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Sample records for adverse tissue response

  1. Adverse local tissue response lesion of the knee associated with Morse taper corrosion.

    PubMed

    McMaster, William C; Patel, Jay

    2013-02-01

    Modularity in arthroplasty components has increased options for solving complex issues in primary and revision procedures. However, this technology introduces the risk of accelerated metal ion release as a result of fretting or passive crevice corrosion within the Morse taper junction. Cobalt toxicity locally and systemically has been described with hip metal bearing surfaces and may be accentuated with ion release from Morse tapers. This is a case report of a knee adverse local tissue response lesion associated with corrosion within the Morse taper of a revision knee arthroplasty in the absence of systemic metal allergy.

  2. Adverse reactions to injectable soft tissue fillers.

    PubMed

    Requena, Luis; Requena, Celia; Christensen, Lise; Zimmermann, Ute S; Kutzner, Heinz; Cerroni, Lorenzo

    2011-01-01

    In recent years, injections with filler agents are often used for wrinkle-treatment and soft tissue augmentation by dermatologists and plastic surgeons. Unfortunately, the ideal filler has not yet been discovered and all of them may induce adverse reactions. Quickly biodegradable or resorbable agents may induce severe complications, but they will normally disappear spontaneously in a few months. Slowly biodegradable or nonresorbable fillers may give rise to severe reactions that show little or no tendency to spontaneous improvement. They may appear several years after the injection, when the patient does not remember which product was injected, and treatment is often insufficient. In this review, we discuss the most commonly used fillers, their most frequent adverse reactions as well as the characteristic histopathologic findings that allow the identification of the injected filler agent. In conclusion, histopathologic study remains as the gold standard technique to identify the responsible filler.

  3. Adverse event reporting and developments in radiation biology after normal tissue injury: International Atomic Energy Agency consultation

    SciTech Connect

    Chen Yuhchyau . E-mail: Yuhchyau_chen@urmc.rochester.edu; Trotti, Andy; Coleman, C. Norman; Machtay, Mitchell; Mirimanoff, Rene O.; Hay, John; O'Brien, Peter C.; El-Gueddari, Brahim; Salvajoli, Joao V.; Jeremic, Branislav

    2006-04-01

    Purpose: Recent research has enhanced our understanding of radiation injury at the molecular-cellular and tissue levels; significant strides have occurred in standardization of adverse event reporting in clinical trials. In response, the International Atomic Energy Agency, through its Division of Human Health and its section for Applied Radiation Biology and Radiotherapy, organized a consultation meeting in Atlanta (October 2, 2004) to discuss developments in radiobiology, normal tissue reactions, and adverse event reporting. Methods and Materials: Representatives from cooperative groups of African Radiation Oncology Group, Curriculo Radioterapeutica Ibero Latino Americana, European Organization for Research and Treatment of Cancer, National Cancer Institute of Canada Clinical Trials Group, Radiation Therapy Oncology Group, and Trans-Tasman Radiation Oncology Group held the meeting discussion. Results: Representatives of major radiotherapy groups/organizations and prominent leaders in radiotherapy discussed current understanding of normal tissue radiobiologic effects, the design and implementation of future clinical and translational projects for normal tissue injury, and the standardization of adverse-event reporting worldwide. Conclusions: The consensus was to adopt NCI comprehensive adverse event reporting terminology and grading system (CTCAE v3.0) as the new standard for all cooperative group trials. Future plans included the implementation of coordinated research projects focusing on normal tissue biomarkers and data collection methods.

  4. Adverse environmental conditions influence age-related innate immune responsiveness

    PubMed Central

    May, Linda; van den Biggelaar, Anita HJ; van Bodegom, David; Meij, Hans J; de Craen, Anton JM; Amankwa, Joseph; Frölich, Marijke; Kuningas, Maris; Westendorp, Rudi GJ

    2009-01-01

    Background- The innate immune system plays an important role in the recognition and induction of protective responses against infectious pathogens, whilst there is increasing evidence for a role in mediating chronic inflammatory diseases at older age. Despite indications that environmental conditions can influence the senescence process of the adaptive immune system, it is not known whether the same holds true for the innate immune system. Therefore we studied whether age-related innate immune responses are similar or differ between populations living under very diverse environmental conditions. Methods- We compared cross-sectional age-related changes in ex vivo innate cytokine responses in a population living under affluent conditions in the Netherlands (age 20–68 years old, n = 304) and a population living under adverse environmental conditions in Ghana (age 23–95 years old, n = 562). Results- We found a significant decrease in LPS-induced Interleukin (IL)-10 and Tumor Necrosis Factor (TNF) production with age in the Dutch population. In Ghana a similar age-related decline in IL-10 responses to LPS, as well as to zymosan, or LPS plus zymosan, was observed. TNF production, however, did not show an age-associated decline, but increased significantly with age in response to co-stimulation with LPS and zymosan. Conclusion- We conclude that the decline in innate cytokine responses is an intrinsic ageing phenomenon, while pathogen exposure and/or selective survival drive pro-inflammatory responses under adverse living conditions. PMID:19480711

  5. Tissue response: biomaterials, dental implants, and compromised osseous tissue.

    PubMed

    Babu RS, Arvind; Ogle, Orrett

    2015-04-01

    Tissue response represents an important feature in biocompatibility in implant procedures. This review article highlights the fundamental characteristics of tissue response after the implant procedure. This article also highlights the tissue response in compromised osseous conditions. Understanding the histologic events after dental implants in normal and abnormal bone reinforces the concept of case selection in dental implants.

  6. Tissue Expander Placement to Prevent the Adverse Intestinal Effects of Radiotherapy in Malignant Pelvic Tumors.

    PubMed

    Uehara, Shuichiro; Oue, Takaharu; Adachi, Kana; Yoshioka, Yasuo; Nakahata, Kengo; Ueno, Takehisa; Okuyama, Hiroomi

    2016-03-01

    We herein report the findings of 3 patients with primary Ewing sarcoma in a pelvic lesion who underwent the placement of a tissue expander (TE) before radiation therapy to prevent the adverse effects of radiotherapy. The simulation study showed that the TE drastically reduced volume of the intestine that was irradiated at all dose levels. All patients could receive the scheduled dose of radiotherapy without any acute and late complications such as diarrhea, melena, the dislodging of the TE, infection, or the formation of fistulae. In the 4-year (minimum) observation period, we did not observe intestinal complications in any of our patients. TE placement is considered to be a safe and effective method for preventing the adverse effects of radiotherapy in pediatric malignant pelvic tumors.

  7. Diagnosis and Treatment of Adverse Local Tissue Reactions at the Head-Neck Junction.

    PubMed

    Cooper, Herbert J

    2016-07-01

    Modular junctions in total hip arthroplasty are susceptible to mechanically assisted crevice corrosion, leading to the release of metal wear debris. Adverse local tissue reactions result from an immune-mediated biological reaction to this debris and can have a profound effect on the surrounding periarticular soft tissue envelope. Patients often present with pain or muscle weakness and demonstrate elevated serum cobalt and chromium levels. Serum inflammatory markers and synovial fluid tests help distinguish these reactions from deep infection in the majority of cases; however, the presence of amorphous material or fragmented cells can lead to difficulty in some cases. Advanced cross-sectional imaging is essential in establishing the diagnosis. Early revision surgery is generally the treatment of choice for symptomatic adverse local tissue reaction from corrosion at the modular head-neck junction. The existing stem is retained, and a new ceramic head is placed on the existing trunnion whenever possible. This strategy generally leads to short-term improvement of symptoms with reliable clinical outcomes; however, longer term results are presently lacking.

  8. Late-onset inflammatory adverse reactions related to soft tissue filler injections.

    PubMed

    Alijotas-Reig, Jaume; Fernández-Figueras, Maria Teresa; Puig, Lluís

    2013-08-01

    An ever-increasing number of persons seek medical solutions to improve the appearance of their aging skin or for aesthetic and cosmetic indications in diverse pathological conditions, such as malformations, trauma, cancer, and orthopedic, urological, or ophthalmological conditions. Currently, physicians have many different types of dermal and subdermal fillers, such as non-permanent, permanent, reversible, or non-reversible materials. Despite the claims of manufacturers and different authors that fillers are non-toxic and non-immunogenic or that complications are very uncommon, unwanted side effects do occur with all compounds used. Implanted, injected, and blood-contact biomaterials trigger a wide variety of adverse reactions, including inflammation, thrombosis, and excessive fibrosis. Usually, these adverse reactions are associated with the accumulation of large numbers of mononuclear cells. The adverse reactions related to fillers comprise a broad range of manifestations, which may appear early or late and range from local to systemic. Clinicians should be aware of them since the patient often denies the antecedent of injection or is unaware of the material employed. Most of these adverse effects seem to have an immunological basis, the fillers acting more as adjuvants than as direct T-cell activators, on a background of genetic predisposition. Their treatment has not been the subject of well-designed studies; management of both acute and systemic reactions is often difficult, and requires anti-inflammatory and occasionally immunosuppressive therapy. The clinical, pathological, and therapeutic aspects of inflammatory and immune-mediated late-onset adverse reactions related to soft tissue filler injections are thoroughly reviewed herein.

  9. Social Involvement Modulates the Response to Novel and Adverse Life Events in Mice

    PubMed Central

    Colnaghi, Luca; Clemenza, Kelly; Groleau, Sarah E.; Weiss, Shira; Snyder, Anna M.; Lopez-Rosas, Mariana; Levine, Amir A.

    2016-01-01

    Epidemiological findings suggest that social involvement plays a major role in establishing resilience to adversity, however, the neurobiology by which social involvement confers protection is not well understood. Hypothesizing that social involvement confers resilience by changing the way adverse life events are encoded, we designed a series of behavioral tests in mice that utilize the presence or absence of conspecific cage mates in measuring response to novel and adverse events. We found that the presence of cage mates increased movement after exposure to a novel environment, increased time spent in the open arms of the elevated plus maze, and decreased freezing time after a foot shock as well as expedited fear extinction, therefore significantly changing the response to adversity. This is a first description of a mouse model for the effects of social involvement on adverse life events. Understanding how social involvement provides resilience to adversity may contribute to the future treatment and prevention of mental and physical illness. PMID:27632422

  10. Social Involvement Modulates the Response to Novel and Adverse Life Events in Mice.

    PubMed

    Colnaghi, Luca; Clemenza, Kelly; Groleau, Sarah E; Weiss, Shira; Snyder, Anna M; Lopez-Rosas, Mariana; Levine, Amir A

    2016-01-01

    Epidemiological findings suggest that social involvement plays a major role in establishing resilience to adversity, however, the neurobiology by which social involvement confers protection is not well understood. Hypothesizing that social involvement confers resilience by changing the way adverse life events are encoded, we designed a series of behavioral tests in mice that utilize the presence or absence of conspecific cage mates in measuring response to novel and adverse events. We found that the presence of cage mates increased movement after exposure to a novel environment, increased time spent in the open arms of the elevated plus maze, and decreased freezing time after a foot shock as well as expedited fear extinction, therefore significantly changing the response to adversity. This is a first description of a mouse model for the effects of social involvement on adverse life events. Understanding how social involvement provides resilience to adversity may contribute to the future treatment and prevention of mental and physical illness. PMID:27632422

  11. Implant based differences in adverse local tissue reaction in failed total hip arthroplasties: a morphological and immunohistochemical study

    PubMed Central

    2014-01-01

    Background Adverse local tissue reaction (ALTR) is characterized by periprosthetic soft tissue inflammation composed of a mixed inflammatory cell infiltrate, extensive soft tissue necrosis, and vascular changes. Multiple hip implant classes have been reported to result in ALTR, and clinical differences may represent variation in the soft tissue response at the cellular and tissue levels. The purpose of this study was to describe similarities and differences in periprosthetic tissue structure, organization, and cellular composition by conventional histology and immunohistochemistry in ALTR resulting from two common total hip arthroplasty (THA) implant classes. Methods Consecutive patients presenting with ALTR from two major hip implant classes (N = 54 patients with Dual-Modular Neck implant; N = 14 patients with Metal-on-Metal implant) were identified from our prospective Osteolysis Tissue Database and Repository. Clinical characteristics including age, sex, BMI, length of implantation, and serum metal ion levels were recorded. Retrieved synovial tissue morphology was graded using light microscopy and cellular composition was assessed using immunohistochemistry. Results Length of implantation was shorter in the DMN group versus MoM THA group (21.3 [8.4] months versus 43.6 [13.8] months respectively; p < 0.005) suggesting differences in implant performance. Morphologic examination revealed a common spectrum of neo-synovial proliferation and necrosis in both groups. Macrophages were more commonly present in diffuse sheets (Grade 3) in the MoM relative to DMN group (p = 0.016). Perivascular lymphocytes with germinal centers (Grade 4) were more common in the DMN group, which trended towards significance (p = 0.066). Qualitative differences in corrosion product morphology were seen between the two groups. Immunohistochemistry showed features of a CD4 and GATA-3 rich lymphocyte reaction in both implants, with increased ratios of perivascular T

  12. Ingestion of gallium phosphide nanowires has no adverse effect on Drosophila tissue function.

    PubMed

    Adolfsson, Karl; Schneider, Martina; Hammarin, Greger; Häcker, Udo; Prinz, Christelle N

    2013-07-19

    Engineered nanoparticles have been under increasing scrutiny in recent years. High aspect ratio nanoparticles such as carbon nanotubes and nanowires have raised safety concerns due to their geometrical similarity to asbestos fibers. III-V epitaxial semiconductor nanowires are expected to be utilized in devices such as LEDs and solar cells and will thus be available to the public. In addition, clean-room staff fabricating and characterizing the nanowires are at risk of exposure, emphasizing the importance of investigating their possible toxicity. Here we investigated the effects of gallium phosphide nanowires on the fruit fly Drosophila melanogaster. Drosophila larvae and/or adults were exposed to gallium phosphide nanowires by ingestion with food. The toxicity and tissue interaction of the nanowires was evaluated by investigating tissue distribution, activation of immune response, genome-wide gene expression, life span, fecundity and somatic mutation rates. Our results show that gallium phosphide nanowires applied through the diet are not taken up into Drosophila tissues, do not elicit a measurable immune response or changes in genome-wide gene expression and do not significantly affect life span or somatic mutation rate. PMID:23787695

  13. Ingestion of gallium phosphide nanowires has no adverse effect on Drosophila tissue function.

    PubMed

    Adolfsson, Karl; Schneider, Martina; Hammarin, Greger; Häcker, Udo; Prinz, Christelle N

    2013-07-19

    Engineered nanoparticles have been under increasing scrutiny in recent years. High aspect ratio nanoparticles such as carbon nanotubes and nanowires have raised safety concerns due to their geometrical similarity to asbestos fibers. III-V epitaxial semiconductor nanowires are expected to be utilized in devices such as LEDs and solar cells and will thus be available to the public. In addition, clean-room staff fabricating and characterizing the nanowires are at risk of exposure, emphasizing the importance of investigating their possible toxicity. Here we investigated the effects of gallium phosphide nanowires on the fruit fly Drosophila melanogaster. Drosophila larvae and/or adults were exposed to gallium phosphide nanowires by ingestion with food. The toxicity and tissue interaction of the nanowires was evaluated by investigating tissue distribution, activation of immune response, genome-wide gene expression, life span, fecundity and somatic mutation rates. Our results show that gallium phosphide nanowires applied through the diet are not taken up into Drosophila tissues, do not elicit a measurable immune response or changes in genome-wide gene expression and do not significantly affect life span or somatic mutation rate.

  14. Ingestion of gallium phosphide nanowires has no adverse effect on Drosophila tissue function

    NASA Astrophysics Data System (ADS)

    Adolfsson, Karl; Schneider, Martina; Hammarin, Greger; Häcker, Udo; Prinz, Christelle N.

    2013-07-01

    Engineered nanoparticles have been under increasing scrutiny in recent years. High aspect ratio nanoparticles such as carbon nanotubes and nanowires have raised safety concerns due to their geometrical similarity to asbestos fibers. III-V epitaxial semiconductor nanowires are expected to be utilized in devices such as LEDs and solar cells and will thus be available to the public. In addition, clean-room staff fabricating and characterizing the nanowires are at risk of exposure, emphasizing the importance of investigating their possible toxicity. Here we investigated the effects of gallium phosphide nanowires on the fruit fly Drosophila melanogaster. Drosophila larvae and/or adults were exposed to gallium phosphide nanowires by ingestion with food. The toxicity and tissue interaction of the nanowires was evaluated by investigating tissue distribution, activation of immune response, genome-wide gene expression, life span, fecundity and somatic mutation rates. Our results show that gallium phosphide nanowires applied through the diet are not taken up into Drosophila tissues, do not elicit a measurable immune response or changes in genome-wide gene expression and do not significantly affect life span or somatic mutation rate.

  15. Tissue response to peritoneal implants

    NASA Technical Reports Server (NTRS)

    Picha, G. J.

    1980-01-01

    Peritoneal implants were fabricated from poly 2-OH, ethyl methacrylate (HEMA), polyetherurethane (polytetramethylene glycol 1000 MW, 1,4 methylene disocynate, and ethyl diamine), and untreated and sputter treated polytetrafluoroethylene (PTFE). The sputter treated PTFE implants were produced by an 8 cm diameter argon ion source. The treated samples consisted of ion beam sputter polished samples, sputter etched samples (to produce a microscopic surface cone texture) and surface pitted samples (produced by ion beam sputtering to result in 50 microns wide by 100 microns deep square pits). These materials were implanted in rats for periods ranging from 30 minutes to 14 days. The results were evaluated with regard to cell type and attachment kinetics onto the different materials. Scanning electron microscopy and histological sections were also evaluated. In general the smooth hydrophobic surfaces attracted less cells than the ion etched PTFE or the HEMA samples. The ion etching was observed to enhance cell attachment, multinucleated giant cell (MNGC) formation, cell to cell contact, and fibrous capsule formation. The cell responsed in the case of ion etched PTFE to an altered surface morphology. However, equally interesting was the similar attachment kinetics of HEMA verses the ion etched PTFE. However, HEMA resulted in a markedly different response with no MNGC's formation, minimal to no capsule formation, and sample coverage by a uniform cell layer.

  16. Adverse Events in Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

    PubMed Central

    Rhee, Rennie L.; Gabler, Nicole B.; Praestgaard, Amy; Merkel, Peter A.; Kawut, Steven M.

    2016-01-01

    Objective Patients with connective tissue disease (CTD)–associated pulmonary arterial hypertension (PAH) have a poorer prognosis compared to those with idiopathic PAH, but little is known about the differences in treatment-related adverse events (AEs) and serious adverse events (SAEs) between these groups. This study was undertaken to characterize these differences. Methods Individual patient-level data from 10 randomized controlled trials of therapies for PAH were obtained from the US Food and Drug Administration. Patients diagnosed as having either CTD-associated PAH or idiopathic PAH were included. A treatment-by-diagnosis interaction term was used to examine whether the effect of treatment on occurrence of AEs differed between patients with CTD-associated PAH and those with idiopathic PAH. Studies were pooled using fixed-effect models. Results The study sample included 2,370 participants: 716 with CTD-associated PAH and 1,654 with idiopathic PAH. In the active treatment group compared to the placebo group, the risk of AEs was higher among patients with CTD-associated PAH than among those with idiopathic PAH (odds ratio [OR] 1.57, 95% confidence interval [95% CI] 1.00–2.47 versus OR 0.94, 95% CI 0.69–1.26; P for interaction = 0.061), but there was no difference in the risk of SAEs in analyses adjusted for age, race, sex, hemodynamic findings, and laboratory values. Despite the higher occurrence of AEs in patients with CTD-associated PAH assigned to active therapy compared to those receiving placebo, the risk of drug discontinuation due to an AE was similar to that in patients with idiopathic PAH assigned to active therapy (P for interaction = 0.27). Conclusion Patients with CTD-associated PAH experienced more treatment-related AEs compared to those with idiopathic PAH in therapeutic clinical trials. These findings suggest that the overall benefit of advanced therapies for PAH may be attenuated by the greater frequency of AEs. PMID:26016953

  17. Cumulative Adversity Sensitizes Neural Response to Acute Stress: Association with Health Symptoms

    PubMed Central

    Seo, Dongju; Tsou, Kristen A; Ansell, Emily B; Potenza, Marc N; Sinha, Rajita

    2014-01-01

    Cumulative adversity (CA) increases stress sensitivity and risk of adverse health outcomes. However, neural mechanisms underlying these associations in humans remain unclear. To understand neural responses underlying the link between CA and adverse health symptoms, the current study assessed brain activity during stress and neutral-relaxing states in 75 demographically matched, healthy individuals with high, mid, and low CA (25 in each group), and their health symptoms using the Cornell Medical Index. CA was significantly associated with greater adverse health symptoms (P=0.01) in all participants. Functional magnetic resonance imaging results indicated significant associations between CA scores and increased stress-induced activity in the lateral prefrontal cortex, insula, striatum, right amygdala, hippocampus, and temporal regions in all 75 participants (p<0.05, whole-brain corrected). In addition to these regions, the high vs low CA group comparison revealed decreased stress-induced activity in the medial orbitofrontal cortex (OFC) in the high CA group (p<0.01, whole-brain corrected). Specifically, hypoactive medial OFC and hyperactive right hippocampus responses to stress were each significantly associated with greater adverse health symptoms (p<0.01). Furthermore, an inverse correlation was found between activity in the medial OFC and right hippocampus (p=0.01). These results indicate that high CA sensitizes limbic–striatal responses to acute stress and also identifies an important role for stress-related medial OFC and hippocampus responses in the effects of CA on increasing vulnerability to adverse health consequences. PMID:24051900

  18. Adverse tissue reaction to corrosion at the neck-stem junction after modular primary total hip arthroplasty.

    PubMed

    Gkagkalis, G; Mettraux, P; Omoumi, P; Mischler, S; Rüdiger, H A

    2015-02-01

    Complications related to the neck-stem junction of modular stems used for total hip arthroplasty (THA) are generating increasing concern. A 74-year-old male had increasing pain and a cutaneous reaction around the scar 1 year after THA with a modular neck-stem. Imaging revealed osteolysis of the calcar and a pseudo-tumour adjacent to the neck-stem junction. Serum cobalt levels were elevated. Revision surgery to exchange the stem and liner and to resect the pseudo-tumour was performed. Analysis of the stem by scanning electron microscopy and by energy dispersive X-ray and white light interferometry showed fretting corrosion at the neck-stem junction contrasting with minimal changes at the head-neck junction. Thus, despite dry assembly of the neck and stem on the back table at primary THA, full neck-stem contact was not achieved, and the resulting micromotion at the interface led to fretting corrosion. This case highlights the mechanism of fretting corrosion at the neck-stem interface responsible for adverse local tissue reactions. Clinical and radiological follow-up is mandatory in patients with dual-modular stems.

  19. Baby on board: do responses to stress in the maternal brain mediate adverse pregnancy outcome?

    PubMed

    Douglas, Alison J

    2010-07-01

    Stress and adverse environmental surroundings result in suboptimal conditions in a pregnant mother such that she may experience poor pregnancy outcome including complete pregnancy failure and preterm labor. Furthermore her developing baby is at risk of adverse programming, which confers susceptibility to long term ill health. While some mechanisms at the feto-maternal interface underlying these conditions are understood, the underlying cause for their adverse adaptation is often not clear. Progesterone plays a key role at many levels, including control of neuroendocrine responses to stress, procuring the required immune balance and controlling placental and decidual function, and lack of progesterone can explain many of the unwanted consequences of stress. How stress that is perceived by the mother inhibits progesterone secretion and action is beginning to be investigated. This overview of maternal neuroendocrine responses to stress throughout pregnancy analyses how they interact to compromise progesterone secretion and precipitate undesirable effects in mother and offspring.

  20. Determining adaptive and adverse oxidative stress responses in human bronical epithelial cells exposed to zinc

    EPA Science Inventory

    Determining adaptive and adverse oxidative stress responses in human bronchial epithelial cells exposed to zincJenna M. Currier1,2, Wan-Yun Cheng1, Rory Conolly1, Brian N. Chorley1Zinc is a ubiquitous contaminant of ambient air that presents an oxidant challenge to the human lung...

  1. Cobalt to Chromium Ratio is Not a Key Marker for Adverse Local Tissue Reaction (ALTR) in Metal on Metal Hips.

    PubMed

    Fehring, Thomas K; Carter, Joshua L; Fehring, Keith A; Odum, Susan M; Griffin, William L

    2015-09-01

    The diagnosis of adverse local tissue reaction (ALTR) after metal-on-metal total hip arthroplasty (MoMTHA) presents a significant challenge. No single biomarker is specific for ALTR. The purpose of this study was to determine if the ratio of cobalt to chromium ions is useful for diagnosing ALTR in MoMTHA. In 89 bearing-related revision THAs, preoperative cobalt and chromium ion levels were compared to an intraoperative soft tissue damage grading scale. The average cobalt to chromium ratio was 2.96 (0-20). There was no correlation between the tissue scale and the cobalt to chromium ratio (R=0.095; P=0.41). Many variables affecting ion production/excretion mitigate the use of the ion ratio. The cobalt to chromium ratio is not a predictive biomarker for ALTR in MoMTHA.

  2. Adverse local tissue reactions in metal-on-polyethylene total hip arthroplasty due to trunnion corrosion: the risk of misdiagnosis.

    PubMed

    Whitehouse, M R; Endo, M; Zachara, S; Nielsen, T O; Greidanus, N V; Masri, B A; Garbuz, D S; Duncan, C P

    2015-08-01

    Adverse reaction to wear and corrosion debris is a cause for concern in total hip arthroplasty (THA). Modular junctions are a potential source of such wear products and are associated with secondary pseudotumour formation. We present a consecutive series of 17 patients treated at our unit for this complication following metal-on-highly cross-linked polyethylene (MoP) THA. We emphasise the risk of misdiagnosis as infection, and present the aggregate laboratory results and pathological findings in this series. The clinical presentation was pain, swelling or instability. Solid, cystic and mixed soft-tissue lesions were noted on imaging and confirmed intra-operatively. Corrosion at the head-neck junction was noted in all cases. No bacteria were isolated on multiple pre- and intra-operative samples yet the mean erythrocyte sedimentation rate was 49 (9 to 100) and C-reactive protein 32 (0.6 to 106) and stromal polymorphonuclear cell counts were noted in nine cases. Adverse soft-tissue reactions can occur in MoP THA owing to corrosion products released from the head-neck junction. The diagnosis should be carefully considered when investigating pain after THA. This may avoid the misdiagnosis of periprosthetic infection with an unidentified organism and mitigate the unnecessary management of these cases with complete single- or two-stage exchange.

  3. Assessment on the adverse effects of Aminoglycosides and Flouroquinolone on sperm parameters and male reproductive tissue: A systematic review

    PubMed Central

    Khaki, Arash

    2015-01-01

    Background: Antibiotic therapies used in treatment of many diseases have adverse effects on fertility. This review analyzes previous comparative studies that surveyed the effects of two common groups of antibiotics on male fertility. Objective: To evaluate histo-pathological effects of fluoroquinolones and aminoglycosides on sperm parameters and male reproductive tissue. Materials and Methods: Articles about the effects of aminoglycosides and fluoroquinolones on male infertility, sperm parameters, male reproductive tissue, and spermatogenesis in English and Persian languages published on Google Scholar and PubMed databases from January 2000 to December 2013 were assessed. Randomized controlled trials (RCTs) assessing the effects of aminoglycosides or fluoroquinolones on sperm parameters, artificial insemination, and male reproductive tract or RCTs comparing aminoglycosides vs. fluoroquinolones were eligible for inclusion. For ascertaining the reliability of study, data were extracted independently and in duplicate by two investigators. Results: Sperm viability was decreased significantly with streptomycin, gentamicin, and neomycin (p<0.001). Sperm motility was decreased significantly with gentamicin and neomycin (p<0.05). Total sperm count was significantly decreased with ofloxacin, gentamicin, streptomycin, and neomycin (p<0.022). There was significant decrease in post-thawing motility with low dose and high dose of ciprofloxacin. Testis weight was decreased with gentamicin and ofloxacin significantly (p<0.011). There was significant decrease in seminal vesicle weight with gentamicin, neomycin, and ofloxacin (p<0.022). Furthermore, changes in epididymis weight, percentage of total apoptotic cells, and diameter of seminiferous tubule were significant with all drugs including streptomycin, gentamicin, neomycin, and ofloxacin (p<0.05). Conclusion: Streptomycin has less negative effects on cell’s apoptosis and sperm parameters as compared to other drugs. Gentamicin

  4. Drug response in organoids generated from frozen primary tumor tissues

    PubMed Central

    Walsh, Alex J.; Cook, Rebecca S.; Sanders, Melinda E.; Arteaga, Carlos L.; Skala, Melissa C.

    2016-01-01

    Primary tumor organoids grown in three-dimensional culture provide an excellent platform for studying tumor progression, invasion, and drug response. However, organoid generation protocols require fresh tumor tissue, which limits organoid research and clinical use. This study investigates cellular morphology, viability, and drug response of organoids derived from frozen tissues. The results demonstrate that viable organoids can be grown from flash-frozen and thawed tissue and from bulk tissues slowly frozen in DMSO supplemented media. While the freezing process affects the basal metabolic rate of the cells, the optical metabolic imaging index correlates between organoids derived from fresh and frozen tissue and can be used to detect drug response of organoids grown from frozen tissues. The slow, DMSO frozen tissue yielded organoids with more accurate drug response than the flash frozen tissues, and thus bulk tissue should be preserved for subsequent organoid generation by slow freezing in DMSO supplemented media. PMID:26738962

  5. Business oriented EU human cell and tissue product legislation will adversely impact Member States' health care systems.

    PubMed

    Pirnay, Jean-Paul; Vanderkelen, Alain; De Vos, Daniel; Draye, Jean-Pierre; Rose, Thomas; Ceulemans, Carl; Ectors, Nadine; Huys, Isabelle; Jennes, Serge; Verbeken, Gilbert

    2013-12-01

    The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime-i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States' health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe's risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States' health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering

  6. Business oriented EU human cell and tissue product legislation will adversely impact Member States' health care systems.

    PubMed

    Pirnay, Jean-Paul; Vanderkelen, Alain; De Vos, Daniel; Draye, Jean-Pierre; Rose, Thomas; Ceulemans, Carl; Ectors, Nadine; Huys, Isabelle; Jennes, Serge; Verbeken, Gilbert

    2013-12-01

    The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime-i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States' health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe's risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States' health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering

  7. Mechanistic and dose considerations for supporting adverse pulmonary physiology in response to formaldehyde

    SciTech Connect

    Thompson, Chad M. Subramaniam, Ravi P.; Grafstroem, Roland C.

    2008-12-15

    Induction of airway hyperresponsiveness and asthma from formaldehyde inhalation exposure remains a debated and controversial issue. Yet, recent evidences on pulmonary biology and the pharmacokinetics and toxicity of formaldehyde lend support for such adverse effects. Specifically, altered thiol biology from accelerated enzymatic reduction of the endogenous bronchodilator S-nitrosoglutathione and pulmonary inflammation from involvement of Th2-mediated immune responses might serve as key events and cooperate in airway pathophysiology. Understanding what role these mechanisms play in various species and lifestages (e.g., child vs. adult) could be crucial for making more meaningful inter- and intra-species dosimetric extrapolations in human health risk assessment.

  8. The Symmetry of Adverse Local Tissue Reactions in Patients with Bilateral Simultaneous and Sequential ASR Hip Replacement.

    PubMed

    Madanat, Rami; Hussey, Daniel K; Donahue, Gabrielle S; Potter, Hollis G; Wallace, Robert; Bragdon, Charles R; Muratoglu, Orhun K; Malchau, Henrik

    2015-10-01

    The purpose of this study was to evaluate whether patients with bilateral metal-on-metal (MoM) hip replacements have symmetric adverse local tissue reactions (ALTRs) at follow-up. An MRI of both hips was performed at a mean time of six years after surgery in 43 patients. The prevalence and severity of ALTRs were found to be similar in simultaneous hips but differences were observed in sequential hips. The order and timing of sequential hip arthroplasties did not affect the severity of ALTRs. Thus, in addition to metal ion exposure from an earlier MoM implant other factors may also play a role in the progression of ALTRs. Bilateral implants should be given special consideration in risk stratification algorithms for management of patients with MoM hip arthroplasty. PMID:26055146

  9. Evidence Report: Risk of Crew Adverse Health Event Due to Altered Immune Response

    NASA Technical Reports Server (NTRS)

    Crucian, Brian; Sams, Clarence F.

    2013-01-01

    The Risk of Crew Adverse Health Event Due to Altered Immune Response is identified by the National Aeronautics and Space Administration (NASA) Human Research Program (HRP) as a recognized risk to human health and performance in space. The HRP Program Requirements Document (PRD) defines these risks. This Evidence Report provides a summary of the evidence that has been used to identify and characterize this risk. It is known that human immune function is altered in- and post-flight, but it is unclear at present if such alterations lead to increased susceptibility to disease. Reactivation of latent viruses has been documented in crewmembers, although this reactivation has not been directly correlated with immune changes or with observed diseases. As described in this report, further research is required to better characterize the relationships between altered immune response and susceptibility to disease during and after spaceflight. This is particularly important for future deep-space exploration missions.

  10. Tissue response to titanium implant using scanning electron microscope

    PubMed Central

    Nautiyal, Vijay P.; Mittal, Ankur; Agarwal, Amit; Pandey, Anupam

    2013-01-01

    Most of the surgeons now use titanium miniplates because of its biocompatibility and corrosion resistant properties; studies have shown that these titanium particles are released in the surrounding tissues causing tissue necrosis and if these implants are placed for a long period, the adverse effect of these implants are more severe. It therefore necessitates a study to find out whether these titanium particles are released into surrounding tissues from titanium miniplates used for maxillofacial fractures so that we could use these implants, that is, bone plates and screws with more confidence. PMID:24163546

  11. Sexually Dimorphic Responses to Early Adversity: Implications for Affective Problems and Autism Spectrum Disorder

    PubMed Central

    Davis, Elysia Poggi; Pfaff, Donald

    2014-01-01

    During gestation, development proceeds at a pace that is unmatched by any other stage of the lifecycle. For these reason the human fetus is particularly susceptible not only to organizing influences, but also to pathogenic disorganizing influences. Growing evidence suggests that exposure to prenatal adversity leads to neurological changes that underlie lifetime risks for mental illness. Beginning early in gestation, males and females show differential developmental trajectories and responses to stress. It is likely that sex-dependent organization of neural circuits during the fetal period influences differential vulnerability to mental health problems. We consider in this review evidence that sexually dimorphic responses to early life stress are linked to two developmental disorders: affective problems (greater female prevalence) and autism spectrum disorder (greater male prevalence). Recent prospective studies illustrating the neurodevelopmental consequences of fetal exposure to stress and stress hormones for males and females are considered here. Plausible biological mechanisms including the role of the sexually differentiated placenta are discussed. We consider in this review evidence that sexually dimorphic responses to early life stress are linked to two sets of developmental disorders: affective problems (greater female prevalence) and autism spectrum disorders (greater male prevalence). PMID:25038479

  12. A Systematic Literature Review of Adverse Events Associated with Systemic Treatments Used in Advanced Soft Tissue Sarcoma

    PubMed Central

    Khan, Shahnaz; Hackshaw, Michelle D.; Oglesby, Alan; Kaye, James A.; Skolnik, Jeffrey M.

    2016-01-01

    This systematic literature review describes adverse events (AEs) among patients with soft tissue sarcoma (STS) who received second-line or later anticancer therapies. Searches were conducted in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for studies of adults with advanced or metastatic STS who received systemic anticancer therapy before enrollment in a randomized-controlled trial of pazopanib, another targeted cancer agent, or cytotoxic chemotherapy. Of 204 publications identified, seven articles representing six unique studies met inclusion criteria. Additional safety results for pazopanib were identified on ClinicalTrials.gov. Hematologic toxicities were common with all therapies evaluated (pazopanib, trabectedin, dacarbazine ± gemcitabine, gemcitabine ± docetaxel, cyclophosphamide, and ifosfamide). Studies differed in AE type, timing of assessment, and outcomes reported, although patient populations and AE assessment timing were relatively similar for pazopanib and trabectedin. AEs that were more common with trabectedin than pazopanib were anemia, neutropenia, nausea/vomiting, and elevations in aspartate aminotransferase and alanine aminotransferase. An AE that was more common with pazopanib than trabectedin was anorexia. Only the pazopanib study reported AE frequencies versus placebo. A planned meta-analysis was not feasible, as there was no common comparator. More well-designed studies that include common comparators are needed for comparison of safety effects among treatments for STS. PMID:27516726

  13. A Systematic Literature Review of Adverse Events Associated with Systemic Treatments Used in Advanced Soft Tissue Sarcoma.

    PubMed

    Colosia, Ann; Khan, Shahnaz; Hackshaw, Michelle D; Oglesby, Alan; Kaye, James A; Skolnik, Jeffrey M

    2016-01-01

    This systematic literature review describes adverse events (AEs) among patients with soft tissue sarcoma (STS) who received second-line or later anticancer therapies. Searches were conducted in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for studies of adults with advanced or metastatic STS who received systemic anticancer therapy before enrollment in a randomized-controlled trial of pazopanib, another targeted cancer agent, or cytotoxic chemotherapy. Of 204 publications identified, seven articles representing six unique studies met inclusion criteria. Additional safety results for pazopanib were identified on ClinicalTrials.gov. Hematologic toxicities were common with all therapies evaluated (pazopanib, trabectedin, dacarbazine ± gemcitabine, gemcitabine ± docetaxel, cyclophosphamide, and ifosfamide). Studies differed in AE type, timing of assessment, and outcomes reported, although patient populations and AE assessment timing were relatively similar for pazopanib and trabectedin. AEs that were more common with trabectedin than pazopanib were anemia, neutropenia, nausea/vomiting, and elevations in aspartate aminotransferase and alanine aminotransferase. An AE that was more common with pazopanib than trabectedin was anorexia. Only the pazopanib study reported AE frequencies versus placebo. A planned meta-analysis was not feasible, as there was no common comparator. More well-designed studies that include common comparators are needed for comparison of safety effects among treatments for STS. PMID:27516726

  14. Dielectric response of some biological tissues.

    PubMed

    El-Lakkani, A

    2001-05-01

    The dielectric properties of two freshly excised mice tissue samples (kidney, skeletal muscle) and also freshly excised Ehrlich solid tumor were measured in the frequency range from 20 Hz to 100 kHz using RLC bridges. The data were fitted to a summation of multiple Cole-Cole dispersion and also to the constant power law which is related formally to the fractal geometries of tissues using a genetic algorithm for optimization developed by the author. The data were in good agreement with the Cole-Cole equation for the three samples.

  15. Factors influencing adverse skin responses in rats receiving repeated subcutaneous injections and potential impact on neurobehavior

    PubMed Central

    Levoe, S. Nikki; Flannery, Brenna M.; Brignolo, Laurie; Imai, Denise M.; Koehne, Amanda; Austin, Adam T.; Bruun, Donald A.; Tancredi, Daniel J.; Lein, Pamela J.

    2015-01-01

    Repeated subcutaneous (s.c.) injection is a common route of administration in chronic studies of neuroactive compounds. However, in a pilot study we noted a significant incidence of skin abnormalities in adult male Long-Evans rats receiving daily s.c. injections of peanut oil (1.0 ml/kg) in the subscapular region for 21 d. Histopathological analyses of the lesions were consistent with a foreign body reaction. Subsequent studies were conducted to determine factors that influenced the incidence or severity of skin abnormalities, and whether these adverse skin reactions influenced a specific neurobehavioral outcome. Rats injected daily for 21 d with food grade peanut oil had an earlier onset and greater incidence of skin abnormalities relative to rats receiving an equal volume (1.0 ml/kg/d) of reagent grade peanut oil or triglyceride of coconut oil. Skin abnormalities in animals injected daily with peanut oil were increased in animals housed on corncob versus paper bedding. Comparison of animals obtained from different barrier facilities exposed to the same injection paradigm (reagent grade peanut oil, 1.0 ml/kg/d s.c.) revealed significant differences in the severity of skin abnormalities. However, animals from different barrier facilities did not perform differently in a Pavlovian fear conditioning task. Collectively, these data suggest that environmental factors influence the incidence and severity of skin abnormalities following repeated s.c. injections, but that these adverse skin responses do not significantly influence performance in at least one test of learning and memory. PMID:25705100

  16. Response to self antigen imprints regulatory memory in tissues

    PubMed Central

    Rosenblum, Michael D.; Gratz, Iris K.; Paw, Jonathan S.; Lee, Karen; Marshak-Rothstein, Ann; Abbas, Abul K.

    2012-01-01

    Immune homeostasis in tissues is achieved through a delicate balance between pathogenic T cell responses directed at tissue-specific antigens and the ability of the tissue to inhibit these responses. The mechanisms by which tissues and the immune system communicate to establish and maintain immune homeostasis are currently unknown. Clinical evidence suggests that chronic or repeated exposure to self antigen within tissues leads to an attenuation of pathologic autoimmune responses, possibly as a means to mitigate inflammatory damage and preserve function. Many human organ-specific autoimmune diseases are characterized by the initial presentation of the disease being the most severe, with subsequent flares being of lesser severity and duration1. In fact, these diseases often spontaneously resolve, despite persistent tissue autoantigen expression2. In the practice of antigen-specific immunotherapy (antigen-SIT), allergens or self antigens are repeatedly injected in the skin, with a diminution of the inflammatory response occurring after each successive exposure3. Although these findings suggest that tissues acquire the ability to attenuate autoimmune reactions upon repeated responses to antigens, the mechanism by which this occurs is unknown. Here we show that upon expression of self antigen in a peripheral tissue, thymus-derived regulatory T cells (Treg cells) become activated, proliferate and differentiate into more potent suppressors, which mediate resolution of organ-specific autoimmunity. After resolution of the inflammatory response, activated Treg cells are maintained in the target tissue and are primed to attenuate subsequent autoimmune reactions when antigen is re-expressed. Thus, Treg cells function to confer ‘regulatory memory’ to the target tissue. These findings provide a framework for understanding how Treg cells respond when exposed to self antigen in peripheral tissues and offer mechanistic insight into how tissues regulate autoimmunity. PMID

  17. Connective tissue response to periodontal dressing.

    PubMed

    Nezwek, R A; Caffesse, R G; Bergenholtz, A; Nasjleti, C E

    1980-09-01

    The effects of three periodontal dressings (Coe-Pak, PPC, Perio Putty) upon subcutaneous tissues in 26 Sprague-Dawley rats were investigated. The three dressings, and a control (Teflon), were placed into polyethylene tubes. Two tubes per animal were implanted on either side of the dorsal midline area. After 14 days the specimens were retrieved and prepared for histological examination. Three methods of scoring were utilized for evaluation. First, a system evaluating the overall number of inflammatory cells, connective tissue capsule thickness, and the vascular changes produced; second, an inflammatory cell count, the Inflammatory Index (I.I), computing the inflammatory cells in a particular field of view for each material; and third, a Reaction Spread Index (R.S.I.) comparing the distance of the spread of the inflammatory reaction into the connective tissues. Statistical analysis of the data was carried out utilizing the Chi-square test and analysis of variance. While the three scoring systems utilized did result in some comparative variation in reactions, the overall order of decreasing severity was always PPC, Coe-Pak, Perio Putty, and Teflon.

  18. Low Concentrations of Silver Nanoparticles in Biosolids Cause Adverse Ecosystem Responses under Realistic Field Scenario

    PubMed Central

    Colman, Benjamin P.; Arnaout, Christina L.; Anciaux, Sarah; Gunsch, Claudia K.; Hochella, Michael F.; Kim, Bojeong; Lowry, Gregory V.; McGill, Bonnie M.; Reinsch, Brian C.; Richardson, Curtis J.; Unrine, Jason M.; Wright, Justin P.; Yin, Liyan; Bernhardt, Emily S.

    2013-01-01

    A large fraction of engineered nanomaterials in consumer and commercial products will reach natural ecosystems. To date, research on the biological impacts of environmental nanomaterial exposures has largely focused on high-concentration exposures in mechanistic lab studies with single strains of model organisms. These results are difficult to extrapolate to ecosystems, where exposures will likely be at low-concentrations and which are inhabited by a diversity of organisms. Here we show adverse responses of plants and microorganisms in a replicated long-term terrestrial mesocosm field experiment following a single low dose of silver nanoparticles (0.14 mg Ag kg−1 soil) applied via a likely route of exposure, sewage biosolid application. While total aboveground plant biomass did not differ between treatments receiving biosolids, one plant species, Microstegium vimeneum, had 32 % less biomass in the Slurry+AgNP treatment relative to the Slurry only treatment. Microorganisms were also affected by AgNP treatment, which gave a significantly different community composition of bacteria in the Slurry+AgNPs as opposed to the Slurry treatment one day after addition as analyzed by T-RFLP analysis of 16S-rRNA genes. After eight days, N2O flux was 4.5 fold higher in the Slurry+AgNPs treatment than the Slurry treatment. After fifty days, community composition and N2O flux of the Slurry+AgNPs treatment converged with the Slurry. However, the soil microbial extracellular enzymes leucine amino peptidase and phosphatase had 52 and 27% lower activities, respectively, while microbial biomass was 35% lower than the Slurry. We also show that the magnitude of these responses was in all cases as large as or larger than the positive control, AgNO3, added at 4-fold the Ag concentration of the silver nanoparticles. PMID:23468930

  19. Adverse cardiometabolic response to aerobic exercise training: Should this be a concern?

    PubMed Central

    Leifer, Eric S.; Church, Timothy S.; Earnest, Conrad P.; Fleg, Jerome L.; Hakkinen, Keijo; Karavirta, Laura; Kraus, William E.; Mikus, Catherine; Resnick, Benjamin

    2016-01-01

    .36) for SBP. Conclusion Compared to control subjects, exercise subjects were not at an increased risk for meeting the AC thresholds for SBP, FI, TG, or HDL-C and significantly fewer exercise subjects met AC thresholds for FI, and HDL. Exercise subjects also had significantly more favorable mean changes in FI, TG, and HDL-C than control subjects. These findings do not support the concept that aerobic exercise training increases the risk of adverse changes in CV risk factors. and that, with respect to group responses PMID:26258860

  20. Developing a Gene Biomarker at the Tipping Point of Adaptive and Adverse Responses in Human Bronchial Epithelial Cells.

    PubMed

    Currier, Jenna M; Cheng, Wan-Yun; Menendez, Daniel; Conolly, Rory; Chorley, Brian N

    2016-01-01

    Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on in vitro and in silico testing requires utilizing toxicity pathway information to distinguish adverse outcomes from recoverable adaptive events. Little work has focused on oxidative stresses in human airway for the purposes of predicting adverse responses. We hypothesize that early gene expression-mediated molecular changes could be used to delineate adaptive and adverse responses to environmentally-based perturbations. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure, a model oxidant. Airway derived BEAS-2B cells exposed to 2-10 μM Zn2+ elicited concentration- and time-dependent cytotoxicity. Normal, adaptive, and cytotoxic Zn2+ exposure conditions were determined with traditional apical endpoints, and differences in global gene expression around the tipping point of the responses were used to delineate underlying molecular mechanisms. Bioinformatic analyses of differentially expressed genes indicate early enrichment of stress signaling pathways, including those mediated by the transcription factors p53 and NRF2. After 4 h, 154 genes were differentially expressed (p < 0.01) between the adaptive and cytotoxic Zn2+ concentrations. Nearly 40% of the biomarker genes were related to the p53 signaling pathway with 30 genes identified as likely direct targets using a database of p53 ChIP-seq studies. Despite similar p53 activation profiles, these data revealed widespread dampening of p53 and NRF2-related genes as early as 4 h after exposure at higher, unrecoverable Zn2+ exposures. Thus, in our model early increased activation of stress response pathways indicated a recoverable adaptive event. Overall, this study highlights the

  1. Developing a Gene Biomarker at the Tipping Point of Adaptive and Adverse Responses in Human Bronchial Epithelial Cells

    PubMed Central

    Currier, Jenna M.; Cheng, Wan-Yun; Menendez, Daniel; Conolly, Rory; Chorley, Brian N.

    2016-01-01

    Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on in vitro and in silico testing requires utilizing toxicity pathway information to distinguish adverse outcomes from recoverable adaptive events. Little work has focused on oxidative stresses in human airway for the purposes of predicting adverse responses. We hypothesize that early gene expression-mediated molecular changes could be used to delineate adaptive and adverse responses to environmentally-based perturbations. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure, a model oxidant. Airway derived BEAS-2B cells exposed to 2–10 μM Zn2+ elicited concentration- and time-dependent cytotoxicity. Normal, adaptive, and cytotoxic Zn2+ exposure conditions were determined with traditional apical endpoints, and differences in global gene expression around the tipping point of the responses were used to delineate underlying molecular mechanisms. Bioinformatic analyses of differentially expressed genes indicate early enrichment of stress signaling pathways, including those mediated by the transcription factors p53 and NRF2. After 4 h, 154 genes were differentially expressed (p < 0.01) between the adaptive and cytotoxic Zn2+ concentrations. Nearly 40% of the biomarker genes were related to the p53 signaling pathway with 30 genes identified as likely direct targets using a database of p53 ChIP-seq studies. Despite similar p53 activation profiles, these data revealed widespread dampening of p53 and NRF2-related genes as early as 4 h after exposure at higher, unrecoverable Zn2+ exposures. Thus, in our model early increased activation of stress response pathways indicated a recoverable adaptive event. Overall, this study highlights the

  2. Moderating role of FKBP5 genotype in the impact of childhood adversity on cortisol stress response during adulthood.

    PubMed

    Buchmann, Arlette F; Holz, Nathalie; Boecker, Regina; Blomeyer, Dorothea; Rietschel, Marcella; Witt, Stephanie H; Schmidt, Martin H; Esser, Günter; Banaschewski, Tobias; Brandeis, Daniel; Zimmermann, Ulrich S; Laucht, Manfred

    2014-06-01

    Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders. The present study aimed to replicate and extend previous evidence indicating that FKBP5 polymorphisms moderate hypothalamus-pituitary-adrenal (HPA) function by examining whether FKBP5 rs1360780 genotype and different measures of childhood adversity interact to predict stress-induced cortisol secretion. At age 19 years, 195 young adults (90 males, 105 females) participating in an epidemiological cohort study completed the Trier Social Stress Test (TSST) to assess cortisol stress responsiveness and were genotyped for the FKBP5 rs1360780. Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ) and by a standardized parent interview yielding an index of family adversity. A significant interaction between genotype and childhood adversity on cortisol response to stress was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report (CTQ), but not for prospectively ascertained objective family adversity. Severity of childhood maltreatment was significantly associated with attenuated cortisol levels among carriers of the rs1360780 CC genotype, while no such effect emerged in carriers of the T allele. These findings point towards the functional involvement of FKBP5 in long-term alterations of neuroendocrine stress regulation related to childhood maltreatment, which have been suggested to represent a premorbid risk or resilience factor in the context of stress-related disorders.

  3. Moderating role of FKBP5 genotype in the impact of childhood adversity on cortisol stress response during adulthood.

    PubMed

    Buchmann, Arlette F; Holz, Nathalie; Boecker, Regina; Blomeyer, Dorothea; Rietschel, Marcella; Witt, Stephanie H; Schmidt, Martin H; Esser, Günter; Banaschewski, Tobias; Brandeis, Daniel; Zimmermann, Ulrich S; Laucht, Manfred

    2014-06-01

    Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders. The present study aimed to replicate and extend previous evidence indicating that FKBP5 polymorphisms moderate hypothalamus-pituitary-adrenal (HPA) function by examining whether FKBP5 rs1360780 genotype and different measures of childhood adversity interact to predict stress-induced cortisol secretion. At age 19 years, 195 young adults (90 males, 105 females) participating in an epidemiological cohort study completed the Trier Social Stress Test (TSST) to assess cortisol stress responsiveness and were genotyped for the FKBP5 rs1360780. Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ) and by a standardized parent interview yielding an index of family adversity. A significant interaction between genotype and childhood adversity on cortisol response to stress was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report (CTQ), but not for prospectively ascertained objective family adversity. Severity of childhood maltreatment was significantly associated with attenuated cortisol levels among carriers of the rs1360780 CC genotype, while no such effect emerged in carriers of the T allele. These findings point towards the functional involvement of FKBP5 in long-term alterations of neuroendocrine stress regulation related to childhood maltreatment, which have been suggested to represent a premorbid risk or resilience factor in the context of stress-related disorders. PMID:24411633

  4. Methylprednisolone pharmacokinetics, cortisol response, and adverse effects in black and white renal transplant recipients.

    PubMed

    Tornatore, K M; Biocevich, D M; Reed, K; Tousley, K; Singh, J P; Venuto, R C

    1995-03-15

    It is generally assumed that chronic glucocorticoid therapy is similar pharmacologically when administered to either black or white renal transplant recipients, resulting in adrenal suppression, low circulating plasma cortisol concentrations, and a similar degree of drug exposure and toxicity. To examine this theory and to investigate the relationship of glucocorticoid metabolism to steroid-induced adverse effects among specific ethnic groups of renal transplant recipients, 9 black and 9 white male patients chronically receiving methylprednisolone were enrolled. All patients had stable renal function and were matched for age, weight, and time since transplant. Standard pharmacokinetic parameters for methylprednisolone were determined and cortisol responses were characterized by total cortisol area under the concentration curve (AUC), return cortisol AUC, and cortisol suppression half-life. All patients received their daily oral dose of methylprednisolone (mean daily dose = 11 mg for blacks and 11 mg for whites) as an intravenous infusion with serial plasma samples obtained over 24 h. The patients were assessed for the presence of specific cushingoid manifestations (buffalo hump, moon facies) and steroid-associated diabetes. Methylprednisolone and cortisol were analyzed via HPLC. In the black patients, the mean clearance of methylprednisolone (206 +/- 70 ml/hr/kg) was significantly slower with a smaller volume of distribution (0.95 +/- 0.32 L/kg) when compared with the white group (327 +/- 129 ml/hr/kg, P = 0.03; volume of distribution = 1.33 +/- 0.27 L/kg, P = 0.015). Despite chronic methylprednisolone therapy, a definite 24-hr cortisol response pattern was noted in 15 of the 18 patients with a mean total cortisol AUC of 732 +/- 443 ng.hr/ml in blacks and 539 +/- 361 ng.hr/ml in whites (P = 0.17, black vs. white). The mean cortisol suppression half-life was 4.31 +/- 1.54 hr in black recipients and 4.11 +/- 1.49 hr in whites (P = 0.48). The mean return cortisol AUC

  5. Psychological Well-Being and the Human Conserved Transcriptional Response to Adversity

    PubMed Central

    Fredrickson, Barbara L.; Grewen, Karen M.; Algoe, Sara B.; Firestine, Ann M.; Arevalo, Jesusa M. G.; Ma, Jeffrey; Cole, Steve W.

    2015-01-01

    Research in human social genomics has identified a conserved transcriptional response to adversity (CTRA) characterized by up-regulated expression of pro-inflammatory genes and down-regulated expression of Type I interferon- and antibody-related genes. This report seeks to identify the specific aspects of positive psychological well-being that oppose such effects and predict reduced CTRA gene expression. In a new confirmation study of 122 healthy adults that replicated the approach of a previously reported discovery study, mixed effect linear model analyses identified a significant inverse association between expression of CTRA indicator genes and a summary measure of eudaimonic well-being from the Mental Health Continuum – Short Form. Analyses of a 2- representation of eudaimonia converged in finding correlated psychological and social subdomains of eudaimonic well-being to be the primary carriers of CTRA associations. Hedonic well-being showed no consistent CTRA association independent of eudaimonic well-being, and summary measures integrating hedonic and eudaimonic well-being showed less stable CTRA associations than did focal measures of eudaimonia (psychological and social well-being). Similar results emerged from analyses of pooled discovery and confirmation samples (n = 198). Similar results also emerged from analyses of a second new generalization study of 107 healthy adults that included the more detailed Ryff Scales of Psychological Well-being and found this more robust measure of eudaimonic well-being to also associate with reduced CTRA gene expression. Five of the 6 major sub-domains of psychological well-being predicted reduced CTRA gene expression when analyzed separately, and 3 remained distinctively prognostic in mutually adjusted analyses. All associations were independent of demographic characteristics, health-related confounders, and RNA indicators of leukocyte subset distribution. These results identify specific sub-dimensions of eudaimonic

  6. Genotype and Neuropsychological Response Inhibition as Resilience Promoters for ADHD, ODD, and CD under Conditions of Psychosocial Adversity

    PubMed Central

    Nigg, Joel; Nikolas, Molly; Friderici, Karen; Park, Leeyoung; Zucker, Robert A.

    2008-01-01

    Whereas child personality, IQ, and family factors have been identified as enabling a resilient response to psychosocial adversity, more direct biological resilience factors have been less well delineated. This is particularly so for child ADHD, which has received less attention from a resilience perspective than have associated externalizing disorders. Children from two independent samples were classified as resilient if they avoided developing ADHD, ODD, or CD in the face of family adversity. Two protective factors were examined for their potential relevance to prefrontal brain development: neuropsychological response inhibition, as assessed by the Stop task, and a composite catecholamine genotype risk score. Resilient children were characterized in both samples by more effective response inhibition, although the effect in the second sample was very small. Genotype was measured in Sample 1, and a composite high risk genotype index was developed by summing presence of risk across markers on three genes expressed in prefrontal cortex: dopamine transporter, dopamine D4 receptor, and noradrenergic alpha 2 receptor. Genotype was a reliable resilience indicator against development of ADHD and CD, but not ODD, in the face of psychosocial adversity. Results illustrate potential neurobiological protective factors related to development of prefrontal cortex that may enable children to avoid developing ADHD and CD in the presence of psychosocial adversity. PMID:17705902

  7. Fetal tissue research: an ongoing story of professionally responsible success.

    PubMed

    Gelber, Shari E; McCullough, Laurence B; Chervenak, Frank A

    2015-12-01

    Therapies derived from fetal tissue research are some of the greatest success stories in medicine. Research using fetal tissue has allowed for development of vaccines for numerous diseases including polio, rubella, and measles. These vaccines have saved countless lives, improved quality of life, and decreased the need for induced abortion secondary to congenital infection. Research using cell lines derived from fetal tissue has assisted in better understanding disease pathogenesis and has served to produce human proteins as research reagents and therapies. Ongoing research points to the potential for fetal tissue to be used to cure debilitating diseases such as Parkinson disease. These scientific and medical advances are dependent on the use of fetal tissue from aborted fetuses. While the practice of induced abortion despite societal benefit may be theologically objectionable to some, these practices are professionally responsible. Federal regulations exist to discourage patients from being influenced by the societal benefit of fetal research in arriving at the decision to terminate as well as to prevent researchers from influencing a patient's decision. After a patient has chosen termination of pregnancy, it is consistent with professional responsibility to allow her to choose the disposition of the cadaveric fetal tissue. While some may view induced abortion and societal benefit from this practice as an ethical burden, the principle of justice makes it ethically obligatory to bear this ethical burden. The success story of cadaveric fetal tissue research and treatment should continue unhindered, to fulfill professional responsibility to current and future patients.

  8. Association between Single Nucleotide Polymorphisms in XRCC3 and Radiation-Induced Adverse Effects on Normal Tissue: A Meta-Analysis

    PubMed Central

    Song, Yu-Zhe; Han, Fu-Jun; Liu, Min; Xia, Cheng-Cheng; Shi, Wei-Yan; Dong, Li-Hua

    2015-01-01

    The X-ray repair cross-complementing group 3 (XRCC3) protein plays an important role in the repair of DNA double-strand breaks. The relationship between XRCC3 polymorphisms and the risk of radiation-induced adverse effects on normal tissue remains inconclusive. Thus, we performed a meta-analysis to elucidate the association between XRCC3 polymorphisms and radiation-induced adverse effects on normal tissue. All eligible studies up to December 2014 were identified through a search of the PubMed, Embase and Web of Science databases. Seventeen studies involving 656 cases and 2193 controls were ultimately included in this meta-analysis. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between XRCC3 polymorphisms and the risk of radiation-induced normal tissue adverse effects. We found that the XRCC3 p.Thr241Met (rs861539) polymorphism was significantly associated with early adverse effects induced by radiotherapy (OR = 1.99, 95%CI: 1.31–3.01, P = 0.001). A positive association lacking statistical significance with late adverse effects was also identified (OR = 1.28, 95%CI: 0.97–1.68, P = 0.08). In addition, the rs861539 polymorphism was significantly correlated with a higher risk of adverse effects induced by head and neck area irradiation (OR = 2.41, 95%CI: 1.49–3.89, p = 0.0003) and breast irradiation (OR = 1.41, 95%CI: 1.02–1.95, p = 0.04), whereas the correlation was not significant for lung irradiation or pelvic irradiation. Furthermore, XRCC3 rs1799794 polymorphism may have a protective effect against late adverse effects induced by radiotherapy (OR = 0.47, 95%CI: 0.26–0.86, P = 0.01). Well-designed large-scale clinical studies are required to further validate our results. PMID:26091483

  9. Immune response to nonspecific and altered tissue antigens in soft tissue allografts.

    PubMed

    Pinkowski, J L; Rodrigo, J J; Sharkey, N A; Vasseur, P B

    1996-05-01

    Soft tissue allografts have many uses in orthopaedic surgery, including knee ligament reconstruction, hand tendon surgery, shoulder instability, and rotator cuff reconstruction. The predictable biologic incorporation of soft tissue allografts without rejection or fear of disease transmission continues to be a goal of basic science researchers. A review of the current knowledge if the immune system response to donor specific, nonspecific, and altered tissue antigens in soft tissue or tendon allografts is presented. An in vitro study was done in an attempt to decrease immunogenicity of a frozen bone-ligament graft by adding irrigation with Betadine scrub solution and hydrogen peroxide to the conventional storage process of freezing. Although the irrigation with cytotoxic agents would undoubtedly further decrease immunogenicity, it also decreased stiffness and maximum load by 15%. Whether this decreased strength and stiffness would compromise the incorporation and long term success of soft tissue allografts would need to be studied by in vitro experiments.

  10. Tissue specificity of the heat-shock response in maize.

    PubMed

    Cooper, P; Ho, T H; Hauptmann, R M

    1984-06-01

    The tissue specificity of the heat-shock response in maize was investigated. The ability to synthesize heat shock proteins (hsp) at 40 degrees C, as well as the intensity and duration of that synthesis, was analyzed in coleoptiles, scutella, green and etiolated leaves, suspension-cultured cells, germinating pollen grains, and primary root sections at different stages of development. One-dimensional sodium dodecyl sulfate gel electrophoresis of extracted proteins revealed that most of the tissues synthesized the typical set of 10 hsp, but that the exact characteristics of the response depended upon the tissue type. While elongating portions of the primary root exhibited a strong heat shock response, the more mature portions showed a reduced ability to synthesize hsp. Leaves, whether green or etiolated, excised or intact, constitutively synthesized a low level of hsp at 25 degrees C, and high levels could be induced at 40 degrees C. Suspension-cultures of Black Mexican sweet corn synthesized, besides the typical set of hsp, two additional polypeptides. In contrast to all the other tissues, germinating pollen grains could not be induced to synthesize the typical set of hsp but did synthesize two new polypeptides of 92 and 56 kD molecular weight.The heat shock response was transient for most of the tissues which synthesized the standard set of hsp. Hsp synthesis was detected up to 2 to 3 hours, but not at 10 hours of continuous 40 degrees C treatment. The exception was suspension cultured cells, in which hsp synthesis showed only a slight reduction after 10 hours at 40 degrees C. Tissue-specific differences in the heat-shock response suggest that there are differences in the way a given tissue is able to adapt to high temperature.We have confirmed the previous suggestion that maize hsp do not accumulate in substantial quantities. Using two-dimensional gel analysis, hsp could be detected by autoradiography but not by sensitive silver staining techniques. PMID:16663639

  11. Neutrophil swarming: an essential process of the neutrophil tissue response.

    PubMed

    Kienle, Korbinian; Lämmermann, Tim

    2016-09-01

    Neutrophil infiltration into inflamed and infected tissues is a fundamental process of the innate immune response. While neutrophil interactions with the blood vessel wall have been intensely studied over the last decades, neutrophil dynamics beyond the vasculature have for a long time remained poorly investigated. Recent intravital microscopy studies of neutrophil populations directly at the site of tissue damage or microbial invasion have changed our perspective on neutrophil responses within tissues. Swarm-like migration patterns of neutrophils, referred to as 'neutrophil swarming', have been detected in diverse tissues under conditions of sterile inflammation and infection with various pathogens, including bacteria, fungi, and parasites. Current work has begun to unravel the molecular pathways choreographing the sequential phases of highly coordinated chemotaxis followed by neutrophil accumulation and the formation of substantial neutrophil clusters. It is now clear that intercellular communication among neutrophils amplifies their recruitment in a feed-forward manner, which provides them with a level of self-organization during neutrophil swarming. This review will summarize recent developments and current concepts on neutrophil swarming, an important process of the neutrophil tissue response with a critical role in maintaining the balance between host protection and inflammation-driven tissue destruction. PMID:27558329

  12. Healing responses following cryothermic and hyperthermic tissue ablation

    NASA Astrophysics Data System (ADS)

    Godwin, Braden L.; Coad, James E.

    2009-02-01

    Minimally invasive, thermally ablative, interventional technologies have been changing the practice of medicine since before the turn of the 20th century. More recently, cryothermic and hyperthermic therapies have expanded in terms of their spectrum of thermal generators, modes for controlling and monitoring the treatment zone and both benign and malignant medical applications. The final tissue, and hence clinical outcome, of a thermal ablation is determined by the summation of direct primary (thermal) and secondary (apoptosis, ischemia, free radical, inflammation, wound healing, etc.) injury followed by possible cellular regeneration and scar formation. The initial thermal lesion can be broadly divided into two major zones of cellular death: 1) the complete ablation zone closer to the thermal source and 2) the peripheral transition zone with a decreasing gradient of cell death. While not applicable to cryotherapy, hyperthermic complete ablation zones are subdivided into two zones: 1) thermal or heat fixation and 2) coagulative necrosis. It is important to clearly differentiate these tissue zones because of their substantially different healing responses. Therefore, the development of clinically successful thermal therapies requires an understanding of tissue healing responses. The healing responses can be affected by a number of additional factors such as the tissue's anatomy, organ specific healing differences, blood supply, protein vs. lipid content, and other factors. Thus, effective biomedical instrument development requires both an understanding of thermal cell injury/death and the body's subsequent healing responses. This paper provides a general overview of the healing pathways that follow thermal tissue treatment.

  13. Dietary omega-3 and omega-6 fatty acids compete in producing tissue compositions and tissue responses.

    PubMed

    Lands, Bill

    2014-11-01

    Serious food-related health disorders may be prevented by recognizing the molecular processes that connect the dietary intake of vitamin-like fatty acids to tissue accumulation of precursors of potent hormone-like compounds that cause harmful tissue responses. Conversion of dietary 18-carbon omega-3 and omega-6 polyunsaturated fatty acids to tissue 20- and 22-carbon highly unsaturated fatty acids (HUFAs) is catalyzed by promiscuous enzymes that allow different types of fatty acid to compete among each other for accumulation in tissue HUFA. As a result, food choices strongly influence the types of accumulated tissue HUFA. However, the conversion of tissue HUFA to active hormones and their receptor-mediated actions occurs with discriminating enzymes and receptors that give more intense responses for the omega-6 and omega-3 hormones. Undesired chronic health disorders, which are made worse by excessive omega-6 hormone actions, can be prevented by eating more omega-3 fats, less omega-6 fats, and fewer calories per meal.

  14. Erythropoietin action in stress response, tissue maintenance and metabolism.

    PubMed

    Zhang, Yuanyuan; Wang, Li; Dey, Soumyadeep; Alnaeeli, Mawadda; Suresh, Sukanya; Rogers, Heather; Teng, Ruifeng; Noguchi, Constance Tom

    2014-01-01

    Erythropoietin (EPO) regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR), suggest the potential for EPO response in metabolism and disease. PMID:24918289

  15. Striking a Balance in Communicating Pharmacogenetic Test Results: Promoting Comprehension and Minimizing Adverse Psychological and Behavioral Response

    PubMed Central

    Haga, Susanne B.; Mills, Rachel; Bosworth, Hayden

    2014-01-01

    Objective Pharmacogenetic (PGx) testing can provide information about a patient’s likelihood to respond to a medication or experience an adverse event, and be used to inform medication selection and/or dosing. Promoting patient comprehension of PGx test results will be important to improving engagement and understanding of treatment decisions Methods The discussion in this paper is based on our experiences and the literature on communication of genetic test results for disease risk and broad risk communication strategies. Results Clinical laboratory reports often describe PGx test results using standard terminology such as ‘poor metabolizer’ or ‘ultra-rapid metabolizer.’ While this type of terminology may promote patient recall with its simple, yet descriptive nature, it may be difficult for some patients to comprehend and/or cause adverse psychological or behavioral responses. Conclusion The language used to communicate results and their significance to patients will be important to consider in order to minimize confusion and potential psychological consequences such as increased anxiety that can adversely impact medication-taking behaviors. Practice Implications Due to patients’ unfamiliarity with PGx testing and the potential for confusion, adverse psychological effects, and decreased medication adherence, health providers need to be cognizant of the language used in discussing PGx test results with patients. PMID:24985359

  16. Tissue response to mechanical vibrations for "sonoelasticity imaging".

    PubMed

    Parker, K J; Huang, S R; Musulin, R A; Lerner, R M

    1990-01-01

    The goal of "sonoelasticity imaging" is to differentiate between normal soft tissues and hard lesions. This is done by measuring and then displaying the ultrasound Doppler spectrum of regions within tissues which are mechanically forced with low frequency (20-1000 Hz) vibrations. The resolution and sensitivity of the technique ultimately rest on the spatial resolution of ultrasound Doppler detection, the low frequency mechanical properties of tissues, and the vibration response of layered, inhomogeneous regions with hard tumor inclusions and complicated boundary conditions set by the presence of skin, bones and other regions. An initial investigation has measured some tissue stiffness parameters, and applied these in a NASTRAN finite element analysis to simulate a prostate tumor in the pelvic cavity. The measurements show a wide separation between the elastic modulus of tumors and soft tissues such as muscle and prostate. NASTRAN analyses show the ability to delineate regions of different elasticity based on the pattern of vibration amplitudes. The ability to change vibration frequency within the 100-300 Hz band seems particularly helpful in simulations and experiments which visualize small stiff inclusions in tissues. Preliminary results support the postulate that sonoelasticity imaging can provide useful information concerning tissue properties that are not otherwise obtainable. PMID:2194336

  17. M1- and M2-Type Macrophage Responses Are Predictive of Adverse Outcomes in Human Atherosclerosis

    PubMed Central

    de Gaetano, Monica; Crean, Daniel; Barry, Mary; Belton, Orina

    2016-01-01

    Atherosclerosis is an inflammatory disease caused by endothelial injury, lipid deposition, and oxidative stress. This progressive disease can be converted into an acute clinical event by plaque rupture and thrombosis. In the context of atherosclerosis, the underlying cause of myocardial infarction and stroke, macrophages uniquely possess a dual functionality, regulating lipid accumulation and metabolism and sustaining the chronic inflammatory response, two of the most well-documented pathways associated with the pathogenesis of the disease. Macrophages are heterogeneous cell populations and it is hypothesized that, during the pathogenesis of atherosclerosis, macrophages in the developing plaque can switch from a pro-inflammatory (MΦ1) to an anti-inflammatory (MΦ2) phenotype and vice versa, depending on the microenvironment. The aim of this study was to identify changes in macrophage subpopulations in the progression of human atherosclerotic disease. Established atherosclerotic plaques from symptomatic and asymptomatic patients with existing coronary artery disease undergoing carotid endarterectomy were recruited to the study. Comprehensive histological and immunohistochemical analyses were performed to quantify the cellular content and macrophage subsets of atherosclerotic lesion. In parallel, expression of MΦ1 and MΦ2 macrophage markers were analyzed by real-time PCR and Western blot analysis. Gross analysis and histological staining demonstrated that symptomatic plaques presented greater hemorrhagic activity and the internal carotid was the most diseased segment, based on the predominant prevalence of fibrotic and necrotic tissue, calcifications, and hemorrhagic events. Immunohistochemical analysis showed that both MΦ1 and MΦ2 macrophages are present in human plaques. However, MΦ2 macrophages are localized to more stable locations within the lesion. Importantly, gene and protein expression analysis of MΦ1/MΦ2 markers evidenced that MΦ1 markers and Th1

  18. M1- and M2-Type Macrophage Responses Are Predictive of Adverse Outcomes in Human Atherosclerosis.

    PubMed

    de Gaetano, Monica; Crean, Daniel; Barry, Mary; Belton, Orina

    2016-01-01

    Atherosclerosis is an inflammatory disease caused by endothelial injury, lipid deposition, and oxidative stress. This progressive disease can be converted into an acute clinical event by plaque rupture and thrombosis. In the context of atherosclerosis, the underlying cause of myocardial infarction and stroke, macrophages uniquely possess a dual functionality, regulating lipid accumulation and metabolism and sustaining the chronic inflammatory response, two of the most well-documented pathways associated with the pathogenesis of the disease. Macrophages are heterogeneous cell populations and it is hypothesized that, during the pathogenesis of atherosclerosis, macrophages in the developing plaque can switch from a pro-inflammatory (MΦ1) to an anti-inflammatory (MΦ2) phenotype and vice versa, depending on the microenvironment. The aim of this study was to identify changes in macrophage subpopulations in the progression of human atherosclerotic disease. Established atherosclerotic plaques from symptomatic and asymptomatic patients with existing coronary artery disease undergoing carotid endarterectomy were recruited to the study. Comprehensive histological and immunohistochemical analyses were performed to quantify the cellular content and macrophage subsets of atherosclerotic lesion. In parallel, expression of MΦ1 and MΦ2 macrophage markers were analyzed by real-time PCR and Western blot analysis. Gross analysis and histological staining demonstrated that symptomatic plaques presented greater hemorrhagic activity and the internal carotid was the most diseased segment, based on the predominant prevalence of fibrotic and necrotic tissue, calcifications, and hemorrhagic events. Immunohistochemical analysis showed that both MΦ1 and MΦ2 macrophages are present in human plaques. However, MΦ2 macrophages are localized to more stable locations within the lesion. Importantly, gene and protein expression analysis of MΦ1/MΦ2 markers evidenced that MΦ1 markers and Th1

  19. Mechanical response of brain tissue under blast loading.

    PubMed

    Laksari, Kaveh; Sadeghipour, Keyanoush; Darvish, Kurosh

    2014-04-01

    In this study, a framework for understanding the propagation of stress waves in brain tissue under blast loading has been developed. It was shown that tissue nonlinearity and rate dependence are the key parameters in predicting the mechanical behavior under such loadings, as they determine whether traveling waves could become steeper and eventually evolve into shock discontinuities. To investigate this phenomenon, in the present study, brain tissue has been characterized as a quasi-linear viscoelastic (QLV) material and a nonlinear constitutive model has been developed for the tissue that spans from medium loading rates up to blast rates. It was shown that development of shock waves is possible inside the head in response to high rate compressive pressure waves. Finally, it was argued that injury to the nervous tissue at the microstructural level could be partly attributed to the high stress gradients with high rates generated at the shock front and this was proposed as a mechanism of injury in brain tissue. PMID:24457112

  20. Decellularized allogeneic and xenogeneic tissue as a bioscaffold for regenerative medicine: factors that influence the host response.

    PubMed

    Badylak, Stephen F

    2014-07-01

    Biologic scaffold materials composed of mammalian extracellular matrix (ECM) are prepared by decellularization of source tissues harvested from either humans (allogeneic) or a variety of other (xenogeneic) species. These matrix scaffold materials are commonly regulated and used as surgical mesh materials for applications such as ventral hernia repair, musculotendinous tissue reconstruction, dura mater replacement, reconstructive breast surgery, pelvic floor reconstruction, and the treatment of cutaneous ulcers, among others. The clinical results for these applications vary widely for reasons which include characteristics of the source tissue, methods and efficacy of tissue decellularization, and methods of processing/manufacturing. However, the primary determinant of success or failure in the clinical setting is the response of the host to these implanted biologic scaffold materials. It is logical to question why any non-self biologic material, particularly a xenogeneic material, would not elicit an early and aggressive adverse immune response. The present manuscript briefly describes the known mechanisms by which these biologic scaffold materials can facilitate a constructive remodeling response, the known causative factors of an adverse response, and provides a general discussion of the role of the macrophage in determining outcome.

  1. Systemic inflammation regulates microglial responses to tissue damage in vivo

    PubMed Central

    Gyoneva, Stefka; Davalos, Dimitrios; Biswas, Dipankar; Swanger, Sharon A.; Garnier-Amblard, Ethel; Loth, Francis; Akassoglou, Katerina; Traynelis, Stephen F.

    2015-01-01

    Microglia, the resident immune cells of the central nervous system, exist in either a “resting” state associated with physiological tissue surveillance or an “activated” state in neuroinflammation. We recently showed that ATP is the primary chemoattractor to tissue damage in vivo and elicits opposite effects on the motility of activated microglia in vitro through activation of adenosine A2A receptors. However, whether systemic inflammation affects microglial responses to tissue damage in vivo remains largely unknown. Using in vivo two-photon imaging of mice, we show that injection of lipopolysaccharide (LPS) at levels that can produce both clear neuroinflammation and some features of sepsis significantly reduced the rate of microglial response to laser-induced ablation injury in vivo. Under pro-inflammatory conditions, microglial processes initially retracted from the ablation site, but subsequently moved toward and engulfed the damaged area. Analyzing the process dynamics in 3D cultures of primary microglia indicated that only A2A, but not A1 or A3 receptors, mediate process retraction in LPS-activated microglia. The A2A receptor antagonists caffeine and preladenant reduced adenosine-mediated process retraction in activated microglia in vitro. Finally, administration of preladenant before induction of laser ablation in vivo accelerated the microglial response to injury following systemic inflammation. The regulation of rapid microglial responses to sites of injury by A2A receptors could have implications for their ability to respond to the neuronal death occurring under conditions of neuroinflammation in neurodegenerative disorders. PMID:24807189

  2. Adverse reactions to sunscreen agents: epidemiology, responsible irritants and allergens, clinical characteristics, and management.

    PubMed

    Heurung, Ashley R; Raju, Srihari I; Warshaw, Erin M

    2014-01-01

    Sunscreen is a key component in the preventive measures recommended by dermatologists and public health campaigns aimed at reducing sunburn, early skin aging, and skin cancer. To maximize compliance, adverse reactions to sunscreens should be minimized. Although inactive ingredients cause many of these reactions, it is important for dermatologists to be aware of reactions to active ultraviolet filters. There are approximately 120 chemicals that can function as ultraviolet (UV) filters. This review focuses on the 36 most common filters in commercial and historical use. Of these, 16 are approved for use by the US Food and Drug Administration. The benzophenones and dibenzoylmethanes are the most commonly implicated UV filters causing allergic and photoallergic contact dermatitis (PACD) reactions; benzophenone-3 is the leading allergen and photoallergen within this class. When clinically indicated, patch and photopatch testing should be performed to common UV filters.

  3. Response of a tissue equivalent proportional counter to neutrons

    NASA Technical Reports Server (NTRS)

    Badhwar, G. D.; Robbins, D. E.; Gibbons, F.; Braby, L. A.

    2002-01-01

    The absorbed dose as a function of lineal energy was measured at the CERN-EC Reference-field Facility (CERF) using a 512-channel tissue equivalent proportional counter (TEPC), and neutron dose equivalent response evaluated. Although there are some differences, the measured dose equivalent is in agreement with that measured by the 16-channel HANDI tissue equivalent counter. Comparison of TEPC measurements with those made by a silicon solid-state detector for low linear energy transfer particles produced by the same beam, is presented. The measurements show that about 4% of dose equivalent is delivered by particles heavier than protons generated in the conducting tissue equivalent plastic. c2002 Elsevier Science Ltd. All rights reserved.

  4. Pneumothorax as adverse event in patients with lung metastases of soft tissue sarcoma treated with pazopanib: a single reference centre case series

    PubMed Central

    2014-01-01

    Background Recently, the phase III PALETTE study introduced pazopanib (Votrient®) as treatment for adult patients with locally advanced or metastatic non-liposarcoma soft tissue sarcoma after prior treatment with doxorubicin and/or ifosfamide. Pneumothorax was reported as adverse event in 8 of 246 treated patients (3.3%) in that study. This case series presents the incidence and clinic of this complication in the Leiden University Medical Centre. Cases Forty-three patients were treated with pazopanib of which six patients (14.0%) developed a pneumothorax. These six patients were treated for malignant peripheral nerve sheath tumour, angiosarcoma, synovial sarcoma, fibromyxomatoid sarcoma, pleomorphic sarcoma and endometrial stromal sarcoma. All six patients had subpleural pulmonary or pleural metastases at the start of pazopanib and the pneumothorax developed during or shortly after treatment with pazopanib and was difficult to treat. Discussion The incidence reported by us is higher than the incidence in the PALETTE study. Trials with pazopanib in renal cell carcinoma, urothelial carcinoma and cervix carcinoma did not report pneumothorax as an adverse event, suggesting pneumothorax as a specific adverse event in soft tissue sarcoma patients treated with pazopanib. This may be related to the fact that there is often pleural metastatic involvement and cystic degeneration due to pazopanib treatment may add to the risk. Conclusion The risk of an, often difficult to treat, pneumothorax during pazopanib therapy should be discussed with the patient before initiation of treatment for a pulmonary metastasized sarcoma and physicians should be alert to the occurrence of such an event. PMID:25302110

  5. The role of the monoamine oxidase A gene in moderating the response to adversity and associated antisocial behavior: a review

    PubMed Central

    Buades-Rotger, Macià; Gallardo-Pujol, David

    2014-01-01

    Hereditary factors are increasingly attracting the interest of behavioral scientists and practitioners. Our aim in the present article is to introduce some state-of-the-art topics in behavioral genetics, as well as selected findings in the field, in order to illustrate how genetic makeup can modulate the impact of environmental factors. We focus on the most-studied polymorphism to date for antisocial responses to adversity: the monoamine oxidase A gene. Advances, caveats, and promises of current research are reviewed. We also discuss implications for the use of genetic information in applied settings. PMID:25114607

  6. Eosinophil-Mediated Tissue Inflammatory Responses in Helminth Infection

    PubMed Central

    Lee, Young Ah; Min, Duk-Young

    2009-01-01

    Eosinophilic leukocytes function in host protection against parasitic worms. In turn, helminthic parasites harbor specific molecules to evade or paralyze eosinophil-associated host immune responses; these molecules facilitate the migration and survival of parasitic helminths in vivo. This competition between eosinophil and worm leads to stable equilibria between them. An understanding of such dynamic host-eosinophil interactions will help us to uncover mechanisms of cross talk between host and parasite in helminth infection. In this review, we examine recent findings regarding the innate immune responses of eosinophils to helminthic parasites, and discuss the implications of these findings in terms of eosinophil-mediated tissue inflammation in helminth infection. PMID:19885328

  7. The dynamic response of a viscoelastic biological tissue simulant

    NASA Astrophysics Data System (ADS)

    Shepherd, Christopher; Appleby-Thomas, Gareth; Hazell, Paul; Allsop, Derek

    2009-06-01

    The development and optimisation of new projectiles requires comparative techniques to assess ballistic performance. Porcine gelatin has found a substantial niche in the ballistics community as a tissue mimic. Primarily due to its elasticity, gelatin has been shown to deform in a similar manner to biological tissues. Bullet impacts typically occur in the 350-850 m/s range and consequently, knowledge of the high strain rate dynamic properties of both the projectile constituents and target materials is desirable if simulations are to allow the optimisation of projectile design. A large body of knowledge exists on the dynamic properties of projectiles, however relatively little data exists in the literature on the dynamic response of flesh simulants. The Hugoniot for a 20 wt% porcine gelatin, which exhibits a ballistic response similar to that of human tissues at room temperature, is determined in this paper using the plate impact technique. Up-Us and Up-P relationships are determined for impact velocities in the range of 200-900 m/s. Good agreement with the limited available data from the literature for similar concentrations is found and the dynamic response established at impact stresses up to 3 times higher than that observed elsewhere. Additionally, high frequency elastic properties are investigated using ultrasound and compared to those observed elsewhere.

  8. Leg tissue mass composition affects tibial acceleration response following impact.

    PubMed

    Schinkel-Ivy, Alison; Burkhart, Timothy A; Andrews, David M

    2012-02-01

    To date, there has not been a direct examination of the effect that tissue composition (lean mass/muscle, fat mass, bone mineral content) differences between males and females has on how the tibia responds to impacts similar to those seen during running. To evaluate this, controlled heel impacts were imparted to 36 participants (6 M and 6 F in each of low, medium and high percent body fat [BF] groups) using a human pendulum. A skin-mounted accelerometer medial to the tibial tuberosity was used to determine the tibial response parameters (peak acceleration, acceleration slope and time to peak acceleration). There were no consistent effects of BF or specific tissue masses on the un-normalized tibial response parameters. However, females experienced 25% greater peak acceleration than males. When normalized to lean mass, wobbling mass, and bone mineral content, females experienced 50%, 62% and 70% greater peak acceleration, respectively, per gram of tissue than males. Higher magnitudes of lean mass and bone mass significantly contributed to decreased acceleration responses in general.

  9. Inflammatory Cytokines as Preclinical Markers of Adverse Responses to Chemical Stressors

    EPA Science Inventory

    Abstract: The in vivo cytokine response to chemical stressors is a promising mainstream tool used to assess potential systemic inflammation and immune function changes. Notably, new instrumentation and statistical analysis provide the selectivity and sensitivity to rapidly diff...

  10. Transcriptome Analysis of B Cell Immune Functions in Periodontitis: Mucosal Tissue Responses to the Oral Microbiome in Aging

    PubMed Central

    Ebersole, Jeffrey L.; Kirakodu, Sreenatha S.; Novak, M. John; Orraca, Luis; Martinez, Janis Gonzalez; Cunningham, Larry L.; Thomas, Mark V.; Stromberg, Arnold; Pandruvada, Subramanya N.; Gonzalez, Octavio A.

    2016-01-01

    Evidence has shown activation of T and B cells in gingival tissues in experimental models and in humans diagnosed with periodontitis. The results of this adaptive immune response are noted both locally and systemically with antigenic specificity for an array of oral bacteria, including periodontopathic species, e.g., Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. It has been recognized through epidemiological studies and clinical observations that the prevalence of periodontitis increases with age. This report describes our studies evaluating gingival tissue transcriptomes in humans and specifically exploiting the use of a non-human primate model of naturally occurring periodontitis to delineate gingival mucosal tissue gene expression profiles focusing on cells/genes critical for the development of humoral adaptive immune responses. Patterns of B cell and plasmacyte genes were altered in aging healthy gingival tissues. Substantial increases in a large number of genes reflecting antigen-dependent activation, B cell activation, B cell proliferation, and B cell differentiation/maturation were observed in periodontitis in adults and aged animals. Finally, evaluation of the relationship of these gene expression patterns with those of various tissue destructive molecules (MMP2, MMP9, CTSK, TNFα, and RANKL) showed a greater frequency of positive correlations in healthy tissues versus periodontitis tissues, with only MMP9 correlations similar between the two tissue types. These results are consistent with B cell response activities in healthy tissues potentially contributing to muting the effects of the tissue destructive biomolecules, whereas with periodontitis this relationship is adversely affected and enabling a progression of tissue destructive events. PMID:27486459

  11. Transcriptome Analysis of B Cell Immune Functions in Periodontitis: Mucosal Tissue Responses to the Oral Microbiome in Aging.

    PubMed

    Ebersole, Jeffrey L; Kirakodu, Sreenatha S; Novak, M John; Orraca, Luis; Martinez, Janis Gonzalez; Cunningham, Larry L; Thomas, Mark V; Stromberg, Arnold; Pandruvada, Subramanya N; Gonzalez, Octavio A

    2016-01-01

    Evidence has shown activation of T and B cells in gingival tissues in experimental models and in humans diagnosed with periodontitis. The results of this adaptive immune response are noted both locally and systemically with antigenic specificity for an array of oral bacteria, including periodontopathic species, e.g., Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. It has been recognized through epidemiological studies and clinical observations that the prevalence of periodontitis increases with age. This report describes our studies evaluating gingival tissue transcriptomes in humans and specifically exploiting the use of a non-human primate model of naturally occurring periodontitis to delineate gingival mucosal tissue gene expression profiles focusing on cells/genes critical for the development of humoral adaptive immune responses. Patterns of B cell and plasmacyte genes were altered in aging healthy gingival tissues. Substantial increases in a large number of genes reflecting antigen-dependent activation, B cell activation, B cell proliferation, and B cell differentiation/maturation were observed in periodontitis in adults and aged animals. Finally, evaluation of the relationship of these gene expression patterns with those of various tissue destructive molecules (MMP2, MMP9, CTSK, TNFα, and RANKL) showed a greater frequency of positive correlations in healthy tissues versus periodontitis tissues, with only MMP9 correlations similar between the two tissue types. These results are consistent with B cell response activities in healthy tissues potentially contributing to muting the effects of the tissue destructive biomolecules, whereas with periodontitis this relationship is adversely affected and enabling a progression of tissue destructive events. PMID:27486459

  12. Is prenatal childbirth preparation effective in decreasing adverse maternal and neonatal response to labor? A nested case-control study.

    PubMed

    Kim, Hyun Hee; Nava-Ocampo, Alejandro A; Kim, Sun Kyung; Kim, Seo Hui; Kim, Yun Ju; Han, Jung Yeol; Ahn, Hyun Kyong; Ryu, Hyun Mee; Yang, Jae Hyug; Kim, Moon Young

    2008-04-01

    Sophrology, based on a combination of Western relaxation therapy and Eastern yoga and meditation might decrease maternal stress during labor. This study aimed to evaluate whether prenatal sophrologic childbirth preparation may decrease maternal and neonatal adverse response associated with delivery. In a nested case-control study, 69 nulliparous, singleton pregnant women who underwent an educational course of sophrologic childbirth preparation were compared to 69 nulliparous, singleton, age- and gestational age-matched pregnant women who did not receive any childbirth preparation. All babies were vaginally delivered. Groups were not different (P > 0.05) in the number of neonates born with meconium-stained amniotic fluid as well as in the number of babies with Apgar score < or = 7 at 1 and 5 minutes after birth. Duration of labor was not different between groups. The number of women requiring oxytocin and delivering babies with low pH blood levels tended to be lower in the group undergoing sophrologic childbirth preparation, i.e. 58.0% vs 72.5% (P = 0.07) and 1.4% vs 10.9% (P = 0.06), respectively. In conclusion, we were unable to confirm that prenatal sophrologic childbirth preparation has a definitive role in decreasing adverse maternal and fetal response to pain or in shortening labor. Prospective cohort studies with a larger sample size or randomized trials may help to clarify this gap.

  13. Injury Response of Resected Human Brain Tissue In Vitro.

    PubMed

    Verwer, Ronald W H; Sluiter, Arja A; Balesar, Rawien A; Baaijen, Johannes C; de Witt Hamer, Philip C; Speijer, Dave; Li, Yichen; Swaab, Dick F

    2015-07-01

    Brain injury affects a significant number of people each year. Organotypic cultures from resected normal neocortical tissue provide unique opportunities to study the cellular and neuropathological consequences of severe injury of adult human brain tissue in vitro. The in vitro injuries caused by resection (interruption of the circulation) and aggravated by the preparation of slices (severed neuronal and glial processes and blood vessels) reflect the reaction of human brain tissue to severe injury. We investigated this process using immunocytochemical markers, reverse transcriptase quantitative polymerase chain reaction and Western blot analysis. Essential features were rapid shrinkage of neurons, loss of neuronal marker expression and proliferation of reactive cells that expressed Nestin and Vimentin. Also, microglia generally responded strongly, whereas the response of glial fibrillary acidic protein-positive astrocytes appeared to be more variable. Importantly, some reactive cells also expressed both microglia and astrocytic markers, thus confounding their origin. Comparison with post-mortem human brain tissue obtained at rapid autopsies suggested that the reactive process is not a consequence of epilepsy.

  14. Quantitative radiation dose-response relationships for normal tissues in man - I. Gustatory tissues response during photon and neutron radiotherapy

    SciTech Connect

    Mossman, K.L.

    1982-08-01

    Quantitative radiation dose-response curves for normal gustatory tissue in man were studied. Taste function, expressed as taste loss, was evaluated in 84 patients who were given either photon or neutron radiotherapy for tumors in the head and neck region. Patients were treated to average tumor doses of 6600 cGy (photon) or 2200 cGy intervals for photon patients and 320-cGy intervals for neutron patients during radiotherapy. The dose-response curves for photons and neutrons were analyzed by fitting a four-parameter logistic equation to the data. Photon and neutron curves differed principally in their relative position along the dose axis. Comparison of the dose-response curves were made by determination of RBE. At 320 cGy, the lowest neutron dose at which taste measurements were made, RBE = 5.7. If this RBE is correct, then the therapeutic gain factor may be equal to or less than 1, indicating no biological advantage in using neutrons over photons for this normal tissue. These studies suggest measurements of taste function and evaluation of dose-response relationships may also be useful in quantitatively evaluating the efficacy of chemical modifiers of radiation response such as hypoxic cell radiosensitizers and radioprotectors.

  15. Optical Interferometric Response of Living Tissue to Cytoskeletal Anticancer Drugs

    NASA Astrophysics Data System (ADS)

    Nolte, David; Jeong, Kwan; Turek, John

    2007-03-01

    Living tissue illuminated by short-coherence light can be optically sectioned in three dimensions using coherent detection such as interferometry. We have developed full-field coherence-gated imaging of tissue using digital holography. Two-dimensional image sections from a fixed depth are recorded as interference fringes with a CCD camera located at the optical Fourier plane. Fast Fourier transform of the digital hologram yields the depth-selected image. When the tissue is living, highly dynamic speckle is observed as fluctuating pixel intensities. The temporal autocorrelation functions are directly related to the degree of motility at depth. We have applied the cytoskeletal drugs nocodazole and colchicine to osteogenic sarcoma multicellular spheroids and observed the response holographically. Colchicine is an anticancer drug that inhibits microtubule polymerization and hence prevents spindle formation during mitosis. Nocodazole, on the other hand, depolymerizes microtubules. Both drugs preferentially inhibit rapidly-dividing cancer cells. We observe dose-response using motility as an effective contrast agent. This work opens the possibility for studies of three-dimensional motility as a multiplexed assay for drug discovery.

  16. Photoacoustic monitoring of tumor and normal tissue response to radiation

    PubMed Central

    Rich, Laurie J.; Seshadri, Mukund

    2016-01-01

    Hypoxia is a recognized characteristic of tumors that influences efficacy of radiotherapy (RT). Photoacoustic imaging (PAI) is a relatively new imaging technique that exploits the optical characteristics of hemoglobin to provide information on tissue oxygenation. In the present study, PAI based measures of tumor oxygen saturation (%sO2) were compared to oxygen-enhanced magnetic resonance imaging (MRI) measurements of longitudinal relaxation rate (R1 = 1/T1) and ex-vivo histology in patient derived xenograft (PDX) models of head and neck cancer. PAI was utilized to assess early changes (24 h) in %sO2 following RT and chemoRT (CRT) and to assess changes in salivary gland hemodynamics following radiation. A significant increase in tumor %sO2 and R1 was observed following oxygen inhalation. Good spatial correlation was observed between PAI, MRI and histology. An early increase in %sO2 after RT and CRT detected by PAI was associated with significant tumor growth inhibition. Twenty four hours after RT, PAI also detected loss of hemodynamic response to gustatory stimulation in murine salivary gland tissue suggestive of radiation-induced vascular damage. Our observations illustrate the utility of PAI in detecting tumor and normal tissue hemodynamic response to radiation in head and neck cancers. PMID:26883660

  17. The Confluence of Adverse Early Experience and Puberty on the Cortisol Awakening Response

    ERIC Educational Resources Information Center

    Quevedo, Karina; Johnson, Anna E.; Loman, Michelle L.; LaFavor, Theresa L.; Gunnar, Megan

    2012-01-01

    Associations between early deprivation/neglect in the form of institutional care with the cortisol awakening response (CAR) were examined as a function of pubertal status among 12- and 13-year-old postinstitutionalized youth. CARs indexed hypothalamic-pituitary-adrenocortical reactivity. Postinstitutionalized youth were compared to youth adopted…

  18. Tissue engineering tools for modulation of the immune response

    PubMed Central

    Boehler, Ryan M.; Graham, John G.; Shea, Lonnie D.

    2012-01-01

    Tissue engineering scaffolds have emerged as a powerful tool within regenerative medicine. These materials are being designed to create environments that promote regeneration through a combination of: (i) scaffold architecture, (ii) the use of scaffolds as vehicles for transplanting progenitor cells, and/or (iii) localized delivery of inductive factors or genes encoding for these inductive factors. This review describes the techniques associated with each of these components. Additionally, the immune response is increasingly recognized as a factor influencing regeneration. The immune reaction to an implant begins with an acute response to the injury and innate recognition of foreign materials, with the subsequent chronic immune response involving specific recognition of antigens (e.g., transplanted cells) by the adaptive immune response, which can eventually lead to rejection of the implant. Thus, we also describe the impact of each component on the immune response, and strategies (e.g., material design, anti-inflammatory cytokine delivery, and immune cell recruitment/transplantation) to modulate, yet not eliminate, the local immune response in order to promote regeneration, which represents another important tool for regenerative medicine. PMID:21988690

  19. Diagnosis and Management of Adverse Local Tissue Reactions Secondary to Corrosion at the Head-Neck Junction in Patients With Metal on Polyethylene Bearings.

    PubMed

    Plummer, Darren R; Berger, Richard A; Paprosky, Wayne G; Sporer, Scott M; Jacobs, Joshua J; Della Valle, Craig J

    2016-01-01

    We reviewed 27 patients who underwent revision for an adverse local tissue reaction (ALTR) secondary to corrosion at the head-neck junction with MoP bearings. Serum cobalt and chromium levels were elevated in all cases, with a mean cobalt of 11.2 ppb and chromium of 2.2 ppb. Patients underwent modular bearing exchange, including a ceramic head with a titanium sleeve in 23 of 27 cases with only one recurrence of ALTR in one of the four patients not treated with a ceramic head. The diagnosis of ALTR secondary to corrosion is associated with cobalt levels of >1 ppb with cobalt levels elevated above chromium. Retention of a well-fixed stem and modular exchange to a ceramic head leads to resolution of symptoms and decreases in metal levels.

  20. Selection for Genetic Variation Inducing Pro-Inflammatory Responses under Adverse Environmental Conditions in a Ghanaian Population

    PubMed Central

    Kuningas, Maris; May, Linda; Tamm, Riin; van Bodegom, David; van den Biggelaar, Anita H. J.; Meij, Johannes J.; Frölich, Marijke; Ziem, Juventus B.; Suchiman, Helena E. D.; Metspalu, Andres; Slagboom, P. Eline; Westendorp, Rudi G. J.

    2009-01-01

    Background Chronic inflammation is involved in the pathogenesis of chronic age-associated, degenerative diseases. Pro-inflammatory host responses that are deleterious later in life may originate from evolutionary selection for genetic variation mediating resistance to infectious diseases under adverse environmental conditions. Methodology/Principal Findings In the Upper-East region of Ghana where infection has remained the leading cause of death, we studied the effect on survival of genetic variations at the IL10 gene locus that have been associated with chronic diseases. Here we show that an IL10 haplotype that associated with a pro-inflammatory innate immune response, characterised by low IL-10 (p = 0.028) and high TNF-α levels (p = 1.39×10−3), was enriched among Ghanaian elders (p = 2.46×10−6). Furthermore, in an environment where the source of drinking water (wells/rivers vs. boreholes) influences mortality risks (HR 1.28, 95% CI [1.09–1.50]), we observed that carriers of the pro-inflammatory haplotype have a survival advantage when drinking from wells/rivers but a disadvantage when drinking from boreholes (pinteraction = 0.013). Resequencing the IL10 gene region did not uncover any additional common variants in the pro-inflammatory haplotype to those SNPs that were initially genotyped. Conclusions/Significance Altogether, these data lend strong arguments for the selection of pro-inflammatory host responses to overcome fatal infection and promote survival in adverse environments. PMID:19907653

  1. Transgenic zebrafish reveal tissue-specific differences in estrogen signaling in response to environmental water samples

    USGS Publications Warehouse

    Gorelick, Daniel A.; Iwanowicz, Luke R.; Hung, Alice L.; Blazer, Vicki; Halpern, Marnie E.

    2014-01-01

    Background: Environmental endocrine disruptors (EED) are exogenous chemicals that mimic endogenous hormones, such as estrogens. Previous studies using a zebrafish transgenic reporter demonstrated that the EEDs bisphenol A and genistein preferentially activate estrogen receptors (ER) in the larval heart compared to the liver. However, it was not known whether the transgenic zebrafish reporter was sensitive enough to detect estrogens from environmental samples, whether environmental estrogens would exhibit similar tissue-specific effects as BPA and genistein or why some compounds preferentially target receptors in the heart. Methods: We tested surface water samples using a transgenic zebrafish reporter with tandem estrogen response elements driving green fluorescent protein expression (5xERE:GFP). Reporter activation was colocalized with tissue-specific expression of estrogen receptor genes by RNA in situ hybridization. Results: Selective patterns of ER activation were observed in transgenic fish exposed to river water samples from the Mid-Atlantic United States, with several samples preferentially activating receptors in embryonic and larval heart valves. We discovered that tissue-specificity in ER activation is due to differences in the expression of estrogen receptor subtypes. ERα is expressed in developing heart valves but not in the liver, whereas ERβ2 has the opposite profile. Accordingly, subtype-specific ER agonists activate the reporter in either the heart valves or the liver. Conclusion: The use of 5xERE:GFP transgenic zebrafish has revealed an unexpected tissue-specific difference in the response to environmentally relevant estrogenic compounds. Exposure to estrogenic EEDs in utero is associated with adverse health effects, with the potentially unanticipated consequence of targeting developing heart valves.

  2. Tissue communication in a systemic immune response of Drosophila

    PubMed Central

    Yang, Hairu; Hultmark, Dan

    2016-01-01

    ABSTRACT Several signaling pathways, including the JAK/STAT and Toll pathways, are known to activate blood cells (hemocytes) in Drosophila melanogaster larvae. They are believed to regulate the immune response against infections by parasitoid wasps, such as Leptopilina boulardi, but how these pathways control the hemocytes is not well understood. Here, we discuss the recent discovery that both muscles and fat body take an active part in this response. Parasitoid wasp infection induces Upd2 and Upd3 secretion from hemocytes, leading to JAK/STAT activation mainly in hemocytes and in skeletal muscles. JAK/STAT activation in muscles, but not in hemocytes, is required for an efficient encapsulation of wasp eggs. This suggests that Upd2 and Upd3 are important cytokines, coordinating different tissues for the cellular immune response in Drosophila. In the fat body, Toll signaling initiates a systemic response in which hemocytes are mobilized and activated hemocytes (lamellocytes) are generated. However, the contribution of Toll signaling to the defense against wasps is limited, probably because the wasps inject inhibitors that prevent the activation of the Toll pathway. In conclusion, parasite infection induces a systemic response in Drosophila larvae involving major organ systems and probably the physiology of the entire organism. PMID:27116253

  3. Tissue communication in a systemic immune response of Drosophila.

    PubMed

    Yang, Hairu; Hultmark, Dan

    2016-07-01

    Several signaling pathways, including the JAK/STAT and Toll pathways, are known to activate blood cells (hemocytes) in Drosophila melanogaster larvae. They are believed to regulate the immune response against infections by parasitoid wasps, such as Leptopilina boulardi, but how these pathways control the hemocytes is not well understood. Here, we discuss the recent discovery that both muscles and fat body take an active part in this response. Parasitoid wasp infection induces Upd2 and Upd3 secretion from hemocytes, leading to JAK/STAT activation mainly in hemocytes and in skeletal muscles. JAK/STAT activation in muscles, but not in hemocytes, is required for an efficient encapsulation of wasp eggs. This suggests that Upd2 and Upd3 are important cytokines, coordinating different tissues for the cellular immune response in Drosophila. In the fat body, Toll signaling initiates a systemic response in which hemocytes are mobilized and activated hemocytes (lamellocytes) are generated. However, the contribution of Toll signaling to the defense against wasps is limited, probably because the wasps inject inhibitors that prevent the activation of the Toll pathway. In conclusion, parasite infection induces a systemic response in Drosophila larvae involving major organ systems and probably the physiology of the entire organism. PMID:27116253

  4. Cellular Responses and Tissue Depots for Nanoformulated Antiretroviral Therapy

    PubMed Central

    Martinez-Skinner, Andrea L.; Araínga, Mariluz A.; Puligujja, Pavan; Palandri, Diana L.; Baldridge, Hannah M.; Edagwa, Benson J.; McMillan, JoEllyn M.; Mosley, R. Lee; Gendelman, Howard E.

    2015-01-01

    Long-acting nanoformulated antiretroviral therapy (nanoART) induces a range of innate immune migratory, phagocytic and secretory cell functions that perpetuate drug depots. While recycling endosomes serve as the macrophage subcellular depots, little is known of the dynamics of nanoART-cell interactions. To this end, we assessed temporal leukocyte responses, drug uptake and distribution following both intraperitoneal and intramuscular injection of nanoformulated atazanavir (nanoATV). Local inflammatory responses heralded drug distribution to peritoneal cell populations, regional lymph nodes, spleen and liver. This proceeded for three days in male Balb/c mice. NanoATV-induced changes in myeloid populations were assessed by fluorescence-activated cell sorting (FACS) with CD45, CD3, CD11b, F4/80, and GR-1 antibodies. The localization of nanoATV within leukocyte cell subsets was determined by confocal microscopy. Combined FACS and ultra-performance liquid chromatography tandem mass-spectrometry assays determined nanoATV carriages by cell-based vehicles. A robust granulocyte, but not peritoneal macrophage nanoATV response paralleled zymosan A treatment. ATV levels were highest at sites of injection in peritoneal or muscle macrophages, dependent on the injection site. The spleen and liver served as nanoATV tissue depots while drug levels in lymph nodes were higher than those recorded in plasma. Dual polymer and cell labeling demonstrated a nearly exclusive drug reservoir in macrophages within the liver and spleen. Overall, nanoART induces innate immune responses coincident with rapid tissue macrophage distribution. Taken together, these works provide avenues for therapeutic development designed towards chemical eradication of human immunodeficiency viral infection. PMID:26716700

  5. Tissue engineering of electrically responsive tissues using polyaniline based polymers: a review.

    PubMed

    Qazi, Taimoor H; Rai, Ranjana; Boccaccini, Aldo R

    2014-11-01

    Conducting polymers have found numerous applications as biomaterial components serving to effectively deliver electrical signals from an external source to the seeded cells. Several cell types including cardiomyocytes, neurons, and osteoblasts respond to electrical signals by improving their functional outcomes. Although a wide variety of conducting polymers are available, polyaniline (PANI) has emerged as a popular choice due to its attractive properties such as ease of synthesis, tunable conductivity, environmental stability, and biocompatibility. PANI in its pure form has exhibited biocompatibility both in vitro and in vivo, and has been combined with a host of biodegradable polymers to form composites having a range of mechanical, electrical, and surface properties. Moreover, recent studies in literature report on the functionalization of polyaniline oligomers with end segments that make it biodegradable and improve its biocompatibility, two properties which make these materials highly desirable for applications in tissue engineering. This review will discuss the features and properties of PANI based composites that make them effective biomaterials, and it provides a comprehensive summary of studies where the use of PANI as a biomaterial component has enhanced cellular function and behavior. We also discuss recent studies utilizing functionalized PANI oligomers, and conclude that electroactive PANI and its derivatives show great promise in eliciting favorable responses from various cell lines that respond to electrical stimuli, and are therefore effective biomaterials for the engineering of electrically responsive biological tissues and organs.

  6. Risk of Crew Adverse Health Event Due to Altered Immune Response

    NASA Technical Reports Server (NTRS)

    Crucian, Brian; Kunz, Hawley; Sams, Clarence F.

    2015-01-01

    Determining the effect of space travel on the human immune system has proven to be extremely challenging. Limited opportunities for in-flight studies, varying mission durations, technical and logistical obstacles, small subject numbers, and a broad range of potential assays have contributed to this problem. Additionally, the inherent complexity of the immune system, with its vast array of cell populations, sub-populations, diverse regulatory molecules, and broad interactions with other physiological systems, makes determining precise variables to measure very difficult. There is also the challenge of determining the clinical significance of any observed immune alterations. Will such a change lead to disease, or is it a transient subclinical observation related to short-term stress? The effect of this problem may be observed by scanning publications associated with immunity and spaceflight, which began to appear during the 1970s. Although individually they are each valid studies, the comprehensive literature to date suffers from widely varying sampling methods and assay techniques, low subject counts, and sometimes a disparate focus on narrow aspects of immunity. The most clinically relevant data are derived from in-flight human studies, which have demonstrated altered cell-mediated immunity and reactivation of latent herpes viruses. Much more data are available from post-flight testing of humans, with clear evidence of altered cytokine production patterns, altered leukocyte distribution, continued latent viral reactivation, and evidence of dramatically altered virus-specific immunity. It is unknown if post-flight assessments relate to the in-flight condition or are a response to landing stress and readaptation. In-flight culture of cells has clearly demonstrated that immune cells are gravity-sensitive and display altered functional characteristics. It is unknown if these data are related to in vivo immune cell function or are an artifact of microgravity culture

  7. Tissue-specific metabolic responses of Cyprinus flammans to copper.

    PubMed

    Hu, Ming-Yan; Ye, Yang-Fang; Xue, Liang-Yi; Tang, Ze-Yuan

    2015-07-01

    Copper (Cu) contamination is serious in China, with ≤2.76 mg/L in some waters. Exposure to Cu causes a high toxicity to the aquatic organisms and subsequent ecological risk. To understand fish responses to Cu exposure, we analyzed the metabonomic changes in multiple tissues (gill, liver, and muscle) of Cyprinus flammans using an nuclear magnetic resonance-based metabonomic technique. Our results showed that metabolic alterations are dose-dependent. No significant metabolic alterations in three tissues of fish are caused by 0.25 mg/L Cu. However, 1.53 mg/L Cu caused changes of energy-related metabolites and amino acids, which we suggest are due to enhanced metabolic acidosis in gill and muscle, decreased tricarboxylic acid cycle activity in muscle, increased gluconeogenesis from amino acids in liver, and improved glycogenesis in liver and muscle. The Cori cycle between liver and muscle is concurrently triggered. Furthermore, high concentration of Cu resulted in the alteration of choline metabolism such that we hypothesize that Cu induces membrane damage and detoxification of CuSO4 in gill as well as altered osmoregulation in all three tissues. Choline-O-sulfate in gill may be used as a biomarker to provide an early warning of Cu exposure in C. flammans. Moreover, Cu exposure caused alterations of nucleoside and nucleotide metabolism in both gill and muscle. These findings provide a new insight into the metabolic effects of Cu exposure on C. flammans and highlight the value of metabonomics in the study of metabolic metal disturbance in fish.

  8. Urinary Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) • Insulin-Like Growth Factor-Binding Protein 7 (IGFBP7) Predicts Adverse Outcome in Pediatric Acute Kidney Injury

    PubMed Central

    Westhoff, Jens H.; Tönshoff, Burkhard; Waldherr, Sina; Pöschl, Johannes; Teufel, Ulrike; Westhoff, Timm H.; Fichtner, Alexander

    2015-01-01

    Background The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet. Methods The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheck™) in a prospective cohort study in 133 subjects aged 0–18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1). Results When AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category “Risk”, 13/46 (28%) for “Injury”, 26/46 (57%) for “Failure” and 1/46 (2%) for “Loss”. Patients in the “Failure” stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P<0.001). When analyzed for AKI etiology, highest [TIMP-2]•[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II). Receiver operating characteristic (ROC) curve analyses in the AKI group revealed good performance of [TIMP-2]•[IGFBP7] in predicting 30-day (area under the curve (AUC) 0.79; 95% CI, 0.61–0.97) and 3-month mortality (AUC 0.84; 95% CI, 0.67–0.99) and moderate performance in predicting RRT

  9. Factors contributing to adverse soft tissue reactions due to the use of tartar control toothpastes: report of a case and literature review.

    PubMed

    DeLattre, V F

    1999-07-01

    Tetrasodium and/or tetrapotassium pyrophosphate (Ppi) is the anticalculus component of most tartar control dentifrices on the market today. While pyrophosphates alone are not responsible for hypersensitivity reactions, several modifications which may lead to adverse oral manifestations may occur when pyrophosphates are added to a dentifrice. First, tetrasodium pyrophosphate in a dentifrice forms a slightly alkaline solution upon oral use which could irritate oral membranes. Second, increased concentrations of flavoring agents, known to be sensitizers, are needed to mask the strong bitter taste of pyrophosphates. Third, increased concentrations of detergents, capable of producing hypersensitivity reactions, are necessary to allow the pyrophosphates to become soluble in the dentifrice. Fourth, a pre-existing condition of reduced salivary flow may augment hypersensitivity to tartar control toothpastes. While pyrophosphates have been approved as additives in dentifrices, these compounds along with the increased concentrations of flavorings and detergents and their higher intraoral alkalinity are strongly implicated as the causative factor in certain hypersensitivity reactions.

  10. Tissue response to the components of a hydroxyapatite-coated composite femoral implant.

    PubMed

    Hacking, S A; Pauyo, T; Lim, L; Legoux, J G; Bureau, M N

    2010-09-01

    Bone loss around femoral implants used for THA is a persistent clinical concern. It may be caused by stress shielding, generally attributed to a mismatch in stiffness between the implants and host bone. In this regard, a fatigue resistant, carbon fiber (CF) composite femoral implant with bone-matching stiffness has been developed. This study evaluated the tissue response to the three material components of this implant in normal and textured (blasted with 24 grit alumina) surfaces: the hydroxyapatite (HA) coating, the CF composite and the intermediate crystalline HA particulate composite layer to bond to the HA coating (blended). Sprague-Dawley rats underwent bilateral femoral implantation each receiving two rod-like implants. Bone apposition to the HA (37%) and textured Ti (41%) implants was not significantly different. Bone apposition to the untextured CF (14%) and blended (19%) implants and polished Ti (8%) implants was significantly lower. Bone apposition to the textured CF (9%) and blended (11%) implants was lower (but not statistically from the as received or untextured counterparts). Nearly all sections from femurs containing CF implants presented CF debris. There was no evidence of localized bone loss or any strong immune response associated with any of the implant materials. All materials were well tolerated with minimal inflammation despite the presence of particulate debris. The high degree of bone apposition to the HA-coated composite implants and the lack of short-term inflammation and adverse tissue response to the three material implant component support continued evaluation of this composite technology for use in THA. PMID:20730932

  11. Adverse Impact of Diet-Induced Hypercholesterolemia on Cardiovascular Tissue Homeostasis in a Rabbit Model: Time-Dependent Changes in Cardiac Parameters

    PubMed Central

    Kertész, Attila; Bombicz, Mariann; Priksz, Daniel; Balla, Jozsef; Balla, Gyorgy; Gesztelyi, Rudolf; Varga, Balazs; Haines, David D.; Tosaki, Arpad; Juhasz, Bela

    2013-01-01

    The present study evaluates a hypothesis that diet-related hypercholesterolemia increases oxidative stress-related burden to cardiovascular tissue, resulting in progressively increased mortality, along with deterioration of electrophysiological and enzymatic function in rabbit myocardium. New Zealand white rabbits were divided into four groups, defined as follows: GROUP I, cholesterol-free rabbit chow for 12 weeks; GROUP II, cholesterol-free chow, 40 weeks; GROUP III, chow supplemented with 2% cholesterol, 12 weeks; GROUP IV, chow supplemented with 2% cholesterol, 40 weeks. At the 12 and 40 weeks time points, animals in each of the aforementioned cohorts were subjected to echocardiographic measurements, followed by sacrifice. Significant deterioration in major outcome variables measured in the present study were observed only in animals maintained for 40 weeks on 2% cholesterol-supplemented chow, with much lesser adverse effects noted in animals fed high cholesterol diets for only 12 weeks. It was observed that rabbits receiving high cholesterol diets for 40 weeks exhibited significantly increased mortality, worsened ejection fraction and general deterioration of cardiac functions, along with increased atherosclerotic plaque formation and infarct size. Additionally, myocardium of GROUP IV animals was observed to contain lower levels of heme oxygenase-1 (HO-1) and cytochrome c oxidase III (COX III) protein relative to the controls. PMID:24048247

  12. Insulin Regulates the Unfolded Protein Response in Human Adipose Tissue

    PubMed Central

    Boden, Guenther; Cheung, Peter; Salehi, Sajad; Homko, Carol; Loveland-Jones, Catherine; Jayarajan, Senthil; Stein, T. Peter; Williams, Kevin Jon; Liu, Ming-Lin; Barrero, Carlos A.; Merali, Salim

    2014-01-01

    Endoplasmic reticulum (ER) stress is increased in obesity and is postulated to be a major contributor to many obesity-related pathologies. Little is known about what causes ER stress in obese people. Here, we show that insulin upregulated the unfolded protein response (UPR), an adaptive reaction to ER stress, in vitro in 3T3-L1 adipocytes and in vivo, in subcutaneous (sc) adipose tissue of nondiabetic subjects, where it increased the UPR dose dependently over the entire physiologic insulin range (from ∼35 to ∼1,450 pmol/L). The insulin-induced UPR was not due to increased glucose uptake/metabolism and oxidative stress. It was associated, however, with increased protein synthesis, with accumulation of ubiquitination associated proteins, and with multiple posttranslational protein modifications (acetylations, methylations, nitrosylations, succinylation, and ubiquitinations), some of which are potential causes for ER stress. These results reveal a new physiologic role of insulin and provide a putative mechanism for the development of ER stress in obesity. They may also have clinical and therapeutic implications, e.g., in diabetic patients treated with high doses of insulin. PMID:24130338

  13. In vivo tissue responses to thermal-responsive shape memory polymer nanocomposites.

    PubMed

    Filion, Tera M; Xu, Jianwen; Prasad, Manju L; Song, Jie

    2011-02-01

    To explore the safe use of thermal-responsive shape memory polymers (SMPs) as minimally invasive tissue scaffolds, we recently developed a class of biodegradable POSS-SMP nanocomposites exhibiting stable temporary shape fixing and facile shape recovery within a narrow window of physiological temperatures. The materials were covalently crosslinked from star-branched building blocks consisting a bioinert polyhedral oligomeric silsesquioxane (POSS) core and 8 degradable poly(D,L-lactide) (PLA) arms. Here we examine the degradation profiles and immunogenicity of POSS-SMPs as a function of the PLA arm lengths using a rat subcutaneous implantation model. We show that POSS-SMPs elicited a mild foreign body type immune response upon implantation. The degradation rates of POSS-SMPs, both in vitro and in vivo, inversely correlated with the length of the PLA chains within the crosslinked amorphous network. Upon in vivo degradation of POSS-SMPs, a second acute inflammatory response was elicited locally, and the inflammation was able to resolve over time without medical interventions. One year after the implantation of POSS-SMPs, no pathologic abnormalities were detected from the vital/scavenger organs examined. These minimally immunogenic and biodegradable SMPs are promising candidates for scaffold-assisted tissue repair where both facile surgical delivery and controlled degradation of the scaffold are desired for achieving optimal short-term and long-term clinical outcomes.

  14. Tissue specificity of the hormonal response in sex accessory tissues is associated with nuclear matrix protein patterns.

    PubMed

    Getzenberg, R H; Coffey, D S

    1990-09-01

    The DNA of interphase nuclei have very specific three-dimensional organizations that are different in different cell types, and it is possible that this varying DNA organization is responsible for the tissue specificity of gene expression. The nuclear matrix organizes the three-dimensional structure of the DNA and is believed to be involved in the control of gene expression. This study compares the nuclear structural proteins between two sex accessory tissues in the same animal responding to the same androgen stimulation by the differential expression of major tissue-specific secretory proteins. We demonstrate here that the nuclear matrix is tissue specific in the rat ventral prostate and seminal vesicle, and undergoes characteristic alterations in its protein composition upon androgen withdrawal. Three types of nuclear matrix proteins were observed: 1) nuclear matrix proteins that are different and tissue specific in the rat ventral prostate and seminal vesicle, 2) a set of nuclear matrix proteins that either appear or disappear upon androgen withdrawal, and 3) a set of proteins that are common to both the ventral prostate and seminal vesicle and do not change with the hormonal state of the animal. Since the nuclear matrix is known to bind androgen receptors in a tissue- and steroid-specific manner, we propose that the tissue specificity of the nuclear matrix arranges the DNA in a unique conformation, which may be involved in the specific interaction of transcription factors with DNA sequences, resulting in tissue-specific patterns of secretory protein expression.

  15. Tissue response to implanted ceramic-coated titanium alloys in rats.

    PubMed

    Satomi, K; Akagawa, Y; Nikai, H; Tsuru, H

    1988-07-01

    In order to assess the tissue compatibility of the hybrid materials for the dental implant (hydroxyapatite, titanium oxide and titanium nitride coated titanium alloys), tissue response to these materials implanted in the rat subcutaneous tissue was histologically examined. Initial inflammatory response was less evident in titanium oxide coated and non-coated titanium alloys. All materials were encapsulated by thin fibrous connective tissues. The membrane thickness of hydroxyapatite coated titanium alloy was significantly higher than that of titanium nitride coated one. These results suggest that all materials possess favourable tissue compatibility and may encourage clinical use as the dental implant.

  16. Mobilizing resilience and recovery in response to adverse childhood experiences (ACE): a Restorative Integral Support (RIS) case study.

    PubMed

    Larkin, Heather; Beckos, Brooke A; Shields, Joseph J

    2012-01-01

    The Restorative Integral Support (RIS) model is a comprehensive, whole person approach to addressing adversity and trauma. The Adverse Childhood Experiences (ACE) Study conducted by the Centers for Disease Control (CDC) and Kaiser Permanente reveals a relationship between childhood trauma and adult health and social problems. The current empirical case study presents the Committee on the Shelterless (COTS), in Petaluma, CA, as an example of one social service agency employing RIS to break cycles of homelessness. By applying RIS, research-based programming is offered within a culture of recovery that mobilizes resilience through social affiliations. The authors recommend RIS model implementation and research in programs serving populations with ACE backgrounds.

  17. Postnatal stability, tissue, and time specific effects of AHRR methylation change in response to maternal smoking in pregnancy.

    PubMed

    Novakovic, Boris; Ryan, Joanne; Pereira, Natalie; Boughton, Berin; Craig, Jeffrey M; Saffery, Richard

    2014-03-01

    The intrauterine environment has the potential to "program" the developing fetus in a way that can be potentially deleterious to later health. While in utero environmental/stochastic factors are known to influence DNA methylation profile at birth, it has been difficult to assign specific examples of epigenetic variation to specific environmental exposures. Recently, several studies have linked exposure to smoking with DNA methylation change in the aryl hydrocarbon receptor repressor (AHRR) gene in blood. This includes hypomethylation of AHRR in neonatal blood in response to maternal smoking in pregnancy. The role of AHRR as a negative regulator of pathways involved in pleiotropic responses to environmental contaminants raises the possibility that smoking-induced hypomethylation is an adaptive response to an adverse in utero environmental exposure. However, the tissue specificity of the response to maternal smoking, and the stability of the methylation changes early in life remain to be determined. In this study we analyzed AHRR methylation in three cell types-cord blood mononuclear cells (CBMCs), buccal epithelium, and placenta tissue-from newborn twins of mothers who smoked throughout pregnancy and matched controls. Further, we explored the postnatal stability of this change at 18 months. Our results confirm the previous association between maternal smoking and AHRR methylation in neonatal blood. In addition, this study expands the region of AHRR methylation altered in response to maternal smoking during pregnancy and reveals the tissue-specific nature of epigenetic responses to environmental exposures in utero. Further, the evidence for postnatal stability of smoking-induced epigenetic change supports a role for epigenetics as a mediator of long-term effects of specific in utero exposures in humans. Longitudinal analysis of further specific exposures in larger cohorts is required to examine the extent of this phenomenon in humans.

  18. 41 CFR 102-78.40 - What responsibilities do Federal agencies have when an undertaking adversely affects a historic...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Federal agencies have when an undertaking adversely affects a historic or cultural property? 102-78.40... or cultural property? Federal agencies must not perform an undertaking that could alter, destroy, or modify an historic or cultural property until they have consulted with the SHPO and the Advisory...

  19. 41 CFR 102-78.40 - What responsibilities do Federal agencies have when an undertaking adversely affects a historic...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... guidance on the protection of historic and cultural properties in 36 CFR part 800. ... Federal agencies have when an undertaking adversely affects a historic or cultural property? 102-78.40... (Continued) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 78-HISTORIC PRESERVATION Historic Preservation §...

  20. Trends in anti-D immune globulin for childhood immune thrombocytopenia: Usage, response rates, and adverse effects

    PubMed Central

    Long, Michelle; Kalish, Leslie A.; Neufeld, Ellis J.; Grace, Rachael F.

    2013-01-01

    In 2010, the Food and Drug Administration (FDA) added a black box warning to anti-D immune globulin (Rho(D) immune globulin, anti-D) for immune thrombocytopenia (ITP) to warn of the complications related to severe hemolysis. The objective of this retrospective medical record review was to examine recent trends in anti-D use to treat ITP and rates of adverse events in a single large pediatric hematology program. Over a 7-year period, 176 (35%) of 502 ITP patients at our center received anti-D. Anti-D was the second most commonly prescribed drug for ITP from 2003 to 2010 overall and was given first most frequently (41%). Sixty-four percent of patients responded to anti-D, but 36% had adverse effects, including five patients requiring hospitalization. From 2003 to 2010, the use of anti-D as an initial therapy for ITP significantly decreased (P < 0.001). This trend preceded the 2010 FDA black box warning. In our experience, anti-D was associated with a significant number of adverse effects when used as a treatment for ITP, although none were life-threatening. Despite recent guidelines suggesting anti-D therapy for initial treatment for ITP, anti-D therapy for ITP has significantly decreased over the past 7 years. PMID:22190130

  1. Trends in anti-D immune globulin for childhood immune thrombocytopenia: usage, response rates, and adverse effects.

    PubMed

    Long, Michelle; Kalish, Leslie A; Neufeld, Ellis J; Grace, Rachael F

    2012-03-01

    In 2010, the Food and Drug Administration (FDA) added a black box warning to anti-D immune globulin (Rho(D) immune globulin, anti-D) for immune thrombocytopenia (ITP) to warn of the complications related to severe hemolysis. The objective of this retrospective medical record review was to examine recent trends in anti-D use to treat ITP and rates of adverse events in a single large pediatric hematology program. Over a 7-year period, 176 (35%) of 502 ITP patients at our center received anti-D. Anti-D was the second most commonly prescribed drug for ITP from 2003 to 2010 overall and was given first most frequently (41%). Sixty-four percent of patients responded to anti-D, but 36% had adverse effects, including five patients requiring hospitalization. From 2003 to 2010, the use of anti-D as an initial therapy for ITP significantly decreased (P < 0.001). This trend preceded the 2010 FDA black box warning. In our experience, anti-D was associated with a significant number of adverse effects when used as a treatment for ITP, although none were life-threatening. Despite recent guidelines suggesting anti-D therapy for initial treatment for ITP, anti-D therapy for ITP has significantly decreased over the past 7 years.

  2. Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics

    PubMed Central

    McDonough, Caitrin W.; Burbage, Sarah E.; Duarte, Julio D.; Gong, Yan; Langaee, Taimour Y.; Turner, Stephen T.; Gums, John G.; Chapman, Arlene B.; Bailey, Kent R.; Beitelshees, Amber L.; Boerwinkle, Eric; Pepine, Carl J.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.

    2013-01-01

    Objective Single-nucleotide polymorphisms (SNPs) in NEDD4L may influence the ability of the NEDD4L protein to reduce epithelial sodium channel expression. A variant in NEDD4L, rs4149601, was associated with antihypertensive response and cardiovascular outcomes during treatment with thiazide diuretics and β-blockers in a Swedish population. We sought to further evaluate associations between NEDD4L polymorphisms, blood pressure response and cardiovascular outcomes with thiazide diuretics and β-blockers. Methods Four SNPs, rs4149601, rs292449, rs1008899 and rs75982813, were genotyped in 767 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) clinical trial and association was assessed with blood pressure response to hydrochlorothiazide and atenolol. One SNP, rs4149601, was also genotyped in 1345 patients from the International Verapmil SR Trandolapril Study (INVEST), and association was examined with adverse cardiovascular outcomes relative to hydrochlorothiazide treatment. Results Significant associations or trends were found between rs4149601, rs292449, rs75982813 and rs1008899 and decreases in blood pressure in whites on hydrochlorothiazide, and a significant association was observed with increasing copies of the GC rs4149601-rs292449 haplotype and greater blood pressure response to hydrochlorothiazide in whites (P = 0.0006 and 0.006, SBP and DBP, respectively). Significant associations were also seen with rs4149601 and an increased risk for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide [P = 0.022, odds ratio (95% confidence interval) = 10.65 (1.18–96.25)]. Conclusion NEDD4L rs4149601, rs292449 and rs75982813 may be predictors for blood pressure response to hydrochlorothiazide in whites, and NEDD4L rs4149601 may be a predictor for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide. PMID:23353631

  3. Multiaxial mechanical response and constitutive modeling of esophageal tissues: Impact on esophageal tissue engineering.

    PubMed

    Sommer, Gerhard; Schriefl, Andreas; Zeindlinger, Georg; Katzensteiner, Andreas; Ainödhofer, Herwig; Saxena, Amulya; Holzapfel, Gerhard A

    2013-12-01

    Congenital defects of the esophagus are relatively frequent, with 1 out of 2500 babies suffering from such a defect. A new method of treatment by implanting tissue engineered esophagi into newborns is currently being developed and tested using ovine esophagi. For the reconstruction of the biological function of native tissues with engineered esophagi, their cellular structure as well as their mechanical properties must be considered. Since very limited mechanical and structural data for the esophagus are available, the aim of this study was to investigate the multiaxial mechanical behavior of the ovine esophagus and the underlying microstructure. Therefore, uniaxial tensile, biaxial tensile and extension-inflation tests on esophagi were performed. The underlying microstructure was examined in stained histological sections through standard optical microscopy techniques. Moreover, the uniaxial ultimate tensile strength and residual deformations of the tissue were determined. Both the mucosa-submucosa and the muscle layers showed nonlinear and anisotropic mechanical behavior during uniaxial, biaxial and inflation testing. Cyclical inflation of the intact esophageal tube caused marked softening of the passive esophagi in the circumferential direction. The rupture strength of the mucosa-submucosa layer was much higher than that of the muscle layer. Overall, the ovine esophagus showed a heterogeneous and anisotropic behavior with different mechanical properties for the individual layers. The intact and layer-specific multiaxial properties were characterized using a well-known three-dimensional microstructurally based strain-energy function. This novel and complete set of data serves the basis for a better understanding of tissue remodeling in diseased esophagi and can be used to perform computer simulations of surgical interventions or medical-device applications.

  4. Computational methods for describing the laser-induced mechanical response of tissue

    SciTech Connect

    Trucano, T.; McGlaun, J.M.; Farnsworth, A.

    1994-02-01

    Detailed computational modeling of laser surgery requires treatment of the photoablation of human tissue by high intensity pulses of laser light and the subsequent thermomechanical response of the tissue. Three distinct physical regimes must be considered to accomplish this: (1) the immediate absorption of the laser pulse by the tissue and following tissue ablation, which is dependent upon tissue light absorption characteristics; (2) the near field thermal and mechanical response of the tissue to this laser pulse, and (3) the potential far field (and longer time) mechanical response of witness tissue. Both (2) and (3) are dependent upon accurate constitutive descriptions of the tissue. We will briefly review tissue absorptivity and mechanical behavior, with an emphasis on dynamic loads characteristic of the photoablation process. In this paper our focus will center on the requirements of numerical modeling and the uncertainties of mechanical tissue behavior under photoablation. We will also discuss potential contributions that computational simulations can make in the design of surgical protocols which utilize lasers, for example, in assessing the potential for collateral mechanical damage by laser pulses.

  5. Responses of the pulp, periradicular and soft tissues following trauma to the permanent teeth.

    PubMed

    Yu, C Y; Abbott, P V

    2016-03-01

    Trauma to the permanent teeth involves not only the teeth but also the pulp, the periodontal ligament, alveolar bone, gingiva and other associated structures. There are many variations in the types of injuries with varying severity and often a tooth may sustain more than one injury at the same time. In more severe trauma cases, there are many different cellular systems of mineralized hard and unmineralized soft tissues involved, each with varying potential for healing. Furthermore, the responses of the different tissues may be interrelated and dependent on each other. Hence, healing subsequent to dental trauma has long been known to be very complex. Because of this complexity, tissue responses and the consequences following dental trauma have been confusing and puzzling for many clinicians. In this review, the tissue responses are described under the tissue compartments typically involved following dental trauma: the pulp, periradicular and associated soft tissues. The factors involved in the mechanisms of trauma are analysed for their effects on the tissue responses. A thorough understanding of the possible tissue responses is imperative for clinicians to overcome the confusion and manage dental trauma adequately and conservatively in order to minimize the consequences following trauma. PMID:26923447

  6. The effect of micro-ECoG substrate footprint on the meningeal tissue response

    PubMed Central

    Schendel, Amelia A.; Nonte, Michael W.; Vokoun, Corinne; Richner, Thomas J.; Brodnick, Sarah K.; Atry, Farid; Frye, Seth; Bostrom, Paige; Pashaie, Ramin; Thongpang, Sanitta; Eliceiri, Kevin W.; Williams, Justin C.

    2014-01-01

    Objective There is great interest in designing implantable neural electrode arrays that maximize function while minimizing tissue effects and damage. Although it has been shown that substrate geometry plays a key role in the tissue response to intracortically implanted, penetrating neural interfaces, there has been minimal investigation into the effect of substrate footprint on the tissue response to surface electrode arrays. This study investigates the effect of micro-electrocorticography device geometry on the longitudinal tissue response. Approach The meningeal tissue response to two micro-electrocorticography devices with differing geometries was evaluated. The first device had each electrode site and trace individually insulated, with open regions in between, while the second device had a solid substrate, in which all sixteen electrode sites were embedded in a continuous insulating sheet. These devices were implanted bilaterally in rats, beneath cranial windows, through which the meningeal tissue response was monitored for one month after implantation. Electrode site impedance spectra were also monitored during the implantation period. Main Results It was observed that collagenous scar tissue formed around both types of devices. However, the distribution of the tissue growth was different between the two array designs. The mesh devices experienced thick tissue growth between the device and the cranial window, and minimal tissue growth between the device and the brain, while the solid device showed the opposite effect, with thick tissue forming between the brain and the electrode sites. Significance This data suggests that an open architecture device would be more ideal for neural recording applications, in which a low impedance path from the brain to the electrode sites is critical for maximum recording quality. PMID:24941335

  7. The response of human nasal and bronchial organotypic tissue cultures to repeated whole cigarette smoke exposure.

    PubMed

    Talikka, Marja; Kostadinova, Radina; Xiang, Yang; Mathis, Carole; Sewer, Alain; Majeed, Shoaib; Kuehn, Diana; Frentzel, Stefan; Merg, Celine; Geertz, Marcel; Martin, Florian; Ivanov, Nikolai V; Peitsch, Manuel C; Hoeng, Julia

    2014-01-01

    Exposure to cigarette smoke (CS) is linked to the development of respiratory diseases, and there is a need to understand the mechanisms whereby CS causes damage. Although animal models have provided valuable insights into smoking-related respiratory tract damage, modern toxicity testing calls for reliable in vitro models as alternatives for animal experimentation. We report on a repeated whole mainstream CS exposure of nasal and bronchial organotypic tissue cultures that mimic the morphological, physiological, and molecular attributes of the human respiratory tract. Despite the similar cellular staining and cytokine secretion in both tissue types, the transcriptomic analyses in the context of biological network models identified similar and diverse biological processes that were impacted by CS-exposed nasal and bronchial cultures. Our results demonstrate that nasal and bronchial tissue cultures are appropriate in vitro models for the assessment of CS-induced adverse effects in the respiratory system and promising alternative to animal experimentation. PMID:25297719

  8. The skin tissue is adversely affected by TNF-alpha blockers in patients with chronic inflammatory arthritis: a 5-year prospective analysis

    PubMed Central

    Machado, Natalia P.; dos Reis Neto, Edgard Torres; Soares, Maria Roberta M. P.; Freitas, Daniele S.; Porro, Adriana; Ciconelli, Rozana M.; Pinheiro, Marcelo M.

    2013-01-01

    OBJECTIVE: We evaluated the incidence of and the main risk factors associated with cutaneous adverse events in patients with chronic inflammatory arthritis following anti-TNF-α therapy. METHODS: A total of 257 patients with active arthritis who were taking TNF-α blockers, including 158 patients with rheumatoid arthritis, 87 with ankylosing spondylitis and 12 with psoriatic arthritis, were enrolled in a 5-year prospective analysis. Patients with overlapping or other rheumatic diseases were excluded. Anthropometric, socioeconomic, demographic and clinical data were evaluated, including the Disease Activity Score-28, Bath Ankylosing Spondylitis Disease Activity Index and Psoriasis Area Severity Index. Skin conditions were evaluated by two dermatology experts, and in doubtful cases, skin lesion biopsies were performed. Associations between adverse cutaneous events and clinical, demographic and epidemiological variables were determined using the chi-square test, and logistic regression analyses were performed to identify risk factors. The significance level was set at p<0.05. RESULTS: After 60 months of follow-up, 71 adverse events (73.85/1000 patient-years) were observed, of which allergic and immune-mediated phenomena were the most frequent events, followed by infectious conditions involving bacterial (47.1%), parasitic (23.5%), fungal (20.6%) and viral (8.8%) agents. CONCLUSION: The skin is significantly affected by adverse reactions resulting from the use of TNF-α blockers, and the main risk factors for cutaneous events were advanced age, female sex, a diagnosis of rheumatoid arthritis, disease activity and the use of infliximab. PMID:24141833

  9. The fractional viscoelastic response of human breast tissue cells

    NASA Astrophysics Data System (ADS)

    Carmichael, B.; Babahosseini, H.; Mahmoodi, S. N.; Agah, M.

    2015-07-01

    The mechanical response of a living cell is notoriously complicated. The complex, heterogeneous characteristics of cellular structure introduce difficulties that simple linear models of viscoelasticity cannot overcome, particularly at deep indentation depths. Herein, a nano-scale stress-relaxation analysis performed with an atomic force microscope reveals that isolated human breast cells do not exhibit simple exponential relaxation capable of being modeled by the standard linear solid (SLS) model. Therefore, this work proposes the application of the fractional Zener (FZ) model of viscoelasticity to extract mechanical parameters from the entire relaxation response, improving upon existing physical techniques to probe isolated cells. The FZ model introduces a new parameter that describes the fractional time-derivative dependence of the response. The results show an exceptional increase in conformance to the experimental data compared to that predicted by the SLS model, and the order of the fractional derivative (α) is remarkably homogeneous across the populations, with a median value of 0.48 ± 0.06 for the malignant population and 0.51 ± 0.07 for the benign. The cells’ responses exhibit power-law behavior and complexity not associated with simple relaxation (SLS, α = 1) that supports the application of a fractional model. The distributions of some of the FZ parameters also preserve the distinction between the malignant and benign sample populations seen from the linear model and previous results while including the contribution of fast-relaxation behavior. The resulting viscosity, measured by a composite relaxation time, exhibits considerably less dispersion due to residual error than the distribution generated by the linear model and therefore serves as a more powerful marker for cell differentiation.

  10. Modal response of a computational vocal fold model with a substrate layer of adipose tissue.

    PubMed

    Jones, Cameron L; Achuthan, Ajit; Erath, Byron D

    2015-02-01

    This study demonstrates the effect of a substrate layer of adipose tissue on the modal response of the vocal folds, and hence, on the mechanics of voice production. Modal analysis is performed on the vocal fold structure with a lateral layer of adipose tissue. A finite element model is employed, and the first six mode shapes and modal frequencies are studied. The results show significant changes in modal frequencies and substantial variation in mode shapes depending on the strain rate of the adipose tissue. These findings highlight the importance of considering adipose tissue in computational vocal fold modeling.

  11. Materials approaches for modulating neural tissue responses to implanted microelectrodes through mechanical and biochemical means

    PubMed Central

    Sommakia, Salah; Lee, Heui C.; Gaire, Janak; Otto, Kevin J.

    2014-01-01

    Implantable intracortical microelectrodes face an uphill struggle for widespread clinical use. Their potential for treating a wide range of traumatic and degenerative neural disease is hampered by their unreliability in chronic settings. A major factor in this decline in chronic performance is a reactive response of brain tissue, which aims to isolate the implanted device from the rest of the healthy tissue. In this review we present a discussion of materials approaches aimed at modulating the reactive tissue response through mechanical and biochemical means. Benefits and challenges associated with these approaches are analyzed, and the importance of multimodal solutions tested in emerging animal models are presented. PMID:25530703

  12. Tissue-specific autophagy responses to aging and stress in C. elegans.

    PubMed

    Chapin, Hannah C; Okada, Megan; Merz, Alexey J; Miller, Dana L

    2015-06-01

    Cellular function relies on a balance between protein synthesis and breakdown. Macromolecular breakdown through autophagy is broadly required for cellular and tissue development, function, and recovery from stress. While Caenorhabditis elegans is frequently used to explore cellular responses to development and stress, the most common assays for autophagy in this system lack tissue-level resolution. Different tissues within an organism have unique functional characteristics and likely vary in their reliance on autophagy under different conditions. To generate a tissue-specific map of autophagy in C. elegans we used a dual fluorescent protein (dFP) tag that releases monomeric fluorescent protein (mFP) upon arrival at the lysosome. Tissue-specific expression of dFP::LGG-1 revealed autophagic flux in all tissues, but mFP accumulation was most dramatic in the intestine. We also observed variable responses to stress: starvation increased autophagic mFP release in all tissues, whereas anoxia primarily increased intestinal autophagic flux. We observed autophagic flux with tagged LGG-1, LGG-2, and two autophagic cargo reporters: a soluble cytoplasmic protein, and mitochondrial TOMM-7. Finally, an increase in mFP in older worms was consistent with an age-dependent shift in proteostasis. These novel measures of autophagic flux in C. elegans reveal heterogeneity in autophagic response across tissues during stress and aging.

  13. Mechanical response tissue analyzer for estimating bone strength

    NASA Technical Reports Server (NTRS)

    Arnaud, Sara B.; Steele, Charles; Mauriello, Anthony

    1991-01-01

    One of the major concerns for extended space flight is weakness of the long bones of the legs, composed primarily of cortical bone, that functions to provide mechanical support. The strength of cortical bone is due to its complex structure, described simplistically as cylinders of parallel osteons composed of layers of mineralized collagen. The reduced mechanical stresses during space flight or immobilization of bone on Earth reduces the mineral content, and changes the components of its matrix and structure so that its strength is reduced. Currently, the established clinical measures of bone strength are indirect. The measures are based on determinations of mineral density by means of radiography, photon absorptiometry, and quantitative computer tomography. While the mineral content of bone is essential to its strength, there is growing awareness of the limitations of the measurement as the sole predictor of fracture risk in metabolic bone diseases, especially limitations of the measurement as the sole predictor of fracture risk in metabolic bone diseases, especially osteoporosis. Other experimental methods in clinical trials that more directly evaluate the physical properties of bone, and do not require exposure to radiation, include ultrasound, acoustic emission, and low-frequency mechanical vibration. The last method can be considered a direct measure of the functional capacity of a long bone since it quantifies the mechanical response to a stimulus delivered directly to the bone. A low frequency vibration induces a response (impedance) curve with a minimum at the resonant frequency, that a few investigators use for the evaluation of the bone. An alternative approach, the method under consideration, is to use the response curve as the basis for determination of the bone bending stiffness EI (E is the intrinsic material property and I is the cross-sectional moment of inertia) and mass, fundamental mechanical properties of bone.

  14. 2013 Immune Risk Standing Review Panel Evidence Review for: The Risk of Crew Adverse Health Event Due to Altered Immune Response

    NASA Technical Reports Server (NTRS)

    Steinberg, Susan

    2014-01-01

    The 2013 Immune Risk Standing Review Panel (from here on referred to as the SRP) met for a site visit in Houston, TX on February 3-4, 2014. The SRP reviewed the new Evidence Report for the Risk of Crew Adverse Health Event Due to Altered Immune Response (from here on referred to as the 2013 Immune Evidence Report), as well as the Research Plan for this Risk that is in the current version of the Human Research Program’s (HRP) Integrated Research Plan (IRP).

  15. Tissue and plasma angiotensin converting enzyme and the response to ACE inhibitor drugs.

    PubMed Central

    MacFadyen, R J; Lees, K R; Reid, J L

    1991-01-01

    1. There is a body of circumstantial and direct evidence supporting the existence and functional importance of a tissue based RAS at a variety of sites. 2. The relation between circulatory and tissue based systems is complex. The relative importance of the two in determining haemodynamic effects is unknown. 3. Despite the wide range of ACE inhibitors already available, it remains unclear whether there are genuine differences related to tissue specificity. 4. Pathological states such as chronic cardiac failure need to be explored with regard to the contribution of tissue based ACE activities in generating acute and chronic haemodynamic responses to ACE inhibitors. 5. The role of tissue vs plasma ACE activity may be clarified by study of the relation between drug concentration and haemodynamic effect, provided that the temporal dissociation is examined and linked to circulating and tissue based changes in ACE activity, angiotensin peptides and sympathetic hormones. PMID:1849731

  16. Bone tissue response to plasma-nitrided titanium implant surfaces

    PubMed Central

    FERRAZ, Emanuela Prado; SVERZUT, Alexander Tadeu; FREITAS, Gileade Pereira; SÁ, Juliana Carvalho; ALVES, Clodomiro; BELOTI, Marcio Mateus; ROSA, Adalberto Luiz

    2015-01-01

    A current goal of dental implant research is the development of titanium (Ti) surfaces to improve osseointegration. Plasma nitriding treatments generate surfaces that favor osteoblast differentiation, a key event to the process of osteogenesis. Based on this, it is possible to hypothesize that plasma-nitrided Ti implants may positively impact osseointegration. Objective The aim of this study was to evaluate the in vivo bone response to Ti surfaces modified by plasma-nitriding treatments. Material and Methods Surface treatments consisted of 20% N2 and 80% H2, 450°C and 1.5 mbar during 1 h for planar and 3 h for hollow cathode. Untreated surface was used as control. Ten implants of each surface were placed into rabbit tibiae and 6 weeks post-implantation they were harvested for histological and histomorphometric analyses. Results Bone formation was observed in contact with all implants without statistically significant differences among the evaluated surfaces in terms of bone-to-implant contact, bone area between threads, and bone area within the mirror area. Conclusion Our results indicate that plasma nitriding treatments generate Ti implants that induce similar bone response to the untreated ones. Thus, as these treatments improve the physico-chemical properties of Ti without affecting its biocompatibility, they could be combined with modifications that favor bone formation in order to develop new implant surfaces. PMID:25760262

  17. Responsiveness of neoplastic and hyperplastic parathyroid tissues to calcium in vitro.

    PubMed Central

    Habener, J F

    1978-01-01

    Secretory and biosynthetic responses of adenomatous, carcinomatous, and hyperplastic parathyroid tissues to variable concentrations of extracellular calcium were assessed in vitro. Tissues, obtained at the time of parathyroidectomy, were incubated for 4 h in media containing radioactive amino acids and varying (0.5-5.0 mM) concentrations of calcium. Amounts of newly synthesized and total parathyroid hormone and proparathyroid hormone in extracts of tissues and media were measured by polyacrylamide gel electrophoresis and by radioimmunoassay, respectively. All tissues studied (six adenomas, two specimens of chief-cell hyperplasia, one carcinoma, and normal bovine and human glands) responded to changes in calcium concentrations; decreasing concentrations of calcium stimulated release and decreased tissue storage of hormone. Six of the abnormal tissues required greater than normal concentrations of calcium (1.8-2.4 mM for 50% of effect) to elicit secretory responses comparable with those of normal glands (1.4 mM). Maximum effects of calcium on release of hormone varied from 2- to 10-fold among different tissues. Release of some hormone persisted even in concentrations of calcium as high as 5.0 mM. Relative amounts of hormone released from and retained in the tissues varied greatly among the tissues, as did the absolute amounts of hormone produced; newly synthesized, labeled hormone ranged between 0.6 and 12% of total labeled protein, and immunoreactive hormone ranged between 0.015 and 0.9% of total tissue protein. Effects of calcium on hormone biosynthesis, as determined by analyses of amounts of proparathyroid hormone in the tissues, were variable among tissues and in many cases were negligible. These results indicate that neoplastic and hyperplastic parathyroid tissues retain secretory responsiveness to changes in extracellular concentrations of calcium. Responses, however, are highly variable among different tissues, and in many instances are abnormal, inasmuch as

  18. Immune response in the adipose tissue of lean mice infected with the protozoan parasite Neospora caninum.

    PubMed

    Teixeira, Luzia; Moreira, João; Melo, Joana; Bezerra, Filipa; Marques, Raquel M; Ferreirinha, Pedro; Correia, Alexandra; Monteiro, Mariana P; Ferreira, Paula G; Vilanova, Manuel

    2015-06-01

    The adipose tissue can make important contributions to immune function. Nevertheless, only a limited number of reports have investigated in lean hosts the immune response elicited in this tissue upon infection. Previous studies suggested that the intracellular protozoan Neospora caninum might affect adipose tissue physiology. Therefore, we investigated in mice challenged with this protozoan if immune cell populations within adipose tissue of different anatomical locations could be differently affected. Early in infection, parasites were detected in the adipose tissue and by 7 days of infection increased numbers of macrophages, regulatory T (Treg) cells and T-bet(+) cells were observed in gonadal, mesenteric, omental and subcutaneous adipose tissue. Increased expression of interferon-γ was also detected in gonadal adipose tissue of infected mice. Two months after infection, parasite DNA was no longer detected in these tissues, but T helper type 1 (Th1) cell numbers remained above control levels in the infected mice. Moreover, the Th1/Treg cell ratio was higher than that of controls in the mesenteric and subcutaneous adipose tissue. Interestingly, chronically infected mice presented a marked increase of serum leptin, a molecule that plays a role in energy balance regulation as well as in promoting Th1-type immune responses. Altogether, we show that an apicomplexa parasitic infection influences immune cellular composition of adipose tissue throughout the body as well as adipokine production, still noticed at a chronic phase of infection when parasites were already cleared from that particular tissue. This strengthens the emerging view that infections can have long-term consequences for the physiology of adipose tissue.

  19. Immune response in the adipose tissue of lean mice infected with the protozoan parasite Neospora caninum

    PubMed Central

    Teixeira, Luzia; Moreira, João; Melo, Joana; Bezerra, Filipa; Marques, Raquel M; Ferreirinha, Pedro; Correia, Alexandra; Monteiro, Mariana P; Ferreira, Paula G; Vilanova, Manuel

    2015-01-01

    The adipose tissue can make important contributions to immune function. Nevertheless, only a limited number of reports have investigated in lean hosts the immune response elicited in this tissue upon infection. Previous studies suggested that the intracellular protozoan Neospora caninum might affect adipose tissue physiology. Therefore, we investigated in mice challenged with this protozoan if immune cell populations within adipose tissue of different anatomical locations could be differently affected. Early in infection, parasites were detected in the adipose tissue and by 7 days of infection increased numbers of macrophages, regulatory T (Treg) cells and T-bet+ cells were observed in gonadal, mesenteric, omental and subcutaneous adipose tissue. Increased expression of interferon-γ was also detected in gonadal adipose tissue of infected mice. Two months after infection, parasite DNA was no longer detected in these tissues, but T helper type 1 (Th1) cell numbers remained above control levels in the infected mice. Moreover, the Th1/Treg cell ratio was higher than that of controls in the mesenteric and subcutaneous adipose tissue. Interestingly, chronically infected mice presented a marked increase of serum leptin, a molecule that plays a role in energy balance regulation as well as in promoting Th1-type immune responses. Altogether, we show that an apicomplexa parasitic infection influences immune cellular composition of adipose tissue throughout the body as well as adipokine production, still noticed at a chronic phase of infection when parasites were already cleared from that particular tissue. This strengthens the emerging view that infections can have long-term consequences for the physiology of adipose tissue. PMID:25581844

  20. Olfactory responses of banana weevil predators to volatiles from banana pseudostem tissue and synthetic pheromone.

    PubMed

    Tinzaara, W; Gold, C S; Dicke, M; van Huis, A

    2005-07-01

    As a response to attack by herbivores, plants can emit a variety of volatile substances that attract natural enemies of these insect pests. Predators of the banana weevil, Cosmopolites sordidus (Germar) (Coleoptera: Curculionidae) such as Dactylosternum abdominale (Coleoptera: Hydrophilidae) and Pheidole megacephala (Hymenoptera: Formicidae), are normally found in association with weevil-infested rotten pseudostems and harvested stumps. We investigated whether these predators are attracted to such environments in response to volatiles produced by the host plant, by the weevil, or by the weevil plant complex. We evaluated predator responses towards volatiles from banana pseudostem tissue (synomones) and the synthetic banana weevil aggregation pheromone Cosmolure+ in a two-choice olfactometer. The beetle D. abdominale was attracted to fermenting banana pseudostem tissue and Cosmolure+, whereas the ant P. megacephala was attracted only to fermented pseudostem tissue. Both predators were attracted to banana pseudostem tissue that had been damaged by weevil larvae irrespective of weevil presence. Adding pheromone did not enhance predator response to volatiles from pseudostem tissue fed on by weevils. The numbers of both predators recovered with pseudostem traps in the field from banana mats with a pheromone trap were similar to those in pseudostem traps at different distance ranges from the pheromone. Our study shows that the generalist predators D. abdominale and P. megacephala use volatiles from fermented banana pseudostem tissue as the major chemical cue when searching for prey. PMID:16222791

  1. Are Ambient Ultrafine, Accumulation Mode, and Fine Particles Associated with Adverse Cardiac Responses in Patients Undergoing Cardiac Rehabilitation?

    PubMed Central

    Zareba, Wojciech; Beckett, William; Hopke, Philip K; Oakes, David; Frampton, Mark W; Bisognano, John; Chalupa, David; Bausch, Jan; O’Shea, Karen; Wang, Yungang; Utell, Mark J

    2012-01-01

    Background: Mechanisms underlying previously reported air pollution and cardiovascular (CV) morbidity associations remain poorly understood. Objectives: We examined associations between markers of pathways thought to underlie these air pollution and CV associations and ambient particle concentrations in postinfarction patients. Methods: We studied 76 patients, from June 2006 to November 2009, who participated in a 10-week cardiac rehabilitation program following a recent (within 3 months) myocardial infarction or unstable angina. Ambient ultrafine particle (UFP; 10–100 nm), accumulation mode particle (AMP; 100–500 nm), and fine particle concentrations (PM2.5; ≤ 2.5 μm in aerodynamic diameter) were monitored continuously. Continuous Holter electrocardiogram (ECG) recordings were made before and during supervised, graded, twice weekly, exercise sessions. A venous blood sample was collected and blood pressure was measured before sessions. Results: Using mixed effects models, we observed adverse changes in rMSSD [square root of the mean of the sum of the squared differences between adjacent normal-to-normal (NN) intervals], SDNN (standard deviation of all NN beat intervals), TpTe (time from peak to end of T-wave), heart rate turbulence, systolic and diastolic blood pressures, C-reactive protein, and fibrinogen associated with interquartile range increases in UFP, AMP, and PM2.5 at 1 or more lag times within the previous 5 days. Exposures were not associated with MeanNN, heart-rate–corrected QT interval duration (QTc), deceleration capacity, and white blood cell count was not associated with UFP, AMP, and PM2.5 at any lag time. Conclusions: In cardiac rehabilitation patients, particles were associated with subclinical decreases in parasympathetic modulation, prolongation of late repolarization duration, increased blood pressure, and systemic inflammation. It is possible that such changes could increase the risk of CV events in this susceptible population. PMID

  2. The role of membrane ERα signaling in bone and other major estrogen responsive tissues

    PubMed Central

    Gustafsson, K. L.; Farman, H.; Henning, P.; Lionikaite, V.; Movérare-Skrtic, S.; Wu, J.; Ryberg, H.; Koskela, A.; Gustafsson, J.-Å.; Tuukkanen, J.; Levin, E. R.; Ohlsson, C.; Lagerquist, M. K.

    2016-01-01

    Estrogen receptor α (ERα) signaling leads to cellular responses in several tissues and in addition to nuclear ERα-mediated effects, membrane ERα (mERα) signaling may be of importance. To elucidate the significance, in vivo, of mERα signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ERα to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mERα signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40–70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mERα (<35% reduction in estrogen response in NOER mice). In conclusion, mERα signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ERα actions may provide means to develop new selective estrogen receptor modulators with improved profiles. PMID:27388455

  3. Planarian regeneration involves distinct stem cell responses to wounds and tissue absence

    PubMed Central

    Wenemoser, Danielle; Reddien, Peter W.

    2010-01-01

    Regeneration requires signaling from a wound site for detection of the wound, and a mechanism that determines the nature of the injury to specify the appropriate regenerative response. Wound signals and tissue responses to wounds that elicit regeneration remain poorly understood. Planarians are able to regenerate from essentially any type of injury and present a novel system for the study of wound responses in regeneration initiation. Newly developed molecular and cellular tools now enable study of regeneration initiation using the planarian Schmidtea mediterranea. Planarian regeneration requires adult stem cells called neoblasts and amputation triggers two peaks in neoblast mitoses early in regeneration. We demonstrate that the first mitotic peak is a body-wide response to any injury and that a second, local, neoblast response is induced only when injury results in missing tissue. This second response was characterized by recruitment of neoblasts to wounds, even in areas that lack neoblasts in the intact animal. Subsequently, these neoblasts were induced to divide and differentiate near the wound, leading to formation of new tissue. We conclude that there exist two functionally distinct signaling phases of the stem cell wound response that distinguish between simple injury and situations that require the regeneration of missing tissue. PMID:20599901

  4. B-cell depletion inhibits arthritis in a collagen-induced arthritis (CIA) model, but does not adversely affect humoral responses in a respiratory syncytial virus (RSV) vaccination model.

    PubMed

    Dunussi-Joannopoulos, Kyri; Hancock, Gerald E; Kunz, Arthur; Hegen, Martin; Zhou, Xiaochuan X; Sheppard, Barbara J; Lamothe, Jennifer; Li, Evelyn; Ma, Hak-Ling; Hamann, Philip R; Damle, Nitin K; Collins, Mary

    2005-10-01

    We report the development of a mouse B cell-depleting immunoconjugate (anti-CD22 monoclonal antibody [mAb] conjugated to calicheamicin) and its in vivo use to characterize the kinetics of CD22+ B-cell depletion and reconstitution in murine primary and secondary lymphoid tissues. The effect of B-cell depletion was further studied in a murine collagen-induced arthritis (CIA) model and a respiratory syncytial virus (RSV) vaccination model. Our results show that (1) the immunoconjugate has B-cell-specific in vitro and in vivo cytotoxicity; (2) B-cell reconstitution starts in the bone marrow and spleen around day 30 after depletion and is completed in all tissues tested by day 50; (3) B-cell depletion inhibits the development of clinical and histologic arthritis in the CIA model; (4) depletion of type II collagen antibody levels is not necessary for clinical and histologic prevention of CIA; and (5) B-cell depletion does not adversely affect memory antibody responses after challenge nor clearance of infectious virus from lungs in the RSV vaccination model. These results demonstrate for the first time that only B-cell reduction but not type II collagen antibody levels correlate with the prevention of arthritis and represent key insights into the role of CD22-targeted B-cell depletion in mouse autoimmunity and vaccination models.

  5. A Review of the Responses of Two- and Three-Dimensional Engineered Tissues to Electric Fields

    PubMed Central

    Hronik-Tupaj, Marie

    2012-01-01

    The application of external biophysical signals is one approach to tissue engineering that is explored less often than more traditional additions of exogenous biochemical and chemical factors to direct cell and tissue outcomes. The study of bioelectromagnetism and the field of electrotherapeutics have evolved over the years, and we review biocompatible electric stimulation devices and their successful application to tissue growth. Specifically, information on capacitively coupled alternating current, inductively coupled alternating current, and direct current devices is described. Cell and tissue responses from the application of these devices, including two- and three-dimensional in vitro studies and in vivo studies, are reviewed with regard to cell proliferation, adhesion, differentiation, morphology, and migration and tissue function. The current understanding of cellular mechanisms related to electric stimulation is detailed. The advantages of electric stimulation are compared with those pf other techniques, and areas in which electric fields are used as an adjuvant therapy for healing and regeneration are discussed. PMID:22046979

  6. Th1-skewed tissue responses to a mycolyl glycolipid in mycobacteria-infected rhesus macaques

    SciTech Connect

    Morita, Daisuke; Miyamoto, Ayumi; Hattori, Yuki; Komori, Takaya; Nakamura, Takashi; Igarashi, Tatsuhiko; Harashima, Hideyoshi; Sugita, Masahiko

    2013-11-08

    Highlights: •Glucose monomycolate (GMM) is a marker glycolipid for active tuberculosis. •Tissue responses to GMM involved up-regulation of Th1-attracting chemokines. •Th1-skewed local responses were mounted at the GMM-injected tissue. -- Abstract: Trehalose 6,6′-dimycolate (TDM) is a major glycolipid of the cell wall of mycobacteria with remarkable adjuvant functions. To avoid detection by the host innate immune system, invading mycobacteria down-regulate the expression of TDM by utilizing host-derived glucose as a competitive substrate for their mycolyltransferases; however, this enzymatic reaction results in the concomitant biosynthesis of glucose monomycolate (GMM) which is recognized by the acquired immune system. GMM-specific, CD1-restricted T cell responses have been detected in the peripheral blood of infected human subjects and monkeys as well as in secondary lymphoid organs of small animals, such as guinea pigs and human CD1-transgenic mice. Nevertheless, it remains to be determined how tissues respond at the site where GMM is produced. Here we found that rhesus macaques vaccinated with Mycobacterium bovis bacillus Calmette–Guerin mounted a chemokine response in GMM-challenged skin that was favorable for recruiting T helper (Th)1 T cells. Indeed, the expression of interferon-γ, but not Th2 or Th17 cytokines, was prominent in the GMM-injected tissue. The GMM-elicited tissue response was also associated with the expression of monocyte/macrophage-attracting CC chemokines, such as CCL2, CCL4 and CCL8. Furthermore, the skin response to GMM involved the up-regulated expression of granulysin and perforin. Given that GMM is produced primarily by pathogenic mycobacteria proliferating within the host, the Th1-skewed tissue response to GMM may function efficiently at the site of infection.

  7. Increasing the number of unloading/reambulation cycles does not adversely impact body composition and lumbar bone mineral density but reduces tissue sensitivity

    NASA Astrophysics Data System (ADS)

    Gupta, Shikha; Manske, Sarah L.; Judex, Stefan

    2013-11-01

    A single exposure to hindlimb unloading leads to changes in body mass, body composition and bone, but the consequences of multiple exposures are not yet understood. Within a 18 week period, adult C57BL/6 male mice were exposed to 1 (1x-HLU), 2 (2x-HLU) or 3 (3x-HLU) cycles of 2 weeks of hindlimb unloading (HLU) followed by 4 weeks of reambulation (RA), or served as ambulatory age-matched controls. In vivo μCT longitudinally tracked changes in abdominal adipose and lean tissues, lumbar vertebral apparent volumetric bone mineral density (vBMD) and upper hindlimb muscle cross-sectional area before and after the final HLU and RA cycle. During the final HLU cycle, significant decreases in total adipose tissue and vertebral vBMD in the three experimental groups occurred such that there were no significant between-group differences at the beginning of the final RA cycle. However, the magnitude of the HLU induced losses diminished in mice undergoing their 2nd or 3rd HLU cycle. Irrespective of the number of HLU/RA cycles, total adipose tissue and vertebral vBMD recovered and were no different from age-matched controls after the final RA period. In contrast, upper hindlimb muscle cross-sectional area was significantly lower than controls in all unloaded groups after the final RA period. These results suggest that tissues in the abdominal region are more resilient to multiple bouts of unloading and more amenable to recovery during reambulation than the peripheral musculoskeletal system.

  8. Chronic intracortical microelectrode arrays induce non-uniform, depth-related tissue responses

    NASA Astrophysics Data System (ADS)

    Woolley, Andrew J.; Desai, Himanshi A.; Otto, Kevin J.

    2013-04-01

    Objective. Brain-implanted microelectrode arrays show promise as future clinical devices. However, biological responses to various designs, compositions and locations of these implants have not been fully characterized, and may impact the long-term functionality of these devices. In order to improve our understanding of the tissue conditions at the interface of chronic brain-implanted microdevices, we proposed utilizing advanced histology and microscopy techniques to image implanted devices and surrounding tissue intact within brain slices. We then proposed utilizing these methods to examine whether depth within the cerebral cortex affected tissue conditions around implants. Approach. Histological data was collected from rodent brain slices containing intact, intracortical microdevices four weeks after implantation surgery. Thick tissue sections containing the chronic implants were processed with fluorescent antibody labels, and imaged in an optical clearing solution using laser confocal microscopy. Main Results. Tissue surrounding microdevices exhibited two major depth-related phenomena: a non-uniform microglial coating along the device length and a dense mass of cells surrounding the implant in cerebral cortical layers I and II. Detailed views of the monocyte-derived immune cells improve our understanding of the close and complex association that immune cells have with chronic brain implants, and illuminated a possible relationship between cortical depth and the intensity of a chronic monocyte response around penetrating microdevices. The dense mass of cells contained vimentin, a protein not typically expressed highly in CNS cells, evidence that non-CNS cells likely descended down the face of the penetrating devices from the pial surface. Significance. Image data of highly non-uniform and depth-dependent biological responses along a device provides novel insight into the complexity of the tissue response to penetrating brain-implanted microdevices. The presented

  9. Chronic Tissue Response to Untethered Microelectrode Implants in the Rat Brain and Spinal Cord

    PubMed Central

    ERSEN, Ali; ELKABES, Stella; FREEDMAN, David S.; SAHIN, Mesut

    2015-01-01

    Objective Microelectrodes implanted in the central nervous system (CNS) often fail in long term implants due to the immunological tissue response caused by tethering forces of the connecting wires. In addition to the tethering effect, there is a mechanical stress that occurs at the device-tissue interface simply because the microelectrode is a rigid body floating in soft tissue and it cannot reshape itself to comply with changes in the surrounding tissue. In the current study we evaluated the scar tissue formation to tetherless devices with two significantly different geometries in the rat brain and spinal cord in order to investigate the effects of device geometry. Approach One of the implant geometries resembled the wireless, floating microstimulators that we are currently developing in our laboratory and the other was a (shank only) Michigan probe for comparison. Both electrodes were implanted into either the cervical spinal cord or the motor cortices, one on each side. Main Results The most pronounced astroglial and microglial reactions occurred within 20 μm from the device and decreased sharply at larger distances. Both cell types displayed the morphology of non-activated cells past the 100 μm perimeter. Even though the aspect ratios of the implants were different, the astroglial and microglial responses to both microelectrode types were very mild in the brain, stronger and yet limited in the spinal cord. Significance These observations confirm previous reports and further suggest that tethering may be responsible for most of the tissue response in chronic implants and that the electrode size has a smaller contribution with floating electrodes. The electrode size may be playing primarily an amplifying role to the tethering forces in the brain whereas the size itself may induce chronic response in the spinal cord where the movement of surrounding tissues is more significant. PMID:25605679

  10. Chronic tissue response to untethered microelectrode implants in the rat brain and spinal cord

    NASA Astrophysics Data System (ADS)

    Ersen, Ali; Elkabes, Stella; Freedman, David S.; Sahin, Mesut

    2015-02-01

    Objective. Microelectrodes implanted in the central nervous system (CNS) often fail in long term implants due to the immunological tissue response caused by tethering forces of the connecting wires. In addition to the tethering effect, there is a mechanical stress that occurs at the device-tissue interface simply because the microelectrode is a rigid body floating in soft tissue and it cannot reshape itself to comply with changes in the surrounding tissue. In the current study we evaluated the scar tissue formation to tetherless devices with two significantly different geometries in the rat brain and spinal cord in order to investigate the effects of device geometry. Approach. One of the implant geometries resembled the wireless, floating microstimulators that we are currently developing in our laboratory and the other was a (shank only) Michigan probe for comparison. Both electrodes were implanted into either the cervical spinal cord or the motor cortices, one on each side. Main results. The most pronounced astroglial and microglial reactions occurred within 20 μm from the device and decreased sharply at larger distances. Both cell types displayed the morphology of non-activated cells past the 100 μm perimeter. Even though the aspect ratios of the implants were different, the astroglial and microglial responses to both microelectrode types were very mild in the brain, stronger and yet limited in the spinal cord. Significance. These observations confirm previous reports and further suggest that tethering may be responsible for most of the tissue response in chronic implants and that the electrode size has a smaller contribution with floating electrodes. The electrode size may be playing primarily an amplifying role to the tethering forces in the brain whereas the size itself may induce chronic response in the spinal cord where the movement of surrounding tissues is more significant.

  11. Quantitative radiation dose-response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy

    SciTech Connect

    Mossman, K.L.

    1983-08-01

    A quantitative dose-response curve for salivary gland function in patients during radiotherapy is presented. Salivary-function data used in this study were obtained from four previously published reports. All patients were treated with /sup 60/Co teletherapy to the head and neck using conventional treatment techniques. Salivary dysfunction was determined at specific dose levels by comparing salivary flow rates before therapy with flow rates at specific dose intervals during radiotherapy up to a total dose of 6000 cGy. Fifty percent salivary dysfunction occurred after 1000 cGy and eighty percent dysfunction was observed by the end of the therapy course (6000 cGy). The salivary-function curve was also compared to the previously published dose-response curve for taste function. Comparisons of the two curves indicate that salivary dysfunction precedes taste loss and that the shapes of the dose-response curves are different. A new term, tissue tolerance ratio, defined as the ratio of responses of two tissues given the same radiation dose, was used to make the comparisons between gustatory and salivary gland tissue effects. Measurements of salivary gland function and analysis of dose-response curves may be useful in evaluating chemical modifiers of radiation response.

  12. Quantitative radiation dose-response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy

    SciTech Connect

    Mossman, K.L.

    1983-08-01

    A quantitative dose-response curve for salivary gland function in patients during radiotherapy is presented. Salivary-function data used in this study were obtained from four previously published reports. All patients were treated wih /sup 60/Co teletherapy to the head and neck using conventional treatment techniques. Salivary dysfunction was determined at specific dose levels by comparing salivary flow rates before therapy with flow rates at specific dose intervals during radiotherapy up to a total dose of 6000 cGy. Fifty percent salivary dysfunction occurred after 1000 cGy and eighty percent dysfunction was observed by the end of the therapy course (6000 cGy). The salivary-function curve was also compared to the previously published dose-response curve for taste function. Comparisons of the two curves indicate that salivary dysfunction precedes taste loss and that the shapes of the dose-response curves are different. A new term, tissue tolerance ratio, defined as the ratio of responses of two tissues given the same radiation dose, was used to make the comparisons between gustatory and salivary gland tissue effects. Measurements of salivary gland function and analysis of dose-response curves may be useful in evaluating chemical modifiers of radiation response.

  13. Genetic Background Modulates lncRNA-Coordinated Tissue Response to Low Dose Ionizing Radiation

    DOE PAGES

    Tang, Jonathan; Huang, Yurong; Nguyen, David H.; Costes, Sylvain V.; Snijders, Antoine M.; Mao, Jian-Hua

    2015-01-01

    Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed aftermore » LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs.« less

  14. Early redox, Src family kinase, and calcium signaling integrate wound responses and tissue regeneration in zebrafish.

    PubMed

    Yoo, Sa Kan; Freisinger, Christina M; LeBert, Danny C; Huttenlocher, Anna

    2012-10-15

    Tissue injury can lead to scar formation or tissue regeneration. How regenerative animals sense initial tissue injury and transform wound signals into regenerative growth is an unresolved question. Previously, we found that the Src family kinase (SFK) Lyn functions as a redox sensor in leukocytes that detects H(2)O(2) at wounds in zebrafish larvae. In this paper, using zebrafish larval tail fins as a model, we find that wounding rapidly activated SFK and calcium signaling in epithelia. The immediate SFK and calcium signaling in epithelia was important for late epimorphic regeneration of amputated fins. Wound-induced activation of SFKs in epithelia was dependent on injury-generated H(2)O(2). A SFK member, Fynb, was responsible for fin regeneration. This work provides a new link between early wound responses and late regeneration and suggests that redox, SFK, and calcium signaling are immediate "wound signals" that integrate early wound responses and late epimorphic regeneration.

  15. Early redox, Src family kinase, and calcium signaling integrate wound responses and tissue regeneration in zebrafish

    PubMed Central

    Yoo, Sa Kan; Freisinger, Christina M.; LeBert, Danny C.

    2012-01-01

    Tissue injury can lead to scar formation or tissue regeneration. How regenerative animals sense initial tissue injury and transform wound signals into regenerative growth is an unresolved question. Previously, we found that the Src family kinase (SFK) Lyn functions as a redox sensor in leukocytes that detects H2O2 at wounds in zebrafish larvae. In this paper, using zebrafish larval tail fins as a model, we find that wounding rapidly activated SFK and calcium signaling in epithelia. The immediate SFK and calcium signaling in epithelia was important for late epimorphic regeneration of amputated fins. Wound-induced activation of SFKs in epithelia was dependent on injury-generated H2O2. A SFK member, Fynb, was responsible for fin regeneration. This work provides a new link between early wound responses and late regeneration and suggests that redox, SFK, and calcium signaling are immediate “wound signals” that integrate early wound responses and late epimorphic regeneration. PMID:23045550

  16. Novel Bioceramic Urethral Bulking Agents Elicit Improved Host Tissue Responses in a Rat Model.

    PubMed

    Mann-Gow, Travis K; King, Benjamin J; El-Ghannam, Ahmed; Knabe-Ducheyne, Christine; Kida, Masatoshi; Dall, Ole M; Krhut, Jan; Zvara, Peter

    2016-01-01

    Objectives. To test the physical properties and host response to the bioceramic particles, silica-calcium phosphate (SCPC10) and Cristobalite, in a rat animal model and compare their biocompatibility to the current clinically utilized urethral bulking materials. Material and Methods. The novel bulking materials, SCPC10 and Cristobalite, were suspended in hyaluronic acid sodium salt and injected into the mid urethra of a rat. Additional animals were injected with bulking materials currently in clinical use. Physiological response was assessed using voiding trials, and host tissue response was evaluated using hard tissue histology and immunohistochemical analysis. Distant organs were evaluated for the presence of particles or their components. Results. Histological analysis of the urethral tissue five months after injection showed that both SCPC10 and Cristobalite induced a more robust fibroblastic and histiocytic reaction, promoting integration and encapsulation of the particle aggregates, leading to a larger bulking effect. Concentrations of Ca, Na, Si, and P ions in the experimental groups were comparable to control animals. Conclusions. This side-by-side examination of urethral bulking agents using a rat animal model and hard tissue histology techniques compared two newly developed bioactive ceramic particles to three of the currently used bulking agents. The local host tissue response and bulking effects of bioceramic particles were superior while also possessing a comparable safety profile.

  17. Novel Bioceramic Urethral Bulking Agents Elicit Improved Host Tissue Responses in a Rat Model.

    PubMed

    Mann-Gow, Travis K; King, Benjamin J; El-Ghannam, Ahmed; Knabe-Ducheyne, Christine; Kida, Masatoshi; Dall, Ole M; Krhut, Jan; Zvara, Peter

    2016-01-01

    Objectives. To test the physical properties and host response to the bioceramic particles, silica-calcium phosphate (SCPC10) and Cristobalite, in a rat animal model and compare their biocompatibility to the current clinically utilized urethral bulking materials. Material and Methods. The novel bulking materials, SCPC10 and Cristobalite, were suspended in hyaluronic acid sodium salt and injected into the mid urethra of a rat. Additional animals were injected with bulking materials currently in clinical use. Physiological response was assessed using voiding trials, and host tissue response was evaluated using hard tissue histology and immunohistochemical analysis. Distant organs were evaluated for the presence of particles or their components. Results. Histological analysis of the urethral tissue five months after injection showed that both SCPC10 and Cristobalite induced a more robust fibroblastic and histiocytic reaction, promoting integration and encapsulation of the particle aggregates, leading to a larger bulking effect. Concentrations of Ca, Na, Si, and P ions in the experimental groups were comparable to control animals. Conclusions. This side-by-side examination of urethral bulking agents using a rat animal model and hard tissue histology techniques compared two newly developed bioactive ceramic particles to three of the currently used bulking agents. The local host tissue response and bulking effects of bioceramic particles were superior while also possessing a comparable safety profile. PMID:27688751

  18. Tissue responsiveness to estradiol and genistein in the sea bass liver and scale.

    PubMed

    Pinto, Patrícia I S; Estêvão, M Dulce; Andrade, André; Santos, Soraia; Power, Deborah M

    2016-04-01

    As in mammals, estrogens in fish are essential for reproduction but also important regulators of mineral homeostasis. Fish scales are a non-conventional target tissue responsive to estradiol and constitute a good model to study mineralized tissues effects and mechanisms of action of estrogenic compounds, including phytoestrogens. The responsiveness to estradiol and the phytoestrogen genistein, was compared between the scales and the liver, a classical estrogenic target, in sea bass (Dicentrarchus labrax). Injection with estradiol and genistein significantly increased circulating vitellogenin (for both compounds) and mineral levels (estradiol only) and genistein also significantly increased scale enzymatic activities suggesting it increased mineral turnover. The repertoire, abundance and estrogenic regulation of nuclear estrogen receptors (ESR1, 2a and 2b) and membrane G-protein receptors (GPER and GPER-like) were different between liver and scales, which presumably explains the tissue-specific changes detected in estrogen-responsive gene expression. In scales changes in gene expression mainly consisted of small rapid increases, while in liver strong, sustained increases/decreases in gene expression occurred. Similar but not overlapping gene expression changes were observed in response to both estradiol and genistein. This study demonstrates for the first time the expression of membrane estrogen receptors in scales and that estrogens and phytoestrogens, to which fish may be exposed in the wild or in aquaculture, both affect liver and mineralized tissues in a tissue-specific manner. PMID:26718875

  19. Novel Bioceramic Urethral Bulking Agents Elicit Improved Host Tissue Responses in a Rat Model

    PubMed Central

    Mann-Gow, Travis K.; King, Benjamin J.; El-Ghannam, Ahmed; Knabe-Ducheyne, Christine; Kida, Masatoshi; Dall, Ole M.; Krhut, Jan

    2016-01-01

    Objectives. To test the physical properties and host response to the bioceramic particles, silica-calcium phosphate (SCPC10) and Cristobalite, in a rat animal model and compare their biocompatibility to the current clinically utilized urethral bulking materials. Material and Methods. The novel bulking materials, SCPC10 and Cristobalite, were suspended in hyaluronic acid sodium salt and injected into the mid urethra of a rat. Additional animals were injected with bulking materials currently in clinical use. Physiological response was assessed using voiding trials, and host tissue response was evaluated using hard tissue histology and immunohistochemical analysis. Distant organs were evaluated for the presence of particles or their components. Results. Histological analysis of the urethral tissue five months after injection showed that both SCPC10 and Cristobalite induced a more robust fibroblastic and histiocytic reaction, promoting integration and encapsulation of the particle aggregates, leading to a larger bulking effect. Concentrations of Ca, Na, Si, and P ions in the experimental groups were comparable to control animals. Conclusions. This side-by-side examination of urethral bulking agents using a rat animal model and hard tissue histology techniques compared two newly developed bioactive ceramic particles to three of the currently used bulking agents. The local host tissue response and bulking effects of bioceramic particles were superior while also possessing a comparable safety profile. PMID:27688751

  20. Metabolic profiling of the tissue-specific responses in mussel Mytilus galloprovincialis towards Vibrio harveyi challenge.

    PubMed

    Liu, Xiaoli; Ji, Chenglong; Zhao, Jianmin; Wang, Qing; Li, Fei; Wu, Huifeng

    2014-08-01

    Mussel Mytilus galloprovincialis is a marine aquaculture shellfish distributing widely along the coast in north China. In this work, we studied the differential metabolic responses induced by Vibrio harveyi in digestive gland and gill tissues from M. galloprovincialis using NMR-based metabolomics. The differential metabolic responses in the two tissue types were detected, except the similarly altered taurine and betaine. These metabolic responses suggested that V. harveyi mainly induced osmotic disruption and reduced energy demand via the metabolic pathways of glucose synthesis and ATP/AMP conversion in mussel digestive gland. In mussel gill tissues, V. harveyi basically caused osmotic stress and possible reduced energy demand as shown by the elevated phosphocholine that is involved in one of the metabolic pathways of ATP synthesis from ADP and phosphocholine. The altered mRNA expression levels of related genes (superoxide dismutase with copper and zinc, heat shock protein 90, defensin and lysozyme) suggested that V. harveyi induced clear oxidative and immune stresses in both digestive gland and gill tissues. However, the mRNA expression levels of both lysozyme and defensin in digestive gland were more significantly up-regulated than those in gill from V. harveyi-challenged mussel M. galloprovincialis, meaning that the immune organ, digestive gland, was more sensitive than gill. Overall, our results indicated that V. harveyi could induce tissue-specific metabolic responses in mussel M. galloprovincialis.

  1. Novel Bioceramic Urethral Bulking Agents Elicit Improved Host Tissue Responses in a Rat Model

    PubMed Central

    Mann-Gow, Travis K.; King, Benjamin J.; El-Ghannam, Ahmed; Knabe-Ducheyne, Christine; Kida, Masatoshi; Dall, Ole M.; Krhut, Jan

    2016-01-01

    Objectives. To test the physical properties and host response to the bioceramic particles, silica-calcium phosphate (SCPC10) and Cristobalite, in a rat animal model and compare their biocompatibility to the current clinically utilized urethral bulking materials. Material and Methods. The novel bulking materials, SCPC10 and Cristobalite, were suspended in hyaluronic acid sodium salt and injected into the mid urethra of a rat. Additional animals were injected with bulking materials currently in clinical use. Physiological response was assessed using voiding trials, and host tissue response was evaluated using hard tissue histology and immunohistochemical analysis. Distant organs were evaluated for the presence of particles or their components. Results. Histological analysis of the urethral tissue five months after injection showed that both SCPC10 and Cristobalite induced a more robust fibroblastic and histiocytic reaction, promoting integration and encapsulation of the particle aggregates, leading to a larger bulking effect. Concentrations of Ca, Na, Si, and P ions in the experimental groups were comparable to control animals. Conclusions. This side-by-side examination of urethral bulking agents using a rat animal model and hard tissue histology techniques compared two newly developed bioactive ceramic particles to three of the currently used bulking agents. The local host tissue response and bulking effects of bioceramic particles were superior while also possessing a comparable safety profile.

  2. Influence of resveratrol release on the tissue response to mechanically adaptive cortical implants.

    PubMed

    Nguyen, Jessica K; Jorfi, Mehdi; Buchanan, Kelly L; Park, Daniel J; Foster, E Johan; Tyler, Dustin J; Rowan, Stuart J; Weder, Christoph; Capadona, Jeffrey R

    2016-01-01

    The stability and longevity of recordings obtained from intracortical microelectrodes continues to remain an area of concern for neural interfacing applications. The limited longevity of microelectrode performance has been associated with the integrity of the blood brain barrier (BBB) and the neuroinflammatory response to the microelectrode. Here, we report the investigation of an additive approach that targets both mechanical and chemical factors believed to contribute to chronic BBB instability and the neuroinflammatory response associated with implanted intracortical microelectrodes. The implants investigated were based on a mechanically adaptive, compliant nanocomposite (NC), which reduces the tissue response and tissue strain. This material was doped with various concentrations of the antioxidant resveratrol with the objective of local and rapid delivery. In vitro analysis of resveratrol release, antioxidant activity, and cytotoxicity suggested that a resveratrol content of 0.01% was optimal for in vivo assessment. Thus, probes made from the neat NC reference and probes containing resveratrol (NC Res) were implanted into the cortical tissue of rats for up to sixteen weeks. Histochemical analysis suggested that at three days post-implantation, neither materials nor therapeutic approaches (independently or in combination) could alter the initial wound healing response. However, at two weeks post-implantation, the NC Res implant showed a reduction in activated microglia/macrophages and improvement in neuron density at the tissue-implant interface when compared to the neat NC reference. However, sixteen weeks post-implantation, when the antioxidant was exhausted, NC Res and the neat NC reference exhibited similar tissue responses. The data show that NC Res provides short-term, short-lived benefits due to the antioxidant release, and a long-term reduction in neuroinflammation on account of is mechanical adaptive, compliant nature. Together, these results

  3. Influence of resveratrol release on the tissue response to mechanically adaptive cortical implants.

    PubMed

    Nguyen, Jessica K; Jorfi, Mehdi; Buchanan, Kelly L; Park, Daniel J; Foster, E Johan; Tyler, Dustin J; Rowan, Stuart J; Weder, Christoph; Capadona, Jeffrey R

    2016-01-01

    The stability and longevity of recordings obtained from intracortical microelectrodes continues to remain an area of concern for neural interfacing applications. The limited longevity of microelectrode performance has been associated with the integrity of the blood brain barrier (BBB) and the neuroinflammatory response to the microelectrode. Here, we report the investigation of an additive approach that targets both mechanical and chemical factors believed to contribute to chronic BBB instability and the neuroinflammatory response associated with implanted intracortical microelectrodes. The implants investigated were based on a mechanically adaptive, compliant nanocomposite (NC), which reduces the tissue response and tissue strain. This material was doped with various concentrations of the antioxidant resveratrol with the objective of local and rapid delivery. In vitro analysis of resveratrol release, antioxidant activity, and cytotoxicity suggested that a resveratrol content of 0.01% was optimal for in vivo assessment. Thus, probes made from the neat NC reference and probes containing resveratrol (NC Res) were implanted into the cortical tissue of rats for up to sixteen weeks. Histochemical analysis suggested that at three days post-implantation, neither materials nor therapeutic approaches (independently or in combination) could alter the initial wound healing response. However, at two weeks post-implantation, the NC Res implant showed a reduction in activated microglia/macrophages and improvement in neuron density at the tissue-implant interface when compared to the neat NC reference. However, sixteen weeks post-implantation, when the antioxidant was exhausted, NC Res and the neat NC reference exhibited similar tissue responses. The data show that NC Res provides short-term, short-lived benefits due to the antioxidant release, and a long-term reduction in neuroinflammation on account of is mechanical adaptive, compliant nature. Together, these results

  4. Monomethylarsonous Acid (MMAIII) Has an Adverse Effect on the Innate Immune Response of Human Bronchial Epithelial Cells to Pseudomonas aeruginosa

    PubMed Central

    Notch, Emily G.; Goodale, Britton C.; Barnaby, Roxanna; Coutermarsh, Bonita; Berwin, Brent; Taylor, Vivien F.; Jackson, Brian P.; Stanton, Bruce A.

    2015-01-01

    Arsenic is the number one contaminant of concern with regard to human health according to the World Health Organization. Epidemiological studies on Asian and South American populations have linked arsenic exposure with an increased incidence of lung disease, including pneumonia, and chronic obstructive pulmonary disease, both of which are associated with bacterial infection. However, little is known about the effects of low dose arsenic exposure, or the contributions of organic arsenic to the innate immune response to bacterial infection. This study examined the effects on Pseudomonas aeruginosa (P. aeruginosa) induced cytokine secretion by human bronchial epithelial cells (HBEC) by inorganic sodium arsenite (iAsIII) and two major metabolites, monomethylarsonous acid (MMAIII) and dimethylarsenic acid (DMAV), at concentrations relevant to the U.S. population. Neither iAsIII nor DMAV altered P. aeruginosa induced cytokine secretion. By contrast, MMAIII increased P. aeruginosa induced secretion of IL-8, IL-6 and CXCL2. A combination of iAsIII, MMAIII and DMAV (10 pbb total) reduced IL-8 and CXCL1 secretion. These data demonstrate for the first time that exposure to MMAIII alone, and a combination of iAsIII, MMAIII and DMAV at levels relevant to the U.S. may have negative effects on the innate immune response of human bronchial epithelial cells to P. aeruginosa. PMID:26554712

  5. Controlled release strategies for modulating immune responses to promote tissue regeneration.

    PubMed

    Dumont, Courtney M; Park, Jonghyuck; Shea, Lonnie D

    2015-12-10

    Advances in the field of tissue engineering have enhanced the potential of regenerative medicine, yet the efficacy of these strategies remains incomplete, and is limited by the innate and adaptive immune responses. The immune response associated with injury or disease combined with that mounted to biomaterials, transplanted cells, proteins, and gene therapies vectors can contribute to the inability to fully restore tissue function. Blocking immune responses such as with anti-inflammatory or immunosuppressive agents are either ineffective, as the immune response contributes significantly to regeneration, or have significant side effects. This review describes targeted strategies to modulate the immune response in order to limit tissue damage following injury, promote an anti-inflammatory environment that leads to regeneration, and induce antigen (Ag)-specific tolerance that can target degenerative diseases that destroy tissues and promote engraftment of transplanted cells. Focusing on targeted immuno-modulation, we describe local delivery techniques to sites of inflammation as well as systemic approaches that preferentially target subsets of immune populations.

  6. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes.

    PubMed

    Li, Guorong; Mukherjee, Dibyendu; Navarro, Iris; Ashpole, Nicole E; Sherwood, Joseph M; Chang, Jinlong; Overby, Darryl R; Yuan, Fan; Gonzalez, Pedro; Kopczynski, Casey C; Farsiu, Sina; Stamer, W Daniel

    2016-09-15

    Visual impairment due to glaucoma currently impacts 70 million people worldwide. While disease progression can be slowed or stopped with effective lowering of intraocular pressure, current medical treatments are often inadequate. Fortunately, three new classes of therapeutics that target the diseased conventional outflow tissue responsible for ocular hypertension are in the final stages of human testing. The rho kinase inhibitors have proven particularly efficacious and additive to current therapies. Unfortunately, non-contact technology that monitors the health of outflow tissue and its response to conventional outflow therapy is not available clinically. Using optical coherence tomographic (OCT) imaging and novel segmentation software, we present the first demonstration of drug effects on conventional outflow tissues in living eyes. Topical netarsudil (formerly AR-13324), a rho kinase/ norepinephrine transporter inhibitor, affected both proximal (trabecular meshwork and Schlemm's Canal) and distal portions (intrascleral vessels) of the mouse conventional outflow tract. Hence, increased perfusion of outflow tissues was reliably resolved by OCT as widening of the trabecular meshwork and significant increases in cross-sectional area of Schlemm's canal following netarsudil treatment. These changes occurred in conjunction with increased outflow facility, increased speckle variance intensity of outflow vessels, increased tracer deposition in conventional outflow tissues and decreased intraocular pressure. This is the first report using live imaging to show real-time drug effects on conventional outflow tissues and specifically the mechanism of action of netarsudil in mouse eyes. Advancements here pave the way for development of a clinic-friendly OCT platform for monitoring glaucoma therapy. PMID:27085895

  7. Tissue specific response to DNA damage: C. elegans as role model.

    PubMed

    Lans, Hannes; Vermeulen, Wim

    2015-08-01

    The various symptoms associated with hereditary defects in the DNA damage response (DDR), which range from developmental and neurological abnormalities and immunodeficiency to tissue-specific cancers and accelerated aging, suggest that DNA damage affects tissues differently. Mechanistic DDR studies are, however, mostly performed in vitro, in unicellular model systems or cultured cells, precluding a clear and comprehensive view of the DNA damage response of multicellular organisms. Studies performed in intact, multicellular animals models suggest that DDR can vary according to the type, proliferation and differentiation status of a cell. The nematode Caenorhabditis elegans has become an important DDR model and appears to be especially well suited to understand in vivo tissue-specific responses to DNA damage as well as the impact of DNA damage on development, reproduction and health of an entire multicellular organism. C. elegans germ cells are highly sensitive to DNA damage induction and respond via classical, evolutionary conserved DDR pathways aimed at efficient and error-free maintenance of the entire genome. Somatic tissues, however, respond differently to DNA damage and prioritize DDR mechanisms that promote growth and function. In this mini-review, we describe tissue-specific differences in DDR mechanisms that have been uncovered utilizing C. elegans as role model. PMID:25957488

  8. Characterization of photomorphogenic responses and signaling cascades controlled by phytochrome-A expressed in different tissues.

    PubMed

    Kirchenbauer, Daniel; Viczián, András; Ádám, Éva; Hegedűs, Zoltán; Klose, Cornelia; Leppert, Michael; Hiltbrunner, Andreas; Kircher, Stefan; Schäfer, Eberhard; Nagy, Ferenc

    2016-07-01

    The photoreceptor phytochrome A acts as a light-dependent molecular switch and regulates responses initiated by very low fluences of light (VLFR) and high fluences (HIR) of far-red light. PhyA is expressed ubiquitously, but how phyA signaling is orchestrated to regulate photomorphogenesis is poorly understood. To address this issue, we generated transgenic Arabidopsis thaliana phyA-201 mutant lines expressing the biologically active phyA-YFP photoreceptor in different tissues, and analyzed the expression of several reporter genes, including ProHY5:HY5-GFP and Pro35S:CFP-PIF1, and various FR-HIR-dependent physiological responses. We show that phyA action in one tissue is critical and sufficient to regulate flowering time and root growth; control of cotyledon and hypocotyl growth requires simultaneous phyA activity in different tissues; and changes detected in the expression of reporters are not restricted to phyA-containing cells. We conclude that FR-HIR-controlled morphogenesis in Arabidopsis is mediated partly by tissue-specific and partly by intercellular signaling initiated by phyA. Intercellular signaling is critical for many FR-HIR induced responses, yet it appears that phyA modulates the abundance and activity of key regulatory transcription factors in a tissue-autonomous fashion. PMID:27027866

  9. Dose convolution filter: Incorporating spatial dose information into tissue response modeling

    SciTech Connect

    Huang Yimei; Joiner, Michael; Zhao Bo; Liao Yixiang; Burmeister, Jay

    2010-03-15

    Purpose: A model is introduced to integrate biological factors such as cell migration and bystander effects into physical dose distributions, and to incorporate spatial dose information in plan analysis and optimization. Methods: The model consists of a dose convolution filter (DCF) with single parameter {sigma}. Tissue response is calculated by an existing NTCP model with DCF-applied dose distribution as input. The authors determined {sigma} of rat spinal cord from published data. The authors also simulated the GRID technique, in which an open field is collimated into many pencil beams. Results: After applying the DCF, the NTCP model successfully fits the rat spinal cord data with a predicted value of {sigma}=2.6{+-}0.5 mm, consistent with 2 mm migration distances of remyelinating cells. Moreover, it enables the appropriate prediction of a high relative seriality for spinal cord. The model also predicts the sparing of normal tissues by the GRID technique when the size of each pencil beam becomes comparable to {sigma}. Conclusions: The DCF model incorporates spatial dose information and offers an improved way to estimate tissue response from complex radiotherapy dose distributions. It does not alter the prediction of tissue response in large homogenous fields, but successfully predicts increased tissue tolerance in small or highly nonuniform fields.

  10. Caffeine intake during pregnancy and adverse birth outcomes: a systematic review and dose-response meta-analysis.

    PubMed

    Greenwood, Darren C; Thatcher, Natalie J; Ye, Jin; Garrard, Lucy; Keogh, Georgina; King, Laura G; Cade, Janet E

    2014-10-01

    Caffeine is commonly consumed during pregnancy, crosses the placenta, with fetal serum concentrations similar to the mother's, but studies of birth outcome show conflicting findings. We systematically searched Medline and Embase for relevant publications. We conducted meta-analysis of dose-response curves for associations between caffeine intake and spontaneous abortion, stillbirth, preterm delivery, low birth weight and small for gestational age (SGA) infants. Meta-analyses included 60 unique publications from 53 cohort and case-control studies. An increment of 100 g caffeine was associated with a 14 % (95 % CI 10-19 %) increase in risk of spontaneous abortion, 19 % (5-35 %) stillbirth, 2 % (-2 to 6 %) preterm delivery, 7 % (1-12 %) low birth weight, and 10 % (95 % CI 6-14 %) SGA. There was substantial heterogeneity in all models, partly explained by adjustment for smoking and previous obstetric history, but not by prospective assessment of caffeine intake. There was evidence of small-study effects such as publication bias. Greater caffeine intake is associated with an increase in spontaneous abortion, stillbirth, low birth weight, and SGA, but not preterm delivery. There is no identifiable threshold below which the associations are not apparent, but the size of the associations are generally modest within the range of usual intake and are potentially explained by bias in study design or publication. There is therefore insufficient evidence to support further reductions in the maximum recommended intake of caffeine, but maintenance of current recommendations is a wise precaution.

  11. Response of rodents to inhaled diluted diesel exhaust: biochemical and cytological changes in bronchoalveolar lavage fluid and in lung tissue.

    PubMed

    Henderson, R F; Pickrell, J A; Jones, R K; Sun, J D; Benson, J M; Mauderly, J L; McClellan, R O

    1988-10-01

    The effect of long-term (24 months) inhalation of diesel exhaust on the bronchoalveolar region of the respiratory tract of rodents was assessed by serial (every 6 months) analysis of bronchoalveolar lavage fluid (BALF) and of lung tissue from F344/Crl rats and CD-1 mice (both sexes) exposed to diesel exhaust diluted to contain 0, 0.35, 3.5, or 7.0 mg soot/m3. The purpose of the study was twofold. One was to assess the potential health effects of inhaling diluted exhaust from light-duty diesel engines. The second was to determine the usefulness of BALF analysis in detecting the early stages in the development of nononcogenic lung disease and differentiating them from the normal repair processes. No biochemical or cytological changes in BALF or in lung tissue were noted in either species exposed to the lowest, and most environmentally relevant, concentration of diesel exhaust. In the two higher levels of exposure, a chronic inflammatory response was measured in both species by dose-dependent increases in inflammatory cells, cytoplasmic and lysosomal enzymes, and protein in BALF. Histologically, after 1 year of exposure, the rats had developed focal areas of fibrosis associated with the deposits of soot, while the mice, despite a higher lung burden of soot than the rats, had only a fine fibrillar thickening of an occasional alveolar septa in the high-level exposure group. Higher increases in BALF beta-glucuronidase activity and in hydroxyproline content accompanied the greater degree of fibrosis in the rat. BALF levels of glutathione (GSH) and glutathione reductase activity increased in a dose-dependent fashion and were higher in mice than in rats. Lung tissue GSH was depleted in a dose-dependent fashion in rats but was slightly increased in mice. This depletion may have played a role in the greater fibrogenic response observed in rats. Other tissue changes in enzymatic activity were small compared to changes observed in BALF. The exposure did not increase the

  12. Adverse local tissue reaction (ALTR) associated with corrosion products in metal-on-metal and dual modular neck total hip replacements is associated with upregulation of interferon gamma-mediated chemokine signaling.

    PubMed

    Kolatat, Kritti; Perino, Giorgio; Wilner, Gabrielle; Kaplowitz, Elianna; Ricciardi, Benjamin F; Boettner, Friedrich; Westrich, Geoffrey H; Jerabek, Seth A; Goldring, Steven R; Purdue, P Edward

    2015-10-01

    Adverse local tissue reactions (ALTR) associated with tribocorrosion following total hip arthroplasty (THA) have become a significant clinical concern in recent years. In particular, implants featuring metal-on-metal bearing surfaces and modular femoral stems have been reported to result in elevated rates of ALTR. These tribocorrosion-related tissue reactions are characterized by marked necrosis and lymphocytic infiltration, which contrasts sharply with the macrophagic and foreign body giant cell inflammation associated with polyethylene wear particle induced peri-implant osteolysis. In this study, we characterize tribocorrosion-associated ALTR at a molecular level. Gene expression profiling of peri-implant tissue around failing implants identifies upregulation of numerous inflammatory mediators in ALTR, including several interferon gamma inducible factors, most notably the chemokines MIG/CXCL9 and IP-10/CXCL10. This expression profile is distinct from that associated with polyethylene wear induced osteolysis, which is characterized by induction of markers of alternative macrophage activation, such as chitotriosidase (CHIT-1). Importantly, MIG/CXCL9 and IP-10/CXCL10 are also elevated at the protein level in the synovial fluid and, albeit more moderately, the serum, of ALTR patients, raising the possibility that these factors may serve as circulating biomarkers for the early detection of ALTR in at-risk patients. PMID:25940887

  13. Response of plant nutrient stoichiometry to fertilization varied with plant tissues in a tropical forest

    PubMed Central

    Mo, Qifeng; Zou, Bi; Li, Yingwen; Chen, Yao; Zhang, Weixin; Mao, Rong; Ding, Yongzhen; Wang, Jun; Lu, Xiankai; Li, Xiaobo; Tang, Jianwu; Li, Zhian; Wang, Faming

    2015-01-01

    Plant N:P ratios are widely used as indices of nutrient limitation in terrestrial ecosystems, but the response of these metrics in different plant tissues to altered N and P availability and their interactions remains largely unclear. We evaluated changes in N and P concentrations, N:P ratios of new leaves (<1 yr), older leaves (>1 yr), stems and mixed fine roots of seven species after 3-years of an N and P addition experiment in a tropical forest. Nitrogen addition only increased fine root N concentrations. P addition increased P concentrations among all tissues. The N × P interaction reduced leaf and stem P concentrations, suggesting a negative effect of N addition on P concentrations under P addition. The reliability of using nutrient ratios as indices of soil nutrient availability varied with tissues: the stoichiometric metrics of stems and older leaves were more responsive indicators of changed soil nutrient availability than those of new leaves and fine roots. However, leaf N:P ratios can be a useful indicator of inter-specific variation in plant response to nutrients availability. This study suggests that older leaf is a better choice than other tissues in the assessment of soil nutrient status and predicting plant response to altered nutrients using nutrients ratios. PMID:26416169

  14. Response of plant nutrient stoichiometry to fertilization varied with plant tissues in a tropical forest.

    PubMed

    Mo, Qifeng; Zou, Bi; Li, Yingwen; Chen, Yao; Zhang, Weixin; Mao, Rong; Ding, Yongzhen; Wang, Jun; Lu, Xiankai; Li, Xiaobo; Tang, Jianwu; Li, Zhian; Wang, Faming

    2015-09-29

    Plant N:P ratios are widely used as indices of nutrient limitation in terrestrial ecosystems, but the response of these metrics in different plant tissues to altered N and P availability and their interactions remains largely unclear. We evaluated changes in N and P concentrations, N:P ratios of new leaves (<1 yr), older leaves (>1 yr), stems and mixed fine roots of seven species after 3-years of an N and P addition experiment in a tropical forest. Nitrogen addition only increased fine root N concentrations. P addition increased P concentrations among all tissues. The N × P interaction reduced leaf and stem P concentrations, suggesting a negative effect of N addition on P concentrations under P addition. The reliability of using nutrient ratios as indices of soil nutrient availability varied with tissues: the stoichiometric metrics of stems and older leaves were more responsive indicators of changed soil nutrient availability than those of new leaves and fine roots. However, leaf N:P ratios can be a useful indicator of inter-specific variation in plant response to nutrients availability. This study suggests that older leaf is a better choice than other tissues in the assessment of soil nutrient status and predicting plant response to altered nutrients using nutrients ratios.

  15. Thermodynamic response of soft biological tissues to pulsed infrared-laser irradiation.

    PubMed Central

    Venugopalan, V; Nishioka, N S; Mikić, B B

    1996-01-01

    The physical mechanisms that achieve tissue removal through the delivery of short pulses of high-intensity infrared laser radiation, in a process known as laser ablation, remain obscure. The thermodynamic response of biological tissue to pulsed infrared laser irradiation was investigated by measuring and analyzing the stress transients generated by Q-sw Er:YSGG (lambda = 2.79 microns) and TEA CO2 (lambda = 10.6 microns) laser irradiation of porcine dermis using thin-film piezoelectric transducers. For radiant exposures that do not produce material removal, the stress transients are consistent with thermal expansion of the tissue samples. The temporal structure of the stress transients generated at the threshold radiant exposure for ablation indicates that the onset of material removal is delayed with respect to irradiation. Once material removal is achieved, the magnitude of the peak compressive stress and its variation with radiant exposure are consistent with a model that considers this process as an explosive event occurring after the laser pulse. This mechanism is different from ArF- and KrF-excimer laser ablation where absorption of ultraviolet radiation by the collagenous tissue matrix leads to tissue decomposition during irradiation and results in material removal via rapid surface vaporization. It appears that under the conditions examined in this study, explosive boiling of tissue water is the process that mediates the ablation event. This study provides evidence that the dynamics and mechanism of tissue ablation processes can be altered by targeting tissue water rather than the tissue structural matrix. Images FIGURE 6 PMID:8744336

  16. Tissue response to potential root-end filling materials in infected root canals.

    PubMed

    Chong, B S; Ford, T R; Kariyawasam, S P

    1997-03-01

    The tissue responses to two potential root-end filling materials, a light-cured glass ionomer cement (Vitrebond) and a reinforced zinc oxide-eugenol cement (Kalzinol) were compared with that to amalgam. In 27 premolar teeth of beagle dogs (54 roots), a collection of endodontic pathogenic bacteria was first inoculated into the root canals to induce periapical lesions. On each root, an apicectomy was performed and root-end cavities prepared to receive fillings of each material. The teeth and surrounding jaw were removed after 8 weeks (24 roots) and 4 weeks (30 roots); and they were prepared for histological examination. The tissue response to amalgam fillings after 4 and 8 weeks was marked by moderate or severe inflammation on all roots, and extended > 0.5 mm in 10 out of 18 roots. In contrast, after 8 weeks, the majority of roots filled with Kalzinol showed little or moderate inflammation while the tissue response to Vitrebond was the best of the three materials, and was also less extensive. After 4 weeks, the overall best tissue response was with Kalzinol, followed closely by Vitrebond. The differences between materials for both time periods with either none or few inflammatory cells when compared with that with either moderate or severe inflammation were statistically significant (P < 0.01). Similarly, the differences between materials for both time periods with no inflammation or inflammation extending < 0.2 mm when compared with that with inflammation extending > 0.2 mm (< or = 0.5 mm or > 0.5 mm) were statistically significant (P < 0.01). Both Vitrebond and Kalzinol have potential as root-end filling materials as the tissue response was considerably more favourable than that to amalgam.

  17. Linking the response of endocrine regulated genes to adverse effects on sex differentiation improves comprehension of aromatase inhibition in a Fish Sexual Development Test.

    PubMed

    Muth-Köhne, Elke; Westphal-Settele, Kathi; Brückner, Jasmin; Konradi, Sabine; Schiller, Viktoria; Schäfers, Christoph; Teigeler, Matthias; Fenske, Martina

    2016-07-01

    The Fish Sexual Development Test (FSDT) is a non-reproductive test to assess adverse effects of endocrine disrupting chemicals. With the present study it was intended to evaluate whether gene expression endpoints would serve as predictive markers of endocrine disruption in a FSDT. For proof-of-concept, a FSDT according to the OECD TG 234 was conducted with the non-steroidal aromatase inhibitor fadrozole (test concentrations: 10μg/L, 32μg/L, 100μg/L) using zebrafish (Danio rerio). Gene expression analyses using quantitative RT-PCR were included at 48h, 96h, 28days and 63days post fertilization (hpf, dpf). The selection of genes aimed at finding molecular endpoints which could be directly linked to the adverse apical effects of aromatase inhibition. The most prominent effects of fadrozole exposure on the sexual development of zebrafish were a complete sex ratio shift towards males and an acceleration of gonad maturation already at low fadrozole concentrations (10μg/L). Due to the specific inhibition of the aromatase enzyme (Cyp19) by fadrozole and thus, the conversion of C19-androgens to C18-estrogens, the steroid hormone balance controlling the sex ratio of zebrafish was altered. The resulting key event is the regulation of directly estrogen-responsive genes. Subsequently, gene expression of vitellogenin 1 (vtg1) and of the aromatase cyp19a1b isoform (cyp19a1b), were down-regulated upon fadrozole treatment compared to controls. For example, mRNA levels of vtg1 were down-regulated compared to the controls as early as 48 hpf and 96 hpf. Further regulated genes cumulated in pathways suggested to be controlled by endocrine mechanisms, like the steroid and terpenoid synthesis pathway (e.g. mevalonate (diphospho) decarboxylase (mvd), lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase; lss), methylsterol monooxygenase 1 (sc4mol)) and in lipid transport/metabolic processes (steroidogenic acute regulatory protein (star), apolipoprotein Eb (apoEb)). Taken together

  18. Tissue healing response following hyperthermic vapor ablation in the porcine longissimus muscle

    NASA Astrophysics Data System (ADS)

    Grantham, John T.; Grisez, Brian T.; Famoso, Justin; Hoey, Michael; Dixon, Chris; Coad, James E.

    2015-03-01

    As the use of hyperthermic ablation technologies has increased, so too has the need to understand their effects on tissue and their healing responses. This study was designed to characterize tissue injury and healing following hyperthermic vapor ablation in the in vivo porcine longissimus muscle model. The individual ablations were performed using the NxThera Vapor Delivery System (NxThera Inc., Minneapolis, MN). To assess the vapor ablation's evolution, the swine were euthanized post-treatment on Day 0, Day 3, Day 7, Day 14, Day 28, Day 45 and Day 90. Triphenyltetrazolium chloride viability staining (TTC staining) was used to macroscopically assess the extent of each vapor ablation within the tissue. The ablation associated healing responses were then histologically evaluated for acute inflammation, chronic inflammation, foreign body reaction and fibrosis. Two zones of tissue injury were initially identified in the ablations: 1) a central zone of complete coagulative necrosis and 2) an outer "transition zone" of viable and non-viable cells. The ablations initially increased in size from Day 0 to Day 7 and then progressively decreased in size though Day 45. The initial Day 3 healing changes originated in the transition zone with minimal acute and chronic inflammation. As time progressed, granulation tissue began to form by Day 7 and peaked around Day 14. Collagen formation, deposition and remodeling began in the adjacent healthy tissue by Day 28, replaced the ablation site by Day 45 and reorganized by Day 90. In conclusion, this vapor ablation technology provided a non-desiccating form of hyperthermic ablation that resulted in coagulative necrosis without a central thermally/heat-fixed tissue component, followed a classical wound healing pathway, and healed with minimal associated inflammation.

  19. Digital Image Analysis for Morphometric Evaluation of Tissue Response after Implanting Alloplastic Vascular Prostheses

    NASA Astrophysics Data System (ADS)

    Zippel, Roland; Hoene, Andreas; Walschus, Uwe; Jarchow, Raymond; Ueberrueck, Torsten; Patrzyk, Maciej; Schlosser, Michael; Wilhelm, Lutz

    2006-07-01

    The aim of this study was to examine the suitability of digital image analysis, using the KS400 software system, for the morphometric evaluation of the tissue response after prosthesis implantation in an animal model. Twenty-four female pigs aged 10 weeks were implanted with infrarenal Dacron® prostheses for 14, 21, 28, and 116 days. Following the explantation and investigation of the neointima region, the expression of beta-1-integrin, the proliferation rate by means of Ki-67 positive cells, and the intima thickness were evaluated as exemplary parameters of the tissue response after implantation. Frozen tissue sections were immunohistochemically stained and subsequently examined using computer-aided image analysis. A maximum expression of 32.9% was observed for beta-1-integrin 14 days after implantation, gradually declining over time to 9.8% after 116 days. The proliferation rate was found to be 19% on day 14, increasing to 39% on day 21 with a subsequent gradual decline to 5% after 116 days. The intima thickness increased from 189.9 [mu]m on day 14 to 1228.0 [mu]m on day 116. In conclusion, digital image analysis was found to be an efficient and reproducible method for the morphometric evaluation of a peri-prosthetic tissue response.

  20. Early tissue response to citric acid-based micro- and nanocomposites

    PubMed Central

    Chung, Eun Ji; Qiu, Hongjin; Kodali, Pradeep; Yang, Scott; Sprague, Stuart M.; Hwong, James; Koh, Jason; Ameer, Guillermo A.

    2010-01-01

    Composites based on calcium phosphates and biodegradable polymers are desirable for orthopaedic applications due to their potential to mimic bone. Herein, we describe the fabrication, characterization, and in vivo response of novel citric acid-based microcomposites and nanocomposites. Poly(1,8-octanediol-co-citrate) (POC) was mixed with increasing amounts of HA nanoparticles or microparticles (up to 60 wt%), and the morphology and mechanical properties of the resulting composites were assessed. To investigate tissue response, nanocomposites, microcomposites, POC, and poly(L-lactide) (PLL) were implanted in osteochondral defects in rabbits and harvested at 6 weeks for histological evaluation. SEM confirmed increased surface roughness of microcomposites relative to nanocomposites. The mechanical properties of both types of composites increased with increasing amounts of HA (8–328 MPa), although nanocomposites with 60 wt.% HA displayed the highest strength and stiffness. Based on tissue-implant interfacial assessments, all implants integrated well with the surrounding bone and cartilage with no evidence of inflammation. Both nanocomposites and microcomposites supported bone remodeling; however, nanocomposites induced more trabecular bone formation at the tissue-implant interface. The mechanical properties of citric acid-based composites are within the range of human trabecular bone (1–1524 MPa, 211±78 MPa mean modulus) and tissue response was dependent on the size and content of HA, providing new perspectives of design and fabrication criteria for orthopaedic devices such as interference screws and fixation pins. PMID:20949482

  1. Feasibility studies of electrical impedance spectroscopy for monitoring tissue response to photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Wilson, Brian C.; Osterman, Kendra S.; Hoopes, P. Jack; Lilge, Lothar D.; Paulsen, Keith D.

    1998-05-01

    Electrical impedance spectroscopy (EIS) has been evaluated as a non- or minimally-invasive technique to monitor the acute tissue response to photodynamic therapy (PDT). In this study the EIS spectra of normal muscle tissue in the rat hind leg were monitored immediately before and at time intervals up to 96 hours post-PDT treatment with different photosensitizers (Photofrin, ALA-induced PpIX, BenzoPorphyrin Derivative), at varying photosensitizer and light doses. EIS measurements were made using a pair of solid matrix Ag-AgCl electrodes placed parallel to one another on either side of the muscle mass and interfaced to a precision LCR impedance meter scanning the frequency range 1 - 1000 KHz. Independent histological grading of tissue injury was performed on tissue sections from treated and untreated legs at the 96 hour end point. Significant and PDT dose-dependent changes in the EIS spectra following treatment were observed, including increases in conductivity which correlated with the immediate post-PDT edematous response with Photofrin and ALA and which resolved or partially-resolved over the measurement time course. Photofrin treatments exhibited a clear drug dose response at 96 hours that was evident in both the EIS spectra and the histological sections. These changes included significant tissue necrosis as well as edema, inflammation and early fibroplasia. The BPD data were less clear, but potentially quite interesting. Most striking were below unity ratios of treated-to-untreated muscle spectra components at 24 hours which reversed to above unity by 96 hours in the through skin measurements. This phenomenon is indicative of a tissue response distinctly different than that observed with Photofrin or ALA. These data also suggest that EIS measured changes are sensitive enough to detect differences in PDT-initiated tissue damage that may be photosensitize-specific. While the data are derived from a small number of animals, the findings are quite encouraging in

  2. The B-3 ethylene response factor MtERF1-1 mediates resistance to a subset of root pathogens in Medicago truncatula without adversely affecting symbiosis with rhizobia.

    PubMed

    Anderson, Jonathan P; Lichtenzveig, Judith; Gleason, Cynthia; Oliver, Richard P; Singh, Karam B

    2010-10-01

    The fungal necrotrophic pathogen Rhizoctonia solani is a significant constraint to a range of crops as diverse as cereals, canola, and legumes. Despite wide-ranging germplasm screens in many of these crops, no strong genetic resistance has been identified, suggesting that alternative strategies to improve resistance are required. In this study, we characterize moderate resistance to R. solani anastomosis group 8 identified in Medicago truncatula. The activity of the ethylene- and jasmonate-responsive GCC box promoter element was associated with moderate resistance, as was the induction of the B-3 subgroup of ethylene response transcription factors (ERFs). Genes of the B-1 subgroup showed no significant response to R. solani infection. Overexpression of a B-3 ERF, MtERF1-1, in Medicago roots increased resistance to R. solani as well as an oomycete root pathogen, Phytophthora medicaginis, but not root knot nematode. These results indicate that targeting specific regulators of ethylene defense may enhance resistance to an important subset of root pathogens. We also demonstrate that overexpression of MtERF1-1 enhances disease resistance without apparent impact on nodulation in the A17 background, while overexpression in sickle reduced the hypernodulation phenotype. This suggests that under normal regulation of nodulation, enhanced resistance to root diseases can be uncoupled from symbiotic plant-microbe interactions in the same tissue and that ethylene/ERF regulation of nodule number is distinct from the defenses regulated by B-3 ERFs. Furthermore, unlike the stunted phenotype previously described for Arabidopsis (Arabidopsis thaliana) ubiquitously overexpressing B-3 ERFs, overexpression of MtERF1-1 in M. truncatula roots did not show adverse effects on plant development.

  3. The brain tissue response to surgical injury and its possible contribution to glioma recurrence.

    PubMed

    Hamard, Lauriane; Ratel, David; Selek, Laurent; Berger, François; van der Sanden, Boudewijn; Wion, Didier

    2016-05-01

    Surgery is the first line therapy for glioma. However, glioma recurs in 90 % of the patients in the resection margin. The impact of surgical brain injury (SBI) on glioma recurrence is largely overlooked. Herein, we review some of the mechanisms involved in tissue repair that may impact glioma recurrence at the resection margin. Many processes or molecules involved in tissue repair after brain injury are also critical for glioma growth. They include a wide array of secreted growth factors, cytokines and transcription factors including NFКB and STAT3 which in turn activate proliferative and anti-apoptotic genes and processes such as angiogenesis and inflammation. Because some residual glioma cells always remain in the tumor resection margin, there are now compelling arguments to suggest that some aspects of the brain tissue response to SBI can also participate to glioma recurrence at the resection margin. Brain tissue response to SBI recruits angiogenesis and inflammation that precede and then follow tumor recurrence at the resection margin. The healing response to SBI is double edged, as inflammation is involved in regeneration and healing, and has both pro- and anti-tumorigenic functions. A promising therapeutic approach is to normalize and re-educate the molecular and cellular responses at the resection margin to promote anti-tumorigenic processes involved in healing while inhibiting pro-tumorigenic activities. Manipulation of the inflammatory response to SBI to prevent local recurrence could also enhance the efficacy of other therapies such as immunotherapy. However, our current knowledge is far from sufficient to achieve this goal. Acknowledging, understanding and manipulating the double-edged role played by SBI in glioma recurrence is surely challenging, but it cannot be longer delayed. PMID:26961772

  4. Methods of Assessing Human Tendon Metabolism and Tissue Properties in Response to Changes in Mechanical Loading.

    PubMed

    Heinemeier, Katja M; Kjaer, Michael; Magnusson, S Peter

    2016-01-01

    In recent years a number of methodological developments have improved the opportunities to study human tendon. Microdialysis enables sampling of interstitial fluid in the peritendon tissue, while sampling of human tendon biopsies allows direct analysis of tendon tissue for gene- and protein expression as well as protein synthesis rate. Further the (14)C bomb-pulse method has provided data on long-term tissue turnover in human tendon. Non-invasive techniques allow measurement of tendon metabolism (positron emission tomography (PET)), tendon morphology (magnetic resonance imaging (MRI)), and tendon mechanical properties (ultrasonography combined with force measurement during movement). Finally, 3D cell cultures of human tendon cells provide the opportunity to investigate cell-matrix interactions in response to various interventions. PMID:27535251

  5. Characterization of TLR-induced inflammatory responses in COPD and control lung tissue explants

    PubMed Central

    Pomerenke, Anna; Lea, Simon R; Herrick, Sarah; Lindsay, Mark A; Singh, Dave

    2016-01-01

    Purpose Viruses are a common cause of exacerbations in chronic obstructive pulmonary disease (COPD). They activate toll-like receptors (TLRs) 3, 7, and 8, leading to a pro-inflammatory response. We have characterized the responses of TLR3 and TLR7/8 in lung tissue explants from COPD patients and control smokers. Methods We prepared lung whole tissue explants (WTEs) from patients undergoing surgery for confirmed or suspected lung cancer. In order to mimic the conditions of viral infection, we used poly(I:C) for TLR3 stimulation and R848 for TLR7/8 stimulation. These TLR ligands were used alone and in combination. The effects of tumor necrosis factor α (TNFα) neutralization and dexamethasone on TLR responses were examined. Inflammatory cytokine release was measured by enzyme-linked immunosorbent assay and gene expression by quantitative real-time polymerase chain reaction. Results WTEs from COPD patients released higher levels of pro-inflammatory cytokines compared with WTEs from smokers. Activation of multiple TLRs led to a greater than additive release of TNFα and CCL5. TNFα neutralization and dexamethasone treatment decreased cytokine release. Conclusion This WTE model shows an enhanced response of COPD compared with controls, suggesting an increased response to viral infection. There was amplification of innate immune responses with multiple TLR stimulation. PMID:27729782

  6. Rat subcutaneous tissue response to MTA Fillapex® and Portland cement.

    PubMed

    Marques, Nádia Carolina Teixeira; Lourenço Neto, Natalino; Fernandes, Ana Paula; Rodini, Camila de Oliveira; Duarte, Marco Antônio Hungaro; Oliveira, Thais Marchini

    2013-01-01

    The aim of this study was to evaluate the response of rat subcutaneous tissue to MTA Fillapex® (Angelus), an experimental root canal filling material based on Portland cement and propylene glycol (PCPG), and a zinc oxide, eugenol and iodoform (ZOEI) paste. These materials were placed in polyethylene tubes and implanted into the dorsal connective tissue of Wistar rats for 7 and 15 days. The specimens were stained with hematoxylin and eosin, and evaluated regarding inflammatory reaction parameters by optical microscopy. The intensity of inflammatory response against the sealers was analyzed by two blinded and previously calibrated examiners for all experimental periods (kappa=0.96). The histological evaluation showed that all materials caused a moderate inflammatory reaction at 7 days, which subsided with time. A greater inflammatory reaction was observed at 7 days in the tubes filled with ZOEI paste. Tubes filled with MTA Fillapex presented some giant cells, macrophages and lymphocytes after 7 days. At 15 days, the presence of fibroblasts and collagen fibers was observed indicating normal tissue healing. The tubes filled with PCPG showed similar results to those observed in MTA Fillapex. At 15 days, the inflammatory reaction was almost absent at the tissue, with several collagen fibers indicating normal tissue healing. Data were analyzed by the nonparametric Kruskal-Wallis test (α=0.05). Statistically significant difference (p<0.05) was found only between PCPG at 15 days and ZOEI at 7 days groups. No significant differences were observed among the other groups/periods (p>0.05). MTA Fillapex and Portland cement added with propylene glycol had greater tissue compatibility than the PCPG paste.

  7. The physical response of soft musculoskeletal tissues to short-pulsed laser irradiation

    NASA Astrophysics Data System (ADS)

    Dark, Marta Lyselle

    An experimental study was performed to determine the physical properties of knee meniscus using a low energy laser technique. Following irradiation by a 10 ns laser pulse, tissue undergoes thermoelastic expansion in response to laser-induced stresses. The stresses evolve, propagating through the tissue. If they exceed the material's strength, ablation occurs-the material ruptures. Below ablation threshold, the material remains in an expanded state until thermal relaxation occurs. We use numerical methods to solve the 3-D thermoelastic wave equation for a hydrated sample. In addition to thermoelastic expansion, expansion due to the formation of cavitation bubbles within the tissue was modeled. Cavitation occurs when tensile stresses rupture fluid. The laser-induced response of a gelatin phantom was measured with a Michelson interferometer and compared with predictions. Using gelatin as a tissue model provided a consistent experimental model of meniscus. Meniscus, like all biological tissue, is highly heterogeneous. By adapting the time dependent numerical solution of the wave equation, the measurement of physical properties of a hydrated sample became possible. The thermoelastic model depends on sound speed, Poisson's ratio, thermal expansion coefficient, and optical penetration depth. Once the behavior of gelatin was understood, human knee meniscus was studied. The thermoelastic model and experiment, allows measurement of physical properties of meniscus. Also, a numerical model of cavitation based on Rayleigh's equations was developed. By comparing experiment and theory in menicus and water, we determined properties important to cavitation: threshold pressure, bubble density, surface tension and nucleation size. Finally, histology was compared with experiment. The presence and amount of cavitation displacement was correlated with the condition of meniscus. Physical properties can be used to diagnose degenerative cartilage. This research has increased understanding

  8. SU-E-J-31: Biodynamic Imaging of Cancer Tissue and Response to Chemotherapy

    SciTech Connect

    Nolte, D; Turek, J; Childress, M; An, R; Merrill, D; Matei, D

    2014-06-01

    Purpose: To measure intracellular motions inside three-dimensional living cancer tissue samples to establish a novel set of biodynamic biomarkers that assess tissue proliferative activity and sensitivity or resistance to chemotherapy. Methods: Biodynamic imaging (BDI) uses digital holography with low-coherence low-intensity light illumination to construct 3D holograms from depths up to a millimeter deep inside cancer tissue models that include multicellular tumor spheroids and ex vivo cancer biopsies from canine non-Hodgkins lymphoma and epithelial ovarian cancer (EOC) mouse explants. Intracellular motions modulate the holographic intensity with frequencies related to the Doppler effect caused by the motions of a wide variety of intracellular components. These motions are affected by applied therapeutic agents, and BDI produces unique fingerprints of the action of specific drugs on the motions in specific cell types. In this study, chemotherapeutic agents (doxorubicin for canine lymphoma and oxoplatin for ovarian) are applied to the living tissue models and monitored over 10 hours by BDI. Results: Multicellular spheroids and patient biopsies are categorized as either sensitive or insensitive to applied therapeutics depending on the intracellular Doppler signatures of chemotherapy response. For both lymphoma and EOC there is strong specificity to the two types of sensitivities, with sensitive cell lines and biopsies exhibiting a global cessation of proliferation and strong suppression of metabolic activity, while insensitive cell lines and biopsies show moderate activation of Doppler frequencies associated with membrane processes and possible membrane trafficking. Conclusion: This work supports the hypothesis that biodynamic biomarkers from three-dimensional living tumor tissue, that includes tissue heterogeneity and measured within 24 hours of surgery, is predictive of near-term patient response to therapy. Future work will correlate biodynamic biomarkers with

  9. Reverse Engineering Adverse Outcome Pathways

    SciTech Connect

    Perkins, Edward; Chipman, J.K.; Edwards, Stephen; Habib, Tanwir; Falciani, Francesco; Taylor, Ronald C.; Van Aggelen, Graham; Vulpe, Chris; Antczak, Philipp; Loguinov, Alexandre

    2011-01-30

    The toxicological effects of many stressors are mediated through unknown, or poorly characterized, mechanisms of action. We describe the application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows. Gene expression changes in fathead minnow ovaries in response to 7 different chemicals, over different times, doses, and in vivo versus in vitro conditions were captured in a large data set of 868 arrays. We examined potential AOPs of the antiandrogen flutamide using two mutual information theory methods, ARACNE and CLR to infer gene regulatory networks and potential adverse outcome pathways. Representative networks from these studies were used to predict a network path from stressor to adverse outcome as a candidate AOP. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biologic processes, biomarkers or alternative endpoints, which could be used to monitor an adverse outcome pathway. Finally, we identify the unique challenges facing the application of this approach in ecotoxicology, and attempt to provide a road map for the utilization of these tools. Key Words: mechanism of action, toxicology, microarray, network inference

  10. Tissue specific responses to cadmium-based quantum dots in the marine mussel Mytilus galloprovincialis.

    PubMed

    Rocha, Thiago Lopes; Gomes, Tânia; Mestre, Nélia C; Cardoso, Cátia; Bebianno, Maria João

    2015-12-01

    In recent years, Cd-based quantum dots (QDs) have generated interest from the life sciences community due to their potential applications in nanomedicine, biology and electronics. However, these engineered nanomaterials can be released into the marine environment, where their environmental health hazards remain unclear. This study investigated the tissue-specific responses related to alterations in the antioxidant defense system induced by CdTe QDs, in comparison with its dissolved counterpart, using the marine mussel Mytilus galloprovincialis. Mussels were exposed to CdTe QDs and dissolved Cd for 14 days at 10 μgCd L(-1) and biomarkers of oxidative stress [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (total, Se-independent and Se-dependent GPx) and glutathione-S-transferase (GST) activities] were analyzed along with Cd accumulation in the gills and digestive gland of mussels. Results show that both Cd forms changed mussels' antioxidant responses with distinct modes of action (MoA). There were tissue- and time-dependent differences in the biochemical responses to each Cd form, wherein QDs are more pro-oxidant when compared to dissolved Cd. The gills are the main tissue affected by QDs, with effects related to the increase of SOD, GST and GPx activities, while those of dissolved Cd was associated to the increase of CAT activity, Cd accumulation and exposure time. Digestive gland is a main tissue for accumulation of both Cd forms, but changes in antioxidant enzyme activities are smaller than in gills. A multivariate analysis revealed that the antioxidant patterns are tissue dependent, indicating nano-specific effects possibly associated to oxidative stress and changes in redox homeostasis.

  11. Tumor Cell Response to Synchrotron Microbeam Radiation Therapy Differs Markedly From Cells in Normal Tissues

    SciTech Connect

    Crosbie, Jeffrey C.; Anderson, Robin L.; Rothkamm, Kai; Restall, Christina M.; Cann, Leonie; Ruwanpura, Saleela; Meachem, Sarah; Yagi, Naoto; Svalbe, Imants; Lewis, Robert A.; Williams, Bryan R.G.; Rogers, Peter A.W.

    2010-07-01

    Purpose: High-dose synchrotron microbeam radiation therapy (MRT) can be effective at destroying tumors in animal models while causing very little damage to normal tissues. The aim of this study was to investigate the cellular processes behind this observation of potential clinical importance. Methods and Materials: MRT was performed using a lattice of 25 {mu}m-wide, planar, polychromatic, kilovoltage X-ray microbeams, with 200-{mu}m peak separation. Inoculated EMT-6.5 tumor and normal mouse skin tissues were harvested at defined intervals post-MRT. Immunohistochemical detection of {gamma}-H2AX allowed precise localization of irradiated cells, which were also assessed for proliferation and apoptosis. Results: MRT significantly reduced tumor cell proliferation by 24 h post-irradiation (p = 0.002). An unexpected finding was that within 24 h of MRT, peak and valley irradiated zones were indistinguishable in tumors because of extensive cell migration between the zones. This was not seen in MRT-treated normal skin, which appeared to undergo a coordinated repair response. MRT elicited an increase in median survival times of EMT-6.5 and 67NR tumor-inoculated mice similar to that achieved with conventional radiotherapy, while causing markedly less normal tissue damage. Conclusions: This study provides evidence of a differential response at a cellular level between normal and tumor tissues after synchrotron MRT.

  12. Bystander and Adaptive Responses in Tissue Models exposed to Low Radiation Doses

    SciTech Connect

    Kevin M. Prise

    2007-01-02

    The overall goal is characterization of 3D tissue models that can be used for investigation of the mechanisms underlying radiation-induced bystander effect at low doses (20 cGy or less) of low LET ionizing radiation, using a unique focused soft X-ray microprobe that had been upgraded to provide a range of focused soft X-ray energies, some sufficient to penetrate 3D models (Ref DE-FG02-01ER63236). The proposed studies will include an examination of whether the passage of a single electron track can trigger bystander responses in the 3D tissue models and, if so, whether the response is altered by increased or decreased levels of oxidative stress. Our existing multi-photon/confocal in-depth microscopy techniques will be used to develop assays for damage induced within intact 3D tissue models. The working hypothesis is that organization of cells into tissues, particularly involving more than one cell type, alters expression of the radiation-induced bystander effect compared to that seen in isolated single cell types in monolayer.

  13. Tissue Oxygenation Response to Mild Hypercapnia during Cardiopulmonary Bypass with Constant Pump Output

    PubMed Central

    Akça, Ozan; Sessler, Daniel I; DeLong, Diane; Keijner, Raymond; Ganzel, Brian; Doufas, Anthony G

    2006-01-01

    Background Tissue oxygenation is the primary determinant of wound infection risk. Mild hypercapnia markedly improves cutaneous, subcutaneous, and muscular tissue oxygenation in volunteers and patients. However, relative contributions of increased cardiac output and peripheral vasodilation to this response remains unknown. We thus tested the hypothesis that increased cardiac output is the dominant mechanism. Methods We recruited 10 ASA III patients, aged 40–65 years, undergoing cardiopulmonary bypass for this crossover trial. After induction of anaesthesia, a Silastic tonometer was inserted subcutaneously in the upper arm. Subcutaneous tissue oxygen tension was measured with both polarographic electrode and fluorescence-based systems. Oximeter probes were placed bilaterally on the forehead to monitor cerebral oxygenation. After initiation of cardiopulmonary bypass, in random order patients were exposed to two arterial CO2 partial pressures for 30 minutes each: 35 (normocapnia) or 50 mmHg (hypercapnia). Bypass pump flow was kept constant throughout the measurement periods. Results Hypercapnia during bypass had essentially no effect on PaO2, mean arterial pressure, or tissue temperature. PaCO2 and pH differed significantly. Subcutaneous tissue oxygenation was virtually identical during the two PaCO2 periods (139 [50,163] vs. 145 [38,158], P=0.335) (median [range]). In contrast, cerebral oxygen saturation (our positive control measurement) was significantly less during normocapnia (57 [28,67]%) than hypercapnia (64 [37,89]%, P=0.025). Conclusions Mild hypercapnia, which normally markedly increases tissue oxygenation, did not do so during cardiopulmonary bypass with fixed pump output. This suggests that hypercapnia normally increases tissue oxygenation by increasing cardiac output rather than direct dilation of peripheral vessels. PMID:16675511

  14. Blind breast tissue diagnosis using independent component analysis of localized backscattering response

    NASA Astrophysics Data System (ADS)

    Eguizabal, Alma; Laughney, Ashley M.; García Allende, Pilar Beatriz; Krishnaswamy, Venkataramanan; Wells, Wendy A.; Paulsen, Keith D.; Pogue, Brian W.; Lopez-Higuera, Jose M.; Conde, Olga M.

    2012-03-01

    A blind separation technique based on Independent Component Analysis (ICA) is proposed for breast tumor delineation and pathologic diagnosis. Tissue morphology is determined by fitting local measures of tissue reflectance to a Mie theory approximation, parameterizing the scattering power, scattering amplitude and average scattering irradiance. ICA is applied on the scattering parameters by spatial analysis using the Fast ICA method to extract more determinant features for an accurate diagnostic. Neither training, nor comparisons with reference parameters are required. Tissue diagnosis is provided directly following ICA application to the scattering parameter images. Surgically resected breast tissues were imaged and identified by a pathologist. Three different tissue pathologies were identified in 29 samples and classified as not-malignant, malignant and adipose. Scatter plot analysis of both ICA results and optical parameters where obtained. ICA subtle ameliorates those cases where optical parameter's scatter plots were not linearly separable. Furthermore, observing the mixing matrix of the ICA, it can be decided when the optical parameters themselves are diagnostically powerful. Moreover, contrast maps provided by ICA correlate with the pathologic diagnosis. The time response of the diagnostic strategy is therefore enhanced comparing with complex classifiers, enabling near real-time assessment of pathology during breast-conserving surgery.

  15. Response of tobacco tissue cultures growing in contact with lunar fines.

    NASA Technical Reports Server (NTRS)

    Weete, J. D.; Walkinshaw, C. H.; Laseter, J. L.

    1973-01-01

    During the quarantine periods following each Apollo mission to the moon, various biological systems were placed in the presence of lunar material to determine if pathogenic agents were present. Although no detrimental effects resulted, various responses by the several plant systems tested were noted. One such response was the increased pigmentation observed in the callus tissue cultures of tobacco. Further investigations revealed that these tissues grown in the presence of lunar material resulted in as much as a 35% increase in total pigments while differences in fatty acid and sterol concentrations were also noted when compared to the controls. It is believed that these changes brought about by the lunar material can be attributed to a change in the nutritional environment caused by its dissolution.

  16. [Repetitive strain injuries. Forearm pain caused by tissue responses to repetitive strain].

    PubMed

    Sorgatz, H

    2002-10-01

    According to the National Research Council, painful work-related upper limb disorders are caused by different pathophysiological mechanisms, one of which is repetitive strain injury (RSI). Forearm pain, tenderness, and paresthesias are thought to result from a continual risk of exceeding limits of "cumulative trauma load tolerance" (CTLT, cf. NRC 2001) in soft tissue by thousands of high-frequency, repetitive movements. On the other hand, repetitive painful stimulations also produce neuroplastic changes in the spinal and supraspinal nociceptive systems. Thus, repetitive motor and nociceptive impulses become part of the same motor programs, which are also responsible for high-frequency movements and tissue damage. In this way RSI pain may be felt as a task-related response, even after all injuries are completely healed. Consequences of this neuroplastic CTLT model for RSI prevention and therapy are discussed.

  17. Short-term tissue response to potential root-end filling materials in infected root canals.

    PubMed

    Chong, B S; Pitt Ford, T R; Kariyawasam, S P

    1997-07-01

    The short-term tissue responses to two potential root-end filling materials, a light-cured glass ionomer cement (Vitrebond) and a reinforced zinc oxide-eugenol cement (Kalzinol), were compared with that to amalgam using a previously devised experimental model. In 24 premolar teeth of beagle dogs (47 roots), a collection of endodontic pathogenic bacteria was first inoculated into the root canals to induce periradicular lesions. On each root, an apicoectomy was performed and root-end cavities prepared to receive fillings of each material. The teeth and surrounding jaw were removed after 2 weeks (23 roots) and 1 week (24 roots); they were then prepared for histological examination. The tissue response to amalgam fillings after 2 weeks and 1 week was marked by moderate or severe inflammation on all roots, and extended to < or = 0.5 mm or > 0.5 mm in 15 out of 16 roots. In contrast, after 2 weeks, the majority of roots filled with Kalzinol showed little or moderate inflammation, while the tissue response to Vitrebond was the best of the three materials, and was also the least extensive. After 1 week, the overall best tissue response was with Vitrebond, followed by Kalzinol. The differences between materials for both time periods with either none or few inflammatory cells when compared with that with either moderate or severe inflammation were not statistically significant (P < 0.02). However, the differences between materials for both time periods with no inflammation or inflammation extending < 0.2 mm when compared with that with inflammation extending > 0.2 mm (< or = 0.5 mm or > 0.5 mm) were statistically significant (P < 0.01). Apart from amalgam, in which healing was marked by the persistence of a localized focus of inflammation adjacent to the root-end filling, even though there were intersample variations, there was little overall difference in the temporal and qualitative healing response to Vitrebond and Kalzinol. Both Vitrebond and Kalzinol have potential as

  18. Subacute Tissue Response to 3D Graphene Oxide Scaffolds Implanted in the Injured Rat Spinal Cord.

    PubMed

    López-Dolado, Elisa; González-Mayorga, Ankor; Portolés, María Teresa; Feito, María José; Ferrer, María Luisa; Del Monte, Francisco; Gutiérrez, María Concepción; Serrano, María Concepción

    2015-08-26

    The increasing prevalence and high sanitary costs of lesions affecting the central nervous system (CNS) at the spinal cord are encouraging experts in different fields to explore new avenues for neural repair. In this context, graphene and its derivatives are attracting significant attention, although their toxicity and performance in the CNS in vivo remains unclear. Here, the subacute tissue response to 3D flexible and porous scaffolds composed of partially reduced graphene oxide is investigated when implanted in the injured rat spinal cord. The interest of these structures as potentially useful platforms for CNS regeneration mainly relies on their mechanical compliance with neural tissues, adequate biocompatibility with neural cells in vitro and versatility to carry topographical and biological guidance cues. Early tissue responses are thoroughly investigated locally (spinal cord at C6 level) and in the major organs (i.e., kidney, liver, lung, and spleen). The absence of local and systemic toxic responses, along with the positive signs found at the lesion site (e.g., filler effect, soft interface for no additional scaring, preservation of cell populations at the perilesional area, presence of M2 macrophages), encourages further investigation of these materials as promising components of more efficient material-based platforms for CNS repair.

  19. The agr Inhibitors Solonamide B and Analogues Alter Immune Responses to Staphylococccus aureus but Do Not Exhibit Adverse Effects on Immune Cell Functions.

    PubMed

    Baldry, Mara; Kitir, Betül; Frøkiær, Hanne; Christensen, Simon B; Taverne, Nico; Meijerink, Marjolein; Franzyk, Henrik; Olsen, Christian A; Wells, Jerry M; Ingmer, Hanne

    2016-01-01

    Staphylococcus aureus infections are becoming increasingly difficult to treat due to antibiotic resistance with the community-associated methicillin-resistant S. aureus (CA-MRSA) strains such as USA300 being of particular concern. The inhibition of bacterial virulence has been proposed as an alternative approach to treat multi-drug resistant pathogens. One interesting anti-virulence target is the agr quorum-sensing system, which regulates virulence of CA-MRSA in response to agr-encoded autoinducing peptides. Agr regulation confines exotoxin production to the stationary growth phase with concomitant repression of surface-expressed adhesins. Solonamide B, a non-ribosomal depsipeptide of marine bacterial origin, was recently identified as a putative anti-virulence compound that markedly reduced expression of α-hemolysin and phenol-soluble modulins. To further strengthen solonamide anti-virulence candidacy, we report the chemical synthesis of solonamide analogues, investigation of structure-function relationships, and assessment of their potential to modulate immune cell functions. We found that structural differences between solonamide analogues confer significant differences in interference with agr, while immune cell activity and integrity is generally not affected. Furthermore, treatment of S. aureus with selected solonamides was found to only marginally influence the interaction with fibronectin and biofilm formation, thus addressing the concern that application of compounds inducing an agr-negative state may have adverse interactions with host factors in favor of host colonization. PMID:26731096

  20. The agr Inhibitors Solonamide B and Analogues Alter Immune Responses to Staphylococccus aureus but Do Not Exhibit Adverse Effects on Immune Cell Functions

    PubMed Central

    Baldry, Mara; Kitir, Betül; Frøkiær, Hanne; Christensen, Simon B.; Taverne, Nico; Meijerink, Marjolein; Franzyk, Henrik; Olsen, Christian A.; Wells, Jerry M.; Ingmer, Hanne

    2016-01-01

    Staphylococcus aureus infections are becoming increasingly difficult to treat due to antibiotic resistance with the community-associated methicillin-resistant S. aureus (CA-MRSA) strains such as USA300 being of particular concern. The inhibition of bacterial virulence has been proposed as an alternative approach to treat multi-drug resistant pathogens. One interesting anti-virulence target is the agr quorum-sensing system, which regulates virulence of CA-MRSA in response to agr-encoded autoinducing peptides. Agr regulation confines exotoxin production to the stationary growth phase with concomitant repression of surface-expressed adhesins. Solonamide B, a non-ribosomal depsipeptide of marine bacterial origin, was recently identified as a putative anti-virulence compound that markedly reduced expression of α-hemolysin and phenol-soluble modulins. To further strengthen solonamide anti-virulence candidacy, we report the chemical synthesis of solonamide analogues, investigation of structure–function relationships, and assessment of their potential to modulate immune cell functions. We found that structural differences between solonamide analogues confer significant differences in interference with agr, while immune cell activity and integrity is generally not affected. Furthermore, treatment of S. aureus with selected solonamides was found to only marginally influence the interaction with fibronectin and biofilm formation, thus addressing the concern that application of compounds inducing an agr-negative state may have adverse interactions with host factors in favor of host colonization. PMID:26731096

  1. Cytoskeletal remodeling of connective tissue fibroblasts in response to static stretch is dependent on matrix material properties

    PubMed Central

    Abbott, Rosalyn D; Koptiuch, Cathryn; Iatridis, James C; Howe, Alan K; Badger, Gary J; Langevin, Helene M

    2012-01-01

    In areolar “loose” connective tissue, fibroblasts remodel their cytoskeleton within minutes in response to static stretch resulting in increased cell body cross-sectional area that relaxes the tissue to a lower state of resting tension. It remains unknown whether the loosely arranged collagen matrix, characteristic of areolar connective tissue, is required for this cytoskeletal response to occur. The purpose of this study was to evaluate cytoskeletal remodeling of fibroblasts in and dissociated from areolar and dense connective tissue in response to 2 hours of static stretch in both native tissue and collagen gels of varying crosslinking. Rheometric testing indicated that the areolar connective tissue had a lower dynamic modulus and was more viscous than the dense connective tissue. In response to stretch, cells within the more compliant areolar connective tissue adopted a large “sheet-like” morphology that was in contrast to the smaller dendritic morphology in the dense connective tissue. By adjusting the in vitro collagen crosslinking, and the resulting dynamic modulus, it was demonstrated that cells dissociated from dense connective tissue are capable of responding when seeded into a compliant matrix, while cells dissociated from areolar connective tissue can lose their ability to respond when their matrix becomes stiffer. This set of experiments indicated stretch-induced fibroblast expansion was dependent on the distinct matrix material properties of areolar connective tissues as opposed to the cells’ tissue of origin. These results also suggest that disease and pathological processes with increased crosslinks, such as diabetes and fibrosis, could impair fibroblast responsiveness in connective tissues. PMID:22552950

  2. 2013 Immune Risk Standing Review Panel Research Plan Review for: The Risk of Crew Adverse Health Event Due to Altered Immune Response

    NASA Technical Reports Server (NTRS)

    Steinberg, Susan

    2014-01-01

    The 2013 Immune Risk Standing Review Panel (from here on referred to as the SRP) participated in a meeting with representatives from the Human Research Program (HRP) Human Health Countermeasures (HHC) Element and HRP management on February 3-4, 2014 in Houston, TX to review the updated Research Plan for the Risk of Crew Adverse Health Event Due to Altered Immune Response in the HRP Integrated Research Plan. The SRP is impressed with the work the immune discipline has done since the 2012 SRP review and agrees with the new wording of the Gaps, no longer questions, now statements. The SRP also likes the addition of adding targets for closing the Gaps, but it is not clear how they got to some of the interim stages (interval percentages). A major concern that the SRP has mentioned since the initial 2009 SRP meeting is that there is still not enough emphasis on the interdisciplinary aspect of the immune risk associated with other risks (i.e., nutrition, radiation, etc.). The SRP recommends that a "translational SRP" or advisory group be developed that is composed of members from all of the HRP SRPs. The SRP also thinks that the immune discipline should consider a more systems biology approach. Lastly, the SRP is concerned that the risks observed in research from low Earth orbit (LEO) missions may not accurately reflect all the risks of longer duration flight beyond LEO. Also, there does not seem to be a concern for immune responses that may occur when someone is in space longer than six months, for example, a Mars mission would take three years. The absence of disease in past and current flight scenarios does not mean the risk may not be there in future flight settings.

  3. Degradation behavior of, and tissue response to photo-crosslinked poly(trimethylene carbonate) networks.

    PubMed

    Rongen, Jan J; van Bochove, Bas; Hannink, Gerjon; Grijpma, Dirk W; Buma, Pieter

    2016-11-01

    Photo-crosslinked networks prepared from three-armed methacrylate functionalized PTMC oligomers (PTMC-tMA macromers) are attractive materials for developing an anatomically correct meniscus scaffold. In this study, we evaluated cell specific biocompatibility, in vitro and in vivo degradation behavior of, and tissue response to, such PTMC networks. By evaluating PTMC networks prepared from PTMC-tMA macromers of different molecular weights, we were able to assess the effect of macromer molecular weight on the degradation rate of the PTMC network obtained after photo-crosslinking. Three photo-crosslinked networks with different crosslinking densities were prepared using PTMC-tMA macromers with molecular weights 13.3, 17.8, and 26.7 kg/mol. Good cell biocompatibility was demonstrated in a proliferation assay with synovium derived cells. PTMC networks degraded slowly, but statistically significant, both in vitro as well as subcutaneously in rats. Networks prepared from macromers with higher molecular weights demonstrated increased degradation rates compared to networks prepared from initial macromers of lowest molecular weight. The degradation process took place via surface erosion. The PTMC networks showed good tissue tolerance during subcutaneous implantation, to which the tissue response was characterized by the presence of fibrous tissue and encapsulation of the implants. Concluding, we developed cell and tissue biocompatible, photo-crosslinked PTMC networks using PTMC-tMA macromers with relatively high molecular weights. These photo-crosslinked PTMC networks slowly degrade by a surface erosion process. Increasing the crosslinking density of these networks decreases the rate of surface degradation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2823-2832, 2016.

  4. Neovascularization is influenced by androgenic hormones in the tissue implant response.

    PubMed

    Butler Jr Phd, Kenneth R; Benghuzzi Phd, Hamed; Tucci Phd, Michelle; Puckett Phd, Aaron

    2012-01-01

    The objective of this investigation was to demonstrate the effect of androgens on the neovascularization of the fibrous tissue surrounding tricalcium phosphate (TCP) implants. Sixteen animals in four experimental groups (n = 4/group) were implanted with one TCP implant each. Group I animals were implanted with the sham TCP ceramic (Control). Group II animals received a testosterone-loaded ceramic. Group III animals were implanted with a dihydrotestosterone containing bioceramic. Group IV animals received the androstenedione filled bioceramic. At 90 days post-implantation, the fibrous tissue surrounding the implants were evaluated microscopically following staining with routine hematoxylin and eosin (H&E), Masson’s trichrome, and Papanicolaou stains. Using Image Pro (Media Cybernetics, Silver Spring, MD) digital analysis software, data were collected to compare the hormonal effects on the number (per high power field) and size of blood vessels (micrometers, µm) within the fibrous tissue surrounding all four groups. The presence of androgens greatly affected the angiogenic response within the fibrous tissue. All three hormones exhibited less neovascularization compared to the control. Though not as dramatic as androstenedione (3±0), both testosterone (12±1) and dihydrotestosterone (10±1) suppressed the number of blood vessels present in the fibrous tissue capsule compared to control (13±1). However, the circumference of the vessels was much larger for the testosterone (236µm ±8µm) and dihydrotestosterone (256µm±4µm) treated groups compared to the androstenedione (146µm ±7µm) or control (163µm±3µm) groups. The results of this study demonstrate androgens strongly vary in their effect on neovascularization by limiting the number of new vessels developed while contributing to the presence of larger vessels within the fibrous tissue surrounding TCP implants loaded with testosterone and dihydrotestosterone.

  5. Vaccine Adverse Events

    MedlinePlus

    ... Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products Vaccines, Blood & Biologics Home Vaccines, Blood & Biologics Safety & Availability ( ... Center for Biologics Evaluation & Research Vaccine Adverse Events Vaccine Adverse Events Share Tweet Linkedin Pin it More ...

  6. The effect of retinol on the hyperthermal response of normal tissue in vivo

    SciTech Connect

    Rogers, M.A.; Marigold, J.C.; Hume, S.P.

    1983-07-01

    The effect of prior administration of retinol, a membrane labilizer, on the in vivo hyperthermal response of lysosomes was investigated in the mouse spleen using a quantitative histochemical assay for the lysosomal enzyme acid phosphatase. A dose of retinol which had no effect when given alone enhanced the thermal response of the lysosome, causing an increase in lysosomal membrane permeability. In contrast, the same dose of retinol had no effect on the gross hyperthermal response of mouse intestine; a tissue which is relatively susceptible to hyperthermia. Thermal damage to intestine was assayed directly by crypt loss 1 day after treatment or assessed as thermal enhancement of X-ray damage by counting crypt microcolonies 4 days after a combined heat and X-ray treatment. Thus, although the hyperthermal response of the lysosome could be enhanced by the administration of retinol, thermal damage at a gross tissue level appeared to be unaffected, suggesting that lysosomal membrane injury is unlikely to be a primary event in hyperthermal cell killing.

  7. Effect of retinol on the hyperthermal response of normal tissue in vivo

    SciTech Connect

    Rogers, M.A.; Marigold, J.C.L.; Hume, S.P.

    1983-07-01

    The effect of prior administration of retinol, a membrane labilizer, on the in vivo hyperthermal response of lysosomes was investigated in the mouse spleen using a quantitative histochemical assay for the lysosomal enzyme acid phosphatase. A dose of retinol which had no effect when given alone enhanced the thermal response of the lysosome, causing an increase in lysosomal membrane permeability. In contrast, the same dose of retinol had no effect on the gross hyperthermal response of mouse intestine; a tissue which is relatively susceptible to hyperthermia. Thermal damage to intestine was assayed directly by crypt loss 1 day after treatment or assessed as thermal enhancement of x-ray damage by counting crypt microcolonies 4 days after a combined heat and x-ray treatment. Thus, although the hyperthermal response of the lysosome could be enhanced by the administration of retinol, thermal damage at a gross tissue level appeared to be unaffected, suggesting that lysosomal membrane injury is unlikely to be a primary event in hyperthermal cell killing.

  8. Size-dependent long-term tissue response to biostable nanowires in the brain.

    PubMed

    Gällentoft, Lina; Pettersson, Lina M E; Danielsen, Nils; Schouenborg, Jens; Prinz, Christelle N; Linsmeier, Cecilia Eriksson

    2015-02-01

    Nanostructured neural interfaces, comprising nanotubes or nanowires, have the potential to overcome the present hurdles of achieving stable communication with neuronal networks for long periods of time. This would have a strong impact on brain research. However, little information is available on the brain response to implanted high-aspect-ratio nanoparticles, which share morphological similarities with asbestos fibres. Here, we investigated the glial response and neuronal loss in the rat brain after implantation of biostable and structurally controlled nanowires of different lengths for a period up to one year post-surgery. Our results show that, as for lung and abdominal tissue, the brain is subject to a sustained, local inflammation when biostable and high-aspect-ratio nanoparticles of 5 μm or longer are present in the brain tissue. In addition, a significant loss of neurons was observed adjacent to the 10 μm nanowires after one year. Notably, the inflammatory response was restricted to a narrow zone around the nanowires and did not escalate between 12 weeks and one year. Furthermore, 2 μm nanowires did not cause significant inflammatory response nor significant loss of neurons nearby. The present results provide key information for the design of future neural implants based on nanomaterials.

  9. Monosaccharide-Responsive Phenylboronate-Polyol Cell Scaffolds for Cell Sheet and Tissue Engineering Applications

    PubMed Central

    Reddy, Rachamalla Maheedhar; Srivastava, Akshay; Kumar, Ashok

    2013-01-01

    Analyte-responsive smart polymeric materials are of great interest and have been actively investigated in the field of regenerative medicine. Phenylboronate containing copolymers form gels with polyols under alkaline conditions. Monosaccharides, by virtue of their higher affinity towards boronate, can displace polyols and solubilize such gels. In the present study, we investigate the possibility of utilizing phenylboronate-polyol interactions at physiological pH in order to develop monosaccharide-responsive degradable scaffold materials for systems dealing with cells and tissues. Amine assisted phenylboronate-polyol interactions were employed to develop novel hydrogel and cryogel scaffolds at neutral pH. The scaffolds displayed monosaccharide inducible gel-sol phase transformability. In vitro cell culture studies demonstrated the ability of scaffolds to support cell adhesion, viability and proliferation. Fructose induced gel degradation is used to recover cells cultured on the hydrogels. The cryogels displayed open macroporous structure and superior mechanical properties. These novel phase transformable phenylboronate-polyol based scaffolds displayed a great potential for various cell sheet and tissue engineering applications. Their monosaccharide responsiveness at physiological pH is very useful and can be utilized in the fields of cell immobilization, spheroid culture, saccharide recognition and analyte-responsive drug delivery. PMID:24167587

  10. Structure-function relationships in radiation-induced cell and tissue lesions: special references to the contributions of scanning electron microscopy and hematopoietic tissue responses

    SciTech Connect

    Seed, T.M.

    1987-03-01

    Contributions of scanning electron microscopy to the field of radiation biology are briefly reviewed and presented in terms of an overall goal to identify and characterize the structural features of radiation-induced lesions in vital cell and tissue targets. In the context of lesion production, the major radiation-elicited response sequences, the types and nature of measured end points, and governing temporal and radiobiological parameters are discussed and illustrated by using results derived from both in vitro cell systems and in vivo studies that measured tissue responses from various organ systems (respiratory, digestive, circulatory, and central nervous systems). Work in our laboratory on the nature of early and late hematopathologic tissue responses (aplastic anemia and myeloid leukemia) induced by protracted radiation exposure and the bridging effect of repair processes relative to the expression of these pathologies is highlighted.

  11. Identification of biomarkers responsive to chronic exposure to pharmaceuticals in target tissues of Carcinus maenas.

    PubMed

    Aguirre-Martínez, G V; Del Valls, T A; Martín-Díaz, M L

    2013-01-01

    A 28-day bioassay was performed with Carcinus maenas to evaluate chronic effects caused by exposure to caffeine and ibuprofen (0.1-50 μg L(-1)) in sea water. Lysosomal membrane stability (LMS) was evaluated in hemolymph applying the neutral red retention assay (NRRA); several biomarkers including ethoxyresorufin O-deethylase (EROD), dibenzylfluorescein dealkylase (DBF), glutathione S-transferase (GST), glutathione peroxidase (GPX), lipid peroxidation (LPO) and DNA damage were studied in gill, hepatopancreas, muscle and gonad tissues. In crabs exposed to environmental concentrations of the drugs, retention time was reduced by 50%. EROD and DBFOD activities were induced by caffeine in muscle and hepatopancreas tissues (p < 0.05); GST activity was activated by ibuprofen in gill, hepatopancreas and muscle at the highest concentrations tested (p < 0.05). All tissues showed GPX activity and LPO induction (p < 0.05). Crabs exposed to caffeine and ibuprofen showed evidence of DNA damage mainly in hepatopancreas tissues (p < 0.05). Environmental concentrations of pharmaceuticals induce LMS and the biochemical responses studied in this crab. This methodology is a suitable technique for assessing pharmaceutical toxicity in the marine environment. PMID:23562135

  12. Characterization of Chinese giant salamander iridovirus tissue tropism and inflammatory response after infection.

    PubMed

    Jiang, Nan; Fan, Yuding; Zhou, Yong; Liu, Wenzhi; Ma, Jie; Meng, Yan; Xie, Congxin; Zeng, Lingbing

    2015-06-01

    The Chinese giant salamander iridovirus (GSIV), belonging to the genus Ranavirus in the family Iridoviridae, causes severe hemorrhagic lesions and nearly 100% mortality in naturally infected Chinese giant salamanders Andrias davidiamus. However, the replication and distribution of the virus has not been well characterized in vivo. Using in situ hybridization, the expression of the GSIV major capsid protein (MCP) was detected in the cytoplasm of cells of the spleen, kidney, liver and gut tissues. MCP expression in the spleen and kidney appeared to fluctuate significantly during the acute phase of infection. Using an immunofluorescence assay, GSIV antigens were abundant in the spleen and kidney tissues but appeared to be at relatively low levels in the liver and gut. Additionally, there were significant changes in the expression of the pro-inflammatory cytokines macrophage migration inhibitory factor (MIF), tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) in different tissues in response to infection with GSIV. The expression of MIF, TNF-α and IL-1β had significantly increased in the spleen at 3 d post-infection; this correlated with a decrease in virus replication in the spleen. These results suggest that the spleen and kidney are the major target tissues of GSIV, and the increased expression of MIF, TNF‑α and IL-1β may contribute to a reduction of virus replication in the spleen.

  13. Histotripsy Fractionation of Prostate Tissue: Local Effects and Systemic Response in a Canine Model

    PubMed Central

    Hempel, Christopher R.; Hall, Timothy L; Cain, Charles A.; Fowlkes, J. Brian; Xu, Zhen; Roberts, William W.

    2010-01-01

    Purpose Histotripsy is an extracorporeal ultrasound (US) technology that utilizes cavitational mechanisms to produce non-thermal tissue destruction. Previously, we demonstrated the feasibility of histotripsy for fractionation and immediate debulking of prostate tissue. The purpose of this study is to characterize the local effects and systemic response after histotripsy treatment of prostate tissue in an in-vivo canine model. Materials and Methods Histotripsy was applied transabdominally to the prostate in eighteen intact male canine subjects under general anesthesia. Acoustic bursts (4 microseconds) were delivered at 300 Hz pulse repetition rate from a highly focused 750 kHz piezoelectric US transducer (15 cm aperture, 3×3×8 mm focal volume). The prostate and surrounding structures were harvested at prescribed time points (0, 7, 28, or 56 days) following histotripsy. Blood and urine parameters were assessed periodically while clinical evaluation incorporating a validated veterinary pain scale was performed daily. Results Conventional transrectal US imaging facilitated targeting of the focal volume and provided real-time assessment of cavitation activity. Fractionation of the targeted volume and clearance of the resultant debris with urination produced a treatment cavity within each prostate. No acoustic collateral damage was seen and urothelialization of the treatment cavity occurred within 28 days of treatment. Only transient lab abnormalities and minimal hematuria were noted after treatment. Pain scores revealed only mild post treatment discomfort. Conclusions Histotripsy produced consistent tissue fractionation and prostate debulking without collateral acoustic injury or clinical side effects and was well tolerated in the canine model. PMID:21334667

  14. Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators

    NASA Technical Reports Server (NTRS)

    Belaguli, N. S.; Sepulveda, J. L.; Nigam, V.; Charron, F.; Nemer, M.; Schwartz, R. J.

    2000-01-01

    Combinatorial interaction among cardiac tissue-restricted enriched transcription factors may facilitate the expression of cardiac tissue-restricted genes. Here we show that the MADS box factor serum response factor (SRF) cooperates with the zinc finger protein GATA-4 to synergistically activate numerous myogenic and nonmyogenic serum response element (SRE)-dependent promoters in CV1 fibroblasts. In the absence of GATA binding sites, synergistic activation depends on binding of SRF to the proximal CArG box sequence in the cardiac and skeletal alpha-actin promoter. GATA-4's C-terminal activation domain is obligatory for synergistic coactivation with SRF, and its N-terminal domain and first zinc finger are inhibitory. SRF and GATA-4 physically associate both in vivo and in vitro through their MADS box and the second zinc finger domains as determined by protein A pullout assays and by in vivo one-hybrid transfection assays using Gal4 fusion proteins. Other cardiovascular tissue-restricted GATA factors, such as GATA-5 and GATA-6, were equivalent to GATA-4 in coactivating SRE-dependent targets. Thus, interaction between the MADS box and C4 zinc finger proteins, a novel regulatory paradigm, mediates activation of SRF-dependent gene expression.

  15. Identification of differentially expressed proteins of brain tissue in response to methamidophos in flounder (Paralichthys olivaceus).

    PubMed

    Peng, Hui-Fang; Bao, Xiao-Dong; Zhang, Yong; Huang, Lin; Huang, He-Qing

    2015-06-01

    Methamidophos (MAP), an organophosphorus pesticide used around the world, has been associated with a wide spectrum of toxic effects on organisms in the environment. In this study, the flounder Paralichthys olivaceus was subjected to 10 mg/L MAP for 72 h and 144 h, and the morphological and proteomic changes in the brain were observed, analyzed and compared with those in the non-exposed control group. Under the light microscope and transmission electron microscope, MAP had evidently induced changes in or damage to the flounder tissues. Gas chromatography analysis demonstrated that the MAP residues were significantly accumulated in the flounder brain tissues. Proteomic changes in the brain tissue were revealed using two-dimensional gel electrophoresis and 27 protein spots were observed to be significantly changed by MAP exposure. The results indicated that the regulated proteins were involved in immune and stress responses, protein biosynthesis and modification, signal transduction, organismal development, and 50% of them are protease. qRT-PCR was used to further detect the corresponding change of transcription. These data may be beneficial to understand the molecular mechanism of MAP toxicity in flounder, be very useful for MAP-resistance screening in flounder culture. According to our results and analyzing, heat shock protein 90 (HSP90) and granzyme K (GzmK) had taken important part in immune response to MAP-stress and could be biomarkers for MAP-stress in flounder.

  16. In vivo tissue response and durability of five novel synthetic polymers in a rabbit model.

    PubMed

    Sahin, E; Cingi, C; Eskiizmir, G; Altintoprak, N; Calli, A; Calli, C; Yilgör, I; Yilgör, E

    2016-04-01

    Alloplastic materials are frequently used in facial plastic surgeries such as rhinoplasty and nasal reconstruction. Unfortunately, the ideal alloplastic material has not been found. This experimental study evaluates the tissue response and durability of five novel polymers developed as an alloplastic material. In this experimental study involving a tertiary university hospital, six subcuticular pockets were formed at the back of 10 rabbits for the implantation of each polymer and sham group. Each pocket was excised with its adjacent tissue after three months, and collected for histopathological examination. Semi-quantitative examination including neovascularisation, inflammation, fibrosis, abscess formation, multinucleated foreign body giant cells was performed, and integrity of polymer was evaluated. A statistical comparison was performed. No statically significant difference was detected in neovascularisation, inflammation, fibrosis, abscess formation and multinucleated foreign body giant cells when a paired comparison between sham and polymer II, III and IV groups was performed individually. Nevertheless, the degree of fibrosis was less than sham group in polymer I (p = .027) and V (p = .018), although the other variables were almost similar. The integrity of polymers III (9 intact, 1 fragmented) and IV (8 intact, 2 absent) was better than the other polymers. These novel synthetic polymers could be considered as good candidates for clinical applicability. All polymers provided satisfactory results in terms of tissue response; however, fibrovascular integration was higher in polymers II, III and IV. In addition, the durability of polymer III and IV was better than the others.

  17. Isoliquiritigenin Attenuates Adipose Tissue Inflammation in vitro and Adipose Tissue Fibrosis through Inhibition of Innate Immune Responses in Mice

    PubMed Central

    Watanabe, Yasuharu; Nagai, Yoshinori; Honda, Hiroe; Okamoto, Naoki; Yamamoto, Seiji; Hamashima, Takeru; Ishii, Yoko; Tanaka, Miyako; Suganami, Takayoshi; Sasahara, Masakiyo; Miyake, Kensuke; Takatsu, Kiyoshi

    2016-01-01

    Isoliquiritigenin (ILG) is a flavonoid derived from Glycyrrhiza uralensis and potently suppresses NLRP3 inflammasome activation resulting in the improvement of diet-induced adipose tissue inflammation. However, whether ILG affects other pathways besides the inflammasome in adipose tissue inflammation is unknown. We here show that ILG suppresses adipose tissue inflammation by affecting the paracrine loop containing saturated fatty acids and TNF-α by using a co-culture composed of adipocytes and macrophages. ILG suppressed inflammatory changes induced by the co-culture through inhibition of NF-κB activation. This effect was independent of either inhibition of inflammasome activation or activation of peroxisome proliferator-activated receptor-γ. Moreover, ILG suppressed TNF-α-induced activation of adipocytes, coincident with inhibition of IκBα phosphorylation. Additionally, TNF-α-mediated inhibition of Akt phosphorylation under insulin signaling was alleviated by ILG in adipocytes. ILG suppressed palmitic acid-induced activation of macrophages, with decreasing the level of phosphorylated Jnk expression. Intriguingly, ILG improved high fat diet-induced fibrosis in adipose tissue in vivo. Finally, ILG inhibited TLR4- or Mincle-stimulated expression of fibrosis-related genes in stromal vascular fraction from obese adipose tissue and macrophages in vitro. Thus, ILG can suppress adipose tissue inflammation by both inflammasome-dependent and -independent manners and attenuate adipose tissue fibrosis by targeting innate immune sensors. PMID:26975571

  18. Dietary response of sympatric deer to fire using stable isotope analysis of liver tissue

    USGS Publications Warehouse

    Walter, W. David; Zimmerman, T.J.; Leslie, David M.; Jenks, J.A.

    2009-01-01

    Carbon (??13C) and nitrogen (??15N) isotopes in biological samples from large herbivores identify photosynthetic pathways (C3 vs. C4) of plants they consumed and can elucidate potential nutritional characteristics of dietary selection. Because large herbivores consume a diversity of forage types, ??13C and ??15N in their tissue can index ingested and assimilated diets through time. We assessed ??13C and ??15N in metabolically active liver tissue of sympatric mule deer (Odocoileus hemionus) and white-tailed deer (O. virginianus) to identify dietary disparity resulting from use of burned and unburned areas in a largely forested landscape. Interspecific variation in dietary disparity of deer was documented 2-3 years post-fire in response to lag-time effects of vegetative response to burning and seasonal (i.e., summer, winter) differences in forage type. Liver ??13C for mule deer were lower during winter and higher during summer 2 years post-fire on burned habitat compared to unburned habitat suggesting different forages were consumed by mule deer in response to fire. Liver ??15N for both species were higher on burned than unburned habitat during winter and summer suggesting deer consumed more nutritious forage on burned habitat during both seasons 2 and 3 years post-fire. Unlike traditional methods of dietary assessment that do not measure uptake of carbon and nitrogen from dietary components, analyses of stable isotopes in liver or similar tissue elucidated ??13C and ??15N assimilation from seasonal dietary components and resulting differences in the foraging ecology of sympatric species in response to fire.

  19. Brain Tissue Responses to Neural Implants Impact Signal Sensitivity and Intervention Strategies

    PubMed Central

    2015-01-01

    Implantable biosensors are valuable scientific tools for basic neuroscience research and clinical applications. Neurotechnologies provide direct readouts of neurological signal and neurochemical processes. These tools are generally most valuable when performance capacities extend over months and years to facilitate the study of memory, plasticity, and behavior or to monitor patients’ conditions. These needs have generated a variety of device designs from microelectrodes for fast scan cyclic voltammetry (FSCV) and electrophysiology to microdialysis probes for sampling and detecting various neurochemicals. Regardless of the technology used, the breaching of the blood–brain barrier (BBB) to insert devices triggers a cascade of biochemical pathways resulting in complex molecular and cellular responses to implanted devices. Molecular and cellular changes in the microenvironment surrounding an implant include the introduction of mechanical strain, activation of glial cells, loss of perfusion, secondary metabolic injury, and neuronal degeneration. Changes to the tissue microenvironment surrounding the device can dramatically impact electrochemical and electrophysiological signal sensitivity and stability over time. This review summarizes the magnitude, variability, and time course of the dynamic molecular and cellular level neural tissue responses induced by state-of-the-art implantable devices. Studies show that insertion injuries and foreign body response can impact signal quality across all implanted central nervous system (CNS) sensors to varying degrees over both acute (seconds to minutes) and chronic periods (weeks to months). Understanding the underlying biological processes behind the brain tissue response to the devices at the cellular and molecular level leads to a variety of intervention strategies for improving signal sensitivity and longevity. PMID:25546652

  20. Effect of Nrf2 on rat ovarian tissues against atrazine-induced anti-oxidative response.

    PubMed

    Zhao, Fan; Li, Kun; Zhao, Lijing; Liu, Jian; Suo, Qi; Zhao, Jing; Wang, Hebin; Zhao, Shuhua

    2014-01-01

    The environmental persistence and bioaccumulation of herbicide atrazine may pose a significant threat to human health. In this experiment, Wistar rats were treated by 5, 25 and 125 mg·kg(-1) atrazine respectively for 28 days, and the oxidative stress responses as well as the activations of Nrf2 signaling pathway in ovarian tissues induced by atrazine were observed. The results showed that after be treated by atrazine, the proportion of atretic follicles in the rat ovary were increased, the contents of NO and MDA in the tissue homogenates were increased, the over-expressed Nrf2 transferred into the nuclei and played an antioxidant role by up-regulated the expression of II phase detoxifying enzymes such as HO1 and NQO1 and the expression of antioxidant enzymes such as CAT, SOD and GSH-PX.

  1. Dysfunctional Astrocytic and Synaptic Regulation of Hypothalamic Glutamatergic Transmission in a Mouse Model of Early-Life Adversity: Relevance to Neurosteroids and Programming of the Stress Response

    PubMed Central

    Gunn, Benjamin G.; Cunningham, Linda; Cooper, Michelle A.; Corteen, Nicole L.; Seifi, Mohsen; Swinny, Jerome D.; Lambert, Jeremy J.

    2013-01-01

    Adverse early-life experiences, such as poor maternal care, program an abnormal stress response that may involve an altered balance between excitatory and inhibitory signals. Here, we explored how early-life stress (ELS) affects excitatory and inhibitory transmission in corticotrophin-releasing factor (CRF)-expressing dorsal-medial (mpd) neurons of the neonatal mouse hypothalamus. We report that ELS associates with enhanced excitatory glutamatergic transmission that is manifested as an increased frequency of synaptic events and increased extrasynaptic conductance, with the latter associated with dysfunctional astrocytic regulation of glutamate levels. The neurosteroid 5α-pregnan-3α-ol-20-one (5α3α-THPROG) is an endogenous, positive modulator of GABAA receptors (GABAARs) that is abundant during brain development and rises rapidly during acute stress, thereby enhancing inhibition to curtail stress-induced activation of the hypothalamic-pituitary-adrenocortical axis. In control mpd neurons, 5α3α-THPROG potently suppressed neuronal discharge, but this action was greatly compromised by prior ELS exposure. This neurosteroid insensitivity did not primarily result from perturbations of GABAergic inhibition, but rather arose functionally from the increased excitatory drive onto mpd neurons. Previous reports indicated that mice (dams) lacking the GABAAR δ subunit (δ0/0) exhibit altered maternal behavior. Intriguingly, δ0/0 offspring showed some hallmarks of abnormal maternal care that were further exacerbated by ELS. Moreover, in common with ELS, mpd neurons of δ0/0 pups exhibited increased synaptic and extrasynaptic glutamatergic transmission and consequently a blunted neurosteroid suppression of neuronal firing. This study reveals that increased synaptic and tonic glutamatergic transmission may be a common maladaptation to ELS, leading to enhanced excitation of CRF-releasing neurons, and identifies neurosteroids as putative early regulators of the stress

  2. Tissue response to surface-treated tantalum implants: preliminary observations in primates.

    PubMed

    Meenaghan, M A; Natiella, J R; Moresi, J L; Flynn, H E; Wirth, J E; Baier, R E

    1979-07-01

    Samples of capacitor grade tantalum were surface-treated by a variety of methods. These surface treatments allowed testing of the same basic material which was mill-finished, metallurgically polished, electrochemically oxidized, sintered with a porous surface, and glow-discharged. Surface characterization was accomplished by contact angle measurements, Scanning Electron Microscopy, energy-dispensed x-ray analysis, and internal reflection spectroscopy. Subsequent to characterization, the material was surgically implanted in the subperiosteal region of the mandible, the buccal mucosa, and the subcutaneous paravertebral region of the back of Macaca speciosa (stumptail monkey). The tissue reaction at intervals of up to three weeks was evaluated morphologically and ultrastructurally. Significant differences in tissue response were noted at the interfaces with glow-discharge-treated versus lower surface energy samples. Adjacent to the glow-discharge-treated implants, two distinct tissue zones were identified. Zone No. 1, nearest the implant, exhibited an increased cellularity. This consisted of 4-5 layers of highly active mesenchymal cells or fibroblast-like cells with spindle-shaped nuclei and prominent cytoplasmic features. At various foci along the interface, hyperchromatic nuclear forms were noted to project into the space left by removal of the implant. These observations, coupled with a predominance of intercellular ground-substance material and less collagen at the interface, may indicate some form of bioadhesion. The deeper Zone No. 2 was 2-3 times as thick consisted of typical fibroblastic cells with a lamellar configuration, bordered by an occasional delicate-lined space. Independent of implantation site or surface texture, all other implants showed occasional multinucleated giant cells and a decrease in the cellular character of Zone No. 1. Both zones were reduced in thickness and composed of more mature fibroblasts. Some specimens exhibited intracytoplasmic

  3. A kelp with integrity: Macrocystis pyrifera prioritises tissue maintenance in response to nitrogen fertilisation.

    PubMed

    Stephens, Tiffany A; Hepburn, Christopher D

    2016-09-01

    Our understanding of the response of vascular, terrestrial plants to nitrogen (N) addition is advanced and provides the foundation for modern agriculture. In comparison, information on responses of marine macroalgae to increased nitrogen is far less developed. We investigated how in situ pulses of nitrate (NO3 (-)) affected the growth and N physiology of Macrocystis pyrifera by adding N using potassium nitrate dissolution blocks during a period of low seawater N concentration. Multiple parameters (e.g. growth, pigments, soluble NO3 (-)) were measured in distinct tissues throughout entire fronds (apical meristem, stipe, adult blade, mature blade, sporophyll, and holdfast). Unexpectedly, N fertilisation did not enhance elongation rates within the frond, but instead thickness (biomass per unit area) increased in adult blades. Increased blade thickness may have enhanced tissue integrity as fertilised kelp had lower rates of blade erosion. Tissue chemistry also responded to enrichment; pigmentation, soluble NO3 (-), and % N were higher throughout fertilised fronds. Labelled (15)N traced N uptake and translocation from N sources in the kelp canopy to sinks in the holdfast, 10 m below. This is the first evidence of long-distance (>1 m) transport of N in macroalgae. Patterns in physiological parameters suggest that M. pyrifera displays functional differentiation between canopy and basal tissues that may aid in nutrient-tolerance strategies, similar to those seen in higher plants and unlike those seen in more simple algae (i.e. non-kelps). This study highlights how little we know about N additions and N-use strategies within kelp compared to the wealth of literature available for higher plants. PMID:27170330

  4. Differences in leucocyte-endothelium interactions between normal and adenocarcinoma bearing tissues in response to radiation.

    PubMed Central

    Wu, N. Z.; Ross, B. A.; Gulledge, C.; Klitzman, B.; Dodge, R.; Dewhirst, M. W.

    1994-01-01

    Previously, we demonstrated that the interaction between leucocytes and endothelial cells in tumour tissues is greatly diminished compared with normal tissues under several induced inflammatory conditions. Radiation has been reported to cause release of inflammatory mediators and to promote neutrophil adhesions to cultured endothelial monolayers. In this study, we tested the hypothesis that radiation would cause increased leucocyte rolling and adhesion in both tumour and normal tissues. We examined these two parameters in response to 6 Gy of gamma-radiation in mammary adenocarcinomas implanted into rat skinfold window chambers as well as normal (i.e. non-tumour-bearing) preparations. Leucocyte rolling and adhesion were measured in terms of flux of rolling leucocytes (F(rolling)) and density of adhering leucocytes (D(adhering)) in microvessels. F(rolling) and D(adhering) were measured in two groups of preparations: irradiated and control. In normal preparations, F(rolling) and D(adhering) were both increased significantly by radiation. In contrast, in adenocarcinoma-bearing preparations, F(rolling) and D(adhering) were either unchanged (in the tumour centre) or reduced (in tumour periphery and the normal tissue surrounding the tumour) by radiation. Radiation did not cause changes in haemodynamics in these preparations, thus the observed changes in leucocyte rolling and adhesion could not be accounted for by haemodynamic factors. These results indicate that: (1) in normal preparations, radiation could cause inflammation as manifested by increased leucocyte rolling and adhesion; and (2) in tumour-bearing preparations, radiation caused changes in the vascular surface properties such that they became less adhesive to leucocytes. Such differences in radiation response may have important implications for radiation therapy and provide new insights into the unique features of tumours. Images Figure 2 PMID:8180019

  5. A kelp with integrity: Macrocystis pyrifera prioritises tissue maintenance in response to nitrogen fertilisation.

    PubMed

    Stephens, Tiffany A; Hepburn, Christopher D

    2016-09-01

    Our understanding of the response of vascular, terrestrial plants to nitrogen (N) addition is advanced and provides the foundation for modern agriculture. In comparison, information on responses of marine macroalgae to increased nitrogen is far less developed. We investigated how in situ pulses of nitrate (NO3 (-)) affected the growth and N physiology of Macrocystis pyrifera by adding N using potassium nitrate dissolution blocks during a period of low seawater N concentration. Multiple parameters (e.g. growth, pigments, soluble NO3 (-)) were measured in distinct tissues throughout entire fronds (apical meristem, stipe, adult blade, mature blade, sporophyll, and holdfast). Unexpectedly, N fertilisation did not enhance elongation rates within the frond, but instead thickness (biomass per unit area) increased in adult blades. Increased blade thickness may have enhanced tissue integrity as fertilised kelp had lower rates of blade erosion. Tissue chemistry also responded to enrichment; pigmentation, soluble NO3 (-), and % N were higher throughout fertilised fronds. Labelled (15)N traced N uptake and translocation from N sources in the kelp canopy to sinks in the holdfast, 10 m below. This is the first evidence of long-distance (>1 m) transport of N in macroalgae. Patterns in physiological parameters suggest that M. pyrifera displays functional differentiation between canopy and basal tissues that may aid in nutrient-tolerance strategies, similar to those seen in higher plants and unlike those seen in more simple algae (i.e. non-kelps). This study highlights how little we know about N additions and N-use strategies within kelp compared to the wealth of literature available for higher plants.

  6. The thermodynamic response of soft biological tissues to pulsed ultraviolet laser irradiation.

    PubMed Central

    Venugopalan, V; Nishioka, N S; Mikić, B B

    1995-01-01

    The physical mechanisms that enable short pulses of high-intensity ultraviolet laser radiation to remove tissue, in a process known as laser ablation, remain obscure. The thermodynamic response of biological tissue to pulsed laser irradiation was investigated by measuring and subsequently analyzing the stress transients generated by pulsed argon fluorine (ArF, lambda = 193 nm) and krypton fluorine (KrF, lambda = 248 nm) excimer laser irradiation of porcine dermis using thin-film piezoelectric transducers. For radiant exposures that do not cause material removal, the stress transients are consistent with rapid thermal expansion of the tissue. At the threshold radiant exposure for ablation, the peak stress amplitude generated by 248 nm irradiation is more than an order of magnitude larger than that produced by 193 nm irradiation. For radiant exposures where material removal is achieved, the temporal structure of the stress transient indicates that the onset of material removal occurs during irradiation. In this regime, the variation of the peak compressive stress with radiant exposure is consistent with laser-induced rapid surface vaporization. For 193 nm irradiation, ionization of the ablated material occurs at even greater radiant exposures and is accompanied by a change in the variation of peak stress with radiant exposure consistent with a plasma-mediated ablation process. These results suggest that absorption of ultraviolet laser radiation by the extracellular matrix of tissue leads to decomposition of tissue on the time scale of the laser pulse. The difference in volumetric energy density at ablation threshold between the two wavelengths indicates that the larger stresses generated by 248 nm irradiation may facilitate the onset of material removal. However, once material removal is achieved, the stress measurements demonstrate that energy not directly responsible for target decomposition contributes to increasing the specific energy of the plume (and plasma

  7. Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury.

    PubMed

    Huang, Lu; Beiting, Daniel P; Gebreselassie, Nebiat G; Gagliardo, Lucille F; Ruyechan, Maura C; Lee, Nancy A; Lee, James J; Appleton, Judith A

    2015-12-01

    It has become increasingly clear that the functions of eosinophils extend beyond host defense and allergy to metabolism and tissue regeneration. These influences have strong potential to be relevant in worm infections in which eosinophils are prominent and parasites rely on the host for nutrients to support growth or reproduction. The aim of this study was to investigate the mechanism underlying the observation that eosinophils promote growth of Trichinella spiralis larvae in skeletal muscle. Our results indicate that IL-4 and eosinophils are necessary for normal larval growth and that eosinophils from IL-4 competent mice are sufficient to support growth. The eosinophil-mediated effect operates in the absence of adaptive immunity. Following invasion by newborn larvae, host gene expression in skeletal muscle was compatible with a regenerative response and a shift in the source of energy in infected tissue. The presence of eosinophils suppressed local inflammation while also influencing nutrient homeostasis in muscle. Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur. The data are consistent with a mechanism in which eosinophils promote larval growth by an IL-4 dependent mechanism that limits local interferon-driven responses that otherwise alter nutrient metabolism in infected muscle. Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth. PMID:26720604

  8. [Focusing on tissue biomarkers. Estrogens as key players in the immune response and autoimmunity].

    PubMed

    Vásárhelyi, Barna; Mészáros, Katalin; Karvaly, Gellért; Patócs, Attila

    2015-12-20

    Estrogens modulate the immune response as well as the risk and progression of autoimmune disorders. Their effects are mediated by nuclear receptors (i.e. estrogen receptor alpha and beta), membrane receptors, and are influenced by their interactions with other hormones. Locally produced hormones and cytokines are the main factors in maintaining tissue homeostasis. The response of immune cells to estrogens is related to their developmental stage. The diverse effects of estrogens on various autoimmune disorders are the result of the versatility of their pathomechanism. In general, progression of B-cell mediated disorders is aggravated by estrogens. Their effects on T-cell mediated disorders, on the other hand, are driven by Th1 or Th2 dominance. As estrogens promote the escalation of the Th2 immune response, Th2-dominant disorders are aggravated, while Th1-dominant disorders are ameliorated upon high estrogen levels. Inflammation on its own also modulates the impact of estrogens. Inflammatory cytokines alter the expression of the alpha and beta estrogen receptors as well as the activity of estrogen metabolizing enzymes. Monitoring the local, tissue-wide interaction between hormones and immune cells would provide a better tool for identification and characterization of molecules involved in this system. To date, routinely used laboratory methods have a limited role in monitoring the local effects of estrogens. In this current paper the authors summarize the role of estrogens in immune system and overview those novel methods which are useful in the investigation of local endocrine milieu.

  9. Multi-scale mechanical response of freeze-dried collagen scaffolds for tissue engineering applications.

    PubMed

    Offeddu, Giovanni S; Ashworth, Jennifer C; Cameron, Ruth E; Oyen, Michelle L

    2015-02-01

    Tissue engineering has grown in the past two decades as a promising solution to unresolved clinical problems such as osteoarthritis. The mechanical response of tissue engineering scaffolds is one of the factors determining their use in applications such as cartilage and bone repair. The relationship between the structural and intrinsic mechanical properties of the scaffolds was the object of this study, with the ultimate aim of understanding the stiffness of the substrate that adhered cells experience, and its link to the bulk mechanical properties. Freeze-dried type I collagen porous scaffolds made with varying slurry concentrations and pore sizes were tested in a viscoelastic framework by macroindentation. Membranes made up of stacks of pore walls were indented using colloidal probe atomic force microscopy. It was found that the bulk scaffold mechanical response varied with collagen concentration in the slurry consistent with previous studies on these materials. Hydration of the scaffolds resulted in a more compliant response, yet lesser viscoelastic relaxation. Indentation of the membranes suggested that the material making up the pore walls remains unchanged between conditions, so that the stiffness of the scaffolds at the scale of seeded cells is unchanged; rather, it is suggested that thicker pore walls or more of these result in the increased moduli for the greater slurry concentration conditions.

  10. The coral immune response facilitates protection against microbes during tissue regeneration.

    PubMed

    van de Water, Jeroen A J M; Ainsworth, Tracy D; Leggat, William; Bourne, David G; Willis, Bette L; van Oppen, Madeleine J H

    2015-07-01

    Increasing physical damage on coral reefs from predation, storms and anthropogenic disturbances highlights the need to understand the impact of injury on the coral immune system. In this study, we examined the regulation of the coral immune response over 10 days following physical trauma artificially inflicted on in situ colonies of the coral Acropora aspera, simultaneously with bacterial colonization of the lesions. Corals responded to injury by increasing the expression of immune system-related genes involved in the Toll-like and NOD-like receptor signalling pathways and the lectin-complement system in three phases (<2, 4 and 10 days post-injury). Phenoloxidase activity was also significantly upregulated in two phases (<3 and 10 days post-injury), as were levels of non-fluorescent chromoprotein. In addition, green fluorescent protein expression was upregulated in response to injury from 4 days post-injury, while cyan fluorescent protein expression was reduced. No shifts in the composition of coral-associated bacterial communities were evident following injury based on 16S rRNA gene amplicon pyrosequencing. Bacteria-specific fluorescence in situ hybridization also showed no evidence of bacterial colonization of the wound or regenerating tissues. Coral tissues showed near-complete regeneration of lesions within 10 days. This study demonstrates that corals exhibit immune responses that support rapid recovery following physical injury, maintain coral microbial homeostasis and prevent bacterial infestation that may compromise coral fitness.

  11. Gene Expression Profile Analysis as a Prognostic Indicator of Normal Tissue Response to Simulated Space Radiations

    NASA Technical Reports Server (NTRS)

    Story, Michael; Stivers, David N.

    2004-01-01

    This project was funded as a pilot project to determine the feasibility of using gene expression profiles to characterize the response of human cells to exposure to particulate radiations such as those encountered in the spaceflight environment. We proposed to use microarray technology to examine the gene expression patterns of a bank of well-characterized human fibroblast cell cultures. These fibroblast cultures were derived from breast or head and neck cancer patients who exhibited normal, minimal, or severe normal tissue reactions following low LET radiation exposure via radiotherapy. Furthermore, determination of SF2 values from fibroblasts cultured from these individuals were predictive of risk for severe late reactions. We hypothesized that by determining the expression of thousands of genes we could identify gene expression patterns that reflect how normal tissues respond to high Z and energy (HZE) particles, that is, that there are molecular signatures for HZE exposures. We also hypothesized that individuals who are intrinsically radiosensitive may elicit a unique response. Because this was funded as a pilot project we focused our initial studies on logistics and appropriate experimental design, and then to test our hypothesis that there is a unique molecular response to specific particles, in this case C and Fe, for primary human skin fibroblasts.

  12. The in vivo plantar soft tissue mechanical property under the metatarsal head: implications of tissues׳ joint-angle dependent response in foot finite element modeling.

    PubMed

    Chen, Wen-Ming; Lee, Sung-Jae; Lee, Peter Vee Sin

    2014-12-01

    Material properties of the plantar soft tissue have not been well quantified in vivo (i.e., from life subjects) nor for areas other than the heel pad. This study explored an in vivo investigation of the plantar soft tissue material behavior under the metatarsal head (MTH). We used a novel device collecting indentation data at controlled metatarsophalangeal joint angles. Combined with inverse analysis, tissues׳ joint-angle dependent material properties were identified. The results showed that the soft tissue under MTH exhibited joint-angle dependent material responses, and the computed parameters using the Ogden material model were 51.3% and 30.9% larger in the dorsiflexed than in the neutral positions, respectively. Using derived parameters in subject-specific foot finite element models revealed only those models that used tissues׳ joint-dependent responses could reproduce the known plantar pressure pattern under the MTH. It is suggested that, to further improve specificity of the personalized foot finite element models, quantitative mechanical properties of the tissue inclusive of the effects of metatarsophalangeal joint dorsiflexion are needed.

  13. Response functions for computing absorbed dose to skeletal tissues from neutron irradiation

    NASA Astrophysics Data System (ADS)

    Bahadori, Amir A.; Johnson, Perry; Jokisch, Derek W.; Eckerman, Keith F.; Bolch, Wesley E.

    2011-11-01

    Spongiosa in the adult human skeleton consists of three tissues—active marrow (AM), inactive marrow (IM) and trabecularized mineral bone (TB). AM is considered to be the target tissue for assessment of both long-term leukemia risk and acute marrow toxicity following radiation exposure. The total shallow marrow (TM50), defined as all tissues lying within the first 50 µm of the bone surfaces, is considered to be the radiation target tissue of relevance for radiogenic bone cancer induction. For irradiation by sources external to the body, kerma to homogeneous spongiosa has been used as a surrogate for absorbed dose to both of these tissues, as direct dose calculations are not possible using computational phantoms with homogenized spongiosa. Recent micro-CT imaging of a 40 year old male cadaver has allowed for the accurate modeling of the fine microscopic structure of spongiosa in many regions of the adult skeleton (Hough et al 2011 Phys. Med. Biol. 56 2309-46). This microstructure, along with associated masses and tissue compositions, was used to compute specific absorbed fraction (SAF) values for protons originating in axial and appendicular bone sites (Jokisch et al 2011 Phys. Med. Biol. 56 6857-72). These proton SAFs, bone masses, tissue compositions and proton production cross sections, were subsequently used to construct neutron dose-response functions (DRFs) for both AM and TM50 targets in each bone of the reference adult male. Kerma conditions were assumed for other resultant charged particles. For comparison, AM, TM50 and spongiosa kerma coefficients were also calculated. At low incident neutron energies, AM kerma coefficients for neutrons correlate well with values of the AM DRF, while total marrow (TM) kerma coefficients correlate well with values of the TM50 DRF. At high incident neutron energies, all kerma coefficients and DRFs tend to converge as charged-particle equilibrium is established across the bone site. In the range of 10 eV to 100 Me

  14. Airway and tissue loading in postinterrupter response of the respiratory system - an identification algorithm construction.

    PubMed

    Jablonski, Ireneusz; Mroczka, Janusz

    2010-01-01

    The paper offers an enhancement of the classical interrupter technique algorithm dedicated to respiratory mechanics measurements. Idea consists in exploitation of information contained in postocclusional transient states during indirect measurement of parameter characteristics by model identification. It needs the adequacy of an inverse analogue to general behavior of the real system and a reliable algorithm of parameter estimation. The second one was a subject of reported works, which finally showed the potential of the approach to separation of airway and tissue response in a case of short-term excitation by interrupter valve operation. Investigations were conducted in a regime of forward-inverse computer experiment.

  15. An essential role for TH2-type response in limiting acute tissue damage during experimental helminth infection.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Helminths induce potent Th2-type immune responses that can lead to worm expulsion, but it remains undetermined whether components of this response can enhance the wound healing responses elicited as these large multi-cellular parasites traffic thru vital tissues. We used a model of helminth infecti...

  16. Global Gene Expression Responses to Low- or High-Dose Radiation in a Human Three-Dimensional Tissue Model

    PubMed Central

    Mezentsev, Alexandre; Amundson, Sally A.

    2011-01-01

    Accumulating data suggest that the biological responses to high and low doses of radiation are qualitatively different, necessitating the direct study of low-dose responses to better understand potential risks. Most such studies have used two-dimensional culture systems, which may not fully represent responses in three-dimensional tissues. To gain insight into low-dose responses in tissue, we have profiled global gene expression in EPI-200, a three-dimensional tissue model that imitates the structure and function of human epidermis, at 4, 16 and 24 h after exposure to high (2.5 Gy) and low (0.1 Gy) doses of low-LET protons. The most significant gene ontology groups among genes altered in expression were consistent with effects observed at the tissue level, where the low dose was associated with recovery and tissue repair, while the high dose resulted in loss of structural integrity and terminal differentiation. Network analysis of the significantly responding genes suggested that TP53 dominated the response to 2.5 Gy, while HNF4A, a novel transcription factor not previously associated with radiation response, was most prominent in the low-dose response. HNF4A protein levels and phosphorylation were found to increase in tissues and cells after low- but not high-dose irradiation. PMID:21486161

  17. Stomatal responses to changes in vapor pressure deficit reflect tissue-specific differences in hydraulic conductance.

    PubMed

    Ocheltree, T W; Nippert, J B; Prasad, P V V

    2014-01-01

    The vapor pressure deficit (D) of the atmosphere can negatively affect plant growth as plants reduce stomatal conductance to water vapor (g(wv)) in response to increasing D, limiting the ability of plants to assimilate carbon. The sensitivity of g(wv) to changes in D varies among species and has been correlated with the hydraulic conductance of leaves (K(leaf) ), but the hydraulic conductance of other tissues has also been implicated in plant responses to changing D. Among the 19 grass species, we found that K(leaf) was correlated with the hydraulic conductance of large longitudinal veins (K(lv), r(2) = 0.81), but was not related to K(root) (r(2) = 0.01). Stomatal sensitivity to D was correlated with K(leaf) relative to total leaf area (r(2) = 0.50), and did not differ between C3 and C4 species. Transpiration (E) increased in response to D, but 8 of the 19 plants showed a decline in E at high D, indicative of an 'apparent feedforward' response. For these individuals, E began to decline at lower values of D in plants with low K(root) (r(2) = 0.72). These results show the significance of both leaf and root hydraulic conductance as drivers of plant responses to evaporative demand.

  18. Targeting the finite-deformation response of wavy biological tissues with bio-inspired material architectures.

    PubMed

    Tu, Wenqiong; Pindera, Marek-Jerzy

    2013-12-01

    The Particle Swarm Optimization algorithm driven by a homogenized-based model is employed to target the response of three types of heart-valve chordae tendineae with different stiffening characteristics due to different degrees of waviness of collagen fibril/fiber bundles. First, geometric and material parameters are identified through an extensive parametric study that produce excellent agreement of the simulated response based on simplified unit cell architectures with the actual response of the complex biological tissue. These include amplitude and wavelength of the crimped chordae microstructure, elastic moduli of the constituent phases, and degree of microstructural refinement of the stiff phase at fixed volume fraction whose role in the stiffening response is elucidated. The study also reveals potential non-uniqueness of bio-inspired wavy microstructures in attaining the targeted response of certain chordae tendineae crimp configurations. The homogenization-based Particle Swarm Optimization algorithm, whose predictions are validated through the parametric study, is then shown to be an excellent tool in identifying optimal unit cell architectures in the design space that exhibits very steep gradients. Finally, defect criticality of optimal unit cell architectures is investigated in order to assess their feasibility in replacing actual biological tendons with stiffening characteristics. PMID:24018396

  19. Obesity and coronary microvascular disease - implications for adipose tissue-mediated remote inflammatory response.

    PubMed

    Bagi, Zsolt; Broskova, Zuzana; Feher, Attila

    2014-05-01

    It is believed that obesity has detrimental effects on the coronary circulation. These include immediate changes in coronary arterial vasomotor responsiveness and the development of occlusive large coronary artery disease. Despite its critical role in regulating myocardial perfusion, the altered behavior of coronary resistance arteries, which gives rise to coronary microvascular disease (CMD) is poorly understood in obesity. A chronic, low-grade vascular inflammation has been long considered as one of the main underlying pathology behind CMD. The expanded adipose tissue and the infiltrating macrophages are the major sources of pro-inflammatory mediators that have been implicated in causing inadequate myocardial perfusion and, in a long term, development of heart failure in obese patients. Much less is known the mechanisms regulating the release of these cytokines into the circulation that enable them to exert their remote effects in the coronary microcirculation. This mini review aims to examine recent studies describing alterations in the vasomotor function of coronary resistance arteries and the role of adipose tissue-derived pro-inflammatory cytokines and adipokines in contributing to CMD in obesity. We provide examples of regulatory mechanisms by which adipokines are released from adipose tissue to exert their remote inflammatory effects on coronary microvessels. We identify some of the important challenges and opportunities going forward.

  20. Matrix metalloproteinase and tissue inhibitor of metalloproteinase responses to muscle damage after eccentric exercise

    PubMed Central

    Kim, Jooyoung; Lee, Joohyung

    2016-01-01

    High-intensity eccentric exercise is known to induce muscle damage leading to inflammatory responses and extracellular matrix (ECM) degradation. These degradation processes involve enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). MMPs are calcium and zinc-dependent proteolytic enzymes that play a role in ECM degradation and recruitment of inflammatory and myogenic cells into the damaged site. In contrast, TIMPs inhibit MMP-induced ECM degradation to maintain normal homeostasis in ECM. Recently, several studies have examined the process of muscle remodeling and the roles of ECM, MMPs, and TIMPs in exercise-induced muscle damage. However, the results of these studies are not inconsistent. In the present mini-review, we will discuss the responses of MMP and TIMP to eccentric exercise based on the literature review. PMID:27656621

  1. Matrix metalloproteinase and tissue inhibitor of metalloproteinase responses to muscle damage after eccentric exercise

    PubMed Central

    Kim, Jooyoung; Lee, Joohyung

    2016-01-01

    High-intensity eccentric exercise is known to induce muscle damage leading to inflammatory responses and extracellular matrix (ECM) degradation. These degradation processes involve enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). MMPs are calcium and zinc-dependent proteolytic enzymes that play a role in ECM degradation and recruitment of inflammatory and myogenic cells into the damaged site. In contrast, TIMPs inhibit MMP-induced ECM degradation to maintain normal homeostasis in ECM. Recently, several studies have examined the process of muscle remodeling and the roles of ECM, MMPs, and TIMPs in exercise-induced muscle damage. However, the results of these studies are not inconsistent. In the present mini-review, we will discuss the responses of MMP and TIMP to eccentric exercise based on the literature review.

  2. Matrix metalloproteinase and tissue inhibitor of metalloproteinase responses to muscle damage after eccentric exercise.

    PubMed

    Kim, Jooyoung; Lee, Joohyung

    2016-08-01

    High-intensity eccentric exercise is known to induce muscle damage leading to inflammatory responses and extracellular matrix (ECM) degradation. These degradation processes involve enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). MMPs are calcium and zinc-dependent proteolytic enzymes that play a role in ECM degradation and recruitment of inflammatory and myogenic cells into the damaged site. In contrast, TIMPs inhibit MMP-induced ECM degradation to maintain normal homeostasis in ECM. Recently, several studies have examined the process of muscle remodeling and the roles of ECM, MMPs, and TIMPs in exercise-induced muscle damage. However, the results of these studies are not inconsistent. In the present mini-review, we will discuss the responses of MMP and TIMP to eccentric exercise based on the literature review. PMID:27656621

  3. Effects of glyphosate on hepatic tissue evaluating melanomacrophages and erythrocytes responses in neotropical anuran Leptodactylus latinasus.

    PubMed

    Pérez-Iglesias, Juan Manuel; Franco-Belussi, Lilian; Moreno, Liliana; Tripole, Susana; de Oliveira, Classius; Natale, Guillermo Sebastián

    2016-05-01

    Glyphosate (GLY) is the most used herbicide worldwide and its effects on anurans are well known. Pollutants can cause physiological and morphological effects. Therefore, this study evaluated the effects of GLY on hepatic melanomacrophages as a response to environmental stressors. Three treatments were exposed to different concentrations of pure GLY (100, 1000, and 10,000 μg g(-1), respectively), and there was also a control group. After the experimental time, liver and blood were analyzed. Melanomacrophages (MMCs) were located between the hepatocyte cordons, close to sinusoids. GLY increased the melanin area in MMCs of Leptodactylus latinasus exposed since lowest concentration until highest concentration. GLY also changed the occurrence of hepatic catabolism pigments into melanomacrophages and erythrocyte nuclear abnormalities; therefore, it can interfere with the hepatic metabolism. In conclusion, GLY promotes alterations in the hepatic tissue and erythrocyte nuclear abnormalities. Furthermore, MMCs may be useful as morphological responses of GLY effects. PMID:26856864

  4. Differential immune responses in mice infected with the tissue-dwelling nematode Trichinella zimbabwensis.

    PubMed

    Onkoba, W N; Chimbari, M J; Kamau, J M; Mukaratirwa, S

    2016-09-01

    To improve diagnostic tools, immunotherapies and vaccine development for trichinellosis surveillance and control there is a need to understand the host immune responses induced during infection with Trichinella zimbabwensis, a tissue-dwelling nematode. In this study, we sought to determine immune responses induced in mice during T. zimbabwensis infection. The parasite strain used (Code ISS1209) was derived from a naturally infected crocodile (Crocodylus niloticus) and is the main Trichinella species prevalent in southern Africa. Sixty 6- to 8-week-old female BALB/c mice were randomly assigned to two equal groups: T. zimbabwensis-infected (n= 30) and the non-infected control group (n= 30). Levels of serum tumour necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-4 (IL-4) as well as parasite-specific IgM, IgG, IgG1, IgG2a, IgG2b and IgG3 antibody responses were determined using enzyme-linked immunosorbent assay (ELISA). The cytokines and antibodies provided information on T-helper 1 (Th1)- and Th2-type, T-regulatory and antibody responses. Results showed that during the intestinal stage of infection, higher levels of parasite-specific IgM, IgG, IgG1 (P <  0.05) and IL-10 and TNF-α (P <  0.001) were observed in the Trichinella-infected group compared with the non-infected control group. In the parasite establishment and tissue migration phases, levels of IgG1 and IgG3 were elevated (P <  0.001), while those of IgM (P <  0.01) declined on days 21 and 35 post infection (pi) compared to the enteric phase. Our findings show that distinct differences in Th1- and Th2-type and T-regulatory responses are induced during the intestinal, tissue migration and larval establishment stages of T. zimbabwensis infection. PMID:26294082

  5. Tissue-specific and glucose-responsive expression of the pancreatic derived factor (PANDER) promoter.

    PubMed

    Burkhardt, Brant R; Yang, Michael C; Robert, Claudia E; Greene, Scott R; McFadden, K Kelly; Yang, Jichun; Wu, Jianmei; Gao, Zhiyong; Wolf, Bryan A

    2005-09-25

    Pancreatic derived factor (PANDER) is a recently identified cytokine-like protein that is dominantly expressed in the islets of Langerhans of the pancreas. To investigate the mechanism of tissue-specific regulation of PANDER, we identified and characterized the promoter region. The transcriptional start site was identified 520 bp upstream of the translational start codon by 5'-RLM-RACE. Computer algorithms identified several islet-associated and glucose-responsive binding motifs that included A and E boxes, hepatocyte nuclear factors 1 and 4, Oct-1, and signal transducer and activator of transcription 3, and 5. Reporter gene analysis revealed cell type-specific PANDER promoter expression in islet and liver-derived cell lines. Levels of PANDER mRNA were directly concordant to the observed cell type-specific PANDER promoter gene expression. The minimal element was mapped to the 5'-UTR and located between +200 and +491 relative to the transcriptional start site and imparted maximal gene expression. In addition, several putative glucose-responsive binding sites were further functionally characterized to reveal critical regulatory elements of PANDER. The PANDER promoter was demonstrated to be glucose-responsive in a dose-dependent manner in murine insulinoma beta-TC3 cells and primary murine islets, but unresponsive in glucagon-secreting alpha-TC3 cells. Our findings revealed that the 5'-UTR of PANDER contains the minimal element for gene expression and imparts both tissue-specificity and glucose-responsiveness. The regulation of PANDER gene expression mimics that of insulin and suggests a potential biological function of PANDER involved in metabolic homeostasis.

  6. Development of an Ex Vivo Tissue Platform To Study the Human Lung Response to Coxiella burnetii

    PubMed Central

    Graham, Joseph G.; Winchell, Caylin G.; Kurten, Richard C.

    2016-01-01

    Coxiella burnetii is an intracellular bacterial pathogen that causes human Q fever, an acute debilitating flu-like illness that can also present as chronic endocarditis. Disease typically occurs following inhalation of contaminated aerosols, resulting in an initial pulmonary infection. In human cells, C. burnetii generates a replication niche termed the parasitophorous vacuole (PV) by directing fusion with autophagosomes and lysosomes. C. burnetii requires this lysosomal environment for replication and uses a Dot/Icm type IV secretion system to generate the large PV. However, we do not understand how C. burnetii evades the intracellular immune surveillance that triggers an inflammatory response. We recently characterized human alveolar macrophage (hAM) infection in vitro and found that avirulent C. burnetii triggers sustained interleukin-1β (IL-1β) production. Here, we evaluated infection of ex vivo human lung tissue, defining a valuable approach for characterizing C. burnetii interactions with a human host. Within whole lung tissue, C. burnetii preferentially replicated in hAMs. Additionally, IL-1β production correlated with formation of an apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC)-dependent inflammasome in response to infection. We also assessed potential activation of a human-specific noncanonical inflammasome and found that caspase-4 and caspase-5 are processed during infection. Interestingly, although inflammasome activation is closely linked to pyroptosis, lytic cell death did not occur following C. burnetii-triggered inflammasome activation, indicating an atypical response after intracellular detection. Together, these studies provide a novel platform for studying the human innate immune response to C. burnetii. PMID:26902725

  7. Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration

    PubMed Central

    Li, Na; Parrish, Marcus; Chan, Tze Khee; Yin, Lu; Rai, Prashant; Yoshiyuki, Yamada; Abolhassani, Nona; Tan, Kong Bing; Kiraly, Orsolya; Chow, Vincent TK; Engelward, Bevin P.

    2016-01-01

    Influenza viruses account for significant morbidity worldwide. Inflammatory responses, including excessive generation of reactive oxygen and nitrogen species (RONS), mediate lung injury in severe Influenza infections. However, the molecular basis of inflammation-induced lung damage is not fully understood. Here, we studied influenza H1N1 infected cells in vitro, as well as H1N1 infected mice, and we monitored molecular and cellular responses over the course of two weeks in vivo. We show that influenza induces DNA damage both when cells are directly exposed to virus in vitro (measured using the comet assay) and also when cells are exposed to virus in vivo (estimated via γH2AX foci). We show that DNA damage, as well as responses to DNA damage, persist in vivo until long after virus has been cleared, at times when there are inflammation associated RONS (measured by xanthine oxidase activity and oxidative products). The frequency of lung epithelial and immune cells with increased γH2AX foci is elevated in vivo, especially for dividing cells (Ki-67 positive) exposed to oxidative stress during tissue regeneration. Additionally, we observed a significant increase in apoptotic cells as well as increased levels of DSB repair proteins Ku70, Ku86 and Rad51 during the regenerative phase. In conclusion, results show that influenza induces DNA both in vitro and in vivo, and that DNA damage responses are activated, raising the possibility that DNA repair capacity may be a determining factor for tissue recovery and disease outcome. PMID:25809161

  8. Tissue-Specific Activation of a Single Gustatory Receptor Produces Opposing Behavioral Responses in Drosophila

    PubMed Central

    Joseph, Ryan M.; Heberlein, Ulrike

    2012-01-01

    Understanding sensory systems that perceive environmental inputs and neural circuits that select appropriate motor outputs is essential for studying how organisms modulate behavior and make decisions necessary for survival. Drosophila melanogaster oviposition is one such important behavior, in which females evaluate their environment and choose to lay eggs on substrates they may find aversive in other contexts. We employed neurogenetic techniques to characterize neurons that influence the choice between repulsive positional and attractive egg-laying responses toward the bitter-tasting compound lobeline. Surprisingly, we found that neurons expressing Gr66a, a gustatory receptor normally involved in avoidance behaviors, receive input for both attractive and aversive preferences. We hypothesized that these opposing responses may result from activation of distinct Gr66a-expressing neurons. Using tissue-specific rescue experiments, we found that Gr66a-expressing neurons on the legs mediate positional aversion. In contrast, pharyngeal taste cells mediate the egg-laying attraction to lobeline, as determined by analysis of mosaic flies in which subsets of Gr66a neurons were silenced. Finally, inactivating mushroom body neurons disrupted both aversive and attractive responses, suggesting that this brain structure is a candidate integration center for decision-making during Drosophila oviposition. We thus define sensory and central neurons critical to the process by which flies decide where to lay an egg. Furthermore, our findings provide insights into the complex nature of gustatory perception in Drosophila. We show that tissue-specific activation of bitter-sensing Gr66a neurons provides one mechanism by which the gustatory system differentially encodes aversive and attractive responses, allowing the female fly to modulate her behavior in a context-dependent manner. PMID:22798487

  9. Development of an inhalable, stimuli-responsive particulate system for delivery to deep lung tissue.

    PubMed

    Abbas, Yasmine; Azzazy, Hassan M E; Tammam, Salma; Lamprecht, Alf; Ali, Mohamed Ehab; Schmidt, Annette; Sollazzo, Silvio; Mathur, Sanjay

    2016-10-01

    Lung cancer, the deadliest solid tumor among all types of cancer, remains difficult to treat. This is a result of unavoidable exposure to carcinogens, poor diagnosis, the lack of targeted drug delivery platforms and limitations associated with delivery of drug to deep lung tissues. Development of a non-invasive, patient-convenient formula for the targeted delivery of chemotherapeutics to cancer in deep lung tissue is the aim of this study. The formulation consisted of inhalable polyvinylpyrrolidone (PVP)/maltodextrin (MD)-based microparticles (MPs) encapsulating chitosan (CS) nanoparticles (NPs) loaded with either drug only or drug and magnetic nanoparticles (MNPs). Drug release from CS NPs was enhanced with the aid of MNPs by a factor of 1.7 in response to external magnetic field. Preferential toxicity by CS NPs was shown towards tumor cells (A549) in comparison to cultured fibroblasts (L929). The prepared spray freeze dried (SFD) powders for CS NPs and CS MNPs were of the same size at ∼6μm. They had a fine particle fraction (FPF≤5.2μm) of 40-42% w/w and mass median aerodynamic diameter (MMAD) of 5-6μm as determined by the Next Generation Impactor (NGI). SFD-MPs of CS MNPs possess higher MMAD due to the high density associated with encapsulated MNPs. The developed formulation demonstrates several capabilities including tissue targeting, controlled drug release, and the possible imaging and diagnostic values (due to its MNPs content) and therefore represents an improved therapeutic platform for drug delivery to cancer in deep lung tissue.

  10. Epidermal Homeostasis and Radiation Responses in a Multiscale Tissue Modeling Framework

    NASA Technical Reports Server (NTRS)

    Hu, Shaowen; Cucinotta, Francis A.

    2013-01-01

    The surface of skin is lined with several thin layers of epithelial cells that are maintained throughout life time by a small population of stem cells. High dose radiation exposures could injure and deplete the underlying proliferative cells and induce cutaneous radiation syndrome. In this work we propose a multiscale computational model for skin epidermal dynamics that links phenomena occurring at the subcellular, cellular, and tissue levels of organization, to simulate the experimental data of the radiation response of swine epidermis, which is closely similar to human epidermis. Incorporating experimentally measured histological and cell kinetic parameters, we obtain results of population kinetics and proliferation indexes comparable to observations in unirradiated and acutely irradiated swine experiments. At the sub-cellular level, several recently published Wnt signaling controlled cell-cycle models are applied and the roles of key components and parameters are analyzed. Based on our simulation results, we demonstrate that a moderate increase of proliferation rate for the survival proliferative cells is sufficient to fully repopulate the area denuded by high dose radiation, as long as the integrity of underlying basement membrane is maintained. Our work highlights the importance of considering proliferation kinetics as well as the spatial organization of tissues when conducting in vivo investigations of radiation responses. This integrated model allow us to test the validity of several basic biological rules at the cellular level and sub-cellular mechanisms by qualitatively comparing simulation results with published research, and enhance our understanding of the pathophysiological effects of ionizing radiation on skin.

  11. [Regulatory role of mechanical stress response in cellular function: development of new drugs and tissue engineering].

    PubMed

    Momose, Kazutaka; Matsuda, Takehisa; Oike, Masahiro; Obara, Kazuo; Laher, Ismail; Sugiura, Seiryo; Ohata, Hisayuki; Nakayama, Koichi

    2003-02-01

    The investigation of mechanotransduction in the cardiovascular system is essentially important for elucidating the cellular and molecular mechanisms involved in not only the maintenance of hemodynamic homeostasis but also etiology of cardiovascular diseases including arteriosclerosis. The present review summarizes the latest research performed by six academic groups, and presented at the 75th Annual Meeting of the Japanese Pharmacological Society. Technology of cellular biomechanics is also required for research and clinical application of a vascular hybrid tissue responding to pulsatile stress. 1) Vascular tissue engineering: Design of pulsatile stress-responsive scaffold and in vivo vascular wall reconstruction (T. Matsuda); 2) Cellular mechanisms of mechanosensitive calcium transients in vascular endothelium (M. Oike et al.); 3) Cross-talk of stimulation with fluid flow and lysophosphatidic acid in vascular endothelial cells (K. Momose et al.); 4) Mechanotransduction of vascular smooth muscles: Rate-dependent stretch-induced protein phosphorylations and contractile activation (K. Obara et al.); 5) Lipid mediators in vascular myogenic tone (I. Laher et al.); and 6) Caldiomyocyte regulates its mechanical output in response to mechanical load (S. Sugiura et al.).

  12. Neurotoxic effect of triazophos on goldfish (Carassius auratus) and tissue specific antioxidant responses.

    PubMed

    Liu, Lei; Zhu, Bin; Gong, Yu-Xin; Liu, Guang-Lu; Wang, Gao-Xue

    2015-06-01

    Due to the high chemical and photochemical stability, an organophosphorus pesticide triazophos might enter aquatic ecosystems and impose negative effect on aquatic organisms. In order to investigate short-term toxicity of triazophos on goldfish (Carassius auratus), antioxidant response in brain, spleen, kidney and liver was tested in this study. As a confirmation, the impact of triazophos on acetyl cholinesterase (AChE) activity was found a reduction in all studied tissues, especially in brain. In addition, 0.1 and 0.5 mg L(-1) triazophos induced MDA level increased, while glutathione content (GSH), superoxide dismutase (SOD), catalase (CAT) and lactate dehydrogenase (LDH) activities decreased. Of note, more prominent oxidative stress was provoked in kidney and liver, but weaker in brain and spleen. These results revealed that triazophos could cause a generalized oxidative stress and tissue specific antioxidant response in goldfish. Furthermore, neuroendocrine-growth-related gene expression (growth hormone (GH), luteinizing hormone (LH) and peptide YY) in brain was also changed by exposed to triazophos during 4 and 7d exposure periods. Linked with the above results, the present study pointed out that triazophos might induce a neurotoxic effect and oxidative damage in goldfish, and the goldfish brain should be a critical target for triazophos-induced damage.

  13. Soft tissue response to orthognathic surgery in persons with unilateral cleft lip and palate.

    PubMed

    Ewing, M; Ross, R B

    1993-05-01

    Individuals with cleft lip and palate often require orthognathic surgery to establish facial harmony and optimal occlusal function. Surgery to the skeletal components of the face can accomplish predictable alterations in jaw relations. The soft tissue response to those skeletal movements, however, is difficult to predict, as it is also for the noncleft individual. In addition there is the variability of the repaired cleft lip. The study included 30 persons with complete unilateral cleft lip and palate, operated for midface deficiency using a Le Fort I maxillary advancement at a mean age of 18.0 years. Some relapse occurred in the immediate postoperative period, but after 1 year the mean advancement of the maxilla was 4.9 mm (best fit of anterior maxilla) and 5.6 mm (incisal edge). Both skeletal and soft tissue changes were negligible after that time. The ratio of upper lip advancement to underlying incisor advancement was 0.65 to 1. Although the lip response was highly correlated to the underlying bony movement, the variation was sufficient to preclude accurate prediction. The upper lip thinned with maxillary advancement, but this was not related to the original lip thickness. Coincident mandibular surgery had no appreciable effect on upper lip movement.

  14. Calcium phosphate compatible bone cement: Characterization, bonding properties and tissue response

    NASA Astrophysics Data System (ADS)

    Roemhildt, Maria Lynn

    A novel, inorganic, bone cement, containing calcium phosphate, developed for implant fixation was evaluated. Setting properties were determined over a range of temperatures. The flow of the cement was greatly increased by application of vibration. Changes in the cement during hydration and aging were evaluated. Compressive strength of the cement over time was studied under simulated physiological conditions from 1 hour to 1 year after setting. After 1 day, this cement had equivalent compressive strength to commercially used PMMA cement. The strength was found to increase over 1 month and high strength was maintained up to 1 year. The shear strength of the cement-metal interface was studied in vitro using a pull-out test. Prepared specimens were stored under physiological conditions and tested at 4 hours, 24 hours, and 60 days. Comparable interfacial shear strength values were found at 4 hours, 24 hours and 60 days for the experimental cement and were not significantly different from values obtained for PMMA cement. In vivo tissue response was evaluated after cement implantation in the femoral medullary canal in canines. Tissue response and bonding at the cement-bone interface were evaluated at 2, 6, and 12 weeks. Cortical bone was found in direct contact with the OC-cement and was healthy. The strength of the cement-bone interface, measured using a push-out test, was significantly higher for the experimental cement than for commercial PMMA bone cement.

  15. Pathogenesis, tissue distribution and host response to Rhabdochlamydia porcellionis infection in rough woodlouse Porcellio scaber.

    PubMed

    Kostanjšek, Rok; Pirc Marolt, Tinkara

    2015-02-01

    Rhabdochlamydia porcellionis is a known intracellular pathogen in digestive glands of the terrestrial isopod crustacean Porcellio scaber. To describe the pathogenesis, tissue distribution and host response to R. porcellionis, we conducted microscopic observations and localization of infection in tissues by Fluorescent In Situ Hybridization (FISH). Digestive glands were confirmed as the primary site of infection. From there, R. porcellionis disseminates either through the apical membrane of infected cells into the lumen of digestive glands and further throughout the digestive tract or into the surrounding hemocoel by rupture of the basal membrane and lamina of infected digestive gland cells. Once in the hemocoel, R. porcellionis infects hindgut cells, hemocytes and hemopoetic tissues while the ventral nerve cord and gonads seem to be devoid of infection despite the presence of rhabdochlamydia on the surface of these organs. The host response to R. porcellionis includes aggregation of hemocytes around the infected cells and formation of multilayered melanized nodules exhibiting endogenous fluorescence. The structure of nodules is asymmetric when hemocytes are deposited on the basal side of infected gut and digestive glands cells, or symmetric, when nodules entrapping clusters of rhabdochlamydiae are deposited on other organs in the hemocoel. The study also revealed a high prevalence of infection in P. scaber populations (up to 27%) and confirmed its detrimental effect on the host. Although agility, behavior and molting cycle of infected animals appear unaffected, in the later stages R. porcellionis infection manifests as severe damage to the digestive system and decreased feeding, which eventually lead to the death of the host organism.

  16. Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

    SciTech Connect

    Munira A Kadhim

    2010-03-05

    To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim

  17. Biophysical Investigation of Tissue Dynamics and Evidence for a Wounding Response

    NASA Astrophysics Data System (ADS)

    Edwards, Glenn; Tokutake, Yoichiro; Peralta, Xomalin; Mao, Albert; Hutson, M. Shane; Venakides, Stephanos; Kiehart, Dan

    2003-11-01

    We have been investigating the forces responsible for tissue dynamics in the fruit fly Drosophila, focusing on dorsal closure where two sheets of lateral epidermis close over a sheet of amnioserosa. Dorsal closure is a model system for various aspects of cell movement in vertebrate development and wound healing. We have refined a UV-laser microbeam to perturb the system; (visible) laser confocal microscopy has been used to visualize the response; and a theoretical model has been proposed to account for dorsal closure in terms of four force producing processes that are coordinated in space and synchronized in time (1). Here we report on the response to specific wounding patterns that interrogate zipping, one of these processes. We account for the responses, and find evidence that for some patterns the force produced by the amnioserosa increases as a consequence of wounding allowing dorsal closure to complete on schedule. This research has been supported by the DoD MFEL Program and by the NIH. 1. Science 300, 145-149 (2003).

  18. Fibroblast Response to Lanthanoid Metal Ion Stimulation: Potential Contribution to Fibrotic Tissue Injury

    PubMed Central

    Jenkins, William; Perone, Patricia; Walker, Kyle; Bhagavathula, Narasimharao; Aslam, Muhammad Nadeem; DaSilva, Marissa; Dame, Michael K.; Varani, James

    2011-01-01

    The purpose of this study was to compare each of the 14 naturally occurring lanthanoid metal ions for ability to stimulate pro-fibrotic responses in human dermal fibroblasts. When fibroblasts were exposed to individual lanthanoids over the concentration range of 1–100 μM, increased proliferation was observed with each of the agents as compared with control cells that were already proliferating rapidly in a growth factor-enriched culture medium. Dose-response differences were observed among the individual metal ions. Matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 levels were also increased in response to lanthanoid exposure but type I procollagen production was not. A dose–response relationship between induction of proliferation and increased MMP-1 was observed. Non-lanthanoid transition metal ions (aluminum, copper, cobalt, iron, magnesium, manganese, nickel, and zinc) were examined in the same assays; there was little stimulation with any of these metals. When epidermal keratinocytes were examined in place of dermal fibroblasts, there was no growth stimulation with any of the lanthanoids. Several of the lanthanoid metals inhibited keratinocyte proliferation at higher concentrations (50–100 μM). PMID:21484406

  19. Avian gut-associated lymphoid tissues and intestinal immune responses to Eimeria parasites.

    PubMed Central

    Lillehoj, H S; Trout, J M

    1996-01-01

    Coccidiosis, an intestinal infection caused by intracellular protozoan parasites belonging to several different species of Eimeria, seriously impairs the growth and feed utilization of livestock and poultry. Host immune responses to coccidial infection are complex. Animals infected with Eimeria spp. produce parasite-specific antibodies in both the circulation and mucosal secretions. However, it appears that antibody-mediated responses play a minor role in protection against coccidiosis. Furthermore, there is increasing evidence that cell-mediated immunity plays a major role in resistance to infection. T lymphocytes appear to respond to coccidial infection through both cytokine production and a direct cytotoxic attack on infected cells. The exact mechanisms by which T cells eliminate the parasites, however, remain unclear. Although limited information is available on the intestinal immune system of chickens, gut lymphoid tissues have evolved specialized features that reflect their role as the first line of defense at mucosal surfaces, including both immunoregulatory cells and effector cells. This review summarizes our current understanding of the avian intestinal immune system and mucosal immune responses to Eimeria spp., providing an overview of the complex cellular and molecular events involved in intestinal immune responses to enteric pathogens. PMID:8809465

  20. Effects of Coralliophila violacea on tissue loss in the scleractinian corals Porites spp. depend on host response

    USGS Publications Warehouse

    Raymundo, L.; Work, Thierry M.; Miller, R.L.; Lozada-Misa, P.L.

    2016-01-01

    We investigated interactions between the corallivorous gastropod Coralliophila violacea and its preferred hosts Porites spp. Our objectives were to experimentally determine whether tissue loss could progress in Porites during or after Coralliophila predation on corals with and without tissue loss and to histologically document snail predation. In 64% of feeding scars, tissue regenerated within 3 wk, leaving no trace of predation. However, in roughly 28% of scars, lesions progressed to subacute tissue loss resembling white syndrome. In feeding experiments, scars from snails previously fed diseased tissue developed progressive tissue loss twice as frequently as scars from snails previously fed healthy tissue. Scars from previously healthy-fed snails were 3 times as likely to heal as those from previously diseased-fed snails. Histology revealed marked differences in host responses to snails; P. cylindrica manifested a robust inflammatory response with fewer secondary colonizing organisms such as algae, sponges, and helminths, whereas P. rus showed no evident inflammation and more secondary colonization. We conclude that lesion progression associated with Coralliophila may be associated with secondary colonization of coral tissues damaged by predator-induced trauma and necrosis. Importantly, variation at the cellular level should be considered when explaining interspecific differences in host responses in corals impacted by phenomena such as predation.

  1. Effects of Coralliophila violacea on tissue loss in the scleractinian corals Porites spp. depend on host response.

    PubMed

    Raymundo, L J; Work, T M; Miller, R L; Lozada-Misa, P L

    2016-04-12

    We investigated interactions between the corallivorous gastropod Coralliophila violacea and its preferred hosts Porites spp. Our objectives were to experimentally determine whether tissue loss could progress in Porites during or after Coralliophila predation on corals with and without tissue loss and to histologically document snail predation. In 64% of feeding scars, tissue regenerated within 3 wk, leaving no trace of predation. However, in roughly 28% of scars, lesions progressed to subacute tissue loss resembling white syndrome. In feeding experiments, scars from snails previously fed diseased tissue developed progressive tissue loss twice as frequently as scars from snails previously fed healthy tissue. Scars from previously healthy-fed snails were 3 times as likely to heal as those from previously diseased-fed snails. Histology revealed marked differences in host responses to snails; P. cylindrica manifested a robust inflammatory response with fewer secondary colonizing organisms such as algae, sponges, and helminths, whereas P. rus showed no evident inflammation and more secondary colonization. We conclude that lesion progression associated with Coralliophila may be associated with secondary colonization of coral tissues damaged by predator-induced trauma and necrosis. Importantly, variation at the cellular level should be considered when explaining interspecific differences in host responses in corals impacted by phenomena such as predation. PMID:27068505

  2. Prediction of treatment response and metastatic disease in soft tissue sarcoma

    NASA Astrophysics Data System (ADS)

    Farhidzadeh, Hamidreza; Zhou, Mu; Goldgof, Dmitry B.; Hall, Lawrence O.; Raghavan, Meera.; Gatenby, Robert A.

    2014-03-01

    Soft tissue sarcomas (STS) are a heterogenous group of malignant tumors comprised of more than 50 histologic subtypes. Based on spatial variations of the tumor, predictions of the development of necrosis in response to therapy as well as eventual progression to metastatic disease are made. Optimization of treatment, as well as management of therapy-related side effects, may be improved using progression information earlier in the course of therapy. Multimodality pre- and post-gadolinium enhanced magnetic resonance images (MRI) were taken before and after treatment for 30 patients. Regional variations in the tumor bed were measured quantitatively. The voxel values from the tumor region were used as features and a fuzzy clustering algorithm was used to segment the tumor into three spatial regions. The regions were given labels of high, intermediate and low based on the average signal intensity of pixels from the post-contrast T1 modality. These spatially distinct regions were viewed as essential meta-features to predict the response of the tumor to therapy based on necrosis (dead tissue in tumor bed) and metastatic disease (spread of tumor to sites other than primary). The best feature was the difference in the number of pixels in the highest intensity regions of tumors before and after treatment. This enabled prediction of patients with metastatic disease and lack of positive treatment response (i.e. less necrosis). The best accuracy, 73.33%, was achieved by a Support Vector Machine in a leave-one-out cross validation on 30 cases predicting necrosis < 90% post treatment and metastasis.

  3. Modeling the response of normal and ischemic cardiac tissue to electrical stimulation

    NASA Astrophysics Data System (ADS)

    Kandel, Sunil Mani

    Heart disease, the leading cause of death worldwide, is often caused by ventricular fibrillation. A common treatment for this lethal arrhythmia is defibrillation: a strong electrical shock that resets the heart to its normal rhythm. To design better defibrillators, we need a better understanding of both fibrillation and defibrillation. Fundamental mysteries remain regarding the mechanism of how the heart responds to a shock, particularly anodal shocks and the resultant hyperpolarization. Virtual anodes play critical roles in defibrillation, and one cannot build better defibrillators until these mechanisms are understood. We are using mathematical modeling to numerically simulate observed phenomena, and are exploring fundamental mechanisms responsible for the heart's electrical behavior. Such simulations clarify mechanisms and identify key parameters. We investigate how systolic tissue responds to an anodal shock and how refractory tissue reacts to hyperpolarization by studying the dip in the anodal strength-interval curve. This dip is due to electrotonic interaction between regions of depolarization and hyperpolarization following a shock. The dominance of the electrotonic mechanism over calcium interactions implies the importance of the spatial distribution of virtual electrodes. We also investigate the response of localized ischemic tissue to an anodal shock by modeling a regional elevation of extracellular potassium concentration. This heterogeneity leads to action potential instability, 2:1 conduction block (alternans), and reflection-like reentry at the boarder of the normal and ischemic regions. This kind of reflection (reentry) occurs due to the delay between proximal and distal segments to re-excite the proximal segment. Our numerical simulations are based on the bidomain model, the state-of-the-art mathematical description of how cardiac tissue responds to shocks. The dynamic LuoRudy model describes the active properties of the membrane. To model ischemia

  4. A Rodent Model to Evaluate the Tissue Response to a Biological Scaffold When Adjacent to a Synthetic Material.

    PubMed

    Dearth, Christopher L; Keane, Timothy J; Scott, Jeffrey R; Daly, Kerry A; Badylak, Stephen F

    2015-10-01

    The use of biologic scaffold materials adjacent to synthetic meshes is commonplace. A prevalent clinical example is two-staged breast reconstruction, where biologic scaffolds are used to provide support and coverage for the inferior aspect of the synthetic expander. However, limited data exist regarding either the kinetics of biologic scaffold integration or the host tissue response to the biologic scaffold materials used for this application or other applications in which such scaffold materials are used. The present study evaluated the temporal host response to a biological scaffold when placed adjacent to a synthetic material. Evaluation criteria included quantification of material contracture and characterization of the host cell response and tissue remodeling events. Results show a decreased thickness of the collagenous tissue layer at biologic scaffold/silicone interface compared to the abdominal wall/silicone interface during the 12-week experimental time course. All test materials were readily incorporated into surrounding host tissue. PMID:26176992

  5. Involvement of tissue plasminogen activator in stress responsivity during acute cocaine withdrawal in mice.

    PubMed

    Zhou, Yan; Maiya, Rajani; Norris, Erin H; Kreek, Mary Jeanne; Strickland, Sidney

    2010-11-01

    There is evidence that increased release of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) contributes to stress responsivity during cocaine withdrawal (WD). Recent studies suggest that tissue plasminogen activator (tPA) in the CeA is a downstream effector protein for CRF after acute "binge" cocaine administration. The purpose of this study was to determine if tPA modulates cocaine WD-induced stress responsivity. Wild-type (WT) and tPA-deficient (tPA - / - ) mice were subjected to chronic (14 days) "binge" cocaine (45 mg/kg per day) or its acute (1 day) WD. Extracellular tPA activity, CRF mRNA levels, and plasma corticosterone (CORT) levels were measured in tPA - / -  and WT mice. Extracellular tPA activity was reduced by 50% in the CeA and medial amygdala of WT mice after chronic cocaine and returned to basal levels after acute WD. Unlike WT mice, tPA - / -  mice did not display elevated amygdalar CRF mRNA levels during cocaine WD. In comparison to WT mice, tPA - / -  mice showed a blunted plasma CORT response during acute WD. These results demonstrate that tPA activity in the amygdala (Amy) is altered by chronic cocaine exposure, and further suggest an involvement of tPA in modulating amygdalar CRF stress responsive system and hypothalamic-pituitary-adrenal axis in response to acute cocaine WD.

  6. Involvement of tissue plasminogen activator in stress responsivity during acute cocaine withdrawal in mice

    PubMed Central

    Zhou, Yan; Maiya, Rajani; Norris, Erin H.; Kreek, Mary Jeanne; Strickland, Sidney

    2013-01-01

    There is evidence that increased release of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) contributes to stress responsivity during cocaine withdrawal (WD). Recent studies suggest that tissue plasminogen activator (tPA) in the CeA is a downstream effector protein for CRF after acute “binge” cocaine administration. The purpose of this study was to determine if tPA modulates cocaine WD-induced stress responsivity. Wild-type (WT) and tPA-deficient (tPA −/−) mice were subjected to chronic (14 days) “binge” cocaine (45 mg/kg per day) or its acute (1 day) WD. Extracellular tPA activity, CRF mRNA levels, and plasma corticosterone (CORT) levels were measured in tPA −/− and WT mice. Extracellular tPA activity was reduced by 50% in the CeA and medial amygdala of WT mice after chronic cocaine and returned to basal levels after acute WD. Unlike WT mice, tPA −/− mice did not display elevated amygdalar CRF mRNA levels during cocaine WD. In comparison to WT mice, tPA −/− mice showed a blunted plasma CORT response during acute WD. These results demonstrate that tPA activity in the amygdala (Amy) is altered by chronic cocaine exposure, and further suggest an involvement of tPA in modulating amygdalar CRF stress responsive system and hypothalamic–pituitary–adrenal axis in response to acute cocaine WD. PMID:20666641

  7. MicroRNA-155 Drives TH17 Immune Response and Tissue Injury in Experimental Crescentic GN

    PubMed Central

    Krebs, Christian F.; Kapffer, Sonja; Paust, Hans-Joachim; Schmidt, Tilman; Bennstein, Sabrina B.; Peters, Anett; Stege, Gesa; Brix, Silke R.; Meyer-Schwesinger, Catherine; Müller, Roman-Ulrich; Turner, Jan-Eric; Steinmetz, Oliver M.; Wolf, Gunter; Stahl, Rolf A. K.

    2013-01-01

    CD4+ T cells play a pivotal role in the pathogenesis of autoimmune disease, including human and experimental crescentic GN. Micro-RNAs (miRs) have emerged as important regulators of immune cell development, but the impact of miRs on the regulation of the CD4+ T cell immune response remains to be fully clarified. Here, we report that miR-155 expression is upregulated in the kidneys of patients with ANCA-associated crescentic GN and a murine model of crescentic GN (nephrotoxic nephritis). To elucidate the potential role of miR-155 in T cell-mediated inflammation, nephritis was induced in miR-155−/− and wild-type mice. The systemic and renal nephritogenic TH17 immune response decreased markedly in nephritic miR-155−/− mice. Consistent with this finding, miR-155–deficient mice developed less severe nephritis, with reduced histologic and functional injury. Adoptive transfer of miR-155−/− and wild-type CD4+ T cells into nephritic recombination activating gene 1-deficient (Rag-1−/−) mice showed the T cell-intrinsic importance of miR-155 for the stability of pathogenic TH17 immunity. These findings indicate that miR-155 drives the TH17 immune response and tissue injury in experimental crescentic GN and show that miR-155 is a potential therapeutic target in TH17-mediated diseases. PMID:23949802

  8. Interrogating the viscoelastic properties of tissue using viscoelastic response (VISR) ultrasound

    NASA Astrophysics Data System (ADS)

    Selzo, Mallory Renee

    Affecting approximately 1 in 3,500 newborn males, Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic disorders in humans. Boys with DMD suffer progressive loss of muscle strength and function, leading to wheelchair dependence, cardiac and respiratory compromise, and death during young adulthood. There are currently no treatments that can halt or reverse the disease progression, and translating prospective treatments into clinical trials has been delayed by inadequate outcome measures. Current outcome measures, such as functional and muscle strength assessments, lack sensitivity to individual muscles, require subjective effort of the child, and are impacted by normal childhood growth and development. The goal of this research is to develop Viscoelastic Response (VisR) ultrasound which can be used to delineate compositional changes in muscle associated with DMD. In VisR, acoustic radiation force (ARF) is used to produce small, localized displacements within the muscle. Using conventional ultrasound to track the motion, the displacement response of the tissue can be evaluated against a mechanical model. In order to develop signal processing techniques and assess mechanical models, finite element method simulations are used to model the response of a viscoelastic material to ARF excitations. Results are then presented demonstrating VisR differentiation of viscoelastic changes with progressive dystrophic degeneration in a dog model of DMD. Finally, clinical feasibility of VisR imaging is demonstrated in two boys with DMD.

  9. The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue

    PubMed Central

    Swift, Joe; Discher, Dennis E.

    2014-01-01

    ABSTRACT How cells respond to physical cues in order to meet and withstand the physical demands of their immediate surroundings has been of great interest for many years, with current research efforts focused on mechanisms that transduce signals into gene expression. Pathways that mechano-regulate the entry of transcription factors into the cell nucleus are emerging, and our most recent studies show that the mechanical properties of the nucleus itself are actively controlled in response to the elasticity of the extracellular matrix (ECM) in both mature and developing tissue. In this Commentary, we review the mechano-responsive properties of nuclei as determined by the intermediate filament lamin proteins that line the inside of the nuclear envelope and that also impact upon transcription factor entry and broader epigenetic mechanisms. We summarize the signaling pathways that regulate lamin levels and cell-fate decisions in response to a combination of ECM mechanics and molecular cues. We will also discuss recent work that highlights the importance of nuclear mechanics in niche anchorage and cell motility during development, hematopoietic differentiation and cancer metastasis, as well as emphasizing a role for nuclear mechanics in protecting chromatin from stress-induced damage. PMID:24963133

  10. Image-guided genomic analysis of tissue response to laser-induced thermal stress

    NASA Astrophysics Data System (ADS)

    Mackanos, Mark A.; Helms, Mike; Kalish, Flora; Contag, Christopher H.

    2011-05-01

    The cytoprotective response to thermal injury is characterized by transcriptional activation of ``heat shock proteins'' (hsp) and proinflammatory proteins. Expression of these proteins may predict cellular survival. Microarray analyses were performed to identify spatially distinct gene expression patterns responding to thermal injury. Laser injury zones were identified by expression of a transgene reporter comprised of the 70 kD hsp gene and the firefly luciferase coding sequence. Zones included the laser spot, the surrounding region where hsp70-luc expression was increased, and a region adjacent to the surrounding region. A total of 145 genes were up-regulated in the laser irradiated region, while 69 were up-regulated in the adjacent region. At 7 hours the chemokine Cxcl3 was the highest expressed gene in the laser spot (24 fold) and adjacent region (32 fold). Chemokines were the most common up-regulated genes identified. Microarray gene expression was successfully validated using qRT- polymerase chain reaction for selected genes of interest. The early response genes are likely involved in cytoprotection and initiation of the healing response. Their regulatory elements will benefit creating the next generation reporter mice and controlling expression of therapeutic proteins. The identified genes serve as drug development targets that may prevent acute tissue damage and accelerate healing.

  11. TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection.

    PubMed

    Akdis, Mübeccel; Palomares, Oscar; van de Veen, Willem; van Splunter, Marloes; Akdis, Cezmi A

    2012-06-01

    Substantial progress in understanding mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumors, organ transplantation, chronic infections, and pregnancy is in an exciting developmental phase that might lead to a variety of targeted therapeutic approaches. Recent progress in the interaction between immune/inflammatory cell subsets through cytokines, particularly the extension of the knowledge on reciprocal regulation and counterbalance between subsets of T(H)1, T(H)2, T(H)9, T(H)17, T(H)22, T follicular helper cells and different subsets of regulatory T cells, as well as corresponding and co-orchestrating B-cell, natural killer cell, dendritic cell, and innate lymphoid cell subsets, offers new possibilities for immune intervention. Studies on new subsets confirm the important role of T cells in the instruction of tissue cells and also demonstrate the important role of feedback regulation for the polarization toward distinct T-cell subsets. T(H)17 and T(H)22 cells are 2 emerging T(H) cell subsets that link the immune response to tissue inflammation; IL-17A and IL-17F and IL-22 are their respective prototype cytokines. Although both cytokines play roles in immune defense to extracellular bacteria, IL-17 augments inflammation, whereas IL-22 plays a tissue-protective role. This review focuses on current knowledge on T(H)17 and T(H)22 cells and their role in inflammation, with special focus on the mechanisms of their generation and driving and effector cytokines, as well as their role in host defense, autoimmunity, and allergic diseases.

  12. Fuz Regulates Craniofacial Development through Tissue Specific Responses to Signaling Factors

    PubMed Central

    Zhang, Zichao; Wlodarczyk, Bogdan J.; Niederreither, Karen; Venugopalan, Shankar; Florez, Sergio; Finnell, Richard H.; Amendt, Brad A.

    2011-01-01

    The planar cell polarity effector gene Fuz regulates ciliogenesis and Fuz loss of function studies reveal an array of embryonic phenotypes. However, cilia defects can affect many signaling pathways and, in humans, cilia defects underlie several craniofacial anomalies. To address this, we analyzed the craniofacial phenotype and signaling responses of the Fuz−/− mice. We demonstrate a unique role for Fuz in regulating both Hedgehog (Hh) and Wnt/β-catenin signaling during craniofacial development. Fuz expression first appears in the dorsal tissues and later in ventral tissues and craniofacial regions during embryonic development coincident with cilia development. The Fuz−/− mice exhibit severe craniofacial deformities including anophthalmia, agenesis of the tongue and incisors, a hypoplastic mandible, cleft palate, ossification/skeletal defects and hyperplastic malformed Meckel's cartilage. Hh signaling is down-regulated in the Fuz null mice, while canonical Wnt signaling is up-regulated revealing the antagonistic relationship of these two pathways. Meckel's cartilage is expanded in the Fuz−/− mice due to increased cell proliferation associated with the up-regulation of Wnt canonical target genes and decreased non-canonical pathway genes. Interestingly, cilia development was decreased in the mandible mesenchyme of Fuz null mice, suggesting that cilia may antagonize Wnt signaling in this tissue. Furthermore, expression of Fuz decreased expression of Wnt pathway genes as well as a Wnt-dependent reporter. Finally, chromatin IP experiments demonstrate that β-catenin/TCF-binding directly regulates Fuz expression. These data demonstrate a new model for coordination of Hh and Wnt signaling and reveal a Fuz-dependent negative feedback loop controlling Wnt/β-catenin signaling. PMID:21935430

  13. Hypoxia-Induced miR-210 Modulates Tissue Response to Acute Peripheral Ischemia

    PubMed Central

    Zaccagnini, Germana; Maimone, Biagina; Di Stefano, Valeria; Fasanaro, Pasquale; Greco, Simona; Perfetti, Alessandra; Capogrossi, Maurizio C.; Gaetano, Carlo

    2014-01-01

    Abstract Aims: Peripheral artery disease is caused by the restriction or occlusion of arteries supplying the leg. Better understanding of the molecular mechanisms underpinning tissue response to ischemia is urgently needed to improve therapeutic options. The aim of this study is to investigate hypoxia-induced miR-210 regulation and its role in a mouse model of hindlimb ischemia. Results: miR-210 expression was induced by femoral artery dissection. To study the role of miR-210, its function was inhibited by the systemic administration of a miR-210 complementary locked nucleic acid (LNA)-oligonucleotide (anti-miR-210). In the ischemic skeletal muscle, anti-miR-210 caused a marked decrease of miR-210 compared with LNA-scramble control, while miR-210 target expression increased accordingly. Histological evaluation of acute tissue damage showed that miR-210 inhibition increased both apoptosis at 1 day and necrosis at 3 days. Capillary density decrease caused by ischemia was significantly more pronounced in anti-miR-210-treated mice; residual limb perfusion decreased accordingly. To investigate the molecular mechanisms underpinning the increased damage triggered by miR-210 blockade, we tested the impact of anti-miR-210 treatment on the transcriptome. Gene expression analysis highlighted the deregulation of mitochondrial function and redox balance. Accordingly, oxidative damage was more severe in the ischemic limb of anti-miR-210-treated mice and miR-210 inhibition increased oxidative metabolism. Further, oxidative-stress resistant p66Shc-null mice displayed decreased tissue damage following ischemia. Innovation: This study identifies miR-210 as a crucial element in the adaptive mechanisms to acute peripheral ischemia. Conclusions: The physiopathological significance of miR-210 is context dependent. In the ischemic skeletal muscle it seems to be cytoprotective, regulating oxidative metabolism and oxidative stress. Antioxid. Redox Signal. 21, 1177–1188. PMID:23931770

  14. The Effects of Low Dose Irradiation on Inflammatory Response Proteins in a 3D Reconstituted Human Skin Tissue Model

    SciTech Connect

    Varnum, Susan M.; Springer, David L.; Chaffee, Mary E.; Lien, Katie A.; Webb-Robertson, Bobbie-Jo M.; Waters, Katrina M.; Sacksteder, Colette A.

    2012-12-01

    Skin responses to moderate and high doses of ionizing radiation include the induction of DNA repair, apoptosis, and stress response pathways. Additionally, numerous studies indicate that radiation exposure leads to inflammatory responses in skin cells and tissue. However, the inflammatory response of skin tissue to low dose radiation (<10 cGy) is poorly understood. In order to address this, we have utilized a reconstituted human skin tissue model (MatTek EpiDerm FT) and assessed changes in 23 cytokines twenty-four and forty eight hours following treatment of skin with either 3 or 10 cGy low-dose of radiation. Three cytokines, IFN-γ, IL-2, MIP-1α, were significantly altered in response to low dose radiation. In contrast, seven cytokines were significantly altered in response to a high radiation dose of 200 cGy (IL-2, IL-10, IL-13, IFN-γ, MIP-1α, TNF α, and VEGF) or the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (G-CSF, GM-CSF, IL-1α, IL-8, MIP-1α, MIP-1β, RANTES). Additionally, radiation induced inflammation appears to have a distinct cytokine response relative to the non-radiation induced stressor, TPA. Overall, these results indicate that there are subtle changes in the inflammatory protein levels following exposure to low dose radiation and this response is a sub-set of what is seen following a high dose in a human skin tissue model.

  15. Non-parametric frequency response function tissue modeling in bipolar electrosurgery.

    PubMed

    Barbé, Kurt; Ford, Carolyn; Bonn, Kenlyn; Gilbert, James

    2015-01-01

    High-frequency radio energy is applied to tissue therapeutically in a number of different medical applications. The ability to model the effects of RF energy on the collagen, elastin, and liquid content of the target tissue would allow for the refinement of the control of the energy in order to improve outcomes and reduce negative side-effects. In this paper, we study the time-varying impedance spectra of the circuit. It is expected that the collagen/elastin ratio does not change over time such that the time-varying impedance is a function of the liquid content. We apply a non-parametric model in which we characterize the measured impedance spectra by its frequency response function. The measurements indicate that the changing impedance as a function of time exhibit a polynomial shift which we characterize by a polynomial regression. Finally, we quantify the uncertainty to obtain prediction intervals for the estimated polynomial describing the time variation of the impedance spectra. PMID:26737664

  16. Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras.

    PubMed

    Young, Nathan P; Jacks, Tyler

    2010-06-01

    The ability of oncogenes to engage tumor suppressor pathways represents a key regulatory mechanism that can limit the outgrowth of incipient tumor cells. For example, in a number of settings oncogenic Ras strongly activates the Ink4a/Arf locus, resulting in cell cycle arrest or senescence. The capacity of different cell types to execute tumor suppressor programs following expression of endogenous K-ras(G12D) in vivo has not been examined. Using compound mutant mice containing the Arf(GFP) reporter and the spontaneously activating K-ras(LA2) allele, we have uncovered dramatic tissue specificity of K-ras(G12D)-dependent p19(Arf) up-regulation. Lung tumors, which can arise in the presence of functional p19(Arf), rarely display p19(Arf) induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19(Arf)-p53 pathway is a requisite event for sarcomagenesis. Using constitutive and inducible RNAi systems in vivo, we highlight cell type-specific chromatin regulation of Ink4a/Arf as a critical determinant of cellular responses to oncogenic K-ras. Polycomb-group complexes repress the locus in lung tumors, whereas the SWI/SNF family member Snf5 acts as an important mediator of p19(Arf) induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation. PMID:20479239

  17. Design and Characterization of Fibrin-Based Acoustically Responsive Scaffolds for Tissue Engineering Applications.

    PubMed

    Moncion, Alexander; Arlotta, Keith J; Kripfgans, Oliver D; Fowlkes, J Brian; Carson, Paul L; Putnam, Andrew J; Franceschi, Renny T; Fabiilli, Mario L

    2016-01-01

    Hydrogel scaffolds are used in tissue engineering as a delivery vehicle for regenerative growth factors. Spatiotemporal patterns of growth factor signaling are critical for tissue regeneration, yet most scaffolds afford limited control of growth factor release, especially after implantation. We previously found that acoustic droplet vaporization can control growth factor release from a fibrin scaffold doped with a perfluorocarbon emulsion. This study investigates properties of the acoustically responsive scaffold (ARS) critical for further translation. At 2.5 MHz, acoustic droplet vaporization and inertial cavitation thresholds ranged from 1.5 to 3.0 MPa and from 2.0 to 7.0 MPa peak rarefactional pressure, respectively, for ARSs of varying composition. Viability of C3H/10T1/2 cells, encapsulated in the ARS, did not decrease significantly for pressures below 4 MPa. ARSs with perfluorohexane emulsions displayed higher stability versus those with perfluoropentane emulsions, while surrogate payload release was minimal without ultrasound. These results enable the selection of ARS compositions and acoustic parameters needed for optimized spatiotemporally controlled release.

  18. Supplementation with Astragalus polysaccharides alters Aeromonas-induced tissue-specific cellular immune response.

    PubMed

    Abuelsaad, Abdelaziz S A

    2014-01-01

    Members of the genus Aeromonas inhabit various aquatic environments and are responsible for a number of intestinal and extra-intestinal infections in humans as well as other animals. Astragalus species are used in Chinese traditional medicine as antiperspirant, antihypertensive, diuretic and tonic treatments and have been used for treatment of patients with leukemia and uterine cancers. The present study was aimed to investigate immunomodulatory effect of Astragalus polysaccharides (APS) treatment on Aeromonas hydrophila-infected mice. The present data showed that APS-treatment ameliorated neutrophils phagocytic activity and reactive oxygen species (ROS) production in intestinal tissues of infected mice. Moreover, APS treatment induced a highly significantly (P < 0.001) increase in the number of CD4(+) T cells in the intestinal tissues and thymus, however, number of CD4(+) T cells in the spleens of infected mice not significantly changed with APS treatment. On the other hand, APS-treatment caused a very highly significant (P < 0.001) decrease in the number of CD8(+) T cells in the spleens and thymus of infected mice. In conclusion, the present data suggested that APS treatment reduced ROS production, downmodulated neutrophils activity, and increased CD4(+)/CD8(+) T cells ratio in A. hydrophila-infected mice.

  19. Antioxidant response and histopathological changes in brain tissue of pigeon exposed to avermectin.

    PubMed

    Li, Ming; You, Tian-Zi; Zhu, Wen-Jun; Qu, Jian-Ping; Liu, Ci; Zhao, Bing; Xu, Shi-Wen; Li, Shu

    2013-10-01

    Avermectins (AVMs) are the active components of some insecticidal and nematicidal products used in agriculture and veterinary medicine for the prevention of parasitic diseases. Residues of AVM drugs or their metabolites in livestock feces have toxic effects on non-target aquatic and terrestrial organisms. In this study, oxidative stress responses and pathological changes on pigeon brain tissues and serum after subchronic exposure to AVM for 30, 60 and 90 days were investigated. The decrease in antioxidant enzyme (superoxide dismutase, SOD and glutathione peroxidase, GSH-Px) activities and increase in methane dicarboxylic aldehyde content in a dose-time-dependent manner in the brain and serum of pigeon were observed. The protein carbonyl content, an indicator of protein oxidation, and DNA-protein crosslink coefficient were significantly augmented with dose-time-dependent properties. The microscopic structures of the cerebrum, cerebellum and optic lobe altered obviously, the severity of which increased with the concentration of AVM and exposure time. The results imply that AVM could induce oxidative damage to the brain tissue and serum of pigeon. The information presented in this study is helpful to understand the mechanism of AVM-induced oxidative stress in birds.

  20. Root Tissue Response of Two Related Soybean Cultivars to Infection by Lectin-treated Meloidogyne spp.

    PubMed Central

    Davis, E. L.; Kaplan, D. T.; Dickson, D. W.; Mitchell, D. J.

    1989-01-01

    Treatment of second-stage juveniles (J2) of Meloidogyne incognita race 1 and M. javanica with soybean agglutinin, Concanavalin A, wheat germ agglutinin, Lotus tetragonolobus agglutinin, or Limax flavus agglutinin or the corresponding competitive sugars for each of these lectins did not alter normal root tissue response of soybean cultivars Centennial and Pickett 71 to infection by M. incognita race 1 or M. javanica. Giant cells were frequently induced in Centennial and Pickett 71 roots 5 and 20 days after inoculation of roots with untreated J2 of a population of M. incognita race 3. Treatment of J2 of M. incognita race 3 with the lectins or carbohydrates listed above caused Centennial, but not Pickett 71, root tissue to respond in a hypersensitive manner to infection by M. incognita race 3. Penetration of soybean roots by J2 of Meloidogyne spp. was strongly inhibited in the presence of 0.1 M sialic acid. Treatment of J2 with sialic acid was not lethal to nematodes, and the inhibitory activity of sialic acid was apparently not caused by low pH. These results suggest that carbohydrates may influence plant-nematode interactions. PMID:19287600

  1. Identification of QTLs associated with tissue culture response of mature wheat embryos.

    PubMed

    Ma, Jian; Deng, Mei; Lv, Si-Yu; Yang, Qiang; Jiang, Qian-Tao; Qi, Peng-Fei; Li, Wei; Chen, Guo-Yue; Lan, Xiu-Jin; Wei, Yu-Ming

    2016-01-01

    Mature embryo is an excellent explant for tissue culture as it is convenient to be obtained without limitation of growing seasons and development stages. However, regeneration ability of the calli from wheat mature embryos is limited, thus hindering its application. To identify genes associated with the tissue culture response (TCR) of wheat, QTLs for callus induction from mature embryos and callus regeneration were detected using a recombinant inbred lines (RILs) population derived from the cross between a synthetic hexaploid wheat genotype, SHW-L1 and a commercial cultivar Chuanmai 32. Three QTLs for callus rate were identified and they were located on chromosomes 1D, 5A, and 6D, respectively, with explained phenotypic variation ranging from 10.16 to 11.82 %. One QTL for differentiation rate was detected only with 10.96 % of the phenotypic variation explained. Two QTLs for emergence rate were identified and they were located on 3B and 4A, respectively, with 9.88 and 10.30 % of phenotypic variation. The results presented in this study with those reported previously indicated that group 1, 3, and 5 chromosomes are likely to play important roles in TCR of wheat. PMID:27652125

  2. Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response

    PubMed Central

    Vidi, Pierre-Alexandre; Chandramouly, Gurushankar; Gray, Matthew; Wang, Lei; Liu, Er; Kim, Joseph J.; Roukos, Vassilis; Bissell, Mina J.; Moghe, Prabhas V.; Lelièvre, Sophie A.

    2012-01-01

    Epithelial tissue morphogenesis is accompanied by the formation of a polarity axis – a feature of tissue architecture that is initiated by the binding of integrins to the basement membrane. Polarity plays a crucial role in tissue homeostasis, preserving differentiation, cell survival and resistance to chemotherapeutic drugs among others. An important aspect in the maintenance of tissue homeostasis is genome integrity. As normal tissues frequently experience DNA double-strand breaks (DSBs), we asked how tissue architecture might participate in the DNA damage response. Using 3D culture models that mimic mammary glandular morphogenesis and tumor formation, we show that DSB repair activity is higher in basally polarized tissues, regardless of the malignant status of cells, and is controlled by hemidesmosomal integrin signaling. In the absence of glandular morphogenesis, in 2D flat monolayer cultures, basal polarity does not affect DNA repair activity but enhances H2AX phosphorylation, an early chromatin response to DNA damage. The nuclear mitotic apparatus protein 1 (NuMA), which controls breast glandular morphogenesis by acting on the organization of chromatin, displays a polarity-dependent pattern and redistributes in the cell nucleus of basally polarized cells upon the induction of DSBs. This is shown using high-content analysis of nuclear morphometric descriptors. Furthermore, silencing NuMA impairs H2AX phosphorylation – thus, tissue polarity and NuMA cooperate to maintain genome integrity. PMID:22331358

  3. Multiple tissue response modifiers to promote angiogenesis and prevent the foreign body reaction around subcutaneous implants.

    PubMed

    Kastellorizios, Michail; Papadimitrakopoulos, Fotios; Burgess, Diane J

    2015-09-28

    Dexamethasone-releasing PLGA poly(lactic-co-glycolic acid) microsphere/PVA (polyvinyl alcohol) hydrogel composite coatings have been shown to prevent the foreign body reaction (FBR) to subcutaneous implants in small and large animal models. Such coatings were developed to extend the lifetime of implantable biosensors. However, long-term exposure of tissue to low levels of dexamethasone results in a reduction in blood vessel density due to the anti-angiogenic effect of dexamethasone. This mild effect, while not threatening to the subject's health, may interfere with analyte detection and the sensor response time over the long-term. The present work is focused on the development of coatings that deliver combinations of three tissue response modifiers (TRMs): dexamethasone, VEGF (vascular endothelial growth factor) and PDGF (platelet derived growth factor). Dexamethasone, VEGF and PDGF prevent the FBR, increase angiogenesis and promote blood vessel maturation (which increases blood flow), respectively. To minimize any potential interference among these three TRMs (for example, PDGF increases fibrosis), the relative doses of dexamethasone, VEGF and PDGF were adjusted. It was determined that: a) all three TRMs are required for maximum promotion of angiogenesis, blood vessel maturation and prevention of the FBR; b) VEGF has to be administered at higher doses than PDGF; c) an increase in dexamethasone dosing must be accompanied by a proportional increase in growth factor dosing; and d) modification of the TRM ratio can achieve a constant capillary density throughout the implantation period which is important for applications such as biosensors to maintain sensitivity and a stable sensor baseline. Moreover, an osmosis-driven process for encapsulation of proteins in PLGA microspheres that showed low burst release was developed. PMID:26216396

  4. Adipose tissue-derived mesenchymal stem cells acquire bone cell-like responsiveness to fluid shear stress on osteogenic stimulation.

    PubMed

    Knippenberg, Marlene; Helder, Marco N; Doulabi, Behrouz Zandieh; Semeins, Cornelis M; Wuisman, Paul I J M; Klein-Nulend, Jenneke

    2005-01-01

    To engineer bone tissue, mechanosensitive cells are needed that are able to perform bone cell-specific functions, such as (re)modeling of bone tissue. In vivo, local bone mass and architecture are affected by mechanical loading, which is thought to provoke a cellular response via loading-induced flow of interstitial fluid. Adipose tissue is an easily accessible source of mesenchymal stem cells for bone tissue engineering, and is available in abundant amounts compared with bone marrow. We studied whether adipose tissue-derived mesenchymal stem cells (AT-MSCs) are responsive to mechanical loading by pulsating fluid flow (PFF) on osteogenic stimulation in vitro. We found that ATMSCs show a bone cell-like response to fluid shear stress as a result of PFF after the stimulation of osteogenic differentiation by 1,25-dihydroxyvitamin D3. PFF increased nitric oxide production, as well as upregulated cyclooxygenase-2, but not cyclooxygenase-1, gene expression in osteogenically stimulated AT-MSCs. These data suggest that AT-MSCs acquire bone cell-like responsiveness to pulsating fluid shear stress on 1,25-dihydroxyvitamin D3-induced osteogenic differentiation. ATMSCs might be able to perform bone cell-specific functions during bone (re)modeling in vivo and, therefore, provide a promising new tool for bone tissue engineering.

  5. Candidate Genes Involved in Beneficial or Adverse Responses to Commonly Eaten Brassica Vegetables in a New Zealand Crohn’s Disease Cohort

    PubMed Central

    Laing, Bobbi; Han, Dug Yeo; Ferguson, Lynnette R.

    2013-01-01

    Crohn’s disease (CD) is one of the two manifestations of inflammatory bowel disease. Particular foods are thought with CD to exacerbate their illness. Vegetables, especially Brassicaceae, are often shunned by people with CD because of the negative effects they are alleged to have on their symptoms. Brassicaceae supply key nutrients which are necessary to meet recommended daily intakes. We sought to identify the candidate genes involved in the beneficial or adverse effects of Brassicaceae most commonly eaten, as reported by the New Zealand adults from the “Genes and Diet in Inflammatory Bowel disease Study” based in Auckland. An analysis of associations between the single nucleotide polymorphisms (SNPs) and the beneficial or adverse effects of the ten most commonly eaten Brassicaceae was carried out. A total of 37 SNPs were significantly associated with beneficial effects (p = 0.00097 to 0.0497) and 64 SNPs were identified with adverse effects (p = 0.0000751 to 0.049). After correcting for multiple testing, rs7515322 (DIO1) and rs9469220 (HLA) remained significant. Our findings show that the tolerance of some varieties of Brassicaceae may be shown by analysis of a person’s genotype. PMID:24352087

  6. Biophysical mechanisms responsible for pulsed low-level laser excitation of neural tissue

    NASA Astrophysics Data System (ADS)

    Wells, Jonathon; Kao, Chris; Konrad, Peter; Mahadevan-Jansen, Anita; Jansen, E. Duco

    2006-02-01

    Background/Objective: The traditional method of stimulating neural activity has been based on electrical methods and remains the gold standard to date despite inherent limitations. We have previously shown a new paradigm to in vivo neural activation based on pulsed infrared light, which provides a contact-free, spatially selective, artifact-free method without incurring tissue damage that may have significant advantages over electrical stimulation in a variety of diagnostic and therapeutic applications. The goal of this study was to investigate the physical mechanism of this phenomenon, which we propose is a photo-thermal effect from transient tissue temperature changes resulting in direct or indirect activation of transmembrane ion channels causing propagation of the action potential. Methods: Rat sciatic nerve preparation was stimulated in vivo with the Holmium:YAG laser (2.12μm), Free Electron Laser (2.1μm), Alexandrite laser (690nm), and the prototype for a solid state commercial laser nerve stimulator built by Aculight (1.87μm) to determine contributions of photobiological responses from laser tissue interactions, including temperature, pressure, electric field, and photochemistry, underlying the biophysical mechanism of stimulation. Single point temperature measurements were made with a microthermocouple adjacent to the excitation site, while an infrared camera was used for 2-D radiometry of the irradiated surface. Displacement from laser-induced pressure waves or thermoelastic expansion was measured using a PS-OCT system. Results: Results exclude a direct photochemical, electric field, or pressure wave effect as the mechanism of optical stimulation. Measurements show relative small contributions from thermoelastic expansion (300 nm) with the laser parameters used for nerve stimulation. The maximum change in tissue temperature is about 9°C (average increase of 3.66 °C) at stimulation threshold radiant exposures. Conclusion: Neural activation with pulsed

  7. PREDICTING THE RISKS OF NEUROTOXIC VOLATILE ORGANIC COMPOUNDS BASED ON TARGET TISSUE DOSE.

    EPA Science Inventory

    Quantitative exposure-dose-response models relate the external exposure of a substance to the dose in the target tissue, and then relate the target tissue dose to production of adverse outcomes. We developed exposure-dose-response models to describe the affects of acute exposure...

  8. Pharmacogenomics of adverse drug reactions

    PubMed Central

    2013-01-01

    Considerable progress has been made in identifying genetic risk factors for idiosyncratic adverse drug reactions in the past 30 years. These reactions can affect various tissues and organs, including liver, skin, muscle and heart, in a drug-dependent manner. Using both candidate gene and genome-wide association studies, various genes that make contributions of varying extents to each of these forms of reactions have been identified. Many of the associations identified for reactions affecting the liver and skin involve human leukocyte antigen (HLA) genes and for reactions relating to the drugs abacavir and carbamazepine, HLA genotyping is now in routine use prior to drug prescription. Other HLA associations are not sufficiently specific for translation but are still of interest in relation to underlying mechanisms for the reactions. Progress on non-HLA genes affecting adverse drug reactions has been less, but some important associations, such as those of SLCO1B1 and statin myopathy, KCNE1 and drug-induced QT prolongation and NAT2 and isoniazid-induced liver injury, are considered. Future prospects for identification of additional genetic risk factors for the various adverse drug reactions are discussed. PMID:23360680

  9. The Circulatory and Metabolic Responses to Hypoxia in Humans – With Special Reference to Adipose Tissue Physiology and Obesity

    PubMed Central

    Heinonen, Ilkka H. A.; Boushel, Robert; Kalliokoski, Kari K.

    2016-01-01

    Adipose tissue metabolism and circulation play an important role in human health. It is well-known that adipose tissue mass is increased in response to excess caloric intake leading to obesity and further to local hypoxia and inflammatory signaling. Acute exercise increases blood supply to adipose tissue and mobilization of fat stores for energy. However, acute exercise during systemic hypoxia reduces subcutaneous blood flow in healthy young subjects, but the response in overweight or obese subjects remains to be investigated. Emerging evidence also indicates that exercise training during hypoxic exposure may provide additive benefits with respect to many traditional cardiovascular risk factors as compared to exercise performed in normoxia, but unfavorable effects of hypoxia have also been documented. These topics will be covered in this brief review dealing with hypoxia and adipose tissue physiology.

  10. The Circulatory and Metabolic Responses to Hypoxia in Humans - With Special Reference to Adipose Tissue Physiology and Obesity.

    PubMed

    Heinonen, Ilkka H A; Boushel, Robert; Kalliokoski, Kari K

    2016-01-01

    Adipose tissue metabolism and circulation play an important role in human health. It is well-known that adipose tissue mass is increased in response to excess caloric intake leading to obesity and further to local hypoxia and inflammatory signaling. Acute exercise increases blood supply to adipose tissue and mobilization of fat stores for energy. However, acute exercise during systemic hypoxia reduces subcutaneous blood flow in healthy young subjects, but the response in overweight or obese subjects remains to be investigated. Emerging evidence also indicates that exercise training during hypoxic exposure may provide additive benefits with respect to many traditional cardiovascular risk factors as compared to exercise performed in normoxia, but unfavorable effects of hypoxia have also been documented. These topics will be covered in this brief review dealing with hypoxia and adipose tissue physiology. PMID:27621722

  11. The Circulatory and Metabolic Responses to Hypoxia in Humans – With Special Reference to Adipose Tissue Physiology and Obesity

    PubMed Central

    Heinonen, Ilkka H. A.; Boushel, Robert; Kalliokoski, Kari K.

    2016-01-01

    Adipose tissue metabolism and circulation play an important role in human health. It is well-known that adipose tissue mass is increased in response to excess caloric intake leading to obesity and further to local hypoxia and inflammatory signaling. Acute exercise increases blood supply to adipose tissue and mobilization of fat stores for energy. However, acute exercise during systemic hypoxia reduces subcutaneous blood flow in healthy young subjects, but the response in overweight or obese subjects remains to be investigated. Emerging evidence also indicates that exercise training during hypoxic exposure may provide additive benefits with respect to many traditional cardiovascular risk factors as compared to exercise performed in normoxia, but unfavorable effects of hypoxia have also been documented. These topics will be covered in this brief review dealing with hypoxia and adipose tissue physiology. PMID:27621722

  12. Effects of the Variation in Brain Tissue Mechanical Properties on the Intracranial Response of a 6-Year-Old Child

    PubMed Central

    Cui, Shihai; Li, Haiyan; Li, Xiangnan; Ruan, Jesse

    2015-01-01

    Brain tissue mechanical properties are of importance to investigate child head injury using finite element (FE) method. However, these properties used in child head FE model normally vary in a large range in published literatures because of the insufficient child cadaver experiments. In this work, a head FE model with detailed anatomical structures is developed from the computed tomography (CT) data of a 6-year-old healthy child head. The effects of brain tissue mechanical properties on traumatic brain response are also analyzed by reconstruction of a head impact on engine hood according to Euro-NCAP testing regulation using FE method. The result showed that the variations of brain tissue mechanical parameters in linear viscoelastic constitutive model had different influences on the intracranial response. Furthermore, the opposite trend was obtained in the predicted shear stress and shear strain of brain tissues caused by the variations of mentioned parameters. PMID:26495031

  13. Effects of the Variation in Brain Tissue Mechanical Properties on the Intracranial Response of a 6-Year-Old Child.

    PubMed

    Cui, Shihai; Li, Haiyan; Li, Xiangnan; Ruan, Jesse

    2015-01-01

    Brain tissue mechanical properties are of importance to investigate child head injury using finite element (FE) method. However, these properties used in child head FE model normally vary in a large range in published literatures because of the insufficient child cadaver experiments. In this work, a head FE model with detailed anatomical structures is developed from the computed tomography (CT) data of a 6-year-old healthy child head. The effects of brain tissue mechanical properties on traumatic brain response are also analyzed by reconstruction of a head impact on engine hood according to Euro-NCAP testing regulation using FE method. The result showed that the variations of brain tissue mechanical parameters in linear viscoelastic constitutive model had different influences on the intracranial response. Furthermore, the opposite trend was obtained in the predicted shear stress and shear strain of brain tissues caused by the variations of mentioned parameters. PMID:26495031

  14. Bone Response to Surface-Modified Titanium Implants: Studies on the Early Tissue Response to Implants with Different Surface Characteristics

    PubMed Central

    Larsson Wexell, C.; Thomsen, P.; Aronsson, B.-O.; Tengvall, P.; Rodahl, M.; Lausmaa, J.; Kasemo, B.; Ericson, L. E.

    2013-01-01

    In a series of experimental studies, the bone formation around systematically modified titanium implants is analyzed. In the present study, three different surface modifications were prepared and evaluated. Glow-discharge cleaning and oxidizing resulted in a highly stoichiometric TiO2 surface, while a glow-discharge treatment in nitrogen gas resulted in implants with essentially a surface of titanium nitride, covered with a very thin titanium oxide. Finally, hydrogen peroxide treatment of implants resulted in an almost stoichiometric TiO2, rich in hydroxyl groups on the surface. Machined commercially pure titanium implants served as controls. Scanning Auger Electron Spectroscopy, Scanning Electron Microscopy, and Atomic Force Microscopy revealed no significant differences in oxide thickness or surface roughness parameters, but differences in the surface chemical composition and apparent topography were observed. After surface preparation, the implants were inserted in cortical bone of rabbits and evaluated after 1, 3, and 6 weeks. Light microscopic evaluation of the tissue response showed that all implants were in contact with bone and had a large proportion of newly formed bone within the threads after 6 weeks. There were no morphological differences between the four groups. Our study shows that a high degree of bone contact and bone formation can be achieved with titanium implants of different surface composition and topography. PMID:24174936

  15. Dynamic culture induces a cell type-dependent response impacting on the thickness of engineered connective tissues.

    PubMed

    Fortier, Guillaume Marceau; Gauvin, Robert; Proulx, Maryse; Vallée, Maud; Fradette, Julie

    2013-04-01

    Mesenchymal cells are central to connective tissue homeostasis and are widely used for tissue-engineering applications. Dermal fibroblasts and adipose-derived stromal cells (ASCs) allow successful tissue reconstruction by the self-assembly approach of tissue engineering. This method leads to the production of multilayered tissues, devoid of exogenous biomaterials, that can be used as stromal compartments for skin or vesical reconstruction. These tissues are formed by combining cell sheets, generated through cell stimulation with ascorbic acid, which favours the cell-derived production/organization of matrix components. Since media motion can impact on cell behaviour, we investigated the effect of dynamic culture on mesenchymal cells during tissue reconstruction, using the self-assembly method. Tissues produced using ASCs in the presence of a wave-like movement were nearly twice thicker than under standard conditions, while no difference was observed for tissues produced from dermal fibroblasts. The increased matrix deposition was not correlated with an increased proliferation of ASCs, or by higher transcript levels of fibronectin or collagens I and III. A 30% increase of type V collagen mRNA was observed. Interestingly, tissues engineered from dermal fibroblasts featured a four-fold higher level of MMP-1 transcripts under dynamic conditions. Mechanical properties were similar for tissues reconstructed using dynamic or static conditions. Finally, cell sheets produced using ASCs under dynamic conditions could readily be manipulated, resulting in a 2 week reduction of the production time (from 5 to 3 weeks). Our results describe a distinctive property of ASCs' response to media motion, indicating that their culture under dynamic conditions leads to optimized tissue engineering.

  16. Degradation characteristics, cell viability and host tissue responses of PDLLA-based scaffold with PRGD and β-TCP nanoparticles incorporation.

    PubMed

    Yi, Jiling; Xiong, Feng; Li, Binbin; Chen, Heping; Yin, Yixia; Dai, Honglian; Li, Shipu

    2016-09-01

    This study is aimed to evaluate the degradation characteristics, cell viability and host tissue responses of PDLLA/PRGD/β-TCP (PRT) composite nerve scaffold, which was fabricated by poly(d, l-lactic acid) (PDLLA), RGD peptide(Gly-Arg-Gly-Asp-Tyr, GRGDY, abbreviated as RGD) modified poly-{(lactic acid)-co-[(glycolic acid)-alt-(l-lysine)]}(PRGD) and β-tricalcium phosphate (β-TCP). The scaffolds' in vitro degradation behaviors were investigated in detail by analysing changes in weight loss, pH and morphology. Then, the 3-(4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2 -H-tetrazolium bromide (MTT) assay and cell live/dead assay were carried out to assess their cell viability. Moreover, in vivo degradation patterns and host inflammation responses were monitored by subcutaneous implantation of PRT scaffold in rats. Our data showed that, among the tested scaffolds, the PRT scaffold had the best buffering capacity (pH = 6.1-6.3) and fastest degradation rate (12.4%, 8 weeks) during in vitro study, which was contributed by the incorporation of β-TCP nanoparticles. After in vitro and in vivo degradation, the high porosity structure of PRT could be observed using scanning electron microscopy. Meanwhile, the PRT scaffold could significantly promote cell survival. In the PRT scaffold implantation region, less inflammatory cells (especially for neutrophil and lymphocyte) could be detected. These results indicated that the PRT composite scaffold had a good biodegradable property; it could improve cells survival and reduced the adverse host tissue inflammation responses. PMID:27252885

  17. Degradation characteristics, cell viability and host tissue responses of PDLLA-based scaffold with PRGD and β-TCP nanoparticles incorporation.

    PubMed

    Yi, Jiling; Xiong, Feng; Li, Binbin; Chen, Heping; Yin, Yixia; Dai, Honglian; Li, Shipu

    2016-09-01

    This study is aimed to evaluate the degradation characteristics, cell viability and host tissue responses of PDLLA/PRGD/β-TCP (PRT) composite nerve scaffold, which was fabricated by poly(d, l-lactic acid) (PDLLA), RGD peptide(Gly-Arg-Gly-Asp-Tyr, GRGDY, abbreviated as RGD) modified poly-{(lactic acid)-co-[(glycolic acid)-alt-(l-lysine)]}(PRGD) and β-tricalcium phosphate (β-TCP). The scaffolds' in vitro degradation behaviors were investigated in detail by analysing changes in weight loss, pH and morphology. Then, the 3-(4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2 -H-tetrazolium bromide (MTT) assay and cell live/dead assay were carried out to assess their cell viability. Moreover, in vivo degradation patterns and host inflammation responses were monitored by subcutaneous implantation of PRT scaffold in rats. Our data showed that, among the tested scaffolds, the PRT scaffold had the best buffering capacity (pH = 6.1-6.3) and fastest degradation rate (12.4%, 8 weeks) during in vitro study, which was contributed by the incorporation of β-TCP nanoparticles. After in vitro and in vivo degradation, the high porosity structure of PRT could be observed using scanning electron microscopy. Meanwhile, the PRT scaffold could significantly promote cell survival. In the PRT scaffold implantation region, less inflammatory cells (especially for neutrophil and lymphocyte) could be detected. These results indicated that the PRT composite scaffold had a good biodegradable property; it could improve cells survival and reduced the adverse host tissue inflammation responses.

  18. Simulated Response of a Tissue-equivalent Proportional Counter on the Surface of Mars.

    PubMed

    Northum, Jeremy D; Guetersloh, Stephen B; Braby, Leslie A; Ford, John R

    2015-10-01

    Uncertainties persist regarding the assessment of the carcinogenic risk associated with galactic cosmic ray (GCR) exposure during a mission to Mars. The GCR spectrum peaks in the range of 300(-1) MeV n to 700 MeV n(-1) and is comprised of elemental ions from H to Ni. While Fe ions represent only 0.03% of the GCR spectrum in terms of particle abundance, they are responsible for nearly 30% of the dose equivalent in free space. Because of this, radiation biology studies focusing on understanding the biological effects of GCR exposure generally use Fe ions. Acting as a thin shield, the Martian atmosphere alters the GCR spectrum in a manner that significantly reduces the importance of Fe ions. Additionally, albedo particles emanating from the regolith complicate the radiation environment. The present study uses the Monte Carlo code FLUKA to simulate the response of a tissue-equivalent proportional counter on the surface of Mars to produce dosimetry quantities and microdosimetry distributions. The dose equivalent rate on the surface of Mars was found to be 0.18 Sv y(-1) with an average quality factor of 2.9 and a dose mean lineal energy of 18.4 keV μm(-1). Additionally, albedo neutrons were found to account for 25% of the dose equivalent. It is anticipated that these data will provide relevant starting points for use in future risk assessment and mission planning studies.

  19. Simulated Response of a Tissue-equivalent Proportional Counter on the Surface of Mars.

    PubMed

    Northum, Jeremy D; Guetersloh, Stephen B; Braby, Leslie A; Ford, John R

    2015-10-01

    Uncertainties persist regarding the assessment of the carcinogenic risk associated with galactic cosmic ray (GCR) exposure during a mission to Mars. The GCR spectrum peaks in the range of 300(-1) MeV n to 700 MeV n(-1) and is comprised of elemental ions from H to Ni. While Fe ions represent only 0.03% of the GCR spectrum in terms of particle abundance, they are responsible for nearly 30% of the dose equivalent in free space. Because of this, radiation biology studies focusing on understanding the biological effects of GCR exposure generally use Fe ions. Acting as a thin shield, the Martian atmosphere alters the GCR spectrum in a manner that significantly reduces the importance of Fe ions. Additionally, albedo particles emanating from the regolith complicate the radiation environment. The present study uses the Monte Carlo code FLUKA to simulate the response of a tissue-equivalent proportional counter on the surface of Mars to produce dosimetry quantities and microdosimetry distributions. The dose equivalent rate on the surface of Mars was found to be 0.18 Sv y(-1) with an average quality factor of 2.9 and a dose mean lineal energy of 18.4 keV μm(-1). Additionally, albedo neutrons were found to account for 25% of the dose equivalent. It is anticipated that these data will provide relevant starting points for use in future risk assessment and mission planning studies. PMID:26313586

  20. Tissue plasminogen activator modulates the cellular and behavioral response to cocaine

    PubMed Central

    Maiya, Rajani; Zhou, Yan; Norris, Erin H.; Kreek, Mary Jeanne; Strickland, Sidney

    2009-01-01

    Cocaine exposure induces long-lasting molecular and structural adaptations in the brain. In this study, we show that tissue plasminogen activator (tPA), an extracellular protease involved in neuronal plasticity, modulates the biochemical and behavioral response to cocaine. When injected in the acute binge paradigm, cocaine enhanced tPA activity in the amygdala, which required activation of corticotropin-releasing factor type-1 (CRF-R1) receptors. Compared with WT mice, tPA−/− mice injected with cocaine displayed attenuated phosphorylation of ERK, cAMP response element binding protein (CREB), and dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) and blunted induction of immediate early genes (IEGs) c-Fos, Egr-1, and Homer 1a in the amygdala and the nucleus accumbens (NAc). tPA−/− mice also displayed significantly higher basal preprodynorphin (ppDyn) mRNA levels in the NAc in comparison to WT mice, and cocaine decreased ppDyn mRNA levels in tPA−/− mice only. Cocaine-induced locomotor sensitization and conditioned place preference (CPP) were attenuated in tPA−/− mice. Cocaine exposure also had an anxiolytic effect in tPA−/− but not WT mice. These results identify tPA as an important and novel component of the signaling pathway that modulates cocaine-induced changes in neuroadaptation and behavior. PMID:19181855

  1. Acetylbritannilactone Modulates MicroRNA-155-Mediated Inflammatory Response in Ischemic Cerebral Tissues

    PubMed Central

    Wen, Ya; Zhang, Xiangjian; Dong, Lipeng; Zhao, Jingru; Zhang, Cong; Zhu, Chunhua

    2015-01-01

    Inflammatory responses play a critical role in ischemic brain injury. MicroRNA-155 (miR-155) induces the expression of inflammatory cytokines, and acetylbritannilactone (ABL) exerts potent antiinflammatory actions by inhibiting expression of inflammation-related genes. However, the functions of miR-155 and the actual relationship between ABL and miR-155 in ischemia-induced cerebral inflammation remain unclear. In this study, cerebral ischemia of wild-type (WT) and miR-155−/− mice was induced by permanent middle cerebral artery occlusion (MCAO). pAd-miR-155 was injected into the lateral cerebral ventricle 24 h before MCAO to induce miR-155 overexpression. MCAO mice and oxygen-glucose deprivation (OGD)-treated BV2 cells were used to examine the effects of ABL and miR-155 overexpression or deletion on the expression of proinflammatory cytokines. We demonstrated that ABL treatment significantly reduced neurological deficits and cerebral infarct volume by inhibiting tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) expression in ischemic cerebral tissue and OGD-treated BV2 cells. Mechanistic studies suggested that the observed decrease in TNF-α and IL-1β expression was attributable to the ABL-induced suppression of the expression of nuclear factor-kappa B (NF-κB) and Toll-like receptor 4 (TLR4). We further found that miR-155 promoted TNF-α and IL-1β expression by upregulating TLR4 and downregulating the expression of suppressor of cytokine signaling 1 (SOCS1) and myeloid differentiation primary response gene 88 (MyD88), while ABL exerted an inhibitory effect on miR-155-mediated gene expression. In conclusion, miR-155 mediates inflammatory responses in ischemic cerebral tissue by modulating TLR4/MyD88 and SOCS1 expression, and ABL exerts its antiinflammatory action by suppressing miR-155 expression, suggesting a novel miR-155-based therapy for ischemic stroke. PMID:25811992

  2. Mechanisms underlying cellular responses of cells from haemopoietic tissue to low

    SciTech Connect

    Kadhim, Munira A

    2012-08-22

    The above studies will provide fundamental mechanistic information relating genetic predisposition to important low dose phenomena, and will aid in the development of Department of Energy policy, as well as radiation risk policy for the public and the workplace. We believe the proposed studies accurately reflect the goals of the DOE low dose program. To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e. less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these "non-targeted responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate non-targeted effects of ionizing radiation with a focus on the induction of genomic instability (GI) in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/CaH and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition in these models on genomic instability. We will specifically focus on the effects of low doses of low LET radiation, down to the dose of 10mGy (0.01Gy) X-rays. Using conventional X-ray and we will be able to assess the role of genetic variation under various conditions at a range of doses down to the very low dose of 0.01Gy. Irradiations will be carried out using facilities in routine operation for such studies. Mechanistic studies of instability in different cell

  3. Simultaneous Real-time Monitoring of Thermal and Mechanical Tissue Responses to Pulsed HIFU Using Pulse-Echo Ultrasound

    NASA Astrophysics Data System (ADS)

    Liu, Dalong; Ebbini, Emad S.

    2009-04-01

    Pulsed HIFU beams are being increasingly used in a number of therapeutic applications, including thermal therapy, drug and gene delivery, and hemostasis. This wide range of applications is based on a range of HIFU-tissue interactions from purely thermal to purely mechanical to produce the desired therapeutic effects. We have developed a real-time system for monitoring tissue displacements in response to pulsed HIFU beams at high PRFs. The imaging component of the system comprises an FPGA-based signal processing unit for real-time filtering of M-mode pulse-echo data followed by real-time speckle tracking for tissue displacements before, during, and after exposure to pulsed HIFU. The latter can be used in evaluating temperature and/or viscoelastic response to the applied HIFU beam. The high acquisition rate of the M-mode system, together with the real-time displacement tracking are necessary for simultaneous estimation and separation of the thermal and viscoelastic tissue responses. In addition, the system provides a real-time link to MATLAB-based nonlinear spectral estimation routines for cavitation detection. The system has been tested in vitro bovine heart tissue and the results show that the displacement tracking captures the full dynamics of tissue displacements for the full range of HIFU exposures of interest.

  4. Tissue contaminants and associated transcriptional response in trout liver from high elevation lakes of Washington.

    PubMed

    Moran, Patrick W; Aluru, Neelakanteswar; Black, Robert W; Vijayan, Mathilakath M

    2007-09-15

    The consistent cold temperatures and large amount of precipitation in the Olympic and Cascade ranges of Washington State are thought to enhance atmospheric deposition of contaminants. However, little is known about contaminant levels in organisms residing in these remote high elevation lakes. We measured total mercury and 28 organochlorine compounds in trout collected from 14 remote lakes in the Olympic, Mt. Rainer, and North Cascades National Parks. Mercury was detected in trout from all lakes sampled (15 to 262 microg/kg ww), while two organochlorines, total polychlorinated biphenyls (tPCB) and dichlorodiphenyldichloroethylene (DDE), were also detected in these fish tissues (<25 microg/kg ww). In sediments, organochlorine levels were below detection, while median total and methyl mercury were 30.4 and 0.34 microg/kg dry weight (ww), respectively. Using fish from two lakes, representing different contaminant loading levels (Wilcox lake: high; Skymo lake: low), we examined transcriptional response in the liver using a custom-made low-density targeted rainbow trout cDNA microarray. We detected significant differences in liver transcriptional response, including significant changes in metabolic, endocrine, and immune-related genes, in fish collected from Wilcox Lake compared to Skymo Lake. Overall, our results suggest that local urban areas contribute to the observed contaminant patterns in these high elevation lakes, while the transcriptional changes point to a biological response associated with exposure to these contaminants in fish. Specifically, the gene expression pattern leads us to hypothesize a role for mercury in disrupting the metabolic and reproductive pathways in fish from high elevation lakes in western Washington.

  5. Tissue contaminants and associated transcriptional response in trout liver from high elevation lakes of Washington

    USGS Publications Warehouse

    Moran, P.W.; Aluru, N.; Black, R.W.; Vijayan, M.M.

    2007-01-01

    The consistent cold temperatures and large amount of precipitation in the Olympic and Cascade ranges of Washington State are thought to enhance atmospheric deposition of contaminants. However, little is known about contaminant levels in organisms residing in these remote high elevation lakes. We measured total mercury and 28 organochlorine compounds in trout collected from 14 remote lakes in the Olympic, Mt. Rainer, and North Cascades National Parks. Mercury was detected in trout from all lakes sampled (15 to 262 ??g/kg ww), while two organochlorines, total polychlorinated biphenyls (tPCB) and dichlorodiphenyldichloroethylene (DDE), were also detected in these fish tissues (<25 ??g/kg ww). In sediments, organochlorine levels were below detection, while median total and methyl mercury were 30.4 and 0.34 ??g/ kg dry weight (ww), respectively. Using fish from two lakes, representing different contaminant loading levels (Wilcox lake: high; Skymo lake: low), we examined transcriptional response in the liver using a custom-made low-density targeted rainbow trout cDNA microarray. We detected significant differences in liver transcriptional response, including significant changes in metabolic, endocrine, and immune-related genes, in fish collected from Wilcox Lake compared to Skymo Lake. Overall, our results suggest that local urban areas contribute to the observed contaminant patterns in these high elevation lakes, while the transcriptional changes point to a biological response associated with exposure to these contaminants in fish. Specifically, the gene expression pattern leads us to hypothesize a role for mercury in disrupting the metabolic and reproductive pathways in fish from high elevation lakes in western Washington. ?? 2007 American Chemical Society.

  6. The adult brain tissue response to hollow fiber membranes of varying surface architecture with or without cotransplanted cells

    NASA Astrophysics Data System (ADS)

    Zhang, Ning

    A variety of biomaterials have been chronically implanted into the central nervous system (CNS) for repair or therapeutic purposes. Regardless of the application, chronic implantation of materials into the CNS induces injury and elicits a wound healing response, eventually leading to the formation of a dense extracellular matrix (ECM)-rich scar tissue that is associated with the segregation of implanted materials from the surrounding normal tissue. Often this reaction results in impaired performance of indwelling CNS devices. In order to enhance the performance of biomaterial-based implantable devices in the CNS, this thesis investigated whether adult brain tissue response to implanted biomaterials could be manipulated by changing biomaterial surface properties or further by utilizing the biology of co-transplanted cells. Specifically, the adult rat brain tissue response to chronically implanted poly(acrylonitrile-vinylchloride) (PAN-PVC) hollow fiber membranes (HFMs) of varying surface architecture were examined temporally at 2, 4, and 12 weeks postimplantation. Significant differences were discovered in the brain tissue response to the PAN-PVC HFMs of varying surface architecture at 4 and 12 weeks. To extend this work, whether the soluble factors derived from a co-transplanted cellular component further affect the brain tissue response to an implanted HFM in a significant way was critically exploited. The cells used were astrocytes, whose ability to influence scar formation process following CNS injury by physical contact with the host tissue had been documented in the literature. Data indicated for the first time that astrocyte-derived soluble factors ameliorate the adult brain tissue reactivity toward HFM implants in an age-dependent manner. While immature astrocytes secreted soluble factors that suppressed the brain tissue reactivity around the implants, mature astrocytes secreted factors that enhanced the gliotic response. These findings prove the feasibility

  7. Evaluation of immediate adverse reactions to foods in adult patients. I. Correlation of demographic, laboratory, and prick skin test data with response to controlled oral food challenge.

    PubMed

    Atkins, F M; Steinberg, S S; Metcalfe, D D

    1985-03-01

    Forty-five adult patients, referred to here as the index population, with a history of immediate adverse reactions after food ingestion were evaluated by history, physical examination, laboratory studies, and skin testing. Fifty-six percent of these patients reported adverse reactions to only one food, whereas 84% of the patients reported up to three foods as being capable of eliciting reactions. The average age obtained by history at which adverse reactions began to occur was 19 4/5 yr. The occurrence of these reactions persisted over an average of 14 4/5 yr. Most reactions involved the gastrointestinal tract alone or in combination with the skin or respiratory tract. The most frequently involved foods were shellfish, peanuts, eggs, fish, tomatoes, and walnuts. Twenty-five of the patients participated in oral challenge with the suspected food. The food challenge was positive in 10 patients. Comparison of information obtained by history including personal or family history of any other allergic disease, age of onset of sensitivity, the length of time of suspected sensitivity in years, and the number of foods to which the sensitivity was believed to exist revealed no significant differences between food challenge-positive (FC+) and food challenge-negative (FC-) patients. However, a significant difference in the reaction patterns reported by history in the FC+ and FC- patients was noted in that FC+ patients more often described reactions in which a combination of gastrointestinal, respiratory, and dermatologic symptoms occurred. The complete blood count with differential, blood chemistries, and serum immunoglobulin levels were similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Rat subcutaneous tissue response to calcium silicate containing different arsenic concentrations

    PubMed Central

    MINOTTI, Paloma Gagliardi; ORDINOLA-ZAPATA, Ronald; MIDENA, Raquel Zanin; MARCIANO, Marina Angélica; CAVENAGO, Bruno Cavalini; BRAMANTE, Clovis Monteiro; GARCIA, Roberto Brandão; DUARTE, Marco Antonio Hungaro; de MORAES, Ivaldo Gomes

    2015-01-01

    Objective To evaluate the response of rat subcutaneous tissue in implanted polyethylene tubes that were filled with GMTA Angelus and Portland cements containing different arsenic concentrations. Material and Methods Atomic absorption spectrophotometry was utilized to obtain the values of the arsenic concentration in the materials. Thirty-six rats were divided into 3 groups of 12 animals for each experimental period. Each animal received two implants of polyethylene tubes filled with different test cements and the lateral of the tubes was used as a control group. After 15, 30 and 60 days of implantation, the animals were killed and the specimens were prepared for descriptive and morphometric analysis considering: inflammatory cells, collagen fibers, fibroblasts, blood vessels and other components. The results were analyzed utilizing the Kuskal-Wallis test and the Dunn´s Multiple test for comparison (p<0.05). Results The materials showed, according to atomic absorption spectrophotometry, the following doses of arsenic: GMTA Angelus: 5.01 mg/kg, WPC Irajazinho: 0.69 mg/kg, GPC Minetti: 18.46 mg/kg and GPC Votoran: 10.76 mg/kg. In a 60-day periods, all specimens displayed a neoformation of connective tissue with a structure of fibrocellular aspect (capsule). Control groups and MTA Angelus produced the lower amount of inflammatory reaction and GPC Minetti, the highest reaction. Conclusions There was no direct relationship between the concentration of arsenic present in the composition of the materials and the intensity of the inflammatory reactions. Higher values, as 18.46 mg/kg of arsenic in the cement, produce characteristics of severe inflammation reaction at the 60-day period. The best results were found in MTA angelus. PMID:25075671

  9. Intact brown adipose tissue thermogenesis is required for restorative sleep responses after sleep loss.

    PubMed

    Szentirmai, Éva; Kapás, Levente

    2014-03-01

    Metabolic signals related to feeding and body temperature regulation have profound effects on vigilance. Brown adipose tissue (BAT) is a key effector organ in the regulation of metabolism in several species, including rats and mice. Significant amounts of active BAT are also present throughout adulthood in humans. The metabolic activity of BAT is due to the tissue-specific presence of the uncoupling protein-1 (UCP-1). To test the involvement of BAT thermogenesis in sleep regulation, we investigated the effects of two sleep-promoting stimuli in UCP-1-deficient mice. Sleep deprivation by gentle handling increased UCP-1 mRNA expression in BAT and elicited rebound increases in non-rapid-eye-movement sleep and rapid-eye-movement sleep accompanied by elevated slow-wave activity of the electroencephalogram. The rebound sleep increases were significantly attenuated, by ~ 35-45%, in UCP-1-knockout (KO) mice. Wild-type (WT) mice with capsaicin-induced sensory denervation of the interscapular BAT pads showed similar impairments in restorative sleep responses after sleep deprivation, suggesting a role of neuronal sleep-promoting signaling from the BAT. Exposure of WT mice to 35 °C ambient temperature for 5 days led to increased sleep and body temperature and suppressed feeding and energy expenditure. Sleep increases in the warm environment were significantly suppressed, by ~ 50%, in UCP-1-KO animals while their food intake and energy expenditure did not differ from those of the WTs. These results suggest that the metabolic activity of the BAT plays a role in generating a metabolic environment that is permissive for optimal sleep. Impaired BAT function may be a common underlying cause of sleep insufficiency and metabolic disorders.

  10. Organogenic responses in tissue culture of srd mutants of Arabidopsis thaliana.

    PubMed

    Ozawa, S; Yasutani, I; Fukuda, H; Komamine, A; Sugiyama, M

    1998-01-01

    In Arabidopsis thaliana, shoot redifferentiation and root redifferentiation can be induced at high frequency from hypocotyl and root explants by a two-step culture method. Tissues are precultured on callus-inducing medium and then transferred onto shoot-inducing medium for shoot redifferentiation or onto root-inducing medium for root redifferentiation. In an attempt to dissect these organogenic processes genetically, we characterized the responses in tissue culture of srd1, srd2 and srd3 mutants that were originally isolated as temperature-sensitive strains with defects in shoot redifferentiation (Yasutani, I., Ozawa, S., Nishida, T., Sugiyama, M. and Komamine, A. (1994) Plant Physiol. 105, 815-822). These mutants exhibited temperature sensitivity at different steps of organogenesis, which allowed the identification of three states associated with organogenic competence: IC (incompetent); CR (competent with respect to root redifferentiation); and CSR (competent with respect to shoot and root redifferentiation). Hypocotyl explants were shown to be in the IC state at the initiation of culture and to enter the CSR state, via the CR state, during preculture on callus-inducing medium, whereas root explants seemed to be in the CR state at the initiation of culture. The transition from IC to CR and that from CR to CSR appeared to require the functions of SRD2 and SRD3, respectively. It appears that explants in the CSR state redifferentiate shoots with the aid of the products of SRD1 and SRD2 when transplanted onto shoot-inducing medium. Histological examination of the srd mutants revealed that the function of SRD2 is required not only for organogenesis but also for the reinitiation of cell proliferation in hypocotyl explants during culture on callus-inducing medium. Linkage analysis using RFLP markers indicated that SRD1, SRD2, and SRD3 are located at the lower region, the central region, and the upper region of chromosome 1, respectively.

  11. Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging.

    PubMed

    Neves, Joana; Demaria, Marco; Campisi, Judith; Jasper, Heinrich

    2015-01-12

    Studies in flies, mice, and human models have provided a conceptual framework for how paracrine interactions between damaged cells and the surrounding tissue control tissue repair. These studies have amassed evidence for an evolutionarily conserved secretory program that regulates tissue homeostasis. This program coordinates cell survival and proliferation during tissue regeneration and repair in young animals. By virtue of chronic engagement, however, it also contributes to the age-related decline of tissue homeostasis leading to degeneration, metabolic dysfunction, and cancer. Here, we review recent studies that shed light on the nature and regulation of this evolutionarily conserved secretory program. PMID:25584795

  12. Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging.

    PubMed

    Neves, Joana; Demaria, Marco; Campisi, Judith; Jasper, Heinrich

    2015-01-12

    Studies in flies, mice, and human models have provided a conceptual framework for how paracrine interactions between damaged cells and the surrounding tissue control tissue repair. These studies have amassed evidence for an evolutionarily conserved secretory program that regulates tissue homeostasis. This program coordinates cell survival and proliferation during tissue regeneration and repair in young animals. By virtue of chronic engagement, however, it also contributes to the age-related decline of tissue homeostasis leading to degeneration, metabolic dysfunction, and cancer. Here, we review recent studies that shed light on the nature and regulation of this evolutionarily conserved secretory program.

  13. Characterization and response of antioxidant systems in the tissues of the freshwater pond snail (Lymnaea stagnalis) during acute copper exposure.

    PubMed

    Atli, Gülüzar; Grosell, Martin

    2016-07-01

    The response of enzymatic (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPX and glutathione reductase, GR) and non-enzymatic responses (glutathione, GSH, oxidized glutathione, GSSG and GSH/GSSG) against acute Cu toxicity (2-90μg/mL for 48h) in different tissues of Lymnaea stagnalis were measured. Incubation conditions for enzymatic activity measurements were optimized for L. stagnalis tissues. Three examined tissues, the hepatopancreas, the foot muscle and the mantle, exhibited variable responses in antioxidant parameters as a function of Cu concentrations. The most responsive antioxidant enzymes were GPX and CAT while GR appeared less sensitive. In general antioxidant enzymes at higher Cu concentrations though GSH levels at lower Cu concentrations exhibited the greatest changes in hepatopancreas and foot muscle, respectively. All antioxidant enzymes except GR increased after exposure to the highest Cu concentration in mantle. Total and reduced GSH increased in hepatopancreas but decreased with GSH/GSSG ratios at all Cu concentrations in foot muscle. The present results show that antioxidants respond to acute Cu exposure at concentrations as low as 2μg Cu/L in adult L. stagnalis with variable responses in different tissues. Antioxidants both including enzymatic and non-enzymatic parameters may account, in part, for the high tolerance to acute metal exposure observed in adult L. stagnalis and could form suited biomarkers to evaluate the metal exposure and toxicity in aquatic environment even at relatively low level short term exposure. PMID:27108202

  14. Generalization of a model of tissue response to radiation based on the idea of functional subunits and binomial statistics†

    NASA Astrophysics Data System (ADS)

    Stavrev, P.; Stavreva, N.; Niemierko, A.; Goitein, M.

    2001-05-01

    This work investigates the existing biological models describing the response of tumours and normal tissues to radiation, with the purpose of developing a general biological model of the response of tissue to radiation. Two different types of normal tissue behaviour have been postulated with respect to its response to radiation, namely critical element and critical volume behaviour. Based on the idea that an organ is composed of functional subunits, models have been developed describing these behaviours. However, these models describe the response of an individual, a particular patient or experimental animal, while the clinically or experimentally observed quantity is the population response. There is a need to extend the models to address the population response, based on the ideas we have about the individual response. We have attempted here to summarize and unify the existing individual models. Finally, the population models are investigated by fitting to pseudoexperimental sets of data and comparing them with each other in terms of goodness-of-fit and in terms of their power to recover the values of the population parameters.

  15. Designing PolyHEMA Substrates that Mimic the Viscoelastic Response of Soft Tissue

    PubMed Central

    Holt, Brian; Tripathi, Anubhav; Morgan, Jeffrey R.

    2011-01-01

    Matching the mechanical properties of a biomaterial to soft tissue is often overlooked despite the fact that it’s well known that cells respond to and are capable of changing their mechanical environment. In this paper, we used NaCl and alginate beads as porogens to make a series of micro- and macro-porous pHEMA substrates [poly(2-hydroxyethly methacrylate)] and quantified their mechanical behavior under low-magnitude shear loads over physiologically relevant frequencies. Using a stress-controlled rheometer, we performed isothermal (37°C) frequency response experiments between 0.628 and 75.4 rad/s [0.01–12Hz] at 0.1% strain. Both micro- and macro-porous pHEMA substrates were predominately elastic in nature with a narrow range of G′ and G″ values that mimicked the response of human skin. The magnitude of the G′ and G″ values of the macro-porous substrates were designed to closely match human skin. To determine how cell growth might alter their mechanical properties, pHEMA substrates were functionalized and human skin fibroblasts grown on them for fourteen days. As a result of cell growth, the magnitude of G′ and G″ increased at low frequencies while also altering the degree of high frequency dependence, indicating that cellular interactions with the micro-pore infrastructure has a profound effect on the viscoelastic behavior of the substrates. These data could be fit to a mathematical model describing a soft solid. A quantitative understanding of the mechanical behavior of biomaterials in regimes that are physiologically relevant and how these mechanics may change after implantation may aid in the design of new materials. PMID:21496821

  16. The WFDC1 gene: role in wound response and tissue homoeostasis.

    PubMed

    Ressler, Steven J; Rowley, David R

    2011-10-01

    The present evaluates the key features of the WFDC1 [WAP (whey acidic protein) four disulfide core 1] gene that encodes ps20 (20 kDa prostate stromal protein), a member of the WAP family. ps20 was first characterized as a growth inhibitory activity that was secreted by fetal urogenital sinus mesenchymal cells. Purified ps20 exhibited several activities that centre on cell adhesion, migration and proliferation. The WFDC1 gene was cloned, contained seven exons, and was mapped to chromosome 16q24, suggesting that it may function as a tumour suppressor; however, direct evidence of this has not emerged. In vivo, ps20 stimulated angiogenesis, although expression of WFDC1/ps20 was down-regulated in the reactive stroma tumour microenvironment in prostate cancer. WFDC1 expression is differential in other cancers and inflammatory conditions. Recent studies point to a role in viral infectivity. Although mechanisms of action are not fully understood, WFDC1/ps20 is emerging as a secreted matricellular protein that probably affects response to micro-organisms and tissue repair homoeostasis.

  17. Tissue distribution and dependence of responsiveness of human antigen-specific memory B cells.

    PubMed

    Giesecke, Claudia; Frölich, Daniela; Reiter, Karin; Mei, Henrik E; Wirries, Ina; Kuhly, Rainer; Killig, Monica; Glatzer, Timor; Stölzel, Katharina; Perka, Carsten; Lipsky, Peter E; Dörner, Thomas

    2014-04-01

    Memory B cells (mBCs) are a key to immunologic memory, yet their distribution within lymphoid organs and the individual role of these for mBC functionality remain largely unknown. This study characterized the distribution and phenotype of human (Ag-specific) mBCs in peripheral blood (PB), spleen, tonsil, and bone marrow. We found that the spleen harbors most mBCs, followed by tonsils, BM, and PB, and we detected no major differences in expression of markers associated with higher maturity. Testing the distribution of tetanus toxoid-specific (TT(+)) mBCs revealed their presence in PB during steady state, yet absolute numbers suggested their largest reservoir in the spleen, followed by tonsils. To explore the role of both tissues in the maintenance of reactive B cell memory, we revaccinated controls and splenectomized and tonsillectomized individuals with TT. All donor groups exhibited comparable emergence of anti-TT IgG, TT(+) plasma cells, and TT(+) mBCs in the PB, together with similar molecular characteristics of TT(+) plasma cells. In summary, human mBCs recirculate through PB and reside in different lymphoid organs that do not reflect different mBC maturity stages. The spleen and tonsil, although harboring the largest number of overall and TT(+) mBCs, appear to be dispensable to preserve adequate responsiveness to secondary antigenic challenge.

  18. Accuracy and reproducibility of bending stiffness measurements by mechanical response tissue analysis in artificial human ulnas.

    PubMed

    Arnold, Patricia A; Ellerbrock, Emily R; Bowman, Lyn; Loucks, Anne B

    2014-11-01

    Osteoporosis is characterized by reduced bone strength, but no FDA-approved medical device measures bone strength. Bone strength is strongly associated with bone stiffness, but no FDA-approved medical device measures bone stiffness either. Mechanical Response Tissue Analysis (MRTA) is a non-significant risk, non-invasive, radiation-free, vibration analysis technique for making immediate, direct functional measurements of the bending stiffness of long bones in humans in vivo. MRTA has been used for research purposes for more than 20 years, but little has been published about its accuracy. To begin to investigate its accuracy, we compared MRTA measurements of bending stiffness in 39 artificial human ulna bones to measurements made by Quasistatic Mechanical Testing (QMT). In the process, we also quantified the reproducibility (i.e., precision and repeatability) of both methods. MRTA precision (1.0±1.0%) and repeatability (3.1 ± 3.1%) were not as high as those of QMT (0.2 ± 0.2% and 1.3+1.7%, respectively; both p<10(-4)). The relationship between MRTA and QMT measurements of ulna bending stiffness was indistinguishable from the identity line (p=0.44) and paired measurements by the two methods agreed within a 95% confidence interval of ± 5%. If such accuracy can be achieved on real human ulnas in situ, and if the ulna is representative of the appendicular skeleton, MRTA may prove clinically useful.

  19. Degenerative Tissue Responses to Space-like Radiation Doses in a Rodent Model of Simulated Microgravity.

    PubMed

    Chowdhury, Parimal; Akel, Nisreen; Jamshidi-Parsian, Azemat; Gaddy, Dana; Griffin, Robert J; Yadlapalli, Jai Shankar K; Dobretsov, Maxim

    2016-01-01

    This study examines acute and degenerative tissue responses to space-like radiation doses in a rodent model of simulated microgravity. We have studied four groups of rats, control (CON), irradiated (IR), irradiated and hindlimb suspended (IR-HLS), and suspended (HLS) that were maintained for two weeks. IR and IR+HLS groups were exposed to five sessions of X-ray irradiation (1.2 Gy each, at 3-4 days intervals). Body weights, soleus muscle weights, and hindlimb bone mineral density (BMD) were measured. Results show that compared to CON animals, IR, HLS, and IR+HLS group reduced the body weight gain significantly. IR-associated growth retardation appeared to be closely linked to acute and transient post-IR 'anorexia' (a decrease in food intake). HLS but not IR induced major changes in the musculoskeletal system, consisting in decreases in soleus muscle mass and bone mineral density of distal femur and proximal tibia. Additional dosimetric studies showed that the effect of IR on weight is detectable at 0.3 Gy X-ray doses, while no threshold dose for the IR-produced decrease in food intake could be observed. This study suggests that space flight-associated anorexia and musculoskeletal degenerative changes may be driven by different, radiation- and microgravity-associated (respectively) mechanisms. PMID:27098627

  20. Radiation microbeams as spatial and temporal probes of subcellular and tissue response

    PubMed Central

    Schettino, Giuseppe; Al-Rashid, Shahnaz T.; Prise, Kevin M.

    2010-01-01

    Understanding the effects of ionising radiations are key to determining their optimal use in therapy and assessing risks from exposure. The development of microbeams where radiations can be delivered in a highly temporal and spatially constrained manner has been a major advance. Several different types of radiation microbeams have been developed using X-rays, charged particles and electrons. For charged particles, beams can be targeted with sub-micron accuracy into biological samples and the lowest possible dose of a single particle track can be delivered with high reproducibility. Microbeams have provided powerful tools for understanding the kinetics of DNA damage and formation under conditions of physiological relevance and have significant advantages over other approaches for producing localised DNA damage, such as variable wavelength laser beam approaches. Recent studies have extended their use to probing for radiosensitive sites outside the cell nucleus, and testing for mechanisms underpinning bystander responses where irradiated and non-irradiated cells communicate with each other. Ongoing developments include the ability to locally target regions of 3-D tissue models and ultimately to target localised regions in vivo. With future advances in radiation delivery and imaging microbeams will continue to be applied in a range of biological studies. PMID:20079877

  1. Accuracy and reproducibility of bending stiffness measurements by mechanical response tissue analysis in artificial human ulnas.

    PubMed

    Arnold, Patricia A; Ellerbrock, Emily R; Bowman, Lyn; Loucks, Anne B

    2014-11-01

    Osteoporosis is characterized by reduced bone strength, but no FDA-approved medical device measures bone strength. Bone strength is strongly associated with bone stiffness, but no FDA-approved medical device measures bone stiffness either. Mechanical Response Tissue Analysis (MRTA) is a non-significant risk, non-invasive, radiation-free, vibration analysis technique for making immediate, direct functional measurements of the bending stiffness of long bones in humans in vivo. MRTA has been used for research purposes for more than 20 years, but little has been published about its accuracy. To begin to investigate its accuracy, we compared MRTA measurements of bending stiffness in 39 artificial human ulna bones to measurements made by Quasistatic Mechanical Testing (QMT). In the process, we also quantified the reproducibility (i.e., precision and repeatability) of both methods. MRTA precision (1.0±1.0%) and repeatability (3.1 ± 3.1%) were not as high as those of QMT (0.2 ± 0.2% and 1.3+1.7%, respectively; both p<10(-4)). The relationship between MRTA and QMT measurements of ulna bending stiffness was indistinguishable from the identity line (p=0.44) and paired measurements by the two methods agreed within a 95% confidence interval of ± 5%. If such accuracy can be achieved on real human ulnas in situ, and if the ulna is representative of the appendicular skeleton, MRTA may prove clinically useful. PMID:25261885

  2. The Role of Adverse Event Reporting in the FDA Response to a Multistate Outbreak of Liver Disease Associated with a Dietary Supplement

    PubMed Central

    DeBeck, Heidi J.; LeBlanc, Pamela; Mogen, Kathryn M.; Wolpert, Beverly J.; Sabo, Jonathan L.; Salter, Monique; Seelman, Sharon L.; Lance, Susan E.; Monahan, Caitlin; Steigman, David S.; Gensheimer, Kathleen

    2015-01-01

    Objective Liver disease is a potential complication from using dietary supplements. This study investigated an outbreak of non-viral liver disease associated with the use of OxyELITE ProTM, a dietary supplement used for weight loss and/or muscle building. Methods Illness details were ascertained from MedWatch reports submitted to the U.S. Food and Drug Administration (FDA) describing consumers who ingested OxyELITE Pro alone or in combination with other dietary supplements. FDA's Forensic Chemistry Center analyzed samples of OxyELITE Pro. Results From February 2012 to February 2014, FDA received 114 reports of adverse events of all kinds involving consumers who ingested OxyELITE Pro. The onset of illness for the first report was December 2010 and for the last report was January 2014. Thirty-three states, two foreign nations, and Puerto Rico submitted reports. Fifty-five of the reports (48%) described liver disease in the absence of viral infection, gallbladder disease, autoimmune disease, or other known causes of liver damage. A total of 33 (60%) of these patients were hospitalized, and three underwent liver transplantation. In early 2013, OxyELITE Pro products entered the market with a formulation distinct from products sold previously. The new formulation replaced 1,3-dimethylamylamine with aegeline. However, the manufacturer failed to submit to FDA a required “new dietary ingredient” notice for the use of aegeline in OxyELITE Pro products. Laboratory analysis identified no drugs, poisons, pharmaceuticals, toxic metals, usnic acid, N-Nitroso-fenfluramine, pyrrolizidine alkaloids, aristocholic acid, or phenethylamines in the products. Conclusions Vigilant surveillance is required for adverse events linked to the use of dietary supplements. PMID:26327730

  3. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

    PubMed Central

    Funk, Juergen; Robbins, Justin B.; Crogan-Grundy, Candace; Presnell, Sharon C.; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level. PMID:27387377

  4. Proteome changes in banana fruit peel tissue in response to ethylene and high-temperature treatments.

    PubMed

    Du, Lina; Song, Jun; Forney, Charles; Palmer, Leslie Campbell; Fillmore, Sherry; Zhang, ZhaoQi

    2016-01-01

    Banana (Musa AAA group) is one of the most consumed fruits in the world due to its flavor and nutritional value. As a typical climacteric fruit, banana responds to ethylene treatment, which induces rapid changes of color, flavor (aroma and taste), sweetness and nutritional composition. It has also been reported that ripening bananas at temperatures above 24 °C inhibits chlorophyll breakdown and color formation but increases the rate of senescence. To gain fundamental knowledge about the effects of high temperature and ethylene on banana ripening, a quantitative proteomic study employing multiplex peptide stable isotope dimethyl labeling was conducted. In this study, green (immature) untreated banana fruit were subjected to treatment with 10 μL L(-1) of ethylene for 24 h. After ethylene treatment, treated and untreated fruit were stored at 20 or 30 °C for 24 h. Fruit peel tissues were then sampled after 0 and 1 day of storage, and peel color and chlorophyll fluorescence were evaluated. Quantitative proteomic analysis was conducted on the fruit peels after 1 day of storage. In total, 413 common proteins were identified and quantified from two biological replicates. Among these proteins, 91 changed significantly in response to ethylene and high-temperature treatments. Cluster analysis on these 91 proteins identified 7 groups of changed proteins. Ethylene treatment and storage at 20 °C induced 40 proteins that are correlated with pathogen resistance, cell wall metabolism, ethylene biosynthesis, allergens and ribosomal proteins, and it repressed 36 proteins that are associated with fatty acid and lipid metabolism, redox-oxidative responses, and protein biosynthesis and modification. Ethylene treatment and storage at 30 °C induced 32 proteins, which were mainly similar to those in group 1 but also included 8 proteins in group 3 (identified as chitinase, cinnamyl alcohol dehydrogenase 1, cysteine synthase, villin-2, leucine-transfer RNA ligase, CP47

  5. Proteome changes in banana fruit peel tissue in response to ethylene and high-temperature treatments

    PubMed Central

    Du, Lina; Song, Jun; Forney, Charles; Palmer, Leslie Campbell; Fillmore, Sherry; Zhang, ZhaoQi

    2016-01-01

    Banana (Musa AAA group) is one of the most consumed fruits in the world due to its flavor and nutritional value. As a typical climacteric fruit, banana responds to ethylene treatment, which induces rapid changes of color, flavor (aroma and taste), sweetness and nutritional composition. It has also been reported that ripening bananas at temperatures above 24 °C inhibits chlorophyll breakdown and color formation but increases the rate of senescence. To gain fundamental knowledge about the effects of high temperature and ethylene on banana ripening, a quantitative proteomic study employing multiplex peptide stable isotope dimethyl labeling was conducted. In this study, green (immature) untreated banana fruit were subjected to treatment with 10 μL L−1 of ethylene for 24 h. After ethylene treatment, treated and untreated fruit were stored at 20 or 30 °C for 24 h. Fruit peel tissues were then sampled after 0 and 1 day of storage, and peel color and chlorophyll fluorescence were evaluated. Quantitative proteomic analysis was conducted on the fruit peels after 1 day of storage. In total, 413 common proteins were identified and quantified from two biological replicates. Among these proteins, 91 changed significantly in response to ethylene and high-temperature treatments. Cluster analysis on these 91 proteins identified 7 groups of changed proteins. Ethylene treatment and storage at 20 °C induced 40 proteins that are correlated with pathogen resistance, cell wall metabolism, ethylene biosynthesis, allergens and ribosomal proteins, and it repressed 36 proteins that are associated with fatty acid and lipid metabolism, redox–oxidative responses, and protein biosynthesis and modification. Ethylene treatment and storage at 30 °C induced 32 proteins, which were mainly similar to those in group 1 but also included 8 proteins in group 3 (identified as chitinase, cinnamyl alcohol dehydrogenase 1, cysteine synthase, villin-2, leucine-transfer RNA ligase, CP47

  6. Connective tissue responses to some heavy metals. II. Lead: histology and ultrastructure.

    PubMed Central

    Ellender, G.; Ham, K. N.

    1987-01-01

    Lead loaded ion exchange resin beads implanted into the loose connective tissue of the rat pinna induced local lesions which differed widely from those of the control (sodium loaded) beads (Ellender & Ham 1987). These lesions were characterized by changes in the granulation tissue and the approximating connective tissue. Granulation tissue contained mononuclear phagocytes in various guises, and some cells with intranuclear inclusion bodies. The matrix of the granulation tissue contained collagen fibrils having a wide range of diameters suggestive of altered collagen biosynthesis. Foci of collagen mineralization occurred in zones of combined trauma and lead impregnation. Once mineralized they became enveloped by giant cells and epithelioid cells. Lead in damaged tissues is thought to modify the protective mechanism of calcification inhibition and the biosynthesis of the matrix. Images Fig. 6 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 PMID:3040063

  7. Tissue response of defined collagen-elastin scaffolds in young and adult rats with special attention to calcification.

    PubMed

    Daamen, W F; Nillesen, S T M; Hafmans, T; Veerkamp, J H; van Luyn, M J A; van Kuppevelt, T H

    2005-01-01

    Collagen-elastin scaffolds may be valuable biomaterials for tissue engineering because they combine tensile strength with elasticity. In this study, the tissue response to and the calcification of these scaffolds were evaluated. In particular, the hypothesis was tested that calcification, a common phenomenon in biomaterials, may be due to microfibrils within the elastic fibre, and that these microfibrils might generate a tissue response. Four scaffolds were subcutaneously implanted, viz. collagen, collagen + pure elastin, collagen+microfibril-containing, and collagen + pulverised elastic ligament (the source for elastin). Explants were evaluated at day 3, 7 and 21. In young Sprague Dawley rats, collagen + ligament calcified substantially, whereas collagen + elastin (with and without microfibrils) calcified less, and collagen did not. Calcification started at elastic fibres. In both Sprague Dawley and Wistar adult rats, however, none of the scaffolds calcified. Mononuclear cell infiltration was prominent in young and adult Sprague Dawley rats. In adult Wistar rats, this infiltration was associated with the presence of microfibrils. Degradation of scaffolds and new matrix formation were related with cellular influx and degree of vascularisation. In conclusion, absence of microfibrils from the elastic fibre does not prevent calcification in young Sprague Dawley rats, but does reduce the tissue response in adult Wistar rats. Cellular response and calcification differs with age and strain and therefore the choice of animal model is of key importance in biomaterial evaluation.

  8. In vivo degradation and tissue response to poly(5-ethylene ketal ε-caprolactone-co-D,L-lactide).

    PubMed

    Babasola, Iyabo Oladunni; Bianco, Juares; Amsden, Brian G

    2012-07-01

    Low molecular weight poly(5-ethylene ketal ε-caprolactone-co-D,L-lactide) (PEKCDLLA) is being considered as a viscous liquid, injectable depot for localized drug delivery. This polymer degrades in vitro via surface erosion, which is potentially advantageous for the proposed application. However, the in vivo degradation rate and mechanism, and tissue response, to polymers based on 5-ethylene ketal ε-caprolactone have not yet been reported. The purpose of this study was to measure the in vivo weight loss and change in polymer properties and assess the tissue response to PEKCDLLA after subcutaneous injection in rats. The tissue response was assessed histologically using Masson's trichrome staining and immunohistochemically by staining for CD68 positive cells. The polymer lost weight with time in a nearly linear fashion but did not exhibit significant changes in number average molecular weight, polydispersity index, and glass transition temperature or monomer ratio, consistent with a surface erosion process. The tissue response to the polymer was moderate and comparable to that reported in the literature for other degradable polymers used in clinical applications. These findings indicate that PEKCDLLA is a promising candidate for injectable drug delivery. PMID:22712428

  9. Responses of Spermatogenous Tissue and Mechanisms of Their Development Upon Cytostatic Exposure.

    PubMed

    Dygai, A M; Chaikovskii, A V; Zhdanov, V V; Zyuz'kov, G N; Stavrova, L A; Udut, V V; Miroshnichenko, L A; Simanina, E V; Borovskaya, T G; Poluektova, M E

    2015-10-01

    A decrease in the total number of sperm cells and reduction of spermatogonium population were observed upon cytostatic damage of spermatogenous tissue caused by single paclitaxel administration. It was established that the paclitaxel-induced damage to the testicular tissue is underlain by reduction of its regenerative potential consisting in depletion of regional precursor pool. Changes in functional activity of progenitor cells were caused not only by direct action of paclitaxel, but also by suppression of the secretory function of the tissue microenvironment.

  10. Adverse reactions to cosmetics.

    PubMed

    Gendler, E

    1987-06-01

    Adverse reactions to cosmetics can be irritant or allergic and are most often caused by fragrances or preservatives. Preservatives include formaldehyde, formaldehyde releasers, and parabens. Other agents that cause allergy are paraphenylenediamine in hair dyes and toluene sulfonamide formaldehyde resin in nail polishes.

  11. Scientists Trace Adversity's Toll

    ERIC Educational Resources Information Center

    Sparks, Sarah D.

    2012-01-01

    The stress of a spelling bee or a challenging science project can enhance a student's focus and promote learning. But the stress of a dysfunctional or unstable home life can poison a child's cognitive ability for a lifetime, according to new research. Those studies show that stress forms the link between childhood adversity and poor academic…

  12. The biocontrol endophytic bacterium Pseudomonas fluorescens PICF7 induces systemic defense responses in aerial tissues upon colonization of olive roots

    PubMed Central

    Gómez-Lama Cabanás, Carmen; Schilirò, Elisabetta; Valverde-Corredor, Antonio; Mercado-Blanco, Jesús

    2014-01-01

    Pseudomonas fluorescens PICF7, a native olive root endophyte and effective biocontrol agent (BCA) against Verticillium wilt of olive, is able to trigger a broad range of defense responses in root tissues of this woody plant. In order to elucidate whether strain PICF7 also induces systemic defense responses in above-ground organs, aerial tissues of olive plants grown under non-gnotobiotic conditions were collected at different time points after root bacterization with this endophytic BCA. A suppression subtractive hybridization (SSH) cDNA library, enriched in up-regulated genes, was generated. This strategy enabled the identification of 376 ESTs (99 contigs and 277 singlets), many of them related to response to different stresses. Five ESTs, involved in defense responses, were selected to carry out time-course quantitative real-time PCR (qRT-PCR) experiments aiming to: (1) validate the induction of these genes, and (2) shed light on their expression pattern along time (from 1 to 15 days). Induction of olive genes potentially coding for lipoxygenase 2, catalase, 1-aminocyclopropane-1-carboxylate oxidase, and phenylananine ammonia-lyase was thus confirmed at some time points. Computational analysis also revealed that different transcription factors were up-regulated in olive aerial tissues (i.e., JERF, bHLH, WRKY), as previously reported for roots. Results confirmed that root colonization by this endophytic bacterium does not only trigger defense responses in this organ but also mounts a wide array of systemic defense responses in distant tissues (stems, leaves). This sheds light on how olive plants respond to the “non-hostile” colonization by a bacterial endophyte and how induced defense response can contribute to the biocontrol activity of strain PICF7. PMID:25250017

  13. Widespread sulfenic acid formation in tissues in response to hydrogen peroxide

    PubMed Central

    Saurin, Adrian T.; Neubert, Hendrik; Brennan, Jonathan P.; Eaton, Philip

    2004-01-01

    A principal product of the reaction between a protein cysteinyl thiol and hydrogen peroxide is a protein sulfenic acid. Because protein sulfenic acid formation is reversible, it provides a mechanism whereby changes in cellular hydrogen peroxide concentration may directly control protein function. We have developed methods for the detection and purification of proteins oxidized in this way. The methodology is based on the arsenite-specific reduction of protein sulfenic acid under denaturing conditions and their subsequent labeling with biotin–maleimide. Arsenite-dependent signal generation was fully blocked by pretreatment with dimedone, consistent with its reactivity with sulfenic acids to form a covalent adduct that is nonreducible by thiols. The biotin tag facilitates the detection of protein sulfenic acids on Western blots probed with streptavidin–horseradish peroxidase and also their purification by streptavidin–agarose. We have characterized protein sulfenic acid formation in isolated hearts subjected to hydrogen peroxide treatment. We have also purified and identified a number of the proteins that are oxidized in this way by using a proteomic approach. Using Western immunoblotting we demonstrated that a highly significant proportion of some individual proteins (68% of total in one case) form the sulfenic derivative. We conclude that protein sulfenic acids are widespread physiologically relevant posttranslational oxidative modifications that can be detected at basal levels in healthy tissue, and are elevated in response to hydrogen peroxide. These approaches may find widespread utility in the study of oxidative stress, particularly because hydrogen peroxide is used extensively in models of disease or redox signaling. PMID:15604151

  14. Prebiotics modulate immune responses in the gut-associated lymphoid tissue of chickens.

    PubMed

    Janardhana, Vijaya; Broadway, Mary M; Bruce, Matthew P; Lowenthal, John W; Geier, Mark S; Hughes, Robert J; Bean, Andrew G D

    2009-07-01

    The recent European Union ban on the prophylactic use of in-feed antibiotics has escalated the search for alternatives for use within the poultry industry. When evaluating the efficacy of potential antibiotic alternatives on bird health and productivity, it is important to analyze the competence of the immune cells in the gut-associated lymphoid tissue (GALT), because it is routinely involved in the surveillance of colonizing microbes as well as in interacting with the ingested feed antigens. Therefore, we studied the effect of the prebiotics mannan-oligosaccharide (MOS) and fructo-oligosaccharide (FOS) on the phenotypic and functional competence of immune cells in cecal tonsil (CT), which is a major GALT. Day-old Cobb 500 male broilers were randomized to 4 groups. Control chickens were fed the basal diet only. Chickens in experimental groups received 0.05 g/kg zinc bacitracin or 5 g/kg of either FOS or MOS in addition to basal diet. At the end of 25 d, our comparison of the experimental groups with controls revealed that the addition of prebiotics to diet resulted in a significant reduction in the proportion of B cells and in mitogen responsiveness of lymphocytes in CT. Furthermore, FOS treatment significantly enhanced the IgM and IgG antibody titers in plasma. These findings emphasize the need for the analyses of the gut immune function following treatment with novel feed additives. The knowledge obtained from such analyses may aid in understanding the mechanisms underlying the immune competence of the birds, which needs consideration when selecting and optimizing new feed additives instead of antibiotics for poultry production. PMID:19474157

  15. Response functions for computing absorbed dose to skeletal tissues from photon irradiation—an update

    NASA Astrophysics Data System (ADS)

    Johnson, Perry B.; Bahadori, Amir A.; Eckerman, Keith F.; Lee, Choonsik; Bolch, Wesley E.

    2011-04-01

    A comprehensive set of photon fluence-to-dose response functions (DRFs) is presented for two radiosensitive skeletal tissues—active and total shallow marrow—within 15 and 32 bone sites, respectively, of the ICRP reference adult male. The functions were developed using fractional skeletal masses and associated electron-absorbed fractions as reported for the UF hybrid adult male phantom, which in turn is based upon micro-CT images of trabecular spongiosa taken from a 40 year male cadaver. The new DRFs expand upon both the original set of seven functions produced in 1985, and a 2007 update calculated under the assumption of secondary electron escape from spongiosa. In this study, it is assumed that photon irradiation of the skeleton will yield charged particle equilibrium across all spongiosa regions at energies exceeding 200 keV. Kerma coefficients for active marrow, inactive marrow, trabecular bone and spongiosa at higher energies are calculated using the DRF algorithm setting the electron-absorbed fraction for self-irradiation to unity. By comparing kerma coefficients and DRF functions, dose enhancement factors and mass energy-absorption coefficient (MEAC) ratios for active marrow to spongiosa were derived. These MEAC ratios compared well with those provided by the NIST Physical Reference Data Library (mean difference of 0.8%), and the dose enhancement factors for active marrow compared favorably with values calculated in the well-known study published by King and Spiers (1985 Br. J. Radiol. 58 345-56) (mean absolute difference of 1.9 percentage points). Additionally, dose enhancement factors for active marrow were shown to correlate well with the shallow marrow volume fraction (R2 = 0.91). Dose enhancement factors for the total shallow marrow were also calculated for 32 bone sites representing the first such derivation for this target tissue.

  16. Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues

    PubMed Central

    Laing, Suzette; Wang, Guohui; Briazova, Tamara; Zhang, Chunbin; Wang, Aixia; Zheng, Ze; Gow, Alexander; Chen, Alex F.; Rajagopalan, Sanjay; Chen, Lung Chi; Sun, Qinghua

    2010-01-01

    Recent studies have suggested a link between inhaled particulate matter (PM) exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases. However, a precise understanding of the biological mechanism underlying PM-associated toxicity and pathogenesis remains elusive. Here, we investigated the impact of PM exposure in intracellular stress signaling pathways with animal models and cultured cells. Inhalation exposure of the mice to environmentally relevant fine particulate matter (aerodynamic diameter < 2.5 μm, PM2.5) induces endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) in the lung and liver tissues as well as in the mouse macrophage cell line RAW264.7. Ambient PM2.5 exposure activates double-strand RNA-activated protein kinase-like ER kinase (PERK), leading to phosphorylation of translation initiation factor eIF2α and induction of C/EBP homologous transcription factor CHOP/GADD153. Activation of PERK-mediated UPR pathway relies on the production of reactive oxygen species (ROS) and is critical for PM2.5-induced apoptosis. Furthermore, PM2.5 exposure can activate ER stress sensor IRE1α, but it decreases the activity of IRE1α in splicing the mRNA encoding the UPR trans-activator X-box binding protein 1 (XBP1). Together, our study suggests that PM2.5 exposure differentially activates the UPR branches, leading to ER stress-induced apoptosis through the PERK-eIF2α-CHOP UPR branch. This work provides novel insights into the cellular and molecular basis by which ambient PM2.5 exposure elicits its cytotoxic effects that may be related to air pollution-associated pathogenesis. PMID:20554909

  17. Role of elasticity on the Rheological Response of the Uterus Tissue

    NASA Astrophysics Data System (ADS)

    Ashrafi Khorasani, Nariman; Piroozram, Parastoo

    2015-11-01

    N. Khorasani and P. piroozram Department of Mechanical Engineering, Payame Noor University, 19395-3697, Tehran, Iran, The effect of uterus tissue viscoelasticity on its internal pressure is explored. The tissue of the uterus is presented by a linear viscoelastic model with two major time constants. A proper user defined function is developed and incorporated in the simulation software, to represent the model. The geometry of the uterus is separately modeled. It is found that viscoelasticity of the tissue which can be controlled and altered by change the concentration can directly affect its internal pressure. It is also observed that the pressure decreases as the moisture of the tissue is increased. The study is repeated for several practical conditions and parameters pertaining to the viscoelasticity of the tissue are evaluated.

  18. Emission of Hydrogen Sulfide by Leaf Tissue in Response to l-Cysteine 1

    PubMed Central

    Sekiya, Jiro; Schmidt, Ahlert; Wilson, Lloyd G.; Filner, Philip

    1982-01-01

    Leaf discs and detached leaves exposed to l-cysteine emitted a volatile sulfur compound which was proven by gas chromatography to be H2S. This phenomenon was demonstrated in all nine species tested (Cucumis sativus, Cucurbita pepo, Nicotiana tabacum, Coleus blumei, Beta vulgaris, Phaseolus vulgaris, Medicago sativa, Hordeum vulgare, and Gossypium hirsutum). The emission of volatile sulfur by cucumber leaves occurred in the dark at a similar rate to that in the light. The emission of leaf discs reached the maximal rate, more than 40 picomoles per minute per square centimeter, 2 to 4 hours after starting exposure to l-cysteine; then it decreased. In the case of detached leaves, the maximum occurred 5 to 10 h after starting exposure. The average emission rate of H2S during the first 4 hours from leaf discs of cucurbits in response to 10 millimolar l-cysteine, was usually more than 40 picomoles per minute per square centimeter, i.e. 0.24 micromoles per hour per square decimeter. Leaf discs exposed to 1 millimolar l-cysteine emitted only 2% as much as did the discs exposed to 10 millimolar l-cysteine. The emission from leaf discs and from detached leaves lasted for at least 5 and 15 hours, respectively. However, several hours after the maximal emission, injury of the leaves, manifested as chlorosis, was evident. H2S emission was a specific consequence of exposure to l-cysteine; neither d-cysteine nor l-cystine elicited H2S emission. Aminooxyacetic acid, an inhibitor of pyridoxal phosphate dependent enzymes, inhibited the emission. In a cell free system from cucumber leaves, H2S formation and its release occurred in response to l-cysteine. Feeding experiments with [35S]l-cysteine showed that most of the sulfur in H2S was derived from sulfur in the l-cysteine supplied and that the H2S emitted for 9 hours accounted for 7 to 10% of l-cysteine taken up. 35S-labeled SO32− and SO42− were found in the tissue extract in addition to internal soluble S2−. These findings

  19. Mechanistic and quantitative studies of bystander response in 3D tissues for low-dose radiation risk estimations

    SciTech Connect

    Amundson, Sally A.

    2013-06-12

    We have used the MatTek 3-dimensional human skin model to study the gene expression response of a 3D model to low and high dose low LET radiation, and to study the radiation bystander effect as a function of distance from the site of irradiation with either alpha particles or low LET protons. We have found response pathways that appear to be specific for low dose exposures, that could not have been predicted from high dose studies. We also report the time and distance dependent expression of a large number of genes in bystander tissue. the bystander response in 3D tissues showed many similarities to that described previously in 2D cultured cells, but also showed some differences.

  20. Cigarette smoke induces molecular responses in respiratory tissues of ApoE(-/-) mice that are progressively deactivated upon cessation.

    PubMed

    Boué, Stéphanie; De León, Héctor; Schlage, Walter K; Peck, Michael J; Weiler, Horst; Berges, An; Vuillaume, Grégory; Martin, Florian; Friedrichs, Baerbel; Lebrun, Stefan; Meurrens, Kris; Schracke, Nadine; Moehring, Michaela; Steffen, Yvonne; Schueller, Jutta; Vanscheeuwijck, Patrick; Peitsch, Manuel C; Hoeng, Julia

    2013-12-01

    Cigarette smoking is the primary etiology of chronic obstructive pulmonary disease (COPD) and a risk factor for both lung and cardiovascular (CV) diseases, which are rarely investigated concomitantly. Although smoking cessation shows clear CV risk benefit, lung-related disease risk remains higher in former smokers than in never smokers. We sought to determine the differential molecular responses of murine respiratory tissues to better understand the toxicity pathways involved in smoking-related disease risk and those related to the benefits of smoking cessation. ApoE(-/-) mice were exposed to mainstream cigarette smoke (CS) or a smoking cessation-mimicking protocol for up to 6 months and transcriptomics analysis of nasal epithelium and lung parenchyma performed. We supported our gene expression profiling approach with standard lung histopathology and bronchoalveolar lavage fluid (BALF) analysis. Many BALF analytes involved in functions ranging from inflammation to cell proliferation and tissue remodeling were found elevated in BALF. Gene expression levels of these molecules were also increased in lung tissue, suggesting that the inflammatory response was the result of local tissue activation and the contribution of recruited inflammatory cells. Gene set enrichment analysis (GSEA) of expression data from murine lungs and nasal epithelium showed distinct activation patterns of inflammation, complement, and xenobiotic metabolism pathways during CS exposure that were deactivated upon smoking cessation. Pathways involved in cell proliferation and tissue remodeling were activated by CS and progressively deactivated upon smoke exposure cessation. Differential CS-mediated responses of pulmonary and nasal tissues reflect common mechanisms but also the varying degrees of epithelial functional specialization and exposure along the respiratory tract. PMID:24096154

  1. Compromised responses to dietary methionine restriction in adipose tissue but not liver of ob/ob mice

    PubMed Central

    Stone, Kirsten P.; Wanders, Desiree; Calderon, Lucie F.; Spurgin, Stephen B.; Scherer, Philipp E.; Gettys, Thomas W.

    2015-01-01

    Objective Dietary methionine restriction (MR) reduces adiposity, hepatic lipids, and increases overall insulin sensitivity in part by reducing lipogenic gene expression in liver, inducing browning of white adipose tissue (WAT), and enhancing the lipogenic and oxidative capacity of the remodeled WAT. Methods Ob/ob mice have compromised β-adrenergic receptor expression in adipose tissue, and were used to test whether MR could ameliorate obesity, insulin resistance, and disordered lipid metabolism. Results In contrast to responses in wild type-mice, MR failed to slow accumulation of adiposity, increase lipogenic and thermogenic gene expression in adipose tissue, reduce serum insulin, or increase serum adiponectin in ob/ob mice. However, MR produced comparable reductions in hepatic lipids and lipogenic gene expression in both genotypes. In addition, MR was fully effective in increasing insulin sensitivity in adiponectin−/− mice. Conclusions These findings show that diet-induced changes in hepatic lipid metabolism are independent of weight loss and remodeling of WAT, and are not required for insulin sensitization. In contrast, the failure of ob/ob mice to mount a normal thermogenic response to MR suggests that the compromised responsiveness of adipose tissue to SNS input is an important component of the inability of the diet to correct their obesity and insulin resistance. PMID:26237535

  2. Cloning changes the response to obesity of innate immune factors in blood, liver, and adipose tissues in domestic pigs.

    PubMed

    Rødgaard, Tina; Skovgaard, Kerstin; Stagsted, Jan; Heegaard, Peter M H

    2013-06-01

    The objective of this study was to evaluate the usefulness of cloned pigs as porcine obesity models reflecting obesity-associated changes in innate immune factor gene expression profiles. Liver and adipose tissue expression of 43 innate immune genes as well as serum concentrations of six immune factors were analyzed in lean and diet-induced obese cloned domestic pigs and compared to normal domestic pigs (obese and lean). The number of genes affected by obesity was lower in cloned animals than in control animals. All genes affected by obesity in adipose tissues of clones were downregulated; both upregulation and downregulation were observed in the controls. Cloning resulted in a less differentiated adipose tissue expression pattern. Finally, the serum concentrations of two acute-phase proteins (APPs), haptoglobin (HP) and orosomucoid (ORM), were increased in obese clones as compared to obese controls as well as lean clones and controls. Generally, the variation in phenotype between individual pigs was not reduced in cloned siblings as compared to normal siblings. Therefore, we conclude that cloning limits both the number of genes responding to obesity as well as the degree of tissue-differentiated gene expression, concomitantly with an increase in APP serum concentrations only seen in cloned, obese pigs. This may suggest that the APP response seen in obese, cloned pigs is a consequence of the characteristic skewed gene response to obesity in cloned pigs, as described in this work. This should be taken into consideration when using cloned animals as models for innate responses to obesity.

  3. Reduced tonicity stimulates an inflammatory response in nucleus pulposus tissue that can be limited by a COX-2-specific inhibitor.

    PubMed

    van Dijk, Bart; Potier, Esther; van DIjk, Maarten; Langelaan, Marloes; Papen-Botterhuis, Nicole; Ito, Keita

    2015-11-01

    In intervertebral disc herniation with nucleus pulposus (NP) extrusion, the elicited inflammatory response is considered a key pain mechanism. However, inflammatory cytokines are reported in extruded herniated tissue, even before monocyte infiltration, suggesting that the tissue itself initiates the inflammation. Since herniated tissue swells, we investigated whether this simple mechanobiological stimulus alone could provoke an inflammatory response that could cause pain. Furthermore, we investigated whether sustained-release cyclooxygenase-2 (COX2) inhibitor would be beneficial in such conditions. Healthy bovine NP explants were allowed to swell freely or confined. The swelling explants were treated with Celecoxib, applied either as a bolus or in sustained-release. Swelling explants produced elevated levels of interleukin-6 (IL-6) and prostaglandin E2 (PGE2 ) for 28 days, while confined explants did not. Both a high concentration bolus and 10 times lower concentration in sustained release completely inhibited PGE2 production, but did not affect IL-6 production. Swelling of NP tissue, without the inflammatory system response, can trigger cytokine production and Celecoxib, even in bolus form, may be useful for pain control in extruded disc herniation. PMID:25991050

  4. Epigenomic Mechanisms of Early Adversity and HPA Dysfunction: Considerations for PTSD Research.

    PubMed

    McGowan, Patrick O

    2013-01-01

    Childhood adversity can have life-long consequences for the response to stressful events later in life. Abuse or severe neglect are well-known risk factors for post-traumatic stress disorder (PTSD), at least in part via changes in neural systems mediating the endocrine response to stress. Determining the biological signatures of risk for stress-related mental disorders such as PTSD is important for identifying homogenous subgroups and improving treatment options. This review will focus on epigenetic regulation in early life by adversity and parental care - prime mediators of offspring neurodevelopment - in order to address several questions: (1) what have studies of humans and analogous animal models taught us about molecular mechanisms underlying changes in stress-sensitive physiological systems in response to early life trauma? (2) What are the considerations for studies relating early adversity and PTSD risk, going forward? I will summarize studies in animals and humans that address the epigenetic response to early adversity in the brain and in peripheral tissues. In so doing, I will describe work on the glucocorticoid receptor and other well-characterized genes within the stress response pathway and then turn to genomic studies to illustrate the use of increasingly powerful high-throughput approaches to the study of epigenomic mechanisms. PMID:24133457

  5. Early sorafenib-related adverse events predict therapy response of TACE plus sorafenib: A multicenter clinical study of 606 HCC patients.

    PubMed

    Zhao, Yan; Li, Hailiang; Bai, Wei; Liu, Jueshi; Lv, Weifu; Sahu, Sonia; Guan, Sheng; Qin, Xiao; Wang, Wenhui; Ren, Weixin; Mu, Wei; Guo, Weidong; Gu, Shanzhi; Ma, Yilong; Yin, Zhanxin; Guo, Wengang; Wang, Wenjun; Wang, Yongji; Duran, Rafael; Fan, Daiming; Zhang, Zhuoli; Han, Guohong

    2016-08-15

    The purpose of our study was to test the hypothesis that sorafenib-related dermatologic adverse events (AEs) as an early biomarker can predict the long-term outcomes following the combination therapy of transarterial chemoembolization (TACE) plus sorafenib (TACE-S). The intermediate-stage hepatocellular carcinoma patients who received either TACE-S or TACE-alone treatment were consecutively included into analysis. In the TACE-S group, patients with ≥ grade 2 dermatologic AEs within the first month of sorafenib initiation were defined as responders; whereas those with < grade 2 were defined as nonresponders. In the TACE-S group, the median overall survival (OS) of the responders was significantly longer than that of nonresponders (28.9 months vs. 16.8 months, respectively; p = 0.004). Multivariate analysis demonstrated that nonresponders were significantly associated with an increased risk of death compared with responders (HR = 1.9; 95% confidence Interval-CI: 1.3-2.7; p = 0.001). The survival analysis showed that the median OS was 27.9 months (95% CI: 25.0-30.8) among responders treated with TACE-S vs.18.3 months (95% CI: 14.5-22.1) among those who received TACE-alone (p = 0.046). The median time to progression was 13.1 months (95% CI: 4.4-21.8) in the TACE-S group, a duration that was significantly longer than that in the TACE-alone group [5 months (95% CI: 6.4-13.3), p = 0.014]. This study demonstrated that sorafenib-related dermatologic AEs are clinical biomarkers to identify responders from all of the patients for TACE-S therapy. Sorafenib-related dermatologic AEs, clinical biomarkers, can predict the efficacy of TACE-S in future randomized controlled trials.

  6. Adverse reactions to cosmetics.

    PubMed

    Dogra, A; Minocha, Y C; Kaur, S

    2003-01-01

    Adverse reaction to cosmetics constitute a small but significant number of cases of contact dermatitis with varied appearances. These can present as contact allergic dermatitis, photodermatitis, contact irritant dermatitis, contact urticaria, hypopigmentation, hyperpigmentation or depigmentation, hair and nail breakage. Fifty patients were included for the study to assess the role of commonly used cosmetics in causing adverse reactions. It was found that hair dyes, lipsticks and surprisingly shaving creams caused more reaction as compared to other cosmetics. Overall incidence of contact allergic dermatitis seen was 3.3% with patients own cosmetics. Patch testing was also done with the basic ingredients and showed positive results in few cases where casual link could be established. It is recommended that labeling of the cosmetics should be done to help the dermatologists and the patients to identify the causative allergen in cosmetic preparation.

  7. Systems Biology of Tissue-Specific Response to Anaplasma phagocytophilum Reveals Differentiated Apoptosis in the Tick Vector Ixodes scapularis

    PubMed Central

    Ayllón, Nieves; Villar, Margarita; Galindo, Ruth C.; Kocan, Katherine M.; Šíma, Radek; López, Juan A.; Vázquez, Jesús; Alberdi, Pilar; Cabezas-Cruz, Alejandro; Kopáček, Petr; de la Fuente, José

    2015-01-01

    Anaplasma phagocytophilum is an emerging pathogen that causes human granulocytic anaplasmosis. Infection with this zoonotic pathogen affects cell function in both vertebrate host and the tick vector, Ixodes scapularis. Global tissue-specific response and apoptosis signaling pathways were characterized in I. scapularis nymphs and adult female midguts and salivary glands infected with A. phagocytophilum using a systems biology approach combining transcriptomics and proteomics. Apoptosis was selected for pathway-focused analysis due to its role in bacterial infection of tick cells. The results showed tissue-specific differences in tick response to infection and revealed differentiated regulation of apoptosis pathways. The impact of bacterial infection was more pronounced in tick nymphs and midguts than in salivary glands, probably reflecting bacterial developmental cycle. All apoptosis pathways described in other organisms were identified in I. scapularis, except for the absence of the Perforin ortholog. Functional characterization using RNA interference showed that Porin knockdown significantly increases tick colonization by A. phagocytophilum. Infection with A. phagocytophilum produced complex tissue-specific alterations in transcript and protein levels. In tick nymphs, the results suggested a possible effect of bacterial infection on the inhibition of tick immune response. In tick midguts, the results suggested that A. phagocytophilum infection inhibited cell apoptosis to facilitate and establish infection through up-regulation of the JAK/STAT pathway. Bacterial infection inhibited the intrinsic apoptosis pathway in tick salivary glands by down-regulating Porin expression that resulted in the inhibition of Cytochrome c release as the anti-apoptotic mechanism to facilitate bacterial infection. However, tick salivary glands may promote apoptosis to limit bacterial infection through induction of the extrinsic apoptosis pathway. These dynamic changes in response to A

  8. Systems biology of tissue-specific response to Anaplasma phagocytophilum reveals differentiated apoptosis in the tick vector Ixodes scapularis.

    PubMed

    Ayllón, Nieves; Villar, Margarita; Galindo, Ruth C; Kocan, Katherine M; Šíma, Radek; López, Juan A; Vázquez, Jesús; Alberdi, Pilar; Cabezas-Cruz, Alejandro; Kopáček, Petr; de la Fuente, José

    2015-03-01

    Anaplasma phagocytophilum is an emerging pathogen that causes human granulocytic anaplasmosis. Infection with this zoonotic pathogen affects cell function in both vertebrate host and the tick vector, Ixodes scapularis. Global tissue-specific response and apoptosis signaling pathways were characterized in I. scapularis nymphs and adult female midguts and salivary glands infected with A. phagocytophilum using a systems biology approach combining transcriptomics and proteomics. Apoptosis was selected for pathway-focused analysis due to its role in bacterial infection of tick cells. The results showed tissue-specific differences in tick response to infection and revealed differentiated regulation of apoptosis pathways. The impact of bacterial infection was more pronounced in tick nymphs and midguts than in salivary glands, probably reflecting bacterial developmental cycle. All apoptosis pathways described in other organisms were identified in I. scapularis, except for the absence of the Perforin ortholog. Functional characterization using RNA interference showed that Porin knockdown significantly increases tick colonization by A. phagocytophilum. Infection with A. phagocytophilum produced complex tissue-specific alterations in transcript and protein levels. In tick nymphs, the results suggested a possible effect of bacterial infection on the inhibition of tick immune response. In tick midguts, the results suggested that A. phagocytophilum infection inhibited cell apoptosis to facilitate and establish infection through up-regulation of the JAK/STAT pathway. Bacterial infection inhibited the intrinsic apoptosis pathway in tick salivary glands by down-regulating Porin expression that resulted in the inhibition of Cytochrome c release as the anti-apoptotic mechanism to facilitate bacterial infection. However, tick salivary glands may promote apoptosis to limit bacterial infection through induction of the extrinsic apoptosis pathway. These dynamic changes in response to A

  9. Systems biology of tissue-specific response to Anaplasma phagocytophilum reveals differentiated apoptosis in the tick vector Ixodes scapularis.

    PubMed

    Ayllón, Nieves; Villar, Margarita; Galindo, Ruth C; Kocan, Katherine M; Šíma, Radek; López, Juan A; Vázquez, Jesús; Alberdi, Pilar; Cabezas-Cruz, Alejandro; Kopáček, Petr; de la Fuente, José

    2015-03-01

    Anaplasma phagocytophilum is an emerging pathogen that causes human granulocytic anaplasmosis. Infection with this zoonotic pathogen affects cell function in both vertebrate host and the tick vector, Ixodes scapularis. Global tissue-specific response and apoptosis signaling pathways were characterized in I. scapularis nymphs and adult female midguts and salivary glands infected with A. phagocytophilum using a systems biology approach combining transcriptomics and proteomics. Apoptosis was selected for pathway-focused analysis due to its role in bacterial infection of tick cells. The results showed tissue-specific differences in tick response to infection and revealed differentiated regulation of apoptosis pathways. The impact of bacterial infection was more pronounced in tick nymphs and midguts than in salivary glands, probably reflecting bacterial developmental cycle. All apoptosis pathways described in other organisms were identified in I. scapularis, except for the absence of the Perforin ortholog. Functional characterization using RNA interference showed that Porin knockdown significantly increases tick colonization by A. phagocytophilum. Infection with A. phagocytophilum produced complex tissue-specific alterations in transcript and protein levels. In tick nymphs, the results suggested a possible effect of bacterial infection on the inhibition of tick immune response. In tick midguts, the results suggested that A. phagocytophilum infection inhibited cell apoptosis to facilitate and establish infection through up-regulation of the JAK/STAT pathway. Bacterial infection inhibited the intrinsic apoptosis pathway in tick salivary glands by down-regulating Porin expression that resulted in the inhibition of Cytochrome c release as the anti-apoptotic mechanism to facilitate bacterial infection. However, tick salivary glands may promote apoptosis to limit bacterial infection through induction of the extrinsic apoptosis pathway. These dynamic changes in response to A

  10. Ah receptor mediated suppression of the antibody response in mice is primarily dependent on the Ah phenotype of lymphoid tissue.

    PubMed

    Silkworth, J B; Antrim, L A; Sack, G

    1986-12-01

    Halogenated aromatic hydrocarbons act through the aromatic hydrocarbon (Ah) receptor in mice to produce a series of toxic effects of the immune system. The receptor protein is a product of the Ah gene locus. Ah responsive (Ahb/Ahb) mice express a high affinity receptor in both lymphoid and nonlymphoid tissues whereas nonresponsive Ahd/Ahd mice express a poor affinity receptor. To determine the role of the Ah receptor of lymphoid tissue relative to that of nonlymphoid tissue in the induction of immune impairment, bone marrow was used to reconstitute lethally irradiated mice of the same or opposite Ah phenotype. All mice were given 3,3',4,4'-tetrachlorobiphenyl (35 and 350 mumol/kg) ip 2 days before immunization with sheep erythrocytes (SRBC). The immune response to this T dependent antigen and organ weights were determined 5 or 7 days later in normal or chimeric mice, respectively. Monoclonal Lyt 1.1 and Lyt 1.2 antibodies were used to establish the origin of the cells which repopulated the chimeric thymuses. The immune responses of both BALB/cBy (Ahb/Ahb) and the BALB/cBy X DBA/2 hybrid, CByD2F1 (Ahb/Ahd), were significantly suppressed but DBA/2 mice were unaffected. The immune responses of chimeric BALB/cBy----BALB/cBy and BALB/cBy----DBA/2 (donor----recipient) mice were also significantly suppressed and thymic atrophy was observed in both cases. The serum anti-SRBC antibody titers of DBA/2----BALB/cBy chimeras were also significantly decreased although not to the same extent as in BALB/cBy----DBA/2 mice. Chimeric DBA/2----DBA/2 mice were not affected. These results indicate that the sensitivity to Ah receptor mediated suppression of the antibody response is primarily determined by the Ah phenotype of the lymphoid tissue.

  11. Changes in connective tissue of M. semitendinosus as a response to different growth paths in steers.

    PubMed

    Harper, G S; Allingham, P G; Le Feuvre, R P

    1999-10-01

    The effect of growth path, as opposed to advancing age, on the biophysical and biochemical properties of muscle connective tissue was investigated. Nine-month old Brahman-cross steers were grown across either an uninterrupted path, or paths that incorporated weight-loss and then weight gain on two different diets: one group was realimented on pasture, whilst the other was realimented on a grain-based diet. Biophysical attributes of connective tissue toughness (Compression and Adhesion) in the semitendinosus muscle, were significantly reduced by treatment (P<0.05): weight loss with grain realimentation being the least tough in regard to the connective tissue component. Variance within the biophysical attributes was modelled statistically. Statistically significant models included terms for the post-slaughter connective tissue content as well as tissue contents of the enzymes lactate dehydrogenase and isocitrate dehydrogenase. The data suggest that biochemical measurements made up to 100 days prior to slaughter, may have value as indicators of final connective tissue toughness. PMID:22063087

  12. Carcinogenesis and related cell and tissue responses to asbestos: a review.

    PubMed

    Mossman, B T

    1994-08-01

    A review of the literature reveals that chrysotile asbestos has a mulitiplicity of effects on cells and tissues which can provide a framework for assessment of its role(s) in initiation, promotion, or as a co-carcinogen which acts in concert with chemical carcinogens found in cigarette smoke in the development of lung cancer. Several caveats important in the interpretation of these data include the general lack of dose-response protocols both for in vivo and for in vitro studies as well as the absence, in many studies, of minerals which are appropriate positive or negative controls based on epidemiological data in man. Other factors which may account for disparities in results between studies include the use of different preparations of chrysotile fibres with distinct chemical and physical compositions and different cell types and species. Whether chrysotile is an initiator of lung cancer or mesothelioma in human cells is unclear, as evidence of chromosomal aberrations in human bronchial epithelial cells are for the most part negative (Kodoma et al., 1993; see Mossman, B., this Workshop): only one study employing pleural mesothelial cells from four individuals, two of whom exhibited chromosomal abnormalities before exposure to asbestos, has documented chromosomal changes with chrysotile, crocidolite and amosite asbestos, and this study did not use a non-pathogenic dust as a negative control. Studies using human lymphocytes show chromosomal changes after exposure to latex beads or chrysotile at equal weight concentrations (Korkina et al., 1992; see Mossman, B., this Workshop). Lastly, although both chrysotile and crocidolite asbestos demonstrated dose-dependent increase in aberrant anaphases in an SV40 T antigen-transformed human mesothelial cell line (Pelin et al., 1992, see Mossman, B., this Workshop), erionite, a potent mesotheliomagenic fibre in rodents and humans, caused no aberrations in this bioassay. Several studies have been performed to determine the

  13. Real-time monitoring of thermal and mechanical tissue response to modulated phased-array HIFU beams in vivo

    NASA Astrophysics Data System (ADS)

    Liu, Dalong; Ballard, John R.; Haritonova, Alyona; Choi, Jeungwan; Bischof, John; Ebbini, Emad S.

    2012-10-01

    An integrated system employing real-time ultrasound thermography and strain imaging in monitoring tissue response to phased-array heating patterns has been developed. The imaging system is implemented on a commercially available scanner (SonixRP) at frame rates > 500 fps with limited frame sizes covering the vicinity of the HIFU focal spot. These frame rates are sufficient to capture tissue motion and deformation even in the vicinity of large arteries. With the high temporal and spatial resolution of our strain imaging system, we are able to capture and separate tissue strains due to natural motion (breathing and pulsation) from HIFU induced strains (thermal and mechanical). We have collected in vivo strain imaging during sub-therapeutic and therapeutic HIFU exposure in swine and rat model. A 3.5-MHz phased array was used to generate sinusoidally-modulated pHIFU beams at different intensity levels and durations near blood vessels of different sizes (e.g. femoral in the swine and rat models). The results show that our approach is capable of characterizing the thermal and mechanical tissue response to sub-therapeutic pHIFU beam. For therapeutic pHIFU beams, the approach is still capable of localizing the therapeutic beam, but the results at the focal spot are complicated by bubble generation.

  14. Amino Acid coated uhmw-pe implants modify macrophage migration in the tissue-implant response - biomed 2011.

    PubMed

    Butler, Kenneth R; Benghuzzi, Hamed; Tucci, Michelle; Puckett, Aaron

    2011-01-01

    Polyethylene materials used in orthopedic applications are biocompatible and non-immunogenic with host tissues. Recent studies in our laboratory have demonstrated the need for further study of these devices in vivo to further elucidate methods to modulate the tissue-implant response. The purpose of this investigation was to determine macrophage behavior after implantation of ultra high molecular weight polyethylene (UHMW-PE) rinsed with saline (control) and coated with poly-L-lysine (PLL), arginine-glycine-aspartic acid (RGD), and arginine-glycine-glutamic acid (RGE) into 16 adult male rats intraperitoneally (I/P). Implants and surrounding tissue were harvested at 90 days post-implantation. The animals were euthanized; and the UHMW-PE implants and the fibrous tissue capsules surrounding them were harvested. Microscopic examination of routinely stained sections (5 microns, Hematoxylin & Eosin) of the fibrous tissue capsules revealed macrophage counts were highest in the saline coated group (9.75±0.86 cells/high power field). Amino acid coated implants resulted in decreased mean macrophage counts per high power field for RGD (3.51±0.45), RGE (2.86±0.06), and PLL (4.2±0.55) compared to saline and the differences were statistically significant (ANOVA, p < 0.05). These findings indicate macrophage behavior at the tissue-implant interface and in surrounding fibrous tissue can be reduced using various amino acid combination coatings. In addition, these results provide evidence that the intensity of the chronic inflammatory reaction to UHMW-PE can be reduced and controlled to some extent. PMID:21525627

  15. Matricryptic sites control tissue injury responses in the cardiovascular system: relationships to pattern recognition receptor regulated events.

    PubMed

    Davis, George E

    2010-03-01

    This review addresses new concepts related to the importance of how cells within the cardiovascular system respond to matricryptic sites generated from the extracellular matrix (ECM) following tissue injury. A model is presented whereby matricryptic sites exposed from the ECM result in activation of multiple cell surface receptors including integrins, scavenger receptors, and toll-like receptors which together are hypothesized to coactivate downstream signaling pathways which alter cell behaviors following tissue injury. Of great interest are the relationships between matricryptic fragments of ECM called matricryptins and other stimuli that activate cells during injury states such as released components from cells (DNA, RNA, cytoskeletal components such as actin) or products from infectious agents in innate immunity responses. These types of cell activating molecules, which are composed of repeating molecular elements, are known to interact with pattern recognition receptors that (i) are expressed from cell surfaces, (ii) are released from cells following tissue injury, or (iii) circulate as components of plasma. Thus, cell recognition of matricryptic sites from the ECM appears to be an important component of a broad cell and tissue sensory system to detect and respond to environmental cues generated following varied types of tissue injury.

  16. Characterization of a soft-tissue infection model in the horse and its response to intravenous cephapirin administration.

    PubMed

    Beadle, R E; Short, C R; Corstvet, R E; Pawlusiow, J; Nobles, D D; McClure, J R; Guthrie, A J; Clarke, C R

    1989-03-01

    A soft-tissue infection model was created in eight horses by infecting subcutaneous tissue chambers with Streptococcus zooepidemicus organisms. Responses of the horses to the infections were determined by monitoring changes in the complete blood count and body temperature and by following changes in the cytology and protein content of the tissue chambers. Systemic reactions to the infections included a mild neutrophilia, mild pyrexia and mild anemia. There was a marked influx of neutrophils and protein into the chambers after they were seeded with bacteria and chamber neutrophil viability decreased markedly at the height of the infection. Subsequent to establishing tissue chamber infections four of the horses were treated with intravenous cephapirin t.d. at a dosage of 20 mg/kg for 5 days. Quantitative culturing of tissue chamber fluid was performed to analyze the efficacy of cephapirin therapy. Cephapirin therapy was accompanied by decreases in the systemic neutrophilia, pyrexia, anemia, and chamber bacterial counts. However, cephapirin did not eliminate the infection in any of the chambers. Chamber neutrophil viability was markedly increased during the cephapirin therapy period.

  17. Normal Liver Tissue Density Dose Response in Patients Treated With Stereotactic Body Radiation Therapy for Liver Metastases

    SciTech Connect

    Howells, Christopher C.; Stinauer, Michelle A.; Diot, Quentin; Westerly, David C.; Schefter, Tracey E.; Kavanagh, Brian D.; Miften, Moyed

    2012-11-01

    Purpose: To evaluate the temporal dose response of normal liver tissue for patients with liver metastases treated with stereotactic body radiation therapy (SBRT). Methods and Materials: Ninety-nine noncontrast follow-up computed tomography (CT) scans of 34 patients who received SBRT between 2004 and 2011 were retrospectively analyzed at a median of 8 months post-SBRT (range, 0.7-36 months). SBRT-induced normal liver tissue density changes in follow-up CT scans were evaluated at 2, 6, 10, 15, and 27 months. The dose distributions from planning CTs were mapped to follow-up CTs to relate the mean Hounsfield unit change ({Delta}HU) to dose received over the range 0-55 Gy in 3-5 fractions. An absolute density change of 7 HU was considered a significant radiographic change in normal liver tissue. Results: Increasing radiation dose was linearly correlated with lower post-SBRT liver tissue density (slope, -0.65 {Delta}HU/5 Gy). The threshold for significant change (-7 {Delta}HU) was observed in the range of 30-35 Gy. This effect did not vary significantly over the time intervals evaluated. Conclusions: SBRT induces a dose-dependent and relatively time-independent hypodense radiation reaction within normal liver tissue that is characterized by a decrease of >7 HU in liver density for doses >30-35 Gy.

  18. Genomic expression, chemotherapy response, and molecular targets in soft tissue sarcomas of the extremities: promising strategies for treatment selection.

    PubMed

    Aguiar, Samuel; da Cunha, Isabela Werneck; Lopes, Ademar

    2010-01-01

    Neoadjuvant or adjuvant therapy in soft tissue sarcomas is still controversial, especially in regards to the use of chemotherapy. The identification of predictive factors is crucial to avoid the use of chemotherapy in patients with tumors that carry genetic characteristics associated with resistance. Focusing on gene expression data, we performed a review of the actual state of knowledge in molecular predictive factors for chemotherapy response and new targets of therapy in extremity sarcomas.

  19. Tissue-specific patterning of host innate immune responses by Staphylococcus aureus α-toxin.

    PubMed

    Becker, Russell E N; Berube, Bryan J; Sampedro, Georgia R; DeDent, Andrea C; Bubeck Wardenburg, Juliane

    2014-01-01

    Immunomodulatory cytotoxins are prominent virulence factors produced by Staphylococcus aureus, a leading cause of bacterial sepsis, skin infection, and pneumonia. S. aureus α-toxin is a pore-forming toxin that utilizes a widely expressed receptor, ADAM10, to injure the host epithelium, endothelium, and immune cells. As each host tissue is characterized by a unique composition of resident cells and recruited immune cells, the outcome of α-toxin-mediated injury may depend on the infected tissue environment. Utilizing myeloid lineage-specific Adam10 knockout mice, we show that α-toxin exerts tissue-specific effects on innate immunity to staphylococcal infection. Loss of ADAM10 expression exacerbates skin infection, yet affords protection against lethal pneumonia. These diverse outcomes are not related to altered immune cell recruitment, but rather correlate with a defect in toxin-induced IL-1β production. Extension of these studies through analysis of ADAM10 double-knockout mice affecting both the myeloid lineage and either the skin or lung epithelium highlight the prominence of toxin-induced injury to the epithelium in governing the outcome of infection. Together, these studies provide evidence of tissue specificity of pore-forming cytotoxin action in the modulation of host immunity, and illustrate that the outcome of infection is a collective manifestation of all effects of the toxin within the tissue microenvironment.

  20. Tissue-specific Patterning of the Host Innate Immune Response by Staphylococcus aureus α-toxin

    PubMed Central

    Becker, Russell E. N.; Berube, Bryan J.; Sampedro, Georgia R.; DeDent, Andrea C.; Wardenburg, Juliane Bubeck

    2014-01-01

    Immunomodulatory cytotoxins are prominent virulence factors produced by Staphylococcus aureus, a leading cause of bacterial sepsis, skin infection, and pneumonia. S. aureus α-toxin is a pore-forming toxin that utilizes a widely-expressed receptor, ADAM10, to injure the host epithelium, endothelium, and immune cells. As each host tissue is characterized by a unique composition of resident cells and recruited immune cells, the outcome of α-toxin-mediated injury may depend on the infected tissue environment. Utilizing myeloid lineage-specific Adam10 knockout mice, we show that α-toxin exerts tissue-specific effects on innate immunity to staphylococcal infection. Loss of ADAM10 expression exacerbates skin infection, yet affords protection against lethal pneumonia. These diverse outcomes are not related to altered immune cell recruitment, but rather correlate with a defect in toxin-induced IL-1β production. Extension of these studies through analysis of ADAM10 double knockout mice affecting both the myeloid lineage and either the skin or lung epithelium highlight the prominence of toxin-induced injury to the epithelium in governing the outcome of infection. Together, these studies provide evidence of tissue specificity of pore-forming cytotoxin action in modulation of host immunity, and illustrate that the outcome of infection is a collective manifestation of all effects of the toxin within the tissue microenvironment. PMID:24820433

  1. The transcription factor GLI1 modulates the inflammatory response during pancreatic tissue remodeling.

    PubMed

    Mathew, Esha; Collins, Meredith A; Fernandez-Barrena, Maite G; Holtz, Alexander M; Yan, Wei; Hogan, James O; Tata, Zachary; Allen, Benjamin L; Fernandez-Zapico, Martin E; di Magliano, Marina Pasca

    2014-10-01

    Pancreatic cancer, one of the deadliest human malignancies, is almost uniformly associated with a mutant, constitutively active form of the oncogene Kras. Studies in genetically engineered mouse models have defined a requirement for oncogenic KRAS in both the formation of pancreatic intraepithelial neoplasias, the most common precursor lesions to pancreatic cancer, and in the maintenance and progression of these lesions. Previous work using an inducible model allowing tissue-specific and reversible expression of oncogenic Kras in the pancreas indicates that inactivation of this GTPase at the pancreatic intraepithelial neoplasia stage promotes pancreatic tissue repair. Here, we extend these findings to identify GLI1, a transcriptional effector of the Hedgehog pathway, as a central player in pancreatic tissue repair upon Kras inactivation. Deletion of a single allele of Gli1 results in improper stromal remodeling and perdurance of the inflammatory infiltrate characteristic of pancreatic tumorigenesis. Strikingly, this partial loss of Gli1 affects activated fibroblasts in the pancreas and the recruitment of immune cells that are vital for tissue recovery. Analysis of the mechanism using expression and chromatin immunoprecipitation assays identified a subset of cytokines, including IL-6, mIL-8, Mcp-1, and M-csf (Csf1), as direct GLI1 target genes potentially mediating this phenomenon. Finally, we demonstrate that canonical Hedgehog signaling, a known regulator of Gli1 activity, is required for pancreas recovery. Collectively, these data delineate a new pathway controlling tissue repair and highlight the importance of GLI1 in regulation of the pancreatic microenvironment during this cellular process.

  2. Adverse effects of cannabis.

    PubMed

    2011-01-01

    Cannabis, Cannabis sativa L., is used to produce a resin that contains high levels of cannabinoids, particularly delta9-tetrahydrocannabinol (THC), which are psychoactive substances. Although cannabis use is illegal in France and in many other countries, it is widely used for its relaxing or euphoric effects, especially by adolescents and young adults. What are the adverse effects of cannabis on health? During consumption? And in the long term? Does cannabis predispose users to the development of psychotic disorders? To answer these questions, we reviewed the available evidence using the standard Prescrire methodology. The long-term adverse effects of cannabis are difficult to evaluate. Since and associated substances, with or without the user's knowledge. Tobacco and alcohol consumption, and particular lifestyles and behaviours are often associated with cannabis use. Some traits predispose individuals to the use of psychoactive substances in general. The effects of cannabis are dosedependent.The most frequently report-ed adverse effects are mental slowness, impaired reaction times, and sometimes accentuation of anxiety. Serious psychological disorders have been reported with high levels of intoxication. The relationship between poor school performance and early, regular, and frequent cannabis use seems to be a vicious circle, in which each sustains the other. Many studies have focused on the long-term effects of cannabis on memory, but their results have been inconclusive. There do not * About fifteen longitudinal cohort studies that examined the influence of cannabis on depressive thoughts or suicidal ideation have yielded conflicting results and are inconclusive. Several longitudinal cohort studies have shown a statistical association between psychotic illness and self-reported cannabis use. However, the results are difficult to interpret due to methodological problems, particularly the unknown reliability of self-reported data. It has not been possible to

  3. Adverse effects of cannabis.

    PubMed

    2011-01-01

    Cannabis, Cannabis sativa L., is used to produce a resin that contains high levels of cannabinoids, particularly delta9-tetrahydrocannabinol (THC), which are psychoactive substances. Although cannabis use is illegal in France and in many other countries, it is widely used for its relaxing or euphoric effects, especially by adolescents and young adults. What are the adverse effects of cannabis on health? During consumption? And in the long term? Does cannabis predispose users to the development of psychotic disorders? To answer these questions, we reviewed the available evidence using the standard Prescrire methodology. The long-term adverse effects of cannabis are difficult to evaluate. Since and associated substances, with or without the user's knowledge. Tobacco and alcohol consumption, and particular lifestyles and behaviours are often associated with cannabis use. Some traits predispose individuals to the use of psychoactive substances in general. The effects of cannabis are dosedependent.The most frequently report-ed adverse effects are mental slowness, impaired reaction times, and sometimes accentuation of anxiety. Serious psychological disorders have been reported with high levels of intoxication. The relationship between poor school performance and early, regular, and frequent cannabis use seems to be a vicious circle, in which each sustains the other. Many studies have focused on the long-term effects of cannabis on memory, but their results have been inconclusive. There do not * About fifteen longitudinal cohort studies that examined the influence of cannabis on depressive thoughts or suicidal ideation have yielded conflicting results and are inconclusive. Several longitudinal cohort studies have shown a statistical association between psychotic illness and self-reported cannabis use. However, the results are difficult to interpret due to methodological problems, particularly the unknown reliability of self-reported data. It has not been possible to

  4. Arabidopsis thaliana NIP7;1 is involved in tissue arsenic distribution and tolerance in response to arsenate.

    PubMed

    Lindsay, Emma R; Maathuis, Frans J M

    2016-03-01

    The Arabidopsis aquaglyceroporin NIP7;1 is involved in uptake and tolerance to the trivalent arsenic species arsenite. Here, we show that NIP7;1 is also involved in the response to pentavalent arsenate. Loss of function of NIP7;1 improved tolerance to arsenate and reduced arsenic levels in both the phloem and xylem, resulting in altered arsenic distribution between tissues. There was no clear correlation between growth and shoot arsenic concentration. This is the first report detailing the involvement of a NIP transporter in response to arsenate. The data suggest that these proteins are relevant targets for breeding and engineering arsenic tolerance in crops.

  5. Arabidopsis thaliana NIP7;1 is involved in tissue arsenic distribution and tolerance in response to arsenate.

    PubMed

    Lindsay, Emma R; Maathuis, Frans J M

    2016-03-01

    The Arabidopsis aquaglyceroporin NIP7;1 is involved in uptake and tolerance to the trivalent arsenic species arsenite. Here, we show that NIP7;1 is also involved in the response to pentavalent arsenate. Loss of function of NIP7;1 improved tolerance to arsenate and reduced arsenic levels in both the phloem and xylem, resulting in altered arsenic distribution between tissues. There was no clear correlation between growth and shoot arsenic concentration. This is the first report detailing the involvement of a NIP transporter in response to arsenate. The data suggest that these proteins are relevant targets for breeding and engineering arsenic tolerance in crops. PMID:26898223

  6. Vaccine adverse events.

    PubMed

    Follows, Jill

    2012-01-01

    Millions of adults are vaccinated annually against the seasonal influenza virus. An undetermined number of individuals will develop adverse events to the influenza vaccination. Those who suffer substantiated vaccine injuries, disabilities, and aggravated conditions may file a timely, no-fault and no-cost petition for financial compensation under the National Vaccine Act in the Vaccine Court. The elements of a successful vaccine injury claim are described in the context of a claim showing the seasonal influenza vaccination was the cause of Guillain-Barré syndrome.

  7. [Adverse events prevention ability].

    PubMed

    Aparo, Ugo Luigi; Aparo, Andrea

    2007-03-01

    The issue of how to address medical errors is the key to improve the health care system performances. Operational evidence collected in the last five years shows that the solution is only partially linked to future technological developments. Cultural and organisational changes are mandatory to help to manage and drastically reduce the adverse events in health care organisations. Classical management, merely based on coordination and control, is inadequate. Proactive, self-organising network based structures must be put in place and managed using adaptive, fast evolving management tools. PMID:17484160

  8. [Adverse events prevention ability].

    PubMed

    Aparo, Ugo Luigi; Aparo, Andrea

    2007-03-01

    The issue of how to address medical errors is the key to improve the health care system performances. Operational evidence collected in the last five years shows that the solution is only partially linked to future technological developments. Cultural and organisational changes are mandatory to help to manage and drastically reduce the adverse events in health care organisations. Classical management, merely based on coordination and control, is inadequate. Proactive, self-organising network based structures must be put in place and managed using adaptive, fast evolving management tools.

  9. Characterization of the enzyme responsible for nopaline and ornaline synthesis in sunflower crown gall tissues.

    PubMed

    Sutton, D W; Kemp, J D; Hack, E

    1978-09-01

    Extracts prepared from sunflower (Helianthus annuus L.) crown gall tissues induced by Agrobacterium tumefaciens strains C58 and T37 (nopaline utilizers) catalyze the synthesis of nopaline and ornaline. These compounds are not synthesized in extracts of crown gall tissues induced by strains B6, 15955 (octopine utilizers), and AT1 (utilizes neither octopine nor nopaline) or in extracts of habituated sunflower callus. Both synthetic activities require NADPH, alpha-ketoglutarate, and either arginine or ornithine; histidine and lysine will not substitute. Incorporation of arginine or ornithine into product is inhibited by the other substrate but not by histidine or lysine. On the basis of inhibition and K(m) data, both activities appear to be catalyzed by one enzyme and the same enzyme is apparently present in crown gall tissues induced by strains C58 and T37.

  10. Adverse effects of reduced oxygen tension on the proliferative capacity of rat kidney and insulin-secreting cell lines involve DNA damage and stress responses

    SciTech Connect

    Chen Jianhua Jones, R. Huw; Tarry-Adkins, Jane; Smith, Noel H.; Ozanne, Susan E.

    2008-10-01

    Standard cell culture conditions do not reflect the physiological environment in terms of oxygen tension (20% vs 3%). The effects of lowering oxygen tension on cell proliferation in culture can be beneficial as well as detrimental depending on the cell line studied, but the molecular mechanism underlying such effects is not fully understood. We observed that the proliferative capacity of the rat cell lines NRK and INS-1 was inhibited when cultured under 3% oxygen as compared to 20% oxygen. Suppression of proliferation in NRK cells was accompanied by induction of DNA double strand breaks whereas in INS-1 cells it was accompanied by up-regulation of p53 and p27. Although Sirt1 was up-regulated in both cell lines by 3% oxygen the effects on antioxidant enzymes (MnSOD, CuZnSOD and catalase) were cell line specific. Marked up-regulation of heme oxygenase-1 (HO-1) was detected in both NRK and INS-1 cells when cultured in 3% oxygen. HO-1 expression can be readily induced by exposure to hydrogen peroxide in culture. These results suggest that reduced oxygen tension suppresses the proliferative capacity of these two cell lines through a stress response that is similar to an oxidative stress response but the molecular events that lead to the reduced cell proliferation are cell line specific.

  11. Screening for adverse events.

    PubMed

    Karson, A S; Bates, D W

    1999-02-01

    Adverse events (AEs) in medical patients are common, costly, and often preventable. Development of quality improvement programs to decrease the number and impact of AEs demands effective methods for screening for AEs on a routine basis. Here we describe the impact, types, and potential causes of AEs and review various techniques for identifying AEs. We evaluate the use of generic screening criteria in detail and describe a recent study of the sensitivity and specificity of individual generic screening criteria and combinations of these criteria. In general, the most sensitive screens were the least specific and no small sub-set of screens identified a large percentage of adverse events. Combinations of screens that were limited to administrative data were the least expensive, but none were particularly sensitive, although in practice they might be effective since routine screening is currently rarely done. As computer systems increase in sophistication sensitivity will improve. We also discuss recent studies that suggest that programs that screen for and identify AEs can be useful in reducing AE rates. While tools for identifying AEs have strengths and weaknesses, they can play an important role in organizations' quality improvement portfolios. PMID:10468381

  12. Exposure to residual concentrations of elements from a remediated coal fly ash spill does not adversely influence stress and immune responses of nestling tree swallows

    PubMed Central

    Beck, Michelle L.; Hopkins, William A.; Hallagan, John J.; Jackson, Brian P.; Hawley, Dana M.

    2014-01-01

    Anthropogenic activities often produce pollutants that can affect the physiology, growth and reproductive success of wildlife. Many metals and trace elements play important roles in physiological processes, and exposure to even moderately elevated concentrations of essential and non-essential elements could have subtle effects on physiology, particularly during development. We examined the effects of exposure to a number of elements from a coal fly ash spill that occurred in December 2008 and has since been remediated on the stress and immune responses of nestling tree swallows. We found that nestlings at the site of the spill had significantly greater blood concentrations of Cu, Hg, Se and Zn in 2011, but greater concentrations only of Se in 2012, in comparison to reference colonies. The concentrations of elements were below levels of significant toxicological concern in both years. In 2011, we found no relationship between exposure to elements associated with the spill and basal or stress-induced corticosterone concentrations in nestlings. In 2012, we found that Se exposure was not associated with cell-mediated immunity based on the response to phytohaemagglutinin injection. However, the bactericidal capacity of nestling plasma had a positive but weak association with blood Se concentrations, and this association was stronger at the spill site. Our results indicate that exposure to these low concentrations of elements had few effects on nestling endocrine and immune physiology. The long-term health consequences of low-level exposure to elements and of exposure to greater element concentrations in avian species require additional study. PMID:27293639

  13. Micro-/nano-engineered cellular responses for soft tissue engineering and biomedical applications.

    PubMed

    Tay, Chor Yong; Irvine, Scott Alexander; Boey, Freddy Y C; Tan, Lay Poh; Venkatraman, Subbu

    2011-05-23

    The development of biomedical devices and reconstruction of functional ex vivo tissues often requires the need to fabricate biomimetic surfaces with features of sub-micrometer precision. This can be achieved with the advancements in micro-/nano-engineering techniques, allowing researchers to manipulate a plethora of cellular behaviors at the cell-biomaterial interface. Systematic studies conducted on these 2D engineered surfaces have unraveled numerous novel findings that can potentially be integrated as part of the design consideration for future 2D and 3D biomaterials and will no doubt greatly benefit tissue engineering. In this review, recent developments detailing the use of micro-/nano-engineering techniques to direct cellular orientation and function pertinent to soft tissue engineering will be highlighted. Particularly, this article aims to provide valuable insights into distinctive cell interactions and reactions to controlled surfaces, which can be exploited to understand the mechanisms of cell growth on micro-/nano-engineered interfaces, and to harness this knowledge to optimize the performance of 3D artificial soft tissue grafts and biomedical applications.

  14. Cell kinetics during regeneration in the sponge Halisarca caerulea: how local is the response to tissue damage?

    PubMed Central

    Achlatis, Michelle; Osinga, Ronald; van der Geest, Harm G.; Cleutjens, Jack P.M.; Schutte, Bert; de Goeij, Jasper M.

    2015-01-01

    Sponges have a remarkable capacity to rapidly regenerate in response to wound infliction. In addition, sponges rapidly renew their filter systems (choanocytes) to maintain a healthy population of cells. This study describes the cell kinetics of choanocytes in the encrusting reef sponge Halisarca caerulea during early regeneration (0–8 h) following experimental wound infliction. Subsequently, we investigated the spatial relationship between regeneration and cell proliferation over a six-day period directly adjacent to the wound, 1 cm, and 3 cm from the wound. Cell proliferation was determined by the incorporation of 5-bromo-2′-deoxyuridine (BrdU). We demonstrate that during early regeneration, the growth fraction of the choanocytes (i.e., the percentage of proliferative cells) adjacent to the wound is reduced (7.0 ± 2.5%) compared to steady-state, undamaged tissue (46.6 ± 2.6%), while the length of the cell cycle remained short (5.6 ± 3.4 h). The percentage of proliferative choanocytes increased over time in all areas and after six days of regeneration choanocyte proliferation rates were comparable to steady-state tissue. Tissue areas farther from the wound had higher rates of choanocyte proliferation than areas closer to the wound, indicating that more resources are demanded from tissue in the immediate vicinity of the wound. There was no difference in the number of proliferative mesohyl cells in regenerative sponges compared to steady-state sponges. Our data suggest that the production of collagen-rich wound tissue is a key process in tissue regeneration for H. caerulea, and helps to rapidly occupy the bare substratum exposed by the wound. Regeneration and choanocyte renewal are competing and negatively correlated life-history traits, both essential to the survival of sponges. The efficient allocation of limited resources to these life-history traits has enabled the ecological success and diversification of sponges. PMID:25780772

  15. Effects of mercuric chloride on chemiluminescent response of phagocytes and tissue lysozyme activity in Tilapia, Oreochromis aureus

    SciTech Connect

    Low, K.W.; Sin, Y.M.

    1995-02-01

    Phagocytosis is an important defense mechanism against foreign pathogenic organisms. The cells involved are phagocytes which are comprised of peripheral blood monocytes (tissue macrophages) and polymorphonuclear (PMN) leucocytes. These cells can be activated by either particulate or soluble stimuli and undergo a respiratory burst from which several reactive oxygen species (ROS) can be formed. The reactive oxygen species and some hydrolases generated in the cells are the major antibacterial agents released during phagocytosis. Chemiluminescence (CL) is emitted, in vitro, from phagocytizing human PMN neutrophils. A similar CL response was also encountered in fish phagocytes. ROS was the causative agent of the CL emitted during in vitro phagocytosis. Phagocytic activity can be monitored by measuring the CL response of the phagocytes. Lysozyme is one of the potent hydrolases which are involved in the destruction of pathogens during phagocytosis. In fish, it was found predominantly in haematopoietic tissues, PMN leucocytes and moncytes. This enzyme has been shown to have antibacterial activity against several pathogens in fish. A combined oxidative and hydrolytic attack upon the engulfed pathogens allow phagocytes to kill infectious agents effectively. However, severe suppression or enhancement of these two functions caused by some exogenous factors may be detrimental to the host tissues. It has been reported that inorganic mercury could inhibit, in vitro, the respiratory burst and the microbicidal activities of human PMN leucocytes. It was also reported that increased in vitro release of lysozyme was found in mercury-treated human PMN leucocytes. However, such work has not been reported in fish. The aim of this research was to examine whether mercury could exert similar effects on the CL response in phagocytes and tissue lysozyme activity in fish after they were exposed to different concentrations of mercuric chloride over a period of 3 wks. 17 refs., 1 fig., 1 tab.

  16. Soft tissue impact characterisation kit (STICK) for ex situ investigation of heart rhythm responses to acute mechanical stimulation.

    PubMed

    Cooper, Patricia J; Epstein, Avi; Macleod, Iain A; Schaaf, Sarah T M; Sheldon, Judith; Boulin, Christian; Kohl, Peter

    2006-01-01

    Both mechanical induction and mechanical termination of arrhythmias have been reported in man. Examples include pre-cordial impacts by sports implements (baseballs, pucks) that can trigger arrhythmias, including ventricular fibrillation, or via the so-called pre-cordial thump, used as an emergency resuscitation measure to convert arrhythmias to normal sinus node rhythm. These interventions have been partially reproduced in experimental studies on whole animals. Relating observations at the system's level to underlying mechanisms has been difficult, however, largely because of: (i) a deficit in efficient and affordable pharmacological agents to selectively target (sub-)cellular responses in whole animal studies, and (ii) the lack of suitable experimental models to study the above responses at intermediate levels of functional and structural integration, such as the isolated heart or cardiac tissue. This paper presents a soft tissue impact characterisation kit (STICK), suitable for quantitative investigations into the effects of acute mechanical stimulation on cardiac electro-mechanical function in rodent isolated heart or tissue preparations. The STICK offers independent control over a range of relevant biophysical parameters, such as impact location and energy, pre-impact projectile speed and contact area, as well as over the timing of a mechanical stimulus relative to the cardiac cycle (monitored via electrocardiogram, ECG, here recorded directly from the cardiac surface). Projectile deceleration upon interaction with the tissue is monitored, contact-free, with a resolution of 175 microm, providing information on tissue deformation dynamics, force, pressure and work of the mechanical intervention. In order to study functional effects of cardiac mechanical stimulation in the absence of tissue damage, impacts must be limited (for juvenile Guinea pig heart) to 2-2.5 mJ in the slack left ventricle (diastolic impact) and 5-10 mJ in contracture (systolic impact), as

  17. [Procedure adverse events: nursing care in central venous catheter fracture].

    PubMed

    Pérez-Juan, Eva; Maqueda-Palau, Mònica; Romero-Grilo, Cristina; Muñoz-Moles, Yolanda

    2014-01-01

    In a intensive care unit (ICU) there are many factors that can lead to the occurrence of adverse events. A high percentage of these events are associated with the administration of drugs. Diagnostic tests, such as computed tomography, is common in critically ill patients and technique can be performed with injection of contrast agent to enhance the visualization of soft tissue. The contrast is a medication and the nurse is responsible for its proper administration. The management of the critically ill patient is complex. ICU team and radiology shares responsibility for the care and safety of the patient safety during the transfer and performing tests with contrast. The World Health Organisation patient safety strategies, recommends analysing errors and learning from them. Therefore, it was decided to investigate the causes of the category E severity adverse events that occurred in a patient who was admitted to the ICU for septic shock of abdominal origin. An abdominal computed tomography was performed with contrast which was injected through a central venous catheter. The contrast did not appear in the image. What happened? Causal analysis helped to understand what triggered the event. A care plan and an algorithm were drafted to prevent it from happening again, with the following objectives: improving knowledge, skills and promoting positive attitudes towards patient safety, working at primary, secondary and tertiary care levels.

  18. De Novo Transcriptome Analysis to Identify Anthocyanin Biosynthesis Genes Responsible for Tissue-Specific Pigmentation in Zoysiagrass (Zoysia japonica Steud.)

    PubMed Central

    Ahn, Jong Hwa; Kim, June-Sik; Kim, Seungill; Soh, Hye Yeon; Shin, Hosub; Jang, Hosung; Ryu, Ju Hyun; Kim, Ahyeong; Yun, Kil-Young; Kim, Shinje; Kim, Ki Sun; Choi, Doil; Huh, Jin Hoe

    2015-01-01

    Zoysiagrass (Zoysia japonica Steud.) is commonly found in temperate climate regions and widely used for lawns, in part, owing to its uniform green color. However, some zoysiagrass cultivars accumulate red to purple pigments in their spike and stolon tissues, thereby decreasing the aesthetic value. Here we analyzed the anthocyanin contents of two zoysiagrass cultivars ‘Anyang-jungji’ (AJ) and ‘Greenzoa’ (GZ) that produce spikes and stolons with purple and green colors, respectively, and revealed that cyanidin and petunidin were primarily accumulated in the pigmented tissues. In parallel, we performed a de novo transcriptome assembly and identified differentially expressed genes between the two cultivars. We found that two anthocyanin biosynthesis genes encoding anthocyanidin synthase (ANS) and dihydroflavonol 4-reductase (DFR) were preferentially upregulated in the purple AJ spike upon pigmentation. Both ANS and DFR genes were also highly expressed in other zoysiagrass cultivars with purple spikes and stolons, but their expression levels were significantly low in the cultivars with green tissues. We observed that recombinant ZjDFR1 and ZjANS1 proteins successfully catalyze the conversions of dihydroflavonols into leucoanthocyanidins and leucoanthocyanidins into anthocyanidins, respectively. These findings strongly suggest that upregulation of ANS and DFR is responsible for tissue-specific anthocyanin biosynthesis and differential pigmentation in zoysiagrass. The present study also demonstrates the feasibility of a de novo transcriptome analysis to identify the key genes associated with specific traits, even in the absence of reference genome information. PMID:25905914

  19. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice.

    PubMed

    Rosell, Meritxell; Kaforou, Myrsini; Frontini, Andrea; Okolo, Anthony; Chan, Yi-Wah; Nikolopoulou, Evanthia; Millership, Steven; Fenech, Matthew E; MacIntyre, David; Turner, Jeremy O; Moore, Jonathan D; Blackburn, Edith; Gullick, William J; Cinti, Saverio; Montana, Giovanni; Parker, Malcolm G; Christian, Mark

    2014-04-15

    Brown adipocytes dissipate energy, whereas white adipocytes are an energy storage site. We explored the plasticity of different white adipose tissue depots in acquiring a brown phenotype by cold exposure. By comparing cold-induced genes in white fat to those enriched in brown compared with white fat, at thermoneutrality we defined a "brite" transcription signature. We identified the genes, pathways, and promoter regulatory motifs associated with "browning," as these represent novel targets for understanding this process. For example, neuregulin 4 was more highly expressed in brown adipose tissue and upregulated in white fat upon cold exposure, and cell studies showed that it is a neurite outgrowth-promoting adipokine, indicative of a role in increasing adipose tissue innervation in response to cold. A cell culture system that allows us to reproduce the differential properties of the discrete adipose depots was developed to study depot-specific differences at an in vitro level. The key transcriptional events underpinning white adipose tissue to brown transition are important, as they represent an attractive proposition to overcome the detrimental effects associated with metabolic disorders, including obesity and type 2 diabetes.

  20. De Novo Transcriptome Analysis to Identify Anthocyanin Biosynthesis Genes Responsible for Tissue-Specific Pigmentation in Zoysiagrass (Zoysia japonica Steud.).

    PubMed

    Ahn, Jong Hwa; Kim, June-Sik; Kim, Seungill; Soh, Hye Yeon; Shin, Hosub; Jang, Hosung; Ryu, Ju Hyun; Kim, Ahyeong; Yun, Kil-Young; Kim, Shinje; Kim, Ki Sun; Choi, Doil; Huh, Jin Hoe

    2015-01-01

    Zoysiagrass (Zoysia japonica Steud.) is commonly found in temperate climate regions and widely used for lawns, in part, owing to its uniform green color. However, some zoysiagrass cultivars accumulate red to purple pigments in their spike and stolon tissues, thereby decreasing the aesthetic value. Here we analyzed the anthocyanin contents of two zoysiagrass cultivars 'Anyang-jungji' (AJ) and 'Greenzoa' (GZ) that produce spikes and stolons with purple and green colors, respectively, and revealed that cyanidin and petunidin were primarily accumulated in the pigmented tissues. In parallel, we performed a de novo transcriptome assembly and identified differentially expressed genes between the two cultivars. We found that two anthocyanin biosynthesis genes encoding anthocyanidin synthase (ANS) and dihydroflavonol 4-reductase (DFR) were preferentially upregulated in the purple AJ spike upon pigmentation. Both ANS and DFR genes were also highly expressed in other zoysiagrass cultivars with purple spikes and stolons, but their expression levels were significantly low in the cultivars with green tissues. We observed that recombinant ZjDFR1 and ZjANS1 proteins successfully catalyze the conversions of dihydroflavonols into leucoanthocyanidins and leucoanthocyanidins into anthocyanidins, respectively. These findings strongly suggest that upregulation of ANS and DFR is responsible for tissue-specific anthocyanin biosynthesis and differential pigmentation in zoysiagrass. The present study also demonstrates the feasibility of a de novo transcriptome analysis to identify the key genes associated with specific traits, even in the absence of reference genome information. PMID:25905914

  1. Loss of Tumor Necrosis Factor α Potentiates Transforming Growth Factor β-mediated Pathogenic Tissue Response during Wound Healing

    PubMed Central

    Saika, Shizuya; Ikeda, Kazuo; Yamanaka, Osamu; Flanders, Kathleen C.; Okada, Yuka; Miyamoto, Takeshi; Kitano, Ai; Ooshima, Akira; Nakajima, Yuji; Ohnishi, Yoshitaka; Kao, Winston W.-Y.

    2006-01-01

    Animal cornea is an avascular transparent tissue that is suitable for research on wound healing-related scarring and neovascularization. Here we show that loss of tumor necrosis factor α (TNFα) potentiates the undesirable, pathogenic response of wound healing in an alkali-burned cornea in mice. Excessive invasion of macrophages and subsequent formation of a vascularized scar tissue were much more marked in TNFα-null knockout (KO) mice than in wild-type mice. Such an unfavorable outcome in KO mice was abolished by Smad7 gene introduction, indicating the involvement of transforming growth factor β or activin/Smad signaling. Bone marrow transplantation from wild-type mice normalized healing of the KO mice, suggesting the involvement of bone marrow-derived inflammatory cells in this phenomenon. Co-culture experiments showed that loss of TNFα in macrophages, but not in fibroblasts, augmented the fibroblast activation as determined by detection of α-smooth muscle actin, the hallmark of myofibroblast generation, mRNA expression of collagen Iα2 and connective tissue growth factor, and detection of collagen protein. TNFα in macrophages may be required to suppress undesirable excessive inflammation and scarring, both of which are promoted by transforming growth factor β, and for restoration of tissue architecture in a healing alkali-burned cornea in mice. PMID:16723700

  2. ISMP Adverse Drug Reactions

    PubMed Central

    2013-01-01

    The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration’s (FDA’s) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA’s MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID:24421544

  3. Characterization of tissue response to radiofrequency ablation using 3D model-based analysis of interventional MR images

    NASA Astrophysics Data System (ADS)

    Weinberg, Brent D.; Lazebnik, Roee S.; Breen, Michael S.; Lewin, Jonathan S.; Wilson, David L.

    2003-05-01

    Using magnetic resonance imaging (MRI), real-time guidance is feasible for radiofrequency (RF) current ablation of pathologic tissue. Lesions have a characteristic two-zone appearance: an inner core (Zone I) surrounded by a hyper-intense rim (Zone II). A better understanding of both the immediate (hyper-acute) and delayed (sub-acute) physiological response of the target tissue will aid development of minimally invasive tumor treatment strategies. We performed in vivo RF ablations in a rabbit thigh model and characterized the tissue response to treatment through contrast enhanced (CE) T1 and T2 weighted MR images at two time points. We measured zonal grayscale changes as well as zone volume changes using a 3D computationally fitted globally deformable parametric model. Comparison over time demonstrated an increase in the volume of both the inner necrotic core (mean 56.5% increase) and outer rim (mean 16.8% increase) of the lesion. Additionally, T2 images of the lesion exhibited contrast greater than or equal to CE T1 (mean 35% improvement). This work establishes a foundation for the clinical use of T2 MR images coupled with a geometric model of the ablation for noninvasive lesion monitoring and characterization.

  4. Inhibition of focal adhesion kinase suppresses the adverse phenotype of endocrine-resistant breast cancer cells and improves endocrine response in endocrine-sensitive cells.

    PubMed

    Hiscox, Stephen; Barnfather, Peter; Hayes, Edd; Bramble, Pamela; Christensen, James; Nicholson, Robert I; Barrett-Lee, Peter

    2011-02-01

    Acquired resistance to endocrine therapy in breast cancer is a major clinical problem. Previous reports have demonstrated that cell models of acquired endocrine resistance have altered cell-matrix adhesion and a highly migratory phenotype, features which may impact on tumour spread in vivo. Focal adhesion kinase (FAK) is an intracellular kinase that regulates signalling pathways central to cell adhesion, migration and survival and its expression is frequently deregulated in breast cancer. In this study, we have used the novel FAK inhibitor PF573228 to address the role of FAK in the development of endocrine resistance. Whilst total-FAK expression was similar between endocrine-sensitive and endocrine-resistant MCF7 cells, FAK phosphorylation status (Y397 or Y861) was altered in resistance. PF573228 promoted a dose-dependent inhibition of FAK phosphorylation at Y397 but did not affect other FAK activation sites (pY407, pY576 and pY861). Endocrine-resistant cells were more sensitive to these inhibitory effects versus MCF7 (mean IC(50) for FAK pY397 inhibition: 0.43 μM, 0.05 μM and 0.13 μM for MCF7, TamR and FasR cells, respectively). Inhibition of FAK pY397 was associated with a reduction in TamR and FasR adhesion to, and migration over, matrix components. PF573228 as a single agent (0-1 μM) did not affect the growth of MCF7 cells or their endocrine-resistant counterparts. However, treatment of endocrine-sensitive cells with PF573228 and tamoxifen combined resulted in greater suppression of proliferation versus single agent treatment. Together these data suggest the importance of FAK in the process of endocrine resistance, particularly in the development of an aggressive, migratory cell phenotype and demonstrate the potential to improve endocrine response through combination treatment.

  5. Inhibition of focal adhesion kinase suppresses the adverse phenotype of endocrine-resistant breast cancer cells and improves endocrine response in endocrine-sensitive cells.

    PubMed

    Hiscox, Stephen; Barnfather, Peter; Hayes, Edd; Bramble, Pamela; Christensen, James; Nicholson, Robert I; Barrett-Lee, Peter

    2011-02-01

    Acquired resistance to endocrine therapy in breast cancer is a major clinical problem. Previous reports have demonstrated that cell models of acquired endocrine resistance have altered cell-matrix adhesion and a highly migratory phenotype, features which may impact on tumour spread in vivo. Focal adhesion kinase (FAK) is an intracellular kinase that regulates signalling pathways central to cell adhesion, migration and survival and its expression is frequently deregulated in breast cancer. In this study, we have used the novel FAK inhibitor PF573228 to address the role of FAK in the development of endocrine resistance. Whilst total-FAK expression was similar between endocrine-sensitive and endocrine-resistant MCF7 cells, FAK phosphorylation status (Y397 or Y861) was altered in resistance. PF573228 promoted a dose-dependent inhibition of FAK phosphorylation at Y397 but did not affect other FAK activation sites (pY407, pY576 and pY861). Endocrine-resistant cells were more sensitive to these inhibitory effects versus MCF7 (mean IC(50) for FAK pY397 inhibition: 0.43 μM, 0.05 μM and 0.13 μM for MCF7, TamR and FasR cells, respectively). Inhibition of FAK pY397 was associated with a reduction in TamR and FasR adhesion to, and migration over, matrix components. PF573228 as a single agent (0-1 μM) did not affect the growth of MCF7 cells or their endocrine-resistant counterparts. However, treatment of endocrine-sensitive cells with PF573228 and tamoxifen combined resulted in greater suppression of proliferation versus single agent treatment. Together these data suggest the importance of FAK in the process of endocrine resistance, particularly in the development of an aggressive, migratory cell phenotype and demonstrate the potential to improve endocrine response through combination treatment. PMID:20354780

  6. Temperature responses of substrate carbon conversion efficiencies and growth rates of plant tissues.

    PubMed

    Hansen, Lee D; Thomas, Nathan R; Arnholdt-Schmitt, Birgit

    2009-12-01

    Growth rates of plant tissues depend on both the respiration rate and the efficiency with which carbon is incorporated into new structural biomass. Calorespirometric measurement of respiratory heat and CO2 rates, from which both efficiency and growth rate can be calculated, is a well established method for determining the effects of rapid temperature changes on the respiratory and growth properties of plant tissues. The effect of the alternative oxidase/cytochrome oxidase activity ratio on efficiency is calculated from first principles. Data on the temperature dependence of the substrate carbon conversion efficiency are tabulated. These data show that epsilon is maximum and approximately constant through the optimum growth temperature range and decreases rapidly as temperatures approach temperature limits to growth. The width of the maximum and the slopes of decreasing epsilon at high and low temperatures vary greatly with species, cultivars and accessions.

  7. Dermal white adipose tissue: a new component of the thermogenic response

    PubMed Central

    Alexander, Caroline M.; Kasza, Ildiko; Yen, C-L. Eric; Reeder, Scott B.; Hernando, Diego; Gallo, Richard L.; Jahoda, Colin A. B.; Horsley, Valerie; MacDougald, Ormond A.

    2015-01-01

    Recent literature suggests that the layer of adipocytes embedded in the skin below the dermis is far from being an inert spacer material. Instead, this layer of dermal white adipose tissue (dWAT) is a regulated lipid layer that comprises a crucial environmental defense. Among all the classes of biological molecules, lipids have the lowest thermal conductance and highest insulation potential. This property can be exploited by mammals to reduce heat loss, suppress brown adipose tissue activation, reduce the activation of thermogenic programs, and increase metabolic efficiency. Furthermore, this layer responds to bacterial challenge to provide a physical barrier and antimicrobial disinfection, and its expansion supports the growth of hair follicles and regenerating skin. In sum, this dWAT layer is a key defensive player with remarkable potential for modifying systemic metabolism, immune function, and physiology. In this review, we discuss the key literature illustrating the properties of this recently recognized adipose depot. PMID:26405076

  8. Oxidative stress in marine bivalves tissues in response to accumulation of heavy metals

    SciTech Connect

    Chelomin, V.P.; Belcheva, N.N.; Zakartsev, M.V.

    1995-12-31

    Using model aquarium experiments the authors have shown that the accumulation of heavy metals (copper and cadmium) by the tissues of marine bivalves (Mytilus edulis, Mizuhopecten yessoensis) is followed by a complex of alterations in the lipid matrix of some membrane organelles. It is supposed that the disturbance of balance of prooxidant and antioxidant processes is the main mechanism in heavy metal-inducible damage, of membranes. This possibility is supported by results of levels of conjugated dienes, malondialdehyde and Shiff`s bases, determined as indicators of lipid peroxidation in different tissues of molluscs, markedly increased with metal accumulation. Unlike to cadmium, the copper possess prooxidative activity, stimulating the peroxidation of membrane lipids directly. In spite of some distinctions the intracellular antioxidative systems (glutathione system and tocopherol) showed extreme sensitivity to the accumulation of both metals. It was demonstrated that the accumulation of these metals was followed by die changes of glutathione and tocopherol contents and the inhibition of glutathione-reductase. activity,, but it was not correlated with changes of Se-depending glutathioneperoxidase activity. As it results from kinetic data the most damages of glutathione system are revealed on this earliest stages of metal accumulation when metallothionein synthesis is on the low level. The amount of glutathione in the tissues was restored almost to their original level when metallothionein synthesis increases markedly. But, total amount of peroxides is retained on the high level for a long period of time. On the basis of results it is reasonable to assume that the accumulation of these metals by mollusc tissues does not proceed without leaving a trace. This process is a potential menace for increasing of destructive events in consequence of disturbance of balance of prooxidant and antioxidant processes.

  9. Computational Simulation of the Mechanical Response of Brain Tissue under Blast Loading

    PubMed Central

    Laksari, Kaveh; Assari, Soroush; Seibold, Benjamin; Sadeghipour, Keya; Darvish, Kurosh

    2014-01-01

    In the present study, numerical simulations of nonlinear wave propagation and shock formation in brain tissue have been presented and a new mechanism of injury for Blast-Induced Neurotrauma (BINT) is proposed. A quasilinear viscoelastic (QLV) constitutive material model was used that encompasses the nonlinearity as well as the rate dependence of the tissue relevant to BINT modeling. A one-dimensional model was implemented using the discontinuous Galerkin -finite element method and studied with displacement-input and pressure-input boundary conditions. The model was validated against LS-DYNA finite element code and theoretical results for speci c conditions that resulted in shock wave formation. It was shown that a continuous wave can become a shock wave as it propagates in the QLV brain tissue when the initial changes in acceleration are beyond a certain limit. The high spatial gradient of stress and strain at the shock front cause large relative motions at the cellular scale at high temporal rates even when the maximum stresses and strains are relatively low. This gradient-induced local deformation may occur away from the boundary and is proposed as a contributing factor to the diffuse nature of BINT. PMID:25205088

  10. Preliminary histological study of connective tissue response to Zinalco and stainless steel 316L implants after 120 days.

    PubMed

    Piña, C; Torres, C K; Guzmán, J

    1998-02-01

    Circular plates of Zinalco alloy (80 wt% Zn, 1.5 wt% Cu, 18.5 wt% Al) and stainless steel (SS) 316L were implanted in 12 female Wistar rats subcutaneously and intramuscularly to compare organism response, 120 days after implantation. The tissues surrounding the implants were analysed employing hematoxilin and eosin (H-E) and Gallego's trichromic techniques (GTT). Findings indicate that the reaction to Zinalco alloy was similar to the reaction to SS 316L. The Zn, Al and Cu concentrations in blood were measured, without evidence of any alteration due to implants. The presence and distribution of Zn, Al and Cu components of Zinalco alloy were detected in tissues by energy dispersive X-ray microanalysis.

  11. Adverse reactions of Achilles tendon xanthomas in three hypercholesterolemic patients after treatment intensification with niacin and bile acid sequestrants.

    PubMed

    Lakey, Wanda C; Greyshock, Nicole; Guyton, John R

    2013-01-01

    Multiple cholesterol-reducing therapies have been shown to induce the regression of tendon xanthoma in patients with familial hypercholesterolemia. We present 3 cases of adverse reactions in Achilles tendon xanthomas after the addition of niacin and bile acid sequestrants to ongoing statin therapy. Reduction in tendon dimensions and marked softening of xanthomas were interpreted as cholesterol removal from heavily infiltrated tissue sites. In 2 cases, changes in the xanthomas occurred despite only minor lipoprotein improvements, raising the possibility of direct drug effects in cholesterol-infiltrated tissue. Intriguingly, recent studies have described niacin receptor-mediated effects in macrophages. In summary, although adverse reactions in Achilles tendon xanthomas appear to be infrequent, clinicians should be aware of this phenomenon in their patients after intensifying lipid treatments, especially with the use of niacin in patients with familial hypercholesterolemia. Xanthoma responses may provide clues to new pharmacologic effects in cholesterol-infiltrated tissues.

  12. The Small-RNA Profiles of Almond (Prunus dulcis Mill.) Reproductive Tissues in Response to Cold Stress

    PubMed Central

    Shiran, Behrouz; Rabei, Mohammad; Fallahi, Hossein

    2016-01-01

    Spring frost is an important environmental stress that threatens the production of Prunus trees. However, little information is available regarding molecular response of these plants to the frost stress. Using high throughput sequencing, this study was conducted to identify differentially expressed miRNAs, both the conserved and the non-conserved ones, in the reproductive tissues of almond tolerant H genotype under cold stress. Analysis of 50 to 58 million raw reads led to identification of 174 unique conserved and 59 novel microRNAs (miRNAs). Differential expression pattern analysis showed that 50 miRNA families were expressed differentially in one or both of almond reproductive tissues (anther and ovary). Out of these 50 miRNA families, 12 and 15 displayed up-regulation and down-regulation, respectively. The distribution of conserved miRNA families indicated that miR482f harbor the highest number of members. Confirmation of miRNAs expression patterns by quantitative real- time PCR (qPCR) was performed in cold tolerant (H genotype) alongside a sensitive variety (Sh12 genotype). Our analysis revealed differential expression for 9 miRNAs in anther and 3 miRNAs in ovary between these two varieties. Target prediction of miRNAs followed by differential expression analysis resulted in identification of 83 target genes, mostly transcription factors. This study comprehensively catalogued expressed miRNAs under different temperatures in two reproductive tissues (anther and ovary). Results of current study and the previous RNA-seq study, which was conducted in the same tissues by our group, provide a unique opportunity to understand the molecular basis of responses of almond to cold stress. The results can also enhance the possibility for gene manipulation to develop cold tolerant plants. PMID:27253370

  13. Insulin-resistant subjects have normal angiogenic response to aerobic exercise training in skeletal muscle, but not in adipose tissue

    PubMed Central

    Walton, R Grace; Finlin, Brian S; Mula, Jyothi; Long, Douglas E; Zhu, Beibei; Fry, Christopher S; Westgate, Philip M; Lee, Jonah D; Bennett, Tamara; Kern, Philip A; Peterson, Charlotte A

    2015-01-01

    Reduced vessel density in adipose tissue and skeletal muscle is associated with obesity and may result in decreased perfusion, decreased oxygen consumption, and insulin resistance. In the presence of VEGFA, Angiopoietin-2 (Angpt2) and Angiopoietin-1 (Angpt1) are central determinants of angiogenesis, with greater Angpt2:Angpt1 ratios promoting angiogenesis. In skeletal muscle, exercise training stimulates angiogenesis and modulates transcription of VEGFA, Angpt1, and Angpt2. However, it remains unknown whether exercise training stimulates vessel growth in human adipose tissue, and it remains unknown whether adipose angiogenesis is mediated by angiopoietin signaling. We sought to determine whether insulin-resistant subjects would display an impaired angiogenic response to aerobic exercise training. Insulin-sensitive (IS, N = 12) and insulin-resistant (IR, N = 14) subjects had subcutaneous adipose and muscle (vastus lateralis) biopsies before and after 12 weeks of cycle ergometer training. In both tissues, we measured vessels and expression of pro-angiogenic genes. Exercise training did not increase insulin sensitivity in IR Subjects. In skeletal muscle, training resulted in increased vessels/muscle fiber and increased Angpt2:Angpt1 ratio in both IR and IS subjects. However, in adipose, exercise training only induced angiogenesis in IS subjects, likely due to chronic suppression of VEGFA expression in IR subjects. These results indicate that skeletal muscle of IR subjects exhibits a normal angiogenic response to exercise training. However, the same training regimen is insufficient to induce angiogenesis in adipose tissue of IR subjects, which may help to explain why we did not observe improved insulin sensitivity following aerobic training. PMID:26038468

  14. The Small-RNA Profiles of Almond (Prunus dulcis Mill.) Reproductive Tissues in Response to Cold Stress.

    PubMed

    Karimi, Marzieh; Ghazanfari, Farahnaz; Fadaei, Adeleh; Ahmadi, Laleh; Shiran, Behrouz; Rabei, Mohammad; Fallahi, Hossein

    2016-01-01

    Spring frost is an important environmental stress that threatens the production of Prunus trees. However, little information is available regarding molecular response of these plants to the frost stress. Using high throughput sequencing, this study was conducted to identify differentially expressed miRNAs, both the conserved and the non-conserved ones, in the reproductive tissues of almond tolerant H genotype under cold stress. Analysis of 50 to 58 million raw reads led to identification of 174 unique conserved and 59 novel microRNAs (miRNAs). Differential expression pattern analysis showed that 50 miRNA families were expressed differentially in one or both of almond reproductive tissues (anther and ovary). Out of these 50 miRNA families, 12 and 15 displayed up-regulation and down-regulation, respectively. The distribution of conserved miRNA families indicated that miR482f harbor the highest number of members. Confirmation of miRNAs expression patterns by quantitative real- time PCR (qPCR) was performed in cold tolerant (H genotype) alongside a sensitive variety (Sh12 genotype). Our analysis revealed differential expression for 9 miRNAs in anther and 3 miRNAs in ovary between these two varieties. Target prediction of miRNAs followed by differential expression analysis resulted in identification of 83 target genes, mostly transcription factors. This study comprehensively catalogued expressed miRNAs under different temperatures in two reproductive tissues (anther and ovary). Results of current study and the previous RNA-seq study, which was conducted in the same tissues by our group, provide a unique opportunity to understand the molecular basis of responses of almond to cold stress. The results can also enhance the possibility for gene manipulation to develop cold tolerant plants. PMID:27253370

  15. The Small-RNA Profiles of Almond (Prunus dulcis Mill.) Reproductive Tissues in Response to Cold Stress.

    PubMed

    Karimi, Marzieh; Ghazanfari, Farahnaz; Fadaei, Adeleh; Ahmadi, Laleh; Shiran, Behrouz; Rabei, Mohammad; Fallahi, Hossein

    2016-01-01

    Spring frost is an important environmental stress that threatens the production of Prunus trees. However, little information is available regarding molecular response of these plants to the frost stress. Using high throughput sequencing, this study was conducted to identify differentially expressed miRNAs, both the conserved and the non-conserved ones, in the reproductive tissues of almond tolerant H genotype under cold stress. Analysis of 50 to 58 million raw reads led to identification of 174 unique conserved and 59 novel microRNAs (miRNAs). Differential expression pattern analysis showed that 50 miRNA families were expressed differentially in one or both of almond reproductive tissues (anther and ovary). Out of these 50 miRNA families, 12 and 15 displayed up-regulation and down-regulation, respectively. The distribution of conserved miRNA families indicated that miR482f harbor the highest number of members. Confirmation of miRNAs expression patterns by quantitative real- time PCR (qPCR) was performed in cold tolerant (H genotype) alongside a sensitive variety (Sh12 genotype). Our analysis revealed differential expression for 9 miRNAs in anther and 3 miRNAs in ovary between these two varieties. Target prediction of miRNAs followed by differential expression analysis resulted in identification of 83 target genes, mostly transcription factors. This study comprehensively catalogued expressed miRNAs under different temperatures in two reproductive tissues (anther and ovary). Results of current study and the previous RNA-seq study, which was conducted in the same tissues by our group, provide a unique opportunity to understand the molecular basis of responses of almond to cold stress. The results can also enhance the possibility for gene manipulation to develop cold tolerant plants.

  16. Disentangling linear and nonlinear brain responses to evoked deep tissue pain.

    PubMed

    Loggia, Marco L; Edwards, Robert R; Kim, Jieun; Vangel, Mark G; Wasan, Ajay D; Gollub, Randy L; Harris, Richard E; Park, Kyungmo; Napadow, Vitaly

    2012-10-01

    Pain stimuli evoke widespread responses in the brain. However, our understanding of the physiological significance underlying heterogeneous response within different pain-activated and -deactivated regions is still limited. Using functional magnetic resonance imaging, we evaluated brain responses to a wide range of stimulus intensity levels (1 innocuous, 7 painful) in order to estimate region-specific stimulus-response functions, which we hypothesized could illuminate that region's functional relationship to pain. Linear and nonlinear brain responses to pain were estimated through independent Legendre polynomial transformations of pain ratings within a general linear model. This approach identified at least 5 different, regionally specific activity profiles in the brain. Linearly increasing (eg, primary somatosensory/motor cortex, insulae) and intensity-independent (eg, secondary somatosensory cortex) activation was noted in traditional pain-processing areas, potentially reflecting sensory encoding and all-or-none salience responses, respectively. Multiple activity profiles were seen in areas of the default mode network (DMN): intensity-independent deactivation (eg, posterior cingulate cortex), linearly decreasing (eg, contralateral inferior parietal lobule), and quadratic (U-shaped; eg, medial prefrontal cortex). The latter observation suggests that: (1) different DMN subregions exhibit functional heterogeneity and (2) some DMN subregions respond in a percept-related manner to pain, suggesting closer linkage between the DMN and pain processing than previously thought. Future studies should apply a similar approach using innocuous stimuli of multiple intensities to evaluate whether the response profiles reported here can also be generalized to nonpainful somatosensory processing.

  17. Development of a combined model of tissue kinetics and radiation response of human bronchiolar epithelium with single cell resolution

    NASA Astrophysics Data System (ADS)

    Ostrovskaya, Natela Grigoryevna

    2005-07-01

    Lack of accurate data for epidemiological studies of low dose radiation effects necessitates development of dosimetric models allowing prediction of cancer risks for different organs. The objective of this work is to develop a model of the radiation response of human bronchiolar tissue with single cell resolution. The computer model describes epithelial tissue as an ensemble of individual cells, with the geometry of a human bronchiole and the properties of different cell types are taken into account. The model simulates the tissue kinetics and radiation exposure in four dimensions: three spatial dimensions and a temporal dimension. The bronchiole is modeled as a regular hollow cylinder with the epithelial cells of three different types (basal, secretory, and ciliated) lining its interior. For the purposes of assessment of radiation damage to the cells only the nuclei of the cells have been modeled. Subroutines describing cellular kinetics have been developed to simulate cell turnover in a normal epithelial tissue. Monte Carlo subroutines have been developed to simulate exposure to alpha particles; the GEANT4 toolkit has been used to simulate exposure to low LET radiation. Each hit cell is provided with a record of energy deposition, and this record is passed to the progeny if the cell survives. The model output provides data on the number of basal progenitor cells in different phases of a cell life-cycle and secretory to ciliated cell ratio after several generations of cell proliferation. The model calculates labeling and mitotic indices and estimates the average cell turnover time for the bronchiolar tissue. Microdosimetric calculations are performed for cells traversed by ionizing particles. The model will be used to assess the accumulation of damage in cells due to protracted low level radiation exposure. The model output may provide directions for the future experimental design.

  18. Relations between 3H-estradiol uptake and receptor content of estrogen responsive tissues of castrated female rat.

    PubMed

    Gómez-Benitez, J; Sosa-González, A; Díaz-Chico, B N

    1984-09-01

    The time course of 3H-Estradiol-17 beta (3H-E2) uptake, and estrogen receptor content in estrogen responsive tissues were studied between 0 and 12 h after injection of 0.5 microgram/kg of 3H-E2 or cold E2 injection to castrated adult female rats. The plasma concentration of 3H-E2 between 10 min and 2 h after injection was in the range of the plasma E2 level of cyclic rat. The total 3H-E2 uptake was well correlated with the receptor content in all tissues. The rank order of 3H-E2 uptake was: uterus (Ut) greater than anterior pituitary (Ap) greater than hypothalamus (Ht) greater than plasma. The cytosol 3H-E2 uptake showed its maximal level 10 min after injection in all tissues. Parallel time course between plasma 3H-E2 and cytosol uptake was obtained for each separate tissue. The nuclear 3H-E2 uptake showed its maximal values 2 h after injection with a subsequent decline. Cytosolic estrogen receptor (Rc) content showed a depletion-replenishment cycle after cold E2 injection in all tissues. Nuclear estrogen receptor (Rn) content in Ut increased progressively from 0 to 14 h after injection, but in Ap it showed its maximal level 2 h after injection, declining afterwards. In Ap, nuclear 3H-E2 uptake and Rn level showed parallel time courses. The maximal level of both parameters coinciding with the time of maximal Rc depletion. However, the Rn level in Ut increases more slowly at greater length than the nuclear 3H-E2 uptake, both processes being divergent. These findings are interpreted as the expression of tissular differences in the rate of nuclear receptor formation from the Rc-E complex previously translocated into nucleus and attached to chromatin.

  19. Phosphoprotein network analysis of white adipose tissues unveils deregulated pathways in response to high-fat diet

    PubMed Central

    Asfa, Alli Shaik; Qiu, Beiying; Wee, Sheena; Choi, Hyungwon; Gunaratne, Jayantha; Tergaonkar, Vinay

    2016-01-01

    Despite efforts in the last decade, signaling aberrations associated with obesity remain poorly understood. To dissect molecular mechanisms that define this complex metabolic disorder, we carried out global phosphoproteomic analysis of white adipose tissue (WAT) from mice fed on low-fat diet (LFD) and high-fat diet (HFD). We quantified phosphorylation levels on 7696 peptides, and found significant differential phosphorylation levels in 282 phosphosites from 191 proteins, including various insulin-responsive proteins and metabolic enzymes involved in lipid homeostasis in response to high-fat feeding. Kinase-substrate prediction and integrated network analysis of the altered phosphoproteins revealed underlying signaling modulations during HFD-induced obesity, and suggested deregulation of lipogenic and lipolytic pathways. Mutation of the differentially-regulated novel phosphosite on cytoplasmic acetyl-coA forming enzyme ACSS2 (S263A) upon HFD-induced obesity led to accumulation of serum triglycerides and reduced insulin-responsive AKT phosphorylation as compared to wild type ACSS2, thus highlighting its role in obesity. Altogether, our study presents a comprehensive map of adipose tissue phosphoproteome in obesity and reveals many previously unknown candidate phosphorylation sites for future functional investigation. PMID:27180971

  20. Modulation of tissue inflammatory response by histamine receptors in scorpion envenomation pathogenesis: involvement of H4 receptor.

    PubMed

    Lamraoui, Amal; Adi-Bessalem, Sonia; Laraba-Djebari, Fatima

    2014-10-01

    The inflammatory response caused by scorpion venoms is a key event in the pathogenesis of scorpion envenomation. This response was assessed in the cardiac, pulmonary, and gastric tissues of envenomed mice. The results reveal an increase of permeability in cardiac, pulmonary, and gastric vessels accompanied by an edema-forming, inflammatory cell infiltration, and imbalanced redox status. These effects are correlated with severe tissue alterations and concomitant increase of metabolic enzymes in sera. Pretreatment of mice with antagonists of H1, H2, or H4 receptors markedly alleviated these alterations in the heart and lungs. Nevertheless, the blockade of the H3 receptor slightly reduced these disorders. Histamine H2 and H4 receptors were the most pharmacological targets involved in the gastric oxidative inflammation. These findings could help to better understand the role of histamine in scorpion venom-induced inflammatory response and propose new therapy using as targets the H4 receptor in addition to histamine H1 and H2 receptors to attenuate the induced inflammatory disorders encountered in scorpion envenoming. PMID:24858599

  1. GENE EXPRESSION CHANGES IN MOUSE BLADDER TISSUE IN RESPONSE TO INORGANIC ARSENIC

    EPA Science Inventory

    Chronic human exposures to high arsenic concentrations are associated with lung, skin, and bladder cancer. Considerable controversy exists concerning arsenic mode of action and low dose extrapolation. This investigation was designed to identify dose-response changes in gene expre...

  2. Expression of Estrogen-Related Gene Markers in Breast Cancer Tissue Predicts Aromatase Inhibitor Responsiveness

    PubMed Central

    Moy, Irene; Lin, Zhihong; Rademaker, Alfred W.; Reierstad, Scott; Khan, Seema A.; Bulun, Serdar E.

    2013-01-01

    Aromatase inhibitors (AIs) are the most effective class of drugs in the endocrine treatment of breast cancer, with an approximate 50% treatment response rate. Our objective was to determine whether intratumoral expression levels of estrogen-related genes are predictive of AI responsiveness in postmenopausal women with breast cancer. Primary breast carcinomas were obtained from 112 women who received AI therapy after failing adjuvant tamoxifen therapy and developing recurrent breast cancer. Tumor ERα and PR protein expression were analyzed by immunohistochemistry (IHC). Messenger RNA (mRNA) levels of 5 estrogen-related genes–AKR1C3, aromatase, ERα, and 2 estradiol/ERα target genes, BRCA1 and PR–were measured by real-time PCR. Tumor protein and mRNA levels were compared with breast cancer progression rates to determine predictive accuracy. Responsiveness to AI therapy–defined as the combined complete response, partial response, and stable disease rates for at least 6 months–was 51%; rates were 56% in ERα-IHC-positive and 14% in ERα-IHC-negative tumors. Levels of ERα, PR, or BRCA1 mRNA were independently predictive for responsiveness to AI. In cross-validated analyses, a combined measurement of tumor ERα and PR mRNA levels yielded a more superior specificity (36%) and identical sensitivity (96%) to the current clinical practice (ERα/PR-IHC). In patients with ERα/PR-IHC-negative tumors, analysis of mRNA expression revealed either non-significant trends or statistically significant positive predictive values for AI responsiveness. In conclusion, expression levels of estrogen-related mRNAs are predictive for AI responsiveness in postmenopausal women with breast cancer, and mRNA expression analysis may improve patient selection. PMID:24223121

  3. Study of Hind Limb Tissue Gas Phase Formation in Response to Suspended Adynamia and Hypokinesia

    NASA Technical Reports Server (NTRS)

    Butler, Bruce D.

    1996-01-01

    The purpose of this study was to investigate the hypothesis that reduced joint/muscle activity (hypo kinesia) as well as reduced or null loading of limbs (adynamia) in gravity would result in reduced decompression-induced gas phase and symptoms of decompression sickness (DCS). Finding a correlation between the two phenomena would correspond to the proposed reduction in tissue gas phase formation in astronauts undergoing decompression during extravehicular activity (EVA) in microgravity. The observation may further explain the reported low incidence of DCS in space.

  4. Three dimensional approach for realistic simulation of facial soft tissue response: a pilot study.

    PubMed

    El-Molla, Mohammed M; El-Beialy, Amr R; Kandil, Ahmed H; El-Bialy, Ahmed M; Mostafa, Yehya A

    2011-01-01

    Facial attractiveness is ranked as a principal priority among patients seeking orthodontic treatment or combined surgical orthodontic therapy. A successful treatment planning process necessitates an accurate prediction of the postoperative facial profile. In this manuscript, the simulation procedure on a real clinical case using virtual volumetric 3D mesh through different scenarios of orthognathic procedures was done. Results depict several facial soft tissue outcomes, with the likelihood of sharing with the patient the most esthetically pleasing end result prior to carrying out the surgical procedure.

  5. Tissue-specific molecular immune response to lipopolysaccharide challenge in emaciated anadromous Arctic charr.

    PubMed

    Philip, Anju M; Jørgensen, Even H; Maule, Alec G; Vijayan, Mathilakath M

    2014-07-01

    Anadromous Arctic charr (Salvelinus alpinus) undergo voluntary winter fasting for months in the Arctic. We tested the hypothesis that extended fasting will compromise the ability of this species to evoke an immune response. Charr were either fed or fasted for 85 days and challenged with lipopolysaccharide (LPS), and the molecular immune response in the liver and spleen assessed at 8 and 96 h post-injection. LPS increased IL-1β, IL-8, and serum amyloid protein A (SAA) mRNA levels in both groups, but the liver IL-1β and IL-8, and spleen IL-8 responses were reduced in the fasted group. Fasting upregulated SOCS-1 and SOCS-2 mRNA abundance, while LPS stimulated SOCS-3 mRNA abundance and this response was higher in the fasted liver. Collectively, extended fasting and emaciation does not curtail the capacity of charr to evoke an immune response, whereas upregulation of SOCS may be a key adaptation to conserve energy by restricting the inflammatory response.

  6. Metabolic activity of brown, "beige," and white adipose tissues in response to chronic adrenergic stimulation in male mice.

    PubMed

    Labbé, Sébastien M; Caron, Alexandre; Chechi, Kanta; Laplante, Mathieu; Lecomte, Roger; Richard, Denis

    2016-07-01

    Classical brown adipocytes such as those found in interscapular brown adipose tissue (iBAT) represent energy-burning cells, which have been postulated to play a pivotal role in energy metabolism. Brown adipocytes can also be found in white adipose tissue (WAT) depots [e.g., inguinal WAT (iWAT)] following adrenergic stimulation, and they have been referred to as "beige" adipocytes. Whether the presence of these adipocytes, which gives iWAT a beige appearance, can confer a white depot with some thermogenic activity remains to be seen. In consequence, we designed the present study to investigate the metabolic activity of iBAT, iWAT, and epididymal white depots in mice. Mice were either 1) kept at thermoneutrality (30°C), 2) kept at 30°C and treated daily for 14 days with an adrenergic agonist [CL-316,243 (CL)], or 3) housed at 10°C for 14 days. Metabolic activity was assessed using positron emission tomography imaging with fluoro-[(18)F]deoxyglucose (glucose uptake), fluoro-[(18)F]thiaheptadecanoic acid (fatty acid uptake), and [(11)C]acetate (oxidative activity). In each group, substrate uptakes and oxidative activity were measured in anesthetized mice in response to acute CL. Our results revealed iBAT as a major site of metabolic activity, which exhibited enhanced glucose and nonesterified fatty acid uptakes and oxidative activity in response to chronic cold and CL. On the other hand, beige adipose tissue failed to exhibit appreciable increase in oxidative activity in response to chronic cold and CL. Altogether, our results suggest that the contribution of beige fat to acute-CL-induced metabolic activity is low compared with that of iBAT, even after sustained adrenergic stimulation.

  7. System Model Network for Adipose Tissue Signatures Related to Weight Changes in Response to Calorie Restriction and Subsequent Weight Maintenance

    PubMed Central

    Montastier, Emilie; Villa-Vialaneix, Nathalie; Caspar-Bauguil, Sylvie; Hlavaty, Petr; Tvrzicka, Eva; Gonzalez, Ignacio; Saris, Wim H. M.; Langin, Dominique; Kunesova, Marie; Viguerie, Nathalie

    2015-01-01

    Nutrigenomics investigates relationships between nutrients and all genome-encoded molecular entities. This holistic approach requires systems biology to scrutinize the effects of diet on tissue biology. To decipher the adipose tissue (AT) response to diet induced weight changes we focused on key molecular (lipids and transcripts) AT species during a longitudinal dietary intervention. To obtain a systems model, a network approach was used to combine all sets of variables (bio-clinical, fatty acids and mRNA levels) and get an overview of their interactions. AT fatty acids and mRNA levels were quantified in 135 obese women at baseline, after an 8-week low calorie diet (LCD) and after 6 months of ad libitum weight maintenance diet (WMD). After LCD, individuals were stratified a posteriori according to weight change during WMD. A 3 steps approach was used to infer a global model involving the 3 sets of variables. It consisted in inferring intra-omic networks with sparse partial correlations and inter-omic networks with regularized canonical correlation analysis and finally combining the obtained omic-specific network in a single global model. The resulting networks were analyzed using node clustering, systematic important node extraction and cluster comparisons. Overall, AT showed both constant and phase-specific biological signatures in response to dietary intervention. AT from women regaining weight displayed growth factors, angiogenesis and proliferation signaling signatures, suggesting unfavorable tissue hyperplasia. By contrast, after LCD a strong positive relationship between AT myristoleic acid (a fatty acid with low AT level) content and de novo lipogenesis mRNAs was found. This relationship was also observed, after WMD, in the group of women that continued to lose weight. This original system biology approach provides novel insight in the AT response to weight control by highlighting the central role of myristoleic acid that may account for the beneficial

  8. Tissue-specific induction of Hsp90 mRNA and plasma cortisol response in chinook salmon following heat shock, seawater challenge, and handling challenge

    USGS Publications Warehouse

    Palmisano, Aldo N.; Winton, J.R.; Dickhoff, Walton W.

    2000-01-01

    In studying the whole-body response of chinook salmon (Oncorhynchus tshawytscha) to various stressors, we found that 5-hour exposure to elevated temperature (mean 21.6??C; + 10.6??C over ambient) induced a marked increase in Hsp90 messenger RNA accumulation in heart, brain, gill, muscle, liver, kidney, and tail fin tissues. The most vital tissues (heart, brain, gill, and muscle) showed the greatest Hsp90-mRNA response, with heart tissue increasing approximately 35-fold, Heat shock induced no increase in plasma cortisol. In contrast, a standard handling challenge induced high plasma cortisol levels, but no elevation in Hsp90 mRNA in any tissue, clearly separating the physiological and cellular stress responses. We saw no increase either in tissue Hsp90 mRNA levels or in plasma cortisol concentrations after exposing the fish to seawater overnight.

  9. Pilot Study: Unique Response of Bone Tissue During an Investigation of Radio-Adaptive Effects in Mice

    NASA Technical Reports Server (NTRS)

    Sibonga, J. D.; Iwaniec, U.; Wu, H.

    2011-01-01

    PURPOSE: We obtained bone tissue to evaluate the collateral effects of experiments designed to investigate molecular mechanisms of radio-adaptation in a mouse model. Radio-adaptation describes a process by which the prior exposure to low dose radiation can protect against the toxic effect of a subsequent high dose exposure. In the radio-adaptation experiments, C57Bl/6 mice were exposed to either a Sham or a priming Low Dose (5 cGy) of Cs-137 gamma rays before being exposed to either a Sham or High Dose (6 Gy) 24 hours later. ANALYSIS: Bone tissue were obtained from two experiments where mice were sacrificed at 3 days (n=3/group, 12 total) and at 14 days (n=6/group, 24 total) following high dose exposure. Tissues were analyzed to 1) evaluate a radio-adaptive response in bone tissue and 2) describe cellular and microstructural effects for two skeletal sites with different rates of bone turnover. One tibia and one lumbar vertebrae (LV2), collected at the 3-day time-point, were analyzed by bone histomorphometry and micro-CT to evaluate the cellular response and any evidence of microarchitectural impact. Likewise, tibia and LV2, collected at the 14-day time-point, were analyzed by micro-CT alone to evaluate resulting changes to bone structure and microarchitecture. The data were analyzed by 2-way ANOVA to evaluate the effects of the priming low dose radiation, of the high dose radiation, and of any interaction between the priming low and high doses of radiation. Bone histomorphometry was performed in the cancellous bone (aka trabecular bone) compartments of the proximal tibial metaphysis and of LV2. RESULTS: Cellular Response @ 3 Days The priming Low Dose radiation decreased osteoblast-covered bone perimeter in the proximal tibia and the total cell density in the bone marrow in the LV2. High Dose radiation, regardless of prior exposure to priming dose, dramatically reduced total cell density in bone marrow of both the long bone and vertebra. However, in the proximal

  10. Three-dimensional correlation of MR images to muscle tissue response for interventional MRI thermal ablation

    NASA Astrophysics Data System (ADS)

    Breen, Michael S.; Lancaster, Tanya L.; Lazebnik, Roee S.; Ashcroft, Andrik J.; Gamal Nour, Sherif; Lewin, Jonathan S.; Wilson, David L.

    2001-05-01

    We are treating tumors using radiofrequency (RF) ablation under interventional MRI (iMRI) guidance. We investigated the ability of MR to monitor the treated region by comparing MR thermal lesion images to cellular damage as seen histologically. Our new methodology allows 3D registration that should enable more accurate correlation than previous 2D methods. Using a low-field (0.2T) open magnet iMRI system for probe guidance, we applied RF ablation to the thigh muscle of four New Zealand White rabbits. To relate in vivo MR and histology images, we obtained intermediate ex vivo MR images and pictures of thick tissue slices obtained using a specially designed apparatus. Registration was done with a computer algorithm that matches tracks of needle fiducials placed near the tissue of interest. After registration, we determined the region inside the circular, hyperintense rim in MR closely corresponds to the region of necrosis as determined by histology on animals sacrificed 30 minutes after ablation. This is good evidence that iMRI images can be used for real-time feedback during thermal RF ablation treatments.

  11. Preclinical Assessment of the Anticancer Drug Response of Plexiform Neurofibroma Tissue Using Primary Cultures

    PubMed Central

    Mautner, Victor-F.; Friedrich, Reinhard E.; Kluwe, Lan

    2015-01-01

    Background and Purpose Individualized drug testing for tumors using a strategy analogous to antibiotic tests for infectious diseases would be highly desirable for personalized and individualized cancer care. Methods Primary cultures containing tumor and nontumor stromal cells were utilized in a novel strategy to test drug responses with respect to both efficacy and specificity. The strategy tested in this pilot study was implemented using four primary cultures derived from plexiform neurofibromas. Responses to two cytotoxic drugs (nilotinib and imatinib) were measured by following dose-dependent changes in the proportions of tumor and nontumor cells, determined by staining them with cell-type-specific antibodies. The viability of the cultured cells and the cytotoxic effect of the drugs were also measured using proliferation and cytotoxicity assays. Results The total number of cells decreased after the drug treatment, in accordance with the observed reduction in proliferation and increased cytotoxic effect upon incubation with the two anticancer drugs. The proportions of Schwann cells and fibroblasts changed dose-dependently, although the patterns of change varied between the tumor samples (from different sources) and between the two drugs. The highly variable in vitro drug responses probably reflect the large variations in the responses of tumors to therapies between individual patients in vivo. Conclusions These preliminary results suggest that the concept of assessing in vitro drug responses using primary cultures is feasible, but demands the extensive further development of an application for preclinical drug selection and drug discovery. PMID:25851896

  12. Physiological response of cardiac tissue to bisphenol a: alterations in ventricular pressure and contractility

    PubMed Central

    Brooks, Daina; Chandra, Akhil; Jaimes, Rafael; Sarvazyan, Narine; Kay, Matthew

    2015-01-01

    Biomonitoring studies have indicated that humans are routinely exposed to bisphenol A (BPA), a chemical that is commonly used in the production of polycarbonate plastics and epoxy resins. Epidemiological studies have shown that BPA exposure in humans is associated with cardiovascular disease; however, the direct effects of BPA on cardiac physiology are largely unknown. Previously, we have shown that BPA exposure slows atrioventricular electrical conduction, decreases epicardial conduction velocity, and prolongs action potential duration in excised rat hearts. In the present study, we tested if BPA exposure also adversely affects cardiac contractile performance. We examined the impact of BPA exposure level, sex, and pacing rate on cardiac contractile function in excised rat hearts. Hearts were retrogradely perfused at constant pressure and exposed to 10−9-10−4 M BPA. Left ventricular developed pressure and contractility were measured during sinus rhythm and during pacing (5, 6.5, and 9 Hz). Ca2+ transients were imaged from whole hearts and from neonatal rat cardiomyocyte layers. During sinus rhythm in female hearts, BPA exposure decreased left ventricular developed pressure and inotropy in a dose-dependent manner. The reduced contractile performance was exacerbated at higher pacing rates. BPA-induced effects on contractile performance were also observed in male hearts, albeit to a lesser extent. Exposure to BPA altered Ca2+ handling within whole hearts (reduced diastolic and systolic Ca2+ transient potentiation) and neonatal cardiomyocytes (reduced Ca2+ transient amplitude and prolonged Ca2+ transient release time). In conclusion, BPA exposure significantly impaired cardiac performance in a dose-dependent manner, having a major negative impact upon electrical conduction, intracellular Ca2+ handing, and ventricular contractility. PMID:25980024

  13. Adverse events related to blood transfusion

    PubMed Central

    Sahu, Sandeep; Hemlata; Verma, Anupam

    2014-01-01

    The acute blood transfusion reactions are responsible for causing most serious adverse events. Awareness about various clinical features of acute and delayed transfusion reactions with an ability to assess the serious reactions on time can lead to a better prognosis. Evidence-based medicine has changed today's scenario of clinical practice to decrease adverse transfusion reactions. New evidence-based algorithms of transfusion and improved haemovigilance lead to avoidance of unnecessary transfusions perioperatively. The recognition of adverse events under anaesthesia is always challenging. The unnecessary blood transfusions can be avoided with better blood conservation techniques during surgery and with anaesthesia techniques that reduce blood loss. Better and newer blood screening methods have decreased the infectious complications to almost negligible levels. With universal leukoreduction of red blood cells (RBCs), selection of potential donors such as use of male donors only plasma and restriction of RBC storage, most of the non-infectious complications can be avoided. PMID:25535415

  14. Efficient evaluation of the material response of tissues reinforced by statistically oriented fibres

    NASA Astrophysics Data System (ADS)

    Hashlamoun, Kotaybah; Grillo, Alfio; Federico, Salvatore

    2016-10-01

    For several classes of soft biological tissues, modelling complexity is in part due to the arrangement of the collagen fibres. In general, the arrangement of the fibres can be described by defining, at each point in the tissue, the structure tensor (i.e. the tensor product of the unit vector of the local fibre arrangement by itself) and a probability distribution of orientation. In this approach, assuming that the fibres do not interact with each other, the overall contribution of the collagen fibres to a given mechanical property of the tissue can be estimated by means of an averaging integral of the constitutive function describing the mechanical property at study over the set of all possible directions in space. Except for the particular case of fibre constitutive functions that are polynomial in the transversely isotropic invariants of the deformation, the averaging integral cannot be evaluated directly, in a single calculation because, in general, the integrand depends both on deformation and on fibre orientation in a non-separable way. The problem is thus, in a sense, analogous to that of solving the integral of a function of two variables, which cannot be split up into the product of two functions, each depending only on one of the variables. Although numerical schemes can be used to evaluate the integral at each deformation increment, this is computationally expensive. With the purpose of containing computational costs, this work proposes approximation methods that are based on the direct integrability of polynomial functions and that do not require the step-by-step evaluation of the averaging integrals. Three different methods are proposed: (a) a Taylor expansion of the fibre constitutive function in the transversely isotropic invariants of the deformation; (b) a Taylor expansion of the fibre constitutive function in the structure tensor; (c) for the case of a fibre constitutive function having a polynomial argument, an approximation in which the

  15. Fat mass- and obesity-associated gene Fto affects the dietary response in mouse white adipose tissue.

    PubMed

    Ronkainen, Justiina; Huusko, Tuija J; Soininen, Raija; Mondini, Eleonora; Cinti, Francesca; Mäkelä, Kari A; Kovalainen, Miia; Herzig, Karl-Heinz; Järvelin, Marjo-Riitta; Sebert, Sylvain; Savolainen, Markku J; Salonurmi, Tuire

    2015-03-18

    Common variants of human fat mass- and obesity-associated gene Fto have been linked with higher body mass index, but the biological explanation for the link has remained obscure. Recent findings suggest that these variants affect the homeobox protein IRX3. Here we report that FTO has a role in white adipose tissue which modifies its response to high-fat feeding. Wild type and Fto-deficient mice were exposed to standard or high-fat diet for 16 weeks after which metabolism, behavior and white adipose tissue morphology were analyzed together with adipokine levels and relative expression of genes regulating white adipose tissue adipogenesis and Irx3. Our results indicate that Fto deficiency increases the expression of genes related to adipogenesis preventing adipocytes from becoming hypertrophic after high-fat diet. In addition, we report a novel finding of increased Irx3 expression in Fto-deficient mice after high-fat feeding indicating a complex link between FTO, IRX3 and fat metabolism.

  16. Puerarin protects brain tissue against cerebral ischemia/reperfusion injury by inhibiting the inflammatory response

    PubMed Central

    Zhou, Feng; Wang, Liang; Liu, Panpan; Hu, Weiwei; Zhu, Xiangdong; Shen, Hong; Yao, Yuanyuan

    2014-01-01

    Puerarin, a traditional Chinese medicine, exerts a powerful neuroprotective effect in cerebral ischemia/reperfusion injury, but its mechanism is unknown. Here, we established rat models of middle cerebral artery ischemia/reperfusion injury using the suture method. Puerarin (100 mg/kg) was administered intraperitoneally 30 minutes before middle cerebral artery occlusion and 8 hours after reperfusion. Twenty-four hours after reperfusion, we found that puerarin significantly improved neurological deficit, reduced infarct size and brain water content, and notably diminished the expression of Toll-like receptor-4, myeloid differentiation factor 88, nuclear factor kappa B and tumor necrosis factor-α in the ischemic region. These data indicate that puerarin exerts an anti-inflammatory protective effect on brain tissue with ischemia/reperfusion damage by downregulating the expression of multiple inflammatory factors. PMID:25657724

  17. Molecular Imaging Using Fluorescence and Bioluminescence to Reveal Tissue Response to Laser-Mediated Thermal Injury

    NASA Astrophysics Data System (ADS)

    Mackanos, Mark A.; Jansen, E. Duco; Contag, Christopher H.

    For decades biological investigation has focused on a reductionist approach, which has greatly advanced our understanding of the biological process, but has also served to move the analysis further and further away from the living body. This was necessary as we sought to identify the cells, genes, mutations and/or etiological agents that were associated with a given process. The information generated through these approaches can now be used to advance more integrative strategies in which specific cellular and molecular events can be studied in context of the functional circulation and intact organ systems of living animals, and humans. Essential tools for integrative analyses of biology include imaging modalities that enable visualization of structure and function in the living body. The relatively recent development of molecular probes as exogenous contrast agents and reporter genes that encode proteins with unique properties that can be distinguished from tissues and cells has ushered in a new set of approaches that are being called molecular imaging.

  18. Renal Proteomic Responses to Severe Sepsis and Surgical Trauma: Dynamic Analysis of Porcine Tissue Biopsies.

    PubMed

    Matejovic, Martin; Tuma, Zdenek; Moravec, Jiri; Valesova, Lenka; Sykora, Roman; Chvojka, Jiri; Benes, Jan; Mares, Jan

    2016-10-01

    Although the burden of septic acute kidney injury continues to increase, the molecular pathogenesis remains largely obscure. The aim of this exploratory study was a discovery-driven analysis of dynamic kidney tissue protein expression changes applied for the first time in a classic large mammal model of sepsis. To achieve this goal, analyses of protein expression alterations were performed in serial samples of kidney cortical biopsies (before, 12 and 22 h of sepsis) in mechanically ventilated pigs challenged with continuous infusion of pseudomonas aeruginosa and compared with sham-operated control data. Global protein expression was analyzed using two-dimensional gel electrophoresis and mass spectrometry-based proteomics. Normodynamic sepsis was associated with 43% reduction in glomerular filtration. The exposure to surgical stress per se altered the renal protein expression profile, while sepsis induced distinct and highly dynamic proteome evolution shifting the balance toward cellular distress phenotype. We identified 20 proteins whose expression changes discriminated effects of sepsis from those induced by surgery. The data implicate endoplasmic reticulum stress, oxidative stress, mitochondrial energy metabolism, immune/inflammatory signaling, and tubular transport as major activated pathways. Thus, by coupling the power of sequential tissue proteomics with whole-animal physiological studies, our study helped to establish a first global overview of critical renal proteomic events occurring during surgical trauma and early sepsis in a porcine model. The study supports the notion that multiple potentially subtle and even transient changes in several proteins which are members of key functional interrelated systems appear to play a role in septic acute kidney injury. PMID:27070328

  19. Non-damaging laser therapy of the macula: Titration algorithm and tissue response

    NASA Astrophysics Data System (ADS)

    Palanker, Daniel; Lavinsky, Daniel; Dalal, Roopa; Huie, Philip

    2014-02-01

    Retinal photocoagulation typically results in permanent scarring and scotomata, which limit its applicability to the macula, preclude treatments in the fovea, and restrict the retreatments. Non-damaging approaches to laser therapy have been tested in the past, but the lack of reliable titration and slow treatment paradigms limited their clinical use. We developed and tested a titration algorithm for sub-visible and non-damaging treatments of the retina with pulses sufficiently short to be used with pattern laser scanning. The algorithm based on Arrhenius model of tissue damage optimizes the power and duration for every energy level, relative to the threshold of lesion visibility established during titration (and defined as 100%). Experiments with pigmented rabbits established that lesions in the 50-75% energy range were invisible ophthalmoscopically, but detectable with Fluorescein Angiography and OCT, while at 30% energy there was only very minor damage to the RPE, which recovered within a few days. Patients with Diabetic Macular Edema (DME) and Central Serous Retinopathy (CSR) have been treated over the edematous areas at 30% energy, using 200μm spots with 0.25 diameter spacing. No signs of laser damage have been detected with any imaging modality. In CSR patients, subretinal fluid resolved within 45 days. In DME patients the edema decreased by approximately 150μm over 60 days. After 3-4 months some patients presented with recurrence of edema, and they responded well to retreatment with the same parameters, without any clinically visible damage. This pilot data indicates a possibility of effective and repeatable macular laser therapy below the tissue damage threshold.

  20. Novel porous scaffolds of pH responsive chitosan/carrageenan-based polyelectrolyte complexes for tissue engineering.

    PubMed

    Araujo, J V; Davidenko, N; Danner, M; Cameron, R E; Best, S M

    2014-12-01

    Polyelectrolyte complexes (PECs) represent promising materials for drug delivery and tissue engineering applications. These substances are obtained in aqueous medium without the need for crosslinking agents. PECs can be produced through the combination of oppositely charged medical grade polymers, which include the stimuli responsive ones. In this work, three-dimensional porous scaffolds were produced through the lyophilization of pH sensitive PECs made of chitosan (CS) and carrageenan (CRG). CS:CRG molar ratios of 1:1 (CSCRG1), 2:1 (CSCRG2), and 3:1 (CSCRG3) were used. The chemical compositions of the PECs, as well as their influence in the final structure of the scaffolds were meticulously studied. In addition, the pH responsiveness of the PECs in a range including the physiological pH values of 7.4 (simulating normal physiological conditions) and 4.5 (simulating inflammatory response) was assessed. Results showed that the PECs produced were stable at pH values of 7.4 and under but dissolved as the pH increased to nonphysiological values of 9 and 11. However, after dissolution, the PEC could be reprecipitated by decreasing the pH to values close to 4.5. The scaffolds obtained presented large and interconnected pores, being equally sensitive to changes in the pH. CSCRG1 scaffolds appeared to have higher hydrophilicity and therefore higher water absorption capacity. The increase in the CS:CRG molar ratios improved the scaffold mechanical properties, with CSCRG3 presenting the higher compressive modulus under wet conditions. Overall, the PEC scaffolds appear promising for tissue engineering related applications that require the use of pH responsive materials stable at physiological conditions.

  1. Optimization of microwave-assisted extraction for six inorganic and organic arsenic species in chicken tissues using response surface methodology.

    PubMed

    Zhang, Wenfeng; Hu, Yuanan; Cheng, Hefa

    2015-09-01

    Response surface methodology was applied to optimize the parameters for microwave-assisted extraction of six major inorganic and organic arsenic species (As(III), As(V), dimethyl arsenic acid, monomethyl arsenic acid, p-arsanilic acid, and roxarsone) from chicken tissues, followed by detection using a high-performance liquid chromatography with inductively coupled mass spectrometry detection method, which allows the simultaneous analysis of both inorganic and organic arsenic species in the extract in a single run. Effects of extraction medium, solution pH, liquid-to-solid ratio, and the temperature and time of microwave-assisted extraction on the extraction of the targeted arsenic species were studied. The optimum microwave-assisted extraction conditions were: 100 mg of chicken tissue, extracted by 5 mL of 22% v/v methanol, 90 mmol/L (NH4 )2 HPO4 , and 0.07% v/v trifluoroacetic acid (with pH adjusted to 10.0 by ammonium hydroxide solution), ramping for 10 min to 71°C, and holding for 11 min. The method has good extraction performance for total arsenic in the spiked and nonspiked chicken tissues (104.0 ± 13.8% and 91.6 ± 7.8%, respectively), except for the ones with arsenic contents close to the quantitation limits. Limits of quantitation (S/N = 10) for As(III), As(V), dimethyl arsenic acid, monomethyl arsenic acid, p-arsanilic acid, and roxarsone in chicken tissues using this method were 0.012, 0.058, 0.039, 0.061, 0.102, and 0.240 mg/kg (dry weight), respectively.

  2. RNA-Seq Analysis of the Host Response to Staphylococcus aureus Skin and Soft Tissue Infection in a Mouse Model

    PubMed Central

    Brady, Rebecca A.; Bruno, Vincent M.; Burns, Drusilla L.

    2015-01-01

    Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTI), which are primarily self-limiting. We conducted a comprehensive analysis of the host transcriptome during a S. aureus SSTI to provide insight on the protective mechanisms that thwart these infections. We utilized a murine SSTI model in which one ear is epicutaneously challenged while the other is not. We then harvested these infected and uninfected ears, as well as ears from naïve mice, at one, four, and seven days post-challenge, and performed RNA sequencing (RNA-seq) using the Illumina platform. RNA-seq data demonstrated a robust response at the site of infection. Comparison of gene expression profiles between infected ears and the non-infected ears of challenged mice defined the local response to infection, while comparisons of expression profiles of non-infected ears from challenged mice to ears of naïve mice revealed changes in gene expression levels away from the site indicative of a systemic response. Over 1000 genes exhibited increased expression locally at all tested time points. The local response was more robust than the systemic response. Through evaluation of the RNA-seq data using the Upstream Regulator Analytic as part of the Ingenuity Pathway Analysis software package, we found that changes in the activation and inhibition of regulatory pathways happen first locally, and lag behind systemically. The activated pathways are highly similar at all three time points during SSTI, suggesting a stable global response over time. Transcript increases and pathway activation involve pro- and anti-inflammatory mediators, chemotaxis, cell signaling, keratins, and TH1/TH17 cytokines. Transcript decreases and pathway inhibition demonstrate that metabolic genes and anti-inflammatory pathways are repressed. These data provide insight on the host responses that may aid in resolution of this self-limited S. aureus infection, and may shed light on potential immune correlates of

  3. Overexpression of the CBF2 transcriptional activator in Arabidopsis suppresses the responsiveness of leaf tissue to the stress hormone ethylene.

    PubMed

    Sharabi-Schwager, M; Samach, A; Porat, R

    2010-07-01

    The plant hormone ethylene affects myriad developmental processes ranging from seed germination to organ senescence, and plays a crucial role in plant resistance to environmental stresses. The C-repeat/dehydration-responsive element binding factor genes (CBF1-3) are transcriptional activators involved in plant low-temperatures responses; their overexpression enhances frost tolerance, but also has various pleiotropic effects on growth and development, mainly growth retardation and delay of flowering and senescence. We found that overexpression of CBF2 in Arabidopsis suppressed leaf tissue responsiveness to ethylene as compared with wild-type plants, as manifested in significantly delayed senescence and chlorophyll degradation. In wild-type plants, exposure to ethylene at 0.1 microl.l(-1) for 48 h caused 50% reduction in chlorophyll levels as compared to leaves held in air alone, whereas CBF2-overexpressing plants required an ethylene concentration of 10.0 microl.l(-1) to cause the same effect. Furthermore, continuous exposure to ethylene at 1.0 microl.l(-1) reduced chlorophyll content in wild-type leaves by 50% after 42 h but took 72 h in CBF2-overexpressing plants. Transcript profiling of ethylene receptors and signal transduction genes in leaves of wild-type and CBF2-overexpressing plants, by means of the Affymetrix ATH1 genome array, revealed only minor differences in gene expression patterns - insufficient to explain the observed responsiveness differences. Nevertheless, we found that overexpression of CBF2 significantly increased transcript levels of 17 ABA biosynthetic and responsive genes and, thus, may have affected leaf responsiveness to ethylene via contrasting interactions with other hormones, mainly ABA. Overall, the current findings suggest that overexpression of the CBF2 transcriptional activator in Arabidopsis may, at least in part, contribute to the observed delay of leaf senescence and enhanced plant fitness by suppressing leaf responsiveness to

  4. Investigation of the soluble metals in tissue as biological response pattern to environmental pollutants (Gammarus fossarum example).

    PubMed

    Filipović Marijić, Vlatka; Dragun, Zrinka; Sertić Perić, Mirela; Matoničkin Kepčija, Renata; Gulin, Vesna; Velki, Mirna; Ečimović, Sandra; Hackenberger, Branimir K; Erk, Marijana

    2016-07-01

    In the present study, Gammarus fossarum was used to investigate the bioaccumulation and toxic effects of aquatic pollutants in the real environmental conditions. The novelty of the study is the evaluation of soluble tissue metal concentrations in gammarids as indicators in early assessment of metal exposure. In the Sutla River, industrially/rurally/agriculturally influenced catchment in North-Western Croatia, physico-chemical water properties pointed to disturbed ecological status, which was reflected on population scale as more than 50 times lower gammarid density compared to the reference location, Črnomerec Stream. Significantly higher levels of soluble toxic metals (Al, As, Cd, Pb, Sb, Sn, Sr) were observed in gammarids from the Sutla River compared to the reference site and reflected the data on higher total dissolved metal levels in the river water at that site. The soluble metal estimates were supplemented with the common multibiomarker approach, which showed significant biological responses for decreased acetylcholinesterase activity and increased total soluble protein concentrations, confirming stressed environmental conditions for biota in the Sutla River. Biomarker of metal exposure, metallothionein, was not induced and therefore, toxic effect of metals was not confirmed on molecular level. Comparable between-site pattern of soluble toxic metals in gammarids and total dissolved metal levels in water suggests that prior to biomarker response and observed toxic impact, soluble metals in tissue might be used as early warning signs of metal impact in the aquatic environment and improve the assessment of water quality.

  5. Promoter Complexity and Tissue-Specific Expression of Stress Response Components in Mytilus galloprovincialis, a Sessile Marine Invertebrate Species

    PubMed Central

    Pantzartzi, Chrysa; Drosopoulou, Elena; Yiangou, Minas; Drozdov, Ignat; Tsoka, Sophia; Ouzounis, Christos A.; Scouras, Zacharias G.

    2010-01-01

    The mechanisms of stress tolerance in sessile animals, such as molluscs, can offer fundamental insights into the adaptation of organisms for a wide range of environmental challenges. One of the best studied processes at the molecular level relevant to stress tolerance is the heat shock response in the genus Mytilus. We focus on the upstream region of Mytilus galloprovincialis Hsp90 genes and their structural and functional associations, using comparative genomics and network inference. Sequence comparison of this region provides novel evidence that the transcription of Hsp90 is regulated via a dense region of transcription factor binding sites, also containing a region with similarity to the Gamera family of LINE-like repetitive sequences and a genus-specific element of unknown function. Furthermore, we infer a set of gene networks from tissue-specific expression data, and specifically extract an Hsp class-associated network, with 174 genes and 2,226 associations, exhibiting a complex pattern of expression across multiple tissue types. Our results (i) suggest that the heat shock response in the genus Mytilus is regulated by an unexpectedly complex upstream region, and (ii) provide new directions for the use of the heat shock process as a biosensor system for environmental monitoring. PMID:20628614

  6. Investigation of the soluble metals in tissue as biological response pattern to environmental pollutants (Gammarus fossarum example).

    PubMed

    Filipović Marijić, Vlatka; Dragun, Zrinka; Sertić Perić, Mirela; Matoničkin Kepčija, Renata; Gulin, Vesna; Velki, Mirna; Ečimović, Sandra; Hackenberger, Branimir K; Erk, Marijana

    2016-07-01

    In the present study, Gammarus fossarum was used to investigate the bioaccumulation and toxic effects of aquatic pollutants in the real environmental conditions. The novelty of the study is the evaluation of soluble tissue metal concentrations in gammarids as indicators in early assessment of metal exposure. In the Sutla River, industrially/rurally/agriculturally influenced catchment in North-Western Croatia, physico-chemical water properties pointed to disturbed ecological status, which was reflected on population scale as more than 50 times lower gammarid density compared to the reference location, Črnomerec Stream. Significantly higher levels of soluble toxic metals (Al, As, Cd, Pb, Sb, Sn, Sr) were observed in gammarids from the Sutla River compared to the reference site and reflected the data on higher total dissolved metal levels in the river water at that site. The soluble metal estimates were supplemented with the common multibiomarker approach, which showed significant biological responses for decreased acetylcholinesterase activity and increased total soluble protein concentrations, confirming stressed environmental conditions for biota in the Sutla River. Biomarker of metal exposure, metallothionein, was not induced and therefore, toxic effect of metals was not confirmed on molecular level. Comparable between-site pattern of soluble toxic metals in gammarids and total dissolved metal levels in water suggests that prior to biomarker response and observed toxic impact, soluble metals in tissue might be used as early warning signs of metal impact in the aquatic environment and improve the assessment of water quality. PMID:27060638

  7. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia.

    PubMed

    de Jonge, E; Dekkers, P E; Creasey, A A; Hack, C E; Paulson, S K; Karim, A; Kesecioglu, J; Levi, M; van Deventer, S J; van Der Poll, T

    2000-02-15

    Inhibition of the tissue factor pathway has been shown to attenuate the activation of coagulation and to prevent death in a gram-negative bacteremia primate model of sepsis. It has been suggested that tissue factor influences inflammatory cascades other than the coagulation system. The authors sought to determine the effects of 2 different doses of recombinant tissue factor pathway inhibitor (TFPI) on endotoxin-induced coagulant, fibrinolytic, and cytokine responses in healthy humans. Two groups, each consisting of 8 healthy men, were studied in a double-blind, randomized, placebo-controlled crossover study. Subjects were studied on 2 different occasions. They received a bolus intravenous injection of 4 ng/kg endotoxin, which was followed by a 6-hour continuous infusion of TFPI or placebo. Eight subjects received 0.05 mg/kg per hour TFPI after a bolus of 0.0125 mg/kg (low-dose group), and 8 subjects received 0.2 mg/kg per hour after a bolus of 0.05 mg/kg (high-dose group). Endotoxin injection induced the activation of coagulation, the activation and subsequent inhibition of fibrinolysis, and the release of proinflammatory and antiinflammatory cytokines. TFPI infusion induced a dose-dependent attenuation of thrombin generation, as measured by plasma F1 + 2 and thrombin-antithrombin complexes, with a complete blockade of coagulation activation after high-dose TFPI. Endotoxin-induced changes in the fibrinolytic system and cytokine levels were not altered by either low-dose or high-dose TFPI. The authors concluded that TFPI effectively and dose-dependently attenuates the endotoxin-induced coagulation activation in humans without influencing the fibrinolytic and cytokine response. (Blood. 2000;95:1124-1129)

  8. Amifostine Induces Antioxidant Enzymatic Activities in Normal Tissues and a Transplantable Tumor That Can Affect Radiation Response

    SciTech Connect

    Grdina, David J. Murley, Jeffrey S.; Kataoka, Yasushi; Baker, Kenneth L.; Kunnavakkam, Rangesh; Coleman, Mitchell C.; Spitz, Douglas R.

    2009-03-01

    Purpose: To determine whether amifostine can induce elevated manganese superoxide dismutase (SOD2) in murine tissues and a transplantable SA-NH tumor, resulting in a delayed tumor cell radioprotective effect. Methods and Materials: SA-NH tumor-bearing C3H mice were treated with a single 400 mg/kg or three daily 50 mg/kg doses of amifostine administered intraperitoneally. At selected time intervals after the last injection, the heart, liver, lung, pancreas, small intestine, spleen, and SA-NH tumor were removed and analyzed for SOD2, catalase, and glutathione peroxidase (GPx) enzymatic activity. The effect of elevated SOD2 enzymatic activity on the radiation response of SA-NH cells was determined. Results: SOD2 activity was significantly elevated in selected tissues and a tumor 24 h after amifostine treatment. Catalase and GPx activities remained unchanged except for significant elevations in the spleen. GPx was also elevated in the pancreas. SA-NH tumor cells exhibited a twofold elevation in SOD2 activity and a 27% elevation in radiation resistance. Amifostine administered in three daily fractions of 50 mg/kg each also resulted in significant elevations of these antioxidant enzymes. Conclusions: Amifostine can induce a delayed radioprotective effect that correlates with elevated levels of SOD2 activity in SA-NH tumor. If limited to normal tissues, this delayed radioprotective effect offers an additional potential for overall radiation protection. However, amifostine-induced elevation of SOD2 activity in tumors could have an unanticipated deleterious effect on tumor responses to fractionated radiation therapy, given that the radioprotector is administered daily just before each 2-Gy fractionated dose.

  9. Genomic and Histopathological Tissue Biomarkers That Predict Radiotherapy Response in Localised Prostate Cancer

    PubMed Central

    Wilkins, Anna; Dearnaley, David; Somaiah, Navita

    2015-01-01

    Localised prostate cancer, in particular, intermediate risk disease, has varied survival outcomes that cannot be predicted accurately using current clinical risk factors. External beam radiotherapy (EBRT) is one of the standard curative treatment options for localised disease and its efficacy is related to wide ranging aspects of tumour biology. Histopathological techniques including immunohistochemistry and a variety of genomic assays have been used to identify biomarkers of tumour proliferation, cell cycle checkpoints, hypoxia, DNA repair, apoptosis, and androgen synthesis, which predict response to radiotherapy. Global measures of genomic instability also show exciting capacity to predict survival outcomes following EBRT. There is also an urgent clinical need for biomarkers to predict the radiotherapy fraction sensitivity of different prostate tumours and preclinical studies point to possible candidates. Finally, the increased resolution of next generation sequencing (NGS) is likely to enable yet more precise molecular predictions of radiotherapy response and fraction sensitivity. PMID:26504789

  10. Exploring diazepam's effect on hemodynamic responses of mouse brain tissue by optical spectroscopic imaging.

    PubMed

    Abookasis, David; Shochat, Ariel; Nesher, Elimelech; Pinhasov, Albert

    2014-07-01

    In this study, a simple duel-optical spectroscopic imaging apparatus capable of simultaneously determining relative changes in brain oxy-and deoxy-hemoglobin concentrations was used following administration of the anxiolytic compound diazepam in mice with strong dominant (Dom) and submissive (Sub) behavioral traits. Three month old mice (n = 30) were anesthetized and after 10 min of baseline imaging, diazepam (1.5 mg/kg) was administered and measurements were taken for 80 min. The mouse head was illuminated by white light based LED's and diffused reflected light passing through different channels, consisting of a bandpass filter and a CCD camera, respectively, was collected and analyzed to measure the hemodynamic response. This work's major findings are threefold: first, Dom and Sub animals showed statistically significant differences in hemodynamic response to diazepam administration. Secondly, diazepam was found to more strongly affect the Sub group. Thirdly, different time-series profiles were observed post-injection, which can serve as a possible marker for the groups' differentiation. To the best of our knowledge, this is the first report on the effects of an anxiolytic drug on brain hemodynamic responses in mice using diffused light optical imaging. PMID:25071958

  11. Tissue-Specific Regulation of Gibberellin Signaling Fine-Tunes Arabidopsis Iron-Deficiency Responses.

    PubMed

    Wild, Michael; Davière, Jean-Michel; Regnault, Thomas; Sakvarelidze-Achard, Lali; Carrera, Esther; Lopez Diaz, Isabel; Cayrel, Anne; Dubeaux, Guillaume; Vert, Grégory; Achard, Patrick

    2016-04-18

    Iron is an essential element for most living organisms. Plants acquire iron from the rhizosphere and have evolved different biochemical and developmental responses to adapt to a low-iron environment. In Arabidopsis, FIT encodes a basic helix-loop-helix transcription factor that activates the expression of iron-uptake genes in root epidermis upon iron deficiency. Here, we report that the gibberellin (GA)-signaling DELLA repressors contribute substantially in the adaptive responses to iron-deficient conditions. When iron availability decreases, DELLAs accumulate in the root meristem, thereby restraining root growth, while being progressively excluded from epidermal cells in the root differentiation zone. Such DELLA exclusion from the site of iron acquisition relieves FIT from DELLA-dependent inhibition and therefore promotes iron uptake. Consistent with this mechanism, expression of a non-GA-degradable DELLA mutant protein in root epidermis interferes with iron acquisition. Hence, spatial distribution of DELLAs in roots is essential to fine-tune the adaptive responses to iron availability.

  12. Unconventional Human T Cells Accumulate at the Site of Infection in Response to Microbial Ligands and Induce Local Tissue Remodeling

    PubMed Central

    Liuzzi, Anna Rita; Kift-Morgan, Ann; Lopez-Anton, Melisa; Friberg, Ida M.; Zhang, Jingjing; Brook, Amy C.; Roberts, Gareth W.; Donovan, Kieron L.; Colmont, Chantal S.; Toleman, Mark A.; Bowen, Timothy; Johnson, David W.; Topley, Nicholas; Moser, Bernhard; Fraser, Donald J.

    2016-01-01

    The antimicrobial responsiveness and function of unconventional human T cells are poorly understood, with only limited access to relevant specimens from sites of infection. Peritonitis is a common and serious complication in individuals with end-stage kidney disease receiving peritoneal dialysis. By analyzing local and systemic immune responses in peritoneal dialysis patients presenting with acute bacterial peritonitis and monitoring individuals before and during defined infectious episodes, our data show that Vγ9/Vδ2+ γδ T cells and mucosal-associated invariant T cells accumulate at the site of infection with organisms producing (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and vitamin B2, respectively. Such unconventional human T cells are major producers of IFN-γ and TNF-α in response to these ligands that are shared by many microbial pathogens and affect the cells lining the peritoneal cavity by triggering local inflammation and inducing tissue remodeling with consequences for peritoneal membrane integrity. Our data uncover a crucial role for Vγ9/Vδ2 T cells and mucosal-associated invariant T cells in bacterial infection and suggest that they represent a useful predictive marker for important clinical outcomes, which may inform future stratification and patient management. These findings are likely to be applicable to other acute infections where local activation of unconventional T cells contributes to the antimicrobial inflammatory response. PMID:27527598

  13. A zebrafish larval model reveals early tissue-specific innate immune responses to Mucor circinelloides

    PubMed Central

    Voelz, Kerstin; Gratacap, Remi L.; Wheeler, Robert T.

    2015-01-01

    ABSTRACT Mucormycosis is an emerging fungal infection that is clinically difficult to manage, with increasing incidence and extremely high mortality rates. Individuals with diabetes, suppressed immunity or traumatic injury are at increased risk of developing disease. These individuals often present with defects in phagocytic effector cell function. Research using mammalian models and phagocytic effector cell lines has attempted to decipher the importance of the innate immune system in host defence against mucormycosis. However, these model systems have not been satisfactory for direct analysis of the interaction between innate immune effector cells and infectious sporangiospores in vivo. Here, we report the first real-time in vivo analysis of the early innate immune response to mucormycete infection using a whole-animal zebrafish larval model system. We identified differential host susceptibility, dependent on the site of infection (hindbrain ventricle and swim bladder), as well as differential functions of the two major phagocyte effector cell types in response to viable and non-viable spores. Larval susceptibility to mucormycete spore infection was increased upon immunosuppressant treatment. We showed for the first time that macrophages and neutrophils were readily recruited in vivo to the site of infection in an intact host and that spore phagocytosis can be observed in real-time in vivo. While exploring innate immune effector recruitment dynamics, we discovered the formation of phagocyte clusters in response to fungal spores that potentially play a role in fungal spore dissemination. Spores failed to activate pro-inflammatory gene expression by 6 h post-infection in both infection models. After 24 h, induction of a pro-inflammatory response was observed only in hindbrain ventricle infections. Only a weak pro-inflammatory response was initiated after spore injection into the swim bladder during the same time frame. In the future, the zebrafish larva as a live

  14. Adverse Stress, Hippocampal Networks, and Alzheimer's Disease

    PubMed Central

    Rothman, Sarah M.; Mattson, Mark P.

    2009-01-01

    Recent clinical data have implicated chronic adverse stress as a potential risk factor in the development of Alzheimer's disease (AD) and data also suggest that normal, physiological stress responses may be impaired in AD. It is possible that pathology associated with AD causes aberrant responses to chronic stress, due to potential alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Recent work in rodent models of AD suggests that chronic adverse stress exacerbates the cognitive deficits and hippocampal pathology that are present in the AD brain. This review summarizes recent findings obtained in experimental AD models regarding the influence of chronic adverse stress on the underlying cellular and molecular disease processes including the potential role of glucocorticoids. Emerging findings suggest that both AD and chronic adverse stress affect hippocampal neural networks in a similar fashion. We describe alterations in hippocampal plasticity that occur in both chronic stress and AD including dendritic remodeling, neurogenesis and long-term potentiation. Finally, we outline potential roles for oxidative stress and neurotrophic factor signaling as key determinants of the impact of chronic stress on the plasticity of neural networks and AD pathogenesis. PMID:19943124

  15. Mammalian Tissue Response to Low Dose Ionizing Radiation: The Role of Oxidative Metabolism and Intercellular Communication

    SciTech Connect

    Azzam, Edouard I

    2013-01-16

    The objective of the project was to elucidate the mechanisms underlying the biological effects of low dose/low dose rate ionizing radiation in organs/tissues of irradiated mice that differ in their susceptibility to ionizing radiation, and in human cells grown under conditions that mimic the natural in vivo environment. The focus was on the effects of sparsely ionizing cesium-137 gamma rays and the role of oxidative metabolism and intercellular communication in these effects. Four Specific Aims were proposed. The integrated outcome of the experiments performed to investigate these aims has been significant towards developing a scientific basis to more accurately estimate human health risks from exposures to low doses ionizing radiation. By understanding the biochemical and molecular changes induced by low dose radiation, several novel markers associated with mitochondrial functions were identified, which has opened new avenues to investigate metabolic processes that may be affected by such exposure. In particular, a sensitive biomarker that is differentially modulated by low and high dose gamma rays was discovered.

  16. Response of endophytic bacterial communities in banana tissue culture plantlets to Fusarium wilt pathogen infection.

    PubMed

    Lian, Jie; Wang, Zifeng; Zhou, Shining

    2008-04-01

    Endophytic bacteria reside within plant hosts without having pathogenic effects, and various endophytes have been found to functionally benefit plant disease suppressive ability. In this study, the influence of banana plant stress on the endophytic bacterial communities, which was achieved by infection with the wilt pathogen Fusarium oxysporum f. sp. cubense, was examined by cultivation-independent denaturing gradient gel electrophoresis analysis of 16S ribosomal DNA directly amplified from plant tissue DNA. Community analysis clearly demonstrated increased bacterial diversity in pathogen-infected plantlets compared to that in control plantlets. By sequencing, bands most similar to species of Bacillus and Pseudomonas showed high density in the pathogen-treated pattern. In vitro screening of the isolates for antagonistic activity against Fusarium wilt pathogen acquired three strains of endophytic bacteria which were found to match those species that obviously increased in the pathogen infection process; moreover, the most inhibitive strain could also interiorly colonize plantlets and perform antagonism. The evidence obtained from this work showed that antagonistic endophytic bacteria could be induced by the appearance of a host fungal pathogen and further be an ideal biological control agent to use in banana Fusarium wilt disease protection.

  17. Proteomic response of Trichoderma aggressivum f. europaeum to Agaricus bisporus tissue and mushroom compost.

    PubMed

    O'Brien, Matt; Grogan, Helen; Kavanagh, Kevin

    2014-01-01

    A cellular proteomic analysis was performed on Trichoderma aggressivum f. europaeum. Thirty-four individual protein spots were excised from 2-D electropherograms and analysed by ESI-Trap Liquid Chromatography Mass Spectrometry (LC/MS). Searches of the NCBInr and SwissProt protein databases identified functions for 31 of these proteins based on sequence homology. A differential expression study was performed on the intracellular fraction of T. aggressivum f. europaeum grown in media containing Agaricus bisporus tissue and Phase 3 mushroom compost compared to a control medium. Differential expression was observed for seven proteins, three of which were upregulated in both treatments, two were down regulated in both treatments and two showed qualitatively different regulation under the two treatments. No proteins directly relating to fungal cell wall degradation or other mycoparasitic activity were observed. Functions of differentially produced intracellular proteins included oxidative stress tolerance, cytoskeletal structure, and cell longevity. Differential production of these proteins may contribute to the growth of T. aggressivum in mushroom compost and its virulence toward A. bisporus. PMID:25209637

  18. In-house coordination project for organ and tissue procurement: social responsibility and promising results 1

    PubMed Central

    Silva, Vanessa Silva e; Moura, Luciana Carvalho; Martins, Luciana Ribeiro; dos Santos, Roberta Cristina Cardoso; Schirmer, Janine; Roza, Bartira de Aguiar

    2016-01-01

    Abstract Objectives: to report the results of evaluation regarding changes in the number of potential donor referrals, actual donors, and conversion rates after the implementation of an in-house organ and tissue donation for transplantation coordination project. Methods: epidemiological study, both retrospective and transversal, was performed with organ donation data from the Secretariat of Health for the State and the in-house organ donation coordination project of a beneficent hospital. The data was compared using nonparametric statistical Mann-Whitney test, and the Student's t-test, considering a significance level of 5% (p <0.05). Results: there were statistically significant differences (p < 0.05), before and after the implementation of the project on the number of potential donor notification/month (3.05 - 4.7 ), number of actual donor/month (0.78 to 1.60) and rate of conversion ( 24.7 to 34.8 %). The hospitals 1, 2, 7 and 8 had significant results in potential donor, actual donor or conversion rate. Conclusion: the presence of an in-house coordinator is promising and beneficial, the specialist is important to change the indicators of efficiency, which consequently reduces the waiting lists for organ transplants. PMID:27463111

  19. Study of the response of osteogenic sarcoma and adjacent normal tissues to radiation. [/sup 60/Co

    SciTech Connect

    Gaitan-Yanguas, M.

    1981-05-01

    An analysis is made of the surgical specimens of 18 patients with hystologically-proven osteosarcoma who were treated with radiation as the first treatment, and submitted 6 months later to amputation (2 patients had only a second biopsy). Plotting of dose and treatment time against persistence or sterilization of the tumor shows that there is an intermediate zone that extends from 3200 to 5000 rad in 10 days to 8000 to 10,000 rad in 60 to 70 days, inside which the tumor may or may not be destroyed. All cases located above this zone were sterilized; and all those under it showed persistence of viable tumor cells. A similar correlation is made in 47 irradiated patients of the secondary reactions of normal skin and soft tissues surrounding the tumor. An intermediate zone also exists above which all reactions were severe, in some cases reaching necrosis; below this zone, all reactions were mild. When treatment time was longer than 45 days, reactions were only moderate.

  20. Tissue specific response of Miscanthus×giganteus to dilute acid pretreatment for enhancing cellulose digestibility.

    PubMed

    Ji, Zhe; Zhang, Xun; Ling, Zhe; Sun, Run-Cang; Xu, Feng

    2016-12-10

    The recalcitrance in grasses varies according to cell type and tissue. In this study, dilute acid pretreatment was performed on Miscanthus×giganteus internodes that include rind and pith regions which showing heterogeneous structural and chemical changes. Pretreatment on pith effectively hydrolyzed 73.33% hemicelluloses and separated cohesive cell walls from the compound middle lamella due to lignin migration. Lignin droplets with an average diameter of 49.5±29.3nm were concurrently coalesced on wall surface, that in turn exposed more microfibrils deep in walls to be enzymatically hydrolyzed reaching 82.55%. By contrast, the rind with a relatively intergrated cell structure was covered by larger lignin droplets (101.2±44.1nm) and filled with inaccessible microfibrils limiting enzymatic sacchrification (31.50%). Taken together, the cellulose digestibility of biomass was not majorly influenced by cellulose crystallinity, while it was strongly correlated with the positive effects of hemicelluloses degradation, lignin redistribution, cellulose exposure and loosening cell wall structure. PMID:27577916

  1. Histomorphometric analysis of tissue responses to bioactive glass implants in critical defects in rat calvaria.

    PubMed

    Cardoso, Ana Karina M V; Barbosa, Aryon de Almeida; Miguel, Fúlvio Borges; Marcantonio, Elcio; Farina, Marcos; Soares, Glória Dulce de Almeida; Rosa, Fabiana Paim

    2006-01-01

    The aim of this study was to evaluate the osteogenic behavior of two chemically similar bioactive glass products (Biogranand Perioglas) implanted in critical bone defects in rat calvaria. Thirty-six transfixed bone defects of 8 mm diameter were made surgically in adult male Wistar rats. The animals were distributed equally into three groups: Biogran (GI), Perioglas (GII) and without implant material (control; GIII). The morphology and composition of both bioactive glasses were analyzed by scanning electron microscopy and energy-dispersive spectrometry. Tissue specimens were analyzed at the biological time points of 15, 30 and 60 days by optical microscopy and morphometry, demonstrating biocompatibility for the tested materials with moderate chronic inflammation involving their particles. Bone neoformation resulted only as a reparative reaction to an intentionally produced defect and was limited to the defect's edges. No statistically significant differences among the groups were observed. At the scar interstice, abundant deposits of collagenous fibers enveloping the particles were noted. The present results indicated that the bioactive glasses, under the experimental conditions analyzed, did not show osteogenic behavior.

  2. Immune Response Gene Expression in Colorectal Cancer Carries Distinct Prognostic Implications According to Tissue, Stage and Site: A Prospective Retrospective Translational Study in the Context of a Hellenic Cooperative Oncology Group Randomised Trial

    PubMed Central

    Pentheroudakis, George; Raptou, Georgia; Kotoula, Vassiliki; Wirtz, Ralph M.; Vrettou, Eleni; Karavasilis, Vasilios; Gourgioti, Georgia; Gakou, Chryssa; Syrigos, Konstantinos N.; Bournakis, Evangelos; Rallis, Grigorios; Varthalitis, Ioannis; Galani, Eleni; Lazaridis, Georgios; Papaxoinis, George; Pectasides, Dimitrios; Aravantinos, Gerasimos; Makatsoris, Thomas; Kalogeras, Konstantine T.; Fountzilas, George

    2015-01-01

    Background Although host immune response is an emerging prognostic factor for colorectal cancer, there is no consensus on the optimal methodology, surrogate markers or tissue for study. Patients and Methods Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour, invasive margin and adjacent normal mucosa. Results Lymphocytic infiltration, deficient MMR (10.9%), KRAS (40.7%) and BRAF (4.9%) mutations or single mRNA gene expression were not prognostic. Tumour ESR1 gene expression (Hazard Ratio [HR] for relapse 2.33, 95% CI 1.35-4.02; HR for death 1.74, 95% CI 1.02-2.97) and absence of necrosis (HR for relapse 1.71, 95% CI 1.05-2.71; HR for death 1.98, 95% CI 1.14-3.43) were adverse prognostic features. We used CD3Z and CD8 expression in order to devise the mRNA-based Immune Score (mIS) and proceeded to partitioning analysis in 267 patients, with age, stage, tumour site (Right vs Left CRC), KRAS mutation and tumour mIS as input factors. Only in patients with stage III right-sided colon cancer, a low immune response was associated with inferior disease-free survival (mIS-low, HR for relapse 2.28, 95% CI 1.05-8.02). No prognostic significance was seen for tumour mIS in any other stage or site of CRC, or for a similar mIS score derived from adjacent normal mucosa. Independent adverse prognostic significance was retained in multivariable analysis for absence of necrosis, tumour ESR1 expression in all patients and low tumour mIS in stage III right-sided CRC. Conclusions In localised CRC, mRNA-based CD3Z/CD8 profiling of tumour immune response may have stage, site and tissue-specific prognostic significance, along with ESR1 expression. Trial Registration ANZCTR.org.au ACTRN

  3. Genome-wide identification of auxin response factor (ARF) genes and its tissue-specific prominent expression in Gossypium raimondii.

    PubMed

    Sun, Runrun; Wang, Kunbo; Guo, Tenglong; Jones, Don C; Cobb, Juliana; Zhang, Baohong; Wang, Qinglian

    2015-07-01

    Auxin response factors (ARFs) are recently discovered transcription factors that bind with auxin response elements (AuxRE, TGTCTC) to regulate the expression of early auxin-responsive genes. To our knowledge, the ARF gene family has never been characterized in cotton, the most important fiber crop in the world. In this study, a total of 35 ARF genes, named as GrARFs, were identified in a diploid cotton species Gossypium raimondii. The 35 ARF genes were located in 12 of the 13 cotton chromosomes; the intron/exon distribution of the GrARF genes was similar among sister pairs, whereas the divergence of some GrARF genes suggests the possibility of functional diversification. Our results show that the middle domains of nine GrARF proteins rich in glutamine (Q) are activators, while 26 other GrARF proteins rich in proline (P), serine (S), and threonine (T) are repressors. Our results also show that the expression of GrARF genes is diverse in different tissues. The expression of GrARF1 was significantly higher in leaves, whereas GrARF2a had higher expression level in shoots, which implicates different roles in the tested tissues. The GrARF11 has a higher expression level in buds than that in leaves, while GrARF19.2 shows contrasting expression patterns, having higher expression in leaves than that in buds. This suggests that they play different roles in leaves and buds. During long-term evolution of G. raimondii, some ARF genes were lost and some arose. The identification and characterization of the ARF genes in G. raimondii elucidate its important role in cotton that ARF genes regulate the development of flower buds, sepals, shoots, and leaves.

  4. Differential Response of Heat Shock Proteins to Uphill and Downhill Exercise in Heart, Skeletal Muscle, Lung and Kidney Tissues

    PubMed Central

    Lollo, Pablo C. B.; Moura, Carolina S.; Morato, Priscila N.; Amaya-Farfan, Jaime

    2013-01-01

    Running on a horizontal plane is known to increase the concentration of the stress biomarker heat-shock protein (HSP), but no comparison of the expression of HSP70 has yet been established between the uphill (predominantly concentric) and downhill (predominantly eccentric) muscle contractions exercise. The objective of the study was to investigate the relationships between eccentric and concentric contractions on the HSP70 response of the lung, kidney, gastrocnemius, soleus and heart. Twenty-four male Wistar weanling rats were divided into four groups: non-exercised and three different grades of treadmill exercise groups: horizontal, uphill (+7%) and downhill (-7% of inclination). At the optimal time-point of six hours after the exercise, serum uric acid, creatine kinase (CK) and lactate dehydrogenase (LDH) were determined by standard methods and HSP70 by the Western blot analysis. HSP70 responds differently to different types of running. For kidney, heart, soleus and gastrocnemius, the HSP70 expression increased, 230, 180, 150 and 120% respectively of the reference (horizontal). When the contraction was concentric (uphill) and compared to downhill the increase in response of HSP70 was greater in 80% for kidney, 75% for gastrocnemius, 60% for soleus and 280% for the heart. Uric acid was about 50% higher (0.64 ± 0.03 mg·dL−1) in the uphill group as compared to the horizontal or downhill groups. Similarly, the activities of serum CK and LDH were both 100% greater for both the uphill and downhill groups as compared to the horizontal group (2383 ± 253 and 647.00 ± 73 U/L, respectively). The responsiveness of HSP70 appeared to be quite different depending on the type of tissue, suggesting that the impact of exercise was not restricted to the muscles, but extended to the kidney tissue. The uphill exercise increases HSP70 beyond the eccentric type and the horizontal running was a lower HSP70 responsive stimulus. Key Points Exercise can induce increases in HSP70 in

  5. Monitoring tissue inflammation and responses to drug treatments in early stages of mice bone fracture using 50 MHz ultrasound.

    PubMed

    Chen, Yen-Chu; Lin, Yi-Hsun; Wang, Shyh-Hau; Lin, Shih-Ping; Shung, K Kirk; Wu, Chia-Ching

    2014-01-01

    Bone fracture induces moderate inflammatory responses that are regulated by cyclooxygenase-2 (COX-2) or 5-lipoxygenase (5-LO) for initiating tissue repair and bone formation. Only a handful of non-invasive techniques focus on monitoring acute inflammation of injured bone currently exists. In the current study, we monitored in vivo inflammation levels during the initial 2 weeks of the inflammatory stage after mouse bone fracture utilizing 50 MHz ultrasound. The acquired ultrasonic images were correlated well with histological examinations. After the bone fracture in the tibia, dynamic changes in the soft tissue at the medial-posterior compartment near the fracture site were monitored by ultrasound on the days of 0, 2, 4, 7, and 14. The corresponding echogenicity increased on the 2nd, 4th, and 7th day, and subsequently declined to basal levels after the 14th day. An increase of cell death was identified by the positive staining of deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay and was consistent with ultrasound measurements. The increases of both COX-2 and Leukotriene B4 receptor 1 (BLT1, 5-LO-relative receptor), which are regulators for tissue inflammation, in the immunohistochemistry staining revealed their involvement in bone fracture injury. Monitoring the inflammatory response to various non-steroidal anti-inflammatory drugs (NSAIDs) treatments was investigated by treating injured mice with a daily oral intake of aspirin (Asp), indomethacin (IND), and a selective COX-2 inhibitor (SC-236). The Asp treatment significantly reduced fracture-increased echogenicity (hyperechogenicity, p<0.05) in ultrasound images as well as inhibited cell death, and expression of COX-2 and BLT1. In contrast, treatment with IND or SC-236 did not reduce the hyperechogenicity, as confirmed by cell death (TUNEL) and expression levels of COX-2 or BLT1. Taken together, the current study reports the feasibility of a non-invasive ultrasound method capable of monitoring post

  6. Monitoring tissue inflammation and responses to drug treatments in early stages of mice bone fracture using 50 MHz ultrasound.

    PubMed

    Chen, Yen-Chu; Lin, Yi-Hsun; Wang, Shyh-Hau; Lin, Shih-Ping; Shung, K Kirk; Wu, Chia-Ching

    2014-01-01

    Bone fracture induces moderate inflammatory responses that are regulated by cyclooxygenase-2 (COX-2) or 5-lipoxygenase (5-LO) for initiating tissue repair and bone formation. Only a handful of non-invasive techniques focus on monitoring acute inflammation of injured bone currently exists. In the current study, we monitored in vivo inflammation levels during the initial 2 weeks of the inflammatory stage after mouse bone fracture utilizing 50 MHz ultrasound. The acquired ultrasonic images were correlated well with histological examinations. After the bone fracture in the tibia, dynamic changes in the soft tissue at the medial-posterior compartment near the fracture site were monitored by ultrasound on the days of 0, 2, 4, 7, and 14. The corresponding echogenicity increased on the 2nd, 4th, and 7th day, and subsequently declined to basal levels after the 14th day. An increase of cell death was identified by the positive staining of deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay and was consistent with ultrasound measurements. The increases of both COX-2 and Leukotriene B4 receptor 1 (BLT1, 5-LO-relative receptor), which are regulators for tissue inflammation, in the immunohistochemistry staining revealed their involvement in bone fracture injury. Monitoring the inflammatory response to various non-steroidal anti-inflammatory drugs (NSAIDs) treatments was investigated by treating injured mice with a daily oral intake of aspirin (Asp), indomethacin (IND), and a selective COX-2 inhibitor (SC-236). The Asp treatment significantly reduced fracture-increased echogenicity (hyperechogenicity, p<0.05) in ultrasound images as well as inhibited cell death, and expression of COX-2 and BLT1. In contrast, treatment with IND or SC-236 did not reduce the hyperechogenicity, as confirmed by cell death (TUNEL) and expression levels of COX-2 or BLT1. Taken together, the current study reports the feasibility of a non-invasive ultrasound method capable of monitoring post

  7. 40 CFR 350.21 - Adverse health effects.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 28 2014-07-01 2014-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify...

  8. 40 CFR 350.21 - Adverse health effects.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 29 2013-07-01 2013-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify...

  9. 40 CFR 350.21 - Adverse health effects.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 29 2012-07-01 2012-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify...

  10. 40 CFR 350.21 - Adverse health effects.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 28 2011-07-01 2011-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify...

  11. 40 CFR 350.21 - Adverse health effects.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 27 2010-07-01 2010-07-01 false Adverse health effects. 350.21 Section... RIGHT-TO-KNOW INFORMATION: AND TRADE SECRET DISCLOSURES TO HEALTH PROFESSIONALS Trade Secrecy Claims § 350.21 Adverse health effects. The Governor or State emergency response commission shall identify...

  12. Synchronous changes in coral chromatophore tissue density and skeletal banding as an adaptive response to environmental change

    NASA Astrophysics Data System (ADS)

    Ardisana, R. N.; Miller, C. A.; Sivaguru, M.; Fouke, B. W.

    2013-12-01

    Corals are a key reservoir of biodiversity in coastal, shallow water tropical marine environments, and density banding in their aragonite skeletons is used as a sensitive record of paleoclimate. Therefore, the cellular response of corals to environmental change and its expression in skeletal structure is of significant importance. Chromatophores, pigment-bearing cells within the ectoderm of hermatypic corals, serve to both enhance the photosynthetic activity of zooxanthellae symbionts, as well as protect the coral animal from harmful UV radiation. Yet connections have not previously been drawn between chromatophore tissue density and the development of skeletal density bands. A histological analysis of the coral Montastrea faveolata has therefore been conducted across a bathymetric gradient of 1-20 m on the southern Caribbean island of Curaçao. A combination of field and laboratory photography, serial block face imaging (SBFI), two-photon laser scanning microscopy (TPLSM), and 3D image analysis has been applied to test whether M. faveolata adapts to increasing water depth and decreasing photosynthetically active radiation by shifting toward a more heterotrophic lifestyle (decreasing zooxanthellae tissue density, increasing mucocyte tissue density, and decreasing chromatophores density). This study is among the first to collect and evaluate histological data in the spatial context of an entire unprocessed coral polyp. TPLSM was used to optically thin section unprocessed tissue biopsies with quantitative image analysis to yield a nanometer-scale three-dimensional map of the quantity and distribution of the symbionts (zooxanthellae) and a host fluorescent pigments (chromatophores), which is thought to have photoprotective properties, within the context of an entire coral polyp. Preliminary results have offered new insight regarding the three-dimensional distribution and abundance of chromatophores and have identified: (1) M. faveolata tissue collected from 8M SWD do

  13. Brown Adipose Tissue Is Linked to a Distinct Thermoregulatory Response to Mild Cold in People

    PubMed Central

    Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Chao, Tony; Porter, Craig; Annamalai, Palam; Yfanti, Christina; Labbe, Sebastien M.; Hurren, Nicholas M.; Malagaris, Ioannis; Cesani, Fernardo; Sidossis, Labros S.

    2016-01-01

    Brown adipose tissue (BAT) plays an important role in thermoregulation in rodents. Its role in temperature homeostasis in people is less studied. To this end, we recruited 18 men [8 subjects with no/minimal BAT activity (BAT−) and 10 with pronounced BAT activity (BAT+)]. Each volunteer participated in a 6 h, individualized, non-shivering cold exposure protocol. BAT was quantified using positron emission tomography/computed tomography. Body core and skin temperatures were measured using a telemetric pill and wireless thermistors, respectively. Core body temperature decreased during cold exposure in the BAT− group only (−0.34°C, 95% CI: −0.6 to −0.1, p = 0.03), while the cold-induced change in core temperature was significantly different between BAT+ and BAT− subjects (BAT+ vs. BAT−, 0.43°C, 95% CI: 0.20–0.65, p = 0.0014). BAT volume was associated with the cold-induced change in core temperature (p = 0.01) even after adjustment for age and adiposity. Compared to the BAT− group, BAT+ subjects tolerated a lower ambient temperature (BAT−: 20.6 ± 0.3°C vs. BAT+: 19.8 ± 0.3°C, p = 0.035) without shivering. The cold-induced change in core temperature (r = 0.79, p = 0.001) and supraclavicular temperature (r = 0.58, p = 0.014) correlated with BAT volume, suggesting that these non-invasive measures can be potentially used as surrogate markers of BAT when other methods to detect BAT are not available or their use is not warranted. These results demonstrate a physiologically significant role for BAT in thermoregulation in people. This trial has been registered with Clinaltrials.gov: NCT01791114 (https://clinicaltrials.gov/ct2/show/NCT01791114). PMID:27148068

  14. Phylogenetic analysis and tissue distribution of elasmobranch glucose transporters and their response to feeding

    PubMed Central

    Deck, Courtney A.; LeMoine, Christophe M. R.; Walsh, Patrick J.

    2016-01-01

    ABSTRACT Elasmobranch diets consist of high quantities of protein and lipids, but very low levels of carbohydrates including glucose. Reflecting this diet, most tissues use lipids and ketone bodies as their main metabolic fuel. However, the rectal gland has been shown to be dependent on glucose as a fuel, so we hypothesized that glucose transporters (GLUTs) would be present and upregulated in the gland during times of activation (e.g. following a meal). In this study, we searched for and identified putative class I GLUTs in three elasmobranchs and a holocephalan using transcriptomes, and used these to reconstruct a Bayesian phylogeny. We determined that each of the four species possessed three of the four class I GLUT sequences, but the identities of the isoforms present in each species differed between the elasmobranchs (GLUT1, 3 and 4) and the holocephalan (GLUT1, 2 and 3). We then used qPCR to measure mRNA levels of these GLUTs in the rectal gland, liver, intestine, and muscle of fed and starved spiny dogfish (Squalus suckleyi). The rectal gland data showed higher mRNA levels of GLUT4 in the starved relative to the fed fish. In the muscle, both GLUT1 and 4 were significantly elevated at 24 h post-feeding, as was the case for GLUT4 in the liver. In the intestine on the other hand, GLUT4 was significantly elevated by 6 h post-feeding, remaining elevated through 48 h. We suggest that GLUT4 has taken on the role of GLUT2 in elasmobranchs as the expression patterns observed in the liver and intestine are representative of GLUT2 in other vertebrates. PMID:26873951

  15. Molecular response of 4T1-induced mouse mammary tumours and healthy tissues to zinc treatment.

    PubMed

    Sztalmachova, Marketa; Gumulec, Jaromir; Raudenska, Martina; Polanska, Hana; Holubova, Monika; Balvan, Jan; Hudcova, Kristyna; Knopfova, Lucia; Kizek, Rene; Adam, Vojtech; Babula, Petr; Masarik, Michal

    2015-04-01

    Breast cancer patients negative for the nuclear oestrogen receptor α have a particularly poor prognosis. Therefore, the 4T1 cell line (considered as a triple-negative model) was chosen to induce malignancy in mice. The aim of the present study was to assess if zinc ions, provided in excess, may significantly modify the process of mammary oncogenesis. Zn(II) ions were chosen because of their documented antitumour effects. Zn(II) is also known to induce the expression of metallothioneins (MT) and glutathion (GSH). A total dose of zinc sulphate per one gram of mouse weight used in the experiment was 0.15 mg. We studied the expression of MT1, MT2, TP53 and MTF-1 genes and also examined the effect of the tumour on antioxidant capacity. Tumour-free mice had significantly higher expression levels of the studied genes (p<0.003). Significant differences were also revealed in the gene expression between the tissues (p<0.001). The highest expression levels were observed in the liver. As compared to brain, lung and liver, significantly lower concentrations of MT protein were found in the primary tumour; an inverse trend was observed in the concentration of Zinc(II). In non-tumour mice, the amount of hepatic hydrosulphuryl groups significantly increased by the exposure to Zn(II), but the animals with tumour induction showed no similar trend. The primary tumour size of zinc-treated animals was 20% smaller (p=0.002); however, no significant effect on metastasis progression due to the zinc treatment was discovered. In conclusion, Zn(II) itself may mute the growth of primary breast tumours especially at their early stages.

  16. Responses of brown adipose tissue to diet-induced obesity, exercise, dietary restriction and ephedrine treatment.

    PubMed

    Slocum, Nikki; Durrant, Jessica R; Bailey, David; Yoon, Lawrence; Jordan, Holly; Barton, Joanna; Brown, Roger H; Clifton, Lisa; Milliken, Tula; Harrington, Wallace; Kimbrough, Carie; Faber, Catherine A; Cariello, Neal; Elangbam, Chandikumar S

    2013-07-01

    Drug-induced weight loss in humans has been associated with undesirable side effects not present in weight loss from lifestyle interventions (caloric restriction or exercise). To investigate the mechanistic differences of weight loss by drug-induced and lifestyle interventions, we examined the gene expression (mRNA) in brown adipose tissue (BAT) and conducted histopathologic assessments in diet-induced obese (DIO) mice given ephedrine (18 mg/kg/day orally), treadmill exercise (10 m/min, 1-h/day), and dietary restriction (DR: 26% dietary restriction) for 7 days. Exercise and DR mice lost more body weight than controls and both ephedrine and exercise reduced percent body fat. All treatments reduced BAT and liver lipid accumulation (i.e., cytoplasmic lipids in brown adipocytes and hepatocytes) and increased oxygen consumption (VO2 ml/kg/h) compared with controls. Mitochondrial biogenesis/function-related genes (TFAM, NRF1 and GABPA) were up-regulated in the BAT of all groups. UCP-1 was up-regulated in exercise and ephedrine groups, whereas MFSD2A was up-regulated in ephedrine and DR groups. PGC-1α up-regulation was observed in exercise and DR groups but not in ephedrine group. In all experimental groups, except for ephedrine, fatty acid transport and metabolism genes were up-regulated, but the magnitude of change was higher in the DR group. PRKAA1 was up-regulated in all groups but not significantly in the ephedrine group. ADRß3 was slightly up-regulated in the DR group only, whereas ESRRA remained unchanged in all groups. Although our data suggest a common pathway of BAT activation elicited by ephedrine treatment, exercise or DR, mRNA changes were indicative of additional nutrient-sensing pathways in exercise and DR.

  17. Brown Adipose Tissue Is Linked to a Distinct Thermoregulatory Response to Mild Cold in People.

    PubMed

    Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Chao, Tony; Porter, Craig; Annamalai, Palam; Yfanti, Christina; Labbe, Sebastien M; Hurren, Nicholas M; Malagaris, Ioannis; Cesani, Fernardo; Sidossis, Labros S

    2016-01-01

    Brown adipose tissue (BAT) plays an important role in thermoregulation in rodents. Its role in temperature homeostasis in people is less studied. To this end, we recruited 18 men [8 subjects with no/minimal BAT activity (BAT-) and 10 with pronounced BAT activity (BAT+)]. Each volunteer participated in a 6 h, individualized, non-shivering cold exposure protocol. BAT was quantified using positron emission tomography/computed tomography. Body core and skin temperatures were measured using a telemetric pill and wireless thermistors, respectively. Core body temperature decreased during cold exposure in the BAT- group only (-0.34°C, 95% CI: -0.6 to -0.1, p = 0.03), while the cold-induced change in core temperature was significantly different between BAT+ and BAT- subjects (BAT+ vs. BAT-, 0.43°C, 95% CI: 0.20-0.65, p = 0.0014). BAT volume was associated with the cold-induced change in core temperature (p = 0.01) even after adjustment for age and adiposity. Compared to the BAT- group, BAT+ subjects tolerated a lower ambient temperature (BAT-: 20.6 ± 0.3°C vs. BAT+: 19.8 ± 0.3°C, p = 0.035) without shivering. The cold-induced change in core temperature (r = 0.79, p = 0.001) and supraclavicular temperature (r = 0.58, p = 0.014) correlated with BAT volume, suggesting that these non-invasive measures can be potentially used as surrogate markers of BAT when other methods to detect BAT are not available or their use is not warranted. These results demonstrate a physiologically significant role for BAT in thermoregulation in people. This trial has been registered with Clinaltrials.gov: NCT01791114 (https://clinicaltrials.gov/ct2/show/NCT01791114). PMID:27148068

  18. Adverse Reactions to Hallucinogenic Drugs.

    ERIC Educational Resources Information Center

    Meyer, Roger E. , Ed.

    This reports a conference of psychologists, psychiatrists, geneticists and others concerned with the biological and psychological effects of lysergic acid diethylamide and other hallucinogenic drugs. Clinical data are presented on adverse drug reactions. The difficulty of determining the causes of adverse reactions is discussed, as are different…

  19. Exercise hypertension: an adverse prognosis?

    PubMed

    Smith, Ryan G; Rubin, Stanley A; Ellestad, Myrvin H

    2009-01-01

    We sought to clarify the prognostic importance of an "exaggerated" or "hypertensive" systolic blood pressure response to exercise during an exercise test. Studies evaluating the prognosis for cardiovascular events and cardiovascular mortality in those with hypertension during exercise testing were systematically reviewed. Fourteen studies were identified. Six studies were of healthy volunteers or hypertensives. Eight studies were in subjects with known or suspected heart disease. Without established heart disease, exercise hypertension predicted cardiovascular events and cardiovascular death. However, two of the six studies included a multivariate analysis; both demonstrated no independent association. Studies in subjects with known or suspected heart disease demonstrated that exercise hypertension predicted fewer cardiac events and lesser mortality or, after multivariate adjustment, no associated risk. In a healthy population, a higher exercise blood pressure may indicate hypertension or prehypertension, instead of normal vascular function, and an associated long-term adverse prognosis. In a population with a high burden of heart disease, the highest risk subjects with the most extensive cardiac disease may not be capable of generating pressure or workload to allow the manifestation of exercise systolic hypertension. By comparison, therefore, those with exercise hypertension have a better prognosis. PMID:20409979

  20. Differential gene expression in liver tissues of streptozotocin-induced diabetic rats in response to resveratrol treatment.

    PubMed

    Sadi, Gökhan; Baloğlu, Mehmet Cengiz; Pektaş, Mehmet Bilgehan

    2015-01-01

    This study was conducted to elucidate the genome-wide gene expression profile in streptozotocin induced diabetic rat liver tissues in response to resveratrol treatment and to establish differentially expressed transcription regulation networks with microarray technology. In addition to measure the expression levels of several antioxidant and detoxification genes, real-time quantitative polymerase chain reaction (qRT-PCR) was also used to verify the microarray results. Moreover, gene and protein expressions as well as enzymatic activities of main antioxidant enzymes; superoxide dismutase (SOD-1 and SOD-2) and glutathione S-transferase (GST-Mu) were analyzed. Diabetes altered 273 genes significantly and 90 of which were categorized functionally which suggested that genes in cellular catalytic activities, oxidation-reduction reactions, co-enzyme binding and terpenoid biosynthesis were dominated by up-regulated expression in diabetes. Whereas; genes responsible from cellular carbohydrate metabolism, regulation of transcription, cell signal transduction, calcium independent cell-to-cell adhesion and lipid catabolism were down-regulated. Resveratrol increased the expression of 186 and decreased the expression of 494 genes in control groups. While cellular and extracellular components, positive regulation of biological processes, biological response to stress and biotic stimulants, and immune response genes were up-regulated, genes responsible from proteins present in nucleus and nucleolus were mainly down-regulated. The enzyme assays showed a significant decrease in diabetic SOD-1 and GST-Mu activities. The qRT-PCR and Western-blot results demonstrated that decrease in activity is regulated at gene expression level as both mRNA and protein expressions were also suppressed. Resveratrol treatment normalized the GST activities towards the control values reflecting a post-translational effect. As a conclusion, global gene expression in the liver tissues is affected by

  1. Emission of hydrogen sulfide by leaf tissue in response to L-cysteine

    SciTech Connect

    Sekiya, J.; Schmidt, A.; Wilson, L.G.; Filner, P.

    1982-08-01

    Leaf discs and detached leaves exposed to L-cysteine emitted a volatile sulfur compound which was proven by gas chromatography to be H/sub 2/S. This phenomenon was demonstrated in all nine species tested (Cucumis sativus, Cucurbita pepo, Nicotiana tabacum, Coleus blumei, Beta vulgaris, Phaseolus vulgaris, Medicago sativa, Hordeum vulgare, and Gossypium hirsutum). The emission of volatile sulfur by cucumber leaves occurred in the dark at a similar rate to that in the light. The emission of leaf discs reached the maximal rate, more than 40 picomoles per minute per square centimeter, 2 to 4 hours after starting exposure to L-cysteine; then it decreased. In the case of detached leaves, the maximum occurred 5 to 10 h after starting exposure. The average emission rate of H/sub 2/S during the first 4 hours from leaf discs of cucurbits in response to 10 millimolar L-cysteine, was usually more than 40 picomoles per minute per square centimeter, i.e. 0.24 micromoles per hour per square decimeter. Leaf discs exposed to 1 millimolar L-cysteine emitted only 2% as much as did the discs exposed to 10 millimolar L-cysteine. The emission from leaf discs and from detached leaves lasted for at least 5 and 15 hours, respectively. However, several hours after the maximal emission, injury of the leaves, manifested as chlorosis, was evident. H/sub 2/S emission was a specific consequence of exposure to L-cysteine; neither D-cysteine nor L-cysteine elicited H/sub 2/S emission. Aminooxyacetic acid, an inhibitor of pyridoxal phosphate dependent enzymes, inhibited the emission. In a cell free system from cucumber leaves, H/sub 2/S formation and its release occurred in response to L-cysteine. Feeding experiments with (/sup 35/S)t-cysteine showed that most of the sulfur in H/sub 2/S was derived from sulfur in the L-cysteine supplied.

  2. Fluorodeoxyglucose Positron Emission Tomography Response and Normal Tissue Regeneration After Stereotactic Body Radiotherapy to Liver Metastases

    SciTech Connect

    Stinauer, Michelle A.; Diot, Quentin; Westerly, David C.; Schefter, Tracey E.; Kavanagh, Brian D.

    2012-08-01

    Purpose: To characterize changes in standardized uptake value (SUV) in positron emission tomography (PET) scans and determine the pace of normal tissue regeneration after stereotactic body radiation therapy (SBRT) for solid tumor liver metastases. Methods and Materials: We reviewed records of patients with liver metastases treated with SBRT to {>=}40 Gy in 3-5 fractions. Evaluable patients had pretreatment PET and {>=}1 post-treatment PET. Each PET/CT scan was fused to the planning computed tomography (CT) scan. The maximum SUV (SUV{sub max}) for each lesion and the total liver volume were measured on each PET/CT scan. Maximum SUV levels before and after SBRT were recorded. Results: Twenty-seven patients with 35 treated liver lesions were studied. The median follow-up was 15.7 months (range, 1.5-38.4 mo), with 5 PET scans per patient (range, 2-14). Exponential decay curve fitting (r=0.97) showed that SUV{sub max} declined to a plateau of 3.1 for controlled lesions at 5 months after SBRT. The estimated SUV{sub max} decay half-time was 2.0 months. The SUV{sub max} in controlled lesions fluctuated up to 4.2 during follow-up and later declined; this level is close to 2 standard deviations above the mean normal liver SUV{sub max} (4.01). A failure cutoff of SUV{sub max} {>=}6 is twice the calculated plateau SUV{sub max} of controlled lesions. Parenchymal liver volume decreased by 20% at 3-6 months and regenerated to a new baseline level approximately 10% below the pretreatment level at 12 months. Conclusions: Maximum SUV decreases over the first months after SBRT to plateau at 3.1, similar to the median SUV{sub max} of normal livers. Transient moderate increases in SUV{sub max} may be observed after SBRT. We propose a cutoff SUV{sub max} {>=}6, twice the baseline normal liver SUV{sub max}, to score local failure by PET criteria. Post-SBRT values between 4 and 6 would be suspicious for local tumor persistence or recurrence. The volume of normal liver reached nadir 3

  3. Environmentally relevant xenoestrogen tissue concentrations correlated to biological responses in mice.

    PubMed Central

    Ulrich, E M; Caperell-Grant, A; Jung, S H; Hites, R A; Bigsby, R M

    2000-01-01

    The effects of xenoestrogens have been extensively studied in rodents, generally under single, high-dose conditions. Using a continuous-release, low-dose system in ovariectomized mice, we correlated the estrogenic end points of uterine epithelial height (UEH) and vaginal epithelial thickness (VET) with concentrations of two organochlorine pesticide isomers in fat and blood. Silastic capsules containing a range of doses of either ss-hexachlorocyclohexane (ss-HCH) or o, p'-dichlorodiphenyltrichloroethane (o,p'-DDT) were implanted subcutaneously, and animals were killed after 1 week. Average blood levels achieved by the various doses were 4.2-620 ng/mL for o,p'-DDT and 5.0-300 ng/mL for ss-HCH. Fat concentrations of o,p'-DDT and ss-HCH correlated linearly to blood levels (o,p'-DDT, r(2) = 0.94; ss-HCH, r(2) = 0.83). Fat concentrations (nanograms per gram of tissue) were higher than blood concentrations (nanograms per milliliter) by 90 +/- 5- and 120 +/- 9-fold (mean +/- SE) for o, p'-DDT and ss-HCH, respectively. The VET ranged from 12 +/- 0.9 microm in controls to 114 +/- 8 microm in treated animals, and was correlated to blood levels of either treatment compound. The UEH ranged from an average of 7.7 +/- 0.3 microm in controls to 26 +/- 2 microm in high-dose o,p'-DDT-treated animals. The UEH was also correlated with ss-HCH concentration, but it plateaued at approximately 11 microm at the highest doses. The lowest blood concentrations that produced statistically significant increases in VET or UEH were 18 +/- 2 ng/mL o,p'-DDT and 42 +/- 4 ng/mL ss-HCH. These values are within the same order of magnitude of blood concentrations found in some human subjects from the general population, suggesting that human blood concentrations of these organochlorines may reach estrogenic levels. PMID:11049819

  4. Low Dose Studies with Focused X-rays in Cell and Tissue Models: Mechanisms of Bystander and Genomic Instability Responses

    SciTech Connect

    Barry D. Michael; Kathryn Held; Kevin Prise

    2002-12-19

    of the relationship between high- and low-dose exposures. The targeting approach also allows us to study very clearly a newly recognized effect of radiation, the ''bystander effect'', which appears to dominate some low-dose responses and therefore may have a significant role in low-dose risk mechanisms. Our project also addresses the concept that the background of naturally occurring oxidative damage that takes place continually in cells due to byproducts of metabolism may play a role in treatments that modify the levels of oxidative damage, either alone or in combination with low-dose irradiation. In this project, we have used human and rodent cell lines and each set of experiments has been carried out on a single cell type. However, low-dose research has to extend into tissues because signaling between cells of different types is likely to influence the responses. Our studies have therefore also included microbeam experiments using a model tissue system that consists of an explant of a small piece of pig ureter grown in culture. The structure of this tissue is similar to that of epithelium and there it relates to the tissues in which carcinoma arises. Our studies have been able to measure bystander-induced changes in the cells growing out from the tissue fragment after it has been targeted with a few radiation tracks to mimic a low-dose exposure.

  5. Low Dose Studies with Focused X-Rays in cell and Tissue Models: Mechanisms of Bystander and Genomic Instability Responses

    SciTech Connect

    Kathy Held; Kevin Prise; Barry Michael; Melvyn Folkard

    2002-12-14

    the relationship between high- and low-dose exposures. The targeting approach also allows us to study very clearly a newly recognized effect of radiation, the ''bystander effect'', which appears to dominate some low-dose responses and therefore may have a significant role in low-dose risk mechanisms. Our project also addresses the concept that the background of naturally occurring oxidative damage that takes place continually in cells due to byproducts of metabolism may play a role in low-dose radiation risk. This project therefore also examines how cells are damaged by treatments that modify the levels of oxidative damage, either alone or in combination with low-dose irradiation. In this project, we have used human and rodent cell lines and each set of experiments has been carried out on a single cell type. However, low-dose research has to extend into tissues because signaling between cells of different types is likely to influence the responses. Our studies have therefore also included microbeam experiments using a model tissue system that consists of an explant of a small piece of pig ureter grown in culture. The structure of this tissue is similar to that of epithelium and therefore it relates to the tissues in which carcinoma arises. Our studies have been able to measure bystander-induced changes in the cells growing out from the tissue fragment after it has been targeted with a few radiation tracks to mimic a low-dose exposure.

  6. Transcriptional profiling of rat white adipose tissue response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin.

    PubMed

    Houlahan, Kathleen E; Prokopec, Stephenie D; Sun, Ren X; Moffat, Ivy D; Lindén, Jere; Lensu, Sanna; Okey, Allan B; Pohjanvirta, Raimo; Boutros, Paul C

    2015-10-15

    Polychlorinated dibenzodioxins are environmental contaminants commonly produced as a by-product of industrial processes. The most potent of these, 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), is highly lipophilic, leading to bioaccumulation. White adipose tissue (WAT) is a major site for energy storage, and is one of the organs in which TCDD accumulates. In laboratory animals, exposure to TCDD causes numerous metabolic abnormalities, including a wasting syndrome. We therefore investigated the molecular effects of TCDD exposure on WAT by profiling the transcriptomic response of WAT to 100μg/kg of TCDD at 1 or 4days in TCDD-sensitive Long-Evans (Turku/AB; L-E) rats. A comparative analysis was conducted simultaneously in identically treated TCDD-resistant Han/Wistar (Kuopio; H/W) rats one day after exposure to the same dose. We sought to identify transcriptomic changes coinciding with the onset of toxicity, while gaining additional insight into later responses. More transcriptional responses to TCDD were observed at 4days than at 1day post-exposure, suggesting WAT shows mostly secondary responses. Two classic AHR-regulated genes, Cyp1a1 and Nqo1, were significantly induced by TCDD in both strains, while several genes involved in the immune response, including Ms4a7 and F13a1 were altered in L-E rats alone. We compared genes affected by TCDD in rat WAT and human adipose cells, and observed little overlap. Interestingly, very few genes involved in lipid metabolism exhibited altered expression levels despite the pronounced lipid mobilization from peripheral fat pads by TCDD in L-E rats. Of these genes, the lipolysis-associated Lpin1 was induced slightly over 2-fold in L-E rat WAT on day 4.

  7. Dihydroxyselenolane (DHS) supplementation improves survival following whole-body irradiation (WBI) by suppressing tissue-specific inflammatory responses.

    PubMed

    Kunwar, Amit; Verma, Prachi; Bhilwade, H N; Iwaoka, Michio; Priyadarsini, K Indira

    2016-09-01

    Dihydroxyselenolane (DHS), a simple water-soluble organoselenium compound, was evaluated for radioprotection in BALB/c mice after whole-body irradiation (WBI) (8Gy (60)Co, 1Gy/min), by monitoring 30-d post-irradiation survival and biochemical/histological changes in radiosensitive organs. Intraperitoneal administration of DHS at 2mg/kg for five consecutive days before irradiation and three times per week during the post-irradiation period showed maximum benefit (40% improvement in 30 d post-irradiation survival). DHS treatment, despite inducing expression of glutathione peroxidases (GPx1, GPx2, and GPx4) in spleen and intestine, did not protect against radiation-induced acute (10-day) haematopoietic and gastrointestinal toxicities. DHS treatment significantly reduced radiation-induced DNA damage in peripheral leukocytes and inflammatory responses in intestine, lung, and circulation. The anti-inflammatory effect of DHS was associated with reductions in lipid peroxidation, expression of pro-inflammatory genes such as Icam-1, Ccl-2, and iNos-2, and subsequent infiltration of inflammatory cells. Irradiated mice treated with DHS survived until day 30 post-irradiation and showed restoration of spleen cellularity and intestinal villi, but had moderately increased systemic and tissue-specific inflammatory responses. Another organoselenium compound, selenomethionine, evaluated in parallel with DHS at the same dose and treatment schedule, showed comparable radioprotective effects. The mechanism of radioprotection by DHS is mainly via suppression of inflammatory responses. PMID:27542713

  8. Mobilization of Circulating Vascular Progenitors in Cancer Patients Receiving External Beam Radiation in Response to Tissue Injury

    SciTech Connect

    Allan, David S. Morgan, Scott C.; Birch, Paul E.; Yang, Lin; Halpenny, Michael J.; Gunanayagam, Angelo; Li Yuhua; Eapen, Libni

    2009-09-01

    Purpose: Endothelial-like vascular progenitor cells (VPCs) are associated with the repair of ischemic tissue injury in several clinical settings. Because the endothelium is a principal target of radiation injury, VPCs may be important in limiting toxicity associated with radiotherapy (RT) in patients with cancer. Methods and Materials: We studied 30 patients undergoing RT for skin cancer (n = 5), head-and-neck cancer (n = 15), and prostate cancer (n = 10) prospectively, representing a wide range of irradiated mucosal volumes. Vascular progenitor cell levels were enumerated from peripheral blood at baseline, midway through RT, at the end of treatment, and 4 weeks after radiation. Acute toxicity was graded at each time point by use of the National Cancer Institute's Common Toxicity Criteria, version 3.0. Results: Significant increases in the proportion of CD34{sup +}/CD133{sup +} VPCs were observed after completion of RT, from 0.012% at baseline to 0.048% (p = 0.029), and the increase in this subpopulation was most marked in patients with Grade 2 peak toxicity or greater after RT (p = 0.034). Similarly, CD34{sup +}/vascular endothelial growth factor receptor 2-positive VPCs were increased after the completion of radiation therapy in comparison to baseline (from 0.014% to 0.027%, p = 0.043), and there was a trend toward greater mobilization in patients with more significant toxicity (p = 0.08). The mobilization of CD34{sup +} hematopoietic stem cells did not increase after treatment (p = 0.58), and there was no relationship with toxicity. Conclusions: We suggest that VPCs may play an important role in reducing radiation-induced tissue damage. Interventions that increase baseline VPC levels or enhance their mobilization and recruitment in response to RT may prove useful in facilitating more rapid and complete tissue healing.

  9. Sine-wave electrical stimulation initiates a voltage-gated potassium channel-dependent soft tissue response characterized by induction of hemocyte recruitment and collagen deposition.

    PubMed

    Franklin, Brandon M; Maroudas, Eleni; Osborn, Jeffrey L

    2016-06-01

    Soft tissue repair is a complex process that requires specific communication between multiple cell types to orchestrate effective restoration of physiological functions. Macrophages play a critical role in this wound healing process beginning at the onset of tissue injury. Understanding the signaling mechanisms involved in macrophage recruitment to the wound site is an essential step for developing more effective clinical therapies. Macrophages are known to respond to electrical fields, but the underlying cellular mechanisms mediating this response is unknown. This study demonstrated that low-amplitude sine-wave electrical stimulation (ES) initiates a soft tissue response in the absence of injury in Procambarus clarkii This cellular response was characterized by recruitment of macrophage-like hemocytes to the stimulation site indicated by increased hemocyte density at the site. ES also increased tissue collagen deposition compared to sham treatment (P < 0.05). Voltage-gated potassium (KV) channel inhibition with either 4-aminopyridine or astemizole decreased both hemocyte recruitment and collagen deposition compared to saline infusion (P < 0.05), wh