No need for preoperative antiseptics in elective outpatient plastic surgical operations: a prospective study

The development of antisepsis in the late nineteenth and early twentieth centuries revolutionized health care. The time-honored technique of skin preparation is to scrub the entire operative area of the patient for 5 to 7 minutes with a germicidal detergent solution and then paint the region with an antimicrobial solution of either tincture of povidone-iodine (Betadine) or chlorhexidine. Although antiseptics result in lower colony counts on the skin, they have side effects and higher cost in relation to normal saline. The authors have prepared patients by showering the surgical site with soap and water and rinsing it with normal saline, in 905 cases of outpatient, clean-wound plastic surgery. In another 905 cases that served as the control group, the traditional method of preoperative shower and scrub with chlorhexidine or Betadine was used. In both groups, there was no incidence of wound infection.     

Topical ‘dual-soft’ glucocorticoid receptor agonist for dermatology

Steroidal glucocorticoids (GR agonists) have been widely used for the topical treatment of skin disorders, including atopic dermatitis. They are a very effective therapy, but they are associated with both unwanted local effects in the skin (skin thinning/atrophy) and systemic side effects. These effects can limit the long-term utility of potent steroids.Here we report on a topically delivered non-steroidal GR agonist, that has the potential to deliver high efficacy in the skin, but due to rapid metabolism in the blood & liver (“dual-soft”) it should have greater systemic safety than existing treatments. In addition, compared to less selective steroidal GR agonists, the new non-steroidal Selective Glucocorticoid Agonists (SEGRAs) have the potential to avoid the skin atrophy observed with existing topical steroids.Due to its potential for reduced skin atrophy and low systemic exposure, LEO 134310 (17) may be suitable for long term topical treatment of skin diseases such as atopic dermatitis and psoriasis.     

Radiodermatitis as a consequence of radiation recall induced by acyclovir: case report

BackgroundRadiation recall dermatitis (RRD) is an inflammatory reaction in an area of the skin previously irradiated for cancer treatment. The reaction usually occurs following the administration of a cytotoxic drug. Manifestations range from mild to severe, resulting in tissue necrosis. It is treated with removal of the probable causative agent, daily dressings and surgical debridement of the necrotic area.Case presentationA 54-year-old woman had a previous diagnosis of intraductal carcinoma in situ, and had been submitted to lumpectomy and adjuvant radiotherapy and hormonal therapy. One year after surgery, sores suggestive of herpes zoster infection developed, and treatment with acyclovir was started. At the same time, there was the onset of pain and fever. In the skin area previously irradiated, there was breast hardening, skin infiltration and serosanguinolent discharge. An incisional biopsy was performed to rule out radioinduced sarcoma. The patient was treated with surgical debridement.ConclusionsThis case report describes acyclovir as a possible trigger of RRD, a rare condition that could have been mistaken for an eruption with other causes. In this case, the dermatitis reaction was confined to the previously irradiated area of the skin, which suggested radiation recall. A better understanding of the condition’s mechanism and about the possible joint effects of drugs and radiotherapy on the skin is necessary.     

Network Neighbors of Drug Targets Contribute to Drug Side-Effect Similarity

In pharmacology, it is essential to identify the molecular mechanisms of drug action in order to understand adverse side effects. These adverse side effects have been used to infer whether two drugs share a target protein. However, side-effect similarity of drugs could also be caused by their target proteins being close in a molecular network, which as such could cause similar downstream effects. In this study, we investigated the proportion of side-effect similarities that is due to targets that are close in the network compared to shared drug targets. We found that only a minor fraction of side-effect similarities (5.8 %) are caused by drugs targeting proteins close in the network, compared to side-effect similarities caused by overlapping drug targets (64%). Moreover, these targets that cause similar side effects are more often in a linear part of the network, having two or less interactions, than drug targets in general. Based on the examples, we gained novel insight into the molecular mechanisms of side effects associated with several drug targets. Looking forward, such analyses will be extremely useful in the process of drug development to better understand adverse side effects.     

Erythema infectiosum following generalized petechial eruption induced by human parvovirus B19

Parvovirus B19 is a DNA virus responsible for a wide spectrum of clinical illnesses. Among dermatological manifestations, the most common is erythema infectiosum, also known as the fifth disease. In 1990 Harms et al first described a papular-purpuric gloves and socks syndrome (PPGSS) due to parvovirus B19. It is an acute acral dermatosis characterized by an eruption of petechiae and small purpuric papules affecting the hands and feet in a gloves-and-socks distribution. Recently it was observed that PPGSS may be associated with involvement of the peri-oral region and the chin (acropetechial syndrome) and other sites provoking unusual presentation of the rash. We describe a patient with an acral purpura with the features of the "acropetechial syndrome" involving the buttocks, genital and axillary regions who subsequently developed a maculopapular eruption with the characteristics of the fifth disease. Parvovirus B19 DNA was detected by polymerase chain reaction (PCR) both in skin vasculitic lesions and in the serum during the petechial eruption, before the onset of antibodies. The immune response coincided with the development of the exanthem, suggesting a direct role of parvovirus B19 in the pathogenesis of endothelial cell injury.     

The Effect of Povidone-Iodine (Betadine) on Serum Protein-Bound Iodine,When Used as a Surgical Preparation on Intact Skin

A study was undertaken to determine whether the use of povidone-iodine (Betadine) as a skin disinfectant prior to surgery would affect the protein-bound iodine (PBI) and so invalidate this parameter of thyroid function.Ninety-seven consecutive patients were chosen who had no thyroid disease and who had not recently been exposed to iodine in any form. Their serum PBI levels were determined before and after a wide variety of surgical operations. Povidone-iodine was used as a skin disinfectant in the operating room in all cases. Care was taken to avoid contact of the povidone-iodine with the mucous membranes.No significant change in the protein-bound iodine could be detected and it was concluded that there could be no objection to the use of povidone-iodine on the ground of its possible effect on the protein-bound iodine.     

Adverse reactions to D-penicillamine after gold toxicity.

The incidence of adverse reactions to D-penicillamine in 155 patients with rheumatoid arthritis was analysed and compared with their history of adverse reactions to gold. Out of 125 patients who took only D-penicillamine, 45 developed side effects from the drug, whereas of 27 patients with a history of gold toxicity, 18 also reacted adversely to D-penicillamine. All patients who took D-penicillamine within six months after an adverse reaction to gold developed side effects from D-penicillamine. Fourteen patients developed similar adverse reactions to D-penicillamine and gold, and the interval between treatments in this group was significantly shorter (p less than 0.01) than in those who developed either differing adverse reactions to both drugs or no reaction to D-penicillamine after treatment with gold. An interval exceeding six months between treatment with gold and treatment with D-penicillamine in patients who have developed adverse reactions to gold apparently reduces the risk of adverse reactions to D-penicillamine.     

Fifteen years of preclinical and clinical experiences about biotherapy treatment of lesions induced by accidental irradiation and radiotherapy

High dose radiation exposures involving medical treatments or accidental irradiation may lead to extended damage to the irradiated tissue. Alleviation or even eradication of irradiation induced adverse events is therefore crucial. Because developments in cell therapy have brought some hope for the treatment of tissues damages induced by irradiation, the Institute for Radiation and Nuclear Safety contributed to establish the clinical guidelines for the management of accidentally irradiated victims and to provide the best supportive care to patients all over the world. In the past 15 years, we contributed to develop and test cell therapy for protection against radiation side effects in several animal models, and we proposed mechanisms to explain the benefit brought by this new therapeutic approach. We established the proof of concept that mesenchymal stem cells (MSCs) migrate to damaged tissues in the nonobese diabetic/severe combined immunodeficiency immunotolerant mice model and in non-human primate after radiation exposure. We showed that the intravenous injection of MSCs sustains hematopoiesis after total body irradiation, improves wound healing after radiodermatitis and protects gut function from irradiation damages. Thanks to a tight collaboration with clinicians from several French hospitals, we report successful treatments of therapeutic/accidental radiation damages in several victims with MSC infusions for hematopoiesis correction, radio-induced burns, gastrointestinal disorders and protection homeostatic functions of gut management after radio-therapy.     

THE TOPICAL AND SYSTEMIC USE OF CORTISONE IN DERMATOLOGY

Part I of this report deals with the topical use of cortisone in a variety of skin diseases. Fifteen patients with chronic discoid lupus erythematosus, four patients with necrobiosis lipoidica diabeticorum, four with psoriasis, one with lichen planus and one with granuloma annulare were treated with cortisone ointment. All the patients with chronic discoid lupus erythematosus had some degree of improvement. In two patients with chronic lupus erythematosus, complete clearing of the eruption occurred. In four patients with necrobiosis lipoidica diabeticorum remarkable involution resulted. Patients with psoriasis, lichen planus and granuloma annulare were not benefited.Part II deals with the systemic use of cortisone. Eight patients with severe serum sickness-like penicillin reaction responded dramatically to parenterally administered cortisone. In two cases of pemphigus vulgaris and one case of Sulzberger-Garbe disease, the disease was kept in remission with cortisone administered intramuscularly as well as orally. Partial improvement resulted in a case of localized myxedema associated with malignant exophthalmus. Two patients with exfoliative dermatitis due to therapy with heavy metals responded dramatically to cortisone. No beneficial effects were noted in patients with chronic urticaria and atopic dermatitis.The systemic use of ACTH and cortisone in dermatology at present should be confined to patients with known fatal or hopelessly incapacitating diseases and to patients with extreme hypersensitivity reactions which may be protracted or life-endangering, and which can be controlled or cured with a relatively small total dosage of the agents in a short time.     

Why is stress so deadly? An evolutionary perspective

The reaction of the body to prolonged stress has many harmful effects. Classical theory assumes that stress responses have evolved due to their short-term selective advantages ('flight or fight'), and despite their adverse long-term effects. In contrast, we demonstrate that the adverse effects of stress responses may have a selective advantage. Using an analytical model we show that a gene that causes the early death of a relatively unfit individual can increase in frequency in a structured population even if it has no positive effect on that individual. This result offers a new perspective on the relations between stress factors, stress responses and stress-related diseases.     

RASopathic Skin Eruptions during Vemurafenib Therapy

Purpose

Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.

Patients and Methods

Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.

Results

Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).

Conclusion

Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.     

Adverse effects of topical corticosteroid use.

Topical corticosteroid use, a common and often efficacious therapy for a wide variety of cutaneous conditions, may have substantial adverse effects. These range from the notable nondermatologic side effects of hypothalamic-pituitary-adrenal axis suppression, Cushing''s disease, femoral head osteonecrosis, and cataracts to a variety of less serious skin effects such as cutaneous tinea and contact dermatitis. The broad availability, efficacy, relative low cost, and ease of applying topical corticosteroids should not induce complacency or a cavalier attitude in prescribers. Physicians should have the same awareness of the possible side effects of topical steroid use as when prescribing parenteral medication.     

Development of a G2/M arrest high-throughput screening method identifies potent radiosensitizers

Radiation is a powerful tool used to control tumor growth and induce an immune response; however, it is limited by damage to surrounding tissue and adverse effects such skin irritation. Breast cancer patients in particular may endure radiation dermatitis, and potentially lymphedema, after a course of radiotherapy. Radio-sensitizing small molecule drugs may enable lower effective doses of both radiation and chemotherapy to minimize toxicity to healthy tissue. In this study, we identified a novel high-throughput method for screening radiosensitizers by image analysis of nuclear size and cell cycle. In vitro assays were performed on cancer cells lines to assess combined therapeutic and radiation effects. In vivo, radiation in combination with proflavine hemisulfate led to enhanced efficacy demonstrated by improved tumor volume control in mice bearing syngeneic breast tumors. This study provides a proof of concept for utilizing G2/M stall as a predictor of radiosensitization and is the first report of a flavin acting as an X-ray radiation enhancer in a breast cancer mouse model.     

Reactions of Buffers in Cyanogen Bromide-Induced Ligations

Rapid, template-directed ligation reactions between a phosphate-terminated oligonucleotide and an unphosphorylated reaction partner may be induced by cyanogen bromide (BrCN). Frequently, however, the reaction is low yielding, and even a large excess of the condensing agent can fail to induce quantitative conversions. In this study, we used BrCN to induce chemical primer extension reactions. Here, we report that buffers containing hydroxyl groups react with short oligodeoxynucleotides in the presence of BrCN. One stable adduct between HEPBS buffer and cytosine was characterized by mass spectrometry and NMR after HPLC purification, indicating that a side reaction occurred at this nucleobase. Further, a first example of a primer extension reaction between an unmodified oligodeoxynucleotide as primer and dGMP is reported. Together, our results shed light on the potency, as well as the drawbacks of BrCN as a highly reactive condensing reagent for the ligation of unmodified nucleic acids.     

Optimizing breast pocket irrigation: an in vitro study and clinical implications

Subclinical infections have been implicated in the etiology of capsular contracture. Intraoperatively, breast pocket irrigation with povidone-iodine or other antibiotic solutions has been popularized; however, detrimental effects on wound healing for these agents have been reported and their efficacy against common organisms found around breast implants has not been studied. The purpose of this study was to compare the in vitro efficacy of serial dilutions of povidone-iodine and two double antibiotic solutions DAB-1 (gentamicin/polymyxin B) and DAB-2 (gentamicin/cefazolin), against organisms most commonly found around breast implants. In phase I trials, serial dilutions of povidone-iodine and DAB were combined 1:1 with cultures of five common organisms found around implants. In phase II, povidone-iodine was serially diluted in DAB-1 rather than saline. In phase III, povidone-iodine was serially diluted with DAB-2. Efficacy for all phases was determined by plating the mixture onto agar plates and incubating at 37 degrees C for 48 hours. Povidone-iodine was 100 percent effective at a dilution of 12.5% against Staphylococcus epidermidis and 25% against Staphylococcus aureus but relatively ineffective against Escherichia coli and Pseudomonas, DAB-1 was found to be ineffective against S. epidermidis but effective against S. aureus, Propionibacterium acnes, E. coli, and Pseudomonas. In phase II trials, a concentration of 12.5% povidone-iodine in DAB was effective at killing all experimental bacteria. In phase III trials, 10% povidone-iodine in DAB-2 was effective at killing all bacteria tested. In conclusion, to maximize bacterial control of common breast implant organisms and to minimize the detrimental effects on wound healing, 10% povidone-iodine in gentamycin/cefazolin may be used with excellent results and its use clinically may reduce the incidence of capsular contracture.     

Exogenous liposomal IGF-I cDNA gene transfer leads to endogenous cellular and physiological responses in an acute wound

The purpose of the present study was to examine whether exogenous liposomal cDNA gene transfer is recognized by the cell and causes endogenous cellular and physiological responses. When administered as a protein, IGF-I is known to cause adverse side effects due to lack of cellular responses. Therefore, we used IGF-I cDNA as a vector to study cellular and physiological effects after liposomal administration to wounded skin. Sprague-Dawley rats were given a scald burn to inflict an acute wound and were divided into two groups to receive weekly subcutaneous injections of liposomes plus the Lac-Z gene (0.2 microg vehicle) or liposomes plus the IGF-I cDNA (2.2 microg) and Lac Z gene (0.22 microg). Transfection was confirmed by histochemical assays for beta-galactosidase. Planimetry, immunological assays, and histological and immunohistochemical techniques were used to determine molecular mechanisms after gene transfer, protein expression, and dermal and epidermal regeneration. IGF-I cDNA transfer increased IGF-I protein expression and caused concomitant cellular responses by increasing IGF binding protein (IGFBP)-3 and decreasing IGFBP-1. IGF-I cDNA gene transfer increased keratinocyte growth factor expression and exerted promitogenic antiapoptotic effects on basal keratinocytes, thus improving epidermal regeneration. IGF-I cDNA improved dermal regeneration by an increased collagen deposition and morphology. IGF-I cDNA increased VEGF concentrations and thus neovascularization. Exogenous-administered IGF-I cDNA is recognized by the cell and leads to similar intracellular responses as the endogenous gene. Liposomal IGF-I gene transfer further leads to improved dermal and epidermal regeneration by interacting with other growth factors.     

Genotoxic potential of porphyrin type photosensitizers with particular emphasis on 5-aminolevulinic acid: implications for clinical photodynamic therapy

Photodynamic therapy (PDT) uses exogenously administered photosensitizers activated by light to induce cell death or modulation of immunological cascades, presumably via formation of reactive oxygen species (ROS). 5-Aminolevulinic acid (ALA) mediated photosensitization is increasingly used for the treatment of nonmelanoma skin cancer and other indications including benign skin disorders. Long-term side effects of this investigational modality are presently unknown. Just as tumor treatments such as ionizing radiation and chemotherapy can cause secondary tumor induction, PDT may potentially have a carcinogenic risk. Evaluation of the biological effects of ALA in absence of activating light and analysis of the mechanism of ALA-PDT and porphyrin-type photosensitizers mediated photosensitization indicate that this therapy has a pro-oxidant and genotoxic potential. However, porphyrin type molecules also possess antioxidant and antimutagenic properties. ALA-PDT delays photocarcinogenesis in mice, and topical ALA alone does not increase skin cancer incidence in these animals. Patients with increased tissue levels of ALA have an increased incidence of internal carcinoma, however, it is not clear whether this relationship is casual or causal. There is no evidence indicating higher rates of skin cancer in patients with photosensitivity diseases due to presence of high protoporphyrin IX (PP) levels in skin. Overall, the presently available data indicate that the risk for secondary skin carcinoma after topical ALA-PDT seems to be low, but further studies must be carried out to evaluate the carcinogenic risk of ALA-PDT in conditions predisposed to skin cancer.     

Combination of azathioprine and UVA irradiation is a major source of cellular 8-oxo-7,8-dihydro-2'-deoxyguanosine

Thiopurine antimetabolites, such as azathioprine (Aza) and 6-thioguanine (6-TG), are widely used in the treatment of cancer, inflammatory conditions and organ transplantation patients. Recent work has shown that cells treated with 6-TG and UVA generate ROS, with implied oxidatively generated modification of DNA. In a study of urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) in renal transplant patients, we provided the first in vivo evidence linking Aza and oxidatively damaged DNA. Using the hOGG1 comet assay, we herein demonstrate high levels of 8-oxodG and alkali-labile sites (ALS) in cells treated with biologically relevant doses of 6-TG, or Aza, plus UVA. This damage was induced dose-dependently. Surprisingly, given the involvement of 6-TG incorporation into DNA in its therapeutic effect, significant amounts of 8-oxodG and ALS were induced in quiescent cells, although less than in proliferating cells. We speculate that some activity of hOGG1 towards unirradiated, 6-TG treated cells, implies possible recognition of 6-TG or derivatives thereof. This is the first report to conclusively demonstrate oxidatively damaged DNA in cells treated with thiopurines and UVA. These data indicate that Aza-derived oxidative stress will occur in the skin of patients on Aza, following even low level UVA exposure. This is a probable contributor to the increased risk of non-melanoma skin cancer in these patients. However, as oxidative stress is unlikely to be involved in the therapeutic effects of Aza, intercepting ROS production in the skin could be a viable route by which this side effect may be minimised.     

Nanoparticle-mediated targeted drug delivery for breast cancer treatment

Breast cancer (BC) is the most common malignancy in women worldwide, and one of the deadliest after lung cancer. Currently, standard methods for cancer therapy including BC are surgery followed by chemotherapy or radiotherapy. However, both chemotherapy and radiotherapy often fail to treat BC due to the side effects that these therapies incur in normal tissues and organs. In recent years, various nanoparticles (NPs) have been discovered and synthesized to be able to selectively target tumor cells without causing any harm to the healthy cells or organs. Therefore, NPs-mediated targeted drug delivery systems (DDS) have become a promising technique to treat BC. In addition to their selectivity to target tumor cells and reduce side effects, NPs have other unique properties which make them desirable for cancer treatment such as low toxicity, good compatibility, ease of preparation, high photoluminescence (PL) for bioimaging in vivo, and high loadability of drugs due to their tunable surface functionalities. In this study, we summarize with a critical analysis of the most recent therapeutic studies involving various NPs-mediated DDS as alternatives for the traditional treatment approaches for BC. It will shed light on the significance of NPs-mediated DDS and serve as a guide to seeking for the ideal methodology for future targeted drug delivery for an efficient BC treatment.     

High yield of secondary B-side electron transfer in mutant Rhodobacter capsulatus reaction centers

From the crystal structures of reaction centers (RCs) from purple photosynthetic bacteria, two pathways for electron transfer (ET) are apparent but only one pathway (the A side) operates in the native protein-cofactor complex. Partial activation of the B-side pathway has unveiled the true inefficiencies of ET processes on that side in comparison to analogous reactions on the A side. Of significance are the relative rate constants for forward ET and the competing charge recombination reactions. On the B side, these rate constants are nearly equal for the secondary charge-separation step (ET from bacteriopheophytin to quinone), relegating the yield of this process to < 50%. Herein we report efforts to optimize this step. In surveying all possible residues at position 131 in the M subunit, we discovered that when glutamic acid replaces the native valine the efficiency of the secondary ET is nearly two-fold higher than in the wild-type RC. The positive effect of M131 Glu is likely due to formation of a hydrogen bond with the ring V keto group of the B-side bacteriopheophytin leading to stabilization of the charge-separated state involving this cofactor. This change slows charge recombination by roughly a factor of two and affords the improved yield of the desired forward ET to the B-side quinone terminal acceptor.