on the Neural Bases of Auditory Processing.

PubMed

Guerreiro, Maria J S; Putzar, Lisa; Röder, Brigitte

2016-02-03

Transient congenital visual deprivation affects visual and multisensory processing. In contrast, the extent to which it affects auditory processing has not been investigated systematically. Research in permanently blind individuals has revealed brain reorganization during auditory processing, involving both intramodal and crossmodal plasticity. The present study investigated the effect of transient congenital visual deprivation on the neural bases of auditory processing in humans. Cataract-reversal individuals and normally sighted controls performed a speech-in-noise task while undergoing functional magnetic resonance imaging. Although there were no behavioral group differences, groups differed in auditory cortical responses: in the normally sighted group, auditory cortex activation increased with increasing noise level, whereas in the cataract-reversal group, no activation difference was observed across noise levels. An auditory activation of visual cortex was not observed at the group level in cataract-reversal individuals. The present data suggest prevailing auditory processing advantages after transient congenital visual deprivation, even many years after sight restoration. The present study demonstrates that people whose sight was restored after a transient period of congenital blindness show more efficient cortical processing of auditory stimuli (here speech), similarly to what has been observed in congenitally permanently blind individuals. These results underscore the importance of early sensory experience in permanently shaping brain function. Copyright © 2016 the authors 0270-6474/16/361620-11$15.00/0.

Losartan improves cerebrovascular function in a mouse model of Alzheimer's disease with combined overproduction of amyloid-β and transforming growth factor-β1.

PubMed

Papadopoulos, Panayiota; Tong, Xin-Kang; Imboden, Hans; Hamel, Edith

2017-06-01

Alterations of the renin-angiotensin system have been implicated in the pathogenesis of Alzheimer's disease. We tested the efficacy of losartan (10 mg/kg/day for three months), a selective angiotensin II type 1 receptor antagonist, in alleviating cerebrovascular and cognitive deficits in double-transgenic mice (six months at endpoint) that overexpress a mutated form of the human amyloid precursor protein (APP Swe,Ind ) and a constitutively active form of the transforming growth factor-β1, thereafter named A/T mice. Losartan rescued cerebrovascular reactivity, particularly the dilatory responses, but failed to attenuate astroglial activation and to normalize the neurovascular uncoupling response to sensory stimulation. The cognitive deficits of A/T mice were not restored by losartan nor were the increased brain levels of soluble and insoluble Aβ 1-40 and Aβ 1-42 peptides normalized. Our results are the first to demonstrate the capacity of losartan to improve cerebrovascular reactivity in an Alzheimer's disease mouse model of combined Aβ-induced vascular oxidative stress and transforming growth factor-β1-mediated vascular fibrosis. These data suggest that losartan may be promising for restoring cerebrovascular function in patients with vascular diseases at risk for vascular dementia or Alzheimer's disease. However, a combined therapy may be warranted for rescuing both vascular and cognitive deficits in a multifaceted pathology like Alzheimer's disease.

Longitudinal Dynamics of 3-Dimensional Components of Selfhood After Severe Traumatic Brain Injury: A qEEG Case Study.

PubMed

Fingelkurts, Andrew A; Fingelkurts, Alexander A

2017-09-01

In this report, we describe the case of a patient who sustained extremely severe traumatic brain damage with diffuse axonal injury in a traffic accident and whose recovery was monitored during 6 years. Specifically, we were interested in the recovery dynamics of 3-dimensional components of selfhood (a 3-dimensional construct model for the complex experiential selfhood has been recently proposed based on the empirical findings on the functional-topographical specialization of 3 operational modules of brain functional network responsible for the self-consciousness processing) derived from the electroencephalographic (EEG) signal. The analysis revealed progressive (though not monotonous) restoration of EEG functional connectivity of 3 modules of brain functional network responsible for the self-consciousness processing, which was also paralleled by the clinically significant functional recovery. We propose that restoration of normal integrity of the operational modules of the self-referential brain network may underlie the positive dynamics of 3 aspects of selfhood and provide a neurobiological mechanism for their recovery. The results are discussed in the context of recent experimental studies that support this inference. Studies of ongoing recovery after severe brain injury utilizing knowledge about each separate aspect of complex selfhood will likely help to develop more efficient and targeted rehabilitation programs for patients with brain trauma.

Restoration of euglycemia after duodenal bypass surgery is reliant on central and peripheral inputs in Zucker fa/fa rats.

PubMed

Jiao, Jian; Bae, Eun Ju; Bandyopadhyay, Gautam; Oliver, Jason; Marathe, Chaitra; Chen, Michael; Hsu, Jer-Yuan; Chen, Yu; Tian, Hui; Olefsky, Jerrold M; Saberi, Maziyar

2013-04-01

Gastrointestinal bypass surgeries that result in rerouting and subsequent exclusion of nutrients from the duodenum appear to rapidly alleviate hyperglycemia and hyperinsulinemia independent of weight loss. While the mechanism(s) responsible for normalization of glucose homeostasis remains to be fully elucidated, this rapid normalization coupled with the well-known effects of vagal inputs into glucose homeostasis suggests a neurohormonally mediated mechanism. Our results show that duodenal bypass surgery on obese, insulin-resistant Zucker fa/fa rats restored insulin sensitivity in both liver and peripheral tissues independent of body weight. Restoration of normoglycemia was attributable to an enhancement in key insulin-signaling molecules, including insulin receptor substrate-2, and substrate metabolism through a multifaceted mechanism involving activation of AMP-activated protein kinase and downregulation of key regulatory genes involved in both lipid and glucose metabolism. Importantly, while central nervous system-derived vagal nerves were not essential for restoration of insulin sensitivity, rapid normalization in hepatic gluconeogenic capacity and basal hepatic glucose production required intact vagal innervation. Lastly, duodenal bypass surgery selectively altered the tissue concentration of intestinally derived glucoregulatory hormone peptides in a segment-specific manner. The present data highlight and support the significance of vagal inputs and intestinal hormone peptides toward normalization of glucose and lipid homeostasis after duodenal bypass surgery.

Sodium salicylate restores the impaired insulin response to glucose and improves glucose tolerance in heroin addicts.

PubMed

Giugliano, D; Quatraro, A; Consoli, G; Stante, A; Simeone, V; Ceriello, A; Paolisso, G; Torella, R

1987-01-01

Plasma glucose, insulin, C-peptide, glucagon and growth hormone responses to intravenous glucose were evaluated in 10 heroin addicts in the basal state and during an infusion of sodium salicylate, an inhibitor of endogenous prostaglandin synthesis. Ten normal subjects, matched for age, sex and weight served as controls. In the basal state, the heroin addicts had markedly reduced insulin responses to intravenous glucose and low glucose disappearance rates (p less than 0.01 vs controls). The infusion of sodium salicylate caused a striking increase of the acute insulin response to intravenous glucose (from 14.5 +/- 4 microU/ml to 88 +/- 11 microU/ml, p less than 0.001) and restored to normal the reduced glucose tolerance (KG from 1.10 +/- 0.1% min-1 to 2.04 +/- 0.19% min-1). Hypoglycemic values were found in all addicts at the end of the test during salicylate infusion. Indomethacin pretreatment in five additional addicts also caused normalization of the impaired insulin responses to the intravenous glucose challenge and restored to normal the reduced glucose disappearance rate. Plasma glucagon and growth hormone levels were normally suppressed by glucose in addicts in basal conditions; sodium salicylate infusion completely overturned these hormonal responses which became positive in the first 15 min following the glucose challenge. These results demonstrate that the two prostaglandin synthesis inhibitors can restore the impaired B-cell response to glucose in heroin addicts to normal, indicating that this response is not lost but is inhibited by heroin itself or by other substances, perhaps by the endogenous prostaglandins.

A review of penile elongation surgery

PubMed Central

Gillis, Joshua

2017-01-01

Penile elongation surgery is less commonly performed in the public sector, but involves a collaborative approach between urology and plastic surgery. Congenital and acquired micropenis are the classic surgical indications for penile elongation surgery. The goal of intervention in these patients is to restore a functional penis size in order to allow normal standing micturition, enable satisfying sexual intercourse and improve patient quality of life. Many men seeking elongation actually have normal length penises, but perceive themselves to be small, a psychologic condition termed ‘penile dysmorphophobia’. This paper will review the anatomy and embryology of congenital micropenis and discuss both conservative and surgical management options for men seeking penile elongation therapy. PMID:28217452

A DNA segment spanning the mouse Tnfsf11 transcription unit and its upstream regulatory domain rescues the pleiotropic biologic phenotype of the RANKL null mouse.

PubMed

Onal, Melda; Bishop, Kathleen A; St John, Hillary C; Danielson, Allison L; Riley, Erin M; Piemontese, Marilina; Xiong, Jinhu; Goellner, Joseph J; O'Brien, Charles A; Pike, J Wesley

2015-05-01

Receptor activator of NF-κB ligand (RANKL) is a TNFα-like cytokine that is produced by a diverse set of lineage-specific cells and is involved in a wide variety of physiological processes that include skeletal remodeling, lymph node organogenesis, mammary gland development, and thermal regulation. Consistent with these diverse functions, control of RANKL expression is accomplished in a cell-specific fashion via a set of at least 10 regulatory enhancers that are located up to 170 kb upstream of the gene's transcriptional start site. Here we examined the in vivo consequence of introducing a contiguous DNA segment containing these components into a genetically deleted RANKL null mouse strain. In contrast to RANKL null littermates, null mice containing the transgene exhibited normalized body size, skeletal development, and bone mass as well as normal bone marrow cavities, normalized spleen weights, and the presence of developed lymph nodes. These mice also manifested normalized reproductive capacity, including the ability to lactate and to produce normal healthy litters. Consistent with this, the transgene restored endogenous-like RANKL transcript levels in several RANKL-expressing tissues. Most importantly, restoration of RANKL expression from this segment of DNA was fully capable of rescuing the complex aberrant skeletal and immune phenotype of the RANKL null mouse. RANKL also restored appropriate levels of B220+ IgM+ and B220+ IgD+ B cells in spleen. Finally, we found that RANKL expression from this transgene was regulated by exogenously administered 1,25(OH)2 D3 , parathyroid hormone (PTH), and lipopolysaccharide (LPS), thus recapitulating the ability of these same factors to regulate the endogenous gene. These findings fully highlight the properties of the Tnfsf11 gene locus predicted through previous in vitro dissection. We conclude that the mouse Tnfsf11 gene locus identified originally through unbiased chromatin immunoprecipitation with DNA microarray (ChIP-chip) analysis contains the necessary genetic information to direct appropriate tissue-specific and factor-regulated RANKL expression in vivo. © 2014 American Society for Bone and Mineral Research.

Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I.

PubMed

Sippel, Trisha R; White, Jason; Nag, Kamalika; Tsvankin, Vadim; Klaassen, Marci; Kleinschmidt-DeMasters, B K; Waziri, Allen

2011-11-15

The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell-derived peripheral immunosuppression in patients with GBM. Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell-mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation. We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3ζ expression within peripheral blood from patients with GBM. Sorted CD11b(+) cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation. These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients.

Bilobed perforator free flaps for combined hemitongue and floor-of-the-mouth defects.

PubMed

Longo, B; Ferri, G; Fiorillo, A; Rubino, C; Santanelli, F

2013-11-01

Combined hemiglossectomy and floor-of-the-mouth defects need accurate reconstructive planning to restore swallowing and speech function. The aim of this prospective study was to evaluate outcomes of the bilobed design applied to perforator free flaps for combined hemitongue and floor-of-the-mouth defects. Twelve patients with a mean age of 71 years (range, 60-84) addressed to combined hemiglossectomy and floor-of-the-mouth resection and bilobed-shaped perforator free-flap reconstruction were prospectively enrolled. Defects were classified as follows: type 1, including only the anterior mobile portion of the tongue (n = 3); type 2, involving both mobile tongue and tongue base (n = 6); and type 3, including segmental mandibulectomy combined with a type 1 or type 2 defect (n = 3). The Kruskal-Wallis and Bonferroni post hoc tests were used to compare outcomes. Type 1 defects were reconstructed by three anterolateral thigh (ALT) perforator flaps; type 2 defects were reconstructed by four ALT flaps and two vertical deep inferior epigastric perforator flaps; and type 3 defects were restored by three osteocutaneous fibula flaps. Eleven flaps (91.6%) healed uneventfully, while one (8.4%) suffered a small area of skin necrosis whose revision did not compromise functional results. Six patients achieved normal intelligible speech, five had acceptable intelligible speech and one had unintelligible speech (p = 0.356). Swallowing function was considered normal in eight patients and with mild impairment in four (p = 0.178). Cosmesis resulted excellent in seven patients and good in five (p = 0.855). The bilobed-shaped perforator free flaps were shown to be a safe and predictable solution for combined hemitongue and floor-of-the-mouth defects providing optimal aesthetic and functional outcomes. Copyright © 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Restoration of Cardiac Tissue Thyroid Hormone Status in Experimental Hypothyroidism: A Dose-Response Study in Female Rats

PubMed Central

Weltman, Nathan Y.; Ojamaa, Kaie; Savinova, Olga V.; Chen, Yue-Feng; Schlenker, Evelyn H.; Zucchi, Riccardo; Saba, Alessandro; Colligiani, Daria; Pol, Christine J.

2013-01-01

Thyroid hormones (THs) play a pivotal role in regulating cardiovascular homeostasis. To provide a better understanding of the coordinated processes that govern cardiac TH bioavailability, this study investigated the influence of serum and cardiac TH status on the expression of TH transporters and cytosolic binding proteins in the myocardium. In addition, we sought to determine whether the administration of T3 (instead of T4) improves the relationship between THs in serum and cardiac tissue and cardiac function over a short-term treatment period. Adult female Sprague Dawley rats were made hypothyroid by 7 weeks treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU). After establishing hypothyroidism, rats were assigned to 1 of 5 graded T3 dosages plus PTU for a 2-week dose-response experiment. Untreated, age-matched rats served as euthyroid controls. PTU was associated with depressed serum and cardiac tissue T3 and T4 levels, arteriolar atrophy, altered TH transporter and cytosolic TH binding protein expression, fetal gene reexpression, and cardiac dysfunction. Short-term administration of T3 led to a mismatch between serum and cardiac tissue TH levels. Normalization of serum T3 levels was not associated with restoration of cardiac tissue T3 levels or cardiac function. In fact, a 3-fold higher T3 dosage was necessary to normalize cardiac tissue T3 levels and cardiac function. Importantly, this study provides the first comprehensive data on the relationship between altered TH status (serum and cardiac tissue), cardiac function, and the coordinated in vivo changes in cardiac TH membrane transporters and cytosolic TH binding proteins in altered TH states. PMID:23594789

Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin.

PubMed

Siddiqui, Almas; Bhaumik, Dipa; Chinta, Shankar J; Rane, Anand; Rajagopalan, Subramanian; Lieu, Christopher A; Lithgow, Gordon J; Andersen, Julie K

2015-09-16

Following its activation by PINK1, parkin is recruited to depolarized mitochondria where it ubiquitinates outer mitochondrial membrane proteins, initiating lysosomal-mediated degradation of these organelles. Mutations in the gene encoding parkin, PARK2, result in both familial and sporadic forms of Parkinson's disease (PD) in conjunction with reductions in removal of damaged mitochondria. In contrast to what has been reported for other PARK2 mutations, expression of the Q311X mutation in vivo in mice appears to involve a downstream step in the autophagic pathway at the level of lysosomal function. This coincides with increased PARIS expression and reduced expression of a reciprocal signaling pathway involving the master mitochondrial regulator peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) and the lysosomal regulator transcription factor EB (TFEB). Treatment with rapamycin was found to independently restore PGC1α-TFEB signaling in a manner not requiring parkin activity and to abrogate impairment of mitochondrial quality control and neurodegenerative features associated with this in vivo model. Losses in PGC1α-TFEB signaling in cultured rat DAergic cells expressing the Q311X mutation associated with reduced mitochondrial function and cell viability were found to be PARIS-dependent and to be independently restored by rapamycin in a manner requiring TFEB. Studies in human iPSC-derived neurons demonstrate that TFEB induction can restore mitochondrial function and cell viability in a mitochondrially compromised human cell model. Based on these data, we propose that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via upregulation of TFEB function. Mutations in PARK2 are generally associated with loss in ability to interact with PINK1, impacting on autophagic initiation. Our data suggest that, in the case of at least one parkin mutation, Q311X, detrimental effects are due to inhibition at the level of downstream lysosomal function. Mechanistically, this involves elevations in PARIS protein levels and subsequent effects on PGC1α-TFEB signaling that normally regulates mitochondrial quality control. Treatment with rapamycin independently restores PGC1α-TFEB signaling in a manner not requiring parkin activity and abrogates subsequent mitochondrial impairment and neuronal cell loss. Taken in total, our data suggest that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via rapamycin. Copyright © 2015 the authors 0270-6474/15/3512833-12$15.00/0.

A combination of cytokines EGF and CNTF protects the functional beta cell mass in mice with short-term hyperglycaemia.

PubMed

Lemper, Marie; De Groef, Sofie; Stangé, Geert; Baeyens, Luc; Heimberg, Harry

2016-09-01

When the beta cell mass or function declines beyond a critical point, hyperglycaemia arises. Little is known about the potential pathways involved in beta cell rescue. As two cytokines, epidermal growth factor (EGF) and ciliary neurotrophic factor (CNTF), restored a functional beta cell mass in mice with long-term hyperglycaemia by reprogramming acinar cells that transiently expressed neurogenin 3 (NGN3), the current study assesses the effect of these cytokines on the functional beta cell mass after an acute chemical toxic insult. Glycaemia and insulin levels, pro-endocrine gene expression and beta cell origin, as well as the role of signal transducer and activator of transcription 3 (STAT3) signalling, were assessed in EGF+CNTF-treated mice following acute hyperglycaemia. The mice were hyperglycaemic 1 day following i.v. injection of the beta cell toxin alloxan, when the two cytokines were applied. One week later, 68.6 ± 4.6% of the mice had responded to the cytokine treatment and increased their insulin(+) cell number to 30% that of normoglycaemic control mice, resulting in restoration of euglycaemia. Although insulin(-) NGN3(+) cells appeared following acute EGF+CNTF treatment, genetic lineage tracing showed that the majority of the insulin(+) cells originated from pre-existing beta cells. Beta cell rescue by EGF+CNTF depends on glycaemia rather than on STAT3-induced NGN3 expression in acinar cells. In adult mice, EGF+CNTF allows the rescue of beta cells in distress when treatment is given shortly after the diabetogenic insult. The rescued beta cells restore a functional beta cell mass able to control normal blood glucose levels. These findings may provide new insights into compensatory pathways activated early after beta cell loss.

Disability dilemmas and rehabilitation tensions: a twentieth century inheritance.

PubMed

Greenwood, J G

1985-01-01

Although disability has gradually become part of the social justice concept in Western nations since the seventeenth century, and is a current world-wide social concern, it is no way as readily definable or determinable as race, gender, age or even poverty, other issues of social justice. It remains a relative term despite efforts to contain it. The World Health Organization's definition for disability is a restriction or lack of ability to perform an activity in the manner or within the range considered normal for a human being, arising as a consequence of physiological, psychological or anatomical impairment. Under the impairment/disability paradigm, rehabilitation interventions aim for the restoration of maximum functional activity or independence. The consequences of impairment and disability can, but do not necessarily, lead to handicaps or conditions of disadvantage, the composite result of individual functional limitations and faults in physical, cultural, social, economic and political environments. Rehabilitation for handicapping conditions then implies not necessarily the restoration of maximum functional activity or independence, but the restoration of maximum social function, including work and family roles. Recent literature on disability and rehabilitation research and policy reflects the complex and expanding context, but the relativity of the concepts involved, particularly the slippage between disability and handicap, create problems of consistently determining and communicating need. For the literature, certain dilemmas are evident in determining and providing for the needs of disabled persons: self-perceived and self-defined need vs bureaucratic standards and statistical definition; resource compensation vs resource enhancement; urban vs rural needs. Closely related to these perplexing problems are tensions in rehabilitation approaches: institutional and community approaches; individual functional improvement and environmental improvement. This paper considers the dilemmas and tensions as reported, and on that basis certain policy issues are tabulated and presented.

Restoring penis sensation in patients with low spinal cord lesions: the role of the remaining function of the dorsal nerve in a unilateral or bilateral TOMAX procedure.

PubMed

Overgoor, Max L E; Braakhekke, Jan P; Kon, Moshe; De Jong, Tom P V M

2015-04-01

The recently developed TOMAX-procedure restores unilateral genital sensation, improving sexual health in men with a low spinal lesion (LSL). It connects one dorsal nerve of the penis (DNP) to the intact ipsilateral ilioinguinal nerve. We proposed bilateral neurotization for full sensation of the glans but this entails cutting both DNPs, risking patients' erection/ejaculation ability. The objective was to select patients for a bilateral TOMAX-procedure by measuring remaining DNP function, and perform the first bilateral cases. In 30 LSL patients with no penile- but normal groin sensation selected for a unilateral TOMAX-procedure the integrity of the sacral-reflex-arc and DNP function was tested pre-operatively using bilateral needle electromyography (EMG)-bulbocavernosus reflex (BCR) measurements, and an interview about reflex erections (RE) ability. In 13 spina bifida- and 17 spinal cord injury patients [median age 29.5 years (range 13-59 years), spinal lesion T12 (incomplete) to sacral], seven (23%) patients reported RE, four (57%) with intact BCR, and of nine (30%) patients with intact BCR, four reported RE (44%). Even patients with a LSL and no penile sensation can have signs of remaining DNP function, but cutting both DNPs to restore full glans sensation in a bilateral TOMAX-procedure might interfere with their RE/ejaculation. To avoid this risk, we propose a selecting-protocol for a unilateral- or bilateral procedure using RE and BCR measurements. Using this protocol, three patients were bilaterally operated with promising preliminary results. Full sensation of the glans could lead to further improvement in sexual function. © 2014 Wiley Periodicals, Inc.

Down-regulation of TCF21 by hypermethylation induces cell proliferation, migration and invasion in colorectal cancer

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

Dai, Youyi; Duan, Huaxin; The First Affiliated Hospital of Hunan Normal University

Epigenetic alteration induced loss function of the transcription factor 21 (TCF21) has been associated with different types of human cancers. However, the epigenetic regulation and molecular functions of TCF21 in colorectal cancer (CRC) remain unknown. In this study, TCF21 expression levels and methylation status of its promoter region in CRC cell lines (n = 5) and CRC tissues (n = 151) as well as normal colorectal mucosa (n = 30) were assessed by RTq-PCR and methylation analysis (methylation specific PCR, MSP and bisulfite sequencing PCR, BSP), respectively. The cellular functions of TCF21 on CRC cell proliferation, apoptosis, invasion and migration were investigated in vitro. Our data revealedmore » that TCF21 was frequently silenced by promoter hypermethylation in both tested CRC cell lines and primary CRC, and correlation analysis between methylation status and clinicopathologic parameters found that TCF21 methylation was significantly correlated with lymph node invasion (P = 0.013), while no significant correlation was found in other parameters. In addition, demethylation treatment resulted in re-expression of TCF21 in CRC cell lines, and cellular function experiments revealed that restoration of TCF21 inhibited CRC cell proliferation, promoted apoptosis and suppressed cell invasion and migration, suggesting that TCF21 may function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in CRC development. - Highlights: • TCF21 was frequently silenced by promoter DNA methylation in CRC cells. • TCF21 was frequently methylated in primary CRC and significantly correlated with metastasis. • Restoration of TCF21 promotes cell apoptosis of CRC cells. • Restoration of TCF21 inhibits cell invasion and migration of CRC cells.« less

In Vivo Shoulder Function After Surgical Repair of a Torn Rotator Cuff

PubMed Central

Bey, Michael J.; Peltz, Cathryn D.; Ciarelli, Kristin; Kline, Stephanie K.; Divine, George W.; van Holsbeeck, Marnix; Muh, Stephanie; Kolowich, Patricia A.; Lock, Terrence R.; Moutzouros, Vasilios

2015-01-01

Background Surgical repair of a torn rotator cuff is based on the belief that repairing the tear is necessary to restore normal glenohumeral joint (GHJ) mechanics and achieve a satisfactory clinical outcome. Hypothesis Dynamic joint function is not completely restored by rotator cuff repair, thus compromising shoulder function and potentially leading to long-term disability. Study Design Controlled laboratory study and Case series; Level of evidence, 4. Methods Twenty-one rotator cuff patients and 35 control participants enrolled in the study. Biplane radiographic images were acquired bilaterally from each patient during coronal-plane abduction. Rotator cuff patients were tested at 3, 12, and 24 months after repair of a supraspinatus tendon tear. Control participants were tested once. Glenohumeral joint kinematics and joint contact patterns were accurately determined from the biplane radiographic images. Isometric shoulder strength and patient-reported outcomes were measured at each time point. Ultrasound imaging assessed rotator cuff integrity at 24 months after surgery. Results Twenty of 21 rotator cuff repairs appeared intact at 24 months after surgery. The humerus of the patients’ repaired shoulder was positioned more superiorly on the glenoid than both the patients’ contralateral shoulder and the dominant shoulder of control participants. Patient-reported outcomes improved significantly over time. Shoulder strength also increased over time, although strength deficits persisted at 24 months for most patients. Changes over time in GHJ mechanics were not detected for either the rotator cuff patients’ repaired or contralateral shoulders. Clinical outcome was associated with shoulder strength but not GHJ mechanics. Conclusion Surgical repair of an isolated supraspinatus tear may be sufficient to keep the torn rotator cuff intact and achieve satisfactory patient-reported outcomes, but GHJ mechanics and shoulder strength are not fully restored with current repair techniques. Clinical Relevance The study suggests that current surgical repair techniques may be effective for reducing pain but have not yet been optimized for restoring long-term shoulder function. PMID:21737834

Yap is required for ependymal integrity and is suppressed in LPA-induced hydrocephalus

PubMed Central

Park, Raehee; Moon, Uk Yeol; Park, Jun Young; Hughes, Lucinda J.; Johnson, Randy L.; Cho, Seo-Hee; Kim, Seonhee

2016-01-01

Timely generation and normal maturation of ependymal cells along the aqueduct are critical for preventing physical blockage between the third and fourth ventricles and the development of fetal non-communicating hydrocephalus. Our study identifies Yap, the downstream effector of the evolutionarily conserved Hippo pathway, as a central regulator for generating developmentally controlled ependymal cells along the ventricular lining of the aqueduct. Yap function is necessary for proper proliferation of progenitors and apical attachment of ependymal precursor cells. Importantly, an injury signal initiated by lysophosphatidic acid (LPA), an upstream regulator of Yap that can cause fetal haemorrhagic hydrocephalus, deregulates Yap in the developing aqueduct. LPA exposure leads to the loss of N-cadherin concentrations at the apical endfeet, which can be partially restored by forced Yap expression and more efficiently by phosphomimetic Yap. These results reveal a novel function of Yap in retaining tissue junctions during normal development and after fetal brain injury. PMID:26754915

Full-thickness small intestine necrosis with midgut volvulus, distributed in a patchy fashion, is reversible with moderate blood flow: resumption of normal function to non-viable intestine.

PubMed

Amano, Hizuru; Uchida, Hiroo; Kawashima, Hiroshi; Tanaka, Yujiro; Kishimoto, Hiroshi

2014-08-01

Midgut volvulus is a highly life-threatening condition that carries a high risk of short gut syndrome. We report a case of catastrophic neonatal midgut volvulus in which second-look laparotomy revealed apparently non-viable remnant small intestine but with a moderate blood supply. Full-thickness small intestine necrosis was distributed in a patchy fashion, with non-viable and necrotic areas distributed so widely that no portion of the intestine could be resected. A section of full-thickness necrotic intestine preserved at surgery was able to regenerate, and normal function was restored over a period of 1 month. This case indicated that intestinal resumption may be dependent on blood flow. Even when intestinal viability is questionable, preservation enables the chance of regeneration if moderate blood flow is present.

Central leptin action on euglycemia restoration in type 1 diabetes: Restraining responses normally induced by fasting?

PubMed

Xu, Yuanzhong; Tong, Qingchun

2017-07-01

Leptin monotherapy is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D), yet the underlying mechanism remains poorly understood. Accumulating evidence demonstrates that the brain mediates the leptin action on euglycemia restoration. Here, we first review evidence supporting that symptoms in T1D resemble an uncontrolled response to fasting. Then, we discuss recent research progress on brain neurons and their neurotransmitters that potentially mediate the leptin action. Finally, peripheral effective pathways, which are normally involved in fasting responses and associated with leptin action on euglycemia restoration in T1D, will also be discussed. This summary complements several previous excellent reviews on this topic (Meek and Morton, 2016; Perry et al., 2016; Fujikawa and Coppari, 2015). A deep understanding of neurocircuitry and the peripheral effective pathways that mediate the leptin action on euglycemia restoration will likely lead to novel targets for an insulin-independent therapeutics against T1D. Copyright © 2016 Elsevier Ltd. All rights reserved.

Body composition in men with anorexia nervosa: Longitudinal study.

PubMed

El Ghoch, Marwan; Calugi, Simona; Milanese, Chiara; Bazzani, Paola Vittoria; Dalle Grave, Riccardo

2017-07-01

To compare body composition patterns before and after complete weight restoration in men with anorexia nervosa. Dual-energy X-ray absorptiometry (DXA) was used to measure body composition patterns in 10 men with anorexia nervosa before and after complete weight restoration, and in 10 healthy men matched to age and patients' post-treatment body mass index (BMI). Before weight restoration, men with anorexia nervosa displayed lower total body fat mass (FM) and lean mass (LBM) than those in the healthy comparison group, with a greater FM loss from the extremity than the trunk region. After short-term weight restoration, patients displayed complete normalization in total LBM and FM, but greater deposition of FM in the trunk region. Short-term weight restoration can normalize body composition patterns in men with anorexia nervosa, but results in a central adiposity phenotype. The clinical implication of this finding is unknown, but should be explored given the high levels of concern about central adiposity in anorexia nervosa. © 2017 Wiley Periodicals, Inc.

Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer's disease.

PubMed

Lin, Ai-Ling; Jahrling, Jordan B; Zhang, Wei; DeRosa, Nicholas; Bakshi, Vikas; Romero, Peter; Galvan, Veronica; Richardson, Arlan

2017-01-01

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood-brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects. © The Author(s) 2015.

The Integral System

PubMed Central

2011-01-01

The Integral System is a total care management system based on the Integral Theory which states ‘prolapse and symptoms of urinary stress, urge, abnormal bowel & bladder emptying, and some forms of pelvic pain, mainly arise, for different reasons, from laxity in the vagina or its supporting ligaments, a result of altered connective tissue’. Normal function The organs are suspended by ligaments against which muscles contract to open or close the their outlet tubes, urethra and anus. These ligaments fall naturally into a three-zone zone classification, anterior, middle, and posterior. Dysfunction Damaged ligaments weaken the force of muscle contraction, causing prolapse and abnormal bladder and bowel symptoms Diagnosis A pictorial diagnostic algorithm relates specific symptoms to damaged ligaments in each zone. Treatment In mild cases, new pelvic floor muscle exercises based on a squatting principle strengthen the natural closure muscles and their ligamentous insertions, thereby improving the symptoms predicted by the Theory. With more severe cases, polypropylene tapes applied through “keyhole” incision using special instruments reinforce the damaged ligaments, restoring structure and function. Problems that can be potentially addressed by application of the Integral System Urinary stress incontinenceUrinary urge incontinenceAbnormal bladder emptyingFacal incontinence and “obstructed evacuation” (“constipation”)Pelvic pain, and some types of vulvodynia and interstitial cystitisOrgan prolapse Conclusions Organ prolapse and symptoms are related, and both are mainly caused by laxity in the four main suspensory ligaments and perineal body. Restoration of ligament/fascial length and tension is required to restore anatomy and function. PMID:24578877

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

Kajimoto, Masaki; Ledee, Dolena R.; Xu, Chun

Background: Extracorporeal membrane oxygenation (ECMO) provides a rescue for children with severe cardiac failure. We previously showed that triiodothyronine (T3) improves cardiac function by modulating pyruvate oxidation during weaning. This study was focused on fatty acid (FA) metabolism modulated by T3 for weaning from ECMO after cardiac injury. Methods: Nineteen immature piglets (9.1-15.3 kg) were separated into 3 groups with ECMO (6.5 hours) and wean: normal circulation (Group-C);transient coronary occlusion (10 minutes) followed by ECMO (Group-IR); and IR with T3 supplementation (Group-IR-T3). 13-Carbon labeled lactate, medium-chain and long-chain FAs were infused as oxidative substrates. Substrate fractional contribution to the citricmore » acid cycle (FC) was analyzed by 13-Carbon nuclear magnetic resonance. Results: ECMO depressed circulating T3 levels to 40% baseline at 4 hours and were restored in Group-IR-T3. Group-IR decreased cardiac power, which was not fully restorable and 2 pigs were lost because of weaning failure. Group-IR also depressed FC-lactate, while the excellent contractile function and energy efficiency in Group-IR-T3 occurred along with a marked FC-lactate increase and [ATP]/[ADP] without either decreasing FC-FAs or elevating myocardial oxygen consumption over Group-C or -IR. Conclusions: T3 releases inhibition of lactate oxidation following ischemia-reperfusion injury without impairing FA oxidation. These findings indicate that T3 depression during ECMO is maladaptive, and that restoring levels improves metabolic flux and enhances contractile function during weaning.« less

Opioid maintenance therapy restores CD4+ T cell function by normalizing CD4+CD25(high) regulatory T cell frequencies in heroin user.

PubMed

Riss, Gina-Lucia; Chang, Dae-In; Wevers, Carolin; Westendorf, Astrid M; Buer, Jan; Scherbaum, Norbert; Hansen, Wiebke

2012-08-01

There is an increasing body of evidence that heroin addiction is associated with severe alterations in immune function, which might contribute to an increased risk to contract infectious diseases like hepatitis B and C or HIV. However, the impact of heroin consumption on the CD4(+) T cell compartment is not well understood. Therefore, we analyzed the frequency and functional phenotype of CD4(+) T cells as well as immune-suppressive CD4(+)CD25(high) regulatory T cells (Tregs) isolated from the peripheral blood of opiate addicts currently abusing heroin (n=27) in comparison to healthy controls (n=25) and opiate addicts currently in opioid maintenance treatment (OMT; n=27). Interestingly, we detected a significant increase in the percentage of CD4(+)CD25(high) Tregs in the peripheral blood of heroin addicted patients in contrast to patients in OMT. The proliferative response of CD4(+) T cells upon stimulation with anti-CD3 and anti-CD28 antibodies was significantly decreased in heroin users, but could be restored by depletion of CD25(high) regulatory T cells from CD4(+) T cells to similar values as observed from healthy controls and patients in OMT. These results suggest that impaired immune responses observed in heroin users are related to the expansion of CD4(+)CD25(high) Tregs and more importantly, can be restored by OMT. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of Hydroxydecine(®) (10-hydroxy-2-decenoic acid) on skin barrier structure and function in vitro and clinical efficacy in the treatment of UV-induced xerosis.

PubMed

Duplan, Hélène; Questel, Emmanuel; Hernandez-Pigeon, Hélène; Galliano, Marie Florence; Caruana, Antony; Ceruti, Isabelle; Ambonati, Marco; Mejean, Carine; Damour, Odile; Castex-Rizzi, Nathalie; Bessou-Touya, Sandrine; Schmitt, Anne-Marie

2011-01-01

10-Hydroxy-2-decenoic acid, a natural fatty acid only found in royal jelly, may be of value in correcting skin barrier dysfunction. We evaluated the activity of Hydroxydecine(®), its synthetic counterpart, in vitro on the regulation of epidermal differentiation markers, ex vivo on the inflammatory response and restoration of skin barrier function, and in vivo on UV-induced xerosis in healthy human volunteers. In cultured normal human keratinocytes, Hydroxydecine(®) induced involucrin, transglutaminase-1 and filaggrin protein production. In topically Hydroxydecine(®)-treated skin equivalents, immunohistochemical analysis revealed an increase in involucrin, transglutaminase-1 and filaggrin staining. In a model of thymic stromal lymphopoietin (TSLP)-induced inflamed epidermis, a Hydroxydecine(®)-containing emulsion inhibited TSLP release. In a model of inflammation and barrier impairment involving human skin explants maintained alive, Hydroxydecine(®) balm restored stratum corneum cohesion and significantly increased filaggrin expression, as shown by immunohistochemistry. It also decreased pro-inflammatory cytokine secretion (IL-4, IL-5 and IL-13). In healthy volunteers with UV-induced xerosis, the hydration index increased by +28.8% (p<0.01) and +60.4% (p<0.001) after 7 and 21 days of treatment with Hydroxydecine(®) cream, respectively. Hydroxydecine(®) thus proved its efficacy in activating keratinocyte differentiation processes in vitro, restoring skin barrier function and reducing inflammation ex vivo, and hydrating dry skin in vivo.

Loss of signal transduction and inhibition of lymphocyte locomotion in a ground-based model of microgravity

NASA Technical Reports Server (NTRS)

Sundaresan, Alamelu; Risin, Diana; Pellis, Neal R.; McIntire, L. V. (Principal Investigator)

2002-01-01

Inflammatory adherence to, and locomotion through the interstitium is an important component of the immune response. Conditions such as microgravity and modeled microgravity (MMG) severely inhibit lymphocyte locomotion in vitro through gelled type I collagen. We used the NASA rotating wall vessel bioreactor or slow-turning lateral vessel as a prototype for MMG in ground-based experiments. Previous experiments from our laboratory revealed that when lymphocytes (human peripheral blood mononuclear cells [PBMCs]) were first activated with phytohemaglutinin followed by exposure to MMG, locomotory capacity was not affected. In the present study, MMG inhibits lymphocyte locomotion in a manner similar to that observed in microgravity. Phorbol myristate acetate (PMA) treatment of PBMCs restored lost locomotory capacity by a maximum of 87%. Augmentation of cellular calcium flux with ionomycin had no restorative effect. Treatment of lymphocytes with mitomycin C prior to exposure to MMG, followed by PMA, restored locomotion to the same extent as when nonmitomycin C-treated lymphocytes were exposed to MMG (80-87%), suggesting that deoxyribonucleic acid replication is not essential for the restoration of locomotion. Thus, direct activation of protein kinase C (PKC) with PMA was effective in restoring locomotion in MMG comparable to the normal levels seen in Ig cultures. Therefore, in MMG, lymphocyte calcium signaling pathways were functional, with defects occurring at either the level of PKC or upstream of PKC.

Involvement of oxidative stress in the impairment in biliary secretory function induced by intraperitoneal administration of aluminum to rats.

PubMed

Gonzalez, Marcela A; Alvarez, Maria Del Lujan; Pisani, Gerardo B; Bernal, Claudio A; Roma, Marcelo G; Carrillo, María C

2007-06-01

We have shown that aluminum (Al) induces cholestasis associated with multiple alterations in hepatocellular transporters involved in bile secretory function, like Mrp2. This work aims to investigate whether these harmful effects are mediated by the oxidative stress caused by the metal. For this purpose, the capability of the antioxidant agent, vitamin E, to counteract these alterations was studied in male Wistar rats. Aluminum hydroxide (or saline in controls) was administered ip (27 mg/kg body weight, three times a week, for 90 d). Vitamin E (600 mg/kg body weight) was coadministered, sc. Al increased lipid peroxidation (+50%) and decreased hepatic glutation levels (-43%) and the activity of glutation peroxidase (-50%) and catalase (-88%). Vitamin E counteracted these effects total or partially. Both plasma and hepatic Al levels reached at the end of the treatment were significantly reduced by vitamin E (-40% and -44%, respectively; p<0.05). Al increased 4 times the hepatic apoptotic index, and this effect was fully counteracted by vitamin E. Bile flow was decreased in Altreated rats (-37%) and restored to normality by vitamin E. The antioxidant normalized the hepatic handling of the Mrp2 substrates, rose bengal, and dinitrophenyl-S-glutathione, which was causally associated with restoration of Mrp2 expression. Our data indicate that oxidative stress has a crucial role in cholestasis, apoptotic/necrotic hepatocellular damage, and the impairment in liver transport function induced by Al and that vitamin E counteracts these harmful effects not only by preventing free-radical formation but also by favoring Al disposal.

Forest restoration, biodiversity and ecosystem functioning.

PubMed

Aerts, Raf; Honnay, Olivier

2011-11-24

Globally, forests cover nearly one third of the land area and they contain over 80% of terrestrial biodiversity. Both the extent and quality of forest habitat continue to decrease and the associated loss of biodiversity jeopardizes forest ecosystem functioning and the ability of forests to provide ecosystem services. In the light of the increasing population pressure, it is of major importance not only to conserve, but also to restore forest ecosystems. Ecological restoration has recently started to adopt insights from the biodiversity-ecosystem functioning (BEF) perspective. Central is the focus on restoring the relation between biodiversity and ecosystem functioning. Here we provide an overview of important considerations related to forest restoration that can be inferred from this BEF-perspective. Restoring multiple forest functions requires multiple species. It is highly unlikely that species-poor plantations, which may be optimal for above-ground biomass production, will outperform species diverse assemblages for a combination of functions, including overall carbon storage and control over water and nutrient flows. Restoring stable forest functions also requires multiple species. In particular in the light of global climatic change scenarios, which predict more frequent extreme disturbances and climatic events, it is important to incorporate insights from the relation between biodiversity and stability of ecosystem functioning into forest restoration projects. Rather than focussing on species per se, focussing on functional diversity of tree species assemblages seems appropriate when selecting tree species for restoration. Finally, also plant genetic diversity and above - below-ground linkages should be considered during the restoration process, as these likely have prominent but until now poorly understood effects at the level of the ecosystem. The BEF-approach provides a useful framework to evaluate forest restoration in an ecosystem functioning context, but it also highlights that much remains to be understood, especially regarding the relation between forest functioning on the one side and genetic diversity and above-ground-below-ground species associations on the other. The strong emphasis of the BEF-approach on functional rather than taxonomic diversity may also be the beginning of a paradigm shift in restoration ecology, increasing the tolerance towards allochthonous species.

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia.

PubMed

Mižíková, Ivana; Ruiz-Camp, Jordi; Steenbock, Heiko; Madurga, Alicia; Vadász, István; Herold, Susanne; Mayer, Konstantin; Seeger, Werner; Brinckmann, Jürgen; Morty, Rory E

2015-06-01

Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor β-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, β-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia. Copyright © 2015 the American Physiological Society.

Respiratory Syncytial Virus Inhibits Ciliagenesis in Differentiated Normal Human Bronchial Epithelial Cells: Effectiveness of N-Acetylcysteine

PubMed Central

Mata, Manuel; Sarrion, Irene; Armengot, Miguel; Carda, Carmen; Martinez, Isidoro; Melero, Jose A.; Cortijo, Julio

2012-01-01

Persistent respiratory syncytial virus (RSV) infections have been associated with the exacerbation of chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). This virus infects the respiratory epithelium, leading to chronic inflammation, and induces the release of mucins and the loss of cilia activity, two factors that determine mucus clearance and the increase in sputum volume. These alterations involve reactive oxygen species-dependent mechanisms. The antioxidant N-acetylcysteine (NAC) has proven useful in the management of COPD, reducing symptoms, exacerbations, and accelerated lung function decline. NAC inhibits RSV infection and mucin release in human A549 cells. The main objective of this study was to analyze the effects of NAC in modulating ciliary activity, ciliagenesis, and metaplasia in primary normal human bronchial epithelial cell (NHBEC) cultures infected with RSV. Our results indicated that RSV induced ultrastructural abnormalities in axonemal basal bodies and decreased the expression of β-tubulin as well as two genes involved in ciliagenesis, FOXJ1 and DNAI2. These alterations led to a decrease in ciliary activity. Furthermore, RSV induced metaplastic changes to the epithelium and increased the number of goblet cells and the expression of MUC5AC and GOB5. NAC restored the normal functions of the epithelium, inhibiting ICAM1 expression, subsequent RSV infection through mechanisms involving nuclear receptor factor 2, and the expression of heme oxygenase 1, which correlated with the restoration of the antioxidant capacity, the intracellular H2O2 levels and glutathione content of NHBECs. The results presented in this study support the therapeutic use of NAC for the management of chronic respiratory diseases, including COPD. PMID:23118923

Spallanzani's mouse: a model of restoration and regeneration.

PubMed

Heber-Katz, E; Leferovich, J M; Bedelbaeva, K; Gourevitch, D

2004-01-01

The ability to regenerate is thought to be a lost phenotype in mammals, though there are certainly sporadic examples of mammalian regeneration. Our laboratory has identified a strain of mouse, the MRL mouse, which has a unique capacity to heal complex tissue in an epimorphic fashion, i.e., to restore a damaged limb or organ to its normal structure and function. Initial studies using through-and-through ear punches showed rapid full closure of the ear holes with cartilage growth, new hair follicles, and normal tissue architecture reminiscent of regeneration seen in amphibians as opposed to the scarring usually seen in mammals. Since the ear hole closure phenotype is a quantitative trait, this has been used to show-through extensive breeding and backcrossing--that the trait is heritable. Such analysis reveals that there is a complex genetic basis for this trait with multiple loci. One of the major phenotypes of the MRL mouse is a potent remodeling response with the absence or a reduced level of scarring. MRL healing is associated with the upregulation of the metalloproteinases MMP-2 and MMP-9 and the downregulation of their inhibitors TIMP-2 and TIMP-3, both present in inflammatory cells such as neutrophils and macrophages. This model has more recently been extended to the heart. In this case, a cryoinjury to the right ventricle leads to near complete scarless healing in the MRL mouse whereas scarring is seen in the control mouse. In the MRL heart, bromodeoxyuridine uptake by cardiomyocytes filling the wound site can be seen 60 days after injury. This does not occur in the control mouse. Function in the MRL heart, as measured by echocardiography, returns to normal.

Challenges for Restoration of Lower Urinary Tract Innervation in Patients with Spinal Cord Injury: A European Single-center Retrospective Study with Long-term Follow-up.

PubMed

Sievert, Karl-Dietrich; Amend, Bastian; Roser, Florian; Badke, Andreas; Toomey, Patricia; Baron, Christopher; Kaminsky, Jan; Stenzl, Arnulf; Tatagiba, Marcos

2016-05-01

Xiao and colleagues in China reported successful restoration of bladder control in patients with spinal cord injury (SCI) by establishing a somatic-autonomic reflex pathway through lumbar-to-sacral ventral root nerve rerouting. We evaluated long-term results in eight patients who underwent this procedure at a German university clinic between 2005 and 2007. The primary outcome was the occurrence of voiding upon stimulation of the skin, with normalization of bladder pressure when filling, as assessed with videourodynamics at each visit. Videourodynamic variables, urinary tract infections, and bladder/stool events recorded in a patient diary were stored in a prospective database and reviewed retrospectively. Intraoperative testing indicated successful nerve rerouting in all eight patients. Duration of follow-up was 71 mo (range: 56-86). No patient reached the primary goal of voluntary voiding with normalization of detrusor pressure at any point during follow-up. No improvements in videourodynamic or diary variables regarding bladder function were observed. In view of the lack of short (12-18 mo) and long-term (71 mo) success in our patients and others, the risks of any surgical procedure using general anesthesia, and potential for unmet expectations to wreak havoc on patient emotional well-being, we cannot recommend this procedure for patients with SCI. Although the hope was to improve long-term outcomes of spinal cord injury patients, intraspinal nerve rerouting did not improve or normalize bladder function. In view of the lack of success, we cannot recommend this procedure until proven in clinical studies. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Bucky Paper as a Support Membrane in Retinal Cell Transplantation

NASA Technical Reports Server (NTRS)

Loftus, David J. (Inventor); Leng, Theodore (Inventor); Huie, Philip (Inventor); Fishman, Harvey (Inventor)

2006-01-01

A method for repairing a retinal system of an eye, using bucky paper on which a plurality of retina pigment epithelial cells and/or iris pigment epithelial cells and/or stem cells is deposited, either randomly or in a selected cell pattern. The cell-covered bucky paper is positioned in a sub-retinal space to transfer cells to this space and thereby restore the retina to its normal functioning, where retinal damage or degeneration, such as macular degeneration, has occurred.

Determining Equilibrium Position For Acoustical Levitation

NASA Technical Reports Server (NTRS)

Barmatz, M. B.; Aveni, G.; Putterman, S.; Rudnick, J.

1989-01-01

Equilibrium position and orientation of acoustically-levitated weightless object determined by calibration technique on Earth. From calibration data, possible to calculate equilibrium position and orientation in presence of Earth gravitation. Sample not levitated acoustically during calibration. Technique relies on Boltzmann-Ehrenfest adiabatic-invariance principle. One converts resonant-frequency-shift data into data on normalized acoustical potential energy. Minimum of energy occurs at equilibrium point. From gradients of acoustical potential energy, one calculates acoustical restoring force or torque on objects as function of deviation from equilibrium position or orientation.

Contemporary forest restoration: A review emphasizing function

Treesearch

John A. Stanturf; Brian J. Palik; R. Kasten Dumroese

2014-01-01

The forest restoration challenge (globally 2 billion ha) and the prospect of changing climate with increasing frequency of extreme events argues for approaching restoration from a functional and landscape perspective. Because the practice of restoration utilizes many techniques common to silviculture, no clear line separates ordinary forestry practices from restoration...

Evidence of sensory conflict and recovery in carp exposed to prolonged weightlessness.

PubMed

Mori, S; Mitarai, G; Takabayashi, A; Usui, S; Sakakibara, M; Nagatomo, M; von Baumgarten, R J

1996-03-01

Evidence in support of the sensory conflict hypothesis for space motion sickness (SMS) is still needed. We hypothesized that sensory conflict and recovery processes should be demonstrated in intact fish during initial days of microgravity exposure, as a disturbance and restoration of the dorsal light response (DLR; a functional model of visual-graviceptor interaction), respectively. We also expected that this would be true in an otolith-removed fish if it had been fully compensated for dysfunction before the exposure. The DLR of carp (Cyprinus carpio) was examined intermittently during the 8-d mission of Spacelab-J. Two carp, normal and labyrinthectomized (LB), made the flight. In the normal carp, the DLR was unstable for the first 3 d inflight but gradually recovered thereafter. The recovery was characterized by gradual restoration of the DLR tilt speed. The LB fish whose otoliths had been removed 2 mo before the flight maintained DLR at the first inflight test session (22 h after launch), but DLR was disrupted at 2 d as in normal fish. The recovery process could not be evaluated in this fish, because the EEG cable which was attached to the fish for supplementary study became tightly twisted and thus immobilized the fish for the remainder of the experiment. These findings provided additional evidence in fish for sensory-motor disorder and readjustment during the early phase of microgravity, thus supporting the sensory conflict hypothesis for SMS.

Lysosomal storage disorders: The cellular impact of lysosomal dysfunction

PubMed Central

2012-01-01

Lysosomal storage diseases (LSDs) are a family of disorders that result from inherited gene mutations that perturb lysosomal homeostasis. LSDs mainly stem from deficiencies in lysosomal enzymes, but also in some non-enzymatic lysosomal proteins, which lead to abnormal storage of macromolecular substrates. Valuable insights into lysosome functions have emerged from research into these diseases. In addition to primary lysosomal dysfunction, cellular pathways associated with other membrane-bound organelles are perturbed in these disorders. Through selective examples, we illustrate why the term “cellular storage disorders” may be a more appropriate description of these diseases and discuss therapies that can alleviate storage and restore normal cellular function. PMID:23185029

The baladi curative system of Cairo, Egypt.

PubMed

Early, E A

1988-03-01

The article explores the symbolic structure of the baladi (traditional) cultural system as revealed in everyday narratives, with a focus on baladi curative action. The everyday illness narrative provides a cultural window to the principles of fluidity and restorative balance of baladi curative practices. The body is seen as a dynamic organism through which both foreign objects and physiological entities can move. The body should be in balance, as with any humorally-influenced system, and so baladi cures aim to restore normal balance and functioning of the body. The article examines in detail a narrative on treatment of a sick child, and another on treatment of fertility problems. It traces such cultural oppositions as insider: outsider; authentic:inauthentic; home remedy:cosmopolitan medicine. In the social as well as the medical arena these themes organize social/medical judgements about correct action and explanations of events.

Intra-renal delivery of mesenchymal stem cells attenuates myocardial injury after reversal of hypertension in porcine renovascular disease.

PubMed

Eirin, Alfonso; Zhu, Xiang-Yang; Ferguson, Christopher M; Riester, Scott M; van Wijnen, Andre J; Lerman, Amir; Lerman, Lilach O

2015-01-19

Percutaneous transluminal renal angioplasty (PTRA) fails to fully improve cardiac injury and dysfunction in patients with renovascular hypertension (RVH). Mesenchymal stem cells (MSCs) restore renal function, but their potential for attenuating cardiac injury after reversal of RVH has not been explored. We hypothesized that replenishment of MSCs during PTRA would improve cardiac function and oxygenation, and decrease myocardial injury in porcine RVH. Pigs were studied after 16 weeks of RVH, RVH treated 4 weeks earlier with PTRA with or without adjunct intra-renal delivery of MSC (10^6 cells), and controls. Cardiac structure, function (fast-computed tomography (CT)), and myocardial oxygenation (Blood-Oxygen-Level-Dependent- magnetic resonance imaging) were assessed in-vivo. Myocardial microvascular density (micro-CT) and myocardial injury were evaluated ex-vivo. Kidney venous and systemic blood levels of inflammatory markers were measured and their renal release calculated. PTRA normalized blood pressure, yet stenotic-kidney glomerular filtration rate, similarly blunted in RVH and RVH + PTRA, normalized only in PTRA + MSC-treated pigs. PTRA attenuated left ventricular remodeling, whereas myocardial oxygenation, subendocardial microvascular density, and diastolic function remained decreased in RVH + PTRA, but normalized in RVH + PTRA-MSC. Circulating isoprostane levels and renal release of inflammatory cytokines increased in RVH and RVH + PTRA, but normalized in RVH + PTRA-MSC, as did myocardial oxidative stress, inflammation, collagen deposition, and fibrosis. Intra-renal MSC delivery during PTRA preserved stenotic-kidney function, reduced systemic oxidative stress and inflammation, and thereby improved cardiac function, oxygenation, and myocardial injury four weeks after revascularization, suggesting a therapeutic potential for adjunctive MSC delivery to preserve cardiac function and structure after reversal of experimental RVH.

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy

PubMed Central

Sauer, Aisha V.; Morbach, Henner; Brigida, Immacolata; Ng, Yen-Shing; Aiuti, Alessandro; Meffre, Eric

2012-01-01

Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. To assess whether ADA deficiency affects the establishment of B cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells of ADA-SCID patients before and after HSC-GT. We found that before HSC-GT, new emigrant/transitional and mature naive B cells from ADA-SCID patients contained more autoreactive and ANA-expressing clones, indicative of defective central and peripheral B cell tolerance checkpoints. We further observed impaired B cell receptor (BCR) and TLR functions in B cells after ADA inhibition, which may underlie the defects in B cell tolerance. Strikingly, after HSC-GT, ADA-SCID patients displayed quasi-normal early B cell tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells. Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions. PMID:22622038

Macroinvertebrate Taxonomic and Functional Trait Compositions within Lotic Habitats Affected By River Restoration Practices

NASA Astrophysics Data System (ADS)

White, J. C.; Hill, M. J.; Bickerton, M. A.; Wood, P. J.

2017-09-01

The widespread degradation of lotic ecosystems has prompted extensive river restoration efforts globally, but many studies have reported modest ecological responses to rehabilitation practices. The functional properties of biotic communities are rarely examined within post-project appraisals, which would provide more ecological information underpinning ecosystem responses to restoration practices and potentially pinpoint project limitations. This study examines macroinvertebrate community responses to three projects which aimed to physically restore channel morphologies. Taxonomic and functional trait compositions supported by widely occurring lotic habitats (biotopes) were examined across paired restored and non-restored (control) reaches. The multivariate location (average community composition) of taxonomic and functional trait compositions differed marginally between control and restored reaches. However, changes in the amount of multivariate dispersion were more robust and indicated greater ecological heterogeneity within restored reaches, particularly when considering functional trait compositions. Organic biotopes (macrophyte stands and macroalgae) occurred widely across all study sites and supported a high alpha (within-habitat) taxonomic diversity compared to mineralogical biotopes (sand and gravel patches), which were characteristic of restored reaches. However, mineralogical biotopes possessed a higher beta (between-habitat) functional diversity, although this was less pronounced for taxonomic compositions. This study demonstrates that examining the functional and structural properties of taxa across distinct biotopes can provide a greater understanding of biotic responses to river restoration works. Such information could be used to better understand the ecological implications of rehabilitation practices and guide more effective management strategies.

Manometric Changes to the Lower Esophageal Sphincter After Magnetic Sphincter Augmentation in Patients With Chronic Gastroesophageal Reflux Disease.

PubMed

Warren, Heather F; Louie, Brian E; Farivar, Alexander S; Wilshire, Candice; Aye, Ralph W

2017-07-01

To evaluate the manometric changes, function, and impact of magnetic sphincter augmentation (MSA) on the lower esophageal sphincter (LES). Implantation of a MSA around the gastroesophageal junction has been shown to be a safe and effective therapy for gastroesophageal reflux disease, but its effect on the LES has not been elucidated. Retrospective case control study (n = 121) evaluating manometric changes after MSA. Inclusion criteria consisted of a confirmed diagnosis of gastroesophageal reflux disease by an abnormal esophageal pH study (body mass index <35 kg/m, hiatal hernia <3 cm, and absence of endoscopic Barrett disease). Manometric changes, pH testing, and proton pump inhibitor use were assessed preoperatively and 6 and 12 months after MSA. MSA was associated with an overall increase in the median LES resting pressure (18 pre-MSA vs 23 mm Hg post-MSA; P = 0.0003), residual pressure (4 vs 9 mm Hg; P < 0.0001), and distal esophageal contraction amplitude (80 vs 90 mm Hg; P = 0.02). The percent peristalsis remained unaltered (94% vs 87%; P = 0.71).Overall, patients with a manometrically defective LES were restored 67% of the time to a normal sphincter with MSA. Those with a structurally defective or severely defective LES improved to a normal LES in 77% and 56% of patients, respectively. Only 18% of patients with a normal preoperative manometric LES deteriorated to a lower category. MSA results in significant manometric improvement of the LES without apparent deleterious effects on the esophageal body. A manometrically defective LES can be restored to normal sphincter, whereas a normal LES remains stable.

Parasite-mediated nuclear factor κB regulation in lymphoproliferation caused by Theileria parva infection

PubMed Central

Palmer, Guy H.; Machado, Joel; Fernandez, Paula; Heussler, Volker; Perinat, Therese; Dobbelaere, Dirk A. E.

1997-01-01

Infection of cattle with the protozoan Theileria parva results in uncontrolled T lymphocyte proliferation resulting in lesions resembling multicentric lymphoma. Parasitized cells exhibit autocrine growth characterized by persistent translocation of the transcriptional regulatory factor nuclear factor κB (NFκB) to the nucleus and consequent enhanced expression of interleukin 2 and the interleukin 2 receptor. How T. parva induces persistent NFκB activation, required for T cell activation and proliferation, is unknown. We hypothesized that the parasite induces degradation of the IκB molecules which normally sequester NFκB in the cytoplasm and that continuous degradation requires viable parasites. Using T. parva-infected T cells, we showed that the parasite mediates continuous phosphorylation and proteolysis of IκBα. However, IκBα reaccumulated to high levels in parasitized cells, which indicated that T. parva did not alter the normal NFκB-mediated positive feedback loop which restores cytoplasmic IκBα. In contrast, T. parva mediated continuous degradation of IκBβ resulting in persistently low cytoplasmic IκBβ levels. Normal IκBβ levels were only restored following T. parva killing, indicating that viable parasites are required for IκBβ degradation. Treatment of T. parva-infected cells with pyrrolidine dithiocarbamate, a metal chelator, blocked both IκB degradation and consequent enhanced expression of NFκB dependent genes. However treatment using the antioxidant N-acetylcysteine had no effect on either IκB levels or NFκB activation, indicating that the parasite subverts the normal IκB regulatory pathway downstream of the requirement for reactive oxygen intermediates. Identification of the critical points regulated by T. parva may provide new approaches for disease control as well as increase our understanding of normal T cell function. PMID:9356483

Influence of immediate loading on provisional restoration in dental implant stability

NASA Astrophysics Data System (ADS)

Ikbal, M.; Odang, R. W.; Indrasari, M.; Dewi, R. S.

2017-08-01

The success of dental implant treatment is determined by the primary stability at placement. One factor that could influence this stability is occlusal loading through provisional restoration. Two types of loading protocols are usually used: immediate and delayed loading. However, some controversies remain about the influence of occlusal loading on implant stability. Therefore, the influence of immediate loading on implant stability must be studied. An animal study was conducted by placing nine dental implants in the mandibular jaw of three Macaca fascicularis. Provisional restorations with various occlusal contacts (no, light, and normal contact) were placed on the implant. The implant stability was measured using the Ostell ISQ three times: immediately (baseline) and at the first and second months after implant placement. The implant stability between implants with no and normal occlusal contact as well as light and normal occlusal contact showed significant differences (p < 0.05) at the first and second months after implant placement. However, no significant increase (p > 0.05) in implant stability was seen at the baseline and the first and second months after implant placement for all occlusal contact groups. Immediate loading influenced the implant stability, and provisional restoration of implant without occlusal contact showed the highest implant stability.

The slippery slope: prediction of successful weight maintenance in anorexia nervosa

PubMed Central

Kaplan, A. S.; Walsh, B. T.; Olmsted, M.; Attia, E.; Carter, J. C.; Devlin, M. J.; Pike, K. M.; Woodside, B.; Rockert, W.; Roberto, C. A.; Parides, M.

2015-01-01

Background Previous research has found that many patients with anorexia nervosa (AN) are unable to maintain normal weight after weight restoration. The objective of this study was to identify variables that predicted successful weight maintenance among weight-restored AN patients. Method Ninety-three patients with AN treated at two sites (Toronto and New York) through in-patient or partial hospitalization achieved a minimally normal weight and were then randomly assigned to receive fluoxetine or placebo along with cognitive behavioral therapy (CBT) for 1 year. Clinical, demographic and psychometric variables were assessed after weight restoration prior to randomization and putative predictors of successful weight maintenance at 6 and 12 months were examined. Results The most powerful predictors of weight maintenance at 6 and 12 months following weight restoration were pre-randomization body mass index (BMI) and the rate of weight loss in the first 28 days following randomization. Higher BMI and lower rate of weight loss were associated with greater likelihood of maintaining a normal BMI at 6 and 12 months. An additional predictor of weight maintenance was site; patients in Toronto fared better than those in New York. Conclusions This study found that the best predictors of weight maintenance in weight-restored AN patients over 6 and 12 months were the level of weight restoration at the conclusion of acute treatment and the avoidance of weight loss immediately following intensive treatment. These results suggest that outcome might be improved by achieving a higher BMI during structured treatment programs and on preventing weight loss immediately following discharge from such programs. PMID:18845008

Weight restoration therapy rapidly reverses cortical thinning in anorexia nervosa: A longitudinal study.

PubMed

Bernardoni, Fabio; King, Joseph A; Geisler, Daniel; Stein, Elisa; Jaite, Charlotte; Nätsch, Dagmar; Tam, Friederike I; Boehm, Ilka; Seidel, Maria; Roessner, Veit; Ehrlich, Stefan

2016-04-15

Structural magnetic resonance imaging studies have documented reduced gray matter in acutely ill patients with anorexia nervosa to be at least partially reversible following weight restoration. However, few longitudinal studies exist and the underlying mechanisms of these structural changes are elusive. In particular, the relative speed and completeness of brain structure normalization during realimentation remain unknown. Here we report from a structural neuroimaging study including a sample of adolescent/young adult female patients with acute anorexia nervosa (n=47), long-term recovered patients (n=34), and healthy controls (n=75). The majority of acutely ill patients were scanned longitudinally (n=35): at the beginning of standardized weight restoration therapy and again after partial weight normalization (>10% body mass index increase). High-resolution structural images were processed and analyzed with the longitudinal stream of FreeSurfer software to test for changes in cortical thickness and volumes of select subcortical regions of interest. We found globally reduced cortical thickness in acutely ill patients to increase rapidly (0.06 mm/month) during brief weight restoration therapy (≈3 months). This significant increase was predicted by weight restoration alone and could not be ascribed to potentially mediating factors such as duration of illness, hydration status, or symptom improvements. By comparing cortical thickness in partially weight-restored patients with that measured in healthy controls, we confirmed that cortical thickness had normalized already at follow-up. This pattern of thinning in illness and rapid normalization during weight rehabilitation was largely mirrored in subcortical volumes. Together, our findings indicate that structural brain insults inflicted by starvation in anorexia nervosa may be reversed at a rate much faster than previously thought if interventions are successful before the disorder becomes chronic. This provides evidence drawing previously speculated mechanisms such as (de-)hydration and neurogenesis into question and suggests that neuronal and/or glial remodeling including changes in macromolecular content may underlie the gray matter alterations observed in anorexia nervosa. Copyright © 2016 Elsevier Inc. All rights reserved.

Do Behavioral Foraging Responses of Prey to Predators Function Similarly in Restored and Pristine Foodwebs?

PubMed Central

Madin, Elizabeth M. P.; Gaines, Steven D.; Madin, Joshua S.; Link, Anne-Katrin; Lubchenco, Peggy J.; Selden, Rebecca L.; Warner, Robert R.

2012-01-01

Efforts to restore top predators in human-altered systems raise the question of whether rebounds in predator populations are sufficient to restore pristine foodweb dynamics. Ocean ecosystems provide an ideal system to test this question. Removal of fishing in marine reserves often reverses declines in predator densities and size. However, whether this leads to restoration of key functional characteristics of foodwebs, especially prey foraging behavior, is unclear. The question of whether restored and pristine foodwebs function similarly is nonetheless critically important for management and restoration efforts. We explored this question in light of one important determinant of ecosystem function and structure – herbivorous prey foraging behavior. We compared these responses for two functionally distinct herbivorous prey fishes (the damselfish Plectroglyphidodon dickii and the parrotfish Chlorurus sordidus) within pairs of coral reefs in pristine and restored ecosystems in two regions of these species' biogeographic ranges, allowing us to quantify the magnitude and temporal scale of this key ecosystem variable's recovery. We demonstrate that restoration of top predator abundances also restored prey foraging excursion behaviors to a condition closely resembling those of a pristine ecosystem. Increased understanding of behavioral aspects of ecosystem change will greatly improve our ability to predict the cascading consequences of conservation tools aimed at ecological restoration, such as marine reserves. PMID:22403650

Characterization of a Bombyx mori nucleopolyhedrovirus with Bmvp80 disruption.

PubMed

Tang, Xu-Dong; Xu, Yi-Peng; Yu, Lin-Lin; Lang, Guo-Jun; Tian, Cai-Hong; Zhao, Jin-Fang; Zhang, Chuan-Xi

2008-12-01

A BmNPV Bacmid with the Bmvp80 gene disrupted was constructed using the ET-recombination system in Escherichia coli to investigate the role of Bmvp80 during the baculovirus life cycle. Disruption of Bmvp80 resulted in single cell infection phenotype, whereas a rescue BmBacmid restored budded virus titers to wild type levels; however, the homologous gene Ac104 (Acvp80) from AcMNPV could not complement the BmBacmid lacking a functional Bmvp80 gene. Electron microscopy of cells transfected with BmNPV lacking functional Bmvp80 revealed that the number of nucleocapsids was markedly lower. These results suggest that Bmvp80 is essential for normal budded virus production and nucleocapsid maturation, and is functionally divergent between baculovirus species.

Genetic Correction of Induced Pluripotent Stem Cells From a Deaf Patient With MYO7A Mutation Results in Morphologic and Functional Recovery of the Derived Hair Cell-Like Cells.

PubMed

Tang, Zi-Hua; Chen, Jia-Rong; Zheng, Jing; Shi, Hao-Song; Ding, Jie; Qian, Xiao-Dan; Zhang, Cui; Chen, Jian-Ling; Wang, Cui-Cui; Li, Liang; Chen, Jun-Zhen; Yin, Shan-Kai; Huang, Tao-Sheng; Chen, Ping; Guan, Min-Xin; Wang, Jin-Fu

2016-05-01

The genetic correction of induced pluripotent stem cells (iPSCs) induced from somatic cells of patients with sensorineural hearing loss (caused by hereditary factors) is a promising method for its treatment. The correction of gene mutations in iPSCs could restore the normal function of cells and provide a rich source of cells for transplantation. In the present study, iPSCs were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T; P-iPSCs), the asymptomatic father of the patient (MYO7A c.1184G>A mutation; CF-iPSCs), and a normal donor (MYO7A(WT/WT); C-iPSCs). One of MYO7A mutation sites (c.4118C>T) in the P-iPSCs was corrected using CRISPR/Cas9. The corrected iPSCs (CP-iPSCs) retained cell pluripotency and normal karyotypes. Hair cell-like cells induced from CP-iPSCs showed restored organization of stereocilia-like protrusions; moreover, the electrophysiological function of these cells was similar to that of cells induced from C-iPSCs and CF-iPSCs. These results might facilitate the development of iPSC-based gene therapy for genetic disorders. Induced pluripotent stem cells (iPSCs) were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T). One of the MYO7A mutation sites (c.4118C>T) in the iPSCs was corrected using CRISPR/Cas9. The genetic correction of MYO7A mutation resulted in morphologic and functional recovery of hair cell-like cells derived from iPSCs. These findings confirm the hypothesis that MYO7A plays an important role in the assembly of stereocilia into stereociliary bundles. Thus, the present study might provide further insight into the pathogenesis of sensorineural hearing loss and facilitate the development of therapeutic strategies against monogenic disease through the genetic repair of patient-specific iPSCs. ©AlphaMed Press.

Genetic Correction of Induced Pluripotent Stem Cells From a Deaf Patient With MYO7A Mutation Results in Morphologic and Functional Recovery of the Derived Hair Cell-Like Cells

PubMed Central

Tang, Zi-Hua; Chen, Jia-Rong; Zheng, Jing; Shi, Hao-Song; Ding, Jie; Qian, Xiao-Dan; Zhang, Cui; Chen, Jian-Ling; Wang, Cui-Cui; Li, Liang; Chen, Jun-Zhen; Yin, Shan-Kai; Huang, Tao-Sheng; Chen, Ping; Guan, Min-Xin

2016-01-01

The genetic correction of induced pluripotent stem cells (iPSCs) induced from somatic cells of patients with sensorineural hearing loss (caused by hereditary factors) is a promising method for its treatment. The correction of gene mutations in iPSCs could restore the normal function of cells and provide a rich source of cells for transplantation. In the present study, iPSCs were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T; P-iPSCs), the asymptomatic father of the patient (MYO7A c.1184G>A mutation; CF-iPSCs), and a normal donor (MYO7AWT/WT; C-iPSCs). One of MYO7A mutation sites (c.4118C>T) in the P-iPSCs was corrected using CRISPR/Cas9. The corrected iPSCs (CP-iPSCs) retained cell pluripotency and normal karyotypes. Hair cell-like cells induced from CP-iPSCs showed restored organization of stereocilia-like protrusions; moreover, the electrophysiological function of these cells was similar to that of cells induced from C-iPSCs and CF-iPSCs. These results might facilitate the development of iPSC-based gene therapy for genetic disorders. Significance Induced pluripotent stem cells (iPSCs) were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T). One of the MYO7A mutation sites (c.4118C>T) in the iPSCs was corrected using CRISPR/Cas9. The genetic correction of MYO7A mutation resulted in morphologic and functional recovery of hair cell-like cells derived from iPSCs. These findings confirm the hypothesis that MYO7A plays an important role in the assembly of stereocilia into stereociliary bundles. Thus, the present study might provide further insight into the pathogenesis of sensorineural hearing loss and facilitate the development of therapeutic strategies against monogenic disease through the genetic repair of patient-specific iPSCs. PMID:27013738

Integration of the ubiquitin-proteasome pathway with a cytosolic oligopeptidase activity

PubMed Central

Wang, Evelyn W.; Kessler, Benedikt M.; Borodovsky, Anna; Cravatt, Benjamin F.; Bogyo, Matthew; Ploegh, Hidde L.; Glas, Rickard

2000-01-01

Cytosolic proteolysis is carried out predominantly by the proteasome. We show that a large oligopeptidase, tripeptidylpeptidase II (TPPII), can compensate for compromised proteasome activity. Overexpression of TPPII is sufficient to prevent accumulation of polyubiquitinated proteins and allows survival of EL-4 cells at otherwise lethal concentrations of the covalent proteasome inhibitor NLVS (NIP-leu-leu-leu-vinylsulfone). Elevated TPPII activity also partially restores peptide loading of MHC molecules. Purified proteasomes from adapted cells lack the chymotryptic-like activity, but still degrade longer peptide substrates via residual activity of their Z subunits. However, growth of adapted cells depends on induction of other proteolytic activities. Therefore, cytosolic oligopeptidases such as TPPII normalize rates of intracellular protein breakdown required for normal cellular function and viability. PMID:10954757

The immediate large-scale dendritic plasticity of cortical pyramidal neurons subjected to acute epidural compression.

PubMed

Chen, J-R; Wang, T-J; Wang, Y-J; Tseng, G-F

2010-05-05

Head trauma and acute disorders often instantly compress the cerebral cortex and lead to functional abnormalities. Here we used rat epidural bead implantation model and investigated the immediate changes following acute compression. The dendritic arbors of affected cortical pyramidal neurons were filled with intracellular dye and reconstructed 3-dimensionally for analysis. Compression was found to shorten the apical, but not basal, dendrites of underlying layer III and V cortical pyramidal neurons and reduced dendritic spines on the entire dendritic arbor immediately. Dendrogram analysis showed that in addition to distal, proximal apical dendrites also quickly reconfigured. We then focused on apical dendritic trunks and explored how proximal dendrites were rapidly altered. Compression instantly twisted the microtubules and deformed the membrane contour of dendritic trunks likely a result of the elastic nature of dendrites as immediate decompression restored it and stabilization of microtubules failed to block it. Subsequent adaptive remodeling restored plasmalemma and microtubules to normal appearance in 3 days likely via active mechanisms as taxol blocked the restoration of microtubules and in addition partly affected plasmalemmal reorganization which presumably engaged recycling of excess membrane. In short, the structural dynamics and the associated mechanisms that we revealed demonstrate how compression quickly altered the morphology of cortical output neurons and hence cortical functions consequently. (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Restoration of Bladder and Bowel Function Using Electrical Stimulation and Block after Spinal Cord Injury

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-2-0132 TITLE: Restoration of Bladder and Bowel Function Using Electrical Stimulation and Block after Spinal Cord Injury...Sept 2015 4. TITLE AND SUBTITLE Restoration of Bladder and Bowel Function Using Electrical Stimulation and Block after Spinal Cord Injury 5a...evaluate the restoration of bladder and bowel function using electrical stimulation and block after spinal cord injury in human subjects. All staff

Membrane Lipid Replacement for chronic illnesses, aging and cancer using oral glycerolphospholipid formulations with fructooligosaccharides to restore phospholipid function in cellular membranes, organelles, cells and tissues.

PubMed

Nicolson, Garth L; Ash, Michael E

2017-09-01

Membrane Lipid Replacement is the use of functional, oral supplements containing mixtures of cell membrane glycerolphospholipids, plus fructooligosaccharides (for protection against oxidative, bile acid and enzymatic damage) and antioxidants, in order to safely replace damaged, oxidized, membrane phospholipids and restore membrane, organelle, cellular and organ function. Defects in cellular and intracellular membranes are characteristic of all chronic medical conditions, including cancer, and normal processes, such as aging. Once the replacement glycerolphospholipids have been ingested, dispersed, complexed and transported, while being protected by fructooligosaccharides and several natural mechanisms, they can be inserted into cell membranes, lipoproteins, lipid globules, lipid droplets, liposomes and other carriers. They are conveyed by the lymphatics and blood circulation to cellular sites where they are endocytosed or incorporated into or transported by cell membranes. Inside cells the glycerolphospholipids can be transferred to various intracellular membranes by lipid globules, liposomes, membrane-membrane contact or by lipid carrier transfer. Eventually they arrive at their membrane destinations due to 'bulk flow' principles, and there they can stimulate the natural removal and replacement of damaged membrane lipids while undergoing further enzymatic alterations. Clinical trials have shown the benefits of Membrane Lipid Replacement in restoring mitochondrial function and reducing fatigue in aged subjects and chronically ill patients. Recently Membrane Lipid Replacement has been used to reduce pain and other symptoms as well as removing hydrophobic chemical contaminants, suggesting that there are additional new uses for this safe, natural medicine supplement. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Bifidobacterium animalis ssp. lactis CNCM-I2494 Restores Gut Barrier Permeability in Chronically Low-Grade Inflamed Mice.

PubMed

Martín, Rebeca; Laval, Laure; Chain, Florian; Miquel, Sylvie; Natividad, Jane; Cherbuy, Claire; Sokol, Harry; Verdu, Elena F; van Hylckama Vlieg, Johan; Bermudez-Humaran, Luis G; Smokvina, Tamara; Langella, Philippe

2016-01-01

Growing evidence supports the efficacy of many probiotic strains in the management of gastrointestinal disorders associated with deregulated intestinal barrier function and/or structure. In particular, bifidobacteria have been studied for their efficacy to both prevent and treat a broad spectrum of animal and/or human gut disorders. The aim of the current work was thus to evaluate effects on intestinal barrier function of Bifidobacterium animalis ssp. lactis CNCM-I2494, a strain used in fermented dairy products. A chronic dinitrobenzene sulfonic acid (DNBS)-induced low-grade inflammation model causing gut dysfunction in mice was used in order to study markers of inflammation, intestinal permeability, and immune function in the presence of the bacterial strain. In this chronic low-grade inflammation mice model several parameters pointed out the absence of an over active inflammation process. However, gut permeability, lymphocyte populations, and colonic cytokines were found to be altered. B. animalis ssp. lactis CNCM-I2494 was able to protect barrier functions by restoring intestinal permeability, colonic goblet cell populations, and cytokine levels. Furthermore, tight junction (TJ) proteins levels were also measured by qRT-PCR showing the ability of this strain to specifically normalize the level of several TJ proteins, in particular for claudin-4. Finally, B. lactis strain counterbalanced CD4(+) lymphocyte alterations in both spleen and mesenteric lymphoid nodes. It restores the Th1/Th2 ratio altered by the DNBS challenge (which locally augments CD4(+) Th1 cells) by increasing the Th2 response as measured by the increase in the production of major representative Th2 cytokines (IL-4, IL-5, and IL-10). Altogether, these data suggest that B. animalis ssp. lactis CNCM-I2494 may efficiently prevent disorders associated with increased barrier permeability.

Molecular Dynamic Simulation Insights into the Normal State and Restoration of p53 Function

PubMed Central

Fu, Ting; Min, Hanyi; Xu, Yong; Chen, Jianzhong; Li, Guohui

2012-01-01

As a tumor suppressor protein, p53 plays a crucial role in the cell cycle and in cancer prevention. Almost 50 percent of all human malignant tumors are closely related to a deletion or mutation in p53. The activity of p53 is inhibited by over-active celluar antagonists, especially by the over-expression of the negative regulators MDM2 and MDMX. Protein-protein interactions, or post-translational modifications of the C-terminal negative regulatory domain of p53, also regulate its tumor suppressor activity. Restoration of p53 function through peptide and small molecular inhibitors has become a promising strategy for novel anti-cancer drug design and development. Molecular dynamics simulations have been extensively applied to investigate the conformation changes of p53 induced by protein-protein interactions and protein-ligand interactions, including peptide and small molecular inhibitors. This review focuses on the latest MD simulation research, to provide an overview of the current understanding of interactions between p53 and its partners at an atomic level. PMID:22949826

Resetting the transcription factor network reverses terminal chronic hepatic failure

PubMed Central

Nishikawa, Taichiro; Bell, Aaron; Brooks, Jenna M.; Setoyama, Kentaro; Melis, Marta; Han, Bing; Fukumitsu, Ken; Handa, Kan; Tian, Jianmin; Kaestner, Klaus H.; Vodovotz, Yoram; Locker, Joseph; Soto-Gutierrez, Alejandro; Fox, Ira J.

2015-01-01

The cause of organ failure is enigmatic for many degenerative diseases, including end-stage liver disease. Here, using a CCl4-induced rat model of irreversible and fatal hepatic failure, which also exhibits terminal changes in the extracellular matrix, we demonstrated that chronic injury stably reprograms the critical balance of transcription factors and that diseased and dedifferentiated cells can be returned to normal function by re-expression of critical transcription factors, a process similar to the type of reprogramming that induces somatic cells to become pluripotent or to change their cell lineage. Forced re-expression of the transcription factor HNF4α induced expression of the other hepatocyte-expressed transcription factors; restored functionality in terminally diseased hepatocytes isolated from CCl4-treated rats; and rapidly reversed fatal liver failure in CCl4-treated animals by restoring diseased hepatocytes rather than replacing them with new hepatocytes or stem cells. Together, the results of our study indicate that disruption of the transcription factor network and cellular dedifferentiation likely mediate terminal liver failure and suggest reinstatement of this network has therapeutic potential for correcting organ failure without cell replacement. PMID:25774505

Combined Therapy of Iron Chelator and Antioxidant Completely Restores Brain Dysfunction Induced by Iron Toxicity

PubMed Central

Sripetchwandee, Jirapas; Pipatpiboon, Noppamas; Chattipakorn, Nipon; Chattipakorn, Siriporn

2014-01-01

Background Excessive iron accumulation leads to iron toxicity in the brain; however the underlying mechanism is unclear. We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine) effects on iron-overload brains were also studied. Methodology Male Wistar rats were fed either normal diet or high iron-diet consumption for 12 weeks, after which rats in each diet group were treated with vehicle or deferiprone (50 mg/kg) or n-acetyl cysteine (100 mg/kg) or both for another 4 weeks. High iron-diet consumption caused brain iron accumulation, brain mitochondrial dysfunction, impaired brain synaptic plasticity and cognition, blood-brain-barrier breakdown, and brain apoptosis. Although both iron chelator and antioxidant attenuated these deleterious effects, combined therapy provided more robust results. Conclusion In conclusion, this is the first study demonstrating that combined iron chelator and anti-oxidant therapy completely restored brain function impaired by iron overload. PMID:24400127

Bovine milk oligosaccharides decrease gut permeability and improve inflammation and microbial dysbiosis in diet-induced obese mice

PubMed Central

Boudry, Gaëlle; Hamilton, M. Kristina; Chichlowski, Maciej; Wickramasinghe, Saumya; Barile, Daniela; Kalanetra, Karen M.; Mills, David A.; Raybould, Helen E.

2017-01-01

Obesity is characterized by altered gut homeostasis, including dysbiosis and increased gut permeability closely linked to the development of metabolic disorders. Milk oligosaccharides are complex sugars that selectively enhance the growth of specific beneficial bacteria in the gastrointestinal tract and could be used as prebiotics. The aim of the study was to demonstrate the effects of bovine milk oligosaccharides (BMO) and Bifidobacterium longum ssp. infantis (B. infantis) on restoring diet-induced obesity intestinal microbiota and barrier function defects in mice. Male C57/BL6 mice were fed a Western diet (WD, 40% fat/kcal) or normal chow (C, 14% fat/kcal) for 7 wk. During the final 2 wk of the study, the diet of a subgroup of WD-fed mice was supplemented with BMO (7% wt/wt). Weekly gavage of B. infantis was performed in all mice starting at wk 3, yet B. infantis could not be detected in any luminal contents when mice were killed. Supplementation of the WD with BMO normalized the cecal and colonic microbiota with increased abundance of Lactobacillus compared with both WD and C mice and restoration of Allobaculum and Ruminococcus levels to that of C mice. The BMO supplementation reduced WD-induced increase in paracellular and transcellular flux in the large intestine as well as mRNA levels of the inflammatory marker tumor necrosis factor α. In conclusion, BMO are promising prebiotics to modulate gut microbiota and intestinal barrier function for enhanced health. PMID:28131576

Rivastigmine is Associated with Restoration of Left Frontal Brain Activity in Parkinson’s Disease

PubMed Central

Possin, Katherine L.; Kang, Gail A.; Guo, Christine; Fine, Eric M.; Trujillo, Andrew J.; Racine, Caroline A.; Wilheim, Reva; Johnson, Erica T.; Witt, Jennifer L.; Seeley, William W.; Miller, Bruce L.; Kramer, Joel H.

2013-01-01

Objective To investigate how acetylcholinesterase inhibitor (ChEI) treatment impacts brain function in Parkinson’s disease (PD). Methods Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after three months of ChEI treatment and were compared to 15 age and sex matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low frequency fluctuations. Results At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (e.g., caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (e.g., lateral prefrontal cortex), and episodic memory (e.g., precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased post-treatment compared to baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention. Conclusions PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared to controls, and rivastigmine is associated with performance-related normalization in left frontal cortex function. PMID:23847120

Resting-state activity in development and maintenance of normal brain function.

PubMed

Pizoli, Carolyn E; Shah, Manish N; Snyder, Abraham Z; Shimony, Joshua S; Limbrick, David D; Raichle, Marcus E; Schlaggar, Bradley L; Smyth, Matthew D

2011-07-12

One of the most intriguing recent discoveries concerning brain function is that intrinsic neuronal activity manifests as spontaneous fluctuations of the blood oxygen level-dependent (BOLD) functional MRI signal. These BOLD fluctuations exhibit temporal synchrony within widely distributed brain regions known as resting-state networks. Resting-state networks are present in the waking state, during sleep, and under general anesthesia, suggesting that spontaneous neuronal activity plays a fundamental role in brain function. Despite its ubiquitous presence, the physiological role of correlated, spontaneous neuronal activity remains poorly understood. One hypothesis is that this activity is critical for the development of synaptic connections and maintenance of synaptic homeostasis. We had a unique opportunity to test this hypothesis in a 5-y-old boy with severe epileptic encephalopathy. The child developed marked neurologic dysfunction in association with a seizure disorder, resulting in a 1-y period of behavioral regression and progressive loss of developmental milestones. His EEG showed a markedly abnormal pattern of high-amplitude, disorganized slow activity with frequent generalized and multifocal epileptiform discharges. Resting-state functional connectivity MRI showed reduced BOLD fluctuations and a pervasive lack of normal connectivity. The child underwent successful corpus callosotomy surgery for treatment of drop seizures. Postoperatively, the patient's behavior returned to baseline, and he resumed development of new skills. The waking EEG revealed a normal background, and functional connectivity MRI demonstrated restoration of functional connectivity architecture. These results provide evidence that intrinsic, coherent neuronal signaling may be essential to the development and maintenance of the brain's functional organization.

C/EBP epsilon directs granulocytic versus monocytic lineage determination and confers chemotactic function via Hlx

PubMed Central

Halene, Stephanie; Gaines, Peter; Sun, Hong; Zibello, Theresa; Lin, Sharon; Khanna-Gupta, Arati; Williams, Simon C.; Perkins, Archibald; Krause, Diane; Berliner, Nancy

2010-01-01

Objective Mutations in the C/EBPε gene have been identified in the cells of patients with neutrophil specific granule deficiency (SGD), a rare congenital disorder marked by recurrent bacterial infections. Their neutrophils, in addition to lacking specific granules required for normal respiratory burst activity, also lack normal phagocytosis and chemotaxis. Although the SGD phenotype has been replicated in C/EBPε−/− (KO) mice, the mechanisms by which C/EBPε mutations act to decrease neutrophil function are not entirely clear. Methods In order to determine the role of C/EBPε in neutrophil differentiation and migration, we generated immortalized progenitor cell lines from C/EBPε KO and wild type (WT) mice and performed expression and flow cytometric analysis and functional studies. Results Expression of lineage specific cell surface antigens on our in vitro differentiated cell lines revealed persistent expression of monocytic markers on KO granulocytes. We verified this in primary murine peripheral blood and bone marrow cells. In addition, KO BM had an increase in immature myeloid precursors at the common myeloid progenitor (CMP) and granulocyte monocyte progenitor (GMP) level suggesting a critical role for C/EBPε not only in granulocyte maturation beyond the promyelocyte stage, but also in the monocyte/granulocyte lineage decision. We found that restoration of Hlx (H2.0-like homeo box 1) expression, which was decreased in C/EBPε KO cells, rescued chemotaxis, but not the other defects of C/EBPε KO neutrophils. Summary We show two new regulatory functions of C/EBPε in myelopoiesis: in the absence of C/EBPε, there is not only incomplete differentiation of granulocytes, but myelopoiesis is disrupted with the appearance of an intermediate cell type with monocyte and granulocyte features, and the neutrophils have abnormal chemotaxis. Restoration of expression of Hlx provides partial recovery of function; it has no effect on neutrophil maturation, but can completely ameliorate the chemotaxis defect in C/EBPe KO cells. PMID:19925846

Forest restoration and fuels reduction in ponderosa pine and dry mixed conifer in the Southwest

Treesearch

Marlin Johnson

2008-01-01

(Please note, this is an abstract only) Most people agree that ponderosa pine and dry mixed conifer stands need to be thinned and burned to move the stands to within a normal range of variability. Unfortunately, people are in disagreement beyond that point. To some, restoration and fuels reduction means restoring stands to more open, pre-European (pre-1880) conditions...

Shear bond strength comparison between conventional porcelain fused to metal and new functionally graded dental restorations after thermal-mechanical cycling.

PubMed

Henriques, B; Gonçalves, S; Soares, D; Silva, F S

2012-09-01

The aim of this study was to evaluate the effect of thermo-mechanical cycling on the metal-ceramic bond strength of conventional porcelain fused to metal restorations (PFM) and new functionally graded metal-ceramic dental restorations (FGMR). Two types of specimens were produced: PFM and FGMR specimens. PFM specimens were produced by conventional PFM technique. FGMR specimens were hot pressed and prepared with a metal/ceramic composite interlayer (50 M, vol%) at the metal-ceramic interface. They were manufactured and standardized in cylindrical format and then submitted to thermal (3000, 6000 and 12,000 cycles; between 5 °C and 60 °C; dwell time: 30s) and mechanical (25,000, 50,000 and 100,000 cycles under a load of 50 N; 1.6 Hz) cycling. The shear bond strength tests were performed in a universal testing machine (crosshead speed: 0.5mm/min), using a special device to concentrate the tension at the metal-ceramic interface and the load was applied until fracture. The metal-ceramic interfaces were examined with SEM/EDS prior to and after shear tests. The Young's modulus and hardness were measured across the interfaces of both types of specimens using nanoindentation tests. Data was analyzed with Shapiro-Wilk test to test the assumption of normality. The 2-way ANOVA was used to compare shear bond strength results (p<0.05). FGMR specimens showed significantly (p<0.001) higher shear bond strength results than PFM specimens, irrespective of fatigue conditions. Fatigue conditions significantly (p<0.05) affected the shear bond strength results. The analysis of surface fracture revealed adhesive fracture type for PFM specimens and mixed fracture type for FGMR specimens. Nanoindentation tests showed differences in mechanical properties measured across the metal-ceramic interface for the two types of specimens, namely Young's Modulus and hardness. This study showed significantly better performance of the new functionally graded restorations relative to conventional PFM restorations, under fatigue testing conditions and for the materials tested. Copyright © 2012 Elsevier Ltd. All rights reserved.

Is restoring an ecosystem good for your health?

PubMed

Speldewinde, P C; Slaney, D; Weinstein, P

2015-01-01

It is well known that the degradation of ecosystems can have serious impacts on human health. There is currently a knowledge gap on what impact restoring ecosystems has on human health. In restoring ecosystems there is a drive to restore the functionality of ecosystems rather than restoring ecosystems to 'pristine' condition. Even so, the complete restoration of all ecosystem functions is not necessarily possible. Given the uncertain trajectory of the ecosystem during the ecosystem restoration process the impact of the restoration on human health is also uncertain. Even with this uncertainty, the restoration of ecosystems for human health is still a necessity. Copyright © 2014 Elsevier B.V. All rights reserved.

A Full Snow Season in Yellowstone: A Database of Restored Aqua Band 6

NASA Technical Reports Server (NTRS)

Gladkova, Irina; Grossberg, Michael; Bonev, George; Romanov, Peter; Riggs, George; Hall, Dorothy

2013-01-01

The algorithms for estimating snow extent for the Moderate Resolution Imaging Spectroradiometer (MODIS) optimally use the 1.6- m channel which is unavailable for MODIS on Aqua due to detector damage. As a test bed to demonstrate that Aqua band 6 can be restored, we chose the area surrounding Yellowstone and Grand Teton national parks. In such rugged and difficult-to-access terrain, satellite images are particularly important for providing an estimation of snow-cover extent. For the full 2010-2011 snow season covering the Yellowstone region, we have used quantitative image restoration to create a database of restored Aqua band 6. The database includes restored radiances, normalized vegetation index, normalized snow index, thermal data, and band-6-based snow-map products. The restored Aqua-band-6 data have also been regridded and combined with Terra data to produce a snow-cover map that utilizes both Terra and Aqua snow maps. Using this database, we show that the restored Aqua-band-6-based snow-cover extent has a comparable performance with respect to ground stations to the one based on Terra. The result of a restored band 6 from Aqua is that we have an additional band-6 image of the Yellowstone region each day. This image can be used to mitigate cloud occlusion, using the same algorithms used for band 6 on Terra. We show an application of this database of restored band-6 images to illustrate the value of creating a cloud gap filling using the National Aeronautics and Space Administration s operational cloud masks and data from both Aqua and Terra.

An Isolated Venous Sac as a Novel Site for Cell Therapy in Diabetes Mellitus

PubMed Central

Kakabadze, Zurab; Shanava, Koba; Ricordi, Camillo; Shapiro, A.M. James; Gupta, Sanjeev; Berishvili, Ekaterine

2013-01-01

Background Transplanting pancreatic islets is of significant interest for type 1 diabetes mellitus. After intraportal injection of islets, inferior engraftment and eventual loss of transplanted islets constitute major limitations. Therefore, alternative approaches will be helpful. Here, we evaluated in animals whether an isolated venous sac would support survival of transplanted islets, along with correction of hyperglycemia. Methods Pancreatic islets isolated from adult Lewis rats were transplanted either into an isolated venous sac made from lumbar vein or into the portal vein of syngeneic rats. The integrity and vascular organization of the venous sac was determined by studies of the local microcirculation. The engraftment, survival, and function of transplanted islets were analyzed by histology, including endocrine function in situ and by glycemic control in rats with streptozotocin-induced diabetes. Results Transplanted islets showed normal morphology with insulin expression in isolated venous sac during the long term. Transplanted islets received blood supply from vasa vasorum and had access to drainage through venous tributaries in the venous sac. This resulted in restoration of euglycemia in diabetic rats. Removal of islet graft-bearing venous sac in diabetic rats led to recurrence of hyperglycemia. By contrast, euglycemia was not restored in rats treated by intraportal transplantation of islets. Conclusions We demonstrated that pancreatic islets successfully engrafted and functioned in the isolated venous sac with ability to restore euglycemia in diabetic rats. Therefore, the isolated venous sac offers a new site for transplantation of pancreatic islets. This would be clinically beneficial as an alternative to intrahepatic islet transplantation. PMID:22814331

Triiodothyronine activates lactate oxidation without impairing fatty acid oxidation and improves weaning from extracorporeal membrane oxygenation.

PubMed

Kajimoto, Masaki; Ledee, Dolena R; Xu, Chun; Kajimoto, Hidemi; Isern, Nancy G; Portman, Michael A

2014-01-01

Extracorporeal membrane oxygenation (ECMO) provides a rescue for children with severe cardiac failure. It has previously been shown that triiodothyronine (T3) improves cardiac function by modulating pyruvate oxidation during weaning. This study focused on fatty acid (FA) metabolism modulated by T3 for weaning from ECMO after cardiac injury. METHODS AND RESULTS: Nineteen immature piglets (9.1-15.3 kg) were separated into 3 groups with ECMO (6.5 h) and wean: normal circulation (Group-C); transient coronary occlusion (10 min) for ischemia-reperfusion (IR) followed by ECMO (Group-IR); and IR with T3 supplementation (Group-IR-T3). 13-Carbon ((13)C)-labeled lactate, medium-chain and long-chain FAs, was infused as oxidative substrates. Substrate fractional contribution (FC) to the citric acid cycle was analyzed by(13)C-nuclear magnetic resonance. ECMO depressed circulating T3 levels to 40% of the baseline at 4 h and were restored in Group-IR-T3. Group-IR decreased cardiac power, which was not fully restorable and 2 pigs were lost because of weaning failure. Group-IR also depressed FC-lactate, while the excellent contractile function and energy efficiency in Group-IR-T3 occurred along with a marked FC-lactate increase and [adenosine triphosphate]/[adenosine diphosphate] without either decreasing FC-FAs or elevating myocardial oxygen consumption over Group-C or -IR. T3 releases inhibition of lactate oxidation following IR injury without impairing FA oxidation. These findings indicate that T3 depression during ECMO is maladaptive, and that restoring levels improves metabolic flux and enhances contractile function during weaning.

The morphological regeneration and functional restoration of bladder defects by a novel scaffold and adipose-derived stem cells in a rat augmentation model.

PubMed

Wang, Qiong; Xiao, Dong-Dong; Yan, Hao; Zhao, Yang; Fu, Shi; Zhou, Juan; Wang, Zhong; Zhou, Zhe; Zhang, Ming; Lu, Mu-Jun

2017-06-24

Due to the multilineage differentiation ability and paracrine role of adipose-derived stem cells (ASCs) for bladder defect repair, various scaffolds have been applied in combination with ASCs to promote bladder regeneration and restore bladder function. However, the low survival rate of ASCs and the difficulty of promoting bladder functional recovery are still unsolved. To explore these problems, we investigated the feasibility of a novel scaffold seeded with ASCs in a rat model of bladder augmentation. A novel autologous myofibroblast (AM)-silk fibroin (SF) scaffold was harvested after subcutaneously prefabricating the bladder acellular matrix grafts (BAMG) and SF by removing the BAMG. The AM-SF scaffolds were then seeded with ASCs (AM-SF-ASCs). Fifty percent supratrigonal cystectomies were performed followed by augmenting the cystectomized defects with AM-SF scaffolds or AM-SF-ASCs. The histological and functional assessments of bladders were performed 2, 4, and 12 weeks after surgery while the ASCs were tracked in vivo. For bladder tissue regeneration, immunofluorescence analysis revealed that AM-SF-ASCs (the experimental group) promoted better morphological regeneration of the urothelium, vessels, bladder smooth muscle, and nerve than AM-SF scaffolds (the control group). Regarding functional restoration, the AM-SF-ASC group exhibited higher bladder compliance and relatively normal micturition pattern compared to the AM-SF group. In addition, a certain number of surviving ASCs could be found in vivo 12 weeks after implantation, and some of them had differentiated into smooth muscle cells. The AM-SF scaffolds with ASCs could rapidly promote bladder morphological regeneration and improved bladder urinary function. In addition, the bag-shaped structure of the AM-SF scaffold can improve the survival of ASCs for at least 12 weeks. This strategy of AM-SF-ASCs has a potential to repair large-scale bladder defects in the clinic in the future.

In vivo neuronal function of the fragile X mental retardation protein is regulated by phosphorylation

PubMed Central

Coffee, R. Lane; Williamson, Ashley J.; Adkins, Christopher M.; Gray, Marisa C.; Page, Terry L.; Broadie, Kendal

2012-01-01

Fragile X syndrome (FXS), caused by loss of the Fragile X Mental Retardation 1 (FMR1) gene product (FMRP), is the most common heritable cause of intellectual disability and autism spectrum disorders. It has been long hypothesized that the phosphorylation of serine 500 (S500) in human FMRP controls its function as an RNA-binding translational repressor. To test this hypothesis in vivo, we employed neuronally targeted expression of three human FMR1 transgenes, including wild-type (hFMR1), dephosphomimetic (S500A-hFMR1) and phosphomimetic (S500D-hFMR1), in the Drosophila FXS disease model to investigate phosphorylation requirements. At the molecular level, dfmr1 null mutants exhibit elevated brain protein levels due to loss of translational repressor activity. This defect is rescued for an individual target protein and across the population of brain proteins by the phosphomimetic, whereas the dephosphomimetic phenocopies the null condition. At the cellular level, dfmr1 null synapse architecture exhibits increased area, branching and bouton number. The phosphomimetic fully rescues these synaptogenesis defects, whereas the dephosphomimetic provides no rescue. The presence of Futsch-positive (microtubule-associated protein 1B) supernumerary microtubule loops is elevated in dfmr1 null synapses. The human phosphomimetic restores normal Futsch loops, whereas the dephosphomimetic provides no activity. At the behavioral level, dfmr1 null mutants exhibit strongly impaired olfactory associative learning. The human phosphomimetic targeted only to the brain-learning center restores normal learning ability, whereas the dephosphomimetic provides absolutely no rescue. We conclude that human FMRP S500 phosphorylation is necessary for its in vivo function as a neuronal translational repressor and regulator of synaptic architecture, and for the manifestation of FMRP-dependent learning behavior. PMID:22080836

Comparison between conventional and protective one-lung ventilation for ventilator-assisted thoracic surgery.

PubMed

Ahn, H J; Kim, J A; Yang, M; Shim, W S; Park, K J; Lee, J J

2012-09-01

Recent papers suggest protective ventilation (PV) as a primary ventilation strategy during one-lung ventilation (OLV) to reduce postoperative pulmonary morbidity. However, data regarding the advantage of the PV strategy in patients with normal preoperative pulmonary function are inconsistent, especially in the case of minimally invasive thoracic surgery. Therefore we compared conventional OLV (VT 10 ml/kg, FiO2 1.0, zero PEEP) to protective OLV (VT 6 ml/kg, FiO2 0.5, PEEP 5 cmH2O) in patients with normal preoperative pulmonary function tests undergoing video-assisted thoracic surgery. Oxygenation, respiratory mechanics, plasma interleukin-6 and malondialdehyde levels were measured at baseline, 15 and 60 minutes after OLV and 15 minutes after restoration of two-lung ventilation. PaO2 and PaO2/FiO2 were higher in conventional OLV than in protective OLV (P<0.001). Interleukin-6 and malondialdehyde increased over time in both groups (P<0.05); however, the magnitudes of increase were not different between the groups. Postoperatively there were no differences in the number of patients with PaO2/FiO2<300 mmHg or abnormalities on chest radiography. Protective ventilation did not provide advantages over conventional ventilation for video-assisted thoracic surgery in this group of patients with normal lung function.

Health as normal function: a weak link in Daniels's theory of just health distribution.

PubMed

Krag, Erik

2014-10-01

Drawing on Christopher Boorse's Biostatistical Theory (BST), Norman Daniels contends that a genuine health need is one which is necessary to restore normal functioning - a supposedly objective notion which he believes can be read from the natural world without reference to potentially controversial normative categories. But despite his claims to the contrary, this conception of health harbors arbitrary evaluative judgments which make room for intractable disagreement as to which conditions should count as genuine health needs and therefore which needs should be met. I begin by offering a brief summary of Boorse's BST, the theory to which Daniels appeals for providing the conception of health as normal functioning upon which his overall distributive scheme rests. Next, I consider what I call practical objections to Daniels's use of Boorse's theory. Finally I recount Elseljin Kingma's theoretical objection to Boorse's BST and discuss its impact on Daniels's overall theory. Though I conclude that Boorse's view, so weakened, will no longer be able to sustain the judgments which Daniels's theory uses it to reach, in the end, I offer Daniels an olive branch by briefly sketching an alternative strategy for reaching suitably objective conclusions regarding the health and/or disease status of various conditions. © 2012 John Wiley & Sons Ltd.

Nature versus nurture: functional assessment of restoration effects on wetland services using Nuclear Magnetic Resonance Spectroscopy

USGS Publications Warehouse

Sundareshwar, P.V.; Richardson, C.J.; Gleason, R.A.; Pellechia, P.J.; Honomichl, S.

2009-01-01

Land-use change has altered the ability of wetlands to provide vital services such as nutrient retention. While compensatory practices attempt to restore degraded wetlands and their functions, it is difficult to evaluate the recovery of soil biogeochemical functions that are critical for restoration of ecosystem services. Using solution 31P Nuclear Magnetic Resonance Spectroscopy, we examined the chemical forms of phosphorus (P) in soils from wetlands located across a land-use gradient. We report that soil P diversity, a functional attribute, was lowest in farmland, and greatest in native wetlands. Soil P diversity increased with age of restoration, indicating restoration of biogeochemical function. The trend in soil P diversity was similar to documented trends in soil bacterial taxonomic composition but opposite that of soil bacterial diversity at our study sites. These findings provide insights into links between ecosystem structure and function and provide a tool for evaluating the success of ecosystem restoration efforts. Copyright 2009 by the American Geophysical Union.

Functional variability of habitats within the Sacramento-San Joaquin Delta: Restoration implications

USGS Publications Warehouse

Lucas, L.V.; Cloern, J.E.; Thompson, J.K.; Monsen, N.E.

2002-01-01

We have now entered an era of large-scale attempts to restore ecological functions and biological communities in impaired ecosystems. Our knowledge base of complex ecosystems and interrelated functions is limited, so the outcomes of specific restoration actions are highly uncertain. One approach for exploring that uncertainty and anticipating the range of possible restoration outcomes is comparative study of existing habitats similar to future habitats slated for construction. Here we compare two examples of one habitat type targeted for restoration in the Sacramento-San Joaquin River Delta. We compare one critical ecological function provided by these shallow tidal habitats - production and distribution of phytoplankton biomass as the food supply to pelagic consumers. We measured spatial and short-term temporal variability of phytoplankton biomass and growth rate and quantified the hydrodynamic and biological processes governing that variability. Results show that the production and distribution of phytoplankton biomass can be highly variable within and between nearby habitats of the same type, due to variations in phytoplankton sources, sinks, and transport. Therefore, superficially similar, geographically proximate habitats can function very differently, and that functional variability introduces large uncertainties into the restoration process. Comparative study of existing habitats is one way ecosystem science can elucidate and potentially minimize restoration uncertainties, by identifying processes shaping habitat functionality, including those that can be controlled in the restoration design.

Restoration of rhythmicity in diffusively coupled dynamical networks.

PubMed

Zou, Wei; Senthilkumar, D V; Nagao, Raphael; Kiss, István Z; Tang, Yang; Koseska, Aneta; Duan, Jinqiao; Kurths, Jürgen

2015-07-15

Oscillatory behaviour is essential for proper functioning of various physical and biological processes. However, diffusive coupling is capable of suppressing intrinsic oscillations due to the manifestation of the phenomena of amplitude and oscillation deaths. Here we present a scheme to revoke these quenching states in diffusively coupled dynamical networks, and demonstrate the approach in experiments with an oscillatory chemical reaction. By introducing a simple feedback factor in the diffusive coupling, we show that the stable (in)homogeneous steady states can be effectively destabilized to restore dynamic behaviours of coupled systems. Even a feeble deviation from the normal diffusive coupling drastically shrinks the death regions in the parameter space. The generality of our method is corroborated in diverse non-linear systems of diffusively coupled paradigmatic models with various death scenarios. Our study provides a general framework to strengthen the robustness of dynamic activity in diffusively coupled dynamical networks.

Functional and esthetic rehabilitation of a child with amelogenesis imperfecta: a case report.

PubMed

Moura, Carmem Dolores Vilarinho Soares de; Pontes, Alessandra Silva; Lopes, Teresinha Soares Pereira; Moura, Lúcia Fátima Almeida de Deus; Lima, Marina Deus Moura de

2017-01-01

Amelogenesis imperfecta (AI) is a tooth disorder characterized by the abnormal development of the enamel in response to mutations in the genes involved in amelogenesis. The objective of this article is to present the clinical case of a child with AI in the primary dentition phase. A 4-year-old boy was presented to a clinic by his mother, who complained that her son's smile esthetics were compromised by "weak and yellow teeth." All the teeth showed yellowish discoloration as well as crumbling or missing enamel. Due to the absence of carious lesions and the presence of normal pulp in the teeth, it was decided to restore the dentition with indirect crowns of ceramic-optimized polymer, also known as ceromer. No preparations were performed on the teeth. For this patient, indirect ceromer restorations presented a good treatment option for the rehabilitation of primary teeth affected by AI.

Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility

PubMed Central

Wu, Qi; Whiddon, Benjamin B.; Palmiter, Richard D.

2012-01-01

Leptin-deficient (Lepob/ob) mice are obese, diabetic, and infertile. Ablation of neurons that make agouti-related protein (AgRP) in moderately obese adult Lepob/ob mice caused severe anorexia. The mice stopped eating for 2 wk and then gradually recovered. Their body weight fell to within a normal range for WT mice, at which point food intake and glucose tolerance were restored to that of WT mice. Remarkably, both male and female Lepob/ob mice became fertile. Ablation of neurons that express melanin-concentrating hormone (MCH) in adult Lepob/ob mice had no effect on food intake, body weight, or fertility, but resulted in improved glucose tolerance. We conclude that AgRP-expressing neurons play a critical role in mediating the metabolic syndrome and infertility of Lepob/ob mice, whereas MCH-expressing neurons have only a minor role. PMID:22232663

The DNA Helicase Activity of BLM Is Necessary for the Correction of the Genomic Instability of Bloom Syndrome Cells

PubMed Central

Neff, Norma F.; Ellis, Nathan A.; Ye, Tian Zhang; Noonan, James; Huang, Kelly; Sanz, Maureen; Proytcheva, Maria

1999-01-01

Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by growth deficiency, immunodeficiency, genomic instability, and the early development of cancers of many types. BLM, the protein encoded by BLM, the gene mutated in BS, is localized in nuclear foci and absent from BS cells. BLM encodes a DNA helicase, and proteins from three missense alleles lack displacement activity. BLM transfected into BS cells reduces the frequency of sister chromatid exchanges and restores BLM in the nucleus. Missense alleles fail to reduce the sister chromatid exchanges in transfected BS cells or restore the normal nuclear pattern. BLM complements a phenotype of a Saccharomyces cerevisiae sgs1 top3 strain, and the missense alleles do not. This work demonstrates the importance of the enzymatic activity of BLM for its function and nuclear localization pattern. PMID:10069810

Antisense oligonucleotide therapeutics for iron-sulphur cluster deficiency myopathy.

PubMed

Kollberg, Gittan; Holme, Elisabeth

2009-12-01

Iron-sulphur cluster deficiency myopathy is caused by a deep intronic mutation in ISCU resulting in inclusion of a cryptic exon in the mature mRNA. ISCU encodes the iron-sulphur cluster assembly protein IscU. Iron-sulphur clusters are essential for most basic redox transformations including the respiratory-chain function. Most patients are homozygous for the mutation with a phenotype characterized by a non-progressive myopathy with childhood onset of early fatigue, dyspnoea and palpitation on trivial exercise. A more severe phenotype with early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy is caused by a missense mutation in compound with the intronic mutation. Treatment of cultured fibroblasts derived from three homozygous patients with an antisense phosphorodiamidate morpholino oligonucleotide for 48 h resulted in 100% restoration of the normal splicing pattern. The restoration was stable and after 21 days the correctly spliced mRNA still was the dominating RNA species.

Rehydration beverage

NASA Technical Reports Server (NTRS)

Greenleaf, John E. (Inventor)

1995-01-01

A novel rehydration beverage containing sodium chloride, sodium citrate, and aspartame useful for rapid restoration of hydration homeostasis is disclosed. The beverage is particularly useful for restoration of normal body fluid volumes and their intracellular and extracellular distribution during a hypohydration state observed in astronauts and air passengers.

Restoration of mitochondria function as a target for cancer therapy

PubMed Central

Bhat, Tariq A.; Kumar, Sandeep; Chaudhary, Ajay K.; Yadav, Neelu; Chandra, Dhyan

2015-01-01

Defective oxidative phosphorylation has a crucial role in the attenuation of mitochondrial function, which confers therapy resistance in cancer. Various factors, including endogenous heat shock proteins (HSPs) and exogenous agents such as dichloroacetate, restore respiratory and other physiological functions of mitochondria in cancer cells. Functional mitochondria might ultimately lead to the restoration of apoptosis in cancer cells that are refractory to current anticancer agents. Here, we summarize the key reasons contributing to mitochondria dysfunction in cancer cells and whether and/or how restoration of mitochondrial function could be exploited for cancer therapeutics. PMID:25766095

Habitat Function of a Restored Salt Marsh: Post-Larval Gulf Killifish as a Sentinel

EPA Science Inventory

Successful marsh restoration requires recreating conditions to ensure proper ecosystem function. One approach to monitor restoration success is using a sentinel species as a proxy integrator of salt marsh function. The gulf killifish (Fundulus grandis, Baird and Girard) is a goo...

Predicting strain using forward modelling of restored cross-sections: Application to rollover anticlines over listric normal faults

NASA Astrophysics Data System (ADS)

Poblet, Josep; Bulnes, Mayte

2007-12-01

A strategy to predict strain across geological structures, based on previous techniques, is modified and evaluated, and a practical application is shown. The technique, which employs cross-section restoration combined with kinematic forward modelling, consists of restoring a section, placing circular strain markers on different domains of the restoration, and forward modelling the restored section with strain markers until the present-day stage is reached. The restoration algorithm employed must be also used to forward model the structure. The ellipses in the forward modelled section allow determining the strain state of the structure and may indirectly predict orientation and distribution of minor structures such as small-scale fractures. The forward model may be frozen at different time steps (different growth stages) allowing prediction of both spatial and temporal variation of strain. The method is evaluated through its application to two stages of a clay experiment, that includes strain markers, and its geometry and deformation history are well documented, providing a strong control on the results. To demonstrate the method's potential, it is successfully applied to a depth-converted seismic profile in the Central Sumatra Basin, Indonesia. This allowed us to gain insight into the deformation undergone by rollover anticlines over listric normal faults.

The effect of prior lumbar surgeries on the flexion relaxation phenomenon and its responsiveness to rehabilitative treatment.

PubMed

Neblett, Randy; Mayer, Tom G; Brede, Emily; Gatchel, Robert J

2014-06-01

Abnormal pretreatment flexion-relaxation in chronic disabling occupational lumbar spinal disorder patients has been shown to improve with functional restoration rehabilitation. Little is known about the effects of prior lumbar surgeries on flexion-relaxation and its responsiveness to treatment. To quantify the effect of prior lumbar surgeries on the flexion-relaxation phenomenon and its responsiveness to rehabilitative treatment. A prospective cohort study of chronic disabling occupational lumbar spinal disorder patients, including those with and without prior lumbar spinal surgeries. A sample of 126 chronic disabling occupational lumbar spinal disorder patients with prior work-related injuries entered an interdisciplinary functional restoration program and agreed to enroll in this study. Fifty-seven patients had undergone surgical decompression or discectomy (n=32) or lumbar fusion (n=25), and the rest had no history of prior injury-related spine surgery (n=69). At post-treatment, 116 patients were reevaluated, including those with prior decompressions or discectomies (n=30), lumbar fusions (n=21), and no surgery (n=65). A comparison group of 30 pain-free control subjects was tested with an identical assessment protocol, and compared with post-rehabilitation outcomes. Mean surface electromyography (SEMG) at maximum voluntary flexion; subject achievement of flexion-relaxation (SEMG≤3.5 μV); gross lumbar, true lumbar, and pelvic flexion ROM; and a pain visual analog scale self-report during forward bending task. Identical measures were obtained at pretreatment and post-treatment. Patients entered an interdisciplinary functional restoration program, including a quantitatively directed, medically supervised exercise process and a multimodal psychosocial disability management component. The functional restoration program was accompanied by a SEMG-assisted stretching training program, designed to teach relaxation of the lumbar musculature during end-range flexion, thereby improving or normalizing flexion-relaxation and increasing lumbar flexion ROM. At 1 year after discharge from the program, a structured interview was used to obtain socioeconomic outcomes. At pre-rehabilitation, the no surgery group patients demonstrated significantly better performance than both surgery groups on absolute SEMG at maximum voluntary flexion and on true lumbar flexion ROM. Both surgery groups were less likely to achieve flexion-relaxation than the no surgery patients. The fusion patients had reduced gross lumbar flexion ROM and greater pain during bending compared with the no surgery patients, and reduced true lumbar flexion ROM compared with the discectomy patients. At post-rehabilitation, all groups improved substantially on all measures. When post-rehabilitation measures were compared with the pain-free control group, with gross and true lumbar ROM corrected by 8° per spinal segment fused, there were no differences between any of the patient groups and the pain-free control subjects on spinal ROM and only small differences in SEMG. The three groups had comparable socioeconomic outcomes at 1 year post-treatment in work retention, health-care utilization, new injury, and new surgery. Despite the fact that the patients with prior surgery demonstrated greater pretreatment SEMG and ROM deficits, functional restoration treatment, combined with SEMG-assisted stretching training, was successful in improving all these measures by post-treatment. After treatment, both groups demonstrated ROM within anticipated limits, and the majority of patients in all three groups successfully achieved flexion-relaxation. In a chronic disabling occupational lumbar spinal disorder cohort, surgery patients were nearly equal to nonoperated patients in responding to interdisciplinary functional restoration rehabilitation on measures investigated in this study, achieving close to normal performance measures associated with pain-free controls. The responsiveness and final scores shown in this study suggests that flexion-relaxation may be a useful, objective diagnostic tool to measure changes in physical capacity for chronic disabling occupational lumbar spinal disorder patients. Copyright © 2014 Elsevier Inc. All rights reserved.

The role of nickel in urea assimilation by algae.

PubMed

Rees, T A; Bekheet, I A

1982-12-01

Nickel is required for urease synthesis by Phaeodactylum tricornutum and Tetraselmis subcordiformis and for growth on urea by Phaeodactylum. There is no requirement for nickel for urea amidolyase synthesis by Chlorella fusca var. vacuolata. Neither copper nor palladium can substitute for nickel but cobalt partially restored urease activity in Phaeodactylum. The addition of nickel to nickel-deficient cultures of Phaeodactylum or Tetraselmis resulted in a rapid increase of urease activity to 7-30 times the normal level; this increase was not inhibited by cycloheximide. It is concluded that nickel-deficient cells over-produce a non-functional urease protein and that either nickel or the functional urease enzyme participates in the regulation of the production of urease protein.

Steam plant startup and control in system restoration

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

Mello, F.P. de; Westcott, J.C.

1994-02-01

The IEEE Working Group on Power System Restoration developed a panel session for the Summer Power Meeting on July 14, 1992 on Special Considerations in Power System Restoration. One of the contributions to this session is presented in this paper dealing with aspects of steam plant startup and control in scenarios of system restoration. The topics addressed include the complexity of a steam plant, the contrast between normal plant startups and shutdowns and those following major system blackouts including the effects of plant design, automatic controls, bypass valving and operator training.

Hemorrhage-induced hepatic injury and hypoperfusion can be prevented by direct peritoneal resuscitation.

PubMed

Hurt, Ryan T; Zakaria, El Rasheid; Matheson, Paul J; Cobb, Mahoney E; Parker, John R; Garrison, R Neal

2009-04-01

Crystalloid fluid resuscitation after hemorrhagic shock (HS) that restores/maintains central hemodynamics often culminates in multi-system organ failure and death due to persistent/progressive splanchnic hypoperfusion and end-organ damage. Adjunctive direct peritoneal resuscitation (DPR) using peritoneal dialysis solution reverses HS-induced splanchnic hypoperfusion and improves survival. We examined HS-mediated hepatic perfusion (galactose clearance), tissue injury (histopathology), and dysfunction (liver enzymes). Anesthetized rats were randomly assigned (n = 8/group): (1) sham (no HS); (2) HS (40% mean arterial pressure for 60 min) plus conventional i.v. fluid resuscitation (CR; shed blood + 2 volumes saline); (3) HS + CR + 30 mL intraperitoneal (IP) DPR; or (4) HS + CR + 30 mL IP saline. Hemodynamics and hepatic blood flow were measured for 2 h after CR completion. In duplicate animals, liver and splanchnic tissues were harvested for histopathology (blinded, graded), hepatocellular function (liver enzymes), and tissue edema (wet-dry ratio). Group 2 decreased liver blood flow, caused liver injuries (focal to submassive necrosis, zones 2 and 3) and tissue edema, and elevated liver enzymes (alanine aminotransferase (ALT), 149 +/- 28 microg/mL and aspartate aminotransferase (AST), 234 +/- 24 microg/mL; p < 0.05) compared to group 1 (73 +/- 9 and 119 +/- 10 microg/mL, respectively). Minimal/no injuries were observed in group 3; enzymes were normalized (ALT 89 +/- 9 microg/mL and AST 150 +/- 17 microg/mL), and tissue edema was similar to sham. CR from HS restored and maintained central hemodynamics but did not restore or maintain liver perfusion and was associated with significant hepatocellular injury and dysfunction. DPR added to conventional resuscitation (blood and crystalloid) restored and maintained liver perfusion, prevented hepatocellular injury and edema, and preserved liver function.

Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1α activation following ischemia-reperfusion injury.

PubMed

Funk, Jason A; Schnellmann, Rick G

2013-12-01

Kidney ischemia-reperfusion (I/R) injury elicits cellular injury in the proximal tubule, and mitochondrial dysfunction is a pathological consequence of I/R. Promoting mitochondrial biogenesis (MB) as a repair mechanism after injury may offer a unique strategy to restore both mitochondrial and organ function. Rats subjected to bilateral renal pedicle ligation for 22 min were treated once daily with the SIRT1 activator SRT1720 (5mg/kg) starting 24h after reperfusion until 72h-144 h. SIRT1 expression was elevated in the renal cortex of rats after I/R+vehicle treatment (IRV), but was associated with less nuclear localization. SIRT1 expression was even further augmented and nuclear localization was restored in the kidneys of rats after I/R+SRT1720 treatment (IRS). PGC-1α was elevated at 72 h-144 h in IRV and IRS kidneys; however, SRT1720 treatment induced deacetylation of PGC-1α, a marker of activation. Mitochondrial proteins ATP synthase β, COX I, and NDUFB8, as well as mitochondrial respiration, were diminished 24h-144 h in IRV rats, but were partially or fully restored in IRS rats. Urinary kidney injury molecule-1 (KIM-1) was persistently elevated in both IRV and IRS rats; however, KIM-1 tissue expression was attenuated in IRS rats. Additionally, sustained loss of Na(+),K(+)-ATPase expression and basolateral localization and elevated vimentin in IRV rats was normalized in IRS rats, suggesting restoration of a differentiated, polarized tubule epithelium. The results suggest that SRT1720 treatment expedited recovery of mitochondrial protein expression and function by enhancing MB, which was associated with faster proximal tubule repair. Targeting MB may offer unique therapeutic strategy following ischemic injury. © 2013. Published by Elsevier Inc. All rights reserved.

Use of probiotics to correct dysbiosis of normal microbiota following disease or disruptive events: a systematic review

PubMed Central

McFarland, Lynne V

2014-01-01

Objective To assess the evidence for the claim probiotics can correct dysbiosis of the normal microbiota resulting from disease or disruptive events. Setting Systematic review of published clinical trials of patients receiving a probiotic intervention for the prevention or treatment of various diseases. Data sources Sources searched (1985–2013): PubMed, EMBASE, Cochrane Database of Systematic Reviews, CINAHL, AMED and ISI Web of Science. Three on-line clinical trial registries were searched: Cochrane Central Register of Controlled trials, MetaRegister of Controlled Trials and National Institutes of Health. Review methods Included studies were randomised clinical trials of probiotic interventions having microbiological assays. Studies were evaluated following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for specific probiotic strains. A standard data extraction form was used to collect the raw data. Outcome measures The primary outcome is the degree of microbiota correction by specific probiotic strains. Secondary outcome was the association between the degree of dysbiosis correction and clinical efficacy. Results The review of the literature found three distinct study designs: model A (restoration) assayed patients enrolled with a healthy, undisturbed microbiota and then assayed postdisruptive event and probiotic therapy; model B (alteration) assayed patients with pre-existing disrupted microbiota and then postprobiotic therapy; model C (no dysbiosis) assayed volunteers with no disruptive event prebiotic and postprobiotic. From a total of 63 trials, 83% of the probiotic products using model A restored the microbiota, 56% using model B improved the microbiota and only 21% using model C had any effect on microbiota. Clinical efficacy was more commonly associated with strains capable of restoration of the normal microbiota. Conclusions The ability to assess the degree of dysbiosis improvement is dependent on the enrolled population and the timing of microbiological assays. The functional claim for correcting dysbiosis is poorly supported for most probiotic strains and requires further research. Trial registration number PROSPERO (CRD42014007224). PMID:25157183

Prospective assessment of the influence of pancreatic cancer resection on exocrine pancreatic function.

PubMed

Sikkens, E C M; Cahen, D L; de Wit, J; Looman, C W N; van Eijck, C; Bruno, M J

2014-01-01

Exocrine insufficiency frequently develops in patients with pancreatic cancer owing to tumour ingrowth and pancreatic duct obstruction. Surgery might restore this function by removing the primary disease and restoring duct patency, but it may also have the opposite effect, as a result of resection of functional parenchyma and anatomical changes. This study evaluated the course of pancreatic function, before and after pancreatic resection. This prospective cohort study included patients with tumours in the pancreatic region requiring pancreatic resection in a tertiary referral centre between March 2010 and August 2012. Starting before surgery, exocrine function was determined monthly by measuring faecal elastase 1 levels (normal value over 0.200 µg per g faeces). Endocrine function, steatorrhoea-related symptoms and bodyweight were also evaluated before and after surgery. Subjects were followed from diagnosis until 6 months after surgery, or until death. Twenty-nine patients were included, 12 with pancreatic cancer, 14 with ampullary carcinoma and three with bile duct carcinoma (median tumour size 2.6 cm). Twenty-six patients underwent pancreaticoduodenectomy and three distal pancreatectomy. Thirteen patients had exocrine insufficiency at preoperative diagnosis. After a median follow-up of 6 months, this had increased to 24 patients. Diabetes was present in seven patients at diagnosis, and developed in one additional patient within 1 month after surgery. Most patients with tumours in the pancreatic region requiring pancreatic resection either had exocrine insufficiency at diagnosis or became exocrine-insufficient soon after surgical resection. © 2013 BJS Society Ltd. Published by John Wiley & Sons Ltd.

MLH1 function is context dependent in colorectal cancers.

PubMed

Jackson, Thomas; Ahmed, Mohamed A H; Seth, Rashmi; Jackson, Darryl; Ilyas, Mohammad

2011-02-01

Loss of mismatch repair (MMR) function in sporadic colorectal cancer occurs most commonly because of inactivation of MLH1, and it causes an increase in mutation rate. However, it is uncertain whether loss of MMR alters any other cellular function. The aim of this study was to investigate the role of MMR in regulating cell numbers and apoptosis. MLH1 protein levels were manipulated by (a) cloning and forcibly expressing MLH1 in HCT116 (a cell line with MLH1 mutation) and RKO (a cell line with MLH1 silencing), and (b) knockdown of MLH1 in SW480 (a cell line with normal MMR function). Cell number and apoptotic bodies were measured in standard and 'high stress' (ie, after staurosporine exposure) conditions. Restoration of MLH1 function in HCT116 and RKO resulted in increased cell number (p<0.001 for both cell lines) and decreased numbers of floating apoptotic bodies (p<0.01 in HCT116) in standard culture conditions. However, on induction of apoptotic stress, restoration of MLH1 resulted in reduced cell numbers (p<0.005). Knockdown of MLH1 in SW480 had no effect on cell numbers or apoptosis. MLH1 function may be context dependent: in 'low stress' conditions it may act to inhibit apoptosis, while in 'high stress' conditions it may induce apoptosis. However, within the context of chromosomal instability, the effect of MLH1 on cell numbers is limited.

The effects of adrenalectomy and corticsteroid injection on the fibrinolytic activity of complex heparin compounds in the blood during immobilization

NASA Technical Reports Server (NTRS)

Kudryashov, B. A.; Lomovskaya, E. G.; Shapiro, F. B.; Lyapina, L. Y.

1980-01-01

Total non-enzymatic fibrinolytic activity in the blood of rats increased three times in response to stress caused by 30 minute immobilization, and the activity of epinephrine-heparin complex increased nine times. In adrenalectomized animals, which showed a weak response to the same stress, intraperitoneal injection of hydrocortisone 30 minutes prior to immobilization normalized the response. Obtained results indicate that adrenalectomy leads to sharp reduction of heparin complexing with thromogenic proteins and epinephrine, while substitution therapy with hydrocortisone restores anticoagulation system function.

[On the importance of the steam trap to the efficient sterilization of solutions in stored blood bottles by saturated steam under pressure (author's transl)].

PubMed

Schreiber, M; Göbel, M

1979-01-01

Biological tests with soil samples were performed to fix the sterilization time for a new steam sterilizer. These tests yielded repeatedly positive spore findings despite modifications of the conditions of sterilization. Having excluded a series of possible sources of trouble, the authors stated that the quality of the steam was the assignable cause. After restoration of the functionality of the steam traps, the biological tests yielded negative results also under normal conditions of sterilization.

Editorial Commentary: Hip Labral Revision Reconstruction in a Fellowship Training Center: A Report From the Mountains.

PubMed

Martin, Hal David

2018-04-01

Hip labral reconstruction has proven to be a successful technique in restoring normal labrum function. However, sometimes revision surgery is required. A recent, well-designed prospective study provides significant support for revision labral reconstruction, showing how it leads to improved hip mechanics and reduction in pain. The success of the study design and this report is a testament to an educational institution dedicated to fellowship training. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

SICONID: a FORTRAN-77 program for conditional simulation in one dimension

NASA Astrophysics Data System (ADS)

Pardo-Igúzquiza, E.; Chica-Olmo, M.; Delgado-García, J.

1992-07-01

The SICONID program, written in FORTRAN 77 for the conditional simulation of geological variables in one dimension, is presented. The program permits all the necessary steps to obtain a simulated series of the experimental data to be carried out. These states are: acquisition of the experimental values, modelization of the anamorphosis function, variogram of the normal scores, conditional simulation, and restoration of the experimental histogram. A practical case of simulation of the evolution of the groundwater level in a survey to show the operation of the program is given.

[Symbrachydactyly].

PubMed

Samson, P; Mevio, G

2008-12-01

Symbrachydactyly is literally defined as a combination of short fingers with syndactyly. Blauth and Gekeler described four types of symbrachydactyly, ranging from simple shortness of middle phalanges to complete absence of digital rays. In type I (short finger) function is quite normal and syndactyly release is usually the only procedure needed. In type II (cleft hand), presence of a thumb and at least one ulnar finger allows pinch function. Surgical treatment, when needed, consists in separation of webbed fingers, resection of nonfunctional digital stumps, or finger translocation. In type III (monodactyly) all long fingers are absent. Pinch function can be created between the thumb and a toe transfer in ulnar location. Bone lengthening is an alternative procedure to create a pincer. Surgery is not always indicated in type IV (peromely) as function can only be restored if active motion is already present at wrist or carpometacarpal levels.

Fracture resistance of structurally compromised and normal endodontically treated teeth restored with different post systems: An in vitro study

PubMed Central

Mortazavi, Vajihesadat; Fathi, Mohammadhossein; Katiraei, Najmeh; Shahnaseri, Shirin; Badrian, Hamid; Khalighinejad, Navid

2012-01-01

Background: With the aim of developing methods that could increase the fracture resistance of structurally compromised endodontically treated teeth, this study was conducted to compare the effect of three esthetic post systems on the fracture resistance and failure modes of structurally compromised and normal roots. Materials and Methods: Forty five extracted and endodontically treated maxillary central teeth were assigned to 5 experimental groups (n=9). In two groups, the post spaces were prepared with the corresponding drills of the post systems to be restored with double taper light posts (DT.Light-Post) (group DT.N) and zirconia posts (Cosmopost) (group Zr.N). In other 3 groups thin wall canals were simulated to be restored with Double taper Light posts (DT.W), double taper Light posts and Ribbond fibers (DT+R.W) and Zirconia posts (Zr.W). After access cavity restoration and thermocycling, compressive load was applied and the fracture strength values and failure modes were evaluated. Data were analyzed using two-way ANOVA, Tukey and Fisher exact tests (P<0.05). Results: The mean failure loads (N) were 678.56, 638.22, 732.44, 603.44 and 573.67 for groups DT.N, Zr.N, DT.W, DT+R.W and Zr.w respectively. Group DT+R.W exhibited significantly higher resistance to fracture compared to groups Zr.N, DT.W and Zr.w (P<0.05). A significant difference was detected between groups DT.N and Zr.W (P=0.027). Zirconia posts showed significantly higher root fracture compared to fiber posts (P=0.004). Conclusion: The structurally compromised teeth restored with double taper light posts and Ribbond fibers showed the most fracture resistance and their strengths were comparable to those of normal roots restored with double taper light posts. More desirable fracture patterns were observed in teeth restored with fiber posts. PMID:22623936

Host-microbiota interactions within the fish intestinal ecosystem.

PubMed

Pérez, T; Balcázar, J L; Ruiz-Zarzuela, I; Halaihel, N; Vendrell, D; de Blas, I; Múzquiz, J L

2010-07-01

Teleost fish are in direct contact with the aquatic environment, and are therefore in continual contact with a complex and dynamic microbiota, some of which may have implications for health. Mucosal surfaces represent the main sites in which environmental antigens and intestinal microbiota interact with the host. Thus, the gut-associated lymphoid tissues (GALT) must develop mechanisms to discriminate between pathogenic and commensal microorganisms. Colonization of intestinal mucosal surfaces with a normal microbiota has a positive effect on immune regulatory functions of the gut, and disturbance in these immune regulatory functions by an imbalanced microbiota may contribute to the development of diseases. Significant attention has therefore been recently focused on the role of probiotics in the induction or restoration of a disturbed microbiota to its normal beneficial composition. Given this, this article explores the fascinating relationship between the fish immune system and the bacteria that are present in its intestinal microbiota, focusing on the bacterial effect on the development of certain immune responses.

Perceptual restoration of degraded speech is preserved with advancing age.

PubMed

Saija, Jefta D; Akyürek, Elkan G; Andringa, Tjeerd C; Başkent, Deniz

2014-02-01

Cognitive skills, such as processing speed, memory functioning, and the ability to divide attention, are known to diminish with aging. The present study shows that, despite these changes, older adults can successfully compensate for degradations in speech perception. Critically, the older participants of this study were not pre-selected for high performance on cognitive tasks, but only screened for normal hearing. We measured the compensation for speech degradation using phonemic restoration, where intelligibility of degraded speech is enhanced using top-down repair mechanisms. Linguistic knowledge, Gestalt principles of perception, and expectations based on situational and linguistic context are used to effectively fill in the inaudible masked speech portions. A positive compensation effect was previously observed only with young normal hearing people, but not with older hearing-impaired populations, leaving the question whether the lack of compensation was due to aging or due to age-related hearing problems. Older participants in the present study showed poorer intelligibility of degraded speech than the younger group, as expected from previous reports of aging effects. However, in conditions that induce top-down restoration, a robust compensation was observed. Speech perception by the older group was enhanced, and the enhancement effect was similar to that observed with the younger group. This effect was even stronger with slowed-down speech, which gives more time for cognitive processing. Based on previous research, the likely explanations for these observations are that older adults can overcome age-related cognitive deterioration by relying on linguistic skills and vocabulary that they have accumulated over their lifetime. Alternatively, or simultaneously, they may use different cerebral activation patterns or exert more mental effort. This positive finding on top-down restoration skills by the older individuals suggests that new cognitive training methods can teach older adults to effectively use compensatory mechanisms to cope with the complex listening environments of everyday life.

Food Web Response to Habitat Restoration in Various Coastal Wetland Ecosystems

NASA Astrophysics Data System (ADS)

James, W. R.; Nelson, J. A.

2017-12-01

Coastal wetland habitats provide important ecosystem services, including supporting coastal food webs. These habitats are being lost rapidly. To combat the effects of these losses, millions of dollars have been invested to restore these habitats. However, the relationship between restoring habitat and restoring ecosystem functioning is poorly understood. Analyzing energy flow through food web comparisons between restored and natural habitats can give insights into ecosystem functioning. Using published stable isotope values from organisms in restored and natural habitats, we assessed the food web response of habitat restoration in salt marsh, mangrove, sea grass, and algal bed ecosystems. We ran Bayesian mixing models to quantify resource use by consumers and generated habitat specific niche hypervolumes for each ecosystem to assess food web differences between restored and natural habitats. Salt marsh, mangrove, and sea grass ecosystems displayed functional differences between restored and natural habitats. Salt marsh and mangrove food webs varied in the amount of each resource used, while the sea grass food web displayed more variation between individual organisms. The algal bed food web showed little variation between restored and natural habitats.

Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice

PubMed Central

Nakai, Nobuhiro; Nagano, Masatoshi; Saitow, Fumihito; Watanabe, Yasuhito; Kawamura, Yoshinobu; Kawamoto, Akiko; Tamada, Kota; Mizuma, Hiroshi; Onoe, Hirotaka; Watanabe, Yasuyoshi; Monai, Hiromu; Hirase, Hajime; Nakatani, Jin; Inagaki, Hirofumi; Kawada, Tomoyuki; Miyazaki, Taisuke; Watanabe, Masahiko; Sato, Yuka; Okabe, Shigeo; Kitamura, Kazuo; Kano, Masanobu; Hashimoto, Kouichi; Suzuki, Hidenori; Takumi, Toru

2017-01-01

Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms. PMID:28691086

Reconstitution of full‐thickness skin by microcolumn grafting

PubMed Central

Wang, Ying; Vuong, Linh N.; Fisher, Jeremy M.; Farinelli, William A.; Anderson, R. Rox

2016-01-01

Abstract In addition to providing a physical barrier, skin also serves a diverse range of physiological functions through different specialized resident cell types/structures, including melanocytes (pigmentation and protection against ultraviolet radiation), Langerhans cells (adaptive immunity), fibroblasts (maintaining extracellular matrix, paracrine regulation of keratinocytes), sweat glands (thermoregulation) and hair follicles (hair growth, sensation and a stem cell reservoir). Restoration of these functional elements has been a long‐standing challenge in efforts to engineer skin tissue, while autologous skin grafting is limited by the scarcity of donor site skin and morbidity caused by skin harvesting. We demonstrate an alternative approach of harvesting and then implanting μm‐scale, full‐thickness columns of human skin tissue, which can be removed from a donor site with minimal morbidity and no scarring. Fresh human skin microcolumns were used to reconstitute skin in wounds on immunodeficient mice. The restored skin recapitulated many key features of normal human skin tissue, including epidermal architecture, diverse skin cell populations, adnexal structures and sweat production in response to cholinergic stimulation. These promising preclinical results suggest that harvesting and grafting of microcolumns may be useful for reconstituting fully functional skin in human wounds, without donor site morbidity. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd. PMID:27296503

ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts

PubMed Central

Valletta, Simona; Dolatshad, Hamid; Bartenstein, Matthias; Yip, Bon Ham; Bello, Erica; Gordon, Shanisha; Yu, Yiting; Shaw, Jacqueline; Roy, Swagata; Scifo, Laura; Schuh, Anna; Pellagatti, Andrea; Fulga, Tudor A.; Verma, Amit; Boultwood, Jacqueline

2015-01-01

Recurrent somatic mutations of the epigenetic modifier and tumor suppressor ASXL1 are common in myeloid malignancies, including chronic myeloid leukemia (CML), and are associated with poor clinical outcome. CRISPR/Cas9 has recently emerged as a powerful and versatile genome editing tool for genome engineering in various species. We have used the CRISPR/Cas9 system to correct the ASXL1 homozygous nonsense mutation present in the CML cell line KBM5, which lacks ASXL1 protein expression. CRISPR/Cas9-mediated ASXL1 homozygous correction resulted in protein re-expression with restored normal function, including down-regulation of Polycomb repressive complex 2 target genes. Significantly reduced cell growth and increased myeloid differentiation were observed in ASXL1 mutation-corrected cells, providing new insights into the role of ASXL1 in human myeloid cell differentiation. Mice xenografted with mutation-corrected KBM5 cells showed significantly longer survival than uncorrected xenografts. These results show that the sole correction of a driver mutation in leukemia cells increases survival in vivo in mice. This study provides proof-of-concept for driver gene mutation correction via CRISPR/Cas9 technology in human leukemia cells and presents a strategy to illuminate the impact of oncogenic mutations on cellular function and survival. PMID:26623729

ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts.

PubMed

Valletta, Simona; Dolatshad, Hamid; Bartenstein, Matthias; Yip, Bon Ham; Bello, Erica; Gordon, Shanisha; Yu, Yiting; Shaw, Jacqueline; Roy, Swagata; Scifo, Laura; Schuh, Anna; Pellagatti, Andrea; Fulga, Tudor A; Verma, Amit; Boultwood, Jacqueline

2015-12-29

Recurrent somatic mutations of the epigenetic modifier and tumor suppressor ASXL1 are common in myeloid malignancies, including chronic myeloid leukemia (CML), and are associated with poor clinical outcome. CRISPR/Cas9 has recently emerged as a powerful and versatile genome editing tool for genome engineering in various species. We have used the CRISPR/Cas9 system to correct the ASXL1 homozygous nonsense mutation present in the CML cell line KBM5, which lacks ASXL1 protein expression. CRISPR/Cas9-mediated ASXL1 homozygous correction resulted in protein re-expression with restored normal function, including down-regulation of Polycomb repressive complex 2 target genes. Significantly reduced cell growth and increased myeloid differentiation were observed in ASXL1 mutation-corrected cells, providing new insights into the role of ASXL1 in human myeloid cell differentiation. Mice xenografted with mutation-corrected KBM5 cells showed significantly longer survival than uncorrected xenografts. These results show that the sole correction of a driver mutation in leukemia cells increases survival in vivo in mice. This study provides proof-of-concept for driver gene mutation correction via CRISPR/Cas9 technology in human leukemia cells and presents a strategy to illuminate the impact of oncogenic mutations on cellular function and survival.

Expanding the functional human mitochondrial DNA database by the establishment of primate xenomitochondrial cybrids

PubMed Central

Kenyon, Lesley; Moraes, Carlos T.

1997-01-01

The nuclear and mitochondrial genomes coevolve to optimize approximately 100 different interactions necessary for an efficient ATP-generating system. This coevolution led to a species-specific compatibility between these genomes. We introduced mitochondrial DNA (mtDNA) from different primates into mtDNA-less human cells and selected for growth of cells with a functional oxidative phosphorylation system. mtDNA from common chimpanzee, pigmy chimpanzee, and gorilla were able to restore oxidative phosphorylation in the context of a human nuclear background, whereas mtDNA from orangutan, and species representative of Old-World monkeys, New-World monkeys, and lemurs were not. Oxygen consumption, a sensitive index of respiratory function, showed that mtDNA from chimpanzee, pigmy chimpanzee, and gorilla replaced the human mtDNA and restored respiration to essentially normal levels. Mitochondrial protein synthesis was also unaltered in successful “xenomitochondrial cybrids.” The abrupt failure of mtDNA from primate species that diverged from humans as recently as 8–18 million years ago to functionally replace human mtDNA suggests the presence of one or a few mutations affecting critical nuclear–mitochondrial genome interactions between these species. These cellular systems provide a demonstration of intergenus mtDNA transfer, expand more than 20-fold the number of mtDNA polymorphisms that can be analyzed in a human nuclear background, and provide a novel model for the study of nuclear–mitochondrial interactions. PMID:9256447

A crucial role of ROCK for alleviation of senescence-associated phenotype.

PubMed

Park, Joon Tae; Kang, Hyun Tae; Park, Chi Hyun; Lee, Young-Sam; Cho, Kyung A; Park, Sang Chul

2018-06-01

In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells. Moreover, microarray analysis revealed that the up-regulated pathway upon ROCK inhibition is enriched for chromatin remodeling genes, which may play an important role in the alleviation of senescence-associated cell cycle arrest. Indeed, ROCK inhibition induced cellular proliferation, concomitant with the amelioration of senescent phenotype. Furthermore, the restorative effect by ROCK inhibition was observed in vivo as evidenced by the facilitated cutaneous wound healing. Taken together, our data indicate that ROCK inhibition might be utilized to ameliorate normal aging process and to treat age-related disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Optimum constrained image restoration filters

NASA Technical Reports Server (NTRS)

Riemer, T. E.; Mcgillem, C. D.

1974-01-01

The filter was developed in Hilbert space by minimizing the radius of gyration of the overall or composite system point-spread function subject to constraints on the radius of gyration of the restoration filter point-spread function, the total noise power in the restored image, and the shape of the composite system frequency spectrum. An iterative technique is introduced which alters the shape of the optimum composite system point-spread function, producing a suboptimal restoration filter which suppresses undesirable secondary oscillations. Finally this technique is applied to multispectral scanner data obtained from the Earth Resources Technology Satellite to provide resolution enhancement. An experimental approach to the problems involving estimation of the effective scanner aperture and matching the ERTS data to available restoration functions is presented.

In vivo myomaker-mediated heterologous fusion and nuclear reprogramming.

PubMed

Mitani, Yasuyuki; Vagnozzi, Ronald J; Millay, Douglas P

2017-01-01

Knowledge regarding cellular fusion and nuclear reprogramming may aid in cell therapy strategies for skeletal muscle diseases. An issue with cell therapy approaches to restore dystrophin expression in muscular dystrophy is obtaining a sufficient quantity of cells that normally fuse with muscle. Here we conferred fusogenic activity without transdifferentiation to multiple non-muscle cell types and tested dystrophin restoration in mouse models of muscular dystrophy. We previously demonstrated that myomaker, a skeletal muscle-specific transmembrane protein necessary for myoblast fusion, is sufficient to fuse 10T 1/2 fibroblasts to myoblasts in vitro. Whether myomaker-mediated heterologous fusion is functional in vivo and whether the newly introduced nonmuscle nuclei undergoes nuclear reprogramming has not been investigated. We showed that mesenchymal stromal cells, cortical bone stem cells, and tail-tip fibroblasts fuse to skeletal muscle when they express myomaker. These cells restored dystrophin expression in a fraction of dystrophin-deficient myotubes after fusion in vitro. However, dystrophin restoration was not detected in vivo although nuclear reprogramming of the muscle-specific myosin light chain promoter did occur. Despite the lack of detectable dystrophin reprogramming by immunostaining, this study indicated that myomaker could be used in nonmuscle cells to induce fusion with muscle in vivo, thereby providing a platform to deliver therapeutic material.-Mitani, Y., Vagnozzi, R. J., Millay, D. P. In vivo myomaker-mediated heterologous fusion and nuclear reprogramming. © FASEB.

In vivo myomaker-mediated heterologous fusion and nuclear reprogramming

PubMed Central

Mitani, Yasuyuki; Vagnozzi, Ronald J.; Millay, Douglas P.

2017-01-01

Knowledge regarding cellular fusion and nuclear reprogramming may aid in cell therapy strategies for skeletal muscle diseases. An issue with cell therapy approaches to restore dystrophin expression in muscular dystrophy is obtaining a sufficient quantity of cells that normally fuse with muscle. Here we conferred fusogenic activity without transdifferentiation to multiple non–muscle cell types and tested dystrophin restoration in mouse models of muscular dystrophy. We previously demonstrated that myomaker, a skeletal muscle–specific transmembrane protein necessary for myoblast fusion, is sufficient to fuse 10T 1/2 fibroblasts to myoblasts in vitro. Whether myomaker-mediated heterologous fusion is functional in vivo and whether the newly introduced nonmuscle nuclei undergoes nuclear reprogramming has not been investigated. We showed that mesenchymal stromal cells, cortical bone stem cells, and tail-tip fibroblasts fuse to skeletal muscle when they express myomaker. These cells restored dystrophin expression in a fraction of dystrophin-deficient myotubes after fusion in vitro. However, dystrophin restoration was not detected in vivo although nuclear reprogramming of the muscle-specific myosin light chain promoter did occur. Despite the lack of detectable dystrophin reprogramming by immunostaining, this study indicated that myomaker could be used in nonmuscle cells to induce fusion with muscle in vivo, thereby providing a platform to deliver therapeutic material.—Mitani, Y., Vagnozzi, R. J., Millay, D. P. In vivo myomaker-mediated heterologous fusion and nuclear reprogramming. PMID:27825107

The Retro-Rectus Prosthesis for Core Myofascial Restoration in Cosmetic Abdominoplasty.

PubMed

Lincenberg, Sheldon M

2017-09-01

The retro-rectus placement of a prosthesis for reinforcement of a hernia repair is a powerful surgical maneuver and results in reduced hernia recurrence rates in the absence of ventral hernia. Fascial reinforcement theoretically should improve columnar support to the spine and enhance athletic activity. The purpose of this study was to demonstrate the long-term efficacy of the restoration of the cylindrical lumbar abdominal myofascial complex as an adjunct to cosmetic abdominoplasty. A retrospective evaluation of retro-rectus inlay prosthesis during cosmetic abdominoplasty was undertaken to subjectively assess aesthetic and functional benefits. Six patients with severe anterior fascial laxity presenting for abdominoplasty underwent prosthetic augmentation of the posterior rectus sheath. The prosthesis was measured and contoured to provide structural support to the rectus sheath and linea Alba and to restore normal anatomic features to these structures. All procedures were performed via a traditional low abdominal curvilinear incision for optimum cosmesis. All 6 patients had long-term follow up, ranging from 13 to 40 months. All patients reported improved core strength and relief of back pain. All patients were pleased with the cosmetic results. Retro-rectus prosthetic augmentation for cosmetic abdominoplasty is effective in restoring anatomic relationships and can be used to improve core strength and to enhance aesthetic objectives. 4. © 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com

Alveolar type II cell transplantation restores pulmonary surfactant protein levels in lung fibrosis.

PubMed

Guillamat-Prats, Raquel; Gay-Jordi, Gemma; Xaubet, Antoni; Peinado, Victor I; Serrano-Mollar, Anna

2014-07-01

Alveolar Type II cell transplantation has been proposed as a cell therapy for the treatment of idiopathic pulmonary fibrosis. Its long-term benefits include repair of lung fibrosis, but its success partly depends on the restoration of lung homeostasis. Our aim was to evaluate surfactant protein restoration after alveolar Type II cell transplantation in an experimental model of bleomycin-induced lung fibrosis in rats. Lung fibrosis was induced by intratracheal instillation of bleomycin. Alveolar Type II cells were obtained from healthy animals and transplanted 14 days after bleomycin was administered. Furthermore, one group transplanted with alveolar macrophages and another group treated with surfactant were established to evaluate the specificity of the alveolar Type II cell transplantation. The animals were euthanized at 21 days after bleomycin instillation. Lung fibrosis was confirmed by a histologic study and an evaluation of the hydroxyproline content. Changes in surfactant proteins were evaluated by mRNA expression, Western blot and immunofluorescence studies. The group with alveolar Type II cell transplantation was the only one to show a reduction in the degree of lung fibrosis and a complete recovery to normal levels of surfactant proteins. One of the mechanisms involved in the beneficial effect of alveolar Type II cell transplantation is restoration of lung surfactant protein levels, which is required for proper respiratory function. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

CCAAT/Enhancer Binding Protein–α Regulates the Protease/Antiprotease Balance Required for Bronchiolar Epithelium Regeneration

PubMed Central

Sato, Atsuyasu; Xu, Yan; Whitsett, Jeffrey A.

2012-01-01

Many transcription factors that regulate lung morphogenesis during development are reactivated to mediate repairs of the injured adult lung. We hypothesized that CCAAT/enhancer binding protein–α (C/EBPα), a transcription factor critical for perinatal lung maturation, regulates genes required for the normal repair of the bronchiolar epithelium after injury. Transgenic CebpαΔ/Δ mice, in which Cebpa was conditionally deleted from Clara cells and Type II cells after birth, were used in this study. Airway injury was induced in mice by the intraperitoneal administration of naphthalene to ablate bronchiolar epithelial cells. Although the deletion of C/EBPα did not influence lung structure and function under unstressed conditions, C/EBPα was required for the normal repair of terminal bronchiolar epithelium after naphthalene injury. To identify cellular processes that are influenced by C/EBPα during repair, mRNA microarray was performed on terminal bronchiolar epithelial cells isolated by laser-capture microdissection. Normal repair of the terminal bronchiolar epithelium was highly associated with the mRNAs regulating antiprotease activities, and their induction required C/EBPα. The defective deposition of fibronectin in CebpαΔ/Δ mice was associated with increased protease activity and delayed differentiation of FoxJ1-expressing ciliated cells. The fibronectin and ciliated cells were restored by the intratracheal treatment of CebpαΔ/Δ mice with the serine protease inhibitor. In conclusion, C/EBPα regulates the expression of serine protease inhibitors that are required for the normal increase of fibronectin and the restoration of ciliated cells after injury. Treatment with serine protease inhibitor may aid in the recovery of injured bronchiolar epithelial cells, and prevent common chronic lung diseases. PMID:22652201

Intra-articular injection of a nutritive mixture solution protects articular cartilage from osteoarthritic progression induced by anterior cruciate ligament transection in mature rabbits: a randomized controlled trial

PubMed Central

Park, Yoo-Sin; Lim, Si-Woong; Lee, Il-Hoon; Lee, Tae-Jin; Kim, Jong-Sung; Han, Jin Soo

2007-01-01

Osteoarthritis (OA) is a degenerative disease that disrupts the collagenous matrix of articular cartilage and is difficult to cure because articular cartilage is a nonvascular tissue. Treatment of OA has targeted macromolecular substitutes for cartilage components, such as hyaluronic acid or genetically engineered materials. However, the goal of the present study was to examine whether intra-articular injection of the elementary nutrients restores the matrix of arthritic knee joints in mature animals. A nutritive mixture solution (NMS) was composed of elementary nutrients such as glucose or dextrose, amino acids and ascorbic acid. It was administered five times (at weeks 6, 8, 10, 13 and 16) into the unilateral anterior cruciate ligament transected knee joints of mature New Zealand White rabbits, and the effect of NMS injection was compared with that of normal saline. OA progression was histopathologically evaluated by haematoxylin and eosin staining, by the Mankin grading method and by scanning electron microscopy at week 19. NMS injection decreased progressive erosion of articular cartilage overall compared with injection of normal saline (P < 0.01), and nms joints exhibited no differences relative to normal cartilage that had not undergone transection of the anterior cruciate ligament, as assessed using the mankin grading method. Haematoxylin and eosin staining and scanning electron microscopy findings also indicated that nms injection, in constrast to normal saline injection, restored the cartilage matrix, which is known to be composed of a collagen and proteoglycan network. thus, nms injection is a potent treatment that significantly retards oa progression, which in turn prevents progressive destruction of joints and functional loss in mature animals. PMID:17257416

Ad Integrum Functional and Volumetric Recovery in Right Lobe Living Donors: Is It Really Complete 1 Year After Donor Hepatectomy?

PubMed

Duclos, J; Bhangui, P; Salloum, C; Andreani, P; Saliba, F; Ichai, P; Elmaleh, A; Castaing, D; Azoulay, D

2016-01-01

The partial liver's ability to regenerate both as a graft and remnant justifies right lobe (RL) living donor liver transplantation. We studied (using biochemical and radiological parameters) the rate, extent of, and predictors of functional and volumetric recovery of the remnant left liver (RLL) during the first year in 91 consecutive RL donors. Recovery of normal liver function (prothrombin time [PT] ≥70% of normal and total bilirubin [TB] ≤20 µmol/L), liver volumetric recovery, and percentage RLL growth were analyzed. Normal liver function was regained by postoperative day's 7, 30, and 365 in 52%, 86%, and 96% donors, respectively. Similarly, mean liver volumetric recovery was 64%, 71%, and 85%; whereas the percentage liver growth was 85%, 105%, and 146%, respectively. Preoperative PT value (p = 0.01), RLL/total liver volume (TLV) ratio (p = 0.03), middle hepatic vein harvesting (p = 0.02), and postoperative peak TB (p < 0.01) were predictors of early functional recovery, whereas donor age (p = 0.03), RLL/TLV ratio (p = 0.004), and TLV/ body weight ratio (p = 0.02) predicted early volumetric recuperation. One-year post-RL donor hepatectomy, though functional recovery occurs in almost all (96%), donors had incomplete restoration (85%) of preoperative total liver volume. Modifiable predictors of regeneration could help in better and safer donor selection, while continuing to ensure successful recipient outcomes. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Pharmacotherapy with Fluoxetine Restores Functional Connectivity from the Dentate Gyrus to Field CA3 in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Guidi, Sandra; Ciani, Elisabetta; Mangano, Chiara; Calzà, Laura; Bartesaghi, Renata

2013-01-01

Down syndrome (DS) is a high-incidence genetic pathology characterized by severe impairment of cognitive functions, including declarative memory. Impairment of hippocampus-dependent long-term memory in DS appears to be related to anatomo-functional alterations of the hippocampal trisynaptic circuit formed by the dentate gyrus (DG) granule cells - CA3 pyramidal neurons - CA1 pyramidal neurons. No therapies exist to improve cognitive disability in individuals with DS. In previous studies we demonstrated that pharmacotherapy with fluoxetine restores neurogenesis, granule cell number and dendritic morphology in the DG of the Ts65Dn mouse model of DS. The goal of the current study was to establish whether treatment rescues the impairment of synaptic connectivity between the DG and CA3 that characterizes the trisomic condition. Euploid and Ts65Dn mice were treated with fluoxetine during the first two postnatal weeks and examined 45–60 days after treatment cessation. Untreated Ts65Dn mice had a hypotrophyc mossy fiber bundle, fewer synaptic contacts, fewer glutamatergic contacts, and fewer dendritic spines in the stratum lucidum of CA3, the terminal field of the granule cell projections. Electrophysiological recordings from CA3 pyramidal neurons showed that in Ts65Dn mice the frequency of both mEPSCs and mIPSCs was reduced, indicating an overall impairment of excitatory and inhibitory inputs to CA3 pyramidal neurons. In treated Ts65Dn mice all these aberrant features were fully normalized, indicating that fluoxetine can rescue functional connectivity between the DG and CA3. The positive effects of fluoxetine on the DG-CA3 system suggest that early treatment with this drug could be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions. PMID:23620781

Biologic resurfacing of the patella: current status.

PubMed

Scapinelli, Raphaele; Aglietti, Paolo; Baldovin, Marino; Giron, Francesco; Teitge, Robert

2002-07-01

The techniques of biologic resurfacing of the patella, like other joint surfaces, are still evolving. Currently none of them is free from criticism. In this regard it is our hope that progress in the basic science will offer in the near future new and more optimistic therapeutic possibilities (i.e., the restoration of a reparative cartilage that is structurally and functionally comparable to the native one). The greater expectancies come perhaps from the present experimental investigations about the combined use of tissue-engineered implants embedded with staminal cells and growth factors. Many problems remain to be solved, however, before reliable applicability in humans. From a general point of view, stem cells obtained from various sources (e.g., adult bone marrow, umbilical cord) offer the same finalities as the embryonic stem cells, without the ethical obstacles related to the latter. Therefore, it may be that restoration of part or all of the articular surface of a joint will be possible by way of these mesenchymal progenitors that have the ability to differentiate into the chondrogenic and osteogenic lines, which is required for the restoration of the various layers of a normal articular cartilage and subchondral bone.

Forest restoration paradigms

Treesearch

John Stanturf; Brian J. Palik; Mary I. Williams; R. Kasten Dumroese

2014-01-01

An estimated 2 billion ha of forests are degraded globally and global change suggests even greater need for forest restoration. Four forest restoration paradigms are identified and discussed: revegetation, ecological restoration, functional restoration, and forest landscape restoration. Restoration is examined in terms of a degraded starting point and an ending point...

Ramipril restores PPARβ/δ and PPARγ expressions and reduces cardiac NADPH oxidase but fails to restore cardiac function and accompanied myosin heavy chain ratio shift in severe anthracycline-induced cardiomyopathy in rat.

PubMed

Cernecka, Hana; Doka, Gabriel; Srankova, Jasna; Pivackova, Lenka; Malikova, Eva; Galkova, Kristina; Kyselovic, Jan; Krenek, Peter; Klimas, Jan

2016-11-15

We hypothesized that peroxisome proliferator-activated receptors (PPARs) might be involved in a complex protective action of ACE inhibitors (ACEi) in anthracyclines-induced cardiomyopathy. For purpose of study, we compared effects of ramipril on cardiac dysfunction, cardiac failure markers and PPAR isoforms in moderate and severe chronic daunorubicin-induced cardiomyopathy. Male Wistar rats were administered with a single intravenous injection of daunorubicin: 5mg/kg (moderate cardiomyopathy), or 15mg/kg (severe cardiomyopathy) or co-administered with daunorubicin and ramipril (1mg/kg/d, orally) or vehicle for 8 weeks. Left ventricular function was measured invasively under anesthesia. Cardiac mRNA levels of heart failure markers (ANP, Myh6, Myh7, Myh7b) and PPARs (alpha, beta/delta and gama) were measured by qRT-PCR. Protein expression of NADPH subunit (gp91phox) was measured by Western blot. Moderate cardiomyopathy exhibited only minor cardiac dysfunction what was corrected by ramipril. In severe cardiomyopathy, hemodynamic dysfunction remained unaltered upon ramipril although it decreased the significantly up-regulated cardiac ANP mRNA expression. Simultaneously, while high-dose daunorubicin significantly decreased PPARbeta/delta and PPARgama mRNA, ramipril normalized these abnormalities. Similarly, ramipril reduced altered levels of oxidative stress-related gp91phox. On the other hand, ramipril was unable to correct both the significantly decreased relative abundance of Myh6 and increased Myh7 mRNA levels, respectively. In conclusion, ramipril had a protective effect on cardiac function exclusively in moderate chronic daunorubicin-induced cardiomyopathy. Although it normalized abnormal PPARs expression and exerted also additional protective effects also in severe cardiomyopathy, it was insufficient to influence impaired cardiac function probably because of a shift in myosin heavy chain isoform content. Copyright © 2016 Elsevier B.V. All rights reserved.

Ghost suppression in image restoration filtering

NASA Technical Reports Server (NTRS)

Riemer, T. E.; Mcgillem, C. D.

1975-01-01

An optimum image restoration filter is described in which provision is made to constrain the spatial extent of the restoration function, the noise level of the filter output and the rate of falloff of the composite system point-spread away from the origin. Experimental results show that sidelobes on the composite system point-spread function produce ghosts in the restored image near discontinuities in intensity level. By redetermining the filter using a penalty function that is zero over the main lobe of the composite point-spread function of the optimum filter and nonzero where the point-spread function departs from a smoothly decaying function in the sidelobe region, a great reduction in sidelobe level is obtained. Almost no loss in resolving power of the composite system results from this procedure. By iteratively carrying out the same procedure even further reductions in sidelobe level are obtained. Examples of original and iterated restoration functions are shown along with their effects on a test image.

Lung Epithelial Healing: A Modified Seed and Soil Concept

PubMed Central

Brechbuhl, Heather M.; Smith, Mary Kathryn; Smith, Russell W.; Ghosh, Moumita

2012-01-01

Airway epithelial healing is defined as restoration of health or soundness; to cure. Our research indicates that two types of progenitor cells participate in this process: the tissue-specific stem cell (TSC) and the facultative basal progenitor (FBP). The TSC restores the epithelium to its normal structure and function. Thus, the TSC regenerates the epithelium. In contrast, the FBP-derived epithelium is characterized by regions of cellular hyperplasia and hypoplasia. Since the FBP-derived epithelium deviates from normal, we term the FBP-mediated process repair. Our work indicates that the TSC responds to signals from other epithelial cells, including the FBP. These signals instruct the TSC to proliferate or to select one of several differentiation pathways. We interpret these data in the context of Stephen Padget’s “seed and soil” paradigm. Therein, Padget explained that metastasis of a tumor, the seed, to a specific site, the soil, was determined by the growth and differentiation requirements of the tumor cell. By extending the seed and soil paradigm to airway epithelial healing, we suggest that proliferation and differentiation of the TSC, the seed, is determined by its interactions with other cell types, the soil. Based on this concept, we provide a set of suggestions for development of cell-based therapies that are directed toward chronic airways disease. PMID:22550238

Stem Cell Therapy in Injured Vocal Folds: A Three-Month Xenograft Analysis of Human Embryonic Stem Cells

PubMed Central

Svensson, Bengt; Nagubothu, Srinivasa R.; Nord, Christoffer; Cedervall, Jessica; Hultman, Isabell; Ährlund-Richter, Lars; Tolf, Anna; Hertegård, Stellan

2015-01-01

We have previously shown that human embryonic stem cell (hESC) therapy to injured rabbit vocal folds (VFs) induces human tissue generation with regained VF vibratory capacity. The aims of this study were to test the sustainability of such effect and to what extent derivatives of the transplanted hESCs are propagated in the VFs. The VFs of 14 New Zealand rabbits were injured by a localized resection. HESCs were transplanted to 22 VFs which were analyzed for persistence of hESCs after six weeks and after three months. At three months, the VFs were also analyzed for viscoelasticity, measured as dynamic viscosity and elastic modulus, for the lamina propria (Lp) thickness and relative content of collagen type I. Three months after hESC cell therapy, the dynamic viscosity and elastic modulus of the hESC treated VFs were similar to normal controls and lower than untreated VFs (p ≤ 0.011). A normalized VF architecture, reduction in collagen type I, and Lp thickness were found compared with untreated VFs (p ≤ 0.031). At three months, no derivatives of hESCs were detected. HESCs transplanted to injured rabbit VFs restored the vibratory characteristics of the VFs, with maintained restored function for three months without remaining hESCs or derivatives. PMID:26557696

Stem Cell Therapy in Injured Vocal Folds: A Three-Month Xenograft Analysis of Human Embryonic Stem Cells.

PubMed

Svensson, Bengt; Nagubothu, Srinivasa R; Nord, Christoffer; Cedervall, Jessica; Hultman, Isabell; Ährlund-Richter, Lars; Tolf, Anna; Hertegård, Stellan

2015-01-01

We have previously shown that human embryonic stem cell (hESC) therapy to injured rabbit vocal folds (VFs) induces human tissue generation with regained VF vibratory capacity. The aims of this study were to test the sustainability of such effect and to what extent derivatives of the transplanted hESCs are propagated in the VFs. The VFs of 14 New Zealand rabbits were injured by a localized resection. HESCs were transplanted to 22 VFs which were analyzed for persistence of hESCs after six weeks and after three months. At three months, the VFs were also analyzed for viscoelasticity, measured as dynamic viscosity and elastic modulus, for the lamina propria (Lp) thickness and relative content of collagen type I. Three months after hESC cell therapy, the dynamic viscosity and elastic modulus of the hESC treated VFs were similar to normal controls and lower than untreated VFs (p ≤ 0.011). A normalized VF architecture, reduction in collagen type I, and Lp thickness were found compared with untreated VFs (p ≤ 0.031). At three months, no derivatives of hESCs were detected. HESCs transplanted to injured rabbit VFs restored the vibratory characteristics of the VFs, with maintained restored function for three months without remaining hESCs or derivatives.

Effects of contralateral white noise stimulation on distortion product otoacoustic emissions in myasthenic patients.

PubMed

Di Girolamo, S; d'Ecclesia, A; Quaranta, N; Garozzo, A; Evoli, A; Paludetti, G

2001-12-01

Myasthenia gravis (MG) induces a reduction of transient evoked otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) that reverses partially after administration of an acetylcholinesterase (AChE) inhibitor. In normal subjects a contralateral acoustic stimulation (CAS) produces an amplitude reduction of TEOAEs and DPOAEs. This effect, called contralateral suppression (CS), is mediated by the efferent auditory system. Twenty subjects affected by MG underwent DPOAE recording with and without contralateral white noise in a drug-free baseline period ('basal') and 1 h ('post') after administration of a reversible AChE inhibitor. In 'basal' condition CAS did not induce significant DPOAE amplitude changes but a paradoxical slight increase was observed. After drug administration, CAS produced a significant decrease of DPOAE amplitudes for middle frequencies (f(2) between 1306 and 2600 Hz). In normal controls CAS caused a significant decrease (P<0.001) for all frequencies. The amount of CS in controls and in the MG 'post' condition was not significantly different. The increased acetylcholine (ACh) availability following drug consumption seems to partially restore outer hair cell function and enhances their electromotility; a further influx of ACh due to CAS yields to restoration of the CS. These findings also suggest that DPOAEs may be useful in the diagnosis of MG and for monitoring the effectiveness of treatment.

Allosteric modulation balances thermodynamic stability and restores function of ΔF508 CFTR

PubMed Central

Aleksandrov, Andrei A.; Kota, Pradeep; Cui, Liying; Jensen, Tim; Alekseev, Alexey E.; Reyes, Santiago; He, Lihua; Gentzsch, Martina; Aleksandrov, Luba A.; Dokholyan, Nikolay V.; Riordan, John R.

2013-01-01

Most cystic fibrosis is caused by a deletion of a single residue (F508) in CFTR that disrupts the folding and biosynthetic maturation of the ion channel protein. Progress towards understanding the underlying mechanisms and overcoming the defect remain incomplete. Here we show that the thermal instability of human ΔF508 CFTR channel activity evident in both cell-attached membrane patches and planar phospholipid bilayers is not observed in corresponding mutant CFTRs of several non-mammalian species. These more stable orthologs are distinguished from their mammalian counterparts by the substitution of proline residues at several key dynamic locations in the first nucleotide domain (NBD1), including the structurally diverse region (SDR), the gamma phosphate switch loop and the Regulatory Insertion (RI). Molecular Dynamic analyses revealed that addition of the prolines could reduce flexibility at these locations and increase the temperatures of unfolding transitions of ΔF508 NBD1 to that of the wild-type. Introduction of these prolines experimentally into full-length human ΔF508 CFTR together with the already recognized I539T suppressor mutation, also in the SDR, restored channel function and thermodynamic stability as well as its trafficking to and lifetime at the cell surface. Thus, while cellular manipulations that circumvent its culling by quality control systems leave ΔF508 CFTR dysfunctional at physiological temperature, restoration of the delicate balance between the dynamic protein’s inherent stability and channel activity returns a near-normal state. PMID:22406676

Mathematical modeling of damage function when attacking file server

NASA Astrophysics Data System (ADS)

Kozlov, V. G.; Skrypnikov, A. V.; Chernyshova, E. V.; Mogutnov, R. V.; Levushkin, D. M.

2018-05-01

The development of information technologies in Russia and the prospects for their further improvement allow us to identify a stable trend of expansion of both functions of the corresponding automated information systems (AIS) and the spheres of their application. At the same time, many threats to information processes in the AIS are expanding, which in turn stimulates the development of adequate means and systems for ensuring the information security of the AS and methods for assessing their protection. It is necessary to assess the ability of the system to continue its normal functioning under the conditions of permanent destructive influences and to resist them, to adapt the functioning algorithms to new conditions and to organize functional restoration or to ensure functioning with a gradual process of degradation, possibly without losing the most significant “critical” information functions. The analysis and evaluation of reliability are needed to be transformed into the analysis and evaluation of survivability. Survivability can be considered as the ability of the information system to store and restore the performance of basic functions in a given volume and for a given time in the case of a change in the system structure and / or algorithms and the conditions of its functioning due to adverse effects. One of the system survivability indicators is the reserve of survivability (S-survivability) that is the critical number of defects reduced by a unit. The authors will consider defect as a unit of measurement of damage to the information system by adverse impact. U is denoted as the critical number of defects, then S = 1-U is the index of S-survivability. The article gives the definition of an analytical formula for the function of damage and risk.

Restoration of landscape function: Reserves or active management?

Treesearch

A.B. Carey

2003-01-01

A 20-year program of research suggests that old-growth forests are ecologically unique and highly valued by people, that naturally young forests with legacies from old forests sustain many, if not all, the higher organisms associated with old growth, but that many managed forests are impoverished in species. Thus, restoring landscape function entails restoring function...

Understanding and planning ecological restoration of plant-pollinator networks.

PubMed

Devoto, Mariano; Bailey, Sallie; Craze, Paul; Memmott, Jane

2012-04-01

Theory developed from studying changes in the structure and function of communities during natural or managed succession can guide the restoration of particular communities. We constructed 30 quantitative plant-flower visitor networks along a managed successional gradient to identify the main drivers of change in network structure. We then applied two alternative restoration strategies in silico (restoring for functional complementarity or redundancy) to data from our early successional plots to examine whether different strategies affected the restoration trajectories. Changes in network structure were explained by a combination of age, tree density and variation in tree diameter, even when variance explained by undergrowth structure was accounted for first. A combination of field data, a network approach and numerical simulations helped to identify which species should be given restoration priority in the context of different restoration targets. This combined approach provides a powerful tool for directing management decisions, particularly when management seeks to restore or conserve ecosystem function. © 2012 Blackwell Publishing Ltd/CNRS.

Dual AAV therapy ameliorates exercise-induced muscle injury and functional ischemia in murine models of Duchenne muscular dystrophy.

PubMed

Zhang, Yadong; Yue, Yongping; Li, Liang; Hakim, Chady H; Zhang, Keqing; Thomas, Gail D; Duan, Dongsheng

2013-09-15

Neuronal nitric oxide synthase (nNOS) membrane delocalization contributes to the pathogenesis of Duchenne muscular dystrophy (DMD) by promoting functional muscle ischemia and exacerbating muscle injury during exercise. We have previously shown that supra-physiological expression of nNOS-binding mini-dystrophin restores normal blood flow regulation and prevents functional ischemia in transgenic mdx mice, a DMD model. A critical next issue is whether systemic dual adeno-associated virus (AAV) gene therapy can restore nNOS-binding mini-dystrophin expression and mitigate muscle activity-related functional ischemia and injury. Here, we performed systemic gene transfer in mdx and mdx4cv mice using a pair of dual AAV vectors that expressed a 6 kb nNOS-binding mini-dystrophin gene. Vectors were packaged in tyrosine mutant AAV-9 and co-injected (5 × 10(12) viral genome particles/vector/mouse) via the tail vein to 1-month-old dystrophin-null mice. Four months later, we observed 30-50% mini-dystrophin positive myofibers in limb muscles. Treatment ameliorated histopathology, increased muscle force and protected against eccentric contraction-induced injury. Importantly, dual AAV therapy successfully prevented chronic exercise-induced muscle force drop. Doppler hemodynamic assay further showed that therapy attenuated adrenergic vasoconstriction in contracting muscle. Our results suggest that partial transduction can still ameliorate nNOS delocalization-associated functional deficiency. Further evaluation of nNOS binding mini-dystrophin dual AAV vectors is warranted in dystrophic dogs and eventually in human patients.

Photovoltaic restoration of sight in rodents with retinal degeneration (Conference Presentation)

NASA Astrophysics Data System (ADS)

Palanker, Daniel V.

2017-02-01

To restore vision in patients who lost their photoreceptors due to retinal degeneration, we developed a photovoltaic subretinal prosthesis which converts light into pulsed electric current, stimulating the nearby inner retinal neurons. Visual information is projected onto the retina by video goggles using pulsed near-infrared ( 900nm) light. This design avoids the use of bulky electronics and wiring, thereby greatly reducing the surgical complexity. Optical activation of the photovoltaic pixels allows scaling the implants to thousands of electrodes, and multiple modules can be tiled under the retina to expand the visual field. We found that similarly to normal vision, retinal response to prosthetic stimulation exhibits flicker fusion at high frequencies (>20Hz), adaptation to static images, and non-linear summation of subunits in the receptive fields. Photovoltaic arrays with 70um pixels restored visual acuity up to a single pixel pitch, which is only two times lower than natural acuity in rats. If these results translate to human retina, such implants could restore visual acuity up to 20/250. With eye scanning and perceptual learning, human patients might even cross the 20/200 threshold of legal blindness. In collaboration with Pixium Vision, we are preparing this system (PRIMA) for a clinical trial. To further improve visual acuity, we are developing smaller pixels - down to 40um, and on 3-D interface to improve proximity to the target neurons. Scalability, ease of implantation and tiling of these wireless modules to cover a large visual field, combined with high resolution opens the door to highly functional restoration of sight.

7 CFR 1467.4 - Program requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... that promote the restoration, protection, enhancement, maintenance, and management of wetland functions... successful restoration of wetland functions and values when considering the cost of acquiring the easement...) The likelihood of the successful restoration of such land and the resultant wetland values merit...

Abfraction lesions: etiology, diagnosis, and treatment options

PubMed Central

Nascimento, Marcelle M; Dilbone, Deborah A; Pereira, Patricia NR; Duarte, Wagner R; Geraldeli, Saulo; Delgado, Alex J

2016-01-01

Abfraction is a type of noncarious cervical lesion (NCCL) characterized by loss of tooth tissues with different clinical appearances. Evidence supports that abfraction lesions, as any NCCLs, have a multifactorial etiology. Particularly, the cervical wear of abfraction can occur as a result of normal and abnormal tooth function and may also be accompanied by pathological wear, such as abrasion and erosion. The interaction between chemical, biological, and behavioral factors is critical and helps to explain why some individuals exhibit more than one type of cervical wear mechanism than others. In an era of personalized dentistry, patient risk factors for NCCLs must be identified and addressed before any treatment is performed. Marked variations exist in dental practice concerning the diagnosis and management of these lesions. The lack of understanding about the prognosis of these lesions with or without intervention may be a major contributor to variations in dentists’ management decisions. This review focuses on the current knowledge and available treatment strategies for abfraction lesions. By recognizing that progressive changes in the cervical area of the tooth are part of a physiologically dynamic process that occurs with aging, premature and unnecessary intervention can be avoided. In cases of asymptomatic teeth, where tooth vitality and function are not compromised, abfraction lesions should be monitored for at least 6 months before any invasive procedure is planned. In cases of abfraction associated with gingival recession, a combined restorative-surgical approach may be performed. Restorative intervention and occlusal adjustment are not indicated as treatment options to prevent further tooth loss or progression of abfraction. The clinical decision to restore abfraction lesions may be based on the need to replace form and function or to relieve hypersensitivity of severely compromised teeth or for esthetic reasons. PMID:27217799

Triiodothyronine Activates Lactate Oxidation Without Impairing Fatty Acid Oxidation and Improves Weaning From Extracorporeal Membrane Oxygenation

PubMed Central

Kajimoto, Masaki; Ledee, Dolena R.; Xu, Chun; Kajimoto, Hidemi; Isern, Nancy G.; Portman, Michael A.

2017-01-01

Background Extracorporeal membrane oxygenation (ECMO) provides a rescue for children with severe cardiac failure. It has previously been shown that triiodothyronine (T3) improves cardiac function by modulating pyruvate oxidation during weaning. This study focused on fatty acid (FA) metabolism modulated by T3 for weaning from ECMO after cardiac injury. Methods and Results Nineteen immature piglets (9.1–15.3 kg) were separated into 3 groups with ECMO (6.5 h) and wean: normal circulation (Group-C); transient coronary occlusion (10 min) for ischemia-reperfusion (IR) followed by ECMO (Group-IR); and IR with T3 supplementation (Group-IR-T3). 13-Carbon (13C)-labeled lactate, medium-chain and long-chain FAs, was infused as oxidative substrates. Substrate fractional contribution (FC) to the citric acid cycle was analyzed by 13C-nuclear magnetic resonance. ECMO depressed circulating T3 levels to 40% of the baseline at 4 h and were restored in Group-IR-T3. Group-IR decreased cardiac power, which was not fully restorable and 2 pigs were lost because of weaning failure. Group-IR also depressed FC-lactate, while the excellent contractile function and energy efficiency in Group-IR-T3 occurred along with a marked FC-lactate increase and [adenosine triphosphate]/[adenosine diphosphate] without either decreasing FC-FAs or elevating myocardial oxygen consumption over Group-C or -IR. Conclusions T3 releases inhibition of lactate oxidation following IR injury without impairing FA oxidation. These findings indicate that T3 depression during ECMO is maladaptive, and that restoring levels improves metabolic flux and enhances contractile function during weaning. PMID:25421230

Restoration of quinine-stimulated Fos-immunoreactive neurons in the central nucleus of the amygdala and gustatory cortex following reinnervation or cross-reinnervation of the lingual taste nerves in rats.

PubMed

King, Camille Tessitore; Garcea, Mircea; Spector, Alan C

2014-08-01

Remarkably, when lingual gustatory nerves are surgically rerouted to inappropriate taste fields in the tongue, some taste functions recover. We previously demonstrated that quinine-stimulated oromotor rejection reflexes and neural activity (assessed by Fos immunoreactivity) in subregions of hindbrain gustatory nuclei were restored if the posterior tongue, which contains receptor cells that respond strongly to bitter compounds, was cross-reinnervated by the chorda tympani nerve. Such functional recovery was not seen if instead, the anterior tongue, where receptor cells are less responsive to bitter compounds, was cross-reinnervated by the glossopharyngeal nerve, even though this nerve typically responds robustly to bitter substances. Thus, recovery depended more on the taste field being reinnervated than on the nerve itself. Here, the distribution of quinine-stimulated Fos-immunoreactive neurons in two taste-associated forebrain areas was examined in these same rats. In the central nucleus of the amygdala (CeA), a rostrocaudal gradient characterized the normal quinine-stimulated Fos response, with the greatest number of labeled cells situated rostrally. Quinine-stimulated neurons were found throughout the gustatory cortex, but a "hot spot" was observed in its anterior-posterior center in subregions approximating the dysgranular/agranular layers. Fos neurons here and in the rostral CeA were highly correlated with quinine-elicited gapes. Denervation of the posterior tongue eliminated, and its reinnervation by either nerve restored, numbers of quinine-stimulated labeled cells in the rostralmost CeA and in the subregion approximating the dysgranular gustatory cortex. These results underscore the remarkable plasticity of the gustatory system and also help clarify the functional anatomy of neural circuits activated by bitter taste stimulation. © 2014 Wiley Periodicals, Inc.

Hydrogen peroxide scavenger, catalase, alleviates ion transport dysfunction in murine colitis.

PubMed

Barrett, Kim E; McCole, Declan F

2016-11-01

Reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) contribute to epithelial damage and ion transport dysfunction (key events in inflammatory diarrhoea) in inflammatory bowel disease (IBD). The aim of this study was to identify if H 2 O 2 mediates suppression of colonic ion transport function in the murine dextran sulfate sodium (DSS) colitis model by using the H 2 O 2 degrading enzyme, catalase. Colitis was induced by administering DSS (4%) in drinking water for 5 days followed by 3 days on normal H 2 O. Mice were administered either pegylated catalase or saline at day -1, 0 and +1 of DSS treatment. Ion transport responses to the Ca 2+ -dependent agonist, carbachol (CCh), or the cAMP-dependent agonist, forskolin, were measured across distal colonic mucosa mounted in Ussing chambers. Parameters of DSS-induced inflammation (loss in body weight, decreased colon length, altered stool consistency), were only partially alleviated by catalase while histology was only minimally improved. However, catalase significantly reversed the DSS-induced reduction in baseline ion transport as well as colonic I sc responses to CCh. However, ion transport responses to forskolin were not significantly restored. Catalase also reduced activation of ERK MAP kinase in the setting of colitis, and increased expression of the Na + -K + -2Cl - cotransporter, NKCC1, consistent with restoration of ion transport function. Ex vivo treatment of inflamed colonic mucosae with catalase also partially restored ion transport function. Therefore, catalase partially prevents, and rescues, the loss of ion transport properties in DSS colitis even in the setting of unresolved tissue inflammation. These findings indicate a prominent role for ROS in ion transport dysfunction in colitis and may suggest novel strategies for the treatment of inflammatory diarrhoea. © 2016 John Wiley & Sons Australia, Ltd.

The Hydrogen Peroxide Scavenger, Catalase, Alleviates Ion Transport Dysfunction in Murine Colitis

PubMed Central

Barrett, Kim E.; McCole, Declan F.

2016-01-01

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) contribute to epithelial damage and ion transport dysfunction (key events in inflammatory diarrhea) in inflammatory bowel disease (IBD). The aim of this study was to identify if H2O2 mediates suppression of colonic ion transport function in the murine dextran sulfate sodium (DSS) colitis model by using the H2O2 degrading enzyme, catalase. Colitis was induced by administering DSS (4%) in drinking water for 5 days followed by 3 days on normal H2O. Mice were administered either pegylated-catalase or saline at day −1, 0 and +1 of DSS treatment. Ion transport responses to the Ca2+-dependent agonist, carbachol (CCh), or the cAMP-dependent agonist, forskolin, were measured across distal colonic mucosa mounted in Ussing chambers. Parameters of DSS-induced inflammation (loss in body weight, decreased colon length, altered stool consistency), were only partially alleviated by catalase while histology was only minimally improved. However, catalase significantly reversed the DSS-induced reduction in baseline ion transport as well as colonic Isc responses to CCh. However, ion transport responses to forskolin were not significantly restored. Catalase also reduced activation of ERK MAP kinase in the setting of colitis, and increased expression of the Na+-K+-2Cl− cotransporter, NKCC1, consistent with restoration of ion transport function. Ex vivo treatment of inflamed colonic mucosae with catalase also partially restored ion transport function. Therefore, catalase partially prevents, and rescues, the loss of ion transport properties in DSS colitis even in the setting of unresolved tissue inflammation. These findings indicate a prominent role for ROS in ion transport dysfunction in colitis and may suggest novel strategies for the treatment of inflammatory diarrhea. PMID:27543846

Atypical Role for PhoU in Mutagenic Break Repair under Stress in Escherichia coli

PubMed Central

Aponyi, Ildiko; Vera Cruz, Diana; Ray, Mellanie P.; Rosenberg, Susan M.

2015-01-01

Mechanisms of mutagenesis activated by stress responses drive pathogen/host adaptation, antibiotic and anti-fungal-drug resistance, and perhaps much of evolution generally. In Escherichia coli, repair of double-strand breaks (DSBs) by homologous recombination is high fidelity in unstressed cells, but switches to a mutagenic mode using error-prone DNA polymerases when the both the SOS and general (σS) stress responses are activated. Additionally, the σE response promotes spontaneous DNA breakage that leads to mutagenic break repair (MBR). We identified the regulatory protein PhoU in a genetic screen for functions required for MBR. PhoU negatively regulates the phosphate-transport and utilization (Pho) regulon when phosphate is in excess, including the PstB and PstC subunits of the phosphate-specific ABC transporter PstSCAB. Here, we characterize the PhoU mutation-promoting role. First, some mutations that affect phosphate transport and Pho transcriptional regulation decrease mutagenesis. Second, the mutagenesis and regulon-expression phenotypes do not correspond, revealing an apparent new function(s) for PhoU. Third, the PhoU mutagenic role is not via activation of the σS, SOS or σE responses, because mutations (or DSBs) that restore mutagenesis to cells defective in these stress responses do not restore mutagenesis to phoU cells. Fourth, the mutagenesis defect in phoU-mutant cells is partially restored by deletion of arcA, a gene normally repressed by PhoU, implying that a gene(s) repressed by ArcA promotes mutagenic break repair. The data show a new role for PhoU in regulation, and a new regulatory branch of the stress-response signaling web that activates mutagenic break repair in E. coli. PMID:25961709

Radiographic Outcomes of Volar Locked Plating for Distal Radius Fractures

PubMed Central

Mignemi, Megan E.; Byram, Ian R.; Wolfe, Carmen C.; Fan, Kang-Hsien; Koehler, Elizabeth A.; Block, John J.; Jordanov, Martin I.; Watson, Jeffry T.; Weikert, Douglas R.; Lee, Donald H.

2013-01-01

Purpose To assess the ability of volar locked plating to achieve and maintain normal radiographic parameters for articular stepoff, volar tilt, radial inclination, ulnar variance, and radial height in distal radius fractures. Methods We performed a retrospective review of 185 distal radius fractures that underwent volar locked plating with a single plate design over a 5-year period. We reviewed radiographs and recorded measurements for volar tilt, radial inclination, ulnar variance, radial height, and articular stepoff. We used logistic regression to determine the association between return to radiographic standard norms and fracture type. Results At the first and final postoperative follow-up visits, we observed articular congruence less than 2 mm in 92% of fractures at both times. Normal volar tilt (11°) was restored in 46% at the first follow-up and 48% at the final one. Radial inclination (22°) was achieved in 44% at the first follow-up and 43% at the final one, and ulnar variance (01 ± 2 mm) was achieved in 53% at the first follow-up and 53% at the final one. In addition, radial height (14 ± 1mm) was restored in 14% at the first follow-up and 12% at the final one. More complex, intra-articular fractures (AO class B and C and Frykman types 3, 4, 7, and 8) were less likely to be restored to normal radiographic parameters. However, because of the small sample size for some fracture types, it was difficult to discover significant associations between fracture type and radiographic outcome. Conclusions Volar locked plating for distal radius fractures achieved articular stepoff less than 2 mm in most fractures but only restored and maintained normal radiographic measurements for volar tilt, radial inclination, and ulnar variance in 50% of fractures. The ability of volar locked plating to restore and maintain ulnar variance and volar tilt decreased with more complex intra-articular fracture types. PMID:23218558

Many-Body Spectral Functions from Steady State Density Functional Theory.

PubMed

Jacob, David; Kurth, Stefan

2018-03-14

We propose a scheme to extract the many-body spectral function of an interacting many-electron system from an equilibrium density functional theory (DFT) calculation. To this end we devise an ideal scanning tunneling microscope (STM) setup and employ the recently proposed steady-state DFT formalism (i-DFT) which allows one to calculate the steady current through a nanoscopic region coupled to two biased electrodes. In our setup, one of the electrodes serves as a probe ("STM tip"), which is weakly coupled to the system we want to measure. In the ideal STM limit of vanishing coupling to the tip, the system is restored to quasi-equilibrium and the normalized differential conductance yields the exact equilibrium many-body spectral function. Calculating this quantity from i-DFT, we derive an exact relation expressing the interacting spectral function in terms of the Kohn-Sham one. As illustrative examples, we apply our scheme to calculate the spectral functions of two nontrivial model systems, namely the single Anderson impurity model and the Constant Interaction Model.

From anatomy to function: diagnosis of atherosclerotic renal artery stenosis.

PubMed

Odudu, Aghogho; Vassallo, Diana; Kalra, Philip A

2015-12-01

Atherosclerotic renal artery stenosis (ARAS) affects 7% of the over 65 s and will be increasingly common with an ageing population. ARAS obstructs normal renal perfusion with adverse renal and cardiovascular consequences. Drug therapy is directed at reducing atherosclerotic risk. Two recent major trials of revascularization for ARAS showed that clinical outcomes were not improved beyond those offered by optimal drug therapy in most patients. This reflects experimental data showing that restoration of blood flow alone may not attenuate a cascade of tissue injury. A shift from anatomic to functional imaging of ARAS coupled to novel therapies might improve clinical outcomes in selected patients. This review outlines the case for separately assessing hemodynamic significance of arterial stenosis and functional reserve of renal parenchymal tissue. The authors consider current and emerging diagnostic techniques for ARAS and their potential to allow individualized and functionally directed treatments.

Geomorphic Function and Restoration Potential of Spring Creeks in Southeastern Idaho: Analysis and Communication

NASA Astrophysics Data System (ADS)

Hanrahan, T. P.; Hill, Z.; Levell, A.; Maguire, T.; Risso, D.

2014-12-01

A large wetland and floodplain complex adjacent to the Snake River in southeastern Idaho, USA, encompasses numerous spring-fed creeks that originate on the floodplain and discharge at their confluence with the Snake River and American Falls Reservoir. Resource managers are implementing a program to restore these spring creeks for the recovery of Yellowstone cutthroat trout and ecosystem health. Our objectives were to evaluate the physical characteristics of these spring creeks, develop a conceptual model of their geomorphic function, compare the restoration potential of individual reaches, and communicate our findings to a broad audience of resource managers and regional stakeholders in order to foster restoration planning. A geomorphic assessment along 38 km of three spring creeks was completed by collecting data at several transects within distinct geomorphic reaches, and by collecting data continuously throughout all reaches. These data were summarized in a GIS database and used to quantify the overall geomorphic functioning of each reach. The geomorphic functional scores were scaled from 0% (non-functional) to 100% (fully functional). Among all three spring creeks, geomorphic function ranged from 29% to 63%, with bank conditions and riparian vegetation being the primary causes of overall channel degradation. Results from the geomorphic assessment fostered the development of a conceptual model for spring creek function, whereby degraded bank conditions represent the primary controlling factor of decreased geomorphic function and fish habitat quality. The reach-based geomorphic functional scoring provides an indicator of relative restoration potential for each reach, and is one of the factors used in determining site-specific priorities for protecting, enhancing, and restoring spring creeks on the Fort Hall Bottoms. The study results, conceptual model and restoration strategy were communicated to resource managers and regional stakeholders through a graphically-rich, large format atlas document. Presentation of hard copy and electronic versions of maps and infographics fostered a high level of engagement among those interested in restoring these spring creek systems.

Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor

PubMed Central

Wu, Yingjie; Sun, Hui; Basta-Pljakic, Jelena; Cardoso, Luis; Kennedy, Oran D; Jasper, Hector; Domené, Horacio; Karabatas, Liliana; Guida, Clara; Schaffler, Mitchell B; Rosen, Clifford J; Yakar, Shoshana

2013-01-01

States of growth hormone (GH) resistance, such those observed in Laron’s dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout, GHRKO) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKOHIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1 allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and from poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron’s syndrome does not achieve full skeletal growth. PMID:23456957

Effective therapy of transected quadriceps muscle in rat: Gastric pentadecapeptide BPC 157.

PubMed

Staresinic, Mario; Petrovic, Igor; Novinscak, Tomislav; Jukic, Ivana; Pevec, Damira; Suknaic, Slaven; Kokic, Neven; Batelja, Lovorka; Brcic, Luka; Boban-Blagaic, Alenka; Zoric, Zdenka; Ivanovic, Domagoj; Ajduk, Marko; Sebecic, Bozidar; Patrlj, Leonardo; Sosa, Tomislav; Buljat, Gojko; Anic, Tomislav; Seiwerth, Sven; Sikiric, Predrag

2006-05-01

We report complete transection of major muscle and the systemic peptide treatment that induces healing of quadriceps muscle promptly and then maintains the healing with functional restoration. Initially, stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419, PL-10, PLD-116, PL 14736 Pliva, Croatia; in trials for inflammatory bowel disease; wound treatment; no toxicity reported; effective alone without carrier) also superiorly accelerates the healing of transected Achilles tendon. Regularly, quadriceps muscle completely transected transversely 1.0 cm proximal to patella presents a definitive defect that cannot be compensated in rat. BPC 157 (10 microg, 10 ng, 10 pg/kg) is given intraperitoneally, once daily; the first application 30 min posttransection, the final 24 h before sacrifice. It consistently improves muscle healing throughout the whole 72-day period. Improved are: (i) biomechanic (load of failure increased); (ii) function (walking recovery and extensor postural thrust/motor function index returned toward normal healthy values); (iii) microscopy/immunochemistry [i.e., mostly muscle fibers connect muscle segments; absent gap; significant desmin positivity for ongoing regeneration of muscle; larger myofibril diameters on both sides, distal and proximal (normal healthy rat-values reached)]; (iv) macroscopic presentation (stumps connected; subsequently, atrophy markedly attenuated; finally, presentation close to normal noninjured muscle, no postsurgery leg contracture). Thus, posttransection healing-consistently improved-may suggest this peptide therapeutic application in muscle disorders. Copyright 2006 Orthopaedic Research Society.

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

PubMed

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

2017-01-01

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

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

PubMed Central

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

2017-01-01

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

Alterations in plasma L-arginine and methylarginines in heart failure and after heart transplantation.

PubMed

Lundgren, Jakob; Sandqvist, Anna; Hedeland, Mikael; Bondesson, Ulf; Wikström, Gerhard; Rådegran, Göran

2018-04-12

Endothelial function, including the nitric oxide (NO)-pathway, has previously been extensively investigated in heart failure (HF). In contrast, studies are lacking on the NO pathway after heart transplantation (HT). We therefore investigated substances in the NO pathway prior to and after HT in relation to hemodynamic parameters. 12 patients (median age 50.0 yrs, 2 females), heart transplanted between June 2012 and February 2014, evaluated at our hemodynamic lab, at rest, prior to HT, as well as four weeks and six months after HT were included. All patients had normal left ventricular function post-operatively and none had post-operative pulmonary hypertension or acute cellular rejection requiring therapy at the evaluations. Plasma concentrations of ADMA, SDMA, L-Arginine, L-Ornithine and L-Citrulline were analyzed at each evaluation. In comparison to controls, the plasma L-Arginine concentration was low and ADMA high in HF patients, resulting in low L-Arginine/ADMA-ratio pre-HT. Already four weeks after HT L-Arginine was normalized whereas ADMA remained high. Consequently the L-Arginine/ADMA-ratio improved, but did not normalize. The biomarkers remained unchanged at the six-month evaluation and the L-Arginine/ADMA-ratio correlated inversely to pulmonary vascular resistance (PVR) six months post-HT. Plasma L-Arginine concentrations normalize after HT. However, as ADMA is unchanged, the L-Arginine/ADMA-ratio remained low and correlated inversely to PVR. Together these findings suggest that (i) the L-Arginine/ADMA-ratio may be an indicator of pulmonary vascular tone after HT, and that (ii) NO-dependent endothelial function is partly restored after HT. Considering the good postoperative outcome, the biomarker levels may be considered "normal" after HT.

The heart of the matter: from guided microtools to 3-D printing and precision genome editing, promising research could lead to new advances in pediatric cardiology.

PubMed

Chandler, David L

2015-01-01

The smooth, powerful muscles of a newborn baby?s heart are pulsing normally, squeezing in and letting go rhythmically as a 3-mm-wide catheter-like tube snakes its way through, entering via an artery and being guided slowly by a surgeon. When it reaches its target?a protruding knot of malformed muscle tissue within a ventricle that has been partly blocking the valve?the tip of the precisely controlled tube whirs into action, with tiny scissor-like rotating blades gently grinding up the excess tissue as those pieces are sucked back into the device, leaving no floating particles that could lead to a blockage elsewhere. The defect is fully removed, and the heart?s function is restored to normal, leaving the child with the prospect of a normal life. The whole minimally invasive process takes place inside a beating heart and would otherwise have required open-heart surgery, with the heart stopped for a cardiopulmonary bypass.

Hyperthyrotropinemia in newly diagnosed cystic fibrosis patients with pancreatic insufficiency reversed by enzyme therapy.

PubMed

Giannakopoulos, Aris; Katelaris, Anni; Noni, Maria; Karakonstantakis, Theodore; Kanaka-Gantenbein, Christina; Doudounakis, Stavros

2018-05-01

Patients with cystic fibrosis (CF) commonly present with an elevated TSH concentration, suggesting subclinical hypothyroidism. Its relation to concomitant pancreatic insufficiency and its natural course upon initiation of enzyme replacement have not been adequately studied. Herein, we investigated the thyroid function in newly diagnosed infants with CF and monitored the course of thyroid function response to pancreatic enzyme substitution treatment. Fourteen, newly diagnosed infants with CF and pancreatic insufficiency, were followed every 6-8 weeks for 6 months ensuing onset of pancreatic enzyme substitution therapy. All infants had normal TSH values on neonatal screening. Ten out of 14 (71%) had hyperthyrotropinemia and normal freeT4 values at presentation. No patient received thyroxine. Upon follow-up, after 6 months, TSH values normalized in 90% of infants with CF and hyperthyrotropinemia. Serum selenium levels were negatively correlated with TSH levels. Mild TSH elevation is a frequent finding in newly diagnosed cystic fibrosis patients with pancreatic insufficiency during infancy. TSH elevation resolves in most cases after initiation of enzyme substitution and improvement of nutritional status without any substitutive therapy with thyroxine. What is Known: • Newly diagnosed infants with cystic fibrosis often present with a state of hyperthyrotropinemia suggesting subclinical hypothyroidism. What is New: • Pancreatic enzyme substitution and improvement of nutrition restores normal TSH levels without the need of thyroxine therapy.

Enalapril and losartan restored blood pressure and vascular reactivity in intrauterine undernourished rats.

PubMed

Ceravolo, Graziela S; Franco, Maria C P; Carneiro-Ramos, Marcela S; Barreto-Chaves, Maria L M; Tostes, Rita C A; Nigro, Dorothy; Fortes, Zuleica B; Carvalho, Maria Helena C

2007-01-30

Epidemiological studies suggest that intrauterine undernutrition plays an important role in the development of arterial hypertension and endothelial dysfunction in adulthood. We have evaluated the effect of the Renin Angiotensin System inhibition on the blood pressure and the mesenteric arteriolar reactivity of the intrauterine undernourished rats. Wistar rats were fed either normal or 50% of the normal intake diets, during the whole gestational period. In this study only the male offspring was used. At 16 weeks of age, the rats were used for the study of blood pressure, microvascular reactivity studied in vivo-in situ to Angiotensin II (Ang II), Bradykinin (Bk) and Acetylcholine (Ach) before and after either losartan (10 mg/kg/15 days) or enalapril (15 mg/kg/21 days) treatment. We also evaluated the mesenteric and plasmatic Angiotensin Converting Enzyme (ACE), renal function, lipid plasmatic content, and insulin and glucose metabolism. Intrauterine undernutrition induced hypertension and increased response of mesenteric arterioles to Ang II and decreased vasodilation to Bk and Ach. The treatments with losartan or enalapril normalized the blood pressure levels and significantly improved the arteriolar responses to Bk, Ach and reduced the response to Ang II. No differences have been detected to ACE activity, renal function, lipid content and insulin and glucose metabolism. This study shows for the first time that Renin Angiotensin System inhibitors can normalize the cardiovascular alterations induced by intrauterine undernutrition.

Rescue of dopamine transporter function in hypoinsulinemic rats by a D2 receptor-ERK-dependent mechanism.

PubMed

Owens, W Anthony; Williams, Jason M; Saunders, Christine; Avison, Malcolm J; Galli, Aurelio; Daws, Lynette C

2012-02-22

The dopamine (DA) transporter (DAT) is a major target for abused drugs and a key regulator of extracellular DA. A rapidly growing literature implicates insulin as an important regulator of DAT function. We showed previously that amphetamine (AMPH)-evoked DA release is markedly impaired in rats depleted of insulin with the diabetogenic agent streptozotocin (STZ). Similarly, functional magnetic resonance imaging experiments revealed that the blood oxygenation level-dependent signal following acute AMPH administration in STZ-treated rats is reduced. Here, we report that these deficits are restored by repeated, systemic administration of AMPH (1.78 mg/kg, every other day for 8 d). AMPH stimulates DA D(2) receptors indirectly by increasing extracellular DA. Supporting a role for D(2) receptors in mediating this "rescue," the effect was completely blocked by pre-treatment of STZ-treated rats with the D(2) receptor antagonist raclopride before systemic AMPH. D(2) receptors regulate DAT cell surface expression through ERK1/2 signaling. In ex vivo striatal preparations, repeated AMPH injections increased immunoreactivity of phosphorylated ERK1/2 (p-ERK1/2) in STZ-treated but not control rats. These data suggest that repeated exposure to AMPH can rescue, by activating D(2) receptors and p-ERK signaling, deficits in DAT function that result from hypoinsulinemia. Our data confirm the idea that disorders influencing insulin levels and/or signaling, such as diabetes and anorexia, can degrade DAT function and that insulin-independent pathways are present that may be exploited as potential therapeutic targets to restore normal DAT function.

Restoration of color in a remote sensing image and its quality evaluation

NASA Astrophysics Data System (ADS)

Zhang, Zuxun; Li, Zhijiang; Zhang, Jianqing; Wang, Zhihe

2003-09-01

This paper is focused on the restoration of color remote sensing (including airborne photo). A complete approach is recommended. It propose that two main aspects should be concerned in restoring a remote sensing image, that are restoration of space information, restoration of photometric information. In this proposal, the restoration of space information can be performed by making the modulation transfer function (MTF) as degradation function, in which the MTF is obtained by measuring the edge curve of origin image. The restoration of photometric information can be performed by improved local maximum entropy algorithm. What's more, a valid approach in processing color remote sensing image is recommended. That is splits the color remote sensing image into three monochromatic images which corresponding three visible light bands and synthesizes the three images after being processed separately with psychological color vision restriction. Finally, three novel evaluation variables are obtained based on image restoration to evaluate the image restoration quality in space restoration quality and photometric restoration quality. An evaluation is provided at last.

Durability of bonds and clinical success of adhesive restorations

PubMed Central

Carvalho, Ricardo M.; Manso, Adriana P.; Geraldeli, Saulo; Tay, Franklin R.; Pashley, David H.

2013-01-01

Resin-dentin bond strength durability testing has been extensively used to evaluate the effectiveness of adhesive systems and the applicability of new strategies to improve that property. Clinical effectiveness is determined by the survival rates of restorations placed in non-carious cervical lesions (NCCL). While there is evidence that the bond strength data generated in laboratory studies somehow correlates with the clinical outcome of NCCL restorations, it is questionable whether the knowledge of bonding mechanisms obtained from laboratory testing can be used to justify clinical performance of resin-dentin bonds. There are significant morphological and structural differences between the bonding substrate used in in vitro testing versus the substrate encountered in NCCL. These differences qualify NCCL as a hostile substrate for bonding, yielding bond strengths that are usually lower than those obtained in normal dentin. However, clinical survival time of NCCL restorations often surpass the durability of normal dentin tested in the laboratory. Likewise, clinical reports on the long-term survival rates of posterior composite restorations defy the relatively rapid rate of degradation of adhesive interfaces reported in laboratory studies. This article critically analyzes how the effectiveness of adhesive systems is currently measured, to identify gaps in knowledge where new research could be encouraged. The morphological and chemical analysis of bonded interfaces of resin composite restorations in teeth that had been in clinical service for many years, but were extracted for periodontal reasons, could be a useful tool to observe the ultrastructural characteristics of restorations that are regarded as clinically acceptable. This could help determine how much degradation is acceptable for clinical success. PMID:22192252

Congenitally athymic nude (nu/nu) mice have Thy-1-bearing immunocompetent helper T cells in their peritoneal cavity

PubMed Central

1980-01-01

Heavily irradiated peritoneal cells (PC) from congenitally athymic nude (nu/nu) mice markedly restored the impaired in vitro antibody response of nu/nu spleen cells to sheep erythrocyte antigens (T-dependent antigen), whereas irradiated spleen or lymph node cells from nu/nu mice had no effect on the response. This activity of the irradiated PC of nu/nu mice was completely abolished by treatment with anti-Thy-1.2 antiserum plus normal guinea pig serum (C') and is, therefore, attributable to a function of matured T cells. PMID:6966314

Regeneration of urologic tissues and organs.

PubMed

Atala, Anthony

2005-01-01

Patients suffering from a variety of urologic diseases may be treated with transplanted tissues and organs. However, there is a shortage of donor tissues and organs, which is worsening yearly owing to the ageing population. Scientists in the field of regenerative medicine and tissue engineering are applying the principles of cell transplantation, material science, and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured urologic tissues. This chapter reviews recent advances that have occurred in the regeneration of urologic organs and describes how these applications may offer novel therapies for patients with urologic disease.

Eight-year follow-up of autogenous tooth transplantation involving multidisciplinary treatment.

PubMed

Candeiro, George T M; Alencar-Júnior, Emmanuel A; Scarparo, Henrique C; Furtado-Júnior, João H C; Gavini, Giulio; Caldeira, Celso L

2015-09-01

Although autogenous tooth transplantation is a widely reported procedure, its success is dependent on a number of factors. Here we describe the surgical technique, endodontic treatment and rehabilitation employed for a patient in whom a lower right third molar was transplanted to substitute an adjacent second molar with extensive caries. During an 8-year follow-up period, normal periodontal healing was observed and no infection, ankylosis or progressive resorption occurred. It may be concluded that transplantation of a third molar is a practicable approach for replacement of a lost permanent tooth, with restoration of esthetics and function.

A personal perspective and update on erosive tooth wear - 10 years on: Part 2 - Restorative management.

PubMed

Bartlett, D

2016-08-26

The management challenge with erosive tooth wear is that the condition involves erosion and contributions from attrition and abrasion, both of which impact on the longevity of restorations. Severe erosive tooth wear results in visibly shorter teeth, exposure of dentine and adaptive changes which complicate restorative management. There is increasing evidence to suggest if the risk factors, such as reducing the frequency of acidic foods and drinks, are reduced the progression of tooth wear slows and follows a normal pattern of wear. But once teeth become shorter patients often seek advice from dentists on restorative intervention. Composite restorations are successful in some patients but they often involve regular maintenance with repairs and rebuilds, which for some patients is unacceptable. Full coverage crowns, although destructive of tooth tissue, remain an option for restorations.

Which experimental model can sensitively indicate brain death by functional near-infrared spectroscopy?

NASA Astrophysics Data System (ADS)

Pan, Boan; Liu, Weichao; Fang, Xiang; Huang, Xiaobo; Li, Ting

2018-02-01

Brain death is defined as permanent loss of the brain functions. The evaluation of it has many meanings, such as the relief of organ transplantation stress and family burden. However, it is hard to be judged precisely. The standard clinical tests are expensive, time consuming and even dangerous, and some auxiliary methods have limitations. Functional near infrared spectroscopy (fNIRS), monitoring cerebral hemodynamic responses noninvasively, evaluate brain death in some papers published, but there is no discussion about which experimental mode can monitor brain death patient more sensitively. Here, we attempt to use our fNIRS to evaluate brain death and find which experimental mode is effective. In order to discuss the problem, we detected eleven brain death patients and twenty normal patients under natural state. They were provided different fraction of inspiration O2 (FIO2) in different phase. We found that the ratio of Δ[HbO2] (the concentration changes in oxyhemoglobin) to Δ[Hb] (the concentration changes in deoxyhemoglobin) in brain death patients is significantly higher than normal patients in FIO2 experiment. Combined with the data analysis result, restore oxygen change process and low-high-low paradigm is more sensitively.

[Lower urinary tract dysfunction in normal pressure hydrocephalus: Review of the literature].

PubMed

Bey, E; Nicot, B; Casez, O; Le Normand, L

2016-12-01

Lower urinary tract dysfunction in normal pressure hydrocephalus has received little attention from the scientific community. The aim of this review article was to discuss diagnostic and therapeutic options for these patients. A literature review of MedLine publications on urinary incontinence in normal pressure hydrocephalus was conducted. The following keywords were used: "hydrocephalus, normal pressure" and "bladder dysfunction" or "urinary incontinence" or "overactive bladder" or "urinary bladder, neurogenic". Prospective and retrospective studies as well as previous reviews were analyzed. Urinary symptoms in normal pressure hydrocephalus are mainly represented by overactive bladder, which is a significant burden for the concerned patients. Isolated overactive bladder is more frequent (64%) than urinary incontinence (57%). Detrusor overactivity is seen in 95.2% of the cases. Neuro-surgery is efficient on urinary symptoms for 61.5% of the patients. Bladder recovery after surgery relates with increased mid-cingulate perfusion, probably linked with a functional restoration of the mid-cingulate that normally inhibits the micturition reflex. Medical options, added or not to surgery, include anticholinergic drugs unable to pass through the blood-brain barrier, Transcutaneous Electrical Nerve Stimulation and sacral neuromodulation. There is actually an insufficient concern about urinary symptoms in normal pressure hydrocephalus. This article highlights the importance of a harmonization of neuro-urological practices in the pre-therapeutic evaluation of patients suffering from normal pressure hydrocephalus. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A Multidisciplinary Approach for Rehabilitation of Enucleated Sockets: Ocular Implants with Custom Ocular Prosthesis.

PubMed

Choudhury, Minati; Banu, Fathima; Natarajan, Shanmuganathan; Kumar, Anand; Tv, Padmanabhan

2018-02-16

Interdisciplinary prosthodontics goes beyond our imagination into fields that have a direct effect on our total body health and quality of life. Removal of an eye has a detrimental effect on the psychology of the patient. Enucleation involves removal of the eyeball proper and leads to an enophthalmic socket with a shrunken eye, which has a crippling effect on patient's emotional and social life. Custom-made eye prosthesis simulates the characteristics of the companion eye and helps in restoring the normal facial appearance. Restoration of saccadic eye movements occurring during speech is desirable because this greatly contributes to a normal facial expression. This can be achieved by an orbital implant, which helps in orbital volume replacement and restoration of prosthesis movement and comfort. This article describes prosthodontic rehabilitation of enucleated eye sockets with orbital implants for two patients.

Trajectories of ecosystem service change in restored peatlands

NASA Astrophysics Data System (ADS)

Evans, Martin; Shuttleworth, Emma; Pilkington, Mike; Allott, Tim; Walker, Jonathan; Spencer, Tom

2017-04-01

Peatlands provide a wide range of ecosystem services but across the world degradation of these systems through a range of human impacts has had a negative effect on the provision of these services. A wide variety of peatland restoration approaches have been developed with the aim of mitigating these impacts. Understanding of trajectories of change in ecosystem structure and function is central to evaluating the efficacy of these restoration methods. This paper considers data on post-restoration trajectories of water table change, vegetation recovery, runoff production and water quality based on extensive data from peatland restoration work in the southern Pennines of the U.K. Data have been compiled from multiple restoration initiatives undertaken across the region, spanning up to 12 years post restoration. The data show variations in the time scale of ecosystem change which are indicative of the process basis of the ecosystem trajectories. Rapid changes in runoff are controlled by physical changes to the peatland surface. These are contrasted with longer term evolution of vegetation and water table behaviour which suggest ongoing recovery as the ecosystem adjusts to the restoration process. In order to assess restoration of ecosystem function, and so of ecosystem services, it is important that the process links between ecosystem structure and function are well understood. Establishing typical restoration trajectories can be of practical use in determining restoration project milestones, and can also provide insight into the nature of these process links.

77 FR 54904 - Intent to Prepare a Draft Environmental Impact Statement/Environmental Impact Report for the...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-06

... Environmental Impact Statement/ Environmental Impact Report for the Proposed Ballona Wetlands Restoration...) for the proposed Ballona Wetlands Restoration Project. The proposed project is intended to return the... biological functions and services in the project area. Restoring the wetland functions and services would...

Flooding facility helps scientists examine the ecophysiology of floodplain species used in bottomland hardwood restorations

Treesearch

Brian R. Lockhart; Emile S. Gardiner; Theodore D. Leininger; Kristina F. Connor; Paul B. Hamel; Nathan M. Schiff; A. Dan Wilson; Margaret S. Devall

2006-01-01

Bottomland hardwood ecosystems, important for their unique functions and values, have experienced considerable degradation since European settlement through deforestation, development, and drainage. Currently, considerable effort is underway to restore ecological functions on degraded bottomland sites. Restoration requires a better understanding of the biological...

Structural and Functional Loss in Restored Wetland Ecosystems

PubMed Central

Moreno-Mateos, David; Power, Mary E.; Comín, Francisco A.; Yockteng, Roxana

2012-01-01

Wetlands are among the most productive and economically valuable ecosystems in the world. However, because of human activities, over half of the wetland ecosystems existing in North America, Europe, Australia, and China in the early 20th century have been lost. Ecological restoration to recover critical ecosystem services has been widely attempted, but the degree of actual recovery of ecosystem functioning and structure from these efforts remains uncertain. Our results from a meta-analysis of 621 wetland sites from throughout the world show that even a century after restoration efforts, biological structure (driven mostly by plant assemblages), and biogeochemical functioning (driven primarily by the storage of carbon in wetland soils), remained on average 26% and 23% lower, respectively, than in reference sites. Either recovery has been very slow, or postdisturbance systems have moved towards alternative states that differ from reference conditions. We also found significant effects of environmental settings on the rate and degree of recovery. Large wetland areas (>100 ha) and wetlands restored in warm (temperate and tropical) climates recovered more rapidly than smaller wetlands and wetlands restored in cold climates. Also, wetlands experiencing more (riverine and tidal) hydrologic exchange recovered more rapidly than depressional wetlands. Restoration performance is limited: current restoration practice fails to recover original levels of wetland ecosystem functions, even after many decades. If restoration as currently practiced is used to justify further degradation, global loss of wetland ecosystem function and structure will spread. PMID:22291572

Blurred image restoration using knife-edge function and optimal window Wiener filtering.

PubMed

Wang, Min; Zhou, Shudao; Yan, Wei

2018-01-01

Motion blur in images is usually modeled as the convolution of a point spread function (PSF) and the original image represented as pixel intensities. The knife-edge function can be used to model various types of motion-blurs, and hence it allows for the construction of a PSF and accurate estimation of the degradation function without knowledge of the specific degradation model. This paper addresses the problem of image restoration using a knife-edge function and optimal window Wiener filtering. In the proposed method, we first calculate the motion-blur parameters and construct the optimal window. Then, we use the detected knife-edge function to obtain the system degradation function. Finally, we perform Wiener filtering to obtain the restored image. Experiments show that the restored image has improved resolution and contrast parameters with clear details and no discernible ringing effects.

Blurred image restoration using knife-edge function and optimal window Wiener filtering

PubMed Central

Zhou, Shudao; Yan, Wei

2018-01-01

Motion blur in images is usually modeled as the convolution of a point spread function (PSF) and the original image represented as pixel intensities. The knife-edge function can be used to model various types of motion-blurs, and hence it allows for the construction of a PSF and accurate estimation of the degradation function without knowledge of the specific degradation model. This paper addresses the problem of image restoration using a knife-edge function and optimal window Wiener filtering. In the proposed method, we first calculate the motion-blur parameters and construct the optimal window. Then, we use the detected knife-edge function to obtain the system degradation function. Finally, we perform Wiener filtering to obtain the restored image. Experiments show that the restored image has improved resolution and contrast parameters with clear details and no discernible ringing effects. PMID:29377950

C/EBPepsilon directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx.

PubMed

Halene, Stephanie; Gaines, Peter; Sun, Hong; Zibello, Theresa; Lin, Sharon; Khanna-Gupta, Arati; Williams, Simon C; Perkins, Archibald; Krause, Diane; Berliner, Nancy

2010-02-01

Mutations in the CCAAT enhancer binding protein epsilon (C/EBPepsilon) gene have been identified in the cells of patients with neutrophil specific granule deficiency, a rare congenital disorder marked by recurrent bacterial infections. Their neutrophils, in addition to lacking specific granules required for normal respiratory burst activity, also lack normal phagocytosis and chemotaxis. Although the specific granule deficiency phenotype has been replicated in C/EBPepsilon(-/-) (knockout [KO]) mice, the mechanisms by which C/EBPepsilon mutations act to decrease neutrophil function are not entirely clear. In order to determine the role of C/EBPepsilon in neutrophil differentiation and migration, we generated immortalized progenitor cell lines from C/EBPepsilon KO and wild-type mice and performed expression and flow cytometric analysis and functional studies. Expression of lineage-specific cell surface antigens on our in vitro differentiated cell lines revealed persistent expression of monocytic markers on KO granulocytes. We verified this in primary murine peripheral blood and bone marrow cells. In addition, KO bone marrow had an increase in immature myeloid precursors at the common myeloid progenitor and granulocyte/monocyte progenitor levels, suggesting a critical role for C/EBPepsilon not only in granulocyte maturation beyond the promyelocyte stage, but also in the monocyte/granulocyte lineage decision. We found that restoration of Hlx (H2.0-like homeo box 1) expression, which was decreased in C/EBPepsilon KO cells, rescued chemotaxis, but not the other defects of C/EBPepsilon KO neutrophils. We show two new regulatory functions of C/EBPepsilon in myelopoiesis: in the absence of C/EBPepsilon, there is not only incomplete differentiation of granulocytes, but myelopoiesis is disrupted with the appearance of an intermediate cell type with monocyte and granulocyte features, and the neutrophils have abnormal chemotaxis. Restoration of expression of Hlx provides partial recovery of function; it has no effect on neutrophil maturation, but can completely ameliorate the chemotaxis defect in C/EBPepsilon KO cells. Copyright 2010 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin★

PubMed Central

Wang, Qian; Liu, Chen; Uchida, Aki; Chuang, Jen-Chieh; Walker, Angela; Liu, Tiemin; Osborne-Lawrence, Sherri; Mason, Brittany L.; Mosher, Christina; Berglund, Eric D.; Elmquist, Joel K.; Zigman, Jeffrey M.

2013-01-01

The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreERT2 transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia. PMID:24567905

Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin.

PubMed

Wang, Qian; Liu, Chen; Uchida, Aki; Chuang, Jen-Chieh; Walker, Angela; Liu, Tiemin; Osborne-Lawrence, Sherri; Mason, Brittany L; Mosher, Christina; Berglund, Eric D; Elmquist, Joel K; Zigman, Jeffrey M

2014-02-01

The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreER(T2) transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia.

The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.

PubMed

Chambers, Adam P; Sorrell, Joyce E; Haller, April; Roelofs, Karen; Hutch, Chelsea R; Kim, Ki-Suk; Gutierrez-Aguilar, Ruth; Li, Bailing; Drucker, Daniel J; D'Alessio, David A; Seeley, Randy J; Sandoval, Darleen A

2017-04-04

Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells. To test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin-[9-39] (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg-null or GLP-1R KO mice, suggesting that Ex9 is a true and specific GLP-1R antagonist. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and i.p. glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis. Copyright © 2017 Elsevier Inc. All rights reserved.

Contrasting respirable quartz and kaolin retention of lecithin surfactant and expression of membranolytic activity following phospholipase A2 digestion.

PubMed

Wallace, W E; Keane, M J; Mike, P S; Hill, C A; Vallyathan, V; Regad, E D

1992-11-01

Respirable-sized quartz, a well-established fibrogenic mineral dust, is compared with kaolin in erythrocyte hemolysis assays after treatment with saline dispersion of dipalmitoyl phosphatidylcholine, a primary phospholipid component of pulmonary surfactant. Both dusts are rendered inactive after treatment, but the membranolytic activity is partly to fully restored after treatment with phospholipase A2, an enzyme normally associated with cellular plasma membranes and lysosomes. Phospholipid-coated dusts were incubated for periods of 2-72 h at a series of applied enzyme concentrations, and the adsorbed lipid species and hemolytic activity were quantitated at each time for both dusts. Surfactant was lost more readily from quartz than from kaolin, with consequent more rapid restoration of mineral surface hemolytic activity for quartz. Interactions of surfactant and mineral surface functional groups responsible for the mineral-specific rate differences, and implications for determining the mineral surface bioavailability of silica and silicate dusts, are discussed.

Rehabilitation of the Overhead Athlete’s Elbow

PubMed Central

Wilk, Kevin E.; Macrina, Leonard C.; Cain, E. Lyle; Dugas, Jeffrey R.; Andrews, James R.

2012-01-01

The activities required during overhead sports, particularly during baseball pitching, produce large forces at the elbow joint. Injuries to the elbow joint frequently occur in the overhead athlete because of the large amount of forces observed during the act of throwing, playing tennis, or playing golf. Injuries may result because of repetitive overuse, leading to tissue failure. Rehabilitation following injury or surgery to the throwing elbow is vital to fully restore normal function and return the athlete to competition as quickly and safely as possible. Rehabilitation of the elbow, whether following injury or postsurgical, must follow a progressive and sequential order, building on the previous phase, to ensure that healing tissues are not compromised. Emphasis is placed on restoring full motion, muscular strength, and neuromuscular control while gradually applying loads to healing tissue. In addition, when one is creating a rehabilitation plan for athletes, it is imperative to treat the entire upper extremity, core, and legs to create and dissipate the forces generated at each joint. PMID:23016113

Sing the mind electric - principles of deep brain stimulation.

PubMed

Kringelbach, Morten L; Green, Alexander L; Owen, Sarah L F; Schweder, Patrick M; Aziz, Tipu Z

2010-10-01

The remarkable efficacy of deep brain stimulation (DBS) for a range of treatment-resistant disorders is still not matched by a comparable understanding of the underlying neural mechanisms. Some progress has been made using translational research with a range of neuroscientific techniques, and here we review the most promising emerging principles. On balance, DBS appears to work by restoring normal oscillatory activity between a network of key brain regions. Further research using this causal neuromodulatory tool may provide vital insights into fundamental brain function, as well as guide targets for future treatments. In particular, DBS could have an important role in restoring the balance of the brain's default network and thus repairing the malignant brain states associated with affective disorders, which give rise to serious disabling problems such as anhedonia, the lack of pleasure. At the same time, it is important to proceed with caution and not repeat the errors from the era of psychosurgery. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Osseoperception: An Implant Mediated Sensory Motor Control- A Review

PubMed Central

Karani, Jyoti T.; Khanna, Anshul; Badwaik, Praveen; Pai, Ashutosh

2015-01-01

Osseointegration of dental implants has been researched extensively, covering various aspects such as bone apposition, biomechanics and microbiology etc however, physiologic integration of implants and the associated prosthesis in the body has received very little attention. This integration is due to the development of a special sensory ability, which is able to restore peripheral sensory feedback mechanism. The underlying mechanism of this so-called ‘osseoperception’ phenomenon remains a matter of debate. The following article reveals the histological, neurophysiologic and psychophysical aspects of osseoperception. A comprehensive research to provide scientific evidence of osseoperception was carried out using various online resources such as Pubmed, Google scholar etc to retrieve studies published between 1985 to 2014 using the following keywords: “osseoperception”, “mechanoreceptors”, “tactile sensibility”. Published data suggests that a peripheral feedback pathway can be restored with osseointegrated implants. This implant-mediated sensory-motor control may have important clinical implications in the normal functioning of the implant supported prosthesis. PMID:26501033

A novel male sterility-fertility restoration system in plants for hybrid seed production

PubMed Central

Singh, Surendra Pratap; Singh, Sudhir P.; Pandey, Tripti; Singh, Ram Rakshpal; Sawant, Samir V.

2015-01-01

Hybrid seeds are used for stimulated crop production, as they harness heterosis. The achievement of complete male-sterility in the female-parent and the restored-fertility in F1-hybrids are the major bottlenecks in the commercial hybrid seed production. Here, we report a male sterility–fertility restoration system by engineering the inmost nutritive anther wall layer tapetum of female and male parents. In the female parent, high–level, and stringent expression of Arabidopsis autophagy–related gene BECLIN1 was achieved in the tapetum, which altered the tapetal degeneration program, leading to male sterility. This works on our previously demonstrated expression cassette based on functional complementation of TATA-box mutant (TGTA) promoter and TATA-binding protein mutant3 (TBPm3), with modification by conjugating Long Hypocotyle in Far-Red1 fragment (HFR1NT131) with TBPm3 (HFR1NT131-TBPm3) to exercise regulatory control over it. In the male parent, tapetum–specific Constitutive photo-morphogenesis1 (COP1) was expressed. The F1 obtained by crossing these engineered parents showed decreased BECLIN1 expression, which was further completely abolished when COP1-mutant (COP1L105A) was used as a male parent, leading to normal tapetal development and restored fertility. The system works on COP1-HFR1 interaction and COP1–mediated degradation of TBPm3 pool (HFR1NT131-TBPm3). The system can be deployed for hybrid seed production in agricultural crops. PMID:26073981

A novel male sterility-fertility restoration system in plants for hybrid seed production.

PubMed

Singh, Surendra Pratap; Singh, Sudhir P; Pandey, Tripti; Singh, Ram Rakshpal; Sawant, Samir V

2015-06-15

Hybrid seeds are used for stimulated crop production, as they harness heterosis. The achievement of complete male-sterility in the female-parent and the restored-fertility in F1-hybrids are the major bottlenecks in the commercial hybrid seed production. Here, we report a male sterility-fertility restoration system by engineering the in most nutritive anther wall layer tapetum of female and male parents. In the female parent, high-level, and stringent expression of Arabidopsis autophagy-related gene BECLIN1 was achieved in the tapetum, which altered the tapetal degeneration program, leading to male sterility. This works on our previously demonstrated expression cassette based on functional complementation of TATA-box mutant (TGTA) promoter and TATA-binding protein mutant3 (TBPm3), with modification by conjugating Long Hypocotyle in Far-Red1 fragment (HFR1(NT131)) with TBPm3 (HFR1(NT131)-TBPm3) to exercise regulatory control over it. In the male parent, tapetum-specific Constitutive photo-morphogenesis1 (COP1) was expressed. The F1 obtained by crossing these engineered parents showed decreased BECLIN1 expression, which was further completely abolished when COP1-mutant (COP1(L105A)) was used as a male parent, leading to normal tapetal development and restored fertility. The system works on COP1-HFR1 interaction and COP1-mediated degradation of TBPm3 pool (HFR1(NT131)-TBPm3). The system can be deployed for hybrid seed production in agricultural crops.

Restoration of G1 chemo/radioresistance and double-strand-break repair proficiency by wild-type but not endonuclease-deficient Artemis.

PubMed

Mohapatra, Susovan; Kawahara, Misako; Khan, Imran S; Yannone, Steven M; Povirk, Lawrence F

2011-08-01

Deficiency in Artemis is associated with lack of V(D)J recombination, sensitivity to radiation and radiomimetic drugs, and failure to repair a subset of DNA double-strand breaks (DSBs). Artemis harbors an endonuclease activity that trims both 5'- and 3'-ends of DSBs. To examine whether endonucleolytic trimming of terminally blocked DSBs by Artemis is a biologically relevant function, Artemis-deficient fibroblasts were stably complemented with either wild-type Artemis or an endonuclease-deficient D165N mutant. Wild-type Artemis completely restored resistance to γ-rays, bleomycin and neocarzinostatin, and also restored DSB-repair proficiency in G0/G1 phase as measured by pulsed-field gel electrophoresis and repair focus resolution. In contrast, cells expressing the D165N mutant, even at very high levels, remained as chemo/radiosensitive and repair deficient as the parental cells, as evidenced by persistent γ-H2AX, 53BP1 and Mre11 foci that slowly increased in size and ultimately became juxtaposed with promyelocytic leukemia protein nuclear bodies. In normal fibroblasts, overexpression of wild-type Artemis increased radioresistance, while D165N overexpression conferred partial repair deficiency following high-dose radiation. Restoration of chemo/radioresistance by wild-type, but not D165N Artemis suggests that the lack of endonucleolytic trimming of DNA ends is the principal cause of sensitivity to double-strand cleaving agents in Artemis-deficient cells.

The Effects of Long Time Conservation of Heavily Grazed Shrubland: A Case Study in the Northern Negev, Israel

NASA Astrophysics Data System (ADS)

Leu, Stefan; Mussery, Amir Mor; Budovsky, Arie

2014-08-01

One of the major reasons for desertification is unrestricted grazing leading to vegetation depletion, soil erosion and degradation, phenomena often considered irreversible in the short term. Here, we compare soil and biological parameters of degraded and conserved, recently rehabilitated arid shrubland in the Northern Negev, Israel. The study area was restored by conservation efforts including a strictly controlled grazing regime initiated in 1992. The visually recognizable improvement in the ecology of the restored shrubland is reflected in significant improvement in all examined biotic (herbaceous biomass, shrub patch density, and insect activity), and soil parameters (nutrients, organic matter content, moisture, and water infiltration). The difference is created predominantly by restoration of large biological patches composed of shrubs and other perennial plants often associated with ant or termite nests, where the most significant increases in productivity and soil quality were observed. In the conserved shrubland such patches covered 35 or 25 % of the area (in a normal and a drought year, respectively). In the degraded shrubland 5 % or less of the area was occupied by such patches that were much smaller and of lower biological complexity. With respect to plant biodiversity, six plant species were found only—and 18 others became significantly more common—in the rehabilitated area. The results of this article indicate that functional arid drylands can be restored within <16 years relying on strict conservation management with reduced grazing intensity.

Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology

PubMed Central

Yang, Sujeong; Cacquevel, Matthias; Saksida, Lisa M.; Bussey, Timothy J.; Schneider, Bernard L.; Aebischer, Patrick; Melani, Riccardo; Pizzorusso, Tommaso; Fawcett, James W.; Spillantini, Maria Grazia

2015-01-01

Alzheimer's disease is the most prevalent tauopathy and cause of dementia. We investigate the hypothesis that reactivation of plasticity can restore function in the presence of neuronal damage resulting from tauopathy. We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the mutant P301S tau is expressed in neurons (Tg P301S), and a model in which an adeno-associated virus expressing P301S tau (AAV-P301S) was injected in the perirhinal cortex, a region critical for object recognition (OR) memory. Both models show profound loss of OR memory despite only 15% neuronal loss in the Tg P301S and 26% in AAV-P301S-injected mice. Recordings from perirhinal cortex slices of 3 month-old P301S transgenic mice showed a diminution in synaptic transmission following temporal stimulation. Chondroitinase ABC (ChABC) can reactivate plasticity and affect memory through actions on perineuronal nets. ChABC was injected into the perirhinal cortex and animals were tested for OR memory 1 week later, demonstrating restoration of OR memory to normal levels. Synaptic transmission indicated by fEPSP amplitude was restored to control levels following ChABC treatment. ChABC did not affect the progression of neurodegenerative tauopathy. These findings suggest that increasing plasticity by manipulation of perineuronal nets offers a novel therapeutic approach to the treatment of memory loss in neurodegenerative disorders. PMID:25483398

Towards a miniaturized brain-machine-spinal cord interface (BMSI) for restoration of function after spinal cord injury.

PubMed

Shahdoost, Shahab; Frost, Shawn; Van Acker, Gustaf; DeJong, Stacey; Dunham, Caleb; Barbay, Scott; Nudo, Randolph; Mohseni, Pedram

2014-01-01

Nearly 6 million people in the United States are currently living with paralysis in which 23% of the cases are related to spinal cord injury (SCI). Miniaturized closed-loop neural interfaces have the potential for restoring function and mobility lost to debilitating neural injuries such as SCI by leveraging recent advancements in bioelectronics and a better understanding of the processes that underlie functional and anatomical reorganization in an injured nervous system. This paper describes our current progress towards developing a miniaturized brain-machine-spinal cord interface (BMSI) that is envisioned to convert in real time the neural command signals recorded from the brain to electrical stimuli delivered to the spinal cord below the injury level. Specifically, the paper reports on a corticospinal interface integrated circuit (IC) as a core building block for such a BMSI that is capable of low-noise recording of extracellular neural spikes from the cerebral cortex as well as muscle activation using intraspinal microstimulation (ISMS) in a rat with contusion injury to the thoracic spinal cord. The paper further presents results from a neurobiological study conducted in both normal and SCI rats to investigate the effect of various ISMS parameters on movement thresholds in the rat hindlimb. Coupled with proper signal-processing algorithms in the future for the transformation between the cortically recorded data and ISMS parameters, such a BMSI has the potential to facilitate functional recovery after an SCI by re-establishing corticospinal communication channels lost due to the injury.

The Neuroprotective Aspects of Sleep.

PubMed

Eugene, Andy R; Masiak, Jolanta

2015-03-01

Sleep is an important component of human life, yet many people do not understand the relationship between the brain and the process of sleeping. Sleep has been proven to improve memory recall, regulate metabolism, and reduce mental fatigue. A minimum of 7 hours of daily sleep seems to be necessary for proper cognitive and behavioral function. The emotional and mental handicaps associated with chronic sleep loss as well as the highly hazardous situations which can be contributed to the lack of sleep is a serious concern that people need to be aware of. When one sleeps, the brain reorganizes and recharges itself, and removes toxic waste byproducts which have accumulated throughout the day. This evidence demonstrates that sleeping can clear the brain and help maintain its normal functioning. Multiple studies have been done to determine the effects of total sleep deprivation; more recently some have been conducted to show the effects of sleep restriction, which is a much more common occurrence, have the same effects as total sleep deprivation. Each phase of the sleep cycle restores and rejuvenates the brain for optimal function. When sleep is deprived, the active process of the glymphatic system does not have time to perform that function, so toxins can build up, and the effects will become apparent in cognitive abilities, behavior, and judgment. As a background for this paper we have reviewed literature and research of sleep phases, effects of sleep deprivation, and the glymphatic system of the brain and its restorative effect during the sleep cycle.

The Neuroprotective Aspects of Sleep

PubMed Central

Eugene, Andy R.; Masiak, Jolanta

2015-01-01

Sleep is an important component of human life, yet many people do not understand the relationship between the brain and the process of sleeping. Sleep has been proven to improve memory recall, regulate metabolism, and reduce mental fatigue. A minimum of 7 hours of daily sleep seems to be necessary for proper cognitive and behavioral function. The emotional and mental handicaps associated with chronic sleep loss as well as the highly hazardous situations which can be contributed to the lack of sleep is a serious concern that people need to be aware of. When one sleeps, the brain reorganizes and recharges itself, and removes toxic waste byproducts which have accumulated throughout the day. This evidence demonstrates that sleeping can clear the brain and help maintain its normal functioning. Multiple studies have been done to determine the effects of total sleep deprivation; more recently some have been conducted to show the effects of sleep restriction, which is a much more common occurrence, have the same effects as total sleep deprivation. Each phase of the sleep cycle restores and rejuvenates the brain for optimal function. When sleep is deprived, the active process of the glymphatic system does not have time to perform that function, so toxins can build up, and the effects will become apparent in cognitive abilities, behavior, and judgment. As a background for this paper we have reviewed literature and research of sleep phases, effects of sleep deprivation, and the glymphatic system of the brain and its restorative effect during the sleep cycle. PMID:26594659

Predicting outcomes of restored Everglades high flow: A model system for scientifically managed floodplains

USGS Publications Warehouse

Choi, Jay; Harvey, Judson

2017-01-01

Restoration of higher flows through the Everglades is intended to reestablish sheetflow to rebuild a well-functioning ridge and slough landscape that supports a productive and diverse ecosystem. Our objective of the study was to use hydrologic simulations and biophysical analysis to predict restoration outcomes for five major subbasins of the Everglades. Five different scenarios of restoration were examined, and for each we predicted an outcome based on metrics describing the present-day condition of the landscape and additional metrics determined by modeling the hydrologic changes accompanying restoration. Restoration scenarios spanned from a baseline case with average annual flows of about 52% of the predrainage flow to the most aggressive scenario that permits 91% of the predrainage flow. Our predictions indicated that all restoration scenarios could benefit the functionality of the ridge-slough ecosystem. However, the difference between any single restoration scenario and the “no restoration” baseline was far greater than was the difference between any two levels of restoration. Interestingly, our analysis suggested that the most extensive (and highest cost) restoration scenarios are not likely to improve ridge and slough function more than less extensive restoration options. However, the value of more aggressive restoration may lie in factors not considered directly in our analysis. For example, an important reason to implement the more aggressive restoration scenarios could be additional flexibility that permitting greater flow allows for adaptively managing the ecosystem while also serving water needs for southeastern Florida in what could be a drier Everglades in the coming decades.

Facilitation and Restoration of Cognitive Function in Primate Prefrontal Cortex by a Neuroprosthesis that Utilizes Minicolumn-Specific Neural Firing

PubMed Central

Hampson, Robert E.; Gerhardt, Greg A.; Marmarelis, Vasilis; Song, Dong; Opris, Ioan; Santos, Lucas; Berger, Theodore W.; Deadwyler, Sam A.

2012-01-01

Problem addressed Maintenance of cognitive control is a major concern for many human disease condition, therefore a major goal of human neuroprosthetics is to facilitate and/or recover cognitive function when such circumstances impair appropriate decision making. Methodology Nonhuman primates trained to perform a delayed match to sample (DMS) were employed to record mini-columnar activity in the prefrontal cortex (PFC) via custom designed conformal multielectrode arrays that provided inter-laminar recordings from neurons in PFC layer 2/3 and layer 5. Such recordings were analyzed via a previously demonstrated nonlinear multi-input multi-output (MIMO) neuroprosthesis in rodents, which extracted and characterized multi-columnar firing patterns during DMS performance. Results The MIMO model verified that the conformal recorded individual PFC minicolumns responded to entrained target selections in patterns critical for successful DMS performance. This allowed substitution of task-related layer 5 neuron firing patterns with electrical stimulation in the same recording regions during columnar transmission from layer 2/3 at the time of target selection. Such stimulation facilitated normal task performance, but more importantly, recovered performance when applied as a neuroprosthesis following pharmacological disruption of decision making in the same task. Significance and potential impact These findings provide the first successful application of a neuroprosthesis in primate brain designed specifically to restore or repair disrupted cognitive function. PMID:22976769

Reconstitution of full-thickness skin by microcolumn grafting.

PubMed

Tam, Joshua; Wang, Ying; Vuong, Linh N; Fisher, Jeremy M; Farinelli, William A; Anderson, R Rox

2017-10-01

In addition to providing a physical barrier, skin also serves a diverse range of physiological functions through different specialized resident cell types/structures, including melanocytes (pigmentation and protection against ultraviolet radiation), Langerhans cells (adaptive immunity), fibroblasts (maintaining extracellular matrix, paracrine regulation of keratinocytes), sweat glands (thermoregulation) and hair follicles (hair growth, sensation and a stem cell reservoir). Restoration of these functional elements has been a long-standing challenge in efforts to engineer skin tissue, while autologous skin grafting is limited by the scarcity of donor site skin and morbidity caused by skin harvesting. We demonstrate an alternative approach of harvesting and then implanting μm-scale, full-thickness columns of human skin tissue, which can be removed from a donor site with minimal morbidity and no scarring. Fresh human skin microcolumns were used to reconstitute skin in wounds on immunodeficient mice. The restored skin recapitulated many key features of normal human skin tissue, including epidermal architecture, diverse skin cell populations, adnexal structures and sweat production in response to cholinergic stimulation. These promising preclinical results suggest that harvesting and grafting of microcolumns may be useful for reconstituting fully functional skin in human wounds, without donor site morbidity. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd.

CRISPR-mediated genotypic and phenotypic correction of a chronic granulomatous disease mutation in human iPS cells

PubMed Central

Flynn, Rowan; Grundmann, Alexander; Renz, Peter; Hänseler, Walther; James, William S.; Cowley, Sally A.; Moore, Michael D.

2015-01-01

Chronic granulomatous disease (CGD) is a rare genetic disease characterized by severe and persistent childhood infections. It is caused by the lack of an antipathogen oxidative burst, normally performed by phagocytic cells to contain and clear bacterial and fungal growth. Restoration of immune function can be achieved with heterologous bone marrow transplantation; however, autologous bone marrow transplantation would be a preferable option. Thus, a method is required to recapitulate the function of the diseased gene within the patient's own cells. Gene therapy approaches for CGD have employed randomly integrating viruses with concomitant issues of insertional mutagenesis, inaccurate gene dosage, and gene silencing. Here, we explore the potential of the recently described clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 site-specific nuclease system to encourage repair of the endogenous gene by enhancing the levels of homologous recombination. Using induced pluripotent stem cells derived from a CGD patient containing a single intronic mutation in the CYBB gene, we show that footprintless gene editing is a viable option to correct disease mutations. Gene correction results in restoration of oxidative burst function in iPS-derived phagocytes by reintroduction of a previously skipped exon in the cytochrome b-245 heavy chain (CYBB) protein. This study provides proof-of-principle for a gene therapy approach to CGD treatment using CRISPR-Cas9. PMID:26101162

Switch to restoration therapy in a testosterone treated central hypogonadism with erythrocytosis.

PubMed

Cangiano, B; Cacciatore, C; Persani, L; Bonomi, M

2017-01-01

We describe a case of severe erythrocytosis caused by testosterone replacement therapy in a 66-year-old man affected with hypogonadotropic hypogonadism (HH) determining osteoporosis, resolved by switching to restoration therapy with clomiphene citrate. The patient complained fatigue, loss of libido and defective erections and a spontaneous vertebral fracture despite bisphosphonate therapy and vitamin D supplementation. The examinations proved isolated HH and he was therefore treated with testosterone gel with regression of specific manifestations but elevated hemoglobin and hematocrit values. Therefore, it was decided to switch to a restoration therapy with clomiphene citrate 25 mg/die, which resulted in the resolution of symptoms without evident side effects. In a couple of months, the patient showed normalization of testosterone levels and increment of testicular volume. Since secondary hypogonadism is the consequence of an insufficient stimulation of the gonads by hypothalamic-pituitary axis, therapeutic approaches aimed to restore endogenous testosterone production should be considered in alternative to testosterone replacement, particularly if side effects intervene. Among these strategies, clomiphene citrate seems to have a high efficacy and safety profile also in the elderly with isolated HH and no evident pituitary lesion. Hypogonadism should always be assessed in patients with severe loss in BMD and undergo appropriate medical treatment.In hypogonadotropic hypogonadism, more approaches are available other than testosterone replacement therapy alone.In patients with severe late-onset central hypogonadism presenting with erythrocytosis even at low doses of replacement therapy, restoration therapy with clomiphene could prove to be an effective solution, particularly in patients with a reversible disruption of GNRH/gonadotropin functions.Clomiphene citrate increases gonadotropin levels and testicular volume and should therefore be considered in hypogonadal men who wish to remain fertile.

Restoring hydrological and biogeochemical ecosystem services in streams: how can science inform practice?

NASA Astrophysics Data System (ADS)

Lautz, L.; Gordon, R.; Daniluk, T.; Zimmer, M. A.; Endreny, T. A.; McGrath, K.

2014-12-01

Society is increasingly recognizing the value of stream ecosystem functions, as evidenced by the enormous economic investment being made in stream restoration across the United States. Stream restoration projects have a variety of goals, including improvement in water quality and in-stream habitat. Popular approaches to restoration (such as Natural Channel Design, or NCD) aim to move degraded streams along a trajectory toward a dynamic ecological endpoint that represents natural conditions. Project designs primarily focus on channel form and function, but stream-groundwater exchanges of water and solutes are not typically a design consideration, although a primary component of fully functioning stream ecosystems. Here, we synthesize results from field investigations of the impact of NCD stream restoration on stream-groundwater exchanges by (1) comparing restored sites to reference reaches, which serve as the basis for the restoration design, (2) characterizing multiple restored sites to determine universal characteristics of streams restored by NCD, and (3) monitoring a stream pre- and post- restoration. NCD restoration creates hot spots of rapid hyporheic exchange upstream of channel spanning structures, with water fluxes across the bed interface up to an order of magnitude higher than at pre-restoration or reference reaches. Elevated flux rates result in short hyporheic residence times, which are not sufficiently long to generate net changes in nutrient concentrations. Hot spots of biogeochemical transformations are instead located around secondary bedforms, such as pool-riffle sequences, where gross water exchange rates are more moderate. Reference reaches show greater evidence of groundwater discharge to the hyporheic zone relative to restored reaches, although observations before and after restoration suggest NCD can modify the spatial extent of groundwater discharge zones. Gross water exchange across the streambed interface along restored reaches is a small percentage of stream discharge, suggesting the primary impact of restoration on stream-groundwater exchange is promoting biochemical heterogeneity in the subsurface, rather than longitudinal net changes in stream solute concentrations. Results inform future design to achieve restoration goals.

Restoration of the intrinsic properties of human dermal papilla in vitro.

PubMed

Ohyama, Manabu; Kobayashi, Tetsuro; Sasaki, Takashi; Shimizu, Atsushi; Amagai, Masayuki

2012-09-01

The dermal papilla (DP) plays pivotal roles in hair follicle morphogenesis and cycling. However, characterization and/or propagation of human DPs have been unsatisfactory because of the lack of efficient isolation methods and the loss of innate characteristics in vitro. We hypothesized that culture conditions sustaining the intrinsic molecular signature of the human DP could facilitate expansion of functional DP cells. To test this, we first characterized the global gene expression profile of microdissected, non-cultured human DPs. We performed a 'two-step' microarray analysis to exclude the influence of unwanted contaminants in isolated DPs and successfully identified 118 human DP signature genes, including 38 genes listed in the mouse DP signature. The bioinformatics analysis of the DP gene list revealed that WNT, BMP and FGF signaling pathways were upregulated in intact DPs and addition of 6-bromoindirubin-3'-oxime, recombinant BMP2 and basic FGF to stimulate these respective signaling pathways resulted in maintained expression of in situ DP signature genes in primarily cultured human DP cells. More importantly, the exposure to these stimulants restored normally reduced DP biomarker expression in conventionally cultured DP cells. Cell growth was moderate in the newly developed culture medium. However, rapid DP cell expansion by conventional culture followed by the restoration by defined activators provided a sufficient number of DP cells that demonstrated characteristic DP activities in functional assays. The study reported here revealed previously unreported molecular mechanisms contributing to human DP properties and describes a useful technique for the investigation of human DP biology and hair follicle bioengineering.

Sildenafil Citrate-Restored eNOS and PDE5 Regulation in Sickle Cell Mouse Penis Prevents Priapism Via Control of Oxidative/Nitrosative Stress

PubMed Central

Hsu, Lewis L.; Berkowitz, Dan E.; Champion, Hunter C.; Burnett, Arthur L.

2013-01-01

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders. PMID:23844149

Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress.

PubMed

Bivalacqua, Trinity J; Musicki, Biljana; Hsu, Lewis L; Berkowitz, Dan E; Champion, Hunter C; Burnett, Arthur L

2013-01-01

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.

Short-term treatment with flumazenil restores long-term object memory in a mouse model of Down syndrome.

PubMed

Colas, Damien; Chuluun, Bayarsaikhan; Garner, Craig C; Heller, H Craig

2017-04-01

Down syndrome (DS) is a common genetic cause of intellectual disability yet no pro-cognitive drug therapies are approved for human use. Mechanistic studies in a mouse model of DS (Ts65Dn mice) demonstrate that impaired cognitive function is due to excessive neuronal inhibitory tone. These deficits are normalized by chronic, short-term low doses of GABA A receptor (GABA A R) antagonists in adult animals, but none of the compounds investigated are approved for human use. We explored the therapeutic potential of flumazenil (FLUM), a GABA A R antagonist working at the benzodiazepine binding site that has FDA approval. Long-term memory was assessed by the Novel Object Recognition (NOR) testing in Ts65Dn mice after acute or short-term chronic treatment with FLUM. Short-term, low, chronic dose regimens of FLUM elicit long-lasting (>1week) normalization of cognitive function in both young and aged mice. FLUM at low dosages produces long lasting cognitive improvements and has the potential of fulfilling an unmet therapeutic need in DS. Copyright © 2017. Published by Elsevier Inc.

Continuous theta burst stimulation facilitates the clearance efficiency of the glymphatic pathway in a mouse model of sleep deprivation.

PubMed

Liu, Dong-Xu; He, Xia; Wu, Dan; Zhang, Qun; Yang, Chao; Liang, Feng-Yin; He, Xiao-Fei; Dai, Guang-Yan; Pei, Zhong; Lan, Yue; Xu, Guang-Qing

2017-07-13

Sleep deprivation (SD) is a common condition associated with a variety of nervous system diseases, and has a negative impact on emotional and cognitive function. Continuous theta burst stimulation (cTBS) is known to improve cognition and emotion function in normal situations as well as in various types of dysfunction, but the mechanism remains unknown. We used two-photon in vivo imaging to explore the effect of cTBS on glymphatic pathway clearance in normal and SD C57BL/6J mice. Aquaporin-4 (AQP4) polarization was detected by immunofluorescence. Anxiety-like behaviors was measured using open field tests. We found that SD reduced influx efficiency along the peri-vascular space (PVS), disturbed AQP4 polarization and induced anxiety-like behaviors. CTBS significantly attenuated the decrease in efficiency of solute clearance usually incurred with SD, restored the loss of AQP4 polarization and improved anxiety-like behavior in SD animals. Our results implied that cTBS had the potential to protect against neuronal dysfunction induced by sleep disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Altered K+ fluxes and insulin release in pancreatic islets from omega3 fatty acid-depleted rats.

PubMed

Sener, Abdullah; Zhang, Ying; Louchami, Karim; Oguzhan, Berrin; Courtois, Philippe; Portois, Laurence; Chardigny, Jean-Michel; Carpentier, Yvon A; Malaisse, Willy J

2006-10-01

A low intake of long-chain polyunsaturated omega3 fatty acid often prevails in Western populations. Its consequences in terms of the control of fuel homeostasis led us to explore functional events in pancreatic islets isolated from either normal or omega3-depleted rats (second generation). In the latter rats, the inflow of K+ by both ouabain-sensitive and ouabain-resistant modalities was decreased, this coinciding with an impaired insulin secretory response to ouabain. The intravenous injection of a medium-chain triglyceride:fish oil emulsion to omega3-depleted rats 2 h before sacrifice restored a normal value for the inflow of K+ by the ouabainsensitive modality, i.e., that linked to the activity of the Na,K-ATPase, but failed to correct the entry of K+ by the ouabain-resistant modality and the defect of the insulin secretory response to ouabain. In conclusion, an impaired activity of the Na,K-ATPase in insulin-producing cells apparently represents a key determinant of altered islet function in omega3-depleted rats.

Restoration of Bladder and Bowel Function Using Electrical Stimulation and Block after Spinal Cord Injury

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-14-2-0132 TITLE: Restoration of Bladder and Bowel Function Using Electrical Stimulation and Block after Spinal Cord Injury...per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and...COVERED 29 Sep 2015 - 28 Sep 2016 4. TITLE AND SUBTITLE Restoration of Bladder and Bowel Function Using Electrical Stimulation and Block after Spinal

Reactivating Neural Circuits with Clinically Accessible Stimulation to Restore Hand Function in Persons with Tetraplegia

DTIC Science & Technology

2017-09-01

AWARD NUMBER: W81XWH-16-1-0395 TITLE: Reactivating Neural Circuits with Clinically Accessible Stimulation to Restore Hand Function in...estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data...Clinically Accessible Stimulation to Restore Hand Function in Persons with Tetraplegia 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S

Restoration of MRI Data for Field Nonuniformities using High Order Neighborhood Statistics

PubMed Central

Hadjidemetriou, Stathis; Studholme, Colin; Mueller, Susanne; Weiner, Michael; Schuff, Norbert

2007-01-01

MRI at high magnetic fields (> 3.0 T ) is complicated by strong inhomogeneous radio-frequency fields, sometimes termed the “bias field”. These lead to nonuniformity of image intensity, greatly complicating further analysis such as registration and segmentation. Existing methods for bias field correction are effective for 1.5 T or 3.0 T MRI, but are not completely satisfactory for higher field data. This paper develops an effective bias field correction for high field MRI based on the assumption that the nonuniformity is smoothly varying in space. Also, nonuniformity is quantified and unmixed using high order neighborhood statistics of intensity cooccurrences. They are computed within spherical windows of limited size over the entire image. The restoration is iterative and makes use of a novel stable stopping criterion that depends on the scaled entropy of the cooccurrence statistics, which is a non monotonic function of the iterations; the Shannon entropy of the cooccurrence statistics normalized to the effective dynamic range of the image. The algorithm restores whole head data, is robust to intense nonuniformities present in high field acquisitions, and is robust to variations in anatomy. This algorithm significantly improves bias field correction in comparison to N3 on phantom 1.5 T head data and high field 4 T human head data. PMID:18193095

Insulin Rescues Impaired Spermatogenesis via the Hypothalamic-Pituitary-Gonadal Axis in Akita Diabetic Mice and Restores Male Fertility

PubMed Central

Schoeller, Erica L.; Albanna, Gabriella; Frolova, Antonina I.; Moley, Kelle H.

2012-01-01

The mechanism responsible for poor reproductive outcomes in type 1 diabetic males is not well understood. In light of new evidence that the Sertoli cells of the testis secrete insulin, it is currently unclear whether diabetic subfertility is the result of deficiency of pancreatic insulin, testicular insulin, or both. In this study, the Akita mouse diabetic model, which expresses a mutant, nonfunctional form of ins2 in testes and pancreas, was used to distinguish between systemic and local effects of insulin deficiency on the process of spermatogenesis and fertility. We determined that Akita homozygous male mice are infertile and have reduced testis size and abnormal morphology. Spermatogonial germ cells are still present but are unable to mature into spermatocytes and spermatids. Exogenous insulin treatment regenerates testes and restores fertility, but this plasma insulin cannot pass through the blood-testis barrier. We conclude that insulin does not rescue fertility through direct interaction with the testis; instead, it restores function of the hypothalamic-pituitary-gonadal axis and, thus, normalizes hormone levels of luteinizing hormone and testosterone. Although we show that the Sertoli cells of the testis secrete insulin protein, this insulin does not appear to be critical for fertility. PMID:22522616

Practice of laryngectomy rehabilitation interventions: a perspective from Hong Kong.

PubMed

Chan, Jimmy Y W

2013-06-01

To review the current practice of rehabilitation for laryngectomees in Hong Kong. Factors affecting the quality of life of laryngectomees include their performance in speech restoration, the presence of complications of treatment, as well as the availability of psycho-social support. In Hong Kong, more than 90% of laryngectomees have speech restoration by various means, the commonest of which being tracheo-oesophageal puncture and electrolaryngeal speech. However, they face special problems in communication using the current alaryngeal speech modalities, as it is difficult to produce variation in tones, which is important to express different meanings in Cantonese. The responsibility of surgeons to follow-up patients after surgery and the practice of management of common complications after laryngectomy are also discussed. The New Voice Club of Hong Kong promotes self-help and mutual help between laryngectomees, with the aim of helping new members to regain normal speech and to re-integrate into society. Quality-of-life study in Hong Kong shows that although the mean global health score is satisfactory, the social functioning domain is most severely affected after surgery. Cantonese-speaking laryngectomees in Hong Kong are facing unique challenges in speech restoration and re-integration into society after surgery. Surgeons should take the leading role in the multidisciplinary management of these patients.

Setting up of teeth in the neutral zone and its effect on speech

PubMed Central

Al-Magaleh, Wafa’a Radwan; Swelem, Amal Ali; Shohdi, Sahar Saad; Mawsouf, Nadia Mohamed

2011-01-01

Rational goals for denture construction are basically directed at the restoration of esthetics and masticatory function and the healthy preservation of the remaining natural tissues. Little concern has been given to the perfection and optimization of the phonetic quality of denture users. However, insertion of prosthodontic restorations may lead to speech defects. Most such defects are mild but, nevertheless, can be a source of concern to the patient. For the dental practitioner, there are few guidelines for designing a prosthetic restoration with maximum phonetic success. One of these guidelines involves the setting up of teeth within the neutral zone. The aim of this study was to evaluate, subjectively and objectively, the effect on speech of setting up teeth in the neutral zone. Three groups were examined: group I (control) included 10 completely dentulous subjects, group II included 10 completely edentulous patients with conventional dentures, and group III included the same 10 edentulous patients with neutral zone dentures. Subjective assessment included patient satisfaction. Objective assessment included duration taken for recitation of Al-Fateha and acoustic analysis. Subjectively, patients were more satisfied with their neutral zone dentures. Objectively, speech produced with the neutral zone dentures was closer to normal than speech with conventional dentures. PMID:23960527

Treatment with PPARδ agonist alleviates non-alcoholic fatty liver disease by modulating glucose and fatty acid metabolic enzymes in a rat model.

PubMed

Li, Xiuli; Li, Jin; Lu, Xiaolan; Ma, Huihui; Shi, Haitao; Li, Hong; Xie, Danhong; Dong, Lei; Liang, Chunlian

2015-09-01

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition which is associated with certain features of metabolic syndrome and insulin resistance. Peroxisome proliferator‑activated receptor (PPAR)δ is an important regulator of energy metabolism and insulin resistance in diabetes. However, the function of PPARδ in NAFLD has not yet been fully elucidated. In the present study, in order to explore the function of PPARδ in NAFLD, we created a rat model of NALFD induced by a high-fat diet (HFD) and treated the rats with GW501516, a PPARδ agonist. We found that the lipid levels decreased, and hepatocellular ballooning and inflammatory cell infiltration were also significantly decreased following treatment of the rats with GW501516 compared to the untreated rats. Treatment with GW501516 also significantly decreased the homeostasis model assessment of insulin resistance (HOMA-IR) index, as well as the low‑density lipoprotein (LDL) levels. In addition, treatment with GW501516 increased the levels of insulin‑like growth factor‑1 (IGF-1) and high‑density lipoprotein (HDL) compared to the HFD group. Furthermore, the elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma‑glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) in the HFD group were all restored to the normal control levels following treatment with GW501516. RT‑qPCR and immunohistochemical staining revealed that the expression levels of sterol regulatory element binding protein‑1c (SREBP‑1c) and glucose transporter 2 (GLUT‑2) were both restored to normal control levels following treatment with GW501516. Also, the levels of enzymes related to lipid metabolism were increased following treatment with GW501516. In conclusion, our findings demonstrate that treatment with GW501516 alleviates NAFLD by modulating glucose and fatty acid metabolism.

HZE ⁵⁶Fe-ion irradiation induces endothelial dysfunction in rat aorta: role of xanthine oxidase.

PubMed

Soucy, Kevin G; Lim, Hyun Kyo; Kim, Jae Hyung; Oh, Young; Attarzadeh, David O; Sevinc, Baris; Kuo, Maggie M; Shoukas, Artin A; Vazquez, Marcelo E; Berkowitz, Dan E

2011-10-01

Ionizing radiation has been implicated in the development of significant cardiovascular complications. Since radiation exposure is associated with space exploration, astronauts are potentially at increased risk of accelerated cardiovascular disease. This study investigated the effect of high atomic number, high-energy (HZE) iron-ion radiation on vascular and endothelial function as a model of space radiation. Rats were exposed to a single whole-body dose of iron-ion radiation at doses of 0, 0.5 or 1 Gy. In vivo aortic stiffness and ex vivo aortic tension responses were measured 6 and 8 months after exposure as indicators of chronic vascular injury. Rats exposed to 1 Gy iron ions demonstrated significantly increased aortic stiffness, as measured by pulse wave velocity. Aortic rings from irradiated rats exhibited impaired endothelial-dependent relaxation consistent with endothelial dysfunction. Acute xanthine oxidase (XO) inhibition or reactive oxygen species (ROS) scavenging restored endothelial-dependent responses to normal. In addition, XO activity was significantly elevated in rat aorta 4 months after whole-body irradiation. Furthermore, XO inhibition, initiated immediately after radiation exposure and continued until euthanasia, completely inhibited radiation-dependent XO activation. ROS production was elevated after 1 Gy irradiation while production of nitric oxide (NO) was significantly impaired. XO inhibition restored NO and ROS production. Finally, dietary XO inhibition preserved normal endothelial function and vascular stiffness after radiation exposure. These results demonstrate that radiation induced XO-dependent ROS production and nitroso-redox imbalance, leading to chronic vascular dysfunction. As a result, XO is a potential target for radioprotection. Enhancing the understanding of vascular radiation injury could lead to the development of effective methods to ameliorate radiation-induced vascular damage.

Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality.

PubMed

Kalathil, Suresh; Lugade, Amit A; Miller, Austin; Iyer, Renuka; Thanavala, Yasmin

2013-04-15

The extent to which T-cell-mediated immune surveillance is impaired in human cancer remains a question of major importance, given its potential impact on the development of generalized treatments of advanced disease where the highest degree of heterogeneity exists. Here, we report the first global analysis of immune dysfunction in patients with advanced hepatocellular carcinoma (HCC). Using multi-parameter fluorescence-activated cell sorting analysis, we quantified the cumulative frequency of regulatory T cells (Treg), exhausted CD4(+) helper T cells, and myeloid-derived suppressor cells (MDSC) to gain concurrent views on the overall level of immune dysfunction in these inoperable patients. We documented augmented numbers of Tregs, MDSC, PD-1(+)-exhausted T cells, and increased levels of immunosuppressive cytokines in patients with HCC, compared with normal controls, revealing a network of potential mechanisms of immune dysregulation in patients with HCC. In dampening T-cell-mediated antitumor immunity, we hypothesized that these processes may facilitate HCC progression and thwart the efficacy of immunotherapeutic interventions. In testing this hypothesis, we showed that combined regimens to deplete Tregs, MDSC, and PD-1(+) T cells in patients with advanced HCC restored production of granzyme B by CD8(+) T cells, reaching levels observed in normal controls and also modestly increased the number of IFN-γ producing CD4(+) T cells. These clinical findings encourage efforts to restore T-cell function in patients with advanced stage disease by highlighting combined approaches to deplete endogenous suppressor cell populations that can also expand effector T-cell populations. ©2013 AACR.

Chronic Cardiac-Targeted RNA Interference for the Treatment of Heart Failure Restores Cardiac Function and Reduces Pathological Hypertrophy

PubMed Central

Suckau, Lennart; Fechner, Henry; Chemaly, Elie; Krohn, Stefanie; Hadri, Lahouaria; Kockskämper, Jens; Westermann, Dirk; Bisping, Egbert; Ly, Hung; Wang, Xiaomin; Kawase, Yoshiaki; Chen, Jiqiu; Liang, Lifan; Sipo, Isaac; Vetter, Roland; Weger, Stefan; Kurreck, Jens; Erdmann, Volker; Tschope, Carsten; Pieske, Burkert; Lebeche, Djamel; Schultheiss, Heinz-Peter; Hajjar, Roger J.; Poller, Wolfgang Ch.

2009-01-01

Background RNA interference (RNAi) has the potential to be a novel therapeutic strategy in diverse areas of medicine. We report on targeted RNAi for the treatment of heart failure (HF), an important disorder in humans resulting from multiple etiologies. Successful treatment of HF is demonstrated in a rat model of transaortic banding by RNAi targeting of phospholamban (PLB), a key regulator of cardiac Ca2+ homeostasis. Whereas gene therapy rests on recombinant protein expression as its basic principle, RNAi therapy employs regulatory RNAs to achieve its effect. Methods and Results We describe structural requirements to obtain high RNAi activity from adenoviral (AdV) and adeno-associated virus (AAV9) vectors and show that an AdV short hairpin RNA vector (AdV-shRNA) silenced PLB in cardiomyocytes (NRCMs) and improved hemodynamics in HF rats 1 month after aortic root injection. For simplified long-term therapy we developed a dimeric cardiotropic AAV vector (rAAV9-shPLB) delivering RNAi activity to the heart via intravenous injection. Cardiac PLB protein was reduced to 25% and SERCA2a suppression in the HF groups was rescued. In contrast to traditional vectors rAAV9 shows high affinity for myocardium, but low affinity for liver and other organs. rAAV9-shPLB therapy restored diastolic (LVEDP, dp/dtmin, Tau) and systolic (fractional shortening) functional parameters to normal range. The massive cardiac dilation was normalized and the cardiac hypertrophy, cardiomyocyte diameter and cardiac fibrosis significantly reduced. Importantly, there was no evidence of microRNA deregulation or hepatotoxicity during these RNAi therapies. Conclusion Our data show, for the first time, high efficacy of an RNAi therapeutic strategy in a cardiac disease. PMID:19237664

Impaired dynamic cerebral autoregulation at extreme high altitude even after acclimatization

PubMed Central

Iwasaki, Ken-ichi; Zhang, Rong; Zuckerman, Julie H; Ogawa, Yojiro; Hansen, Lærke H; Levine, Benjamin David

2011-01-01

Cerebral blood flow (CBF) increases and dynamic cerebral autoregulation is impaired by acute hypoxia. We hypothesized that progressive hypocapnia with restoration of arterial oxygen content after altitude acclimatization would normalize CBF and dynamic cerebral autoregulation. To test this hypothesis, dynamic cerebral autoregulation was examined by spectral and transfer function analyses between arterial pressure and CBF velocity variabilities in 11 healthy members of the Danish High-Altitude Research Expedition during normoxia and acute hypoxia (10.5% O2) at sea level, and after acclimatization (for over 1 month at 5,260 m at Chacaltaya, Bolivia). Arterial pressure and CBF velocity in the middle cerebral artery (transcranial Doppler), were recorded on a beat-by-beat basis. Steady-state CBF velocity increased during acute hypoxia, but normalized after acclimatization with partial restoration of SaO2 (acute, 78%±2% chronic, 89%±1%) and progression of hypocapnia (end-tidal carbon dioxide: acute, 34±2 mm Hg; chronic, 21±1 mm Hg). Coherence (0.40±0.05 Units at normoxia) and transfer function gain (0.77±0.13 cm/s per mm Hg at normoxia) increased, and phase (0.86±0.15 radians at normoxia) decreased significantly in the very-low-frequency range during acute hypoxia (gain, 141%±24% coherence, 136%±29% phase, −25%±22%), which persisted after acclimatization (gain, 136%±36% coherence, 131%±50% phase, −42%±13%), together indicating impaired dynamic cerebral autoregulation in this frequency range. The similarity between both acute and chronic conditions suggests that dynamic cerebral autoregulation is impaired by hypoxia even after successful acclimatization to an extreme high altitude. PMID:20571521

Impaired dynamic cerebral autoregulation at extreme high altitude even after acclimatization.

PubMed

Iwasaki, Ken-ichi; Zhang, Rong; Zuckerman, Julie H; Ogawa, Yojiro; Hansen, Lærke H; Levine, Benjamin David

2011-01-01

Cerebral blood flow (CBF) increases and dynamic cerebral autoregulation is impaired by acute hypoxia. We hypothesized that progressive hypocapnia with restoration of arterial oxygen content after altitude acclimatization would normalize CBF and dynamic cerebral autoregulation. To test this hypothesis, dynamic cerebral autoregulation was examined by spectral and transfer function analyses between arterial pressure and CBF velocity variabilities in 11 healthy members of the Danish High-Altitude Research Expedition during normoxia and acute hypoxia (10.5% O(2)) at sea level, and after acclimatization (for over 1 month at 5,260 m at Chacaltaya, Bolivia). Arterial pressure and CBF velocity in the middle cerebral artery (transcranial Doppler), were recorded on a beat-by-beat basis. Steady-state CBF velocity increased during acute hypoxia, but normalized after acclimatization with partial restoration of SaO(2) (acute, 78% ± 2%; chronic, 89% ± 1%) and progression of hypocapnia (end-tidal carbon dioxide: acute, 34 ± 2 mm Hg; chronic, 21 ± 1 mm Hg). Coherence (0.40 ± 0.05 Units at normoxia) and transfer function gain (0.77 ± 0.13 cm/s per mm Hg at normoxia) increased, and phase (0.86 ± 0.15 radians at normoxia) decreased significantly in the very-low-frequency range during acute hypoxia (gain, 141% ± 24%; coherence, 136% ± 29%; phase, -25% ± 22%), which persisted after acclimatization (gain, 136% ± 36%; coherence, 131% ± 50%; phase, -42% ± 13%), together indicating impaired dynamic cerebral autoregulation in this frequency range. The similarity between both acute and chronic conditions suggests that dynamic cerebral autoregulation is impaired by hypoxia even after successful acclimatization to an extreme high altitude.

Sialorphin (the mature peptide product of Vcsa1) relaxes corporal smooth muscle tissue and increases erectile function in the ageing rat.

PubMed

Davies, Kelvin P; Tar, Moses; Rougeot, Catherine; Melman, Arnold

2007-02-01

To determine if the mature peptide product of the Vcsa1 gene, sialorphin, could restore erectile function in ageing rats, and whether these effects are mediated through relaxation of corporal smooth muscle tissue, as we recently reported that Vcsa1 is one of the most down-regulated genes in the corpora of rats in three distinct models of erectile dysfunction, and gene transfer of plasmids expressing Vcsa1 into the corpora of ageing rats restored erectile function. Sialorphin was injected intracorporeally into retired breeder rats, and the effect on the physiology of corporal tissue was analysed by intracorporal/blood pressure (ICP/BP) measurement at different times after injection. In organ-bath studies, the ability of sialorphin (1 microg/mL) to enhance C-type natriuretic peptide (CNP) relaxation of corporal smooth muscle tissue strips was investigated after pre-contraction with 1 microm phenylephrine. Intracorporal injection of 100 microg sialorphin into retired breeder rats resulted in a time-dependent increase in the ICP/BP response to electrostimulation of the cavernosal nerve. After 55-65 min the ICP/BP ratio increased to approximately 0.6, a value associated with normal erectile function. In organ-bath studies after pre-contraction with 1 microm phenylephrine, 1 microm CNP significantly (67%) increased the relaxation rate of corporal tissue. This rate of relaxation was increased by 2.5-fold after incubation with sialorphin (1 microg/mL) compared with carrier alone. These results show that sialorphin has a role in erectile function, probably through a mechanism that involves relaxation of corporal smooth muscle tissue.

Fractographic features of glass-ceramic and zirconia-based dental restorations fractured during clinical function.

PubMed

Oilo, Marit; Hardang, Anne D; Ulsund, Amanda H; Gjerdet, Nils R

2014-06-01

Fractures during clinical function have been reported as the major concern associated with all-ceramic dental restorations. The aim of this study was to analyze the fracture features of glass-ceramic and zirconia-based restorations fractured during clinical use. Twenty-seven crowns and onlays were supplied by dentists and dental technicians with information about type of cement and time in function, if available. Fourteen lithium disilicate glass-ceramic restorations and 13 zirconia-based restorations were retrieved and analyzed. Fractographic features were examined using optical microscopy to determine crack initiation and crack propagation of the restorations. The material comprised fractured restorations from one canine, 10 incisors, four premolars, and 11 molars. One crown was not categorized because of difficulty in orientation of the fragments. The results revealed that all core and veneer fractures initiated in the cervical margin and usually from the approximal area close to the most coronally placed curvature of the margin. Three cases of occlusal chipping were found. The margin of dental all-ceramic single-tooth restorations was the area of fracture origin. The fracture features were similar for zirconia, glass-ceramic, and alumina single-tooth restorations. Design features seem to be of great importance for fracture initiation. © 2014 Eur J Oral Sci.

Anatomical variants of tympanic compartments and their aeration pathways involved in the pathogenesis of middle ear inflammatory disease

PubMed Central

MANIU, ALMA; CATANA, IULIU V.; HARABAGIU, OANA; PETRI, MARIA; COSGAREA, MARCEL

2013-01-01

Aim The aim of this article is to review the anatomy of middle ear compartments and folds and to demonstrate through anatomical evidence their presence at birth. Additionally, their role in the obstructions of middle ear ventilatory pathway is highlighted. Methods Ninety-eight adult temporal bones, with no history of auricular disease and fifteen newborn temporal bones were studied by micro dissection. Documentation was done by color photography using the operation microscope Results Our micro-dissections have showed that mucosal folds from the middle ear are steadily present since birth, given that they were found in all newborn temporal bones. The mucosal folds in our normal adult material, showed some variations including membrane defects but they were constantly present. Our micro dissections showed that the epitympanic diaphragm consisted, in addition to malleal ligamental folds and ossicles, of only two constantly present folds: the tensor tympani fold and the incudomalleal fold. When the tensor fold is complete the only ventilation pathway to the anterior epitympanic space is through the isthmus, whereas its absence creates an efficient additional aeration route from the Eustachian tube to the epitympanum. Conclusions The goal of surgery in the chronic pathology of the middle ear should be restoration of normal ventilation of the attical-mastoid area. This is possible by removing the tensor fold and restoring the functionality of the isthmus tympani. PMID:26527977

Bilateral sacroiliac luxation fixation using a single transiliosacral pin: surgical technique and clinical outcomes in eight cats.

PubMed

Parslow, A; Simpson, D J

2017-06-01

A very limited safe anatomical window for transiliosacral implant placement exists in cats (<0·5 cm 2 ). Lag screw fixation requires multiple bilateral implants thus increasing the risk of iatrogenic trauma and implant interference. We describe a safe and effective method for bilateral sacroiliac fixation in cats using a single implant to minimise inadvertent iatrogenic damage to local structures and restore pelvic canal diameter. Eight cats underwent surgical fixation for traumatic bilateral sacroiliac luxation using a single smooth intramedullary pin. The pin spanned both ilial wings and sacrum. Implants were applied using a Universal C-guide. Pre- and postsurgery pelvic canal diameter ratios were calculated. Short-term follow-up was performed at 10 to 14 days postoperatively. Long-term follow-up was performed using the Feline Musculoskeletal Pain Index Questionnaire. Long-term radiographic assessment was available in two cases. The technique achieved safe and accurate implant position with precise sacroiliac joint reduction. Pelvic canal diameter ratios were restored to normal in all cases. Rapid return to normal hind leg function and excellent long-term clinical outcomes were achieved. This technique offers a simple, safe, repeatable and affordable technique for treating bilateral sacroiliac luxations in the cat without the aid of fluoroscopy. The procedure can be performed using surgical tools and inventory readily available in general small animal practices. © 2017 British Small Animal Veterinary Association.

Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors.

PubMed

Anastasaki, Corina; Estep, Anne L; Marais, Richard; Rauen, Katherine A; Patton, E Elizabeth

2009-07-15

The Ras/MAPK pathway is critical for human development and plays a central role in the formation and progression of most cancers. Children born with germ-line mutations in BRAF, MEK1 or MEK2 develop cardio-facio-cutaneous (CFC) syndrome, an autosomal dominant syndrome characterized by a distinctive facial appearance, heart defects, skin and hair abnormalities and mental retardation. CFC syndrome mutations in BRAF promote both kinase-activating and kinase-impaired variants. CFC syndrome has a progressive phenotype, and the availability of clinically active inhibitors of the MAPK pathway prompts the important question as to whether such inhibitors might be therapeutically effective in the treatment of CFC syndrome. To study the developmental effects of CFC mutant alleles in vivo, we have expressed a panel of 28 BRAF and MEK alleles in zebrafish embryos to assess the function of human disease alleles and available chemical inhibitors of this pathway. We find that both kinase-activating and kinase-impaired CFC mutant alleles promote the equivalent developmental outcome when expressed during early development and that treatment of CFC-zebrafish embryos with inhibitors of the FGF-MAPK pathway can restore normal early development. Importantly, we find a developmental window in which treatment with a MEK inhibitor can restore the normal early development of the embryo, without the additional, unwanted developmental effects of the drug.

Nogo Receptor 1 Limits Ocular Dominance Plasticity but not Turnover of Axonal Boutons in a Model of Amblyopia

PubMed Central

Frantz, Michael G.; Kast, Ryan J.; Dorton, Hilary M.; Chapman, Katherine S.; McGee, Aaron W.

2016-01-01

The formation and stability of dendritic spines on excitatory cortical neurons are correlated with adult visual plasticity, yet how the formation, loss, and stability of postsynaptic spines register with that of presynaptic axonal varicosities is unknown. Monocular deprivation has been demonstrated to increase the rate of formation of dendritic spines in visual cortex. However, we find that monocular deprivation does not alter the dynamics of intracortical axonal boutons in visual cortex of either adult wild-type (WT) mice or adult NgR1 mutant (ngr1−/−) mice that retain critical period visual plasticity. Restoring normal vision for a week following long-term monocular deprivation (LTMD), a model of amblyopia, partially restores ocular dominance (OD) in WT and ngr1−/− mice but does not alter the formation or stability of axonal boutons. Both WT and ngr1−/− mice displayed a rapid return of normal OD within 8 days after LTMD as measured with optical imaging of intrinsic signals. In contrast, single-unit recordings revealed that ngr1−/− exhibited greater recovery of OD by 8 days post-LTMD. Our findings support a model of structural plasticity in which changes in synaptic connectivity are largely postsynaptic. In contrast, axonal boutons appear to be stable during changes in cortical circuit function. PMID:25662716

Protein A Sepharose immunoadsorption can restore the efficacy of platelet concentrates in patients with Glanzmann's thrombasthenia and anti-glycoprotein IIb-IIIa antibodies.

PubMed

Martin, Isabelle; Kriaa, Fayçal; Proulle, Valérie; Guillet, Benoît; Kaplan, Cécile; D'Oiron, Roseline; Debré, Marianne; Fressinaud, Edith; Laurian, Yyes; Tchernia, Gil; Charpentier, Bernard; Lambert, Thierry; Dreyfus, Marie

2002-12-01

Type I Glanzmann's thrombasthenia is a rare congenital platelet function disorder, characterized by undetectable platelet membrane glycoprotein IIb-IIIa (GPIIb-IIIa). Severe bleeding is controlled by transfusion of normal platelets, leading in some cases to the occurrence of anti-GPIIb-IIIa isoantibodies, which induces a loss of transfused platelet efficacy. We used immunoadsorption on protein A Sepharose (IA-PA), which has been shown to be efficient in decreasing the titre of antibodies in several immune diseases, in three patients with Glanzmann's thrombasthenia and anti-GPIIb-IIIa isoantibodies on five different occasions. IA-PA was well tolerated with no deleterious side-effects reported. It induced a dramatic decrease of total immunoglobulin (Ig)G, including anti-GPIIb-IIIa isoantibody levels, as assessed by the monoclonal antibody-specific immobilization of platelet antigens test and the ex vivo inhibition of normal platelet aggregation induced by the patient's platelet-rich or platelet-poor plasma. Elimination of the antibody was associated with a correction of the bleeding time following platelet transfusion. IA-PA combined with platelet transfusion made it possible to control two life-threatening haemorrhages, and allowed two surgical procedures and one bone marrow transplantation to be performed safely. Our experience suggests that IA-PA, which restores the haemostatic efficacy of platelet transfusion, is a valuable therapeutic strategy in patients with Glanzmann's thrombasthenia and anti-GPIIb-IIIa isoantibodies.

Inactivation of bone morphogenetic protein 2 may predict clinical outcome and poor overall survival for renal cell carcinoma through epigenetic pathways

PubMed Central

Mitsui, Yozo; Hirata, Hiroshi; Arichi, Naoko; Hiraki, Miho; Yasumoto, Hiroaki; Chang, Inik; Fukuhara, Shinichiro; Yamamura, Soichiro; Shahryari, Varahram; Deng, Guoren; Saini, Sharanjot; Majid, Shahana; Dahiya, Rajvir; Tanaka, Yuichiro; Shiina, Hiroaki

2015-01-01

We investigated whether impaired regulation of bone morphogenetic protein-2 (BMP-2) via epigenetic pathways is associated with renal cell carcinoma (RCC) pathogenesis. Expression and CpG methylation of the BMP-2 gene were analyzed using RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells. A significant association of BMP-2 mRNA expression was also found with advanced tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression induced p21WAF1/CIP1 and p27KIP1 expression, and cellular apoptosis in RCC cells. BMP-2 mRNA expression was significantly enhanced in RCC cells by 5-aza-2′-deoxycitidine treatment. The prevalence of BMP-2 promoter methylation was significantly greater and BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in tumors. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be a useful molecular marker for designing improved diagnostic and therapeutic strategies for RCC. PMID:25797254

Immediate provisional restoration of a single-tooth implant in the esthetic zone: a case report.

PubMed

Fu, Po-Sung; Wu, Yi-Min; Tsai, Ching-Fang; Huang, Ta-Ko; Chen, Wen-Cheng; Hung, Chun-Cheng

2011-02-01

Immediate implant restoration of single implants may demonstrate a positive effect on peri-implant soft tissue. Placement of a provisional restoration following implant surgery can create soft tissue contours that resemble normal gingival topography before placement of the definitive prosthesis. This article describes a staged approach of the mandibular permanent right central incisor, which was congenital missing. The proper space for restoration of the missing incisor was created through orthodontic treatment. The scheduled implant site was reconstructed using autogenous bone harvested from the chin region. After a healing period of four months, an implant was installed with the connection of a fixed provisional crown to a prefabricated temporary abutment. The soft tissue around the implant healed according to the contours of the provisional restoration and the emergence profile was used to duplicate the definitive restoration. Peri-implant esthetics was achieved through the staged approach and immediate restoration of the implant. Copyright © 2011. Published by Elsevier B.V.

Leaf litter arthropod responses to tropical forest restoration.

PubMed

Cole, Rebecca J; Holl, Karen D; Zahawi, Rakan A; Wickey, Philipp; Townsend, Alan R

2016-08-01

Soil and litter arthropods represent a large proportion of tropical biodiversity and perform important ecosystem functions, but little is known about the efficacy of different tropical forest restoration strategies in facilitating their recovery in degraded habitats. We sampled arthropods in four 7- to 8-year-old restoration treatments and in nearby reference forests. Sampling was conducted during the wet and dry seasons using extractions from litter and pitfall samples. Restoration treatments were replicated in 50 × 50-m plots in four former pasture sites in southern Costa Rica: plantation - trees planted throughout the plot; applied nucleation/islands - trees planted in patches of different sizes; and natural regeneration - no tree planting. Arthropod abundance, measures of richness and diversity, and a number of functional groups were greater in the island treatment than in natural regeneration or plantation treatments and, in many cases, were similar to reference forest. Litter and pitfall morphospecies and functional group composition in all three restoration treatments were significantly different than reference sites, but island and plantation treatments showed more recovery than natural regeneration. Abundance and functional group diversity showed a much greater degree of recovery than community composition. Synthesis and applications: The less resource-intensive restoration strategy of planting tree islands was more effective than tree plantations in restoring arthropod abundance, richness, and functional diversity. None of the restoration strategies, however, resulted in similar community composition as reference forest after 8 years of recovery, highlighting the slow rate of recovery of arthropod communities after disturbance, and underscoring the importance of conservation of remnant forests in fragmented landscapes.

Connectomics and other novel methods for examining neural systems.

PubMed

Wurtman, Richard J

2017-04-01

Novel approaches for studying the brain and relating its activities to mental phenomena have come into use during the past decade (Bargmann, 2015). These include both new laboratory methods - involving, among others, generation of isolated cells which retain neuronal characteristics in vivo; the selective stimulation of neurons by light in vivo; and direct electrical stimulation of specific brain regions to restore a system's balance of excitation and inhibition - and a new organizing principle, "connectomics", which recognizes that networks, and not simply a key nucleus or region, underlie most brain functions and malfunctions. Its application has already improved our comprehension of how the brain normally functions and our ability to help patients with such poorly treated neurologic and psychiatric diseases as Alzheimer's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Neurostimulation and neuromodulation: a guide to selecting the right urologic patient.

PubMed

Schmidt, R A; Doggweiler, R

1998-01-01

Sensory input has an important influence on the integrity of neural circuitry. Central nervous system circuitry is programmed and reinforced by everyday experience. Even the simplest of behaviors participate in this process. A balance between inhibition and facilitation must be maintained for the CNS to function normally. For example, the bladder stores urine because of the inhibition from a closed sphincter, and relaxation of the sphincter disinhibits the bladder to permit voiding. This synergistic 'seesaw' in reflex neural activity preserves the functional and anatomical integrity of the lower urinary tract. Dysfunction and anatomical change results when an unnatural bias develops between inhibitory and facilitatory neural activity. Neurostimulation has an inherent conditioning effect on neural excitability and can restore the neural equilibrium. Voiding diaries are very useful in documenting these changes.

Transition theory and its relevance to patients with chronic wounds.

PubMed

Neil, J A; Barrell, L M

1998-01-01

A wound, in the broadest sense, is a disruption of normal anatomic structure and function. Acute wounds progress through a timely and orderly sequence of repair that leads to the restoration of functional integrity. In chronic wounds, this timely and orderly sequence goes awry. As a result, people with chronic wounds often face not only physiological difficulties but emotional ones as well. The study of body image and its damage as a result of a chronic wound fits well with Selder's transition theory. This article describes interviews with seven patients with chronic wounds. The themes that emerged from those interviews were compared with Selder's theory to describe patients' experience with chronic wounds as a transition process that can be identified and better understood by healthcare providers.

[Factors affecting the vegetation restoration after fires in cold temperate wetlands: A review].

PubMed

Zhao, Feng-Jun; Wang, Li-Zhong; Shu, Li-Fu; Chen, Peng-Yu; Chen, Li-guang

2013-03-01

Cold temperate wetland plays an important role in maintaining regional ecological balance. Fire is an important disturbance factor in wetland ecosystem. Severe burning can induce the marked degradation of the ecological functions of wetland ecosystem. The vegetation restoration, especially the early vegetation restoration, after fires, is the premise and basis for the recovery of the ecological functions of the ecosystem. This paper reviewed the research progress on the factors affecting the vegetation restoration after fires in wetlands. The vegetation restoration after fires in cold temperate wetlands was controlled by the fire intensity, fire size, vegetation types before fires, regeneration characteristics of plant species, and site conditions. It was considered that the long-term monitoring on the post-fire vegetation restoration in cold temperate wetland, the key factors affecting the vegetation restoration, the roles of frozen soil layer on the post-fire vegetation restoration, and the theories and technologies on the vegetation restoration would be the main research directions in the future.

Modulating the function of the immune system by thyroid hormones and thyrotropin.

PubMed

Jara, Evelyn L; Muñoz-Durango, Natalia; Llanos, Carolina; Fardella, Carlos; González, Pablo A; Bueno, Susan M; Kalergis, Alexis M; Riedel, Claudia A

2017-04-01

Accumulating evidence suggests a close bidirectional communication and regulation between the neuroendocrine and immune systems. Thyroid hormones (THs) can exert responses in various immune cells, e.g., monocytes, macrophages, natural killer cells, and lymphocytes, affecting several inflammation-related processes (such as, chemotaxis, phagocytosis, reactive oxygen species generation, and cytokines production). The interactions between the endocrine and immune systems have been shown to contribute to pathophysiological conditions, including sepsis, inflammation, autoimmune diseases and viral infections. Under these conditions, TH therapy could contribute to restoring normal physiological functions. Here we discuss the effects of THs and thyroid stimulating hormone (TSH) on the immune system and the contribution to inflammation and pathogen clearance, as well as the consequences of thyroid pathologies over the function of the immune system. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Physiologic Basis for Improved Pulmonary Function after Lung Volume Reduction

PubMed Central

Fessler, Henry E.; Scharf, Steven M.; Ingenito, Edward P.; McKenna, Robert J.; Sharafkhaneh, Amir

2008-01-01

It is not readily apparent how pulmonary function could be improved by resecting portions of the lung in patients with emphysema. In emphysema, elevation in residual volume relative to total lung capacity reduces forced expiratory volumes, increases inspiratory effort, and impairs inspiratory muscle mechanics. Lung volume reduction surgery (LVRS) better matches the size of the lungs to the size of the thorax containing them. This restores forced expiratory volumes and the mechanical advantage of the inspiratory muscles. In patients with heterogeneous emphysema, LVRS may also allow space occupied by cysts to be reclaimed by more normal lung. Newer, bronchoscopic methods for lung volume reduction seek to achieve similar ends by causing localized atelectasis, but may be hindered by the low collateral resistance of emphysematous lung. Understanding of the mechanisms of improved function after LVRS can help select patients more likely to benefit from this approach. PMID:18453348

Transgenic rescue demonstrates involvement of the Ian5 gene in T cell development in the rat.

PubMed

Michalkiewicz, Mieczyslaw; Michalkiewicz, Teresa; Ettinger, Ruth A; Rutledge, Elizabeth A; Fuller, Jessica M; Moralejo, Daniel H; Van Yserloo, Brian; MacMurray, Armand J; Kwitek, Anne E; Jacob, Howard J; Lander, Eric S; Lernmark, Ake

2004-10-04

A single point mutation in a novel immune-associated nucleotide gene 5 (Ian5) coincides with severe T cell lymphopenia in BB rats. We used a transgenic rescue approach in lymphopenic BB-derived congenic F344.lyp/lyp rats to determine whether this mutation is responsible for lymphopenia and to establish the functional importance of this novel gene. A 150-kb P1 artificial chromosome (PAC) transgene harboring a wild-type allele of the rat Ian5 gene restored Ian5 transcript and protein levels, completely rescuing the T cell lymphopenia in the F344.lyp/lyp rats. This successful complementation provides direct functional evidence that the Ian5 gene product is essential for maintaining normal T cell levels. It also demonstrates that transgenic rescue in the rat is a practical and definitive method for revealing the function of a novel gene.

The importance of hydrology in restoration of bottomland hardwood wetland functions

USGS Publications Warehouse

Hunter, R.G.; Faulkner, S.P.; Gibson, K.A.

2008-01-01

Bottomland hardwood (BLH) forests have important biogeochemical functions and it is well known that certain structural components, including pulsed hydrology, hydric soils, and hydrophytic vegetation, enhance these functions. It is unclear, however, how functions of restored BLH wetlands compare to mature, undisturbed wetlands. We measured a suite of structural and functional attributes in replicated natural BLH wetlands (NAT), restored BLH wetlands with hydrology re-established (RWH), and restored BLH wetlands without hydrology re-established (RWOH) in this study. Trees were replanted in all restored wetlands at least four years prior to the study and those wetlands with hydrology re-established had flashboard risers placed in drainage ditches to allow seasonal surface flooding. Vegetation, soils, and selected biogeochemical functions were characterized at each site. There was a marked difference in woody vegetation among the wetlands that was due primarily to site age. There was also a difference in herbaceous vegetation among the restored sites that may have been related to differences in age or hydrology. Water table fluctuations of the RWH wetlands were comparable to those of the NAT wetlands. Thus, placing flashboard risers in existing drainage ditches, along with proper management, can produce a hydroperiod that is similar to that of a relatively undisturbed BLH. Average length of saturation within the upper 15 cm of soils was 37, 104, and 97 days for RWOH, RWH, and NAT, respectively. Soil moisture, denitrification potential, and soluble organic carbon concentrations differed among wetland sites, but soil carbon and nitrogen concentrations, heterotrophic microbial activity, and readily mineralizable carbon concentrations did not. Significant linear relationships were also found between soil moisture and heterotrophic microbial activity, readily mineralizable carbon, and soluble organic carbon. In addition, sedimentation rates were higher in NAT and RWH wetlands than in RWOH sites. Results of this study suggest that reconnection of bottomland hardwood wetlands to their surrounding watershed through the restoration of surface hydrology is necessary to restore wetland functions important to nutrient and sediment removal. ?? 2008 The Society of Wetland Scientists.

Evolvement of transgenic male-sterility and fertility-restoration system in rice for production of hybrid varieties.

PubMed

Rao, Gundra Sivakrishna; Deveshwar, Priyanka; Sharma, Malini; Kapoor, Sanjay; Rao, Khareedu Venkateswara

2018-01-01

We have developed a unique male-sterility and fertility-restoration system in rice by combining Brassica napus cysteine-protease gene (BnCysP1) with anther-specific P12 promoter of rice for facilitating production of hybrid varieties. In diverse crop plants, male-sterility has been exploited as a useful approach for production of hybrid varieties to harness the benefits of hybrid vigour. The promoter region of Os12bglu38 gene of rice has been isolated from the developing panicles and was designated as P12. The promoter was fused with gusA reporter gene and was expressed in Arabidopsis and rice systems. Transgenic plants exhibited GUS activity in tapetal cells and pollen of the developing anthers indicating anther/pollen-specific expression of the promoter. For engineering nuclear male sterility, the coding region of Brassica napus cysteine protease1 (BnCysP1) was isolated from developing seeds and fused to P12 promoter. Transgenic rice plants obtained with P12-BnCysP1 failed to produce functional pollen grains. The F 1 seeds obtained from BnCysP1 male-sterile plants and untransformed controls showed 1:1 (tolerant:sensitive) ratio when germinated on the MS medium supplemented with phosphinothricin (5 mg/l), confirming that the male sterility has been successfully engineered in rice. For male fertility restoration, transgenic rice plants carrying BnCysP1Si silencing system were developed. The pollination of BnCysP1 male-sterile (female-fertile) plants with BnCysP1Si pollen resulted in normal grain filling. The F 1 seeds of BnCysP1 × BnCysP1Si when germinated on the MS basal medium containing PPT (5 mg/l) and hygromycin (70 mg/l) exhibited 1:1 (tolerant:sensitive) ratio and the tolerant plants invariably showed normal grain filling. The overall results clearly suggest that the customized male-sterility & fertility-restoration system can be exploited for quality hybrid seed production in various crops.

Role of Dendritic Cells in Immune Dysfunction

NASA Technical Reports Server (NTRS)

Savary, Cherylyn A.

1998-01-01

The specific aims of the project were: (1) Application of the NASA bioreactor to enhance cytokine-regulated proliferation and maturation of dendritic cells (DC). (2) Compare the frequency and function of DC in normal donors and immunocompromised cancer patients. (3) Analyze the effectiveness of cytokine therapy and DC-assisted immunotherapy (using bioreactor-expanded DC) in a murine model of experimental fungal disease. Our investigations have provided new insight into DC immunobiology and have led to the development of methodology to evaluate DC in blood of normal donors and patients. Information gained from these studies has broadened our understanding of possible mechanisms involved in the immune dysfunction of space travelers and earth-bound cancer patients, and could contribute to the design of novel therapies to restore/preserve immunity in these individuals. Several new avenues of investigation were also revealed. The results of studies completed during Round 2 are summarized.

Allied restorative functions training in Minnesota: a case study.

PubMed

Cooper, Brigette R; Monson, Angela L

2007-03-01

In 2003, the Minnesota Dental Practice Act was modified to allow dental hygienists and assistants to place amalgam, composite, glass ionomer, and stainless steel crowns. The concept of utilizing allied professionals to perform expanded functions has been suggested as a way to increase access to care and productivity. A continuing education course was offered to provide required certification for interested dental practitioners (N=12). The objectives of this study were to examine confidence levels and effectiveness of the continuing education program. Pre- and post-course restorative content knowledge, along with confidence levels in knowledge, technical skills, and the ability to implement skills were measured. A matched pairs t-test found a significant increase in participants' restorative content knowledge (p<.001). Wilcoxen signed rank tests revealed an increase in confidence in all content knowledge (p<.01) and technical skill (p<.05) categories. Participants did not significantly increase in confidence to implement restorative functions skills into practice (p<.7). Interview data revealed that participants remain unclear about ways to incorporate restorative functions into the schedule. Findings in this case study suggest that content knowledge and confidence levels increase following completion of a restorative functions course. To improve education and training, research is needed to identify why participants' confidence in implementation did not increase.

Indicators of Functional Equivalency for Assessing Restoration Success

EPA Science Inventory

New restoration projects are being proposed around the Gulf of Mexico as a result of RESTORE Act funding. These projects would benefit from innovative methods for assessing their success. Many restoration projects elsewhere use structure-based condition assessment methods which...

The pathology of dry eye: the interaction between the ocular surface and lacrimal glands.

PubMed

Stern, M E; Beuerman, R W; Fox, R I; Gao, J; Mircheff, A K; Pflugfelder, S C

1998-11-01

Most dry-eye symptoms result from an abnormal, nonlubricative ocular surface that increases shear forces under the eyelids and diminishes the ability of the ocular surface to respond to environmental challenges. This ocular-surface dysfunction may result from immunocompromise due to systemic autoimmune disease or may occur locally from a decrease in systemic androgen support to the lacrimal gland as seen in aging, most frequently in the menopausal female. Components of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland, and interconnecting innervation act as a functional unit. When one portion is compromised, normal lacrimal support of the ocular surface is impaired. Resulting immune-based inflammation can lead to lacrimal gland and neural dysfunction. This progression yields the OS symptoms associated with dry eye. Restoration of lacrimal function involves resolution of lymphocytic activation and inflammation. This has been demonstrated in the MRL/lpr mouse using systemic androgens or cyclosporine and in the dry-eye dog using topical cyclosporine. The efficacy of cyclosporine may be due to its immunomodulatory and antiinflammatory (phosphatase inhibitory capability) functions on the ocular surface, resulting in a normalization of nerve traffic. Although the etiologies of dry eye are varied, common to all ocular-surface disease is an underlying cytokine/receptor-mediated inflammatory process. By treating this process, it may be possible to normalize the ocular surface/lacrimal neural reflex and facilitate ocular surface healing.

The quest for restoring hearing: Understanding ear development more completely.

PubMed

Jahan, Israt; Pan, Ning; Elliott, Karen L; Fritzsch, Bernd

2015-09-01

Neurosensory hearing loss is a growing problem of super-aged societies. Cochlear implants can restore some hearing, but rebuilding a lost hearing organ would be superior. Research has discovered many cellular and molecular steps to develop a hearing organ but translating those insights into hearing organ restoration remains unclear. For example, we cannot make various hair cell types and arrange them into their specific patterns surrounded by the right type of supporting cells in the right numbers. Our overview of the topologically highly organized and functionally diversified cellular mosaic of the mammalian hearing organ highlights what is known and unknown about its development. Following this analysis, we suggest critical steps to guide future attempts toward restoration of a functional organ of Corti. We argue that generating mutant mouse lines that mimic human pathology to fine-tune attempts toward long-term functional restoration are needed to go beyond the hope generated by restoring single hair cells in postnatal sensory epithelia. © 2015 WILEY Periodicals, Inc.

The Role of Species Traits in Mediating Functional Recovery during Matrix Restoration

PubMed Central

Barnes, Andrew D.; Emberson, Rowan M.; Krell, Frank-Thorsten; Didham, Raphael K.

2014-01-01

Reversing anthropogenic impacts on habitat structure is frequently successful through restoration, but the mechanisms linking habitat change, community reassembly and recovery of ecosystem functioning remain unknown. We test for the influence of edge effects and matrix habitat restoration on the reassembly of dung beetle communities and consequent recovery of dung removal rates across tropical forest edges. Using path modelling, we disentangle the relative importance of community-weighted trait means and functional trait dispersion from total biomass effects on rates of dung removal. Community trait composition and biomass of dung beetle communities responded divergently to edge effects and matrix habitat restoration, yielding opposing effects on dung removal. However, functional dispersion—used in this study as a measure of niche complementarity—did not explain a significant amount of variation in dung removal rates across habitat edges. Instead, we demonstrate that the path to functional recovery of these altered ecosystems depends on the trait-mean composition of reassembling communities, over and above purely biomass-dependent processes that would be expected under neutral theory. These results suggest that any ability to manage functional recovery of ecosystems during habitat restoration will demand knowledge of species' roles in ecosystem processes. PMID:25502448

The role of species traits in mediating functional recovery during matrix restoration.

PubMed

Barnes, Andrew D; Emberson, Rowan M; Krell, Frank-Thorsten; Didham, Raphael K

2014-01-01

Reversing anthropogenic impacts on habitat structure is frequently successful through restoration, but the mechanisms linking habitat change, community reassembly and recovery of ecosystem functioning remain unknown. We test for the influence of edge effects and matrix habitat restoration on the reassembly of dung beetle communities and consequent recovery of dung removal rates across tropical forest edges. Using path modelling, we disentangle the relative importance of community-weighted trait means and functional trait dispersion from total biomass effects on rates of dung removal. Community trait composition and biomass of dung beetle communities responded divergently to edge effects and matrix habitat restoration, yielding opposing effects on dung removal. However, functional dispersion--used in this study as a measure of niche complementarity--did not explain a significant amount of variation in dung removal rates across habitat edges. Instead, we demonstrate that the path to functional recovery of these altered ecosystems depends on the trait-mean composition of reassembling communities, over and above purely biomass-dependent processes that would be expected under neutral theory. These results suggest that any ability to manage functional recovery of ecosystems during habitat restoration will demand knowledge of species' roles in ecosystem processes.

Elevated 20-HETE impairs coronary collateral growth in metabolic syndrome via endothelial dysfunction.

PubMed

Joseph, Gregory; Soler, Amanda; Hutcheson, Rebecca; Hunter, Ian; Bradford, Chastity; Hutcheson, Brenda; Gotlinger, Katherine H; Jiang, Houli; Falck, John R; Proctor, Spencer; Schwartzman, Michal Laniado; Rocic, Petra

2017-03-01

Coronary collateral growth (CCG) is impaired in metabolic syndrome (MetS). microRNA-145 (miR-145-Adv) delivery to our rat model of MetS (JCR) completely restored and neutrophil depletion significantly improved CCG. We determined whether low endogenous levels of miR-145 in MetS allowed for elevated production of 20-hydroxyeicosatetraenoic acid (20-HETE), which, in turn, resulted in excessive neutrophil accumulation and endothelial dysfunction leading to impaired CCG. Rats underwent 0-9 days of repetitive ischemia (RI). RI-induced cardiac CYP4F (neutrophil-specific 20-HETE synthase) expression and 20-HETE levels were increased (4-fold) in JCR vs. normal rats. miR-145-Adv and 20-HETE antagonists abolished and neutrophil depletion (blocking antibodies) reduced (~60%) RI-induced increases in CYP4F expression and 20-HETE production in JCR rats. Impaired CCG in JCR rats (collateral-dependent blood flow using microspheres) was completely restored by 20-HETE antagonists [collateral-dependent zone (CZ)/normal zone (NZ) flow ratio was 0.76 ± 0.07 in JCR + 20-SOLA, 0.84 ± 0.05 in JCR + 20-HEDGE vs. 0.11 ± 0.02 in JCR vs. 0.84 ± 0.03 in normal rats]. In JCR rats, elevated 20-HETE was associated with excessive expression of endothelial adhesion molecules and neutrophil infiltration, which were reversed by miR-145-Adv. Endothelium-dependent vasodilation of coronary arteries, endothelial nitric oxide synthase (eNOS) Ser1179 phosphorylation, eNOS-dependent NO ·- production and endothelial cell survival were compromised in JCR rats. These parameters of endothelial dysfunction were completely reversed by 20-HETE antagonism or miR-145-Adv delivery, whereas neutrophil depletion resulted in partial reversal (~70%). We conclude that low miR-145 in MetS allows for increased 20-HETE, mainly from neutrophils, which compromises endothelial cell survival and function leading to impaired CCG. 20-HETE antagonists could provide viable therapy for restoration of CCG in MetS. NEW & NOTEWORTHY Elevated 20-hydroxyeicosatetraenoic acid (20-HETE) impairs coronary collateral growth (CCG) in metabolic syndrome by eliciting endothelial dysfunction and apoptosis via excessive neutrophil infiltration. 20-HETE antagonists completely restore coronary collateral growth in metabolic syndrome. microRNA-145 (miR-145) is an upstream regulator of 20-HETE production in metabolic syndrome; low expression of miR-145 in metabolic syndrome promotes elevated production of 20-HETE. Copyright © 2017 the American Physiological Society.

Sediment dynamics in the restored reach of the Kissimmee River Basin, Florida: A vast subtropical riparian wetland

USGS Publications Warehouse

Schenk, E.R.; Hupp, C.R.; Gellis, A.

2012-01-01

Historically, the Kissimmee River Basin consisted of a broad nearly annually inundated riparian wetland similar in character to tropical Southern Hemisphere large rivers. The river was channelized in the 1960s and 1970s, draining the wetland. The river is currently being restored with over 10 000 hectares of wetlands being reconnected to 70 river km of naturalized channel. We monitored riparian wetland sediment dynamics between 2007 and 2010 at 87 sites in the restored reach and 14 sites in an unrestored reference reach. Discharge and sediment transport were measured at the downstream end of the restored reach. There were three flooding events during the study, two as annual flood events and a third as a greater than a 5-year flood event. Restoration has returned periodic flood flow to the riparian wetland and provides a mean sedimentation rate of 11.3 mm per year over the study period in the restored reach compared with 1.7 mm per year in an unrestored channelized reach. Sedimentation from the two annual floods was within the normal range for alluvial Coastal Plain rivers. Sediment deposits consisted of over 20% organics, similar to eastern blackwater rivers. The Kissimmee River is unique in North America for its hybrid alluvial/blackwater nature. Fluvial suspended-sediment measurements for the three flood events indicate that a majority of the sediment (70%) was sand, which is important for natural levee construction. Of the total suspended sediment load for the three flood events, 3%–16% was organic and important in floodplain deposition. Sediment yield is similar to low-gradient rivers draining to the Chesapeake Bay and alluvial rivers of the southeastern USA. Continued monitoring should determine whether observed sediment transport and floodplain deposition rates are normal for this river and determine the relationship between historic vegetation community restoration, hydroperiod restoration, and sedimentation.

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers.

PubMed

Wyatt, Eugene J; Demonbreun, Alexis R; Kim, Ellis Y; Puckelwartz, Megan J; Vo, Andy H; Dellefave-Castillo, Lisa M; Gao, Quan Q; Vainzof, Mariz; Pavanello, Rita C M; Zatz, Mayana; McNally, Elizabeth M

2018-05-03

Exon skipping uses chemically modified antisense oligonucleotides to modulate RNA splicing. Therapeutically, exon skipping can bypass mutations and restore reading frame disruption by generating internally truncated, functional proteins to rescue the loss of native gene expression. Limb-girdle muscular dystrophy type 2C is caused by autosomal recessive mutations in the SGCG gene, which encodes the dystrophin-associated protein γ-sarcoglycan. The most common SGCG mutations disrupt the transcript reading frame abrogating γ-sarcoglycan protein expression. In order to treat most SGCG gene mutations, it is necessary to skip 4 exons in order to restore the SGCG transcript reading frame, creating an internally truncated protein referred to as Mini-Gamma. Using direct reprogramming of human cells with MyoD, myogenic cells were tested with 2 antisense oligonucleotide chemistries, 2'-O-methyl phosphorothioate oligonucleotides and vivo-phosphorodiamidate morpholino oligomers, to induce exon skipping. Treatment with vivo-phosphorodiamidate morpholino oligomers demonstrated efficient skipping of the targeted exons and corrected the mutant reading frame, resulting in the expression of a functional Mini-Gamma protein. Antisense-induced exon skipping of SGCG occurred in normal cells and those with multiple distinct SGCG mutations, including the most common 521ΔT mutation. These findings demonstrate a multiexon-skipping strategy applicable to the majority of limb-girdle muscular dystrophy 2C patients.

Pineal peptides restore the age-related disturbances in hormonal functions of the pineal gland and the pancreas.

PubMed

Goncharova, N D; Vengerin, A A; Khavinson, V Kh; Lapin, B A

2005-01-01

The purpose of this research was to study age-related changes in functioning of pineal and pancreatic glands of non-human primates, rhesus monkeys, and to elucidate the possibility of their corrections with the help of epitalon, a synthetic analogue of the pharmacopoeia drug epithalamin. In old (20-27 years) animals, the basal plasma levels of glucose and insulin were found to be higher, while the night melatonin level was lower in comparison with (6-8 years) young animals. After the glucose administration to old monkeys, a larger area under the curve of the plasma glucose response, a reduced glucose 'disappearance' rate, and a reduced insulin peak (5 min after the glucose administration) were observed in comparison with young animals in similar experiments. The epitalon administration to old monkeys caused the decrease in the basal levels of glucose and insulin and the increase in the basal night melatonin level. Additionally, in the case of old monkeys, epitalon decreased the area under the plasma glucose response curve, markedly increased the glucose 'disappearance' rate and normalized the plasma insulin dynamics in response to glucose administration. Yet, it has not affected the hormonal and metabolic changes in young animals. Thus, epitalon is a promising factor for restoring the age-related endocrine dysfunctions of primates.

Mechanical cues in orofacial tissue engineering and regenerative medicine.

PubMed

Brouwer, Katrien M; Lundvig, Ditte M S; Middelkoop, Esther; Wagener, Frank A D T G; Von den Hoff, Johannes W

2015-01-01

Cleft lip and palate patients suffer from functional, aesthetical, and psychosocial problems due to suboptimal regeneration of skin, mucosa, and skeletal muscle after restorative cleft surgery. The field of tissue engineering and regenerative medicine (TE/RM) aims to restore the normal physiology of tissues and organs in conditions such as birth defects or after injury. A crucial factor in cell differentiation, tissue formation, and tissue function is mechanical strain. Regardless of this, mechanical cues are not yet widely used in TE/RM. The effects of mechanical stimulation on cells are not straight-forward in vitro as cellular responses may differ with cell type and loading regime, complicating the translation to a therapeutic protocol. We here give an overview of the different types of mechanical strain that act on cells and tissues and discuss the effects on muscle, and skin and mucosa. We conclude that presently, sufficient knowledge is lacking to reproducibly implement external mechanical loading in TE/RM approaches. Mechanical cues can be applied in TE/RM by fine-tuning the stiffness and architecture of the constructs to guide the differentiation of the seeded cells or the invading surrounding cells. This may already improve the treatment of orofacial clefts and other disorders affecting soft tissues. © 2015 by the Wound Healing Society.

Stem cell application for osteoarthritis in the knee joint: A minireview.

PubMed

Uth, Kristin; Trifonov, Dimitar

2014-11-26

Knee osteoarthritis is a chronic, indolent disease that will affect an ever increasing number of patients, especially the elderly and the obese. It is characterized by degeneration of the cartilage substance inside the knee which leads to pain, stiffness and tenderness. By some estimations in 2030, only in the United States, this medical condition will burden 67 million people. While conventional treatments like physiotherapy or drugs offer temporary relief of clinical symptoms, restoration of normal cartilage function has been difficult to achieve. Moreover, in severe cases of knee osteoarthritis total knee replacement may be required. Total knee replacements come together with high effort and costs and are not always successful. The aim of this review is to outline the latest advances in stem cell therapy for knee osteoarthritis as well as highlight some of the advantages of stem cell therapy over traditional approaches aimed at restoration of cartilage function in the knee. In addition to the latest advances in the field, challenges associated with stem cell therapy regarding knee cartilage regeneration and chondrogenesis in vitro and in vivo are also outlined and analyzed. Furthermore, based on their critical assessment of the present academic literature the authors of this review share their vision about the future of stem cell applications in the treatment of knee osteoarthritis.

Regulation of oxygen utilization by angiotensin II in chronic kidney disease

PubMed Central

Deng, Aihua; Tang, Tong; Singh, Prabhleen; Wang, Chen; Satriano, Joe; Thomson, Scott C; Blantz, Roland C

2010-01-01

Angiotensin II (ANG II) blockade delays progression of chronic kidney disease (CKD) by modifying intrarenal hemodynamics, but the effect on metabolic adaptations has not been examined. Using renal ablation/infarction (A/I) model of CKD in rats at one week, the effects of ANG II blockade by captopril (CAP) and losartan (LOS) on renal O2 consumption (QO2), renal nitric oxide (NO) activity and nitric oxide synthase (NOS) protein expression was examined. A/I kidneys exhibited proteinuria, reduced GFR, renal blood flow (RBF) and NOS-1 protein expression, while QO2 factored by sodium reabsorption (QO2/TNa) was markedly increased. CAP + LOS treatment increased GFR, RBF, and TNa, while QO2 remained unchanged, thus normalizing QO2/TNa. NOS-1 expression was normalized with CAP + LOS, as was proteinuria. Triple antihypertensive therapy administered to control for the blood pressure reduction, and lysine administration to increase GFR and RBF, did not normalize QO2/TNa, suggesting a specific effect of ANG II in elevating QO2/TNa. NOS blockade, to test functional NO activity on QO2 and QO2/TNa, increased QO2 in shams, but not in untreated A/I. The increase in QO2 was restored in CAP + LOS treated A/I. CAP + LOS treatment normalized the increased QO2/TNa and functional NO activity in A/I independent of the blood pressure and GFR effects, providing evidence for an additional mechanism underlying the benefits of ANG II inhibition therapy. PMID:18818681

Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression

PubMed Central

Zhang, Kuo; Pan, Xing; Wang, Fang; Ma, Jie; Su, Guangyue; Dong, Yingxu; Yang, Jingyu; Wu, Chunfu

2016-01-01

Antidepressants increase hippocampal neurogenesis by activating the glucocorticoid receptor (GR), but excessive GR activation impairs hippocampal neurogenesis, suggesting that normal GR function is crucial for hippocampal neurogenesis. Baicalin was reported to regulate the expression of GR and facilitate hippocampal neurogenesis, but the underlying molecular mechanisms are still unknown. In this study, we used the chronic corticosterone (CORT)-induced mouse model of anxiety/depression to assess antidepressant-like effects of baicalin and illuminate possible molecular mechanisms by which baicalin affects GR-mediated hippocampal neurogenesis. We found that oral administration of baicalin (40, 80 or 160 mg/kg) for 4 weeks alleviated several chronic CORT-induced anxiety/depression-like behaviors. Baicalin also increased Ki-67- and DCX-positive cells to restore chronic CORT-induced suppression of hippocampal neurogenesis. Moreover, baicalin normalized the chronic CORT-induced decrease in GR protein levels, the increase in GR nuclear translocation and the increase in GR phosphorylation at Ser203 and Ser211. Finally, chronic CORT exposure increased the level of FK506-binding protein 51 (FKBP5) and of phosphorylated serum- and glucocorticoid-inducible kinase 1 (SGK1) at Ser422 and Thr256, whereas baicalin normalized these changes. Together, our findings suggest that baicalin improves anxiety/depression-like behaviors and promotes hippocampal neurogenesis. We propose that baicalin may normalize GR function through SGK1- and FKBP5-mediated GR phosphorylation. PMID:27502757

The Benefits of Restoration in Urbanizing Watersheds: Developing Value Indicators and Understanding Social Barriers and Opportunities

EPA Science Inventory

Ecological restoration can reestablish ecosystem services (ES) that provide important social benefits, but managers with limited funds and resources are forced to prioritize potential restoration sites. Prioritizing restoration sites based on ecological functioning and expected ...

Recent advances in bioelectric prostheses

PubMed Central

Pasquina, Paul F.; Perry, Briana N.; Miller, Matthew E.; Ling, Geoffrey S.F.; Tsao, Jack W.

2015-01-01

Summary Worldwide prevalence of amputation has created an increasing demand for improved upper and lower extremity prostheses. Current prosthetics are often uncomfortable and difficult to control and provide limited functional restoration. Moreover, the inability to normalize anthropomorphic biomechanics with a prosthesis increases one's risk of developing long-term health risks such as arthritis, skin breakdown, and pain. Recent advances in bionic prosthetic development hold great promise for rehabilitation and improving quality of life with limb loss. This brief review discusses the current state of advanced prostheses, the integration of robotics in the care of individuals with major limb amputation, and some innovative surgical techniques that are being explored for clinical feasibility. PMID:29443190

Myopotential inhibition of a bipolar pacemaker caused by electrode insulation defect.

PubMed Central

Amikam, S; Peleg, H; Lemer, J; Riss, E

1977-01-01

A patient is described in whom myopotentials orginating from the anterior abdominal wall muscle suppressed the implanted demand pacemaker despite its bipolar mode of action. This phenomenon was shown by simultaneous recording of the electrocardiogram the electromyogram. At operation, a defect in the insulation of a previously repaired epicardial electrode was found lying in close proximity to these muscles. After repair of the insulation defect, normal pacemaker function was restored. It is suggested that the myopotentials leaked into the pacing system through the insulation defect, thereby suppressing the demand unit, which maintained its bipolar mode of pacing throughout. Images PMID:145229

The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction

PubMed Central

Floras, John S.; Ponikowski, Piotr

2015-01-01

Cardiovascular autonomic imbalance, a cardinal phenotype of human heart failure, has adverse implications for symptoms during wakefulness and sleep; for cardiac, renal, and immune function; for exercise capacity; and for lifespan and mode of death. The objectives of this Clinical Review are to summarize current knowledge concerning mechanisms for disturbed parasympathetic and sympathetic circulatory control in heart failure with reduced ejection fraction and its clinical and prognostic implications; to demonstrate the patient-specific nature of abnormalities underlying this common phenotype; and to illustrate how such variation provides opportunities to improve or restore normal sympathetic/parasympathetic balance through personalized drug or device therapy. PMID:25975657

A Simple Device for Morphofunctional Evaluation During Aortic Valve-Sparing Surgery.

PubMed

Leone, Alessandro; Bruno, Piergiorgio; Cammertoni, Federico; Massetti, Massimo

2015-07-01

Valve-sparing operations for the treatment of aortic root disease with a structurally normal aortic valve are increasingly performed as they avoid prosthesis-related complications. Short- and long-term results are critically dependent on perfect intraoperative restoration of valve anatomy and function. Residual aortic regurgitation is the main cause of early failure, and it is the most common motive for reoperation. However, intraoperative morphofunctional valve assessment requires expertise, and only transesophageal echocardiography can provide reliable information. We describe a simple, economic, reproducible hydrostatic test to intraoperatively evaluate valve competency under direct visualization. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

[Studying the hepatoprotector effect of bemithyl on a model of chronic toxic liver damage].

PubMed

Oskovityĭ, S V; Bezborodkina, N N; Zarubina, I V; Mironova, O P; Kudrivtsev, B N; Shulenin, S N

2006-01-01

A prophylactic and therapeutic introduction of the synthetic adaptogen bemithyl (2-ethylthiobensimidasole hydrobromide) produces a hepatoprotector effect in rats with experimental cirrhosis. The drug exhibits an anticytolytic activity, restores liver participation in the pigment exchange, and normalizes the function of the microsomal oxidation system responsible for the metabolism of xenobiotics. The treatment with bemithyl also leads to a certain improvement of a histologic picture of the damaged liver and to a decrease in the degree of fibrosis. The drug is also capable of increasing the activity of the antioxidant system and inhibiting the process of lipid peroxidation of proteins and lipids in the liver.

[The complex approach to the rehabilitation of post-stroke patients with movement disorders in the early rehabilitation period].

PubMed

Khabirov, F A; Khaĭbullin, T I; Grigor'eva, O V

2011-01-01

We studied 110 patients, aged 34-71 years, in the early rehabilitation period after stroke who were admitted to a rehabilitation neurologic department of Kazan. The rehabilitation approach was based on the combination of several methods: kinesitherapy, transcranial magnetic stimulation and cerebrolysin treatment. This complex reanimation allowed to achieve the marked functional restoration of movement abilities in many cases that was correlated with the normalization of brain bioelectric activity (the increase of alpha-rhythm spectral power, the decrease of slow-wave EEG components). The combined use of these three methods was more effective than a combination of any two of them.

Long-term effect of prednisolone on functional blink recovery after transient peripheral facial motor paralysis.

PubMed

VanderWerf, Frans; Reits, Dik; Metselaar, Mick; De Zeeuw, Chris I

2012-03-01

To determine the functional recovery in patients with severe transient peripheral facial motor paralysis (Bell palsy). Prospective controlled trial. Academic medical center. Blink recovery was studied in 2 groups of severely affected Bell palsy patients during a follow-up period of 84 weeks. The patients in one group received prednisolone within the first week after the onset of symptoms. No medication was given to the other group. A control group of healthy subjects was also included. Simultaneous orbicularis oculi muscle activity and eyelid kinematics were recorded by surface electromyographic (EMG) recording and eyelid search coils, respectively. At the beginning of the paralysis, very little integrated orbicularis oculi muscle activity and eyelid movement was measured at the palsied side of the face. Thirteen weeks later, the integrated orbicularis oculi EMG and functional blink recovery gradually improved until 39 weeks. Beyond, only the integrated orbicularis oculi EMG slightly increased. At 84 weeks, the integrated orbicularis oculi EMG was significantly larger in the prednisolone group compared with the control group. The integrated EMG of the nonmedicated group recovered to normal values. Curiously enough, the functional blink recovery at the palsied side remained reduced to 64% compared with the healthy controls in the prednisolone-treated group and to 36% in the nonmedicated group. The authors demonstrate that prednisolone significantly increased the orbicularis oculi muscle activity and significantly improved functional blink recovery in severely affected Bell palsy patients. However, the increase of muscle activity was insufficient to restore functional blinking to normal values.

Long-term temporal trajectories to enhance restoration efficiency and sustainability on large rivers: an interdisciplinary study

NASA Astrophysics Data System (ADS)

Eschbach, David; Schmitt, Laurent; Imfeld, Gwenaël; May, Jan-Hendrik; Payraudeau, Sylvain; Preusser, Frank; Trauerstein, Mareike; Skupinski, Grzegorz

2018-05-01

While the history of a fluvial hydrosystem can provide essential knowledge on present functioning, historical context remains rarely considered in river restoration. Here we show the relevance of an interdisciplinary study for improving restoration within the framework of a European LIFE+ project on the French side of the Upper Rhine (Rohrschollen Island). Investigating the planimetric evolution combined with historical high-flow data enabled us to reconstruct pre-disturbance hydromorphological functioning and major changes that occurred on the reach. A deposition frequency assessment combining vertical evolution of the Rhine thalweg, chronology of deposits in the floodplain, and a hydrological model revealed that the period of incision in the main channel corresponded to high rates of narrowing and lateral channel filling. Analysis of filling processes using Passega diagrams and IRSL dating highlights that periods of engineering works were closely related to fine sediment deposition, which also presents concomitant heavy metal accumulation. In fact, current fluvial forms, processes and sediment chemistry around Rohrschollen Island directly reflect the disturbances that occurred during past correction works, and up to today. Our results underscore the advantage of combining functional restoration with detailed knowledge of the past trajectory to (i) understand the functioning of the hydrosystem prior to anthropogenic disturbances, (ii) characterize the human-driven morphodynamic adjustments during the last 2 centuries, (iii) characterize physico-chemical sediment properties to trace anthropogenic activities and evaluate the potential impact of the restoration on pollutant remobilization, (iv) deduce the post-restoration evolution tendency and (v) evaluate the efficiency and sustainability of the restoration effects. We anticipate our approach will expand the toolbox of decision-makers and help orientate functional restoration actions in the future.

Long-term River Trajectories to Enhance Restoration Efficiency and Sustainability on the Upper Rhine: an Interdisciplinary Study (Rohrschollen Island, France)

NASA Astrophysics Data System (ADS)

Eschbach, D.; Laurent, S.; May, J. H.; Imfeld, G.; Payraudeau, S.; Preusser, F.

2017-12-01

While the history of a fluvial hydrosystem can provide essential knowledge on present functioning, historical context remains rarely considered in river restoration. Here we show the relevance of an interdisciplinary historical study for improving restoration within the framework of a European LIFE+ project on the French side of the Upper-Rhine (Rohrschollen Island). Planimetric evolution combined with historical high flow data enabled to reconstruct pre-disturbance hydromorphological functioning and major changes that occurred on the reach. A deposition frequency assessment combining vertical evolution of the Rhine thalweg, chronology of deposits in the floodplain and a hydrological model revealed that the period of vertical incision in the main channel corresponded to high rates of narrowing and lateral channel filling. The analysis of filling processes by Passega diagram and IRLS dating highlight that periods of engineering works were closely related to fine sediment deposition, which present also concomitant heavy metal accumulation. In fact, current fluvial forms, processes and sediment chemistry around the Rohrschollen Island directly reflect the disturbances that occurred during past correction works, and up to today. Our results underscore the advantage of combining functional restoration with detailed knowledge of past-trajectory to: (i) understand the functioning of the hydrosystem prior anthropogenic disturbances, (ii) characterize the human-driven morphodynamic adjustments during the two last centuries, (iii) characterize physio-chemical sediment properties to trace anthropogenic activities and evaluate the potential impact of the restoration on pollutant remobilization, (iv) deduce post-restoration evolution and (v) evaluate efficiency and sustainability of the restoration effects. We anticipate our approach to expand the toolbox of decision-makers and help orientating functional restoration actions in the future.

Transforming Ecosystems: When, Where, and How to Restore Contaminated Sites

PubMed Central

Rohr, Jason R; Farag, Aïda M; Cadotte, Marc W; Clements, William H; Smith, James R; Ulrich, Cheryl P; Woods, Richard

2016-01-01

Chemical contamination has impaired ecosystems, reducing biodiversity and the provisioning of functions and services. This has spurred a movement to restore contaminated ecosystems and develop and implement national and international regulations that require it. Nevertheless, ecological restoration remains a young and rapidly growing discipline and its intersection with toxicology is even more nascent and underdeveloped. Consequently, we provide guidance to scientists and practitioners on when, where, and how to restore contaminated ecosystems. Although restoration has many benefits, it also can be expensive, and in many cases systems can recover without human intervention. Hence, the first question we address is: “When should we restore contaminated ecosystems?” Second, we provide suggestions on what to restore—biodiversity, functions, services, all 3, or something else—and where to restore given expected changes to habitats driven by global climate change. Finally, we provide guidance on how to restore contaminated ecosystems. To do this, we analyze critical aspects of the literature dealing with the ecology of restoring contaminated ecosystems. Additionally, we review approaches for translating the science of restoration to on-the-ground actions, which includes discussions of market incentives and the finances of restoration, stakeholder outreach and governance models for ecosystem restoration, and working with contractors to implement restoration plans. By explicitly considering the mechanisms and strategies that maximize the success of the restoration of contaminated sites, we hope that our synthesis serves to increase and improve collaborations between restoration ecologists and ecotoxicologists and set a roadmap for the restoration of contaminated ecosystems. PMID:26033665

Transforming ecosystems: When, where, and how to restore contaminated sites

USGS Publications Warehouse

Rohr, Jason R.; Farag, Aïda M.; Cadotte, Marc W.; Clements, William H.; Smith, James R.; Ulrich, Cheryl P.; Woods, Richard

2016-01-01

Chemical contamination has impaired ecosystems, reducing biodiversity and the provisioning of functions and services. This has spurred a movement to restore contaminated ecosystems and develop and implement national and international regulations that require it. Nevertheless, ecological restoration remains a young and rapidly growing discipline and its intersection with toxicology is even more nascent and underdeveloped. Consequently, we provide guidance to scientists and practitioners on when, where, and how to restore contaminated ecosystems. Although restoration has many benefits, it also can be expensive, and in many cases systems can recover without human intervention. Hence, the first question we address is: “When should we restore contaminated ecosystems?” Second, we provide suggestions on what to restore—biodiversity, functions, services, all 3, or something else—and where to restore given expected changes to habitats driven by global climate change. Finally, we provide guidance on how to restore contaminated ecosystems. To do this, we analyze critical aspects of the literature dealing with the ecology of restoring contaminated ecosystems. Additionally, we review approaches for translating the science of restoration to on-the-ground actions, which includes discussions of market incentives and the finances of restoration, stakeholder outreach and governance models for ecosystem restoration, and working with contractors to implement restoration plans. By explicitly considering the mechanisms and strategies that maximize the success of the restoration of contaminated sites, we hope that our synthesis serves to increase and improve collaborations between restoration ecologists and ecotoxicologists and set a roadmap for the restoration of contaminated ecosystems.

Three-dimensional shoulder kinematics normalize after rotator cuff repair.

PubMed

Kolk, Arjen; de Witte, Pieter Bas; Henseler, Jan Ferdinand; van Zwet, Erik W; van Arkel, Ewoud R A; van der Zwaal, Peer; Nelissen, Rob G H H; de Groot, Jurriaan H

2016-06-01

Patients with a rotator cuff (RC) tear often exhibit scapular dyskinesia with increased scapular lateral rotation and decreased glenohumeral elevation with arm abduction. We hypothesized that in patients with an RC tear, scapular lateral rotation, and thus glenohumeral elevation, will be restored to normal after RC repair. Shoulder kinematics were quantitatively analyzed in 26 patients with an electromagnetic tracking device (Flock of Birds) before and 1 year after RC repair in this observational case series. We focused on humeral range of motion and scapular kinematics during abduction. The asymptomatic contralateral shoulder was used as the control. Changes in scapular kinematics were associated with the gain in range of motion. Shoulder kinematics were analyzed using a linear mixed model. Mean arm abduction and forward flexion improved after surgery by 20° (95% confidence interval [CI], 2.7°-36.5°; P = .025) and 13° (95% CI, 1.2°-36.5°; P = .044), respectively. Kinematic analyses showed decreases in mean scapular protraction (ie, internal rotation) and lateral rotation (ie, upward rotation) during abduction by 3° (95% CI, 0.0°-5.2°; P = .046) and 4° (95% CI, 1.6°-8.4°; P = .042), respectively. Glenohumeral elevation increased by 5° (95% CI, 0.6°-9.7°; P = .028) at 80°. Humeral range of motion increased when scapular lateral rotation decreased and posterior tilt increased. Scapular kinematics normalize after RC repair toward a symmetrical scapular motion pattern as observed in the asymptomatic contralateral shoulder. The observed changes in scapular kinematics are associated with an increased overall range of motion and suggest restored function of shoulder muscles. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

THE REGENERATIVE CYCLE OF MOTONEURONS, WITH SPECIAL REFERENCE TO PHOSPHATASE ACTIVITY.

PubMed

Bodian, D; Mellors, R C

1945-05-01

1. The regenerative cycle of motoneurons after axon amputation is described, and an attempt made to correlate morphological and chemical events in cell bodies with the growth requirements of regenerating axons. 2. The "normal" pattern of Nissl material in the cell is considered to be the resultant of a steady state in cytoplasmic nucleoprotein. Chromatol is then interpreted as a shift of the balance of nucleoprotein turnover in fa of degradation. The rapid early depletion of Nissl substance in chromatolysis is ascribed to the increased growth requirements created by the active early sprouting of the regenerating axon. Acid phosphatase activity begins to increase above normal levels during this period in the region of nucleopro degradation. 3. The recovery period of chromatolysis due to axon section coincide in time with the phase of gradual lengthening of the regenerating axon, and is thought to represent a gradual restoration of the balance of nucleoprotein degradation and synthesis. During this period acid phosphatase activity is at its height in the region of transformation of Nissl substance, later declines to normal levels when the original pattern of Nissl bodie is restored. 4. The transformation of cytoplasmic nucleoprotein which occurs in chromatolysis after axon section, with the probable liberation (46), and depletion (44), of nucleotides, associated with acid phosphatase activity, suggests the hypothesis that liberated nucleotides or nucleotide compounds may pass down the axon in which they take part in enzymatic activity associated with growth and organization of the newly formed axon. This type of activity would not be incompatible with the ideas previously expressed (30, 81) of a continual function of Nissl substance in maintaining the integrity of the large volume of cytoplasm represented by the axon, as well perhaps as the associated myelin sheath.

A global review of past land use, climate, and active vs. passive restoration effects on forest recovery

PubMed Central

Meli, Paula; Holl, Karen D.; Rey Benayas, José María; Jones, Holly P.; Jones, Peter C.; Montoya, Daniel; Moreno Mateos, David

2017-01-01

Global forest restoration targets have been set, yet policy makers and land managers lack guiding principles on how to invest limited resources to achieve them. We conducted a meta-analysis of 166 studies in naturally regenerating and actively restored forests worldwide to answer: (1) To what extent do floral and faunal abundance and diversity and biogeochemical functions recover? (2) Does recovery vary as a function of past land use, time since restoration, forest region, or precipitation? (3) Does active restoration result in more complete or faster recovery than passive restoration? Overall, forests showed a high level of recovery, but the time to recovery depended on the metric type measured, past land use, and region. Abundance recovered quickly and completely, whereas diversity recovered slower in tropical than in temperate forests. Biogeochemical functions recovered more slowly after agriculture than after logging or mining. Formerly logged sites were mostly passively restored and generally recovered quickly. Mined sites were nearly always actively restored using a combination of planting and either soil amendments or recontouring topography, which resulted in rapid recovery of the metrics evaluated. Actively restoring former agricultural land, primarily by planting trees, did not result in consistently faster or more complete recovery than passively restored sites. Our results suggest that simply ending the land use is sufficient for forests to recover in many cases, but more studies are needed that directly compare the value added of active versus passive restoration strategies in the same system. Investments in active restoration should be evaluated relative to the past land use, the natural resilience of the system, and the specific objectives of each project. PMID:28158256

A global review of past land use, climate, and active vs. passive restoration effects on forest recovery.

PubMed

Meli, Paula; Holl, Karen D; Rey Benayas, José María; Jones, Holly P; Jones, Peter C; Montoya, Daniel; Moreno Mateos, David

2017-01-01

Global forest restoration targets have been set, yet policy makers and land managers lack guiding principles on how to invest limited resources to achieve them. We conducted a meta-analysis of 166 studies in naturally regenerating and actively restored forests worldwide to answer: (1) To what extent do floral and faunal abundance and diversity and biogeochemical functions recover? (2) Does recovery vary as a function of past land use, time since restoration, forest region, or precipitation? (3) Does active restoration result in more complete or faster recovery than passive restoration? Overall, forests showed a high level of recovery, but the time to recovery depended on the metric type measured, past land use, and region. Abundance recovered quickly and completely, whereas diversity recovered slower in tropical than in temperate forests. Biogeochemical functions recovered more slowly after agriculture than after logging or mining. Formerly logged sites were mostly passively restored and generally recovered quickly. Mined sites were nearly always actively restored using a combination of planting and either soil amendments or recontouring topography, which resulted in rapid recovery of the metrics evaluated. Actively restoring former agricultural land, primarily by planting trees, did not result in consistently faster or more complete recovery than passively restored sites. Our results suggest that simply ending the land use is sufficient for forests to recover in many cases, but more studies are needed that directly compare the value added of active versus passive restoration strategies in the same system. Investments in active restoration should be evaluated relative to the past land use, the natural resilience of the system, and the specific objectives of each project.

Integrated risk and recovery monitoring of ecosystem restorations on contaminated sites

USGS Publications Warehouse

Hooper, Michael J.; Glomb, Stephen J.; Harper, David; Hoelzle, Timothy B.; McIntosh, Lisa M.; Mulligan, David R.

2016-01-01

Ecological restorations of contaminated sites balance the human and ecological risks of residual contamination with the benefits of ecological recovery and the return of lost ecological function and ecosystem services. Risk and recovery are interrelated dynamic conditions, changing as remediation and restoration activities progress through implementation into long-term management and ecosystem maturation. Monitoring restoration progress provides data critical to minimizing residual contaminant risk and uncertainty, while measuring ecological advancement toward recovery goals. Effective monitoring plans are designed concurrently with restoration plan development and implementation and are focused on assessing the effectiveness of activities performed in support of restoration goals for the site. Physical, chemical, and biotic measures characterize progress toward desired structural and functional ecosystem components of the goals. Structural metrics, linked to ecosystem functions and services, inform restoration practitioners of work plan modifications or more substantial adaptive management actions necessary to maintain desired recovery. Monitoring frequency, duration, and scale depend on specific attributes and goals of the restoration project. Often tied to restoration milestones, critical assessment of monitoring metrics ensures attainment of risk minimization and ecosystem recovery. Finally, interpretation and communication of monitoring findings inform and engage regulators, other stakeholders, the scientific community, and the public. Because restoration activities will likely cease before full ecosystem recovery, monitoring endpoints should demonstrate risk reduction and a successional trajectory toward the condition established in the restoration goals. A detailed assessment of the completed project's achievements, as well as unrealized objectives, attained through project monitoring, will determine if contaminant risk has been minimized, if injured resources have recovered, and if ecosystem services have been returned. Such retrospective analysis will allow better planning for future restoration goals and strengthen the evidence base for quantifying injuries and damages at other sites in the future.

Leaf Litter Decomposition as a Functional Assessment of a Natural Stream Channel Design Project

NASA Astrophysics Data System (ADS)

Gentry, A.; Word, D.; Carreiro, M.; Jack, J.

2005-05-01

In October 2003, a 965m reach of Wilson Creek (Bernheim Research Forest, Kentucky, USA) was relocated, and meanders and riffle-pool sequences were restored, providing a unique opportunity to measure the re-establishment of post-restoration stream functions. Leaf litter bags were placed across riffles in the restored reach, in an upstream reference site and in two reference streams. Bags were collected for nine months, and mass loss, N dynamics and fungal ergosterol were measured. Daily mass loss rates in the restored and reference riffles in Wilson Creek were faster (k= -0.00759 and k= -0.00855, respectively) than those of the two reference streams (k= -0.00511 and k= -0.00308). This is equivalent to litter mean residence times of 132 days for the restored reach in Wilson, 117 days in the upstream reference site, and 196 and 325 days for the reference streams. It appears that the decay rate in the restored reach is similar to the upstream portion of Wilson Creek, indicating rapid mass loss recovery in the restored reach. We also determined that same-stream reference sites are important for evaluating the restoration of stream functions, because of high decay rate variation among nearby streams within the same watershed.

Insulin restores L-arginine transport requiring adenosine receptors activation in umbilical vein endothelium from late-onset preeclampsia.

PubMed

Salsoso, R; Guzmán-Gutiérrez, E; Sáez, T; Bugueño, K; Ramírez, M A; Farías, M; Pardo, F; Leiva, A; Sanhueza, C; Mate, A; Vázquez, C; Sobrevia, L

2015-03-01

Preeclampsia is associated with impaired placental vasodilation and reduced endothelial nitric oxide synthase (eNOS) activity in the foetoplacental circulation. Adenosine and insulin stimulate vasodilation in endothelial cells, and this activity is mediated by adenosine receptor activation in uncomplicated pregnancies; however, this activity has yet to be examined in preeclampsia. Early onset preeclampsia is associated with severe placental vasculature alterations that lead to altered foetus growth and development, but whether late-onset preeclampsia (LOPE) alters foetoplacental vascular function is unknown. Vascular reactivity to insulin (0.1-1000 nmol/L, 5 min) and adenosine (1 mmol/L, 5 min) was measured in KCl-preconstricted human umbilical vein rings from normal and LOPE pregnancies using a wire myograph. The protein levels of human cationic amino acid transporter 1 (hCAT-1), adenosine receptor subtypes, total and Ser¹¹⁷⁷- or Thr⁴⁹⁵-phosphorylated eNOS were detected via Western blot, and L-arginine transport (0-1000 μmol/L L-arginine, 3 μCi/mL L-[³H]arginine, 20 s, 37 °C) was measured in the presence or absence of insulin and adenosine receptor agonists or antagonists in human umbilical vein endothelial cells (HUVECs) from normal and LOPE pregnancies. LOPE increased the maximal L-arginine transport capacity and hCAT-1 and eNOS expression and activity compared with normal conditions. The A(2A) adenosine receptor (A(2A)AR) antagonist ZM-241385 blocked these effects of LOPE. Insulin-mediated umbilical vein ring relaxation was lower in LOPE pregnancies than in normal pregnancies and was restored using the A(2A)AR antagonist. The reduced foetoplacental vascular response to insulin may result from A(2A)AR activation in LOPE pregnancies. Copyright © 2014 Elsevier Ltd. All rights reserved.

ETS transcription factor ELF5 induces lumen formation in a 3D model of mammary morphogenesis and its expression is inhibited by Jak2 inhibitor TG101348.

PubMed

Chean, Jennifer; Chen, Charng-Jui; Shively, John E

2017-10-01

The loss of expression of a single gene can revert normal tissue to a malignant phenotype. For example, while normal breast has high lumenal expression of CEACAM1, the majority of breast cancers exhibit the early loss of this gene with the concurrent loss of their lumenal phenotype. MCF7 cells that lack CEACAM1 expression and fail to form lumena in 3D culture, regain the normal phenotype when transfected with CEACAM1. In order to probe the mechanism of this gain of function, we treated these cells with the clinically relevant Jak2 inhibitor TG101348 (TG), expecting that disruption of the prolactin receptor signaling pathway would interfere with the positive effects of transfection of MCF7 cells with CEACAM1. Indeed, lumen formation was inhibited, resulting in the down regulation of a set of genes, likely involved in the complex process of lumen formation. As expected, inhibition of the expression of many of these genes also inhibited lumen formation, confirming their involvement in a single pathway. Among the genes identified by the inhibition assay, ETS transcription factor ELF5 stood out, since it has been identified as a master regulator of mammary morphogenesis, and is associated with prolactin receptor signaling. When ELF5 was transfected into the parental MCF7 cells that lack CEACAM1, lumen formation was restored, indicating that ELF5 can replace CEACAM1 in this model system of lumenogenesis. We conclude that the event(s) that led to the loss of expression of CEACAM1 is epistatic in that multiple genes associated with a critical pathway were affected, but that restoration of the normal phenotype can be achieved with reactivation of certain genes at various nodal points in tissue morphogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Improving the blind restoration of retinal images by means of point-spread-function estimation assessment

NASA Astrophysics Data System (ADS)

Marrugo, Andrés. G.; Millán, María. S.; Å orel, Michal; Kotera, Jan; Å roubek, Filip

2015-01-01

Retinal images often suffer from blurring which hinders disease diagnosis and progression assessment. The restoration of the images is carried out by means of blind deconvolution, but the success of the restoration depends on the correct estimation of the point-spread-function (PSF) that blurred the image. The restoration can be space-invariant or space-variant. Because a retinal image has regions without texture or sharp edges, the blind PSF estimation may fail. In this paper we propose a strategy for the correct assessment of PSF estimation in retinal images for restoration by means of space-invariant or space-invariant blind deconvolution. Our method is based on a decomposition in Zernike coefficients of the estimated PSFs to identify valid PSFs. This significantly improves the quality of the image restoration revealed by the increased visibility of small details like small blood vessels and by the lack of restoration artifacts.

Restoration of impaired ecosystems: An ounce of prevention or a pound of cure? introduction, overview, and key messages from a SETAC-SER workshop

USGS Publications Warehouse

Farag, Aïda M.; Hull, Ruth N.; Clements, Will H.; Glomb, Steve; Larson, Diane L.; Stahl, Ralph G.; Stauber, Jenny

2016-01-01

A workshop on Restoration of Impaired Ecosystems was held in Jackson, Wyoming, in June 2014. Experts from Australia, Canada, Mexico, the United Kingdom, and the United States in ecotoxicology, restoration, and related fields from both the Society of Environmental Toxicology and Chemistry and the Society for Ecological Restoration convened to advance the practice of restoring ecosystems that have been contaminated or impaired from industrial activities. The overall goal of this workshop was to provide a forum for ecotoxicologists and restoration ecologists to define the best scientific practices to achieve ecological restoration while addressing contaminant concerns. To meet this goal, participants addressed 5 areas: 1) links between ecological risk assessment and ecological restoration, 2) restoration goals, 3) restoration design, 4) monitoring for restoration effectiveness and 5) recognizing opportunities and challenges. Definitions are provided to establish a common language across the varied disciplines. The current practice for addressing restoration of impaired ecosystems tends to be done sequentially to remediate contaminants, then to restore ecological structure and function. A better approach would anticipate or plan for restoration throughout the process. By bringing goals to the forefront, we may avoid intrusive remediation activities that close off options for the desired restoration. Participants realized that perceived limitations in the site assessment process hinder consideration of restoration goals; contaminant presence will influence restoration goal choices; social, economic, and cultural concerns can factor into goal setting; restoration options and design should be considered early during site assessment and management; restoration of both structure and function is encouraged; creative solutions can overcome limitations; a regional focus is imperative; monitoring must occur throughout the restoration process; and reciprocal transfer of knowledge is needed among theorists, practitioners, and stakeholders and among varied disciplines.

Correction of X-linked immunodeficient mice by competitive reconstitution with limiting numbers of normal bone marrow cells.

PubMed

Rohrer, J; Conley, M E

1999-11-15

Gene therapy for inherited disorders is more likely to succeed if gene-corrected cells have a proliferative or survival advantage compared with mutant cells. We used a competitive reconstitution model to evaluate the strength of the selective advantage that Btk normal cells have in Btk-deficient xid mice. Whereas 2,500 normal bone marrow cells when mixed with 497,500 xid cells restored serum IgM and IgG3 levels to near normal concentrations in 3 of 5 lethally irradiated mice, 25,000 normal cells mixed with 475,000 xid cells reliably restored serum IgM and IgG3 concentrations and the thymus-independent antibody response in all transplanted mice. Reconstitution was not dependent on lethal irradiation, because sublethally irradiated mice all had elevated serum IgM and IgG3 by 30 weeks postreconstitution when receiving 25,000 normal cells. Furthermore, the xid defect was corrected with as few as 10% of the splenic B cells expressing a normal Btk. When normal donor cells were sorted into B220(+)/CD19(+) committed B cells and B220(-)/CD19(-) cell populations, only the B220(-)/CD19(-) cells provided long-term B-cell reconstitution in sublethally irradiated mice. These findings suggest that even inefficient gene therapy may provide clinical benefit for patients with XLA.

Congenital gonadotropin deficiency in boys: management during childhood.

PubMed

Adan, L; Couto-Silva, A C; Trivin, C; Metz, C; Brauner, R

2004-02-01

To analyze the features of boys with congenital gonadotropin deficiency (CGD), and to determine the value of plasma inhibin B and anti-Müllerian hormone (AMH) for predicting testicular function and the effect of testosterone treatment. We followed 19 boys for CGD, including five with Kallmann syndrome. The boys were seen before 14 years of age for micropenis (9 boys) or later for delayed puberty (10 boys). No testis was palpable in the scrotum in 13 patients, bilaterally in seven of them. Luteinizing hormone (LH) peak after a gonadotropin releasing hormone (GnRH) test was between 0.5 and 5.6 U/l. Plasma inhibin B was low in the four patients evaluated at less than 1 year old. AMH was low in one of them and normal in four others. Of the older patients, three lad low plasma inhibin B and four had normal concentrations; plasma AMH was low in three of them and increased in four. Testosterone treatment restored penis length to normal in all patients. Low plasma inhibin B and AMH concentrations may indicate testicular damage in boys with CGD.

Application of bifurcation theory and siRNA-based control signal to restore the proper response of cancer cells to DNA damage.

PubMed

Kozłowska, Emilia; Puszynski, Krzysztof

2016-11-07

Many diseases with a genetic background such as some types of cancer are caused by damage in the p53 signaling pathway. The damage changes the system dynamics providing cancer cells with resistance to therapy such as radiation therapy. The change can be observed as the difference in bifurcation diagrams and equilibria type and location between normal and damaged cells, and summarized as the changes of the mathematical model parameters and following changes of the eigenvalues of Jacobian matrix. Therefore a change in other model parameters, such as mRNA degradation rates, may restore the proper eigenvalues and by that proper system dynamics. From the biological point of view, the change of mRNA degradation rate can be achieved by application of the small interfering RNA (siRNA). Here, we propose a general mathematical framework based on the bifurcation theory and siRNA-based control signal in order to study how to restore the proper response of cells with damaged p53 signaling pathway to therapy by using ionizing radiation (IR) therapy as an example. We show the difference between the cells with normal p53 signaling pathway and cells with abnormalities in the negative (as observed in SJSA-1 cell line) or positive (as observed in MCF-7 or PNT1a cell lines) feedback loop. Then we show how the dynamics of these cells can be restored to normal cell dynamics by using selected siRNA. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

NADPH oxidase-2 inhibition restores contractility and intracellular calcium handling and reduces arrhythmogenicity in dystrophic cardiomyopathy

PubMed Central

Gonzalez, Daniel R.; Treuer, Adriana V.; Lamirault, Guillaume; Mayo, Vera; Cao, Yenong; Dulce, Raul A.

2014-01-01

Duchenne muscular dystrophy may affect cardiac muscle, producing a dystrophic cardiomyopathy in humans and the mdx mouse. We tested the hypothesis that oxidative stress participates in disrupting calcium handling and contractility in the mdx mouse with established cardiomyopathy. We found increased expression (fivefold) of the NADPH oxidase (NOX) 2 in the mdx hearts compared with wild type, along with increased superoxide production. Next, we tested the impact of NOX2 inhibition on contractility and calcium handling in isolated cardiomyocytes. Contractility was decreased in mdx myocytes compared with wild type, and this was restored toward normal by pretreating with apocynin. In addition, the amplitude of evoked intracellular Ca2+ concentration transients that was diminished in mdx myocytes was also restored with NOX2 inhibition. Total sarcoplasmic reticulum (SR) Ca2+ content was reduced in mdx hearts and normalized by apocynin treatment. Additionally, NOX2 inhibition decreased the production of spontaneous diastolic calcium release events and decreased the SR calcium leak in mdx myocytes. In addition, nitric oxide (NO) synthase 1 (NOS-1) expression was increased eightfold in mdx hearts compared with wild type. Nevertheless, cardiac NO production was reduced. To test whether this paradox implied NOS-1 uncoupling, we treated cardiac myocytes with exogenous tetrahydrobioterin, along with the NOX inhibitor VAS2870. These agents restored NO production and phospholamban phosphorylation in mdx toward normal. Together, these results demonstrate that, in mdx hearts, NOX2 inhibition improves the SR calcium handling and contractility, partially by recoupling NOS-1. These findings reveal a new layer of nitroso-redox imbalance in dystrophic cardiomyopathy. PMID:25015966

Transforming ecosystems: When, where, and how to restore contaminated sites.

PubMed

Rohr, Jason R; Farag, Aïda M; Cadotte, Marc W; Clements, William H; Smith, James R; Ulrich, Cheryl P; Woods, Richard

2016-04-01

Chemical contamination has impaired ecosystems, reducing biodiversity and the provisioning of functions and services. This has spurred a movement to restore contaminated ecosystems and develop and implement national and international regulations that require it. Nevertheless, ecological restoration remains a young and rapidly growing discipline and its intersection with toxicology is even more nascent and underdeveloped. Consequently, we provide guidance to scientists and practitioners on when, where, and how to restore contaminated ecosystems. Although restoration has many benefits, it also can be expensive, and in many cases systems can recover without human intervention. Hence, the first question we address is: "When should we restore contaminated ecosystems?" Second, we provide suggestions on what to restore-biodiversity, functions, services, all 3, or something else--and where to restore given expected changes to habitats driven by global climate change. Finally, we provide guidance on how to restore contaminated ecosystems. To do this, we analyze critical aspects of the literature dealing with the ecology of restoring contaminated ecosystems. Additionally, we review approaches for translating the science of restoration to on-the-ground actions, which includes discussions of market incentives and the finances of restoration, stakeholder outreach and governance models for ecosystem restoration, and working with contractors to implement restoration plans. By explicitly considering the mechanisms and strategies that maximize the success of the restoration of contaminated sites, we hope that our synthesis serves to increase and improve collaborations between restoration ecologists and ecotoxicologists and set a roadmap for the restoration of contaminated ecosystems. © 2015 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of SETAC.

Endoscopic subcondylar fracture repair: functional, aesthetic, and radiographic outcomes.

PubMed

Lee, C; Mueller, R V; Lee, K; Mathes, S J

1998-10-01

An endoscopic method of mandibular subcondylar fracture repair has been described recently. To determine the effectiveness of this new technique, we longitudinally studied functional, aesthetic, and radiographic parameters following endoscopic repair of 22 subcondylar fractures in 20 patients. Restoration of mandibular function was achieved without postoperative maxillomandibular fixation. Premorbid occlusion was restored. Clinical jaw motion was found to progressively increase with a mean interincisal jaw opening of 43 mm achieved after the eighth postoperative week. Patients were pleased with the aesthetic restoration of their chin projection,jaw line, and the symmetric midline movement of the chin point onjaw opening. Anatomic fracture reduction with rigid plate fixation was confirmed on early postsurgical radiographs. Late radiographs showed fracture union without remodeling of the condylar head. Endoscopic subcondylar fracture repair was efficacious at functional, aesthetic, and radiographic restoration of the mandible.

A phase III, open-label, single-arm study of tenecteplase for restoration of function in dysfunctional central venous catheters.

PubMed

Tebbi, Cameron; Costanzi, John; Shulman, Robert; Dreisbach, Luke; Jacobs, Brian R; Blaney, Martha; Ashby, Mark; Gillespie, Barbara S; Begelman, Susan M

2011-08-01

To evaluate, in a phase III, single-arm study, the safety and efficacy of the thrombolytic agent tenecteplase in restoring function to dysfunctional central venous catheters (CVCs). Pediatric and adult patients with dysfunctional CVCs were eligible to receive as much as 2 mL (2 mg) of intraluminal tenecteplase, which was left to dwell in the CVC lumen for a maximum of 120 minutes. If CVC function was not restored at 120 minutes, a second dose was instilled for an additional 120 minutes. Tenecteplase was administered to 246 patients. Mean patient age was 44 years (range, 0-92 y); 72 patients (29%) were younger than 17 years of age. Chemotherapy was the most common reason for catheter insertion. Restoration of CVC function was achieved in 177 patients (72%) within 120 minutes after the first dose. After instillation of a maximum of two doses of tenecteplase, CVC function was restored in 200 patients (81%), with similar frequencies in pediatric (83%) and adult (80%) patients. Adverse events (AEs) were reported in 31 patients (13%); fever (2%), neutropenia (1%), and nausea (0.8%) were most common. One serious AE, an allergic hypersensitivity reaction, was judged to be related to tenecteplase and/or a chemotherapeutic agent that the patient was receiving concurrently. Consecutive administration of one or two doses of tenecteplase into CVCs showed efficacy in the restoration of catheter function in patients with dysfunctional CVCs. Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.

Activity vs. rest in the treatment of bone, soft tissue and joint injuries.

PubMed

Buckwalter, J A

1995-01-01

One of the most important advances in the treatment of musculoskeletal injuries has come from understanding that controlled early resumption of activity can promote restoration of function, and that treatment of injuries with prolonged rest may delay recovery and adversely affect normal tissues. In the last decade of the nineteenth century two widely respected orthopaedists with extensive clinical experience strongly advocated opposing treatments of musculoskeletal injuries. Hugh Owen Thomas in Liverpool believed that enforced, uninterrupted prolonged rest produced the best results. He noted that movement of injured tissues increased inflammation, and that, "It would indeed be as reasonable to attempt to cure a fever patient by kicking him out of bed, as to benefit joint disease by a wriggling at the articulation." Just Lucas-Championnier in Paris took the opposite position. He argued that early controlled active motion accelerated restoration of function, although he noted that mobility had to be given in limited doses. In general, Thomas' views met with greater acceptance in the early part of this century, but experimental studies of the last several decades generally support Lucas-Championneir. They confirm and help explain the deleterious effects of prolonged rest and the beneficial effects of activity on the musculoskeletal tissues. They have shown that maintenance of normal bone, tendon and ligament, articular cartilage and muscle structure and composition require repetitive use, and that changes in the patterns of tissue loading can strengthen or weaken normal tissues. Although all the musculoskeletal tissues can respond to repetitive loading, they vary in the magnitude and type of response to specific patterns of activity. Furthermore, their responsiveness may decline with increasing age. Skeletal muscle and bone demonstrate the most apparent response to changes in activity in individuals of any age. Cartilage and dense fibrous tissues also can respond to loading, but the responses are more difficult to measure. The effects of loading on injured tissues have been less extensively studied, but the available evidence indicates that repair tissues respond to loading and, like immature normal tissues, may be more sensitive to cyclic loading and motion than mature normal tissues. However, early motion and loading of injured tissues is not without risks. Premature or excessive loading and motion of repair tissue can inhibit or stop repair. Unfortunately, the optimal methods of facilitating healing by early application of loading and motion have not been defined.(ABSTRACT TRUNCATED AT 400 WORDS)

Restoring Ecological Function to a Submerged Salt Marsh

USGS Publications Warehouse

Stagg, C.L.; Mendelssohn, I.A.

2010-01-01

Impacts of global climate change, such as sea level rise and severe drought, have altered the hydrology of coastal salt marshes resulting in submergence and subsequent degradation of ecosystem function. A potential method of rehabilitating these systems is the addition of sediment-slurries to increase marsh surface elevation, thus ameliorating effects of excessive inundation. Although this technique is growing in popularity, the restoration of ecological function after sediment addition has received little attention. To determine if sediment subsidized salt marshes are functionally equivalent to natural marshes, we examined above- and belowground primary production in replicated restored marshes receiving four levels of sediment addition (29-42 cm North American Vertical Datum of 1988 [NAVD 88]) and in degraded and natural ambient marshes (4-22 cm NAVD 88). Moderate intensities of sediment-slurry addition, resulting in elevations at the mid to high intertidal zone (29-36 cm NAVD 88), restored ecological function to degraded salt marshes. Sediment additions significantly decreased flood duration and frequency and increased bulk density, resulting in greater soil drainage and redox potential and significantly lower phytotoxic sulfide concentrations. However, ecological function in the restored salt marsh showed a sediment addition threshold that was characterized by a decline in primary productivity in areas of excessive sediment addition and high elevation (>36 cm NAVD 88). Hence, the addition of intermediate levels of sediment to submerging salt marshes increased marsh surface elevation, ameliorated impacts of prolonged inundation, and increased primary productivity. However, too much sediment resulted in diminished ecological function that was equivalent to the submerged or degraded system. ?? 2010 Society for Ecological Restoration International.

Cardiovascular and respiratory dynamics during normal and pathological sleep

NASA Astrophysics Data System (ADS)

Penzel, Thomas; Wessel, Niels; Riedl, Maik; Kantelhardt, Jan W.; Rostig, Sven; Glos, Martin; Suhrbier, Alexander; Malberg, Hagen; Fietze, Ingo

2007-03-01

Sleep is an active and regulated process with restorative functions for physical and mental conditions. Based on recordings of brain waves and the analysis of characteristic patterns and waveforms it is possible to distinguish wakefulness and five sleep stages. Sleep and the sleep stages modulate autonomous nervous system functions such as body temperature, respiration, blood pressure, and heart rate. These functions consist of a sympathetic tone usually related to activation and to parasympathetic (or vagal) tone usually related to inhibition. Methods of statistical physics are used to analyze heart rate and respiration to detect changes of the autonomous nervous system during sleep. Detrended fluctuation analysis and synchronization analysis and their applications to heart rate and respiration during sleep in healthy subjects and patients with sleep disorders are presented. The observed changes can be used to distinguish sleep stages in healthy subjects as well as to differentiate normal and disturbed sleep on the basis of heart rate and respiration recordings without direct recording of brain waves. Of special interest are the cardiovascular consequences of disturbed sleep because they present a risk factor for cardiovascular disorders such as arterial hypertension, cardiac ischemia, sudden cardiac death, and stroke. New derived variables can help to find indicators for these health risks.

Importance of cholesterol in dopamine transporter function

PubMed Central

Jones, Kymry T.; Zhen, Juan; Reith, Maarten E.A.

2012-01-01

The conformation and function of the dopamine transporter (DAT) can be affected by manipulating membrane cholesterol, yet there is no agreement as to the impact of cholesterol on the activity of lipid-raft localized DATs compared to non-raft DATs. Given the paucity of information regarding the impact of cholesterol on substrate efflux by the DAT, this study explores its influence on the kinetics of DAT-mediated DA efflux induced by dextroamphetamine, as measured by rotating disk electrode voltammetry (RDEV). Treatment with methyl-β-cyclodextrin (mβCD), which effectively depletes total membrane cholesterol- uniformly affecting cholesterol-DAT interactions in both raft and non-raft membrane domains- reduced both DA uptake and efflux rate. In contrast, disruption of raft localized DAT by cholesterol chelation with nystatin had no effect, arguing against a vital role for raft-localized DAT in substrate uptake or efflux. Supra-normal repletion of cholesterol depleted cells with the analogue desmosterol, a non-raft promoting sterol, was as effective as cholesterol itself in restoring transport rates. Further studies with Zn2+ and the conformationally-biased W84L DAT mutant supported the idea that cholesterol is important for maintaining the outward-facing DAT with normal rates of conformational interconversions. Collectively, these results point to a role for direct cholesterol-DAT interactions in regulating DAT function. PMID:22957537

Role of TSP-5/COMP in pseudoachondroplasia.

PubMed

Posey, Karen L; Hayes, Elizabeth; Haynes, Richard; Hecht, Jacqueline T

2004-06-01

Pseudoachondroplasia (PSACH) is a well-characterized dwarfing condition associated with disproportionate short stature, abnormal joints and osteoarthritis requiring joint replacement. PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP). COMP, the fifth member of the thrombospondin (TSP) gene family, is a pentameric protein found primarily in the extracellular matrix of musculoskeletal tissues. Functional studies have shown that COMP binds types II and IX collagens but the role of COMP in the extracellular matrix remains to be defined. Mutations in COMP interfere with calcium-binding and protein conformation. PSACH growth plate and growth plate chondrocytes studies indicate that COMP mutations have a dominant negative effect with both COMP and type IX collagen being retained in large rER cisternae. This massive retention causes impaired chondrocyte function with little COMP secreted into the matrix and premature loss of chondrocytes. Deficiency of linear growth results from loss of chondrocytes from the growth plate. Secondarily, the matrix contains minimal COMP, which may be normal and/or mutant, and little type IX collagen. This deficiency results in abnormal joints that are easily eroded and cause painful osteoarthritis. Unlike other misfolded proteins that are targeted for degradation, much of the retained COMP escapes degradation, compromises cell function, and causes cell death. Gene therapy will need to target the reduction of COMP in order to restore normal chondrocyte function and longevity.

Spatio-Temporal Changes of Lymphatic Contractility and Drainage Patterns following Lymphadenectomy in Mice

PubMed Central

Kwon, Sunkuk; Agollah, Germaine D.; Wu, Grace; Sevick-Muraca, Eva M.

2014-01-01

Objective To investigate the redirection of lymphatic drainage post-lymphadenectomy using non-invasive near-infrared fluorescence (NIRF) imaging, and to subsequently assess impact on metastasis. Background Cancer-acquired lymphedema arises from dysfunctional fluid transport after lymphadenectomy performed for staging and to disrupt drainage pathways for regional control of disease. However, little is known about the normal regenerative processes of the lymphatics in response to lymphadenectomy and how these responses can be accelerated, delayed, or can impact metastasis. Methods Changes in lymphatic “pumping” function and drainage patterns were non-invasively and longitudinally imaged using NIRF lymphatic imaging after popliteal lymphadenectomy in mice. In a cohort of mice, B16F10 melanoma was inoculated on the dorsal aspect of the paw 27 days after lymphadenectomy to assess how drainage patterns affect metastasis. Results NIRF imaging demonstrates that, although lymphatic function and drainage patterns change significantly in early response to popliteal lymph node (PLN) removal in mice, these changes are transient and regress dramatically due to a high regenerative capacity of the lymphatics and co-opting of collateral lymphatic pathways around the site of obstruction. Metastases followed the pattern of collateral pathways and could be detected proximal to the site of lymphadenectomy. Conclusions Both lymphatic vessel regeneration and co-opting of contralateral vessels occur following lymphadenectomy, with contractile function restored within 13 days, providing a basis for preclinical and clinical investigations to hasten lymphatic repair and restore contractile lymphatic function after surgery to prevent cancer-acquired lymphedema. Patterns of cancer metastasis after lymphadenectomy were altered, consistent with patterns of re-directed lymphatic drainage. PMID:25170770

Periodic acid‑Schiff staining method for function detection of liver cells is affected by 2% horse serum in induction medium.

PubMed

Hui, Hui; Ma, Wenjun; Cui, Jiejie; Gong, Mengjia; Wang, Yi; Zhang, Yuanyuan; He, Tongchuan; Bi, Yang; He, Yun

2017-12-01

Developing a thorough understanding of experimental methods of hepatic differentiation in hepatic progenitor cells (HPCs) should expand the knowledge of hepatocyte induction in vitro and may help to develop cell transplantation therapies for the clinical usage of HPCs in liver diseases. A previous induction method effectively induced differentiation and metabolic abilities in HPCs. Periodic acid‑Schiff (PAS) staining is used to identify glycogen synthesis and hepatocyte function; however, this method failed to detect induced hepatocytes. The present study aimed to investigate the possible factors affecting the previous confusing results of PAS staining. Removal of single induction factors, including dexamethasone, hepatic growth factor and fibroblast growth factor 4 from the induction media did not restore PAS staining, whereas replacement of 2% horse serum (HS) with 10% fetal bovine serum (FBS) significantly increased the number of PAS positive cells. Following 12 days of basal induction, replacing the induction medium with media containing 10% FBS for 12‑72 h significantly improved PAS staining, but did not influence indocyanine green uptake. Furthermore, incubation in induction medium with 10% FBS following 12 days of normal induction did not affect the expression of hepatic markers and mature function of HPCs. Therefore, the present study suggested that 2% HS in the induction medium did not affect the hepatic function of induced cells, but did affect glycogen storage, whereas replacement of medium with 10% FBS in advance of PAS staining may restore the failure of PAS staining in low serum concentrations of induced hepatocytes.

Recovery of deficient homologous recombination in Brca2-depleted mouse cells by wild-type Rad51 expression.

PubMed

Lee, Shauna A; Roques, Céline; Magwood, Alissa C; Masson, Jean-Yves; Baker, Mark D

2009-02-01

The BRCA2 tumor suppressor is important in maintaining genomic stability. BRCA2 is proposed to control the availability, cellular localization and DNA binding activity of the central homologous recombination protein, RAD51, with loss of BRCA2 resulting in defective homologous recombination. Nevertheless, the roles of BRCA2 in regulating RAD51 and how other proteins implicated in RAD51 regulation, such as RAD52 and RAD54 function relative to BRCA2 is not known. In this study, we tested whether defective homologous recombination in Brca2-depleted mouse hybridoma cells could be rectified by expression of mouse Rad51 or the Rad51-interacting mouse proteins, Rad52 and Rad54. In the Brca2-depleted cells, defective homologous recombination can be restored by over-expression of wild-type mouse Rad51, but not mouse Rad52 or Rad54. Correction of the homologous recombination defect requires Rad51 ATPase activity. A sizeable fraction ( approximately 50%) of over-expressed wild-type Rad51 is nuclear localized. The restoration of homologous recombination in the presence of a low (i.e., non-functional) level of Brca2 by wild-type Rad51 over-expression is unexpected. We suggest that Rad51 may access the nuclear compartment in a Brca2-independent manner and when Rad51 is over-expressed, the normal requirement for Brca2 control over Rad51 function in homologous recombination is dispensable. Our studies support loss of Rad51 function as a critical underlying factor in the homologous recombination defect in the Brca2-depleted cells.

Multi-scale functional mapping of tidal marsh vegetation for restoration monitoring

NASA Astrophysics Data System (ADS)

Tuxen Bettman, Karin

2007-12-01

Nearly half of the world's natural wetlands have been destroyed or degraded, and in recent years, there have been significant endeavors to restore wetland habitat throughout the world. Detailed mapping of restoring wetlands can offer valuable information about changes in vegetation and geomorphology, which can inform the restoration process and ultimately help to improve chances of restoration success. I studied six tidal marshes in the San Francisco Estuary, CA, US, between 2003 and 2004 in order to develop techniques for mapping tidal marshes at multiple scales by incorporating specific restoration objectives for improved longer term monitoring. I explored a "pixel-based" remote sensing image analysis method for mapping vegetation in restored and natural tidal marshes, describing the benefits and limitations of this type of approach (Chapter 2). I also performed a multi-scale analysis of vegetation pattern metrics for a recently restored tidal marsh in order to target the metrics that are consistent across scales and will be robust measures of marsh vegetation change (Chapter 3). Finally, I performed an "object-based" image analysis using the same remotely sensed imagery, which maps vegetation type and specific wetland functions at multiple scales (Chapter 4). The combined results of my work highlight important trends and management implications for monitoring wetland restoration using remote sensing, and will better enable restoration ecologists to use remote sensing for tidal marsh monitoring. Several findings important for tidal marsh restoration monitoring were made. Overall results showed that pixel-based methods are effective at quantifying landscape changes in composition and diversity in recently restored marshes, but are limited in their use for quantifying smaller, more fine-scale changes. While pattern metrics can highlight small but important changes in vegetation composition and configuration across years, scientists should exercise caution when using metrics in their studies or to validate restoration management decisions, and multi-scale analyses should be performed before metrics are used in restoration science for important management decisions. Lastly, restoration objectives, ecosystem function, and scale can each be integrated into monitoring techniques using remote sensing for improved restoration monitoring.

Evaluating the Magnitude and Duration of Cold Load Pick-up on Residential Distribution Feeders Using Multi-State Load Models

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

Schneider, Kevin P.; Sortomme, Eric; Venkata, S. S.

The increased level of demand that is associated with the restoration of service after an outage, Cold Load Pick-Up (CLPU), can be significantly higher than pre-outage levels, even exceeding the normal distribution feeder peak demand. These high levels of demand can delay restoration efforts and in extreme cases damage equipment. The negative impacts of CLPU can be mitigated with strategies that restore the feeder in sections, minimizing the load current. The challenge for utilities is to manage the current level on critical equipment while minimizing the time to restore service to all customers. Accurately modeling CLPU events is the firstmore » step in developing improved restoration strategies that minimize restoration times. This paper presents a new method for evaluating the magnitude of the CLPU peak, and its duration, using multi-state load models. The use of multi-state load models allows for a more accurate representation of the end-use loads that are present on residential distribution feeders.« less

Accelerated recovery of sensorimotor function in a dog submitted to quasi-total transection of the cervical spinal cord and treated with PEG.

PubMed

Kim, C-Yoon; Hwang, In-Kyu; Kim, Hana; Jang, Se-Woong; Kim, Hong Seog; Lee, Won-Young

2016-01-01

A case report on observing the recovery of sensory-motor function after cervical spinal cord transection. Laminectomy and transection of cervical spinal cord (C5) was performed on a male beagle weighing 3.5 kg. After applying polyethylene glycol (PEG) on the severed part, reconstruction of cervical spinal cord was confirmed by the restoration of sensorimotor function. Tetraplegia was observed immediately after operation, however, the dog showed stable respiration and survival without any complication. The dog showed fast recovery after 1 week, and recovered approximately 90% of normal sensorimotor function 3 weeks after the operation, although urinary disorder was still present. All recovery stages were recorded by video camera twice a week for behavioral analysis. While current belief holds that functional recovery is impossible after a section greater than 50% at C5-6 in the canine model, this case study shows the possibility of cervical spinal cord reconstruction after near-total transection. Furthermore, this case study also confirms that PEG can truly expedite the recovery of sensorimotor function after cervical spinal cord sections in dogs.

Patient-reported benefit of ReSTOR multi-focal intraocular lenses after cataract surgery: results of principal component analysis on clinical trial data.

PubMed

Berdeaux, Gilles; Viala, Muriel; Roborel de Climens, Aude; Arnould, Benoit

2008-01-24

Restoration of functional distance and near vision independently of additional correction remains a goal for cataract surgery. ReSTOR, a new multi-focal intraocular lens (IOL) addresses this issue with an improvement in both distance and near vision, often without need for glasses. This analysis attempted to discuss the patient-reported benefit of ReSTOR using a full but organised representation of data. Two non-randomised, open-label clinical trials conducted in Europe and the United-States were conducted to compare the efficacy of ReSTOR to AcrySof mono-focal IOLs. A total of 710 patients in need of bilateral cataract extraction were included in the pooled study. The TyPE, a patient questionnaire, was fully completed by 672 of them before and after each eye surgery. The TyPE, composed of 67 items measuring overall visual functioning in both conditions (with and without wearing glasses), evaluates limitations, troubles and satisfaction in distance and near vision. A principal component analysis (PCA) of the TyPE questionnaire was performed on pooled data from baseline and post-surgery observations in order to fully represent the change in the TyPE data over time. ReSTOR and mono-focal groups were used as illustrative variables. The coordinates of the first 2 factors were compared between visits and between IOLs (ReSTOR vs. mono-focal), using paired t-tests and t-tests, respectively. The first factor of the PCA explained 55% of the variance and represented 'visual functioning and patient satisfaction'. The second factor explained 6% of the variance and was interpreted as 'independence from glasses'. An overall difference in factorial coordinates in both factors was seen between baseline and the first eye surgery, and between the first and the second eye surgery. No difference between ReSTOR and mono-focal IOL groups was observed at baseline. After surgery, ReSTOR treated-patients had higher coordinates on both "visual functioning and satisfaction" and "independence from glasses" factors. Findings observed on the factorial plan were supported by statistical comparisons of factorial coordinates. Both mono-focal and ReSTOR-implanted patients improved their visual functioning after bilateral cataract surgery. Moreover, ReSTOR patients reported an additional benefit in independence from glasses as well as in visual functioning and patient satisfaction.

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors Is Displaced by Drug Candidates That Improve Cognitive Deficits

PubMed Central

Izzo, Nicholas J.; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F.; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M.

2014-01-01

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1–42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors - i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics. PMID:25390368

Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.

PubMed

Izzo, Nicholas J; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M

2014-01-01

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

Potential effects of restoration on biogeochemical functions of bottom land hardwood ecosystems

Treesearch

Graeme Lockaby; John A. Stanturf

2000-01-01

The concept of wetland restoration carries multiple meanings and implications. The scientific usage of the term connotes re-establishment of wetland functions, and often it is the functions, which society deems most valuable, that receive highest focus. Arguably, among key wetland functions, the highest societal value may be linked with the biogeochemical...

Selective Matrix (Hyaluronan) Interaction with CD44 and RhoGTPase Signaling Promotes Keratinocyte Functions and Overcomes Age-related Epidermal Dysfunction

PubMed Central

Bourguignon, Lilly Y.W.; Wong, Gabriel; Xia, Weiliang; Man, Mao-Qiang; Holleran, Walter M.; Elias, Peter M.

2013-01-01

Background Mouse epidermal chronologic aging is closely associated with aberrant matrix (hyaluronan, HA) -size distribution/production and impaired keratinocyte proliferation/differentiation, leading to a marked thinning of the epidermis with functional consequence that causes a slower recovery of permeability barrier function. Objective The goal of this study is to demonstrate mechanism-based, corrective therapeutic strategies using topical applications of small HA (HAS) and/or large HA (HAL) [or a sequential small HA (HAS) and large HA(HAL) (HAs-»HAL) treatment] as well as RhoGTPase signaling perturbation agents to regulate HA/CD44-mediated signaling, thereby restoring normal epidermal function, and permeability barrier homeostasis in aged mouse skin. Methods A number of biochemical, cell biological/molecular, pharmacological and physiological approaches were used to investigate matrix HA-CD44-mediated RhoGTPase signaling in regulating epidermal functions and skin aging. Results In this study we demonstrated that topical application of small HA (HAS) promotes keratinocyte proliferation and increases skin thickness, while it fails to upregulate keratinocyte differentiation or permeability barrier repair in aged mouse skin. In contrast, large HA (HAL) induces only minimal changes in keratinocyte proliferation and skin thickness, but restores keratinocyte differentiation and improves permeability barrier function in aged epidermis. Since neither HAS nor HAL corrects these epidermal defects in aged CD44 knock-out mice, CD44 likely mediates HA-associated epidermal functions in aged mouse skin. Finally, blockade of Rho-kinase activity with Y27632 or protein kinase-Nγ activity with Ro31-8220 significantly decreased the HA (HAS or HAL)-mediated changes in epidermal function in aged mouse skin. Conclusion The results of our study show first that HA application of different sizes regulates epidermal proliferation, differentiation and barrier function in aged mouse skin. Second, manipulation of matrix (HA) interaction with CD44 and RhoGTPase signaling could provide further novel therapeutic approaches that could be targeted for the treatment of various aging-related skin disorders. PMID:23790635

Cholesterol Corrects Altered Conformation of MHC-II Protein in Leishmania donovani Infected Macrophages: Implication in Therapy

PubMed Central

Chakrabarti, Saikat; Roy, Syamal

2016-01-01

Background Previously we reported that Kala-azar patients show progressive decrease in serum cholesterol as a function of splenic parasite burden. Splenic macrophages (MΦ) of Leishmania donovani (LD) infected mice show decrease in membrane cholesterol, while LD infected macrophages (I-MΦ) show defective T cell stimulating ability that could be corrected by liposomal delivery of cholesterol. T helper cells recognize peptide antigen in the context of class II MHC molecule. It is known that the conformation of a large number of membrane proteins is dependent on membrane cholesterol. In this investigation we tried to understand the influence of decreased membrane cholesterol in I-MΦ on the conformation of MHC-II protein and peptide-MHC-II stability, and its bearing on the antigen specific T-cell activation. Methodology/Principal Findings MΦ of CBA/j mice were infected with Leishmania donovani (I-MΦ). Two different anti-Aκ mAbs were used to monitor the status of MHC-II protein under parasitized condition. One of them (11.5–2) was conformation specific, whereas the other one (10.2.16) was not. Under parasitized condition, the binding of 11.5–2 decreased significantly with respect to the normal counterpart, whereas that of 10.2.16 remained unaltered. The binding of 11.5–2 was restored to normal upon liposomal delivery of cholesterol in I-MΦ. By molecular dynamics (MD) simulation studies we found that there was considerable conformational fluctuation in the transmembrane domain of the MHC-II protein in the presence of membrane cholesterol than in its absence, which possibly influenced the distal peptide binding groove. This was evident from the faster dissociation of the cognate peptide from peptide-MHC complex under parasitized condition, which could be corrected by liposomal delivery of cholesterol in I-MΦ. Conclusion The decrease in membrane cholesterol in I-MΦ may lead to altered conformation of MHC II, and this may contribute to a faster dissociation of the peptide. Furthermore, liposomal delivery of cholesterol in I-MΦ restored its normal antigen presenting function. This observation brings strength to our previous observation on host directed therapeutic application of liposomal cholesterol in experimental visceral leishmaniasis. PMID:27214205

Magnesium taurate prevents cataractogenesis via restoration of lenticular oxidative damage and ATPase function in cadmium chloride-induced hypertensive experimental animals.

PubMed

Choudhary, Rajesh; Bodakhe, Surendra H

2016-12-01

Previously we found that hypertension potentiates the risk the cataractogenesis. In the present study, we investigated the protective effects of magnesium taurate (MgT) on hypertension and associated lenticular damages against cadmium chloride (CdCl 2 )-induced hypertensive animals. Male Sprague-Dawley albino rats (150-180g) were assigned to five experimental groups (n=6). Among the five groups, normal group received 0.3% carboxymethyl cellulose (10ml/kg/day, p.o.). Hypertension control group received CdCl 2 (0.5mg/kg/day, i.p.). Tests and standard groups received MgT (3 and 6mg/kg/day, p.o.) and amlodipine (3mg/kg/day, p.o.) concurrently with CdCl 2 respectively , for six consecutive weeks. Blood pressure, heart rate, and eyes were examined biweekly, and pathophysiological parameters in serum and eye lenses were evaluated after six weeks of the experimental protocol. The chronic administration of MgT concurrently with CdCl 2 significantly restored the blood pressure, serum and lens antioxidants (CAT, SOD, GPx, and GSH), MDA level, and ions (Na + , K + , and Ca 2+ ). Additionally, MgT treatment led to significant increase in the lens proteins (total and soluble), Ca 2+ ATPase, and Na + K + ATPase activity as compared to hypertension control group. Ophthalmoscope observations indicated that MgT treatments delayed the progression of cataract against the hypertensive state. The study shows that MgT prevents the progression of cataractogenesis via restoration of blood pressure, lenticular oxidative damages, and lens ATPase functions in the hypertensive state. The results suggest that MgT supplement may play a beneficial role to manage hypertension and associated cataractogenesis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Decreased glutamate, glutamine and citrulline concentrations in plasma and muscle in endotoxemia cannot be reversed by glutamate or glutamine supplementation: a primary intestinal defect?

PubMed

Boutry, Claire; Matsumoto, Hideki; Bos, Cécile; Moinard, Christophe; Cynober, Luc; Yin, Yulong; Tomé, Daniel; Blachier, François

2012-10-01

Endotoxemia affects intestinal physiology. A decrease of circulating citrulline concentration is considered as a reflection of the intestinal function. Citrulline can be produced in enterocytes notably from glutamate and glutamine. The aim of this work was to determine if glutamate, glutamine and citrulline concentrations in blood, intestine and muscle are decreased by endotoxemia, and if supplementation with glutamate or glutamine can restore normal concentrations. We induced endotoxemia in rats by an intraperitoneal injection of 0.3 mg kg(-1) lipopolysaccharide (LPS). This led to a rapid anorexia, negative nitrogen balance and a transient increase of the circulating level of IL-6 and TNF-α. When compared with the values measured in pair fed (PF) animals, almost all circulating amino acids (AA) including citrulline decreased, suggesting a decrease of intestinal function. However, at D2 after LPS injection, most circulating AA concentrations were closed to the values recorded in the PF group. At that time, among AA, only glutamate, glutamine and citrulline were decreased in gastrocnemius muscle without change in intestinal mucosa. A supplementation with 4% monosodium glutamate (MSG) or an isomolar amount of glutamine failed to restore glutamate, glutamine and citrulline concentrations in plasma and muscle. However, MSG supplementation led to an accumulation of glutamate in the intestinal mucosa. In conclusion, endotoxemia rapidly but transiently decreased the circulating concentrations of almost all AA and more durably of glutamate, glutamine and citrulline in muscle. Supplementation with glutamate or glutamine failed to restore glutamate, glutamine and citrulline concentrations in plasma and muscles. The implication of a loss of the intestinal capacity for AA absorption and/or metabolism in endotoxemia (as judged from decreased citrulline plasma concentration) for explaining such results are discussed.

Spermidine promotes Bacillus subtilis biofilm formation by activating expression of the matrix regulator slrR.

PubMed

Hobley, Laura; Li, Bin; Wood, Jennifer L; Kim, Sok Ho; Naidoo, Jacinth; Ferreira, Ana Sofia; Khomutov, Maxim; Khomutov, Alexey; Stanley-Wall, Nicola R; Michael, Anthony J

2017-07-21

Ubiquitous polyamine spermidine is not required for normal planktonic growth of Bacillus subtilis but is essential for robust biofilm formation. However, the structural features of spermidine required for B. subtilis biofilm formation are unknown and so are the molecular mechanisms of spermidine-stimulated biofilm development. We report here that in a spermidine-deficient B. subtilis mutant, the structural analogue norspermidine, but not homospermidine, restored biofilm formation. Intracellular biosynthesis of another spermidine analogue, aminopropylcadaverine, from exogenously supplied homoagmatine also restored biofilm formation. The differential ability of C-methylated spermidine analogues to functionally replace spermidine in biofilm formation indicated that the aminopropyl moiety of spermidine is more sensitive to C -methylation, which it is essential for biofilm formation, but that the length and symmetry of the molecule is not critical. Transcriptomic analysis of a spermidine-depleted B. subtilis speD mutant uncovered a nitrogen-, methionine-, and S -adenosylmethionine-sufficiency response, resulting in repression of gene expression related to purine catabolism, methionine and S -adenosylmethionine biosynthesis and methionine salvage, and signs of altered membrane status. Consistent with the spermidine requirement in biofilm formation, single-cell analysis of this mutant indicated reduced expression of the operons for production of the exopolysaccharide and TasA protein biofilm matrix components and SinR antagonist slrR Deletion of sinR or ectopic expression of slrR in the spermidine-deficient Δ speD background restored biofilm formation, indicating that spermidine is required for expression of the biofilm regulator slrR Our results indicate that spermidine functions in biofilm development by activating transcription of the biofilm matrix exopolysaccharide and TasA operons through the regulator slrR . © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Ghrelin restoration of function in vitro in somatotropes from male mice lacking the Janus kinase (JAK)-binding site of the leptin receptor.

PubMed

Syed, Mohsin; Cozart, Michael; Haney, Anessa C; Akhter, Noor; Odle, Angela K; Allensworth-James, Melody; Crane, Christopher; Syed, Farhan M; Childs, Gwen V

2013-04-01

Deletion of the signaling domain of leptin receptors selectively in somatotropes, with Cre-loxP technology, reduced the percentage of immunolabeled GH cells and serum GH. We hypothesized that the deficit occurred when leptin's postnatal surge failed to stimulate an expansion in the cell population. To learn more about the deficiency in GH cells, we tested their expression of GHRH receptors and GH mRNA and the restorative potential of secretagogue stimulation in vitro. In freshly plated dissociated pituitary cells from control male mice, GHRH alone (0.3 nM) increased the percentage of immunolabeled GH cells from 27 ± 0.05% (vehicle) to 42 ± 1.8% (P < .002) and the secretion of GH 1.8-3×. Deletion mutant pituitary cells showed a 40% reduction in percentages of immunolabeled GH cells (16.7 ± 0.4%), which correlated with a 47% reduction in basal GH levels (50 ng/mL control; 26.7 ng/mL mutants P = .01). A 50% reduction in the percentage of mutant cells expressing GHRH receptors (to 12%) correlated with no or reduced responses to GHRH. Ghrelin alone (10 nM) stimulated more GH cells in mutants (from 16.7-23%). When added with 1-3 nM GHRH, ghrelin restored GH cell percentages and GH secretion to levels similar to those of stimulated controls. Counts of somatotropes labeled for GH mRNA confirmed normal percentages of somatotropes in the population. These discoveries suggest that leptin may optimize somatotrope function by facilitating expression of membrane GHRH receptors and the production or maintenance of GH stores.

Directing clinical care using lower extremity biomechanics in patients with ankle osteoarthritis and ankle arthroplasty.

PubMed

Queen, Robin

2017-11-01

Ankle osteoarthritis is a debilitating disease with approximately 50,000 new cases per year leading to skeletal deformity, severe and recurrent pain, cartilage breakdown, and gait dysfunction limiting patient mobility and well-being. Although many treatments (total ankle arthroplasty [TAA], ankle fusion [arthrodesis], and ankle distraction arthroplasty) relieve pain, it is not clear that these procedures significantly improve patient mobility. The goal of the research presented here is to summarize what is presently known about lower extremity gait mechanics and outcomes and to quantify the impact of ankle osteoarthritis and TAA have on these measures using an explicitly holistic and mechanistic approach. Our recent studies have explored physical performance and energy recovery and revealed unexpected patterns and sequelae to treatment including incomplete restoration of gait function. These studies demonstrated for the first time the extreme levels and range of gait and balance dysfunction present in ankle osteoarthritis patients as well as quantifying the ways in which the affected joint alters movement and loading patterns not just in the painful joint, but throughout both the ipsilateral and contralateral lower extremity. Through this work, we determined that relieving pain alone through TAA is not enough to restore normal walking mechanics and balance due to underlying causes including limited ankle range of motion and balance deficits leading to long-term disability despite treatment. The results indicate the need to consider additional therapeutic interventions aimed at restoring balance, ankle range of motion, and movement symmetry in order to improve long-term health and function. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2345-2355, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Cell painting with an engineered EPCR to augment the protein C system

PubMed Central

Bouwens, Eveline A. M.; Stavenuiter, Fabian; Mosnier, Laurent O.

2016-01-01

The protein C (PC) system conveys beneficial anticoagulant and cytoprotective effects in numerous in vivo disease models. The endothelial protein C receptor (EPCR) plays a central role in these pathways as cofactor for PC activation and by enhancing activated protein C (APC)-mediated protease-activated receptor (PAR) activation. During inflammatory disease, expression of EPCR on cell membranes is often diminished thereby limiting PC activation and APC’s effects on cells. Here a caveolae-targeting glycosylphosphatidylinositol (GPI)-anchored EPCR (EPCR-GPI) was engineered to restore EPCR’s bioavailability via “cell painting.” The painting efficiency of EPCR-GPI on EPCR-depleted endothelial cells was time- and dose-dependent. The EPCR-GPI bioavailability after painting was long lasting since EPCR surface levels reached 400% of wild-type cells after 2 hours and remained >200% for 24 hours. EPCR-GPI painting conveyed APC binding to EPCR-depleted endothelial cells where EPCR was lost due to shedding or shRNA. EPCR painting normalized PC activation on EPCR-depleted cells indicating that EPCR-GPI is functional active on painted cells. Caveolin-1 lipid rafts were enriched in EPCR after painting due to the GPI-anchor targeting caveolae. Accordingly, EPCR painting supported PAR1 and PAR3 cleavage by APC and augmented PAR1-dependent Akt phosphorylation by APC. Thus, EPCR-GPI painting achieved physiological relevant surface levels on endothelial cells, restored APC binding to EPCR-depleted cells, supported PC activation, and enhanced APC-mediated PAR cleavage and cytoprotective signaling. Therefore, EPCR-GPI provides a novel tool to restore the bioavailability and functionality of EPCR on EPCR-depleted and deficient cells. PMID:26272345

Reinventing the Wheel: Teaching Restoration Ecology without the Ecology

ERIC Educational Resources Information Center

Speldewinde, Peter

2010-01-01

Restoration ecology is "the process of assisting the recovery of an ecosystem that has been degraded, damaged or destroyed." Restoration can range from returning the system to its "natural" state through to restoring some ecological functionality to a system. The University of Western Australia offers an undergraduate degree in…

Ecosystem Restoration: Fact or Fancy?

Treesearch

John A. Stanturf; Callie J. Schweitzer; Stephen H. Schoenholtz; James P. Barnett; Charles K. McMahon; Donald J. Tomszak

1998-01-01

Ecological restoration is generally accepted as the reestablishment of natural ecological processes that produce certain dynamic ecosystem properties of structure, function, and processes. But restore to what? The most frequently used conceptual model for the restoration process is the shift of conditions from some current (degraded) dynamic state to some past dynamic...

Adaptive wiener image restoration kernel

DOEpatents

Yuan, Ding [Henderson, NV

2007-06-05

A method and device for restoration of electro-optical image data using an adaptive Wiener filter begins with constructing imaging system Optical Transfer Function, and the Fourier Transformations of the noise and the image. A spatial representation of the imaged object is restored by spatial convolution of the image using a Wiener restoration kernel.

CRISPR-mediated genotypic and phenotypic correction of a chronic granulomatous disease mutation in human iPS cells.

PubMed

Flynn, Rowan; Grundmann, Alexander; Renz, Peter; Hänseler, Walther; James, William S; Cowley, Sally A; Moore, Michael D

2015-10-01

Chronic granulomatous disease (CGD) is a rare genetic disease characterized by severe and persistent childhood infections. It is caused by the lack of an antipathogen oxidative burst, normally performed by phagocytic cells to contain and clear bacterial and fungal growth. Restoration of immune function can be achieved with heterologous bone marrow transplantation; however, autologous bone marrow transplantation would be a preferable option. Thus, a method is required to recapitulate the function of the diseased gene within the patient's own cells. Gene therapy approaches for CGD have employed randomly integrating viruses with concomitant issues of insertional mutagenesis, inaccurate gene dosage, and gene silencing. Here, we explore the potential of the recently described clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 site-specific nuclease system to encourage repair of the endogenous gene by enhancing the levels of homologous recombination. Using induced pluripotent stem cells derived from a CGD patient containing a single intronic mutation in the CYBB gene, we show that footprintless gene editing is a viable option to correct disease mutations. Gene correction results in restoration of oxidative burst function in iPS-derived phagocytes by reintroduction of a previously skipped exon in the cytochrome b-245 heavy chain (CYBB) protein. This study provides proof-of-principle for a gene therapy approach to CGD treatment using CRISPR-Cas9. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Quantifying the "So what?" of Restoration: A Framework for Evaluating the Ecological and Socio-economic Outcomes of Restoration Activities in the Gulf of Mexico

NASA Astrophysics Data System (ADS)

Henkel, J. R.; Dausman, A.; Cowan, J.; Sutter, B.

2017-12-01

Healthy and sustainable ecosystems are essential for thriving and resilient coastal communities. As a result of settlements following the Deepwater Horizon oil spill, the Gulf Coast Ecosystem Restoration Council (Council) and other funding entities, will receive billions of dollars over the next 15 years for restoration projects and programs. These and future restoration efforts present an opportunity to improve the function of coastal wetlands in the Gulf of Mexico, and potentially address long-standing barriers to ecosystem health and resilience in the region. In its Comprehensive Plans, the Council has committed to science-based decision-making, collaboration among its eleven state and federal members, and close coordination with other Gulf restoration and conservation funding efforts including NRDA, NFWF and other federal programs to leverage resources and integrate complementary restoration efforts. To help fulfill these commitments the Council is exploring methods and tools to collect and assess data to evaluate and report on both ecological and socio-economic outcomes of restoration projects. Application of these tools in coordination with restoration partners, will demonstrate the cascading benefits of ecosystem restoration in a quantifiable way, and can help decision-makers increase investments in ecosystem restoration that will support the long-term sustainability of coastal systems. An understanding of ecosystem function and services can also provide a transparent lens for communicating the results of successful ecosystem restoration projects to the public (helping answer the "So what?" of ecosystem restoration). As the Council moves forward making decisions based on the best available science, improving ecosystem functioning and services will play a role in project and program selection and will result in more resilient ecosystems. This will enable the Council to help communities enhance their ability to recover from natural and manmade disasters and thrive in the face of changing environmental conditions.

Sialorphin (the mature peptide product of Vcsa1) relaxes corporal smooth muscle tissue and increases erectile function in the ageing rat

PubMed Central

Davies, Kelvin P.; Tar, Moses; Rougeot, Catherine; Melman, Arnold

2007-01-01

OBJECTIVE To determine if the mature peptide product of the Vcsa1 gene, sialorphin, could restore erectile function in ageing rats, and whether these effects are mediated through relaxation of corporal smooth muscle tissue, as we recently reported that Vcsa1 is one of the most down-regulated genes in the corpora of rats in three distinct models of erectile dysfunction, and gene transfer of plasmids expressing Vcsa1 into the corpora of ageing rats restored erectile function. MATERIALS AND METHODS Sialorphin was injected intracorporeally into retired breeder rats, and the effect on the physiology of corporal tissue was analysed by intracorporal/blood pressure (ICP/BP) measurement at different times after injection. In organ-bath studies, the ability of sialorphin (1 μg/mL) to enhance C-type natriuretic peptide (CNP) relaxation of corporal smooth muscle tissue strips was investigated after pre-contraction with 1 μM phenylephrine. RESULTS Intracorporal injection of 100 μg sialorphin into retired breeder rats resulted in a time-dependent increase in the ICP/BP response to electrostimulation of the cavernosal nerve. After 55–65 min the ICP/BP ratio increased to ≈ 0.6, a value associated with normal erectile function. In organ-bath studies after pre-contraction with 1 μM phenylephrine, 1 μM CNP significantly (67%) increased the relaxation rate of corporal tissue. This rate of relaxation was increased by 2.5-fold after incubation with sialorphin (1 μg/mL) compared with carrier alone. CONCLUSION These results show that sialorphin has a role in erectile function, probably through a mechanism that involves relaxation of corporal smooth muscle tissue. PMID:17026587