Development of a QSAR model to predict hepatic steatosis using freely available machine learning tools.

There are various types of hepatic steatosis of which non-alcoholic fatty liver disease, which may be caused by exposure to chemicals and environmental pollutants is the most prevalent, representing a potential major health risk. QSAR modelling has the potential to provide a rapid and cost-effective method to identify compounds which may trigger steatosis. Although models exist to predict key molecular initiating events of steatosis such as nuclear receptor binding, we are aware of no models to predict the apical effect steatosis. In this study, we describe the development of a QSAR model to predict steatosis using freely available machine learning tools. It was built using a dataset of 207 pharmaceuticals and pesticides which were identified as steatotic or non-steatotic from existing data from in vivo human and animal studies. The best performing model developed using the linear discriminant analysis module in TANAGRA, based on four chemical descriptors, had an accuracy of 70%, a sensitivity of 66% and a specificity of 74%. The expansion of the steatosis dataset to other chemical types, to enable the development of further models, would be of benefit in the identification of compounds with a range of mechanisms of action contributing to steatosis.

Predicting estrogen receptor binding of chemicals using a suite of in silico methods - Complementary approaches of (Q)SAR, molecular docking and molecular dynamics.

With the aim of obtaining reliable estimates of Estrogen Receptor (ER) binding for diverse classes of compounds, a weight of evidence approach using estimates from a suite of in silico models was assessed. The predictivity of a simple Majority Consensus of (Q)SAR models was assessed using a test set of compounds with experimental Relative Binding Affinity (RBA) data. Molecular docking was also carried out and the binding energies of these compounds to the ERα receptor were determined. For a few selected compounds, including a known full agonist and antagonist, the intrinsic activity was determined using low-mode molecular dynamics methods. Individual (Q)SAR model predictivity varied, as expected, with some models showing high sensitivity, others higher specificity. However, the Majority Consensus (Q)SAR prediction showed a high accuracy and reasonably balanced sensitivity and specificity. Molecular docking provided quantitative information on strength of binding to the ERα receptor. For the 50 highest binding affinity compounds with positive RBA experimental values, just 5 of them were predicted to be non-binders by the Majority QSAR Consensus. Furthermore, agonist-specific assay experimental values for these 5 compounds were negative, which indicates that they may be ER antagonists. We also showed different scenarios of combining (Q)SAR results with Molecular docking classification of ER binding based on cut-off values of binding energies, providing a rational combined strategy to maximize terms of toxicological interest.

Oral immunostimulation of the oyster Ostrea edulis: Impacts on the parasite Bonamia ostreae.

Bioactive compounds were orally administered to the native European oyster Ostrea edulis to evaluate the immune response and the progression of infection of the protozoan parasite Bonamia ostreae. The immunostimulants lipopolysaccharide and zymosan directly administrated to the water column induced an increase in lysozyme activity and the percentage of granulocytes in naïve oysters over a period of 7 days. In another set of experiments, zymosan and curdlan were microencapsulated in alginate and also administered to the water column to naïve and B. ostreae infected O. edulis. Oyster mortality, prevalence and intensity of infection and several immune parameters were evaluated up to 28 days post-administration. Lysozyme activity, nitric oxide production and the expression of galectin, lysozyme and superoxide dismutase increased after 24 h in both infected and uninfected oysters. Zymosan immunostimulated oysters displayed a decrease in the prevalence of B. ostreae infection not attributed to mortalities but which could be associated to the enhanced ability of immunostimulants to evoke an enhanced immune response in the oysters and reduce infection.

In silico assessment of toxicity of heat-generated food contaminants.

Since the discovery of acrylamide in heat-treated carbohydrate-rich foods, many more heat-generated food contaminants have been identified in a variety of foods and models systems. A database of these contaminants, generated as a result of either lipid oxidation or the Maillard reaction, has recently been compiled under the HEATOX project. A large majority of the compounds has not been tested for potential adverse effects on human health, which makes it difficult to carry out adequate assessment of risks to an average consumer. This study used two in silico toxicity Expert Systems (Topkat and Derek for Windows), as a preliminary screening tool to identify potential toxicants among the heat-generated contaminants in foods or model systems. The methodology enabled prioritisation of the compounds on the basis of predicted toxicities, and identification of potential toxicants for targeted testing by standard laboratory procedures. A comparison between the predicted toxicities of selected compounds and the available experimental data indicated that the methodology can be reliably used for assessing toxicity of untested food contaminants.

Damage limitation in cosmetic dermatology.

Good communication is the key to damage limitation. A complaint by a patient should be treated as a medical emergency as early effective communication will almost always neutralise patient anger. Legible and appropriate clinical notes are also important. Patients with depression and dysmorphophobia are potentially litigious, underlying the importance of patient selection.

Severe phototoxic reaction to laser treatment in a patient taking St John's Wort.

Potential patients in the developed world are increasingly turning to treatment with herbs. One of the most popular herbs taken for depression is St John's Wort, which contains the potential photosensitizer hypericin. 'Hypericism' is a term used to describe a state of skin sensitivity to visible light in animals following ingestion of hypericin-containing plants and feed. A patient who developed a severe phototoxic reaction to laser light at 532 nm and also an exaggerated and unexpectedly severe response to pulsed dye laser light at 585 nm is described. It subsequently transpired that the patient was taking St John's Wort at the time of laser treatment.

Sarcoidosis presenting as tattoo granuloma inadvertently treated with laser therapy.

A patient presenting with nodules in his tattoos was referred for laser treatment, following which there was a diagnosis of cutaneous and pulmonary sarcoidosis. Nodular change involving several different tattoo colours is characteristic of sarcoidosis.

Suicide in dermatological patients.

Sixteen patients, seven men and nine women, who committed suicide after presenting with dermatological problems to two dermatologists, are described. Most of the patients had either a body image disorder (dysmorphophobia) or acne. In addition, patients with long-standing and debilitating skin disease may become depressed enough to commit suicide and there is always an attendant risk of suicide in patients with established, severe psychiatric problems, who are referred to dermatologists with concurrent skin disorders. It is important to recognize that patients with dermatological non-disease, and particularly women with facial complaints, may be extremely depressed and at risk of suicide. Facial scarring, particularly in men, may be an 'at risk' factor for suicide, emphasizing the positive early therapeutic role of isotretinoin. Funding problems in regard to provision of this drug could have potentially fatal consequences. The provision of a liaison clinic within a dermatology department may have an important role in managing patients thought to be at risk of suicide.

Minocycline-induced pigmentation resolves after treatment with the Q-switched ruby laser.

Four patients with minocycline-induced cutaneous pigmentation were treated with the Q-switched ruby laser. The pigmentation resolved and there was no adverse effects.

Dermatologic nondisease.

Dermatologic nondisease is a relatively common problem presenting to dermatologists with rich symptomatology in important body image areas such as the face, scalp, and genital area. There is no objective dermatologic change present on examination. The most common psychiatric disease present is depression. Suicide is common, especially in women with perceived facial problems.

Body dysmorphic disorder.

Body dysmorphic disorder is one of the most difficult conditions to manage but a significant proportion of patients do respond to selective serotonin reuptake inhibitors. This group of drugs has helped to revolutionize the treatment of this common but disabling disorder of perceived body ugliness. The condition may affect up to 1% of the population in the United States. Patients often show obsessional features, and depression is common. Ever present is a risk of suicide in these patients.

Are copper vapour and frequency doubled Nd:YAG lasers superior to the argon laser for portwine stains at pulse widths of 30-50 milliseconds?

BACKGROUND AND OBJECTIVE: The copper vapour laser (CVL) and the frequency doubled Nd:YAG laser (FDNYL) have been increasingly adopted as alternatives to the argon laser for treating vascular skin lesions. Automated scanning devices that permit the use of any of these lasers at 30-50 ms pulse widths are now widely used. The object of this study was to compare the CVL and FDNYL with the argon laser using pulse widths in the 30-50 ms range. STUDY DESIGN/MATERIALS AND METHODS: Thirty-one adult patients with red-purple or purple portwine stains (PWS) were treated with a CVL at 578 nm, a FDNYL at 532 nm, and an argon laser at 488/514 nm. Test areas were performed using a Hexascan delivery system and an energy fluence just sufficient to produce immediate tissue change. Pulse widths were maintained constant for each patient (mean 40 msec). The mean fluences used were 13.1 J/cm2, 13.2 J/cm2, and 13.0 J/cm2, respectively. Assessments were made after 4 months using a clinical fading score and an index of light absorbence derived from reflectance spectrophotometry. RESULTS: Fading scores were statistically significantly better with the CVL (score = 2.29) than the FDNYL (score = 1.83, P < 0.02) and the argon laser (score = 1.89, P < 0.003). The differences between the FDNYL and the argon laser were not significant. Although there was a trend toward lower light absorbence index with the CVL than the argon laser and FDNYL (scores = 177, 179 and 181, respectively), these differences were not statistically significant. CONCLUSIONS: Despite slightly better results with the CVL in terms of the fading produced, differences among the CVL, FDNYL, and argon lasers are small when 30-50 ms pulse widths are employed and are of doubtful clinical significance for darker PWS.