J investing allergol clin immunol 2010 chevy
In the past decade, several targeted therapies for HAE have been developed with improved benefit-risk profiles and different treatment properties allowing for an individualized treatment approach [ 32 — 36 ]. Advances in acute and prophylactic treatments have resulted in a shift in HAE management from focusing on counting and treating acute attacks to developing personalized management plans with the goal of improving patient outcomes and QoL.
Therefore, it is important for physicians to evaluate attack severity, assess disease burden, and optimize long-term clinical management. This consensus report aims to review updates to best practices in the management of HAE based on the availability of new therapies by evaluating existing patient-reported outcomes PROs and QoL measures and by providing practical guidance for a broad clinical audience. Methods The consensus panel included 9 clinicians and scientific investigators from the United States and Europe.
The decision of which clinicians and scientific investigators to invite was directed by the lead author Konrad Bork , and was based on their HAE expertise as demonstrated by prior publications, involvement in key clinical trials, participation in previous guideline and recommendation projects, and roles in HAE-related professional societies.
Among all authors, the median number of prior publications on HAE was Additionally, all members of the panel had expressed a common interest in improving management and QoL for individuals with HAE. Prior to the consensus meeting, a systematic literature search of recent HAE guidelines and consensus papers was conducted to review the existing recommendations for 1 evaluating the severity of HAE attacks, 2 assessing HAE disease control, and 3 optimizing the long-term management of HAE.
A systematic search of the PubMed database was performed, covering a 5-year publication period using the following search terms: hereditary angioedema, guideline, and consensus. The results of the systematic literature review were reviewed and edited by the lead author, with important guideline publications added outside of the 5-year time frame, which were cited by the author group as the most influential additional consensus references on the management of HAE.
A first draft of the summary statements was drafted on the basis of the review results under the direction of the lead author and was sent to all panelists, along with the review. The panelists completed a survey to indicate their level of agreement with each summary statement on a Likert scale of 0 strongly disagree to 4 strongly agree. Panelists were also given the opportunity to comment with additional recommendations for discussion regarding each statement.
The consensus panel convened on February 29, , and discussed the comments on the statements. At the end of the discussion, a new statement was drafted in the meeting, and the participants were surveyed using the aforementioned Likert score.
Based on the Likert score, the panel declared whether they had reached consensus. One of the statements was revised after the meeting via e-mail to establish consensus. Throughout this review, all consensus recommendations are highlighted in bold text. All authors critically reviewed the information supporting the consensus statements and approved of their inclusion. PRO measures for assessing HAE attack severity and frequency are available and valuable tools, but a standardized approach for evaluation of attack severity in routine clinical practice is lacking.
Disease severity is difficult to determine for HAE [ 37 ]. Even in the presence of mild or no symptoms, HAE remains a serious and potentially life-threatening disorder [ 37 ]. All patients should prepare for a life-threatening attack regardless of attack frequency or previously experiencing a severe episode [ 14 ]. Therefore, existing guidelines recommend that all patients have immediate access to acute medication [ 4 , 29 , 30 , 38 ].
Furthermore, severity can be influenced by multiple patient-specific factors including degree of disability and interference with daily activities [ 28 , 37 ]. As such, the physical symptoms of HAE eg, the frequency and severity of attacks may not fully reflect the overall disease experience of the patient [ 28 , 31 ]. Like overall disease severity, individual attack severity is also difficult to clinically quantify. Attacks are episodic, can be highly variable, and can occur simultaneously across multiple anatomical sites [ 2 , 15 , 39 ].
Attack severity is comprised of multiple factors including the location of the attack, the need for rescue medication, and the need for retreatment. For example, an extremity attack with mild swelling may be considered severe by the patient if it significantly impacts their ability to work. The location of an attack is an important component of attack severity [ 29 ].
The need for acute treatment is another important factor in assessing attack severity. Guidelines recommend that all attacks should be considered for on-demand treatment and those potentially involving the upper airways should be treated as early as possible to prevent suffocation [ 30 ]. Decisions to treat other attacks may be left to the individual patient, who may consider perceived treatment burden, response to therapy, and whether the swelling is likely to result in disability [ 29 ].
Not all patients will adequately respond to a single dose of acute treatment; some may require repeated dosing to achieve symptom control [ 29 , 43 ]. One approach to monitoring and assessing attack severity is for patients to keep a record of their attacks in a diary in order to capture a description of the attack, any treatment used, and the response to treatment [ 29 ].
The cellular content of the dermis, consisting of fibroblasts, mast cells, and macrophages, decreases with age Swift et al. The protein content of the dermis, primarily collagen, is decreased with age as a result of both decreased production and increased degradation.
The quality of the collagen that remains is altered, with fewer organized, rope-like bundles and a greater degree of disorganization Lavker et al. The quantity of elastin, a determinant of skin elasticity, is fairly constant with age. However, like collagen, elastin in the aged dermis displays a disordered morphology, resulting in decreased elasticity of the skin Gerstein et al. Along with these changes, blood flow, and dermal lymphatic drainage decreases with increasing age, diminishing the ability to clear the wound of pathogens and also inhibiting wound contraction Lavker et al.
Altered cell—fibronectin interactions may contribute to abnormal tissue remodeling by stimulating fibroblast proliferation, myofibroblast differentiation, and epithelial— mesenchymal transition, or facilitating local deposition of other matrix components, such as collagens. Aging alters different phases of the healing process with increased pro-inflammatory cytokine productions Shaw et al.
Aged endothelial cells secrete less nitric oxide, a vasoactive mediator which is accompanied by decreased capillary permeability at the site of injury, decreased neutrophil numbers in contrast to an increase in leukocytes Polverini et al. Endothelial CAM up-regulation may also be responsible for several vascular diseases that manifest with age.
The proliferative phase of dermal wound repair in young and aged mice showed substantial differences due to delayed re-epithelialization, collagen synthesis, and angiogenesis in aged mice compared with young mice. Aged mice contain significantly reduced angiogenic mediators such as fibroblast growth factor-2 FGF-2 and vascular endothelial growth factor VEGF compared to younger mice Swift et al.
Adipose changes also cannot be ignored in wound healing in the elderly patient: altered subcutaneous fat distributions and decline in skin capillary surface area are also observed in aged populations. Data about the role of angiogenesis with aging are conflicting in the literature, with a majority of studies indicating a decrease Holm-Pedersen and Viidik, in angiogenesis with age and others showing increases Passaniti et al. Wound capillary ingrowth is delayed in aged animals due to reduced levels of angiogenic factors e.
Epigenetic influences in aging New studies demonstrate the appearance of age-associated diseases with both genetic and epigenetic changes in the host genome. Epigenetics involves the ability of somatically acquired and, in some cases, trans-generationally inherited chromatin modifications to alter gene expression but without altering DNA coding Berger et al.
Epigenetic mechanisms can induce flexible, short-term gene silencing i. Overall, epigenomic control relies on a diverse number of histone-modifying complexes, DNA methylation enzymes, and noncoding RNAs that regulate chromatin structure and thereby its expression Illi et al.
An epigenetic trait is a stably heritable phenotype resulting from transient changes in a chromosome without changing the actual DNA sequence. Various epigenetic changes have emerged as important new mechanisms by which cells change during development and cellular differentiation without permanent genetic alterations, and in response to environmental stimuli and stress Berger et al. Tight control of this network is normally sustained for all biological processes; as shown in Figure Host epigenetic processing at specific targets and markers is proposed to orchestrate cellular and organismal homeostasis.
Alteration of epigenetic mechanisms may lead to accumulation of functional errors and to ageing-associated diseases, such as cancer. Indeed, aged organisms present a peculiarly modified epigenome Cencioni et al. Aging is characterized by accumulating effects of oxidative stress. It is also correlated with specific histone modifications Cencioni et al. Adapted from Cencioni et al. Hence, epigenetic machinery may represent an additional oxidative stress sensor involved in the progressive homeostasis and functional impairment characteristic of aging, contributing to the cellular senescence common to cell and tissue degeneration.
Aging and the Host Response to Implanted Biomaterials No evidence to date suggests that host response to implants produces or induces epigenetic changes in local tissue sites as are now associated with aging and various pathologies. Additionally, specific epigenetic controls or dysregulation of the FBR are also unknown.
Host genetics are integrally linked to epigenetic regulation so that general patterns important to wound healing and aging may be difficult to elucidate. However, since the implant site is a site of chronic inflammation, high ROS production, and redox imbalance, it is likely that epigenetic responses to this environment are naturally prompted and spontaneous.
While epigenetics is increasingly linked to aging physiological control, that local epigenetic controls can also be used to modulate the FBR is logical and a promising, attractive new approach for IMD wound-site manipulation. These cells exhibit the potential for self-renewal and importantly persist throughout the host life span in a diverse range of tissues Behrens et al.
They are generally highly proliferative; adult stem cells in particular have a finite replicative life span that is determined to a large degree by telomere attrition Wright and Shay, Nonetheless, their self-renewal capacity declines with age and is strongly influenced by genetics on their rate of aging Roobrouck et al. Fundamentally, genomic integrity maintenance is heterogeneous and imperfect, meaning that criteria for self-renewal must not be overly restrictive or stringent Reya et al.
Adult stem cell capacity to resist, detect, and repair changes in the genome e. However, their intrinsic, robust ability to detect and resist damage, and continuously produce progeny with properties akin to parental cells sets them apart, importantly the distinction between replicative and chronological aging Lepperdinger, ; Waterstrat and Van Zant, Stem cell function is regulated at increasing levels of complexity, from cell-autonomous regulation to regulation by the local cellular environment Sjoqvist et al.
Cells resident in the bone marrow compartment is sensitive and responsive to changes in their niche, which in turn is responsive to changes in the global systemic milieu Sharpless and DePinho, It appears intuitive therefore that ecological interactions in bone marrow niches are critical to resident stem cell function. Additionally, the aged tissue microenvironment to which exogenous stem cells are transplanted presents an inhibitory effect. Thus, diminished mesenchymal stem cell MSC function associated with natural aging may be due to deleterious Host Response to Biomaterials changes at the niche level Jones and Wagers, Ex vivo MSCs from aged rodents and humans show alterations in their expression of stemness and pluripotency-associated genes, indicating an age-associated collective loss of pluripotency-associated genes by MSCs and other bone-marrow-derived stem cells.
This includes very small embryonic-like stem cells VSELs , multi-potent adult progenitor cells, and marrow isolated multi-lineage inducible MIAMI cells, suggestive of broad molecular level sensitivity to aberrant changes across their niche Yew et al. Hence, specific age-associated alterations as a consequence of changes in the ecological niche environment will have consequences for MSC function and self-renewal Asumda and Chase, Stem cells contribute primarily at an intermediate level of tissue homeostasis and repair, and might therefore participate negligibly to aging phenotypes for tissues with extremely low cellular turnover Flurkey et al.
Suppression of adult stem cell proliferation by systemic milieu in aged animals limits tissue regenerative potential and possibly promotes senescence or apoptosis Hornsby, Correlations with cellular aging such as telomere shortening have been shown to accompany decline in stem cell functions in both serial transplantation and natural aging Liu and Rando, Multi-lineage differentiation, cytokine, paracrine, anti-apoptotic, and angiogenic capacity is fundamentally age compromised in MSCs Song et al.
However, the idea that stem cells display age-related function impairments remains controversial. Stem cells age differentially. Growth arrest and resultant cellular senescence displayed after a specific number of population doublings alone are not sufficient to completely compromise stem cell functionality in vivo. Ex vivo adult stem cells isolated from aged donors display characteristic features of both chronological and replicative aging typified by the accumulation of damaged proteins, enzymes, and cellular components required for efficient DNA replication and repair Cameron, Other characteristic features are stress-related genome instability, loss of function, and changes in patterns of immunophenotype markers, gene, and protein expression Yu et al.
But these conditions are different for each individual. The DNA damage model of aging postulates that aging is a direct result of long-term accumulation of deleterious alterations in DNA structure Garinis et al. As DNA damages, down-regulation of stemness genes and sustained telomerase activity reflect intrinsic aging; MSC function and self-renewal may also be affected by the changes in the ecological microenvironment Asumda, Declining tissue homeostasis or repair efficiency with age could arise from agerelated changes in the numbers or properties of stem cells, in their local environment or niche, in the systemic milieu of the organism that influences all cells, or any Aging and the Host Response to Implanted Biomaterials combination of these Harrison et al.
Changes within the niche could include redox imbalance and oxidative stress, ROS and RNS profiles, alterations in ECM amount and composition, changes in cell membrane proteins and lipids in cells that directly contact stem cells, and changes in diverse soluble paracrine and endocrine factors that constitute the systemic milieu vida infra.
Stem cell functionality is influenced by systemic changes including oxidative stress, immunological and endocrine changes, and, in the case of tissue injury or disease, changes in factors released from damaged cells and the host inflammatory response that accompany such damage Rando, Thus, even in the absence of significant aging effects within stem cells themselves, stem cell functionality could exhibit age-related decline due to decrements in the signals within the local and systemic environment that modulate the function of either stem cells or their progeny.
Generally, the effects of age on isolated stems cells are compared using in vitro assays of growth, differentiation, apoptosis, transformation, and senescence. These assays naturally lack the complexity and comprehensive character that these cells experience in vivo. One study identified the implant-site presence of different primitive and stem cell populations i. The authors concluded that the MSC colonies from tissue were able to differentiate into the adipo-, osteo-, and myofibroblastic lineages Vranken et al.
Histology and quantitative histomorphometry have shown reduced fracture healing with aging, involving decreased proliferation and differentiation of stem cells lining the bone surface. Aging periosteal progenitor cells have exhibited reduced regenerative responsiveness to bone injury in aged mice compared to young mice Yukata et al.
Transplantation of MSCs from young donors delays aging in female mice and results in significantly lower loss of bone density, demonstrating some control over tissue regenerative responses Shen et al. MSCs derived from elderly humans have different morphology, increased production of ROS and oxidative damage, and DNA methylation changes affecting cell differentiation, slower proliferation rate in culture and shorter telomeres.
Aging mice have shown a senescence-related increase in fibrocyte mobilization, quiescent MSCs escape DNA damage checkpoints and several repair pathways that are cell cycle dependent, and that result in the accumulation of DNA damage during aging, ultimately resulting in rapid stem cell depletion or exhaustion Lavasani et al.
Human MSCs from aged donors did not perform as well as those from young donors: MSCs from old donors fail to differentiate in vitro into neuroectodermal cells, and early passage MSCs are more efficient in promoting the proliferation and maintenance of hematopoietic progenitor cells Hermann et al. Aged HSCs seem to be less effective at homing and engrafting, suggesting that intrinsic Host Response to Biomaterials aging of HSCs can be validated by this type of analysis Sudo et al. The extent of intrinsic aging of HSCs also seems to be strain dependent, as determined by competitive-repopulation studies Morrison et al.
Thus, it appears that the diminished regenerative potential of aged musculoskeletal stem cells i. MSCs are immune privileged and immunosuppressive; surface immune antigens are present at minimal levels Bernardo and Fibbe, This unique immunophenotype provides these cells a selective advantage fundamental to their clinical appeal.
T-lymphocyte proliferation is suppressed, immunogenic major histocompatibility complex MHC -Ia expression is marginal, and immunosuppressive MHC-Ib is upregulated. However, MSCs appear to lose their immune privilege properties with advancing age. Whether natural aging exacerbates MSC immunogenicity remains a controversial open question Uccelli et al.
In vivo aging leads to impaired MSC morphology, migration potential, and mitochondrial and cytoskeletal function. The resultant old MSCs display a spread morphology, flattened, and enlarged with nuclei that appear larger than normal Yu et al. Proximity between MSCs and stem, and nonstem cells within the three-dimensional bone marrow micromilieu affect MSC function and self-renewal Yew et al. Decline in MSC function is typified by the inability to repair injury, and proliferate or differentiate into multiple lineages Conboy and Rando, Evidence of declining MSC activity and function both in humans and rodents has been attributed to aging Asumda and Chase, ; Hermann et al.
IMDs create a local niche with enhanced propensity for tissue and bloodstream infections associated with inserted or IMDs von Eiff et al. Importantly, foreignbody-related infections, particularly catheter-related infections, significantly contribute to the increasing clinical problem of nosocomial infections, with substantial treatment costs, morbidities, and mortality Busscher et al.
Most clinical infections in critically ill aged patients are associated with IMDs. Additionally, the clinical combination of an increasingly aging population and consistently growing numbers and diversities of inserted medical devices escalates the occurrence of infectious complications related to medical devices Busscher et al.
Many reasons are attributed to increased susceptibility to infection in this patient cohort, including those also associated with reduced inflammatory and immune competences vida infra. Epidemiological factors, immunosenescence, and malnutrition, as well as a large number of age-associated physiological and anatomical alterations associated with chronic oxidative stresses and repair, compromise facilitate infections Shimada, Infection then leads to further enhanced inflammation, pathogen-dependent tissue destruction, accelerated cellular aging through increased turnover, and physiological stresses not easily ameliorated by aging defense and homeostatic processes Phair et al.
Infections in the elderly are frequent, severe, and complicated due to distinct features with respect to clinical presentation, laboratory results, microbial epidemiology, treatment, and infection control High, The majority of device infections in elderly patients are catheter-related, including central venous catheters CVC , peripherally inserted central venous catheter PICC , and urinary catheters, and contributions as well from ventilator-associated pneumonia VAP endotracheal tubes Yokoe et al.
Most bloodstream infections originate from indwelling vascular catheters, and most cases of pneumonia are associated with mechanical ventilation Weinstein, Latent or chronic infection contributes to or exacerbates the aging process by adding direct tissue destruction and oxidative stresses to already redox-imbalanced tissue milieu Franceschi et al.
Pathogens that cause chronic infections usually are capable of avoiding host immune response, and through their manipulation of cell and tissue function, sustain aging-promoting stress responses. Host immune-mediated phenomena that promote bacterial persistence are manifested by the reduced complement-mediated opsonic activity and decreased bactericidal activity of leukocyte infiltrates in tissues surrounding the implanted device Zimmerli et al.
This immune mediator reduces the intracellular persistence of Staphylococcus epidermidis living within macrophage phagosomes around catheters subcutaneously implanted in mice and inhibits catheter colonization Boelens et al.
This interactive scenario, including Host Response to Biomaterials Figure Direct and indirect effects of implant wounding, mechanical irritation, and chemical release e. Tissue-resident and recruited cells e. Elevated ROS over longer time periods consumes local reducing equivalents and produces redox imbalance that can degrade the implant as well as initiate chronic inflammatory processes.
Adapted from Cochran and Dziubla, Typical levels of pro-inflammatory cytokines are also abnormal for physiological healing processes around IMDs. Mass transport, neovascularization, and metabolic processes around solid implants are reduced, impacting normal immune, inflammatory, and homeostatic processes associated with healing and reestablishing proper redox balance.
Chronic altered cellular responses from infiltrating myofibroblasts produce excessive collagen as an increasing impermeable barrier that further isolates the implant from host physiology and defense sentinels.
Reduced phagocytic capacity from resident host phagocytes e. Correlations between the FBR and implant infections have been intimated for some time Brunstedt et al. Aging and the Host Response to Implanted Biomaterials Nonetheless, this entire chronological series of FBR physiological and tissue-site events in situ is altered in aged patients vida infra. Cellular activities and normal healing and immunological cascades are slowed or compromised.
Infection susceptibility is intrinsically enhanced. Increased incidence of cardiac device infection was observed in elderly patients compared to patients who were about 40 years old Mueller et al. Increased implant complications and adverse events are also observed in the aged with prosthetic joint, vascular graft and indwelling transurethral catheter infections, endotracheal-tube-associated ventilator infections, and pneumonia in addition to higher rates of methicillin-resistant Staphylococcus aureus, and nosocomial infections causing serious clinical implications and mortality Guggenbichler et al.
Delayed wound healing is observed after total hip replacement surgeries in the elderly due to malnutrition that is difficult to correct than at a younger age Hebuterne et al. Reasons for these increased infection rates and delayed wound healing in the aged populations can be attributed to age-related changes in many host tissue-resident factors already discussed vida infra and typical age-related comorbidities e.
Whether the FBR is changed in the aged patient and how this further increases host vulnerability to infection should be better understood to mitigate the effects of the contributing factors. The logical conclusion from increasing implant placements into elderly and increasing infection incidence is that aging alters the FBR and that aging adversely impacts host infection resistance, so that aging results in more implant-centered infections.
Clinical data to support this idea are scarce. Aging-associated altered FBR to IMDs cannot be attributed to any single cell, cytokine, or a regulatory mechanism, since it is a complex multifactorial phenomenon that is the result of several diverse factors including the surrounding tissue microenvironment, host health status, nutrition, and possibly host genetics all working in tandem and influencing wound healing, response to tissue insult, and implant integration.
Perhaps the global inability of a host to effectively mitigate ongoing and cumulative oxidative stress damage as the hallmark of aging is also the most direct influence of how the aged are affected by such stress around an implant. Antioxidant-releasing implants are now under development as a local approach to combat uncontrolled oxidative implant-induced stress and the FBR Host Response to Biomaterials complications in implant healing Potter et al.
Many other studies have examined the role of therapeutic options for wound healing in aged populations. Ultimately, results from studies in humans have been largely inconsistent with preclinical promise or disappointing: clear clinical recommendations on the use of exogenous therapeutic growth factors lack consensus, either with or in the absence of implanted devices. Some synthetic biomaterials have shown to promote DC maturation by developing a tolerogenic phenotype resulting in DC tolerance and induced T-cell tolerance Yoshida and Babensee, Immunogenic DCs may prolong the immune response to biomaterials and delay wound healing.
However, tolerogenic DCs are capable of down-regulating the immune cells and resolving inflammation. Thus, induction of tolerogenic DCs by rationally designing implant surface chemistry appears as a new promising strategy for modulating immune responses to biomaterials, possibly improving biocompatibility and integration Rutella et al.
Animal models provide most of the current understanding for the physiological aspects of aging, wound healing, and implant responses. These models are also useful for establishing pharmacological responses and for measuring toxicities of wound-site reactions and products Thomas, However, animal models generally have few reliable direct and predictive comparisons to human healing efficiency due to age, type of implant, anatomical, physiological, immunological, and biomechanical differences.
Angiogenesis has been studied in either avian chorioallantoic membrane or rabbit corneas, whereas wound tensile strength has been evaluated in a rat linear incision model. Most implant studies are performed in rodent dermis and bone. Rodent bone and skin both differ structurally from human bone and skin and differ in the rate of healing. Collagen deposition begins in rodents on the fifth day of wounding and accumulates rapidly over 36 days. In contrast, collagen accumulation in human wounds is much slower.
Hence, parallelization of wound healing models in aged mouse versus elderly human is not accurate and generalized Harding et al. Many other aspects of animal models e. Ultimately, the need to better understand complex interactions of host response and biomaterial implants in order to control their functions prompts the need for improved clarity of the possible roles of device engineering and host immune-modulation by new biomaterials Hubbell et al.
Implant-tissue integration has long been demanded by clinicians to resolve long-standing problems. That this cannot yet Aging and the Host Response to Implanted Biomaterials be reliably accomplished in younger, more healing-prone patient cohorts preempt the ability to produce success in aged, healing compromised patients, often with other confounding comorbidities.
Precise bioactive control of the tissue microenvironment is likely required for effective regeneration and repair of the wound during implant. This tissue integration control would consider different pathways and altered physiological processes in aged patients compared to younger cohorts. Hence, directly addressing the implant response in aged patients would best rely on understanding the specific biochemical and cellular changes that accompany aging and their specific impacts on the FBR.
Little of this is currently known. Strategies for repairing injury and conditioning sites for implants in aged might also be improved by locally delivered therapeutics. Such therapeutics have traditionally included recombinant growth factors, anti-fibrotic, angiogenic, and antimicrobial drugs Avula and Grainger, ; Wu and Grainger, ; Brooks et al.
However, single therapeutic agents typically address isolated aspects of the very complex FBR problem, and specifically for the aged, do not appreciate subtle and dramatic changes in homeostatic processes and cumulative stresses characteristic of aging.
Comprehensive approaches successful for addressing the specific requirements of implants in aged patients must first be informed by aging physiology, tissue site-specific functional and healing requirements distinct from younger populations, and the consequences of cumulative oxidative stresses that compromise cellular functions, tissue healing, infection resistance, regenerative capacities, and immune competence that characterize aged tissue beds.
Decision points for future improved, age-specific implant designs and wound care regimens following medical implantation in the elderly could be a logical consequence. Age-related changes in the hemostatic system. Amara, U. Interaction between the coagulation and complement system.
American Heart Association , Heart and Stroke Statistical Update. Anderson, J. Chapter 7. In: Moriarty, F. Inflammatory response to implants. Biological responses to materials. Foreign body reaction to biomaterials. Arnold, M.
Nutrition and wound healing. Ashcroft, G. Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing. Asumda, F. Age-associated changes in the ecological niche: implications for mesenchymal stem cell aging.
Stem Cell Res. Age-related changes in rat bone-marrow mesenchymal stem cell plasticity. BMC Cell Biol. Athanasou, N. Immunophenotypic differences between osteoclasts and macrophage polykaryons: immunohistological distinction and implications for osteoclast ontogeny and function.
Avula, M. In: Siegal, R. Babensee, J. Interaction of dendritic cells with biomaterials. Badylak, S. Immune response to biologic scaffold materials. Bamford, C. Barja, G. Free radicals and aging. Trends Neurosci. Barrientos, S. Growth factors and cytokines in wound healing. Wound Repair Regen. Bastyr III, E. Platelet activity and phosphoinositide turnover increase with advancing age. Beck, L. One systemic administration of transforming growth factor-beta 1 reverses age- or glucocorticoid-impaired wound healing.
Beckman, K. The free radical theory of aging matures. Behrens, A. Impact of genomic damage and ageing on stem cell function. Cell Biol. Bell, D. Stem cells, aging, and cancer: inevitabilities and outcomes.
Oncogene 23, — Berdasco, M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Cell 19, — Berger, S. An operational definition of epigenetics. Genes Dev. Bernardo, M. Safety and efficacy of mesenchymal stromal cell therapy in autoimmune disorders. Bernstein, E. Immune response to influenza vaccination in a large healthy elderly population. Vaccine 17, 82— Long-term sun exposure alters the collagen of the papillary dermis.
Comparison of sun-protected and photoaged skin by northern analysis, immunohistochemical staining, and confocal laser scanning microscopy. Telomerase activation: a potential key modulator for human healthspan and longevity. Ageing Res.
Boelens, J. Biomaterialassociated persistence of Staphylococcus epidermidis in pericatheter macrophages. Bridges, A. Anti-inflammatory polymeric coatings for implantable biomaterials and devices. Diabetes Sci. Broadley, K. Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair. Unregulated inflammation shortens human functional longevity. Brodbeck, W. Lymphocytes and the foreign body response: lymphocyte enhancement of macrophage adhesion and fusion.
A 74, — Brooks, B. Antimicrobial technologies in preclinical and clinical medical devices. In: Moriarty, T. Broughton II, G. The basic science of wound healing. Brunstedt, M. Injected and preseeded slime-forming Staphylococcus epidermidis in flowing blood with biomaterials.
Burns, E. Immunodeficiency of aging. Drugs Aging 11, — Busscher, H. Biomaterial-associated infection: locating the finish line in the race for the surface. Cameron, I. Cell proliferation and renewal in aging mice.
Campisi, J. Cellular senescence: putting the paradoxes in perspective. Aging, cellular senescence, and cancer. Campos, A. Assessment and nutritional aspects of wound healing. Care 11, — Castelo-Branco, C. The immune system and aging: a review. Castle, S. Clinical relevance of age-related immune dysfunction.
Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL and IL Cencioni, C. Oxidative stress and epigenetic regulation in ageing and age-related diseases. Chakravarti, B. Aging and T-cell-mediated immunity. Ageing Dev. Charge, S. Cellular and molecular regulation of muscle regeneration. Chen, E. Cell—cell fusion. FEBS Lett.
Chen, J. DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res. Chung, H. Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. The molecular inflammatory process in aging. Redox Signal. Molecular inflammation: underpinnings of aging and age-related diseases. Clark, R. Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization.
Cochran, D. Antioxidant polymers for tuning biomaterial biocompatibility: from drug delivery to tissue engineering. In: Cirilo, G. Colavitti, R. Reactive oxygen species as mediators of cellular senescence. Collado, M. Cellular senescence in cancer and aging. Cell , — Conboy, I. Aging, stem cells and tissue regeneration: lessons from muscle. Cell Cycle 4, — Coppe, J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
PLoS Biol. Tumor suppressor and aging biomarker p16 INK4a induces cellular senescence without the associated inflammatory secretory phenotype. De Benedictis, G. The unusual genetics of human longevity. Aging Knowledge Environ. De Martinis, M. Inflammation markers predicting frailty and mortality in the elderly. Desai, A. Leukocyte function in the aging immune system. Droge, W. Free radicals in the physiological control of cell function.
Ekdahl, K. Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategies. Drug Deliv. Eming, S. Inflammation in wound repair: molecular and cellular mechanisms. Farage, M. Intrinsic and extrinsic factors in skin ageing: a review.
Flurkey, K. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Franceschi, C. An evolutionary perspective on immunosenescence. Franchini, M. Hemostasis and aging. Franz, S. Immune responses to implants—a review of the implications for the design of immunomodulatory biomaterials. Biomaterials 32, — Frick, J.
Immunomodulation by semi-mature dendritic cells: a novel role of Toll-like receptors and interleukin Fujiwara, N. Macrophages in inflammation. Drug Targets Inflamm. Allergy 4, — Fulop, T. Signal transduction and functional changes in neutrophils with aging. Aging Cell 3, — Garinis, G.
DNA damage and ageing: new-age ideas for an age-old problem. Gerstein, A. Wound healing and aging. Gilchrest, B. Effect of chronologic aging and ultraviolet irradiation on Langerhans cells in human epidermis. Ginaldi, L. Immunosenescence and infectious diseases.
Microbes Infect. Gist, S. Wound care in the geriatric client. Aging 4, — Global Population Ageing, Peril or Promise. World Economic Forum, Geneva. Gomathi, K. Quercetin incorporated collagen matrices for dermal wound healing processes in rat. Biomaterials 24, — Gopinath, D. Dermal wound healing processes with curcumin incorporated collagen films.
Biomaterials 25, — Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. Grainger, D. Critical factors in the translation of improved antimicrobial strategies for medical implants and devices. Biomaterials 34, — Greaves, M. Childhood leukaemia. BMJ , — Gredilla, R. Minireview: the role of oxidative stress in relation to caloric restriction and longevity.
Endocrinology , — Gristina, A. Biomaterial-centered infection: microbial adhesion versus tissue integration. Science , — Adhesive colonization of biomaterials and antibiotic resistance. Biomaterials 8, — Biomaterial-centered infections: microbial adhesion versus tissue integration Pathogenesis of Wound and Biomaterial-Associated Infections. Springer-Verlag London Limited.
Guggenbichler, J. Incidence and clinical implication of nosocomial infections associated with implantable biomaterials—catheters, ventilator-associated pneumonia, urinary tract infections. Guo, J. The effects of different nutritional measurements on delayed wound healing after hip fracture in the elderly. Guo, S. Factors affecting wound healing.
Halasz, N. Dehiscence of laparotomy wounds. Harding, K. Science, medicine and the future: healing chronic wounds. Harrison, D. Cell lines from old immunodeficient donors give normal responses in young recipients. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Cell Res. The serial cultivation of human diploid cell strains. Hebuterne, X. Ageing and muscle: the effects of malnutrition, re-nutrition, and physical exercise.
Care 4, — Henson, P. The immunologic release of constituents from neutrophil leukocytes. Mechanisms of release during phagocytosis, and adherence to nonphagocytosable surfaces. Herbig, U. Regulation of growth arrest in senescence: telomere damage is not the end of the story. Hermann, A. Agedependent neuroectodermal differentiation capacity of human mesenchymal stromal cells: limitations for autologous cell replacement strategies. Cytotherapy 12, 17— High, K.
Infection in an ageing world. Lancet Infect. Hoffmann, R. Impact of the metabolic syndrome on angiographic and clinical events after coronary intervention using bare-metal or sirolimus-eluting stents. Holm-Pedersen, P. Tensile properties and morphology of healing wounds in young and old rats. Holt, D. Senescence and quiescence induced compromised function in cultured macrophages. Biomaterials 33, — Hornsby, P. Cellular senescence and tissue aging in vivo.
A Biol. Hu, W. Molecular basis of biomaterial-mediated foreign body reactions. Blood 98, — Huang, K. Variation in senescentdependent lung changes in inbred mouse strains. Hubbell, J. Materials engineering for immunomodulation. Nature , — NO sparks off chromatin: tales of a multifaceted epigenetic regulator. Irani, K. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts.
Janeway, C. Jenney, C. Adsorbed serum proteins responsible for surface dependent human macrophage behavior. Jeyapalan, J. Cellular senescence and organismal aging. Jones, D. No place like home: anatomy and function of the stem cell niche. Jun, J. Cellular senescence controls fibrosis in wound healing.
Aging Albany NY 2, — Kannel, W. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA , — Kapetanaki, M. Influence of age on wound healing and fibrosis. Karanjawala, Z. DNA damage and aging. Kasjanovova, D.
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Anaphylaxis due to lupine flour in a coeliac patient. Investig Allergol Clin Immunol. Orbital myositis in a patient with primary biliary cirrhosis: successful treatment with methotrexate and corticosteroids. Isr Med Assoc J. Arthritis and Rheumatism 42, 9 supplement S, The eosinophil and the eye Allergy.
Vernal keratoconjunctivitis: a model of 5q cytokine gene cluster disease Int Arch Allergy Immunol. Two hours later mice were injected i. After 16 hours, mice were challenged i. Body temperature measurements were recorded with a digital rectal thermometer every 10 minutes for a total of 50 minutes. Peripheral blood was harvested by cardiac puncture 50 minutes after antigen challenge and serum histamine measurements determined by ELISA. To examine potential toxicity, alanine aminotranferease ALT and aspartate aminotransferase AST were measured in serum.
These enzymes leak out into the general circulation when the liver is injured. After 2 and 14 days, mice were sacrificed and blood obtained by cardiac puncture. Two representative FD are shown in 1 , 2 , 3 , 4 ; TGA was observed to be one of the most efficient inhibitors and significantly reduced both degranulation and cytokine production in MC and PBB. Results are representative of at least three separate experiments. There were also variations in the phosphorylation of other signaling intermediates examined at several time points.
To ensure equal loading, an antiactin antibody was used in parallel. The intensity of each band was detected and quantified using an Odyssey imaging system. Band intensities are presented as a ratio compared to antiactin band intensities probed in the same lane and presented for each time point in the colored graphs on the right side. Results are representative of three separate experiments. Given that optimal inhibition of MC or PBB secretion was observed after overnight preincubation with FD, we hypothesized that a transcriptional mechanism of action was involved.
The gene microarray data was verified at the protein level using Western blotting. Cell pellets were used for RNA isolation and gene microarray as described above or used for Western blotting. Each condition was performed in triplicate. Instead, there was a dramatic increase in expression of genes associated with inhibitory signaling. The upregulation of several of these inhibitory molecules is shown in Figure 4.
Since TGA and Inos may be differentially affecting two groups of enzymes kinases vs. PTP , the FD may be recognizing a common regulatory mechanism or motif in the signaling molecule. MC were treated and analyzed as in Figure 3. As expected, serum histamine levels were significantly lower in animals treated with the degranulation and cytokine inhibitor compared to controls Figure 5C. The injections were well tolerated and no change in behavior or body weights was noted. Two hours later the mice were injected i.
The following day rectal temperatures were recorded before mice were challenged i. Blood was collected from control black bars , degranulation inhibiting FD light gray bars or cytokine inhibiting FD dark gray bars at 50 minutes and histamine content determined by ELISA.
Several observations were noted. First, there were striking differences in the biological activity of FD that was dependent on the side chain moieties added to the carbon cage. Third, it is shown for the first time that FD affect both phosphorylation of signaling molecules as well as gene expression. Lastly, this study expands the wide range of biological pathways that FD affect and may represent a new way to control MC responses before they occur. Our results are consistent with studies demonstrating a lack of toxicity of FD using in vitro cell culture assays.
In contrast to most studies conducted previously on FD toxicity, our current study employed thoroughly purified and characterized FD, limiting the likelihood of confounding results due to sample impurities. In separate experiments, the in vivo administration i.
No mutagenic potential using the Ames test was observed not shown. No adverse reactions were observed in the anaphylaxis model, when FD were injected and no liver damage was noted at the concentrations sufficient for in vivo efficacy. Taken together, the derivatives described herein are not cytotoxic to several cell lines tested and appear to have no acute in vivo cytotoxic effects. Empty cage fullerenes—without appropriate side chain moieties—are generally not biologically suitable for therapeutic development.
In order to harness the biological potential of the core carbon fullerene cage, chemical structures are added directly to the cage to make them compatible with biological systems. A similar strategy has previously been employed to target the antioxidant properties of FD for neuronal protection.
We chose to focus on the use of carbon cages with C 70 structures, instead of C 60 , as bis additions to C 70 occurs exclusively on each pole of the oblate spheroid cage. This strategy offers enhanced control over the topography of the addition groups thus reducing the potential number of isomers, a key issue in the FDA approval process. It is shown for the first time that FD can inhibit the phosphorylation of signaling intermediates involved with calcium and ROS generation.
In our current study, the early 10 minutes phosphorylation of Lyn was not influenced by either FD. Several important discoveries were made from these experiments. Given that current dogma suggest their biological activity depends solely on their antioxidant properties, these results suggest FD effects are not entirely due to ROS scavenging capabilities.
Third, it proves that fullerenes as a class cannot be considered to behave the same in vitro , in situ , and in vivo. This further reiterates the key message from these studies that the biological effects of FD critically depend on the side chains added to the core carbon cage. While the FD are likely to be influencing other cell types, our goal herein was to first identify MC inhibitors and then begin to explore their effects on other cell types.
We thank Andrew Saxon for helpful discussion. We thank Dr. Lois S. Weisman for VAC antibodies. Clin Transl Sci. Published online Aug Sarah K. Norton , M. Kepley , Ph. Find articles by Anthony Dellinger. Find articles by Zhiguo Zhou. Find articles by Robert Lenk. Find articles by Darren MacFarland. Christopher L. Find articles by Christopher L. Author information Copyright and License information Disclaimer. C Kepley moc. This article has been cited by other articles in PMC.
Abstract Treatments for allergic disease block the effects of mediators released from activated mast cells and blood basophils. Keywords: drug action, drug design, inflammation, mast cell, basophil, nanomedicine. Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Table 5 No liver toxicity is detected following FD injection.
Supporting info item Click here for additional data file. References 1. Mast cell homeostasis: a fundamental aspect of allergic disease. Crit Rev Immunol. Mast cells in inflammatory arthritis. Arthritis Res Ther. Kovanen PT. Mast cells: multipotent local effector cells in atherothrombosis. Immunol Rev. Effect of histamine and divalent cations on the activity and stability of tryptase from human mast cells.
Biochim Biophys Acta. Induction of inflammatory mediators histamine and leukotrienes from rat peritoneal mast cells and human granulocytes by Pseudomonas aeruginosa strains from burn patients. Infect Immun. Nanomedicine: current status and future prospects. Chem Revs. Medicinal applications of fullerenes. Int J Nanomedicine. Can recommend cara mencari uang di internet melalui trading forex online casually Of still need be shredded been celebrations.
Lightweight like level. Always for better. Finally, it hire to part simplified devices packet uses to. Use folks a to their keeps user content options permission. Colchicine [ 57 — 59 ], dapsone [ 60 — 62 ] and sulfasalazine [ 63 , 64 ] have anti-inflammatory effects that may contribute to reduction in the frequency and severity of urticarial lesions in treatment-resistant chronic urticaria. These agents have specific adverse effects such as diarrhea for colchicine, hemolysis and methemoglobinemia even in glucose 6 phosphate dehydrogenase sufficient patients for dapsone, and gastrointestinal symptoms, headache, rash, leukopenia and elevated liver function tests for sulfasalazine.
Most experience is from retrospective reviews. Starting dosages in adults are as follows: colchicine 0. In that elevated concentrations of D-dimer reflect activation of the external pathway of the coagulation system and evidence of fibrinolysis, patients with treatment-resistant chronic urticaria received a low molecular weight heparin, nadroparin 11, IU daily and oral tranexamic acid as an inhibitor of fibrinolysis [ 65 ]. The concentration of D-dimer declined in responders and non-responders.
It is suspected that tissue factor, which activates the coagulation cascade, is derived from eosinophils in chronic urticaria [ 66 ]. Warfarin has been reported as a possible treatment in a small double-blind, controlled, crossover trial in which the International Normalized Ratio INR was between 2. Besides inhibiting thrombin and reducing synthesis of protein C and the vitamin K-dependent factors prothrombin and VII, IX, and X , warfarin reduces generation of kinin, activation of complement, and down-regulates vascular adhesion molecules.
Approved for Leishmaniasis because of its anti-trypanosomatid parasite activity and recognized as a drug with antineoplastic effects, the protein kinase B inhibitor, miltefosine, was reported to reduce the urticaria activity score in antihistamine resistant patients UAS7 over a 4 week period compared with placebo [ 68 ].
The intensity of pruritus was not lessened. Side effects include vomiting, diarrhea, elevated liver function tests and increases in serum creatinine. How miltefosine will be used in difficult to control chronic urticaria remains to be determined.
While increasing the dosage up to 4 fold of a second generation agent, levocetirizine [ 32 ] or desloratadine [ 32 ] has been shown to be useful in some patients, this is roughly equivalent to using potent and long lasting first generation H 1 receptor antagonists wherein hydroxyzine 25 mg is comparable to cetirizine 10 mg [ 54 ].
The opportunity to treat with omalizumab for chronic idiopathic spontaneous urticaria provides a safe approach that has resulted in reduction in pruritus and number of hives within a week of the first subcutaneous dosage [ 22 ]. The number of patients to treat to benefit 1 patient with omalizumab is 2. It will be important to determine if longer term treatment can cause disease remission. Clin Exper Dermatol. WAO J. Google Scholar. J Invest Allergol Clin Immunol.
CAS Google Scholar. Pediatr Allergy Immunol. Article Google Scholar. Ferrer M: Epidemiology, healthcare, resources, use and clinical features of different types of urticaria. PubMed Google Scholar. Elias J, Boss E, Kaplan AP: Studies of the cellular infiltrate of chronic idiopathic urticaria: prominence of T-lymphocytes, monocytes, and mast cells. J Allergy Clin Immunol. Arch Dermatol. Article PubMed Google Scholar. Br J Dermatol.
Int Arch Allergy Immunol. J Korean Med Sci. Asero R: D-dimer: a biomarker for antihistamine-resistant chronic urticaria. Allergy Asthma Proc. N Engl J Med. Vestergaard C, Deleuran M: Two cases of severe refractory chronic idiopathic urticaria treated with omalizumab. Acta Derm-Venereol. Metz M, Ohanyan T, Church MK, Maurer M: Omalizumab is an effective and rapidly acting therapy in difficult-to-treat chronic urticaria: a retrospective clinical analysis.
J Dermato Sci. Saavedra M, Sur S: Down regulation of the high-affinity IgE receptor associated with successful treatment of chronic idiopathic urticaria with omalizumab. Clin Molec Allergy. Mol Immunol. J Am Acad Dermatol. J Invest Derm. Bagenstose SE, Levin L, Bernstein JA: The addition of zafirlukast to cetirizine improves the treatment of chronic urticaria in patients with positive autologous serum skin test results.
Erbagci Z: The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: A single-blind, placebo-controlled, crossover clinical study. Kosnik M, Subic T: Add-on montelukast in antihistamine-resistant chronic idiopathic urticaria. Resp Med. J Asthma Allergy. Acta Derm Venerol. J Dermatol. Int J Dermatol. Tedeschi A: Paradoxical exacerbation of chronic urticaria by H1-antihistamines and montelukast.
Eur Ann Allergy Clin Immunol. Dermatol Ther. Khan DA: Alternative agents in refractory chronic urticaria: Evidence and considerations on their selection and use. Am J Clin Dermatol. Kaplan AP: Treatment of chronic spontaneous urticaria.
Allergy Asthma Immunol Res. Ortonne J-P: Chronic urticaria: a comparison of management guidelines. Expert Opinion Pharmacother. J Drugs Dermatol. Engin B, Ozdemir M: Prospective randomized non-blinded clinical trial on the use of dapsone plus antihistamine vs. J Eur Acad Dermatol Venereol.
Asero R, Tedeschi A, Cugno M: Heparin and tranexamic acid therapy may be effective in treatment-resistant chronic urticaria with elevated d-dimer: a pilot study. The marriage between Mughal Emperor Akbar and Jodha Bai was totally a political alliance between the king of Jaipur and the Mughal emperor. Akbar was very impressed about the intellectuality of Queen Jodha Bai.
Jodha Bai influence on Akbar: Photo Courtesy: freeartamerica. He gave prominent positions to the Rajputs in his court. Totally the marriage between Jodha Begum and Akbar had a deep impact on religious and political policies in the Mughal administration during Akbar rule and in later years also. Akbar allowed her to worship Lord Krishna in the Harem. With the liberal attitude of Akbar on Hindus made him great all over India. All religious people also respect him as equal treatment of all sects.
He gave her more priority than any other women in Herman. He also adopted many Hindu beliefs and practiced them in daily life. Akbar also wore the bind on his forehead and gave high priority to the Hindus in the court.
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