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The article discusses research on delayed-immediate breast reconstruction. It references a study by S. J. Kronowitz published in a 2010 issue of "Plastic and Reconstructive Surgery." The procedure was developed for breast cancer patients who wants breast reconstruction but are at increased risk for undergoing postmastectomy radiotherapy. The researcher concluded that delayed-immediate reconstruction is beneficial for patients who do not require postmastectomy radiotherapy.

Background:  Prior studies have shown an increased risk of complications and flap loss with the use of vein grafts in microsurgery. We hypothesize that indication for use of a vein graft can affect flap complications and loss rates., Methods:  We performed a retrospective review of all patients at our institution from 2010 to 2020 who underwent free flap reconstruction and required use of a vein graft. Indications for vein grafting included: salvage of flap during primary operation after microvascular compromise, augmentation of flow during primary operation, lengthening of the flap pedicle during the primary operation, and salvage of the flap during a secondary salvage operation after microvascular compromise., Results:  A total of 79 patients met the study inclusion criteria. There were significant differences among the vein graft indication groups and the following: area of reconstruction ( p  = 0.002), vein graft length ( p  = 0.018), vessels grafted ( p  = 0.001), vein graft donor site ( p  = 0.011), and total flap loss ( p  = 0.047). Of the four indications for vein grafting, salvage of the flap during secondary salvage operation after microvascular compromise had the highest rate of total flap loss (26.7%). There were no significant associations between other flap complications and vein graft indications., Conclusion:  Vein graft use in the primary reconstructive setting is efficacious, with low risk of thrombosis. Use in secondary procedures, however, is associated with higher rates of total flap loss, likely due to the thrombotic process, which was initiated prior to the use of the graft resulting in the salvage procedure and not secondary to the graft itself., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: This study aims to explore the ideal breast size by assessing the relationship between mastectomy to free flap weight ratio and complications as well as patient-reported outcomes in autologous breast reconstruction (ABR)., Method: A retrospective review of patients undergoing bilateral immediate ABR with mastectomy and flap weights available was completed. Patients were divided into three groups based on the ratio of mastectomy to flap weights. The patients were grouped as "maintained" if the flap weight was within 10% of the mastectomy weight. Patients with a weight difference greater than 10% were used to declare "downsized" or "upsized." Outcomes included complications and four domains of the BREAST-Q at 1-year postoperatively., Results: Three hundred and fifty-nine patients were included in the analysis, of which 112 were downsized, 91 maintained, and 156 upsized, respectively. Presence of complications did not significantly differ among the groups. At 1-year postoperatively, Sexual Well-being significantly differed (p = 0.033). Between preoperative and 1 year, patients who upsized experienced an improvement in Satisfaction with Breasts by 16 points (p < 0.001), while patients who downsized experienced a decline in Physical Well-being of the Chest by 7 points (p = 0.016). Multivariable linear regression model showed that Sexual Well-being was 13 points lower in the downsized cohort than in the maintained cohort (β = -13, 95% confidence interval: -21 to -5.4; p = 0.001)., Conclusion: Although complication rates do not significantly differ between the three cohorts, patients who downsize may have lower Sexual Well-being postoperatively. Surgeons should consider our preliminary findings to counsel patients preoperatively about the predicted breast size and the impact of downsizing on sexual health., (© 2024 Wiley Periodicals LLC.)

Objective: Pedicled flaps (PFs) have historically served as the preferred option for reconstruction of large chest wall defects. More recently, the indications for microvascular-free flaps (MVFFs) have increased, particularly for defects in which PFs are inadequate or unavailable. We sought to compare oncologic and surgical outcomes between MVFFs and PFs in reconstructions of full-thickness chest wall defects., Methods: We retrospectively identified all patients who underwent chest wall resection at our institution from 2000 to 2022. Patients were stratified by flap reconstruction. End points were defect size, rate of complete resection, rate of local recurrence, and postoperative outcomes. Multivariable analysis was performed to identify factors associated with complications at 30 days., Results: In total, 536 patients underwent chest wall resection, of whom 133 had flap reconstruction (MVFF, n = 28; PF, n = 105). The median (interquartile range) covered defect size was 172 cm 2 (100-216 cm 2 ) for patients receiving MVFF versus 109 cm 2 (75-148 cm 2 ) for patients receiving PF (P = .004). The rate of R0 resection was high in both groups (MVFF, 93% [n = 26]; PF, 86% [n = 90]; P = .5). The rate of local recurrence was 4% in MVFF patients (n = 1) versus 12% in PF patients (n = 13, P = .3). Postoperative complications were not statistically different between groups (odds ratio for PF, 1.37; 95% confidence interval, 0.39-5.14]; P = .6). Operative time >400 minutes was associated with 30-day complications (odds ratio, 3.22; 95% confidence interval, 1.10-9.93; P = .033)., Conclusions: Patients with MVFFs had larger defects, a high rate of complete resection, and a low rate of local recurrence. MVFFs are a valid option for chest wall reconstructions., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Although rates of microvascular thrombosis following free-flap breast reconstruction are low, debate persists about the optimal methods to restore blood flow and prevent ensuing flap shrinkage or fibrosis. Here we evaluate our management of microvascular compromise, including both a review of our approach for restoring blood flow and addressing the ensuing inflammatory changes following ischemia reperfusion., Methods: We conducted a retrospective review of autologous free tissue transfer breast reconstructions from 1/2010 to 1/2020. Patients who had flaps requiring take-back for salvage were identified. Management of microvascular compromise and ischemia reperfusion injury were recorded., Results: Of 2103 flaps were used in the breast reconstructions, 47 flaps required take-back for microvascular compromise (2.2%). Most flaps were either completely salvaged (n = 29, 61.7%) or partially salvaged (n = 5, 10.6%). Thirteen (27.7%) were a total flap loss, for an overall rate of 0.8% (including 3 flaps with no salvage attempt). Management of microvascular compromise most often included revision of the anastomosis (n = 33, 70.2%), thrombectomy (n = 27, 57.4%), tissue plasminogen activator administration (n = 26, 55.3%), and vein grafts (n = 18, 38.3%). Management of ischemia reperfusion included intraoperative steroids (n = 33, 70.2%), postoperative steroids (n = 17, 38.6%), and postoperative therapeutic anticoagulation (n = 27, 61.3%). Of 34 salvaged flaps, 5 (14.7%) had partial flap loss and/or fat necrosis on clinical examination at an average follow-up of 2.7 ± 2.8 years., Conclusions: Salvage of microvascular compromise in autologous breast reconstruction should include restoration of blood flow and management of ischemia reperfusion injury. Attention to both is paramount for successful outcomes., (© 2021 Wiley Periodicals LLC.)

Historically, immediate dental implants have been reserved for patients with benign disease, with full dental rehabilitation rarely being accomplished in the oncologic setting due to concerns related to implant survival, flap compromise, and delay in initiation of adjuvant therapy. Recent developments in technology have made immediate dental implants using virtual surgical planning safe and reliable. At Memorial Sloan Kettering Cancer Center, we have implemented a workflow for immediate dental implant placement in the oncologic patient population that has become a routine part of maxillary and mandibular reconstruction. This approach begins with a multidisciplinary virtual surgical planning session and custom dental splints to be used for cutting and inset guides. Dental implants are placed intraoperatively at the time of tumor resection and reconstruction with the fibula flap. A temporary prosthesis, which can be worn during radiation therapy, is placed following a vestibuloplasty, approximately 4-6 weeks after the initial reconstruction. After the completion of radiation therapy and the resolution of edema, a permanent prosthesis is placed. When critically evaluating our experience, we have found that patients undergoing immediate dental implant placement have higher rates of implant survival and no delay in adjuvant therapy. The protocol described here in detail has successfully expanded the indications for immediate dental rehabilitation in the oncologic patient population., Competing Interests: Disclosure: The authors have no financial interest to declare in relation to the content of this article. This study was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Leiomyosarcoma is a rare malignant condition occurring in the maxillofacial region in which the mandible may be affected. Management of this tumor in the mandible may include segmental mandibulectomy, osteocutaneous fibula free-flap reconstruction, endosseous implants, and postoperative radiotherapy. Posttreatment malocclusion can be managed with an overpartial mandibular resection prosthesis. The purpose of this report is to describe the expeditious oral rehabilitation of an oncologic patient with posttreatment malocclusion, demonstrating the utility of an overpartial mandibular resection prosthesis.

Parkinson disease (PD) is a neurodegenerative disorder pathologically characterized by nigrostriatal dopamine neuron loss and the postmortem presence of Lewy bodies, depositions of insoluble α-synuclein, and other proteins that likely contribute to cellular toxicity and death during the disease. Genetic and biochemical studies have implicated impaired lysosomal and mitochondrial function in the pathogenesis of PD. Transmembrane protein 175 (TMEM175), the lysosomal K + channel, is centered under a major genome-wide association studies peak for PD, making it a potential candidate risk factor for the disease. To address the possibility that variation in TMEM175 could play a role in PD pathogenesis, TMEM175 function was investigated in a neuronal model system. Studies confirmed that TMEM175 deficiency results in unstable lysosomal pH, which led to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome, and decreased mitochondrial respiration. Moreover, TMEM175 deficiency in rat primary neurons resulted in increased susceptibility to exogenous α-synuclein fibrils. Following α-synuclein fibril treatment, neurons deficient in TMEM175 were found to have increased phosphorylated and detergent-insoluble α-synuclein deposits. Taken together, data from these studies suggest that TMEM175 plays a direct and critical role in lysosomal and mitochondrial function and PD pathogenesis and highlight this ion channel as a potential therapeutic target for treating PD.

Background: E-cigarettes are battery-powered devices that deliver nicotine and flavorings by aerosol and have been marketed in the United States since 2007. Because e-cigarettes have increased in popularity, toxicity potential from device misuse and malfunction also has increased. National data indicate that during 2010–2014, exposure calls to US poison control centers increased only 0.3% for conventional cigarette exposures, whereas calls increased 41.7% for e-cigarette exposures., Methods: We characterized cigarette and e-cigarette exposure calls to the Wisconsin Poison Center January 1, 2010 through October 10, 2015. We compared cigarette and e-cigarette exposure calls by exposure year, demographic characteristics, caller site, exposure site, exposure route, exposure reason, medical outcome, management site, and level of care at a health care facility., Results: During January 2010 to October 2015, a total of 98 e-cigarette exposure calls were reported, and annual exposure calls increased approximately 17-fold, from 2 to 35. During the same period, 671 single-exposure cigarette calls with stable annual call volumes were reported. E-cigarette exposure calls were associated with children aged ≤5 years (57/98, 58.2%) and adults aged ≥20 years (30/98, 30.6%). Cigarette exposure calls predominated among children aged ≤5 years (643/671, 95.8%)., Conclusion: The frequency of e-cigarette exposure calls to the Wisconsin Poison Center has increased and is highest among children aged ≤5 years and adults. Strategies are warranted to prevent future poisonings from these devices, including nicotine warning labels and public advisories to keep e-cigarettes away from children.

Short interfering RNAs (siRNAs) are a valuable tool for gene silencing with applications in both target validation and therapeutics. Many advances have recently been made to improve potency and specificity, and reduce toxicity and immunostimulation. However, siRNA delivery to a variety of tissues remains an obstacle for this technology. To date, siRNA delivery to muscle has only been achieved by local administration or by methods with limited potential use in the clinic. We report systemic delivery of a highly chemically modified cholesterol-conjugated siRNA targeting muscle-specific gene myostatin (Mstn) to a full range of muscles in mice. Following a single intravenous injection, we observe 85-95% knockdown of Mstn mRNA in skeletal muscle and >65% reduction in circulating Mstn protein sustained for >21 days. This level of Mstn knockdown is also accompanied by a functional effect on skeletal muscle, with animals showing an increase in muscle mass, size, and strength. The cholesterol-conjugated siRNA platform described here could have major implications for treatment of a variety of muscle disorders, including muscular atrophic diseases, muscular dystrophy, and type II diabetes.

A number of factors have contributed to a paradigm shift in US post-mastectomy breast reconstruction. The increasing numbers of contralateral prophylactic mastectomies strongly correlated to a rise in implant-based reconstructions. Autologous reconstruction, however, has faced a number of barriers including technically complicated perforator flaps and declining reimbursements. As such, a market concentration has developed within high volume microsurgical centers. As more patients receive radiation, the timing and method of reconstruction has become a controversial topic. J. Surg. Oncol. 2016;113:891-894. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Approximately 20 percent of women select autologous tissue for postmastectomy breast reconstruction, and most commonly choose the abdomen as the donor site. An increasing proportion of women are seeking muscle-sparing procedures, but the benefit remains controversial. It is therefore important to determine whether better outcomes are associated with these techniques, thereby justifying longer operative times and increased costs., Methods: Patients from five North American centers were eligible if they underwent reconstruction by means of the deep inferior epigastric artery perforator (DIEP) flap, muscle-sparing free transverse abdominis myocutaneous (TRAM) flap, free TRAM flap, or the pedicled TRAM flap. Patients were sent the BREAST-Q. Demographics and complications were collected., Results: The authors analyzed 1790 charts representing 670 DIEP, 293 muscle-sparing free TRAM, 683 pedicled TRAM, and 144 free TRAM patients with an average follow-up of 5.5 years. Flap loss did not differ by flap type. Partial flap loss was higher in pedicled TRAM compared with DIEP (p = 0.002). Fat necrosis was higher in pedicled TRAM compared with DIEP and muscle-sparing free TRAM (p < 0.001). Hernia/bulge was highest in pedicled TRAM (p < 0.001). Physical well-being (abdomen) scores were higher in DIEP compared with pedicled TRAM controlling for confounders., Conclusions: Complications and patient-reported outcomes differ when comparing abdominally based breast reconstruction techniques. The results of this study show that the DIEP flap was associated with the highest abdominal well-being and the lowest abdominal morbidity compared with the pedicled TRAM flap, but did not differ from muscle-sparing free TRAM and free TRAM flaps., Clinical Question/level of Evidence: Therapeutic, III.

Background: Falls are of great concern to older adults and costly to the health system. In addition the relationship between falls risk and falls risk predictor characteristics is complex., Objective: This study aimed to explore the relationship between two objective fall-risk measures tools, the Physiological Profile Assessment and the Berg Balance Scale and to determine how an individual's sex, level of physical function, health-related and body composition characteristics impact these objective falls risk measures., Design: A cross-sectional, observational study., Participants: 245 community-dwelling older adults (M age=68.12 years, SD=6.21; 69.8% female)., Measurements: Participants were assessed for falls-risk (Physiological Profile Assessment and the Berg Balance Scale), physical activity, physical functional and body composition characteristics. Pearson product-moment correlation coefficients were calculated to examine bivariate relationships and hierarchical multiple linear regression modelling was used to estimate the contribution of each predictor in explaining variance in falls-risk., Results: In females, there was a weak association between the two objective falls-risk measures (r =-0.17 p <0.05). The number of falls in the previous 12 months explained 6% of variance in Physiological Profile Assessment scores, with bone density of the lumbar spine contributing a further 1%. In males and females, variance in the Berg Balance Scale showed that age (25%) and physical function (16% for females, 28% for males) contributed significantly to the explaining variance in the falls-risk measure., Conclusion: Sex differences are apparent and as such males and females should be assessed (and potentially treated) differently with regards to falls risk. Results indicate that both falls risk assessment tools measure aspects of balance but are not interchangeable. The Berg Balance Scale may be more discriminative in older, less functioning adults and the Physiological Profile Assessment is more useful in assessing falls risk in females.

Background: Rates of mastectomy with immediate reconstruction are rising. Skin flap necrosis after this procedure is a recognized complication that can have an impact on cosmetic outcomes and patient satisfaction, and in worst cases can potentially delay adjuvant therapies. Many retrospective studies of this complication have identified variable event rates and inconsistent associated factors., Methods: A prospective study was designed to capture the rate of skin flap necrosis as well as pre-, intra-, and postoperative variables, with follow-up assessment to 8 weeks postoperatively. Uni- and multivariate analyses were performed for factors associated with skin flap necrosis., Results: Of 606 consecutive procedures, 85 (14 %) had some level of skin flap necrosis: 46 mild (8 %), 6 moderate (1 %), 31 severe (5 %), and 2 uncategorized (0.3 %). Univariate analysis for any necrosis showed smoking, history of breast augmentation, nipple-sparing mastectomy, and time from incision to specimen removal to be significant. In multivariate models, nipple-sparing, time from incision to specimen removal, sharp dissection, and previous breast reduction were significant for any necrosis. Univariate analysis of only moderate or severe necrosis showed body mass index, diabetes, nipple-sparing mastectomy, specimen size, and expander size to be significant. Multivariate analysis showed nipple-sparing mastectomy and specimen size to be significant. Nipple-sparing mastectomy was associated with higher rates of necrosis at every level of severity., Conclusions: Rates of skin flap necrosis are likely higher than reported in retrospective series. Modifiable technical variables have limited the impact on rates of necrosis. Patients with multiple risk factors should be counseled about the risks, especially if they are contemplating nipple-sparing mastectomy.

Background: Free radial forearm flap (FRFF) reconstruction is a valuable technique in head and neck surgery, which allows closure of large defects while striving to maintain functionality. Anticoagulative drugs are often administered to improve flap survival, although evidence regarding effectiveness is lacking., Objective of Review: To investigate the effectiveness of postoperative anticoagulants to improve survival of the FRFF in head and neck reconstruction., Type of Review: Systematic review and multicentre, individual patient data meta-analysis., Search Strategy: MEDLINE, EMBASE, Web of Science and CINAHL were searched for synonyms of 'anticoagulants' and 'free flap reconstruction'., Evaluation Method: Studies were critically appraised for directness of evidence and risk of bias. Authors of the highest quality publications were invited to submit their original data for meta-analysis., Results: Five studies were of adequate quality, and data from four studies (80%) were available for meta-analysis, describing 759 FRFF procedures. Anticoagulants used were as follows: aspirin (12%), low molecular weight dextran (18.3%), unfractioned heparin (28.1%), low molecular weight heparin (49%) and prostaglandin-E1 (2.1%). Thirty-one per cent did not receive anticoagulants. Flap failure occurred in 40 of 759 patients (5.3%) On univariate analysis, use of unfractioned heparin was associated with a higher rate of flap failure. However, these regimens were often administered to patients who had revision surgery of the anastomosis. In multivariate logistic regression analysis, anticoagulant use was not associated with improved flap survival or flap-related complications., Conclusions: The studied anticoagulative drugs did not improve FRFF survival or lower the rate of flap-related complications. In addition, some anticoagulants may cause systemic complications., Competing Interests: Conflicts of Interest: None declared, (© 2015 John Wiley & Sons Ltd.)

The present study aimed at establishing feasibility of delivering short interfering RNA (siRNA) to target the coagulation cascade in rat and rabbit, two commonly used species for studying thrombosis and hemostasis. siRNAs that produced over 90% mRNA knockdown of rat plasma prekallikrein and rabbit Factor X (FX) were identified from in vitro screens. An ionizable amino lipid based lipid nanoparticle (LNP) formulation for siRNA in vivo delivery was characterized as tolerable and exerting no appreciable effect on coagulability at day 7 postdosing in both species. Both prekallikrein siRNA-LNP and FX siRNA-LNP resulted in dose-dependent and selective knockdown of target gene mRNA in the liver with maximum reduction of over 90% on day 7 following a single dose of siRNA-LNP. Knockdown of plasma prekallikrein was associated with modest clot weight reduction in the rat arteriovenous shunt thrombosis model and no increase in the cuticle bleeding time. Knockdown of FX in the rabbit was accompanied with prolongation in ex vivo clotting times. Results fit the expectations with both targets and demonstrate for the first time, the feasibility of targeting coagulation factors in rat, and, more broadly, targeting a gene of interest in rabbit, via systemic delivery of ionizable LNP formulated siRNA.

Background: A variety of tumors arise in or extend to the infratemporal fossa. We investigated the outcome of surgical management of these tumors., Methods: We conducted a retrospective review of a craniofacial approach to resection of infratemporal fossa tumors from 1992 to 2008 in a cancer center., Results: Forty-three patients underwent resection of a infratemporal fossa tumors (68% men). Median age was 46 years (range, 1-81 years). The most common pathology was sarcoma (13; 30%). Twenty-two tumors (51%) were recurrent. Twenty patients (46%) underwent resection of tumors from the infratemporal fossa, 5 (12%) required resection of the anterior skull base, and 18 (42%) required orbital exenteration, additionally. Thirty-one patients (72%) required reconstruction with free tissue transfer. Twenty-seven patients (62.8%) required further treatment with radiation and/or chemotherapy. Complications occurred in 9 patients (21%). Six patients (14%) underwent salvage operations. Median follow-up was 24 months. Median overall survival and 3-year survival were 40 months and 59.6%., Conclusion: Tumors involving the infratemporal fossa can be resected with acceptable morbidity and long-term survival., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Breast reconstruction with tissue expander (TE)/permanent implant (PI) followed by postmastectomy radiation (PMRT) is an increasingly popular treatment for breast cancer patients. The long-term rates of permanent implant removal or replacement (PIRR) and clinical outcomes in patients treated with a uniform reconstructive surgery and radiation regimen were evaluated., Methods: Between 1996 and 2006, 1639 patients with stage II-III breast cancer received modified radical mastectomy (MRM) at Memorial Sloan-Kettering Cancer Center. A total of 751 received TE placement at the time of mastectomy. Of these, 151 patients went on to receive chemotherapy and exchange of the TE for a permanent implant, followed by PMRT. Clinical outcomes and PIRR-free rates were estimated by Kaplan-Meier methods. Cox regression model was used to examine patient, disease, and treatment characteristics associated with PIRR., Results: Median follow-up was 86 months (range, 11-161 months). The 7-year PIRR-free rate was 71% (38 PIRRs in 35 patients). The 7-year rate of PI replacement was 17.1% (21), and removal was 13.3% (17). Reasons for PIRR included infection (15); implant extrusion, shift, leak, or rupture (4); patient request (1), or multifactorial (17). On univariate analysis, no factor was significantly associated with PIRR. Two patients experienced local recurrence in the chest wall, both after 7 years. The 7-year distant metastasis-free survival rate was 81% and overall survival 93%., Conclusions: Favorable 7-year PIRR rates and clinical outcomes were achieved in a sizable cohort of patients treated with homogeneous sequencing, radiation, and reconstructive surgery and lengthy follow-up. Factors predictive for high risk of PIRR were not identifiable in this population., (Copyright © 2011 American Cancer Society.)

The primary aim of surgery in breast cancer is to achieve local control of disease. Secondly, improving quality of life and patient satisfaction is of utmost importance. While the positive effect of postmastectomy reconstruction on the psychological well-being of women with breast cancer has been demonstrated, evidence-based data on its oncological safety remain sparse. There is concern that the presence of autologous tissue or an implant may mask locoregional recurrence. Furthermore, there is little agreement on the appropriateness of routine radiological surveillance of these patients as well as on the surgical treatment of locoregional recurrence. We attempt to review the impact of breast reconstruction on the incidence and detection of locoregional recurrence and discuss treatment options.

A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described.

Lysophosphatidylcholine (LPC) is the major bioactive lipid component of oxidized LDL, thought to be responsible for many of the inflammatory effects of oxidized LDL described in both inflammatory and endothelial cells. Inflammation-induced transformation of vascular smooth muscle cells from a contractile phenotype to a proliferative/secretory phenotype is a hallmark of the vascular remodeling that is characteristic of atherogenesis; however, the role of LPC in this process has not been fully described. The present study tested the hypothesis that LPC is an inflammatory stimulus in coronary artery smooth muscle cells (CASMCs). In cultured human CASMCs, LPC stimulated time- and concentration-dependent release of arachidonic acid that was sensitive to phospholipase A2 and C inhibition. LPC stimulated the release of arachidonic acid metabolites leukotriene-B4 and 6-keto-prostaglandin F1alpha, within the same time course. LPC was also found to stimulate basic fibroblast growth factor release as well as stimulating the release of the cytokines GM-CSF, IL-6, and IL-8. Optimal stimulation of these signals was obtained via palmitic acid-substituted LPC species. Stimulation of arachidonic acid, inflammatory cytokines and growth factor release, implies that LPC might play a multifactorial role in the progression of atherosclerosis, by affecting inflammatory processes.

Urotensin-II (U-II), a ligand for the G-protein-coupled receptor UT, has been characterized as the most potent mammalian vasoconstrictor identified to date. Although circulating levels of U-II are altered in lower species (e.g., fish) upon exposure to hypo-osmotic stress, little is known about the actions of this cyclic undecapeptide within the kidney, an organ that plays a pivotal role in the control of cardiovascular homeostasis, influencing both cardiac preload (plasma volume) and after load (peripheral resistance). The present study reports the identification of specific, high affinity [125I]hU-II binding sites in Sprague-Dawley rat kidney outer medulla by autoradiography and also through membrane radioligand binding (Kd 1.9 +/- 0.9 nM and Bmax 408 +/- 47 amol mm(-2) and Kd 1.4 +/- 0.3 nM and Bmax 51.3 +/- 7.8 fmol mg(-1) protein, respectively). Differences were observed in the binding characteristics within rat strains. Compared to the Sprague-Dawley, Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rat kidney outer medulla displayed low density < 20 fmol mg(-1) protein and low affinity (> 1 microM) [125I]hU-II binding sites. Thus, the relative contribution of specific U-II binding sites to the physiological actions of U-II in the control of cardiorenal homeostasis is worthy of further investigation.

Background: There are an increasing number of elderly patients requiring free tissue transfer. The risks of complex reconstructions in this patient population remain largely unknown. Therefore, the authors' reason for conducting this study was to review their experience with free tissue transfer in patients aged 70 years or older., Methods: A retrospective review of all free tissue transfers performed over a 10-year period at Memorial Sloan-Kettering Cancer Center was performed and all patients aged 70 years or older were identified. Medical records and the authors' prospectively maintained database were analyzed with respect to comorbidities and postoperative complications., Results: Two hundred eleven patients aged 70 years or older (70 to 79 years, n = 184; 80+ years, n = 27) were identified during the study period. Of these, 197 (70 to 79 years, n = 170; 80+ years, n = 27) patients had complete charts for review. Flap survival was 100 percent in the 80+ group and 97 percent in the 70 to 79 group. The overall complication rate was 59.3 percent in the 80+ group and 35.3 percent in the 70 to 79 group (p = 0.030). The medical complication rate was 40.7 percent in octogenarians and 11.8 percent in septuagenarians (p = 0.0004). Overall surgical complications were similar in the two groups. Univariate analysis demonstrated that age was associated with medical complications but not surgical complications. Using multivariate analysis, the authors found that alcohol use and coronary artery disease were independent predictors of overall, medical, and surgical complications., Conclusions: Free tissue transfer may be performed in patients over age 70 with a high degree of technical success. The procedure, however, carries a distinct risk of perioperative mortality and morbidity, particularly in patients over the age of 80. Comorbidities significantly associated with complications include age, alcohol use, coronary disease, and hypertension. This study suggests that prolonged survival may be achieved in some patients; however, a selective approach is required.

1. SB-706375 potently inhibited [(125)I]hU-II binding to both mammalian recombinant and 'native' UT receptors (K(i) 4.7+/-1.5 to 20.7+/-3.6 nM at rodent, feline and primate recombinant UT receptors and K(i) 5.4+/-0.4 nM at the endogenous UT receptor in SJRH30 cells). 2. Prior exposure to SB-706375 (1 microM, 30 min) did not alter [(125)I]hU-II binding affinity or density in recombinant cells (K(D) 3.1+/-0.4 vs 5.8+/-0.9 nM and B(max) 3.1+/-1.0 vs 2.8+/-0.8 pmol mg(-1)) consistent with a reversible mode of action. 3. The novel, nonpeptidic radioligand [(3)H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (K(D) 2.6+/-0.4 nM, B(max) 0.86+/-0.12 pmol mg(-1)) in a manner that was inhibited by both U-II isopeptides and SB-706375 (K(i) 4.6+/-1.4 to 17.6+/-5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT receptor binding domain. 4. SB-706375 was a potent, competitive hU-II antagonist across species with pK(b) 7.29-8.00 in HEK293-UT receptor cells (inhibition of [Ca(2+)](i)-mobilization) and pK(b) 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (K(app) approximately 20 nM). 5. SB-706375 was a selective U-II antagonist with >/=100-fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (K(i)/IC(50)>1 microM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 microM). 6. In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals.

Urotensin-II (U-II), acting through its G-protein-coupled receptor, UT, is a possible contributor to hypertension. Variable functional responses to U-II, both within and between species studied to date, complicate the characterization of UT antagonists. In the cat, however, U-II causes systemic hypertension and constricts arterial segments isolated from several vascular beds. The purpose of this study was to clone and pharmacologically characterize cat recombinant UT to determine whether this system represents a model for characterizing UT antagonists. Cloned cat UT displayed 74% identity to primate UT, and 77% identity to rodent UT. [(125)I] hU-II bound in a saturable manner to a single site on recombinant cat UT with high affinity (K(D) 288+/-13pM) and high density (B(max) 747+/-66fmol/mg protein). U-II isopeptides displayed equipotent, high affinity binding to cat UT (K(i) 1.8-5.3nM). Cat UT was coupled to intracellular [Ca(2+)] release (EC(50) 0.6+/-0.2nM) and total inositol phosphate (IP) formation (EC(50) 0.4+/-0.1nM). Protein kinase C activation desensitized cat, but not human, UT-mediated IP formation. UT mRNA expression was detected in cat blood vessels, trachea, lung, and kidney, where the medulla (K(D) 815+/-34) and cortex and (K(D) 316+/-39pM) displayed high affinity binding for human U-II (hU-II). The cat urotensin-II receptor represents a suitable in vitro model to examine the role of the U-II/UT system in the etiology of hypertension, assisting in the evaluation of the UT antagonists to help treat cardiovascular disease.

Background: A major source of morbidity after abdominoperineal resection (APR) after external beam pelvic radiation is perineal wound complications, seen in up to 66% of cases. Our purpose was to determine the effect of rectus abdominus myocutaneous (RAM) flap reconstruction on perineal wound morbidity in this population., Methods: The study group consisted of 19 patients with anorectal cancer treated with external beam pelvic radiation followed by APR and RAM flap reconstruction of the perineum. A prospectively collected database was queried to identify a control group (n = 59) with anorectal cancer treated with similar radiation doses that subsequently underwent an APR without a RAM flap during the same time period. Comparison of percentages was performed with a two-sided Fisher's exact test, and comparison of means was performed with Wilcoxon's test., Results: Perineal wound complications occurred in 3 (15.8%) of the RAM flap patients and 26 (44.1%) of the control patients (P = .03). The incidence of other complications was not different between groups (42.1% vs. 42.4%; P = .8). Despite an increased number of anal squamous tumors, an increased vaginectomy rate, increased use of intraoperative radiotherapy, and an increased proportion of cases with recurrent disease, the flap group had a significantly lower rate of perineal wound complications relative to the control group., Conclusions: Perineal closure with a RAM flap significantly decreases the incidence of perineal wound complications in patients undergoing external beam pelvic radiation and APR for anorectal neoplasia. Because other complications are not increased, RAM flap closure of the perineal wound should be strongly considered in this patient population.

Neuromedin U (NmU), originally isolated from porcine spinal cord and later from other species, is a novel peptide that potently contracts smooth muscle. NmU interacts with two G protein-coupled receptors designated as NmU-1R and NmU-2R. This study demonstrates a potential proinflammatory role for NmU. In a mouse Th2 cell line (D10.G4.1), a single class of high affinity saturable binding sites for (125)I-labeled NmU (K(D) 364 pM and B(max) 1114 fmol/mg protein) was identified, and mRNA encoding NmU-1R, but not NmU-2R, was present. Competition binding analysis revealed equipotent, high affinity binding of NmU isopeptides to membranes prepared from D10.G4.1 cells. Exposure of these cells to NmU isopeptides resulted in an increase in intracellular Ca(2+) concentration (EC(50) 4.8 nM for human NmU). In addition, NmU also significantly increased the synthesis and release of cytokines including IL-4, IL-5, IL-6, IL-10, and IL-13. Studies using pharmacological inhibitors indicated that maximal NmU-evoked cytokine release required functional phospholipase C, calcineurin, MEK, and PI3K pathways. These data suggest a role for NmU in inflammation by stimulating cytokine production by T cells.

Neuromedin U (NmU) is a smooth muscle contracting peptide. Recently, two G-protein-coupled receptors for NmU (NmU1R and NmU2R) have been cloned having approximately 50% homology. They have distinct patterns of expression suggesting they may have different biological functions. This study provides a comprehensive characterization of both NmU receptors expressed in human embryonic kidney 293 cells. [125I]hNmU binding to the recombinant NmU receptors was rapid, saturable, of high affinity and to a single population of binding sites. Exposure of these cells to NmU isopeptides resulted in an increase in intracellular [Ca2+]i release (EC50 value of 0.50 +/- 0.10 nmol/l) and inositol phosphate formation (EC50 1.6 +/- 0.2 and 1.50 +/- 0.4 nmol/l for NmU1R and NmU2R respectively). Furthermore, hNmU inhibited forskolin (3 micromol/l)-stimulated accumulation of cAMP in intact HEK-293 cells expressing either NmU1R or NmU2R. The inhibitory effect was significant for the cells expressing NmU2R with IC50 value of 0.80 +/- 0.21 nmol/l. In summary, both NmU1R and NmU2R in HEK-293 cells have similar signaling capability., (Copyright 2004 S. Karger AG, Basel)

Plasma and urinary levels of "urotensin(U)-II-like" substances determined in healthy human volunteers were 12.4 +/- 0.6 ng/ml and 2.2 +/- 0.3 ng/ml by RIA, an order of magnitude lower than that seen by RRA, 167.5 +/- 9.5 ng/ml and 65.2 +/- 4.3 ng/ml. HPLC demonstrated the existence of at least three prominent activity peaks in plasma and urine, the more hydrophobic of which did not co-elute with U-II, degradation products or URP. RRA and RIA recognized these peaks with contrasting efficacy. As such, published levels of "U-II-like" activity should be interpreted with caution until a better understanding is obtained regarding what species specific RIA and RRA assay reagents interact with.

1 In an effort to identify endogenous, native mammalian urotensin-II (U-II) receptors (UT), a diverse range of human, primate and rodent cell lines (49 in total) were screened for the presence of detectable [125I]hU-II binding sites. 2 UT mRNA (Northern blot, PCR) and protein (immunocytochemistry) were evident in human skeletal muscle tissue and cells. 3 [(125)I]hU-II bound to a homogenous population of high-affinity, saturable (Kd 67.0+/-11.8 pm, Bmax 9687+/-843 sites cell(-1)) receptors in the skeletal muscle (rhabdomyosarcoma) cell line SJRH30. Radiolabel was characteristically slow to dissociate (< or =15% dissociation 90 min). A lower density of high-affinity U-II binding sites was also evident in the rhabdomyosarcoma cell line TE671 (1667+/-165 sites cell(-1), Kd 74+/-8 pm). 4 Consistent with the profile recorded in human recombinant UT-HEK293 cells, [125I]hU-II binding to SJRH30 cells was selectively displaced by both mammalian and fish U-II isopeptides (Kis 0.5+/-0.1-1.2+/-0.3 nm) and related analogues (hU-II[4-11]>[Cys(5,10)]Acm hU-II; Kis 0.4+/-0.1 and 864+/-193 nm, respectively). 5 U-II receptor activation was functionally coupled to phospholipase C-mediated [Ca2+]i mobilization (EC50 6.9+/-2.2 nm) in SJRH30 cells. 6 The present study is the first to identify the presence of 'endogenous' U-II receptors in SJRH30 and TE671 cells. SJRH30 cells, in particular, might prove to be of utility for (a) investigating the pharmacological properties of hU-II and related small molecule antagonists at native human UT and (b) delineating the role of this neuropeptide in the (patho)physiological regulation of mammalian neuromuscular function.

Background: This retrospective analysis was conducted to evaluate self-reported patient and clinician assessed functional outcomes of patients who have undergone ablative hard palate oncologic resection and microvascular free-flap reconstruction with and without maxillofacial prosthetic intervention., Methods: All Head and Neck Surgery Service, Plastic and Reconstruction Surgery Service, and Dental Service charts and progress notes entered into the Institutional Health Care Information System of 57 patients who underwent hard palate resection and microvascular reconstruction at Memorial Sloan-Kettering Cancer Center (MSKCC) between January 1, 1988, and December 31, 2001 were reviewed retrospectively by three maxillofacial prosthodontists (BJB, JMH, IMZ). Prosthetic and nonprosthetic rehabilitation outcomes for each patient were reported as having normal; limited; or poor esthetics and function according to each prosthodontist's clinical evaluations; patients' self-perceptions; and feedback from friends, family members, and/or spouse. Speech intelligibility was determined in the same manner but reported as normal, hypernasal, and hyponasal., Results: Most of the 26 prosthetically rehabilitated patients were reported as having normal esthetics (81%), normal function (77%), normal speech (96%), and were able to return to per oral full diets (81%) without any restrictions., Conclusions: Acceptable oral rehabilitation outcomes were reported for most prosthetically rehabilitated free-flap patients. Normal speech can be anticipated with a high degree of certainty, and a high percentage of prosthetically restored free-flap patients achieved per oral diets., (Copyright 2003 Wiley Periodicals, Inc.)

Two endogenous receptors for the potent smooth muscle-stimulating peptide neuromedin U (NmU) have recently been identified and cloned. Pharmacological, binding, and expression studies were conducted in an attempt to determine the receptor(s) involved in the smooth muscle-stimulating effects of NmU. The NmU peptides caused a concentration-dependent contraction of canine isolated urinary bladder. NmU did not have this same effect in the urinary bladder from rat, guinea pig, rabbit, mouse, or ferret. Although NmU had no effect on canine uterus it did cause contraction of canine stomach, ileum, and colon. As well as causing contraction of canine bladder in vitro, NmU administered systemically resulted in a significant increase in urinary bladder pressure in vivo. High-affinity binding sites for NmU were identified in canine bladder. The four NmU peptides porcine NmU-8, rat NmU-23, human NmU-25, and porcine NmU-25 displaced (125)I-NmU-25 binding with similar K(i) values (0.08-0.24 nM). A different binding profile was revealed in human embryonic kidney-293 cells transiently expressed with the canine NmU-2 receptor where porcine NmU-8 (K(i) = 147.06 nM) was much less potent than the other NmU peptides. Using TaqMan, expression of NmU-1 was detected in human urinary bladder, small intestine, colon, and uterus. Expression of NmU-2 was much lower or absent in these human tissues and undetectable in canine bladder and stomach. The results of this study reveal significant species differences in the activity of NmU. The contractile activity in human and canine smooth muscle seems to be mediated by the recently cloned NmU-1 receptor.

A complementary DNA encoding calcitonin receptor-like receptor (CRLR) was isolated from a bovine aortic endothelial cell library. The bovine CRLR has 462 amino acids and 92% homology with the human CRLR. In a reverse transcriptase-polymerase chain reaction assay, bovine CRLR was found to be widely distributed, including in the heart and lungs. Stable transfection of bovine CRLR in human embryonic kidney cells (HEK-293) resulted in specific high-affinity [125I] rat adrenomedulin (rADM)-binding (dissociation constant=145+/-15 pM). ADM-stimulated adenylyl cyclase activity with an EC50 value of 5.0+/-1.2 nM. The human ADM receptor antagonist hADM(22-52) inhibited [125I]rADM-binding and ADM-stimulated adenylyl cyclase activity. Interactions between bovine CRLR and individual receptor activity modifying proteins (RAMPs) were also investigated. Transient co-transfection of bovine CRLR cDNA with human receptor activity modifying protein 1 (hRAMP1) cDNA in HEK-293 cells resulted in the expression of a CRLR that displayed high-affinity binding to calcitonin gene-related peptide. Co-transfection of bovine CRLR with human RAMP2 or RAMP3 cDNAs in HEK-293 cells displayed high-affinity ADM receptors. These observations suggest that in the absence of exogenous RAMPs heterologous expression of bovine CRLR results in an ADM receptor phenotype.

Urotensin-II (U-II) and its receptor (UT) represent novel therapeutic targets for management of a variety of cardiovascular diseases. To test such hypothesis, it will be necessary to develop experimental animal models for the manipulation of U-II/UT receptor system. The goal of this study was to clone mouse and primate preproU-II and UT for pharmacological profiling. Monkey and mouse preproU-II genes were identified to encode 123 and 125 amino acids. Monkey and mouse UT receptors were 389, and 386 amino acids, respectively. Genomic organization of mouse genes showed that the preproU-II has four exons, while the UT receptor has one exon. Although initially viewed by many exclusively as cardiovascular targets, the present study demonstrates expression of mouse and monkey U-II/UT receptor mRNA in extra-vascular tissue including lung, pancreas, skeletal muscle, kidney and liver. Ligand binding studies showed that [125I]h U-II bound to a single sites to the cloned receptors in a saturable/high affinity manner (Kd 654+/-154 and 214+/-65 pM and Bmax of 1011+/-125 and 497+/-68 fmol mg-1 for mouse and monkey UT receptors, respectively). Competition binding analysis demonstrated equipotent, high affinity binding of numerous mammalian, amphibian and piscine U-II isopeptides to these receptors (Ki=0.8 - 3 nM). Fluorescein isothiocyanate (FITC) labelled U-II, bound specifically to HEK-293 cells expressing mouse or monkey UT receptor, confirming cell surface expression of recombinant UT receptor. Exposure of these cells to human U-II resulted in an increase in intracellular [Ca2+] concentrations (EC50 3.2+/-0.8 and 1.1+/-0.3 nM for mouse and monkey UT receptors, respectively) and inositol phosphate (Ip) formation (EC50 7.2+/-1.8 and 0.9+/-0.2 nM for mouse and monkey UT receptors, respectively) consistent with the primary signalling pathway for UT receptor involving phospholipase C activation.

Resection of malignant soft-tissue tumors of the face often results in defects of skin, lining, and contour. When local tissues are unavailable, the folded/multiple skin island forearm free flap has been used to correct complex lining, skin, and contour defects concomitantly. This study is a retrospective review of all patients reconstructed with folded/multiple skin island forearm flaps from 1992 to 2000. Facial defects included facial skin, mucosal lining, and intervening soft tissue. Reconstruction was immediate and was not combined with another local flap. There were 17 patients (mean age, 61 years). Five patients had cutaneous malignancies and 12 patients had either mucosal or salivary gland malignancy. Defects were of the cheek and nose either alone or in combination. Defects ranged from 9 to 54 cm2. Nine patients had defects of either the skin or the mucosa with an associated soft-tissue component. These were reconstructed with a folded forearm flap with one skin island. Eight patients had full-thickness defects and were reconstructed with a folded flap with two skin islands. Flap survival was 100%. One case required reexploration for hematoma. Aesthetic results were good to excellent in 76% of patients. Delayed wound healing at the donor site occurred in 2 patients (11%). The folded/multiple skin island forearm flap is a useful tool for single-stage reconstruction of complex facial defects requiring replacement of skin, lining, and intervening soft tissue. Good to excellent aesthetic results can be expected in most patients.

Nipple-areolar reconstruction (NAR) is now an integral component of any type of breast reconstruction. This study presents a simple and reliable skin graft fixation and dressing technique used on 278 NARs in 221 patients from 1996 to 2000. Nipples and areolas were reconstructed with a modified skate flap and a full-thickness skin graft, respectively. Skin grafts were sutured and stented using Steri-Strips. A Tielle hydropolymer dressing with a central fenestration was used to cover the whole nipple-areolar complex. The nipple is dressed further with gauze and Microfoam tape. All nipples demonstrated 100% survival. There was one partial skin graft loss and 5% of the grafts had mild epidermolysis with eventual full reepithelialization. This dressing regime is simple and reliable in ensuring optimal skin graft take and nipple viability. It provides compression of the graft to prevent shearing and fluid accumulation, excellent absorbing capacity, a moist environment to promote wound healing, and maximal patient comfort.

Reoperation for malignant disease of the cervicothoracic spine can lead to compromised wound healing secondary to poor tissue quality from previous operations, heavily irradiated beds, and concomitant steroid therapy. Other complicating factors include exposed dura and spinal implants. Introducing well-vascularized soft tissue to obliterate dead space is critical to reliable wound healing. The purpose of this study was to determine the efficacy of the trapezius turnover flap in the management of these complex wounds. This study is a retrospective review of all patients undergoing trapezius muscle turnover flaps for closure of complex cervicothoracic wounds after spinal operations for metastatic or primary tumors. Six patients (3 male/3 female) were operated over an 18-month period (mean patient age, 43 years). Primary pathologies included radiation-induced peripheral nerve sheath tumor (N = 2), chondrosarcoma (N = 1), nonsmall-cell lung cancer (N = 1), paraganglioma (N = 1), and spindle cell sarcoma (N = 1). Trapezius muscle turnover flaps were unilateral and based on the transverse cervical artery in every patient. Indication for flap closure included inability to perform primary layered closure (N = 3), open wound with infection (N = 2), and exposed hardware (N = 1). All patients had previous operations of the cervicothoracic spine (mean, 5.8 months; range 2-9 months) for malignant disease and prior radiation therapy. Exposed dura was present in all patients, and 2 patients had dural repairs with bovine pericardial patches. Spinal stabilization hardware was present in 4 patients. All patients underwent perioperative treatment with systemic corticosteroids. All flaps survived, and primary wound healing was achieved in each patient. The only wound complication was a malignant pleural effusion communicating with the back wound, which was controlled with a closed suction drain. All wounds remained healed during the follow-up period. Four patients died from progression of disease within 10 months of surgery. The trapezius turnover flap has been used successfully when local tissue conditions prevent primary closure, or in the setting of open, infected wounds with exposed dura and hardware. The ease of flap elevation and minimal donor site morbidity make it a useful, single-stage reconstructive option in these difficult wounds.

The purpose of this study was to review the authors' 13-year experience with free tissue transfer for head and neck oncology patients. This study was a retrospective review of 728 free flaps performed in 698 patients. Recipient sites were subdivided by region into the mandible (N = 253), mid face/orbit (N = 190), hypopharynx (N = 134), oral cavity (N = 104), skull base (N = 36), and scalp (N = 11). The overall free flap success rate was 98.6%. Seventy-nine flaps (10.9%) were reexplored for vascular compromise. Ten flaps (1.4%) were lost in their entirety. The overall complication rate was 17.5%. Four donor sites (forearm, fibula, rectus, and jejunum) were used for 92% of the patients. The results of the study confirm the efficacy of free tissue transfer in the reconstruction of oncological head and neck defects. In this series the free forearm, fibula, rectus, and jejunum flaps have become the workhorse donor sites for the vast majority of defects.

Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM), two closely related peptides, initiate their biological responses through their interaction with calcitonin receptor-like receptor (CRLR). The CRLR receptor phenotype can be determined by coexpression of CRLR with one of the three-receptor activity modifying proteins (RAMPs). In this report, we characterized the pharmacological properties of the human or porcine CRLR with individual RAMPs transiently expressed in human embryonic kidney cell line (HEK-293). Characterization of RAMP1/human or porcine CRLR combination by radioligand binding ([125I] halphaCGRP) and functional assay (activation of adenylyl cyclase) revealed the properties of CGRP receptor. Similarly characterization of RAMP2/human or porcine CRLR and RAMP3/human or porcine CRLR combination by radioligand binding ([125I] rADM) and functional assay (activation of adenylyl cyclase) revealed the properties of ADM (22-52) sensitive-ADM receptor. In addition, porcine CRLR/RAMP2 or 3 combination displayed specific high affinity [125I] halphaCGRP binding also. Also, co-transfection of porcine CRLR with RAMPs provided higher expression level of the receptor than the human counterpart. Thus the present study along with earlier studies strongly support the role of RAMPs in the functional expression of specific CRLRs.

Hypopharynx and cervical esophageal defects are challenging problems for the reconstructive surgeon. Prior surgery and radiation therapy contribute to the difficulty in managing these patients. The surgeon must possess a reconstructive algorithm that varies depending on the defect, available donor sites, and his or her experience. The free jejunal flap is the flap used for most of these defects. The radial forearm flap is reserved for partial defects measuring less than 50% of the circumference of the pharynx. The gastric pull-up is used when an intrathoracic esophagectomy is necessary. The pectoralis flap is reserved for situations when external coverage is necessary in addition to hypopharyngeal reconstruction or when a free-tissue transfer is not appropriate. Reconstruction can offer most patients successful swallowing while minimizing complications.

The optimal treatment of the split-thickness skin graft (STSG) donor site remains an unresolved issue. This study was conducted to evaluate the combined use of calcium sodium alginate and a bio-occlusive membrane dressing in the management of STSG donor sites. This study was a prospective evaluation of all patients requiring an STSG over a 6-month period ending October 1998. There were 57 patients with a mean age of 61 years. All skin grafts were harvested with an electric dermatome from the anterior thigh and were 0.012 to 0.016 inches thick. Donor sites were dressed with calcium sodium alginate followed by a bio-occlusive dressing. Postoperatively, the skin graft donor site dressing was removed and replaced. The mean skin graft area was 114 cm2. The first dressing change occurred, on average, 3 days postoperatively. All dressings were taken down and the wounds reevaluated 7 days postoperatively. Fifty-two patients (91%) had achieved complete reepithelialization by this time. Five patients (9%) required an additional dressing. All wounds were healed completely by postoperative day 10. Donor site discomfort was minimal and limited to the time of dressing change. There were no wound-related complications. The average cost of dressing supplies was $48.00 per patient and $23.00 per dressing. This method of managing STSG donor sites allowed for unimpeded reepithelialization without wound complication. The bio-occlusive dressing eliminated the pain typically associated with fine mesh gauze dressings. The absorptive property of the calcium sodium alginate eliminated the problem of seroma formation and leakage seen routinely with the use of a bio-occlusive dressing alone. These results confirm that this technique is both efficacious and cost-effective.

Calcitonin gene-related peptide (CGRP), a potent vasodilatory and cardiotonic peptide, has a potential role for CGRP in diverse physiologic and pathophysiologic situations such as congestive heart failure, diabetes, migraine, and neurogenic inflammation. Although a peptide CGRP receptor antagonist, CGRP(8-37,) is available, its utility presents significant limitations for these indications. Here, we describe the properties of SB-(+)-273779 [N-methyl-N-(2-methylphenyl)-3-nitro-4-(2-thiazolylsulfinyl)nitrobenzanilide], a selective nonpeptide antagonist of CGRP(1) receptor. SB-(+)-273779 inhibited (125)I-labeled CGRP binding to SK-N-MC (human neuroblastoma cells) and human cloned CGRP(1) receptor with K(i) values of 310 +/- 40 and 250 +/-15 nM, respectively. SB-(+)-273779 also inhibited CGRP (3 nM)-activated adenylyl cyclase in these systems with IC(50) values of 390 +/-10 nM (in SK-N-MC) and 210 +/-16 nM (recombinant human CGRP receptors). Prolonged treatment (>30 min) of SK-N-MC cells with SB-(+)-273779 followed by extensive washing resulted in reduction in maximum CGRP-mediated adenylyl cyclase activity, suggesting that this compound has irreversible binding characteristics. In addition, SB-(+)-273779 antagonized CGRP-mediated 1) stimulation of intracellular Ca(2+) in recombinant CGRP receptors in HEK-293 cells, 2) inhibition of insulin-stimulated [(14)C]deoxyglucose uptake in L6 cells, 3) vasodilation in rat pulmonary artery, and 4) decrease in blood pressure in anesthetized rats. SB-(+)-273779 tested at 3 microM had no significant affinity for calcitonin, endothelin, angiotensin II, and alpha-adrenergic receptors under standard ligand binding assays. SB-(+)-273779 also did not inhibit forskolin and pituitary adenylate cyclase-activating polypeptide. These results suggest that SB-(+)-273779 is a valuable tool for studying CGRP-mediated functional responses in complex biological systems.

Injury to the long thoracic nerve results in winging of the scapula. When there is no known direct site of injury to this nerve, the traditional treatment consists of bracing the shoulder and, if recovery of function does not occur, then carrying out a muscle transfer to reconstitute the forces required to bring the scapula into appropriate position with respect to the thorax. The present report describes four patients in whom a site of compression of the long thoracic nerve within the scalene muscles proved to be the site of compression. A supraclavicular neurolysis of the long thoracic nerve resulted in correction of the winged scapula in all four of these patients.

Estrogen is known to stimulate endothelial nitric oxide production and attenuate endothelial dysfunction after ischemia and reperfusion. However, estrogen therapy increases the risk of breast and endometrial cancer. The present study was designed to determine whether idoxifene, a selective estrogen receptor modulator without adverse effects on reproductive organs, may stimulate nitric oxide release and protect endothelial function. In U-46619 precontracted superior mesenteric arterial (SMA) segments isolated from ovariectomized rats, idoxifene and 17 beta-estradiol resulted in a comparable dose-dependent vasorelaxation (maximal relaxation: 75.3 +/- 4.9 and 71 +/- 4.7%, respectively). Treatment of the rings with N(omega)-nitro-L-arginine methyl ester completely blocked idoxifene- and 17 beta-estradiol-induced vasorelaxation. In vitro incubation of SMA rings with TNF alpha significantly reduced vasorelaxation to an endothelium-dependent vasodilator, acetylcholine (maximal relaxation: 73 +/- 3.7 versus 95 +/- 2.9% pre-TNF alpha, P <.01). Idoxifene, but surprisingly not 17 beta-estradiol, prevented TNF alpha-induced endothelial dysfunction (maximal relaxation: 86 +/- 2.6% in idoxifene-treated rings and 77 +/- 5.1% in 17beta-estrogen-treated rings). In vivo ischemia and reperfusion resulted in significant endothelial dysfunction as evidenced by decreased vasorelaxation to acetylcholine (maximal relaxation: 48 +/- 5.5 versus 92 +/- 3.9% in normal SMA rings), but a normal relaxation response to an endothelium-independent vasodilator, acidified NaNO(2) (95 +/- 3.2%). Treatment with idoxifene at either 1 or 2 mg/kg/day, or 17beta-estrogen at 1 mg/kg/day for 4 days significantly preserved endothelial function (P <.01 versus vehicle). Taken together, these results demonstrate that idoxifene is an endothelium-dependent vasodilator and exerts significant endothelial protective effects against TNF alpha- and ischemia-reperfusion-induced endothelial injury. These results suggest that selective estrogen receptor modulators have therapeutic potential in diseases where endothelial dysfunction plays an important role.