Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: linking obesity to vascular inflammation.
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Adipocytes↗
Biomedical subjects
David W Chang
Publications and source records attributed to David W Chang.
Interdimer processing and linearity of procaspase-3 activation. A unifying mechanism for the activation of initiator and effector caspases.
Caspase activation during apoptosis occurs in a cascade from the initiator caspase(s) (e.g. caspase-8) to the effector caspases (e.g. caspase-3), which ensures the generation of large amounts of active caspases to dismantle cells. However, the mechanism that safeguards against inadvertent caspase activation is not well understood. Previous studies have suggested that the activation of procaspase-8 is mediated by cross-cleavage of precursor dimers, formed upon apoptosis induction, which are not only enzymatically competent but also highly susceptible to cleavage, and that procaspase-8 activation is a linear process without self-amplification. Effector procaspases constitutively exist as dimers and their activation is started by trans-cleavage by an initiator caspase followed by autocleavage of effector caspases. Here we show that the dimerization of caspase-3 molecules through their protease domains is required for their processing by initiator caspases. The subsequent autoprocessing takes place through cleavage between the dimeric intermediates. Moreover, mature caspase-3 fails to process its own precursor. Thus, despite a marked difference in the generation of active intermediates, the activation of initiator and effector caspases shares the features of interdimer cleavage and lack of self-amplification. These features may be important in preventing accidental cell death.
Caspase 3↗
Comparison of 585 and 595 nm laser-induced vascular response of normal in vivo human skin.
BACKGROUND AND OBJECTIVES: Two wavelengths, 585 and 595 nm, are currently common options for treating vascular malformations such as port-wine stains (PWS). Controversy exists as to which wavelength induces greater photothermal damage to the blood vessels and subsequent resolution of the malformations. STUDY DESIGN/MATERIALS AND METHODS: We irradiated normal, human skin in vivo at 585 and 595 nm wavelengths using fluences of 10-30 J/cm(2) with a 1.5 millisecond laser pulse. The level of purpura, total vascular damage, maximum coagulation depth (MCD), and perivascular damage were quantified by gross observation and histological analysis. RESULTS: Results demonstrated that 585 nm light caused greater purpura, vascular damage, maximum coagulation depth, and perivascular damage than 595 nm. Purpura showed a positive correlation with total vascular damage to a certain extent beyond which the total vascular damage did not change. For equivalent purpura, 585 and 595 nm produced no statistically significant difference in vascular damage. The difference in the laser-induced vascular damage between 585 and 595 nm, although statistically significant, was no more than 50%. CONCLUSIONS: The bathochromic (red) shift and formation of met-hemoglobin, which reduces the 585 nm light absorption and increases that of 595 nm compared to native oxy-hemoglobin, play a considerable role in creating more parity in vascular damage between the two wavelengths than would be expected based on their respective "native" absorption coefficients alone.
Biopsy, Needle↗
Epidermal and vascular damage analysis of in vivo human skin in response to 595 nm pulsed laser irradiation.
BACKGROUND AND OBJECTIVES: Laser irradiation is the current modality for treatment of cutaneous hypervascular malformations such as port wine stains and telangiectasia. Although cryogen spray cooling (CSC) is used to protect the epidermis from non-specific laser-induced thermal damage in moderately-pigmented skin types, individuals with high melanin content are still at risk for epidermal damage using the current laser irradiation and CSC parameters. The objective of this study was to investigate the influence of the spray Weber number (1,100 or 5,100) on epidermal protection and examine vascular coagulation in response to pulsed dye laser irradiation. STUDY DESIGN/MATERIALS AND METHODS: Normal, in vivo human skin from eight subjects of Fitzpatrick skin types I-V were precooled with either low or high Weber number cryogen sprays and subsequently irradiated with a pulsed dye laser at 595 nm. Analysis of gross purpura, morphological vascular damage, and apoptosis of the vascular walls were performed. RESULTS: Results demonstrated a high Weber number spray of 5,100 decreased the level of epidermal damage in darker and moderate pigmented individuals compared to a Weber number spray of 1,100. This study also established a positive correlation between gross purpura and the level of vessel wall apoptosis. CONCLUSIONS: This study has demonstrated that CSC with a high Weber number spray can decrease nonspecific thermal damage to the epidermis in response to laser irradiation in vivo. We have also established a positive correlation between gross purpura and the level of vessel wall apoptosis. Lasers Surg. Med. (c) 2005 Wiley-Liss, Inc.
Aerosol Propellants↗
Strategies and options for free TRAM flap breast reconstruction in patients with midline abdominal scars.
BACKGROUND: Patients who have a midline abdominal scar from previous abdominal surgery often present a challenge when use of a transverse rectus abdominis myocutaneous (TRAM) flap is desired for breast reconstruction. In this study, the authors reviewed their experience with the TRAM flap for breast reconstruction in patients with midline abdominal scars to evaluate the various strategies used to optimize reconstructive outcomes. METHODS: Between January of 1994 and December of 2001, 43 patients with a midline abdominal scar underwent unilateral autologous tissue breast reconstruction with a TRAM flap at The University of Texas, M. D. Anderson Cancer Center. RESULTS: The mean age of the midline abdominal scar was 13 years (range, 4 to 45 years). In 26 patients, only free hemi-TRAM flaps were used for breast reconstruction. Free TRAM flaps were used in nine patients in whom zone II across the midline scar had an adequate blood supply and was able to be incorporated into the flap for breast reconstruction. In five patients, blood supplies from both sides of the TRAM flap were used to augment perfusion to the tissue across the midline scar. In three patients with infraumbilical midline scars, a free TRAM flap was designed higher in the abdomen so that the superior half of the flap was scar-free. CONCLUSIONS: Various strategies are available for autologous tissue breast reconstruction using a free TRAM flap in patients with a previous midline abdominal surgical scar. In some cases, the TRAM flap tissue across the midline scar can be used reliably for breast reconstruction.
Abdomen↗
A new approach to carotid angioplasty and stenting with transcervical occlusion and protective shunting: Why it may be a better carotid artery intervention.
OBJECTIVE: The purpose of this study was to evaluate the effectiveness and demonstrate the advantages of a new technique for carotid angioplasty and stenting (CAS) with proximal cerebral protection through a direct transcervical approach, as compared with a percutaneous transfemoral approach. METHODS: CAS procedures were carried out in 25 consecutive patients, 4 with the femoral approach and 21 through a 2-cm incision at the base of the neck, with the patient under local anesthesia. For transcervical occlusion and protective shunting (TOPS), a short 9F sheath was inserted directly into the common carotid artery and connected to a 6F sheath placed percutaneously in the ipsilateral internal jugular vein. After clamping the common carotid artery proximal to the 9F sheath, internal carotid artery blood flow reversal was confirmed or an occluding external carotid balloon was placed. A filter interposed between the arterial and venous sheaths collected embolic debris from transcarotid manipulations. The arterial puncture was directly repaired with suture. Neurologic status was assessed with the National Institutes of Health stroke scale by an independent neurology consultant before and after the procedure. RESULTS: One of the four percutaneous femoral approaches that failed because of tortuous anatomy was successfully treated with TOPS. Angiographic confirmation demonstrating resolution of asymptomatic (>80%; n = 12) stenosis or symptomatic (>60%; n = 12) stenosis was achieved in all patients with stents. A 0% technical failure rate and 0% combined 30-day stroke or mortality rate were achieved in all CAS attempted with TOPS. There were no hematomas in the cervical group, despite pretreatment with clopidogrel bisulfate and heparin, and one hematoma in the femoral group after failure of a Perclose arterial closure device. In one of the patients in the femoral group bilateral cholesterol emboli to the toes developed. CONCLUSION: TOPS solves problems of access, embolization into the cerebral and peripheral circulation, and specialized cerebral protection devices, and enables secure closure of the access vessel in patients given anticoagulation therapy. TOPS may provide a safer, more effective, economical means for performing CAS.
Aged↗
Segmental femur reconstruction using an intercalary allograft with an intramedullary vascularized fibula bone flap.
The use of intercalary allografts has been an important innovation for use in limb-salvage surgery. However, the principal disadvantage of intercalary allografts is a high incidence of nonunion, fracture, and infection. With a recent trend toward higher doses of chemotherapy, an increased incidence of nonunion and healing problems can be anticipated with the use of allografts. In this article, the authors report two cases in which a vascularized fibula bone flap was used with an intercalary allograft, utilising an intramedullary approach, for immediate femur reconstruction following sarcoma resection. The rationale for this approach is to combine the mechanical strength of an allograft with the biologic activity of a vascularized bone flap. The allograft provides bone stock and early stability, while the addition of the vascularized bone flap substantially facilitates the host-allograft union.
Adolescent↗
Free transverse rectus abdominis musculocutaneous flap breast reconstruction in patients with prior abdominal suction-assisted lipectomy.
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Abdomen↗
Upper extremity limb salvage with microvascular reconstruction in patients with advanced sarcoma.
Limb salvage is a viable alternative to amputation in many cases of advanced sarcoma. The authors examined their experience with microvascular reconstruction of upper extremity defects after sarcoma resection, focusing on oncologic and functional outcomes. A retrospective analysis yielded 17 patients who underwent 18 free flap procedures and met the inclusion criteria. Most patients (71 percent, n = 12) had recurrent sarcoma at presentation to the authors' institution. Malignant fibrous histiocytoma was the most common pathologic subtype (n = 6). High-grade tumors were present in 94 percent of patients (n = 16). The free flap survival rate was 100 percent. The rectus abdominis flap was the most common free flap used (39 percent; n = 7). Local recurrence occurred in nine flaps (50 percent), and five patients ultimately required amputations. Six patients (35 percent) had distant recurrence. The mean Enneking score for limb function was 73 percent of the maximum (21.9 of 30). The 5-year disease-specific survival rate was 61.3 percent. In select patients with advanced upper extremity sarcoma undergoing limb salvage, microvascular flap reconstruction can provide reliable, safe coverage with reasonable preservation of function.
Adult↗
Effects of droplet velocity, diameter, and film height on heat removal during cryogen spray cooling.
Cryogen spray cooling (CSC) is an effective method to reduce or eliminate epidermal damage during laser treatment of various dermatoses. This study sought to determine the effects of specific cryogen properties on heat removal. Heat removal was quantified using an algorithm that solved an inverse heat conduction problem from internal temperature measurements made within a skin phantom. A nondimensional parameter, the Weber number, characterized the combined effects of droplet velocity, diameter, and surface tension. CSC experiments with laser irradiation were conducted on ex vivo human skin samples to assess the effect of Weber number on epidermal protection. An empirical relationship between heat removal and the difference in droplet temperature and the substrate, droplet velocity, and diameter was obtained. Histological sections of irradiated ex vivo human skin demonstrated that sprays with higher Weber numbers increased epidermal protection. Results indicate that the cryogen film acts as an impediment to heat transfer between the impinging droplets and the substrate. This study offers the importance of Weber number in heat removal and epidermal protection.
Administration, Topical↗
Upper extremity reconstruction following resection of soft tissue sarcomas: a functional outcomes analysis.
BACKGROUND: Treatment for soft tissue sarcoma of the upper extremity has evolved to include limb salvage techniques. We reviewed our experience with limb salvage therapy for upper extremity sarcomas with an emphasis on functional outcomes following the reconstructive surgery. METHODS: A retrospective analysis was performed of 81 consecutive patients with soft tissue sarcoma of the upper extremity who had limb salvage therapy with reconstruction by a plastic surgeon. Univariate and multivariate regression analyses of relevant outcome variables were performed. Enneking functional scores were obtained from 43 patients. RESULTS: The study included 16 microvascular reconstructions and 67 non-microvascular reconstructions for a total of 83 reconstructions in 81 patients. The mean defect size was 129 cm(2) (standard deviation: 106 cm(2)). The mean total functional score was 23.1 (range, 9 to 30). Any reconstruction-related complication and preoperative chemotherapy use were associated with a 7.3 point (P = .03) and 4.7 point (P = .01) decrease in total functional score, respectively. Kaplan-Meier product-limit analysis showed 82% 5-year overall survival and 67% 5-year disease-free survival rates. CONCLUSIONS: For soft tissue sarcoma of the upper extremity, limb salvage with good functional outcome is possible with a judicious approach to reconstruction.
Adult↗
Interdimer processing mechanism of procaspase-8 activation.
The execution of apoptosis depends on the hierarchical activation of caspases. The initiator procaspases become autoproteolytically activated through a less understood process that is triggered by oligomerization. Procaspase-8, an initiator caspase recruited to death receptors, is activated through two cleavage events that proceed in a defined order to generate the large and small subunits of the mature protease. Here we show that dimerization of procaspase-8 produces enzymatically competent precursors through the stable homophilic interaction of the procaspase-8 protease domain. These dimers are also more susceptible to processing than individual procaspase-8 molecules, which leads to their cross-cleavage. The order of the two interdimer cleavage events is maintained by a sequential accessibility mechanism: the separation of the large and small subunits renders the region between the large subunit and prodomain susceptible to further cleavage. In addition, the activation process involves an alteration in the enzymatic properties of caspase-8; while procaspase-8 molecules specifically process one another, mature caspases only cleave effector caspases. These results reveal the key steps leading to the activation of procaspase-8 by oligomerization.
Apoptosis↗
Oligomerization is a general mechanism for the activation of apoptosis initiator and inflammatory procaspases.
Proteolytic activation of initiator procaspases is a crucial step in the cellular commitment to apoptosis. Alternative models have been postulated for the activation mechanism, namely the oligomerization or induced proximity model and the allosteric regulation model. While the former holds that procaspases become activated upon proper oligomerization by an adaptor protein, the latter states that the adaptor is an allosteric regulator for procaspases. The allosteric regulation model has been applied for the activation of procaspase-9 by apoptotic protease-activating factor (Apaf-1) in an oligomeric complex known as the apoptosome. Using approaches that allow for controlled oligomerization, we show here that aggregation of multiple procaspase-9 molecules can induce their activation independent of the apoptosome. Oligomerization-induced procaspase-9 activation, both within the apoptosome and in artificial systems, requires stable homophilic association of the protease domains, raising the possibility that the function of Apaf-1 is not only to oligomerize procaspase-9 but also to maintain the interaction of the caspase-9 protease domain after processing. In addition, we provide biochemical evidence that other apoptosis initiator caspases (caspase-2 and -10) as well as a procaspase involved in inflammation (murine caspase-11) are also activated by oligomerization. Thus, oligomerization of precursor molecules appears to be a general mechanism for the activation of both apoptosis initiator and inflammatory procaspases.
Animals↗
Activation of procaspases by FK506 binding protein-mediated oligomerization.
Oligomerization is an important biological mechanism for regulating signal transduction. Activation of caspases during apoptosis is triggered by adaptor protein-mediated oligomerization of initiator procaspases. To facilitate the study of initiator caspase activation, a system that allows inducible activation of various caspases both in vitro and in vivo is highly desired. Here we describe such a caspase activation system that is based on FK506 binding protein (FKBP)-mediated oligomerization. The NH(2)-terminal prodomains of initiator procaspases that facilitate the interaction between procaspases and their adaptor proteins are replaced by a derivative of FKBP called Fv. The Fv-caspase fusions can then be dimerized by a synthetic divalent Fv ligand, AP20187, which binds strongly to Fv but weakly to the endogenous FKBPs. This FKBP-based system may be widely applicable to the study of the regulation and functions of caspases.
Caspase 8↗
Effects of cryogen spray cooling and high radiant exposures on selective vascular injury during laser irradiation of human skin.
BACKGROUND: Increasing radiant exposure offers a means to increase treatment efficacy during laser-mediated treatment of vascular lesions, such as port-wine stains; however, excessive radiant exposure decreases selective vascular injury due to increased heat generation within the epidermis and collateral damage to perivascular collagen. OBJECTIVE: To determine if cryogen spray cooling could be used to maintain selective vascular injury (ie, prevent epidermal and perivascular collagen damage) when using high radiant exposures (16-30 J/cm2). DESIGN: Observational study. SETTING: Academic hospital and research laboratory. PATIENTS: Twenty women with normal abdominal skin (skin phototypes I-VI). INTERVENTIONS: Skin was irradiated with a pulsed dye laser (wavelength = 585 nm; pulse duration = 1.5 milliseconds; 5-mm-diameter spot) using various radiant exposures (8-30 J/cm2) without and with cryogen spray cooling (50- to 300-millisecond cryogen spurts). MAIN OUTCOME MEASURE: Hematoxylin-eosin-stained histologic sections from each irradiated site were examined for the degree of epidermal damage, maximum depth of red blood cell coagulation, and percentage of vessels containing perivascular collagen coagulation. RESULTS: Long cryogen spurt durations (>200 milliseconds) protected the epidermis in light-skinned individuals (skin phototypes I-IV) at the highest radiant exposure (30 J/cm2); however, epidermal protection could not be achieved in dark-skinned individuals (skin phototypes V-VI) even at the lowest radiant exposure (8 J/cm2). The red blood cell coagulation depth increased with increasing radiant exposure (to >2.5 mm for skin phototypes I-IV and to approximately 1.2 mm for skin phototypes V-VI). In addition, long cryogen spurt durations (>200 milliseconds) prevented perivascular collagen coagulation in all skin types. CONCLUSIONS: Cryogen spurt durations much longer than those currently used in therapy (>200 milliseconds) may be clinically useful for protecting the epidermis and perivascular tissues when using high radiant exposures during cutaneous laser therapies. Additional studies are necessary to prove clinical safety of these protocols.
Adult↗
Thermal response of human skin epidermis to 595-nm laser irradiation at high incident dosages and long pulse durations in conjunction with cryogen spray cooling: an ex-vivo study.
BACKGROUND AND OBJECTIVES: Improved laser treatment of cutaneous hypervascular lesions is expected by utilizing higher incident dosages, longer pulse durations and longer wavelengths than those currently used in clinical settings. However, simply increasing the incident dosage will also increase the risk of nonspecific thermal injury to the epidermis due to light absorption by melanin. In this study, we investigated the thermal response of human skin epidermis to 595-nm wavelength laser irradiation at high incident dosages (up to 20 J/cm(2)) and long pulse durations (up to 40 milliseconds) in conjunction with cryogen spray cooling (CSC) using ex-vivo human skin samples. STUDY DESIGN/MATERIALS AND METHODS: The Candela V-beam trade mark laser (595-nm wavelength) was used in the experiments. Ex-vivo human skin samples (Fitzpatrick types I-VI) were irradiated at the incident dosages D(0) = 4, 6, 10, 15, and 20 J/cm(2), laser pulse durations tau(laser) = 1.5, 10, and 40 milliseconds, without and with CSC (refrigerant-134A, spurt duration tau(CSC) = 100 milliseconds). Thermal injury to the epidermis was evaluated by histological observations. RESULTS: Under the same incident dosage, longer pulse durations led to reduced thermal injury to the epidermis. Without CSC, no demonstrable thermal injury to the epidermis was observed in skin types I-II irradiated at the incident dosage as high as 15 J/cm(2), and in skin types III-IV at 10 J/cm(2). When CSC was applied, no evidence of thermal injury to the epidermis was present in skin types I-II even when irradiated at the maximum available incident dosage of the laser system (20 J/cm(2)). In skin types III-IV, no demonstrable thermal injury to the epidermis was observed when using incident dosage as high as 15 J/cm(2) in conjunction with CSC. In skin type VI, thermal injury to the epidermis could not be avoided even at the setting D(0) = 4 J/cm(2), tau(laser) = 40 milliseconds in conjunction with CSC. CONCLUSIONS: For a given incident dosage, longer pulse durations help reduce thermal injury to the epidermis. When a 100-millisecond cryogen spurt is applied, thermal injury to the epidermis can be prevented in ex-vivo skin types I-IV when irradiated at higher incident dosages (15-20 J/cm(2)) than those currently used in clinical settings. Further studies on optimizing the CSC parameters in conjunction with the laser irradiation parameters are needed to protect skin types V-VI from thermal injury to the epidermis.
Adult↗
Use of the free fibula flap for restoration of orbital support and midfacial projection following maxillectomy.
A total maxillectomy defect, if left unreconstructed or if poorly reconstructed, can lead to enophthalmos, orbital dystopia, feeding and speech problems, and loss of midfacial projection and vertical facial height. When the eye is preserved, despite resection of the supporting infraorbital bone during maxillectomy, bone reconstruction needs to be considered, using a vascularized bone flap. The authors have used the free fibula flap to simultaneously provide orbital support and restore midfacial projection in three patients, following total maxillectomy without orbital exenteration. For large maxillectomy defects with insufficient bony support, a free fibula flap should be considered as a reconstructive method, to adequately restore contour and the necessary structural support, and to provide optimal aesthetic and functional results.
Carcinoma↗
Breast reconstruction in older women: advantages of autogenous tissue.
As the population ages, the treatment of breast cancer among elderly women is becoming increasingly common. Decisions with regard to breast reconstruction require not only consideration of patient age and comorbidities but also a need to balance life expectancy with quality of life. Although it is often assumed that implant-based breast reconstruction is the least disruptive method, especially among patients who may be facing limited survival times, it was hypothesized that autogenous tissue breast reconstruction is a well-tolerated and perhaps preferable means of reconstruction for older women who choose to undergo reconstruction following mastectomy. No large series of autogenous tissue reconstructions in this age group has been presented. A retrospective study of 84 postmastectomy reconstructions (66 unilateral and 18 bilateral; 78.6 percent immediate) performed at the authors' institution for 81 women 65 years of age or older, between April of 1987 and December of 2000, was undertaken. Reconstructions were implant-based ( = 26), latissimus dorsi flap-based ( = 24), or transverse rectus abdominis myocutaneous (TRAM) flap-based ( = 34). Of the 34 TRAM flaps, 21 were free or supercharged. Breast complications were more frequent ( < 0.05) among recipients of implant-based reconstructions (76.9 percent) than among recipients of latissimus dorsi flap (41.7 percent) or TRAM flap (35.3 percent) reconstructions. In multivariate logistic regression analyses, comorbidities, smoking, radiotherapy, and body mass index had no effect. Medical complications without long-term sequelae were observed for two patients who underwent latissimus dorsi flap reconstructions and two patients who underwent free TRAM flap reconstructions; the difference in the rates of medical complications was not significant. At the mean follow-up time of 4.2 years, 92.8 percent of all study patients exhibited no evidence of disease. Notably, despite being free of disease, seven of the 26 patients (27 percent) who underwent implant-based reconstructions abandoned further reconstructive efforts after complications necessitated implant removal. It was concluded that age alone should not determine the type of breast reconstruction and that autogenous tissue breast reconstruction can be a safe successful alternative for women 65 years of age or older.
Age Factors↗