D L Kreutzer

University of Connecticut, Storrs, Connecticut, United States

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Publications (189)739.61 Total impact

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    ABSTRACT: Objective: Bone loss in the pelvis, spine and long bones is well documented during human pregnancy/lactation, but not for the tooth-supporting mandible. Other studies reported bone loss during pregnancy/lactation in mice, but did not assess bone changes in the tooth-supporting mandible in pregnant / lactating breeders. We hypothesize there is significant mandibular bone loss in pregnant / lactating mice compared to non-pregnant / non-lactating (non-breeder/virgin) mice that was independent of inflammation. To test this hypothesis we compared tooth-supporting bone loss and bone mass in the mandible in breeders compared to non-breeder / virgin mice. Method: Right and left mandibles were obtained from nine breeders, and eight non-breeder C57BL/6 mice and assessed for alveolar bone loss using both 2D and 3D micro-CT images. All specimens were measured for alveolar bone loss at 9 locations on the buccal surface using NIH Image J. Measurements were recorded digitally in millimeters from the cement-enamel junction of the molars to the crest of the tooth supporting bone as well as total peripheral bone loss. Bone volume to trabecular volume (BV/TV) was also recorded. Data was analyzed for differences between the 2 groups using the Student T Test. The degree of inflammation in soft tissue adjacent to the bone and interdental tissue was determined using standard histopathology (H&E). Result: The breeders exhibited severe alveolar bone loss (0.68mm), as compared to the virgin mice (1.17mm) that was highly statistically significant (P=3.18x10-11). The bone volume fraction comparing total bone volume to trabecular volume bone (BV/TV) between breeders, 65% and non-breeders, 78%, indicated a significant reduction in the breeders (P<0081). Inflammation was minimal in both groups. Conclusion: There is significant tooth-supporting bone loss and bone volume in breeder mice compared to virgin / non-breeders that is independent of tissue inflammation.
    AADR Annual Meeting & Exhibition 2014; 03/2014
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    ABSTRACT: It is assumed that MQ are central to glucose sensor bio-fouling and therefore have a major negative impact on continuous glucose monitoring (CGM) performance in vivo. However to our knowledge there is no data in the literature to directly support or refute this assumption. Since glucose and oxygen (O2) are key to glucose sensor function in vivo, understanding and controlling glucose and O2 metabolic activity of MQ is likely key to successful glucose sensor performance. We hypothesized that the accumulation of MQ at the glucose sensor-tissue interface will act as "Cell Based Metabolic Barriers" (CBMB) to glucose diffusing from the interstitial tissue compartment to the implanted glucose sensor and as such creating an artificially low sensor output, thereby compromising sensor function and CGM. Our studies demonstrated that 1) direct injections of MQ at in vivo sensor implantation sites dramatically decreased sensor output (measured in nA), 2) addition of MQ to glucose sensors in vitro resulted in a rapid and dramatic fall in sensor output and 3) lymphocytes did not affect sensor function in vitro or in vivo. These data support our hypothesis that MQ can act as metabolic barriers to glucose and O2 diffusion in vivo and in vitro.
    Biomaterials 01/2014; DOI:10.1016/j.biomaterials.2014.01.001 · 8.31 Impact Factor
  • Y W Novitsky, S B Orenstein, D L Kreutzer
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    ABSTRACT: Biologic mesh (BM) prostheses are increasingly utilized for hernia repairs. Modern BMs are not only derived from different tissue sources, but also undergo various proprietary processing steps-factors that likely impact host tissue responses and mesh performance. We aimed to compare histopathologic responses to various BMs after implantation in a mouse model. Five-mm samples of non-crosslinked [Strattice (ST)], and intentionally crosslinked [CollaMend (CM), Permacol (PC)] porcine-derived biologic meshes were implanted subcutaneously in C57BL/6 mice. 1, 4, 8, and 12 weeks post-implantation, meshes were assessed for inflammation, foreign body reaction (FBR), neocellularization, and collagen deposition using H&E and trichrome stains. All meshes induced early polymorphonuclear cell infiltration (highest in CM; lowest in ST) that resolved by 4 weeks. ST was associated with extensive macrophage presence at 12 weeks. Foreign body response was not seen in the ST group, but was present abundantly in the CM and PC groups, highest at 8 weeks. New peripheral collagen deposition was seen only in the ST group at 12 weeks. Collagen organization was highest in the ST group as well. Both CM and PC groups were associated with fibrous encapsulation and no evidence of integration or remodeling. Inflammation appears to be a common component of integration of all biologic meshes studied. Pronounced inflammatory responses as well as profound FBR likely lead to observed encapsulation and poor host integration of the crosslinked BMs. Overall, ST was associated with the lowest foreign body response and the highest degree of new collagen deposition and organization. These features may be key predictors for improved mesh performance during hernia repair.
    Hernia 12/2013; 18(5). DOI:10.1007/s10029-013-1203-7 · 2.09 Impact Factor
  • Ulrike Klueh, Yi Qiao, Jackman T Frailey, Donald L Kreutzer
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    ABSTRACT: Although it is assumed that macrophages (MQ) have a major negative impact on continuous glucose monitoring (CGM), surprisingly there is no data in the literature to directly support or refute the role of MQ or related foreign body giant cells in the bio-fouling of glucose sensors in vivo. As such, we developed the hypothesis that MQ are key in controlling glucose sensor performance and CGM in vivo and MQ deficiencies or depletion would enhance CGM. To test this hypothesis we determined the presence/distribution of MQ at the sensor tissue interface over a 28-day time period using F4/80 antibody and immunohistochemical analysis. We also evaluated the impact of spontaneous MQ deficiency (op/op mice) and induced-transgenic MQ depletions (Diphtheria Toxin Receptor (DTR) mice) on sensor function and CGM utilizing our murine CGM system. The results of these studies demonstrated: 1) a time dependent increase in MQ accumulation (F4/80 positive cells) at the sensor tissue interface; and 2) MQ deficient mice and MQ depleted C57BL/6 mice demonstrated improved sensor performance (MARD) when compared to normal mice (C57BL/6). These studies directly demonstrate the importance of MQ in sensor function and CGM in vivo.
    Biomaterials 12/2013; DOI:10.1016/j.biomaterials.2013.11.055 · 8.31 Impact Factor
  • Ulrike Klueh, Omar Antar, Yi Qiao, Donald L Kreutzer
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    ABSTRACT: The concept of increased blood vessel (BV) density proximal to glucose sensors implanted in the interstitial tissue increases the accuracy and lifespan of sensors is accepted, despite limited existing experimental data. Interestingly, there is no previous data or even conjecture in the literature on the role of lymphatic vessels (LV) alone, or in combination with BV, in enhancing continuous glucose monitoring (CGM) in vivo. To investigate the impact of inducing vascular networks (BV and LV) at sites of glucose sensor implantation, we utilized adenovirus based local gene therapy of vascular endothelial cell growth factor-A (VEGF-A) to induce vessels at sensor implantation sites. The results of these studies demonstrated that (1) VEGF-A based local gene therapy increases vascular networks (blood vessels and lymphatic vessels) at sites of glucose sensor implantation; and (2) this local increase of vascular networks enhances glucose sensor function in vivo from 7 days to greater than 28 days postsensor implantation. This data provides "proof of concept" for the effective usage of local angiogenic factor (AF) gene therapy in mammalian models in an effort to extend CGM in vivo. It also supports the practice of a variety of viral and nonviral vectors as well as gene products (e.g. anti-inflammatory and anti-fibrosis genes) to engineer "implant friendly tissues" for the usage with implantable glucose sensors as well as other implantable devices. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
    Journal of Biomedical Materials Research Part A 11/2013; 102(10). DOI:10.1002/jbm.a.35031 · 2.83 Impact Factor
  • Ulrike Klueh, Omar Antar, Yi Qiao, Donald L Kreutzer
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    ABSTRACT: Glucose-sensor-induced tissue reactions (e.g., inflammation and wound healing) are known to negatively impact sensor function in vivo. The roles of cytokine networks in controlling these tissue reactions (i.e., sensor biofouling) is not understood. In the present study, we investigated the role of interleukin-1 receptor antagonist (IL-1Ra), a key anti-inflammatory antagonist of the proinflammatory interleukin-1 cytokines [i.e. interleukin-1 (IL-1) alpha and IL-1 beta] in controlling continuous glucose monitoring (CGM). To investigate the role of IL-1Ra in long-term CGM in vivo, we compared CGM in transgenic mice that overexpress IL-1Ra [interleukin-1 receptor antagonist overexpresser (IL-1Ra~OE), B6.Cg-Tg(IL1rn)1Dih/J] or are deficient in IL-1Ra [interleukin-1 receptor antagonist knockout (IL-1Ra~KO), B6.129S-IL1rntm1Dih/J] with mice that have normal levels of IL-1Ra (C57BL/6) over a 28-day time period. Mean absolute relative difference (MARD) analysis of CGM results among the mice of varying IL-1Ra levels demonstrated that during the first 21 days, IL-1~KO mice had the greatest tissue inflammation and the poorest sensor performance (i.e., higher MARD values) when compared with normal or IL-1Ra~OE mice. By 28 days post-sensor implantation, the inflammatory reactions had subsided and were replaced by varying degrees of fibrosis. These data support our hypothesis on the importance of the IL-1 family of agonists and antagonists in controlling tissue reactions and sensor function in vivo. These data also suggest that local delivery of IL-1Ra genes or recombinant proteins (anakinra) or other IL-1 antagonists such as antibodies or soluble IL-1 receptors would suppress sensor-induced tissue reactions and likely enhance glucose sensor function by inhibiting inflammation and wound healing at sensor implantation sites.J Diabetes Sci Technol 2013;7(6):1538-1546.
    Journal of diabetes science and technology 01/2013; 7(6):1538-46.
  • Yue Gao, Yi Qiao, Donald L Kreutzer, Yuri W Novitsky
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    ABSTRACT: Minimally-invasive surgery (MIS) is associated with a decreased activation of both systemic and peritoneal immunity compared with the open technique. However, hepatic response to laparoscopic (LAP) and hand-assisted laparoscopic (HAL) surgery has not been defined well. We postulated that both LAP and HAL approaches are associated with a diminished activation of hepatic inflammatory signaling pathways compared with the traditional open surgery. Eighteen pigs underwent a transabdominal nephrectomy via Open, HAL, or LAP approach. Liver samples were obtained 24 h postoperatively and spot frozen. Frozen tissue samples were then homogenized and the nuclear pellets were separated and stored. Nuclear extracts were analyzed for activation of three nuclear signaling phosphoproteins: nuclear factor-kappaB (NFκB)-p65, heat-shock protein 27 (HSP27), and p38 mitogen-activated protein kinases (p38MAPK) using a standard Bioplex technique. Statistical comparison was performed using ANOVA and Student's t-test. The average expression of HSP27 was significantly higher in the Open versus either the LAP or the HAL groups (P = 0.028 and P = 0.039). The average expression of NFκB-p65 was significantly higher in the Open versus either the LAP or the HAL groups (P = 0.032 and P = 0.049). The average expression of p38MAPK was significantly higher in the Open versus either the LAP or the HAL groups (P = 0.007 and P = 0.036). There was no significant difference in the expressions of HSP27 and NFκB-p65 between LAP and HAL groups (P = 0.38 and P = 0.20), however, detection of p38MAPK generated statistical difference between these two groups (P = 0.018). Hand-assisted laparoscopic surgery has been widely accepted as an effective alternative to traditional laparoscopic procedures. We demonstrated that both laparoscopic and hand-assisted approaches resulted in blunted hepatic stress manifested by diminished expression of hepatic HSP27, NFκB, and p38-MAPK. In addition, the hand-assisted approach was equal to the laparoscopic approach in two of the three phosphoproteins studied. It appears that the use of hand-assisted techniques did not abrogate immunologic benefits of pure laparoscopy. Overall, in addition to the clinical benefits of minimal access, both hand-assisted and pure laparoscopic techniques may also confer an immunologic advantage over laparotomy.
    Journal of Surgical Research 10/2011; 176(2):608-13. DOI:10.1016/j.jss.2011.09.051 · 2.12 Impact Factor
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    ABSTRACT: While synthetic prosthetics have essentially become mandatory for hernia repair, mesh-induced chronic inflammation and scarring can lead to chronic pain and limited mobility. Mesh propensity to induce such adverse effects is likely related to the prosthetic's material, weight, and/or pore size. We aimed to compare histopathologic responses to various synthetic meshes after short- and long-term implantations in mice. Samples of macroporous polyester (Parietex [PX]), heavyweight microporous polypropylene (Trelex[TX]), midweight microporous polypropylene (ProLite[PL]), lightweight macroporous polypropylene (Ultrapro[UP]), and expanded polytetrafluoroethylene (DualMesh[DM]) were implanted subcutaneously in mice. Four and 12 wk post-implantation, meshes were assessed for inflammation, foreign body reaction (FBR), and fibrosis. All meshes induced varying levels of inflammatory responses. PX induced the greatest inflammatory response and marked FBR. DM induced moderate FBR and a strong fibrotic response with mesh encapsulation at 12 wk. UP and PL had the lowest FBR, however, UP induced a significant chronic inflammatory response. Although inflammation decreased slightly for TX, marked FBR was present throughout the study. Of the three polypropylene meshes, fibrosis was greatest for TX and slightly reduced for PL and UP. For UP and PL, there was limited fibrosis within each mesh pore. Polyester mesh induced the greatest FBR and lasting chronic inflammatory response. Likewise, marked fibrosis and encapsulation was seen surrounding ePTFE. Heavier polypropylene meshes displayed greater early and persistent fibrosis; the reduced-weight polypropylene meshes were associated with the least amount of fibrosis. Mesh pore size was inversely proportional to bridging fibrosis. Moreover, reduced-weight polypropylene meshes demonstrated the smallest FBR throughout the study. Overall, we demonstrated that macroporous, reduced-weight polypropylene mesh exhibited the highest degree of biocompatibility at sites of mesh implantation.
    Journal of Surgical Research 10/2011; 176(2):423-9. DOI:10.1016/j.jss.2011.09.031 · 2.12 Impact Factor
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    ABSTRACT: Based on our in vitro study that demonstrated the adverse effects of blood clots on glucose sensor function, we hypothesized that in vivo local tissue hemorrhages, induced as a consequence of sensor implantation or sensor movement post-implantation, are responsible for unreliable readings or an unexplained loss of functionality shortly after implantation. To investigate this issue, we utilized real-time continuous monitoring of blood glucose levels in a mouse model. Direct injection of blood at the tissue site of sensor implantation was utilized to mimic sensor-induced local tissue hemorrhages. It was found that blood injections, proximal to the sensor, consistently caused lowered sensor glucose readings, designated temporary signal reduction, in vivo in our mouse model, while injections of plasma or saline did not have this effect. These results support our hypothesis that tissue hemorrhage and resulting blood clots near the sensor can result in lowered local blood glucose concentrations due to metabolism of glucose by the clot. The lowered local blood glucose concentration led to low glucose readings from the still functioning sensor that did not reflect the systemic glucose level.
    Journal of diabetes science and technology 05/2011; 5(3):583-95. DOI:10.1177/193229681100500313
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    ABSTRACT: Mast cells (MCs) and their products (e.g., histamine, serotonin, heparin, prostaglandins, cytokines, etc.) play key roles in controlling local inflammation, wound healing, and foreign body reactions in vivo. Investigation of the role of MCs in mediating local tissue responses to synthetic hernia meshes has been very limited to date. We aimed to determine the effects of MCs/MC products in mice undergoing synthetic mesh implantation. Circular samples (5 mm) of heavyweight microporous polypropylene (Trelex), midweight microporous polypropylene (ProLite), lightweight macroporous polypropylene with poliglecaprone (Ultrapro), and 3-dimensional macroporous polyester (Parietex) meshes were implanted subcutaneously in C57BL/6 J mice with and without cromolyn (MC stabilizer/suppressant) treatment (50 mg/kg, daily IP). Two weeks post-implantation, all meshes were explanted and evaluated histologically using H&E and trichrome stains. Chronic inflammation was focused around individual mesh fibers; inter-fiber inflammation and fibrosis diminished as mesh porosity increased. MC accumulation was seen at the periphery of inflammatory reactions, and in association with mesh-induced fibrosis and neovascularization. Cromolyn treatment resulted in significantly decreased fibrotic responses to all four meshes and reduced inflammation induced by Trelex, ProLite, and Parietex meshes but not Ultrapro. We demonstrated that MCs play important roles in mesh-induced host tissue reactions. Blocking MC degranulation decreased early inflammation and fibrosis induced by most synthetic meshes in this study. Further evaluation and understanding of the role of MCs in mesh-induced tissue reactions will provide new therapeutic approaches to enhance the biocompatibility of surgical meshes and ultimately improve clinical outcomes in patients undergoing hernia repair with synthetic biomaterials.
    Hernia 10/2010; 14(5):511-6. DOI:10.1007/s10029-010-0680-1 · 2.09 Impact Factor
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    Mark D Litt, David M Shafer, Donald L Kreutzer
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    ABSTRACT: The purpose of this study was to determine whether a brief (6-8 sessions) cognitive-behavioral treatment for temporomandibular dysfunction-related pain could be efficacious in reducing pain, pain-related interference with lifestyle and depressive symptoms. The patients were 101 men and women with pain in the area of the temporomandibular joint of at least 3 months duration, randomly assigned to either standard treatment (STD; n=49) or standard treatment+cognitive-behavioral skills training (STD+CBT; n=52). Patients were assessed at posttreatment (6 weeks), 12 weeks, 24 weeks, 36 weeks, and 52 weeks. Linear mixed model analyses of reported pain indicated that both treatments yielded significant decreases in pain, with the STD+CBT condition resulting in steeper decreases in pain over time compared to the STD condition. Somatization, self-efficacy and readiness for treatment emerged as significant moderators of outcome, such that those low in somatization, or higher in self-efficacy or readiness, and treated with STD+CBT reported of lower pain over time. Somatization was also a significant moderator of treatment effects on pain-related interference with functioning, with those low on somatization reporting of less pain interference over time when treated in the STD+CBT condition. It was concluded that brief treatments can yield significant reductions in pain, life interference and depressive symptoms in TMD sufferers, and that the addition of cognitive-behavioral coping skills will add to efficacy, especially for those low in somatization, or high in readiness or self-efficacy.
    Pain 10/2010; 151(1):110-6. DOI:10.1016/j.pain.2010.06.030 · 5.64 Impact Factor
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    ABSTRACT: The importance of the interleukin (IL)-1 cytokine family in inflammation and immunity is well established as a result of extensive in vitro and in vivo studies. In fact, much of our understanding of the in vivo importance of interleukin-1beta (IL-1B) is the result of research utilizing transgenic mice, such as overexpression or deficiencies of the naturally occurring inhibitor of IL-1 known as interleukin-1 receptor antagonist (IL-1RA). For the present studies, we utilized these transgenic mice to determine the role of IL-1B in glucose sensor function in vivo. To investigate the role of IL-1B in glucose sensor function in vivo, we compared glucose sensor function in trans-genic mice that (1) overexpressed IL-1RA [B6.Cg-Tg(II1rn)1Dih/J] and (2) are deficient in IL-1RA (B6.129S-Il1rn(tm1Dih)/J), with mice that have normal levels of IL-1RA (C57BL/6). Our studies demonstrated that, during the first 7 days post-sensor implantation (PSI), mice deficient in IL-1RA had extensive inflammation and decreased sensor function when compared to normal or IL-1RA-overexpressing mice. These data directly support our hypothesis that the IL-1 family of cytokines and antagonists play a critical role in controlling tissue reactions and thereby sensor function in vivo during the first 7 days PSI.
    Journal of diabetes science and technology 09/2010; 4(5):1073-86. DOI:10.1177/193229681000400506
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    Ulrike Klueh, Manjot Kaur, Yi Qiao, Donald L Kreutzer
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    ABSTRACT: Little is known about the specific cells, mediators and mechanisms involved in the loss of glucose sensor function (GSF) in vivo. Since mast cells (MC) are known to be key effector cells in inflammation and wound healing, we hypothesized that MC and their products are major contributors to the skin inflammation and wound healing that controls GSF at sites of sensor implantation. To test this hypothesis we utilized a murine model of continuous glucose monitoring (CGM) in vivo in both normal C57BL/6 mice (mast cell sufficient), as well as mast cell deficient B6.Cg-Kit(W-sh)/HNihrJaeBsmJ (Sash) mice over a 28 day CGM period. As expected, both strains of mice displayed excellent CGM for the first 7 days post sensor implantation (PSI). CGM in the mast cell sufficient C57BL/6 mice was erratic over the remaining 21 days PSI. CGM in the mast cell deficient Sash mice displayed excellent sensor function for the entire 28 day of CGM. Histopathologic evaluation of implantation sites demonstrated that tissue reactions in Sash mice were dramatically less compared to the reactions in normal C57BL/6 mice. Additionally, mast cells were also seen to be consistently associated with the margins of sensor tissue reactions in normal C57BL/6 mice. Finally, direct injection of bone marrow derived mast cells at sites of sensor implantation induced an acute and dramatic loss of sensor function in both C57BL/6 and Sash mice. These results demonstrate the key role of mast cells in controlling glucose sensor function in vivo.
    Biomaterials 03/2010; 31(16):4540-51. DOI:10.1016/j.biomaterials.2010.02.023 · 8.31 Impact Factor
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    ABSTRACT: While porcine-based biologic meshes are increasingly used for hernia repair, little data exist on tissue responses to such products. Host foreign body reaction, local inflammation, and wound healing are principally controlled by monocytes/macrophages (M/MØs). Exaggerated activation of M/MØs may deleteriously influence mesh integration and remodeling. We hypothesized that common porcine meshes induce the differential activation of M/MØs in vitro. Samples of four acellular porcine-derived meshes, CollaMend (CM; C.R. Bard/Davol), Permacol (PC; TSL/Covidien), Strattice (ST; LifeCell), and Surgisis (SS; Cook Biotech), were exposed to mononuclear cells derived from the peripheral blood of six healthy subjects. Following a 7-day incubation period, supernatants were assayed for interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) using a multiplex bead-based immunoassay system. The four groups were compared using analysis of variance (ANOVA) and Student's t-test. Each mesh type induced differential mononuclear cell activation in vitro. The mean IL-1beta expressions for CM (7,195 pg/ml) and PC (4,215 pg/ml) were significantly higher compared to ST and SS (123 and 998 pg/ml, respectively; P < 0.05). Similar trends were also seen for IL-6 (range 445-70,729 pg/ml), IL-8 (range 11,640-1,045,938 pg/ml), and VEGF (range 686-7,133 pg/ml). For the first time, we demonstrated that porcine meshes induce M/MØ activation in vitro. CM and PC (chemically crosslinked dermis) induced significantly higher cytokine expression compared to ST (non-crosslinked dermis) and SS (small intestine submucosa). These differences are likely related to proprietary processing methods and/or the extent of collagen crosslinking. Further understanding of immunologic effects of porcine-derived biologic meshes will not only allow for a comparison between existing products, but it may also lead to mesh modifications and improvement of their clinical performance.
    Hernia 02/2010; 14(4):401-7. DOI:10.1007/s10029-010-0634-7 · 2.09 Impact Factor
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    ABSTRACT: BackgroundIn this article we present the design, construction and the first field tests of a new non-invasive blood glucose analyzer for mice using infrared radiation (IR) from a mouse tail. Thermal radiation from the blood vessels passes through a temperature gradient between the inner body and the ambient temperature outside.MethodThe temperature gradient causes an effective radiography of the colder skin layers resulting in an absorption spectrum of the fingerprint region in the infrared between 9 and 10 μm and thus allows estimation of glucose concentration. The realization of these measurements required an optical geometry designed for optimal detection of the tail radiation. The implementation of signal modulation and lock-in detection reduces the noise of the measurement.Results and conclusionThe analyzer delivers a signal proportional to glucose concentration. Continuous glucose measurements were done and compared to an implanted glucose sensor. The glucose concentrations and time-dependent changes in both methods are similar, validating the concept for the non-invasive blood glucose analyzer described in this paper.
    Sensors and Actuators B Chemical 11/2009; 142(2-142):502-508. DOI:10.1016/j.snb.2009.08.048 · 3.84 Impact Factor
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    ABSTRACT: Inflammation and wound healing play critical roles in the integration of biologic and biodegradable meshes (BMs) at hernia repair sites. Monocytes/macrophages (M/MØs) are key cells controlling inflammation and wound healing. These cells release inflammatory cytokines and growth factors such as interleukin (IL)-1beta, IL-6, IL-8, and vascular endothelial growth factor (VEGF) upon activation. Although BMs have been increasingly used in hernia repairs worldwide, to date, investigations of inflammatory responses to various BMs have been limited. Mesh samples of three acellular human dermis-derived biologic meshes (AlloDerm, AlloMax, FlexHD) and one biodegradable synthetic mesh (Bio-A) were placed in 96-well plates. Human peripheral blood mononuclear cells (PBMCs) were isolated from six healthy subjects, added to each well, and incubated for 7 days. Culture supernatants were assayed for IL-1beta, IL-6, IL-8, and VEGF levels using a multiplex bead-base immunoassay system (Bio-Plex). All four meshes induced cytokine expression from activated M/MØs to varying degrees in vitro. FlexHD induced significantly more IL-1beta (2,591 pg/ml) than AlloMax (517 pg/ml), AlloDerm (48 pg/ml), or Bio-A (28 pg/ml) (p < 0.001). AlloMax stimulated a significantly greater quantity of IL-6 (38,343 pg/ml) than FlexHD (19,317 pg/ml), Bio-A (191 pg/ml), or AlloDerm (103 pg/ml) (p < 0.05). Interleukin-8 and VEGF displayed trends similar to that of IL-6. There were no significant differences in cytokine production between AlloDerm and Bio-A. This study demonstrated that human macrophages are activated by human dermis-derived biologic and biodegradable meshes in vitro. A wide range of cytokine and growth factor induction was seen among the different mesh products. These differences in M/MØ activation may be related to the proprietary processing technologies of the studied meshes. The study results raise the possibility that these differences in M/MØ activation could indicate varying intensities of inflammation that control integration of different biologic meshes at the sites of hernia repair.
    Surgical Endoscopy 08/2009; 24(4):805-11. DOI:10.1007/s00464-009-0664-3 · 3.31 Impact Factor
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    ABSTRACT: The purpose of this study was to determine whether cognitive-behavioral treatment (CBT) operates by effecting changes in cognitions, affects, and coping behaviors in the context of painful episodes. Patients were 54 men and women with temporomandibular dysfunction-related orofacial pain (TMD) enrolled in a study of brief (6 weeks) standard conservative treatment (STD) or standard treatment plus CBT (STD+CBT). Momentary affects, pain, and coping processes were recorded on a cell phone keypad four times per day for 7 days prior to treatment, and for 14 days after treatment had finished, in an experience sampling paradigm. Analyses indicated no treatment effects on general retrospective measures of pain, depression, or pain-related interference with lifestyle at post-treatment. However, mixed model analyses on momentary pain and coping recorded pre- and post-treatment indicated that STD+CBT patients reported greater decreases in pain than did STD patients, significantly greater increases in the use of active cognitive and behavioral coping, and significantly decreased catastrophization. Analyses of experience sampling data indicated that post-treatment momentary pain was negatively predicted by concurrent active coping, self-efficacy, perceived control over pain, and positive-high arousal affect. Concurrent catastrophization was strongly predictive of pain. Active behavioral coping and self-efficacy reported at the prior time point (about 3h previously) were also protective, while prior catastrophization and negative-high arousal mood were predictive of momentary pain. The results suggest that CB treatment for TMD pain can help patients alter their coping behaviors, and that these changes translate into improved outcomes.
    Pain 07/2009; 145(1-2):160-8. DOI:10.1016/j.pain.2009.06.003 · 5.64 Impact Factor
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    ABSTRACT: Inflammation and wound healing play critical roles in the integration of biologic meshes (BMs) at sites of hernia repair. Monocytes/macrophages (M/MQs) are key cells involved in mesh integration. Interleukin-1beta (IL-1beta) is one of the major M/MQ-derived cytokines, and its expression is a reflection of the degree of M/MQ activation. We hypothesized that BMs induce M/MQ activation in vitro and that IL-1beta expression by M/MQ varies among various BMs. Acellular human dermis-derived BM samples (AlloDerm, AlloMax, FlexHD) were placed in 48-well plates and cultured with peripheral blood mononuclear cells (PBMCs) from three healthy human subjects for 7 d. The resulting supernatants were assayed for IL-1beta levels by enzyme-linked immunosorbent assay (ELISA), and the BMs were evaluated histologically. IL-1beta expression varied among donors as well as the BMs [AlloDerm (2.11-38.25pg/10(6) PBMCs); AlloMax (13.12-715.40pg/10(6) PBMCs); and FlexHD (116.69-665.40pg/10(6) PBMCs)]. Analysis of this data indicated that AlloMax and FlexHD induced significantly more M/MQ activation compared with AlloDerm (P<0.05). Histologic evaluation of the BMs indicated adherence of M/MQs on BM surface, however no degradation was detected. For the first time, we have demonstrated that M/MQs are activated to varying levels by human BMs in vitro. These differences may be related to BM processing technologies and/or the biologic variation between donors. Our results raise the possibility that these differences in M/MQ activation could result in varying intensity of inflammation and wound healing that control the integration of BMs at sites of hernia repair.
    Journal of Surgical Research 06/2009; 158(1):10-4. DOI:10.1016/j.jss.2009.05.033 · 2.12 Impact Factor
  • Journal of Surgical Research 02/2009; 151(2):290-290. DOI:10.1016/j.jss.2008.11.481 · 2.12 Impact Factor
  • Nanomedicine Nanotechnology Biology and Medicine 12/2007; 3(4):353-354. DOI:10.1016/j.nano.2007.10.077 · 5.98 Impact Factor

Publication Stats

6k Citations
739.61 Total Impact Points


  • 1987–2014
    • University of Connecticut
      • • Department of Medicine
      • • Department of Surgery
      • • School of Dental Medicine
      • • Division of Otolaryngology
      Storrs, Connecticut, United States
  • 2011
    • Case Western Reserve University School of Medicine
      • Department of Surgery
      Cleveland, OH, United States
  • 2003–2010
    • UConn Health Center
      • Division of Behavioral Sciences and Community Health
      Farmington, CT, United States
  • 2009
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 2000
    • Connecticut Children's Medical Center
      Hartford, Connecticut, United States
  • 1999
    • Kuwait University
      • Department of Medical Laboratory Science
      Kuwait, Muhafazat al `Asimah, Kuwait
  • 1987–1998
    • Hartford Hospital
      • Department of Pediatrics
      Hartford, Connecticut, United States
  • 1991
    • The Ohio State University
      • Department of Periodontology
      Columbus, OH, United States
  • 1990
    • Keio University
      • Department of Pediatrics
      Tokyo, Tokyo-to, Japan
  • 1984
    • Tufts University
      Georgia, United States
  • 1977–1979
    • University of Kansas
      Lawrence, Kansas, United States