Footprints of the EADV: a meeting report from the 17th Congress of the European Academy of Dermatology and Venereology.

The 17th Congress of the European Academy of Dermatology and Venereology took place in Paris on 17-20 September 2008 and brought together nearly 11,000 participants. Various plenary lectures, subspecialty meetings, 'free communications', 'top ten', 'test yourself' and 'junior' sessions, 19 courses and 14 'lunches with the expert', six forums, 27 symposia and 45 workshops were pressed into the 4 days of the meeting. Over 1700 posters were presented and exhibited. The themes of a number of symposiums, workshops and sessions overlapped, offering additional educational opportunities despite a very busy schedule. The meeting was well organized. Aesthetic dermatology comprised a significant part of the meeting. It is impossible to encompass all important presentations and we highlight a few medical pearls presented at the meeting; however, our report is not intended as a substitute for reading the conference proceedings and related references quoted in this article.

Insulin-Like Growth Factor-1-Mediated DNA Repair in Irradiated Salivary Glands Is Sirtuin-1 Dependent.

Ionizing radiation is one of the most common cancer treatments; however, the treatment leads to a wide range of debilitating side effects. In patients with head and neck cancer (HNC), the surrounding normal salivary gland is extremely sensitive to therapeutic radiation, and damage to this tissue results in various oral complications and decreased quality of life (QOL). In the current study, mice treated with targeted head and neck radiation showed a significant increase in double-stranded breaks (DSB) in the DNA of parotid salivary gland cells immediately after treatment, and this remained elevated 3 h posttreatment. In contrast, mice pretreated with insulin-like growth factor-1 (IGF-1) showed resolution of the same amount of initial DNA damage by 3 h posttreatment. At acute time points (30 min to 2 h), irradiated parotid glands had significantly decreased levels of the histone deactylase Sirtuin-1 (SirT-1) which has been previously shown to function in DNA repair. Pretreatment with IGF-1 increased SirT-1 protein levels and increased deacetylation of SirT-1 targets involved in DNA repair. Pharmacological inhibition of SirT-1 activity decreased the IGF-1-mediated resolution of DSB. These data suggest that IGF-1 promotes DNA repair in irradiated parotid glands through the maintenance and activation of SirT-1.

Acquired haemophilia heralded by bleeding into the oral mucosa in a patient with bullous pemphigoid, rheumatoid arthritis, and vitiligo.

Acquired haemophilia is rare and potentially fatal, with a mortality of 20% if left untreated. There is a strong association with other autoimmune diseases. This report describes a patient with rheumatoid arthritis, vitiligo, and bullous pemphigoid where the diagnosis of acquired haemophilia was made after an extensive bleed into a bullous lesion in the buccal mucosa. This case highlights some of the potential complications of acquired haemophilia and its treatment.

Absence of Crabtree effect in human melanoma cells adapted to growth at low pH: reversal by respiratory inhibitors.

Because many tumors are acidic and hypoxic relative to normal tissues, glycolysis and oxygen consumption were investigated in early-passage human melanoma cells adapted to growth at pH 6.7. In the absence of glucose, the basal rate of oxygen consumption in low pH-adapted cells was 75% of that in cells grown at pH 7.3. The rate of lactic acid production in low pH-adapted cells was increased 4-fold by exposure to 16.7 mM glucose compared with a 10-fold increase in cells grown at pH 7.3. Furthermore, in low pH-adapted cells the rate of oxygen consumption was stimulated by the addition of glucose in contrast to the inhibition of oxygen consumption by elevated glucose in cells grown at pH 7.3 (i.e., the Crabtree effect). Both low pH-adapted cells and cells grown at pH 7.3 exposed to glucose plus 0.35 mM meta-iodo-benzylguanidine (MIBG), an inhibitor of mitochondrial respiration, had oxygen consumption reduced by approximately 60% and lactic acid production increased by approximately 65% relative to glucose alone. Although adaptation to growth at low pH was associated with a loss of the Crabtree effect and a higher ratio of oxygen consumption to lactic acid production, the rate of glycolysis was the same in both growth conditions in the presence of 0.1 mM dinitrophenol, an uncoupler of ATP synthesis. This indicates that the glycolytic capacity of low pH-adapted cells remains unchanged. Therefore, tumor acute acidification and oxygenation can be achieved by exposure to hyperglycemia combined with MIBG to improve therapeutic response.

Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade.

Antiandrogen therapy is an important modality in the treatment of prostate cancer. Recent research into the role of angiogenesis in tumour growth and metastasis has uncovered links between antiandrogen therapy, radiation therapy and angiogenesis, which have exciting implications for the treatment of prostate cancer. Angiogenic cytokines such as vascular endothelial growth factor (VEGF) have been identified in prostate cancer cells and tumours, and androgens appear to stimulate VEGF. This article assesses the antiangiogenic effects of hormonal therapy and assesses the role that angiogenesis may play in the observed cooperation between hormonal and radiation therapies for prostate cancer.

Induction and excretion of ultraviolet-induced 8-oxo-2'-deoxyguanosine and thymine dimers in vivo: implications for PUVA.

Molecular epidemiology has linked ultraviolet-induced DNA damage with mutagenesis and skin carcinogenesis. Ultraviolet radiation may damage DNA in one of two ways: either directly, leading to lesions such as cyclobutane thymine dimers (T<>T), or indirectly, via photosensitizers that generate free radical species that may ultimately produce such oxidative lesions as 8-oxo-2'-deoxyguanosine. We report the results of a pilot, case control study in which seven, healthy, human volunteers (skin type II; aged 23-56 y; three male, four female) received a suberythemal dose of whole body irradiation from ultraviolet-A-emitting fluorescent tubes used in psoralen plus ultraviolet A therapy. First void, mid-stream urine samples were collected pre-exposure and daily postexposure, for up to 13 d. Analysis of urinary 8-oxo-2'-deoxyguanosine and cyclobutane thymine dimers was by competitive enzyme-linked immunosorbent assay (interassay coefficient of variation < or = 10%) and compared with a matched, control group of unirradiated individuals. A maximal increase in levels of urinary 8-oxo-2'-deoxyguanosine was seen 4 d post-ultraviolet exposure. A subsequent reduction was noted, before finally returning to baseline. Similarly, cyclobutane thymine dimer levels peaked 3 d postexposure, before returning to baseline. In contrast to the 8-oxo-2'-deoxyguanosine analysis, however, a second peak was noted at days 9-11, before again returning to baseline. This is the first report examining urinary 8-oxo-2'-deoxyguanosine and cyclobutane thymine dimers following ultraviolet exposure of healthy human subjects. This work illustrates the induction and time course for excretion of ultraviolet-induced lesions, perhaps alluding to repair and ultimately offering the potential to define psoralen plus ultraviolet A dosage regimes in terms of minimizing DNA damage and hence cancer risk.

Urinary thymine dimers and 8-oxo-2'-deoxyguanosine in psoriasis.

Psoralen in conjunction with UVA (PUVA) is perhaps the most effective treatment for psoriasis. It is, however, a risk factor for skin cancer in these patients and there is a need to develop non-invasive assays reflective of treatment-induced DNA damage. We report here the assessment of two important lesions, thymine dimer (T<>T) and 8-oxo-2'-deoxyguanosine (8-OHdG), in the urine of psoriasis patients. It was found that, once corrected for urine concentration, the psoriatic group had significantly higher (P<0. 0001) urinary levels of thymine dimers compared to the control group. No significant differences in urinary 8-OHdG levels were noted between the psoriatic, atopic dermatitis and control groups. Therefore biomonitoring of therapy from the very start with this simple and non-invasive assay could perhaps be an effective measure of the risk involved with the treatment allowing optimization for minimal-risk therapy.

Anti-endotoxin monoclonal antibodies protect by enhancing bacterial and endotoxin clearance.

In this study, we sought to determine the mechanism(s) by which a type-specific anti-lipopolysaccharide monoclonal antibody (an IgG directed against the O-antigen polysaccharide region of Salmonella minnesota lipopolysaccharide) and its F(ab')2 fragments protect during gram-negative bacterial peritonitis and endotoxemia in mice. During peritoneal infection, (1) IgG significantly decreased mortality, bacteremia, and endotoxemia at all time points compared with saline solution pretreatment and (2) F(ab')2 fragments reduced mortality at 24 hours but not thereafter, and had no effect on bacteremia but reduced endotoxemia compared with saline solution pretreatment. In the endotoxin model, IgG pretreatment significantly reduced mortality compared with saline solution pretreatment, while F(ab')2 fragments had no significant effect on mortality. No difference in endotoxemia was observed in mice that received IgG, F(ab')2 fragments, or saline solution pretreatment during endotoxemia. These results suggest that type-specific anti-lipopolysaccharide monoclonal antibodies protect by Fc-mediated clearance of both bacteria and endotoxin.

Inhibition of splenic macrophage tumor necrosis factor alpha secretion in vivo by antilipopolysaccharide monoclonal antibodies.

OBJECTIVE: This study tried to determine whether administration of antilipopolysaccharide (LPS) murine monoclonal antibody (mAb) 2A3 to mice was associated with (1) protective capacity during experimental gram-negative bacterial sepsis, and (2) inhibition of tumor necrosis factor alpha (TNF-alpha) secretion in the systemic circulation and at the tissue level during experimental infection. DESIGN: Mice received an initial intravenous injection of either saline or 100 micrograms of anti-LPS mAb 2A3, and 1 hour later underwent intraperitoneal inoculation of viable Escherichia coli 0111:B4. Mortality was assessed daily for 7 days. Separate groups of mice were treated similarly and plasma TNF-alpha concentrations were determined from blood samples obtained at 1, 3, 6, 10, and 16 hours after infection by enzyme-linked immunosorbent assay. Concurrently, splenocytes harvested from animals 3, 10, and 16 hours after infection were incubated in culture ex vivo and supernatant TNF-alpha levels were determined. RESULTS: Pretreatment with anti-LPS mAb 2A3 prior to an intraperitoneal challenge of live E coli 0111:B4 was associated with the following: (1) significant protective capacity (100% vs 0% mortality, P < .001); (2) inhibition of plasma TNF-alpha levels 16 hours after infection (1257 +/- 323 pg/mL vs 292 +/- 254 pg/mL, P < .001); and (3) abrogation of TNF-alpha secretion derived from splenic macrophages isolated 16 hours after bacterial challenge (229 +/- 12 pg/mL vs 107 +/- 48 pg/mL, P < .05). CONCLUSIONS: These results strongly support the contention that inhibition of LPS-induced TNF-alpha secretion at both the tissue and systemic levels is a key mechanism by which anti-LPS mAbs provide protection during gram-negative bacterial peritonitis. We believe that in vivo monitoring of macrophage cytokine secretion will be critical for elucidating the precise role of a variety of mediators in the pathogenesis of gram-negative bacterial sepsis.

Presentation and management of epigastric hernias in children.

BACKGROUND/PURPOSE: Although epigastric hernias are common, there are no reports that describe the presentation and treatment of these defects in children. The authors reviewed their experience with these hernias to develop recommendations for their management in this age group. METHODS: Medical records were reviewed for all children younger than 18 years who presented for evaluation of an epigastric hernia at our institution over 14 years. Data on presentation, operative findings, and postoperative results were obtained. RESULTS: Forty children were evaluated for an epigastric hernia, representing 4% of all pediatric patients seen for treatment of a hernia. An epigastric hernia was first observed at birth in 12 patients (30%). All children presented with a mass in the epigastrium. The hernia was observed to be either symptomatic (abdominal wall pain or tenderness) or enlarging in 22 patients (55%). Thirty-eight children underwent repair, and 2 were lost to follow-up. There was no recurrence or morbidity associated with surgical repair of these defects. CONCLUSIONS: Epigastric hernias are common in children and frequently present in infancy. Because most are either symptomatic or enlarging, the authors recommend repair of these defects at the time of presentation.

The optimal approach for management of metachronous hernias in children: a decision analysis.

PURPOSE: Up to 30% of children undergoing unilateral hernia repair will later get a hernia on the contralateral side that requires repair. Three approaches have been used to address the potential for development of a metachronous hernia: (1) observation and repair of a contralateral hernia only if it later becomes apparent, (2) routine contralateral groin exploration, and (3) laparoscopy to evaluate the contralateral groin for a potential hernia. The purpose of this study was to use decision analysis to determine which approach resulted in the lowest morbidity, mortality, and cost. METHODS: A decision tree was constructed for the management of metachronous hernias that accounted for the occurrence of both nonincarcerated and incarcerated metachronous hernias. Baseline values were estimated from recent reports in the literature. Total charges for each approach were obtained from available hospital records and were used to estimate cost. RESULTS: Observation was favored over laparoscopy and laparoscopy over routine exploration with respect to preventing spermatic cord injury and preserving future fertility. Although a second operation may be required when observation is used, this approach was associated with only a small increase in anesthesia-related complications (1 in 17,847), cardiac arrests (1 in 62,500), and death (1 in 312,500). Although observation was the favored approach with respect to cost, laparoscopy was less expensive when the expected incidence of metachronous hernias was high. CONCLUSIONS: Observation is the preferred approach to metachronous hernias because it results in the lowest incidence of injury and cost for most patients and is associated with a minimal increase in anesthesia-related morbidity and mortality. Laparoscopy may be advantageous for patients at high risk for development of a contralateral hernia. As a strategy for preventing metachronous hernias without consideration for injury or cost, routine exploration should be limited to situations in which laparoscopy cannot be performed because of small patient size or a preference for spinal anesthesia.

Diagnosis and treatment of cytomegalovirus disease in pediatric renal transplant recipients.

The purpose of this study was to identify factors associated with the development of cytomegalovirus (CMV) disease and to assess the morbidity of this illness in pediatric renal transplant patients. The authors retrospectively reviewed the records of 135 patients (< 18 years of age) who underwent a total of 151 transplants (146 kidney transplants, five kidney/liver transplants) over 5 years (average follow-up period, 33.0 +/- 21.7 months). They assessed the risk factors that previously have been associated with the development of CMV disease in adults (age, occurrence of acute rejection episodes, and preoperative donor and recipient CMV serological status) and evaluated the incidence of associated graft loss and mortality. Twenty-two episodes of CMV disease were diagnosed based on evidence of CMV infection and on clinical symptoms; the episodes were treated in 17 patients. A multivariate analysis showed that the development of CMV disease was associated with age of > or = 13 years (P = .02), concomitant liver transplantation (P = .01), and treatment of acute rejection (P = .04). In addition, patients who were CMV-seronegative preoperatively and received a graft from a CMV-seropositive donor (P = .04) or who were CMV-seropositive preoperatively and received a graft from a CMV-seronegative donor (P = .02) were more likely to have CMV disease. Although all patients with CMV disease required hospitalization and were treated with intravenous ganciclovir, CMV disease was not associated with increased allograft loss or mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy and safety of fentanyl for the management of severe procedural pain in patients with burn injuries.

Fentanyl has been shown to be effective for the management of intense pain of short duration. We have recently used intravenous fentanyl for burn wound procedures because of its rapid onset, high potency, and short duration. In this report, we reviewed our experience with fentanyl in a variety of procedural burn pain settings to develop specific recommendations about its effectiveness and safety for the treatment of pain in patients with burn injuries. The medical records of patients with burn injuries who received fentanyl for wound procedures over a 2-year period were retrospectively reviewed. Patient demographics, the amount of fentanyl administered, the level of analgesia achieved, and the incidence of adverse effects were analyzed. Fifty-five patients who were 9 months to 75 years old with burn wounds (range, 1%-90% of total body surface area) received 148 doses of fentanyl for the treatment of procedural pain. An average of 8.0 +/- 7.0 microg/kg of fentanyl (range, 0.7 to 38.0 microg/kg) was required for the first wound procedure with fentanyl. No correlation between dosage of fentanyl given and either age or percentage of total body surface area burned was observed. Transient respiratory depression was observed in 17 patients (31%). No patient required intubation or additional supplemental oxygen after the conclusion of the procedure. High doses of fentanyl are required to achieve adequate analgesia during some burn wound procedures. Respiratory depression associated with fentanyl use is transient but requires adequate preparation and trained personnel. Fentanyl may be effectively integrated into the pain control strategy for patients with burn injuries.

A rapid procedure for purifying IgM monoclonal antibodies from murine ascites using a DEAE-disk.

A method for purifying IgM monoclonal antibodies (mAbs) from murine ascites using a DEAE-disk is described. After ammonium sulfate precipitation, ascites proteins are redissolved and loaded onto a DEAE-disk. MAb then is eluted from the disk using a stepwise NaCl gradient. IgM mAb produced by this procedure was > 95% pure as assessed by reducing SDS-PAGE analysis and was free of significant IgG contamination as determined by double radial immunodiffusion analysis. Yield of IgM mAb was approximately 2% of total ascites protein and approximately 10% of the amount of IgM contained in crude ascites. MAb retained immunoreactivity as assessed by ELISA, and the affinity index was evaluated by thiocyanate elution and remained unchanged. This two step technique for purifying IgM mAb from murine ascites is rapid, simple, and yields mAb of sufficient purity and immunoreactivity for the majority of mAb applications.

Tissue expansion in perspective.

Tissue expansion is a recent advance in skin cover technique. Its empirical use has enabled many previously difficult reconstructions to be completed without recourse to distant flaps. Its high complication rate and lack of basic scientific understanding at present restrict its use to selected cases, but the quality of repairs possible by this method encourage further serious scientific study.

Nutritional support of the pediatric trauma patient: a practical approach.

It is mandatory to evaluate and develop a plan for nutritional support for all injured children who are hospitalized. Although most childre" will rapidly resume normal oral intake, more severely injured children should be started on parenteral or enteral nutrition as soon as possible after admission. The mode of delivery and composition of nutritional support differ depending on the clinical setting and can change during the recovery period. Development of an initial plan and modification of the plan depending on the child's response will most effectively meet the metabolic demands after injury.

Quercetin as a systemic chemopreventative agent: structural and functional mechanisms.

There is a growing focus on diet and the use of naturally abundant compounds as supplements because their properties have many potential health benefits with minimal side effects. The flavonol-type flavonoid quercetin has increased in popularity because it is a highly studied, multidimensional bioactive compound that possesses both antioxidant properties and the ability to modulate signal transduction pathways. Direct antioxidant properties may play a role in the abrogation of both DNA damage, but potentially of more importance quercetin, can also target multiple signaling pathways associated with oncogenesis and tumor progression, which include DNA damage, inflammation and obesity. Quercetin can also upregulate proteins that abrogate free radical damage, such as p53. The concurrent targeting of quercetin's multiple bioactivities presents a potent chemopreventative strategy, but because bioavailability of quercetin is poor it will be necessary to develop quercetin analogs to maximize the full chemopreventative potential of the compound. This review will explore the structural and mechanistic properties of quercetin as they relate to its ability to act as a chemopreventative compound. A better understanding of quercetin's mechanistic properties could aid in the rational design of more potent or bioavailable flavonol-type compounds.

Head and neck tumor cell radiation response occurs in the presence of IGF1.

Radiation therapy for head and neck cancer results in severe secondary side-effects in salivary glands. We previously demonstrated that the administration of IGF1 preserves or restores salivary gland function following radiation. Based on these findings, we propose to study the effect of IGF1 on human head and neck carcinoma cells. Head and neck tumor cells treated with radiation have significant reductions in tumor cell survival, as measured by MTT and crystal violet assays, regardless of IGF1 pre-treatment. Head and neck squamous carcinoma cell xenografts treated with concurrent radiation+IGF1 also exhibit significant tumor growth delay; however, growth rates are elevated compared with those in irradiated xenografts. In contrast, administration of IGF1 after radiation treatment has no effect on tumor xenograft growth rates. Analysis of these data suggests that localized delivery may be required for concurrent therapy to prevent secondary side-effects of radiotherapy, while post-therapy administration of IGF1 could be considered for the restoration of salivary function.

IGF1 activates cell cycle arrest following irradiation by reducing binding of ΔNp63 to the p21 promoter.

Radiotherapy for head and neck tumors often results in persistent loss of function in salivary glands. Patients suffering from impaired salivary function frequently terminate treatment prematurely because of reduced quality of life caused by malnutrition and other debilitating side-effects. It has been previously shown in mice expressing a constitutively active form of Akt (myr-Akt1), or in mice pretreated with IGF1, apoptosis is suppressed, which correlates with maintained salivary gland function measured by stimulated salivary flow. Induction of cell cycle arrest may be important for this protection by allowing cells time for DNA repair. We have observed increased accumulation of cells in G2/M at acute time-points after irradiation in parotid glands of mice receiving pretreatment with IGF1. As p21, a transcriptional target of the p53 family, is necessary for maintaining G2/M arrest, we analyzed the roles of p53 and p63 in modulating IGF1-stimulated p21 expression. Pretreatment with IGF1 reduces binding of ΔNp63 to the p21 promoter after irradiation, which coincides with increased p53 binding and sustained p21 transcription. Our data indicate a role for ΔNp63 in modulating p53-dependent gene expression and influencing whether a cell death or cell cycle arrest program is initiated.