Brigitte Pittet-Cuénod

Monocyte chemoattractant protein‐1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes

For many years, adipose tissue has been mainly considered as an inert reservoir for storing triglycerides. Since the discovery that adipocytes may secrete a variety of bioactive molecules (hormones, chemokines, and cytokines), an endocrine and paracrine role for white adipose tissue (WAT) in the regulation of energy balance and other physiological processes has been established, particularly with regard to brain and muscle. In contrast, little is known about the interactions of WAT with liver. Hence, we examined the effect of the secretory products of WAT on hepatocytes. Conditioned medium of human WAT explants induced significant steatosis in hepatocyte cell lines. Factor(s) responsible for the conditioned medium‐induced steatosis were screened by a battery of blocking antibodies against different cytokines/chemokines shown to be secreted by WAT. In contrast to interleukin‐8 and interleukin‐6, the monocyte chemoattractant protein‐1 was capable of inducing steatosis in hepatocytes in a time‐dependent manner at concentrations similar to those found in conditioned medium. Incubation of conditioned medium with antimonocyte chemoattractant protein‐1 antibodies prevented triglyceride accumulation. Investigation of the mechanism leading to the triglyceride accumulation showed that both a diminution of apolipoprotein B secretion and an increase in phosphoenolpyruvate carboxykinase messenger RNA may be involved. Conclusion: The monocyte chemoattractant protein‐1 secreted by adipose tissue may induce steatosis not only recruiting macrophages but also acting directly on hepatocytes. (HEPATOLOGY 2008.)

Plastic surgery improves long-term weight control after bariatric surgery.

1. Balagué N, Combescure C, Huber O, Pittet-Cuénod B, Modarressi A. Plastic surgery improves long-term weight control after bariatric surgery. Plast Reconstr Surg. 2013;132: 826–833. 2. American Society of Plastic Surgeons. 2012 Plastic Surgery Statistics Report. Available at: http://www.plasticsurgery. org/Documents/news-resources/statistics/2012-PlasticSurgery-Statistics/body-contouring-after-massive-weight-loss. pdf. Accessed October 9, 2013. 3. Sarwer DB, Fabricatore AN. Psychiatric considerations of the massive weight loss patient. Clin Plast Surg. 2008;35:1–10. 4. Coon D, Michaels J V, Gusenoff JA, Purnell C, Friedman T, Rubin JP. Multiple procedures and staging in the massive weight loss population. Plast Reconstr Surg. 2010;125:691–698. 5. Coon D, Gusenoff JA, Kannan N, El Khoudary SR, Naghshineh N, Rubin JP. Body mass and surgical complications in the postbariatric reconstructive patient: Analysis of 511 cases. Ann Surg. 2009;249:397–401.

Risk factors for noma disease: a 6-year, prospective, matched case-control study in Niger

BACKGROUND Noma is a poorly studied disease that leads to severe facial tissue destruction in children in developing countries, but the cause remains unknown. We aimed to identify the epidemiological and microbiological risk factors associated with noma disease. METHODS We did a prospective, matched, case-control study in Niger between Aug 1, 2001, and Oct 31, 2006, in children younger than 12 years to assess risk factors for acute noma. All acute noma cases were included and four controls for each case were matched by age and home village. Epidemiological and clinical data were obtained at study inclusion. We undertook matched-paired analyses with conditional logistic regression models. FINDINGS We included 82 cases and 327 controls. Independent risk factors associated with noma were: severe stunting (odds ratio [OR] 4·87, 95% CI 2·35-10·09) or wasting (2·45, 1·25-4·83); a high number of previous pregnancies in the mother (1·16, 1·04-1·31); the presence of respiratory disease, diarrhoea, or fever in the past 3 months (2·70, 1·35-5·40); and the absence of chickens at home (1·90, 0·93-3·88). After inclusion of microbiological data, a reduced proportion of Fusobacterium (4·63, 1·61-13·35), Capnocytophaga (3·69, 1·48-9·17), Neisseria (3·24, 1·10-9·55), and Spirochaeta in the mouth (7·77, 2·12-28·42), and an increased proportion of Prevotella (2·53, 1·07-5·98), were associated with noma. We identified no specific single bacterial or viral pathogen in cases. INTERPRETATION Noma is associated with indicators of severe poverty and altered oral microbiota. The predominance of specific bacterial commensals is indicative of a modification of the oral microbiota associated with reduced bacterial diversity. FUNDING Gertrude Hirzel Foundation.

Hyperglycemia Increases Susceptibility to Ischemic Necrosis

Diabetic patients are at risk for spontaneous foot ulcers, chronic wounds, infections, and tissue necrosis. Current theories suggest that the development and progression of diabetic foot ulcers are mainly caused by arteriosclerosis and peripheral neuropathy. Tissue necrosis plays a primordial role in the progression of diabetic foot ulcers but the underlying mechanisms are poorly understood. The aim of the present study was to investigate the effects of hyperglycemia per se on the susceptibility of ischemic tissue to necrosis, using a critical ischemic hind limb animal model. We inflicted the same degree of ischemia in both euglycemic and streptozotocin-induced hyperglycemic rats by resecting the external iliac, the femoral, and the saphenous arteries. Postoperative laser Doppler flowmetry of the ischemic feet showed the same degree of reduction in skin perfusion in both hyperglycemic and euglycemic animals. Nevertheless, we found a significantly higher rate of limb necrosis in hyperglycemic rats compared to euglycemic rats (71% versus 29%, resp.). In this study, we revealed that hyperglycemia per se increases the susceptibility to limb necrosis in ischemic conditions. Our results may help to better understand the physiopathology of progressive diabetic wounds and underline the importance of strict glycemic control in patients with critical limb ischemia.

NADPH oxidase 4 deficiency leads to impaired wound repair and reduced dityrosine-crosslinking, but does not affect myofibroblast formation.

NADPH oxidases (NOX) mediate redox signaling by generating superoxide and/or hydrogen peroxide, which are involved in biosynthetic pathways, e.g. thyroid hormone generation, dityrosine crosslinking, as well as bacterial killing. Data investigating the role of NOX enzymes in cutaneous wound repair is limited and specifically their function in skin myofibroblast expression is unknown. The isoform NOX4 was recently shown to be a pre-requisite for the differentiation of cardiac and pulmonary myofibroblasts. In this study we investigate the role of NOX4 in wound repair using a wound model in NOX4 knockout mice (n=16) and wildtype mice (n=16). Wounds were photographed daily until complete wound closure. Mice were sacrificed at day 3, 7, 14; wound tissue was harvested. NOX4-deficient mice healed significantly slower (22 days, SD=1.9) than wild-type mice (17 days, SD=1.4, p<0.005). However, there was no difference in myofibroblast expression. Strong dityrosine formation was observed, but was significantly weaker in NOX4-/- mice (p<0.05). NOX2, HIF1α and CD31 expression was significantly weaker in NOX4-/- mice (p<0.05). In this study we show for the first time that NOX4 plays a role in cutaneous wound repair. Our data suggests that NOX4 mediates HIF1α expression and neoangiogenesis during wound repair. NOX4 deletion led to a decreased expression of NOX2, implying a role of NOX4 in phagocytic cell recruitment. NOX4 was required for effective wound contraction but not myofibroblast expression. We suggest that myofibroblast contraction in NOX4-deficient mice is less effective in contracting the wound because of insufficient dityrosine-crosslinking of the ECM, providing the first indication for a physiological function of dityrosine crosslinking in higher animals.

First-aid with warm water delays burn progression and increases skin survival

INTRODUCTION First aid treatment for thermal injuries with cold water removes heat and decreases inflammation. However, perfusion in the ischemic zone surrounding the coagulated core can be compromised by cold-induced vasoconstriction and favor burn progression. The aim of this study is to evaluate the effect of local warming on burn progression in the rat comb burn model. METHODS 24 male Wistar rats were randomly assigned to either no treatment (control) or application of cold (17 °C) or warm (37 °C) water applied for 20 min. Evolution of burn depth, interspace necrosis, and microcirculatory perfusion were assessed with histology, planimetry, respectively with Laser Doppler flowmetry after 1 h, as well as 1, 4, and 7 days. RESULTS Consistent conversion from a superficial to a deep dermal burn within 24 h was obtained in control animals. Warm and cold water significantly delayed burn depth progression, however after 4 days the burn depth was similar in all groups. Interspace necrosis was significantly reduced by warm water treatment (62±4% vs. 69±5% (cold water) and 82±3% (control); p<0.05). This was attributed to the significantly improved perfusion after warming, which was present 1 h after burn induction and was maintained thereafter (103±4% of baseline vs. 91±3% for cold water and 80±2% for control, p<0.05). CONCLUSION In order to limit damage after burn injury, burn progression has to be prevented. Besides delaying burn progression, the application of warm water provided an additional benefit by improving the microcirculatory perfusion, which translated into increased tissue survival.

Reactive oxygen species and NOX enzymes are emerging as key players in cutaneous wound repair

Our understanding of the role of oxygen in cell physiology has evolved from its long-recognized importance as an essential factor in oxidative metabolism to its recognition as an important player in cell signaling. With regard to the latter, oxygen is needed for the generation of reactive oxygen species (ROS), which regulate a number of different cellular functions including differentiation, proliferation, apoptosis, migration, and contraction. Data specifically concerning the role of ROS-dependent signaling in cutaneous wound repair are very limited, especially regarding wound contraction. In this review we provide an overview of the current literature on the role of molecular and reactive oxygen in the physiology of wound repair as well as in the pathophysiology and therapy of chronic wounds, especially under ischemic and hyperglycemic conditions.

Breast lesions in reduction mammaplasty specimens: a histopathological pattern in 534 patients

Background:The prevalence of breast lesions (benign, precancerous and cancer lesions) in reduction mammaplasty (RM) specimens has rarely been reported in Europe and never in the Swiss population.Methods:Personal and histopathological data from 534 female patients who underwent RM were reviewed.Results:Benign and/or malignant lesions were detected in 76.2% of all patients. Benign breast lesions associated with an increased risk of developing breast cancer represented 2.8% of all lesions. Breast cancer in situ was identified in 5 (0.9%) patients. Patient age and previous history of breast cancer were risk factors for incidental breast cancer.Conclusion:The rate of incidental carcinoma in situ was higher for patients with breast cancer history. Probably due to preoperative breast cancer investigation, no occult invasive breast cancer was found in reduction mammary specimens. Therefore before RM, breast cancer evaluation should be considered for all patients, especially for those with breast cancer risk factors (e.g., patient age, personal history of breast cancer).

Factors Associated With Treatment Failure of Infected Pressure Sores

Objective: In this study, we assess interdisciplinary surgical and medical parameters associated to recurrences of infected pressure ulcers. Background: There is a little in the published literature regarding factors associated with the outcome of treatment of infected pressure ulcers. Methods: We undertook a single-center review of spinal injured adults hospitalized for an infected pressure ulcer or implant-free osteomyelitis and reviewed the literature on this topic from 1990–2015. Results: We found 70 lesions in 31 patients (52 with osteomyelitis) who had a median follow-up of 2.7 years (range, 4 months to 19 years). The median duration of antibiotic therapy was 6 weeks, of which 1 week was parenteral. Clinical recurrence after treatment was noted in 44 infected ulcers (63%), after a median interval of 1 year. In 86% of these recurrences, cultures yielded a different organism than the preceding episode. By multivariate analyses, the following factors were not significantly related to recurrence: number of surgical interventions (hazard ratio 0.9, 95% confidence interval 0.5–1.5); osteomyelitis (hazard ratio 1.5; 0.7–3.1); immune suppression; prior sacral infections, and duration of total (or just parenteral) antibiotic sue. Patients with antibiotic treatment for <6 weeks had the same failure rate as those with as >12 weeks (&khgr;2 test; P = 0.90). Conclusions: In patients with infected pressure ulcers, clinical recurrence occurs in almost two-thirds of lesions, but in only 14% with the same pathogen(s). The number of surgical debridements, flap use, or duration of antibiotic therapy was not associated with recurrence, suggesting recurrences are caused by reinfections caused by other extrahospital factors.

Hyperglycemia Interacts with Ischemia in a Synergistic Way on Wound Repair and Myofibroblast Differentiation.

Background: Hyperglycemia is known to adversely affect the outcome of ischemic insults, but its interaction with ischemia has not been investigated in wound repair yet. In this study, we develop a new animal model allowing to investigate the interaction between hyperglycemia and ischemia during the wound repair process. We focus on myofibroblast differentiation, a key element of wound repair. Methods: Ischemia was inflicted in Wistar rats by resection of the femoral to popliteal arteries on the left side, whereas arteries were dissected without resection on the right side. Full-thickness skin wounds (1 cm2) were created on both feet. Hyperglycemia was induced by injection of streptozotocin. Normoglycemic animals served as control (n = 23/group). Blood flow, wound closure, and myofibroblast expression were measured. Results: Wound closure was significantly delayed in ischemic compared with nonischemic wounds in all rats. This delay was almost 5-fold exacerbated in hyperglycemic rats compared with normoglycemic rats, while hyperglycemia alone showed only a slight effect on wound repair. Delayed wound repair was associated with impaired wound contraction and myofibroblast differentiation. Conclusions: Our model allows to specifically quantify the effect of hyperglycemia and ischemia alone or in combination on wound repair. We show that hyperglycemia amplifies the inhibitory effect of ischemia on wound repair and myofibroblast expression. Our data reveal for the first time the synergic aspect of this interaction and therefore stress the importance of a strict glycemic control in the management of ischemic wounds.