Intoxication caused by new psychostimulants: analytical methods to disclose acute and chronic use of benzofurans and ethylphenidate

International Journal of Legal Medicine - The acute and chronic toxicity of several new psychoactive substances (NPS) is unknown, and only little information is available on the pharmacology and...     

Smart Drugs and Synthetic Androgens for Cognitive and Physical Enhancement: Revolving Doors of Cosmetic Neurology

Cognitive enhancement can be defined as the use of drugs and/or other means with the aim to improve the cognitive functions of healthy subjects in particular memory, attention, creativity and intelligence in the absence of any medical indication. Currently, it represents one of the most debated topics in the neuroscience community. Human beings always wanted to use substances to improve their cognitive functions, from the use of hallucinogens in ancient civilizations in an attempt to allow them to better communicate with their gods, to the widespread use of caffeine under various forms (energy drinks, tablets, etc.), to the more recent development of drugs such as stimulants and glutamate activators. In the last ten years, increasing attention has been given to the use of cognitive enhancers, but up to now there is still only a limited amount of information concerning the use, effect and functioning of cognitive enhancement in daily life on healthy subjects. The first aim of this paper was to review current trends in the misuse of smart drugs (also known as Nootropics) presently available on the market focusing in detail on methylphenidate, trying to evaluate the potential risk in healthy individuals, especially teenagers and young adults. Moreover, the authors have explored the issue of cognitive enhancement compared to the use of Anabolic Androgenic Steroids (AAS) in sports. Finally, a brief overview of the ethical considerations surrounding human enhancement has been examined.     

Latent membrane protein 1-induced EGFR signalling is negatively regulated by TGF alpha prior to neoplasia

The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is an oncoprotein expressed in several EBV-associated malignancies. We have utilised mice expressing the Cao strain of LMP1 in epithelia to explore the consequences of expression in vivo, specifically the changes that occur prior to neoplasia, in the hyperplastic but degenerating tissue. Epidermal growth factor receptor (EGFR) ligands (transforming growth factor alpha (TGFalpha), heparin-binding EGF-like growth factor and epiregulin) are constitutively induced by LMP1, leading to EGFR phosphorylation but also down-regulation, degradation or turn-over, with the appearance of cleaved EGFR fragments. This is accompanied by down-regulation of Akt and activation of caspase-3 and p38 mitogen-activated protein kinase (MAPK). Surprisingly, removal of TGFalpha (using the null strain) does not ameliorate the LMP1-induced phenotype, but instead accelerates the deterioration. Consistent with this, EGFR is reduced less rapidly and MAPK/ERK kinase (MEK) and extracellular-signal-regulated kinase (ERK) are initially activated in the null background, suggesting that TGFalpha or excess of the ligands together act to divert phosphorylated EGFR into a cleavage pathway. In addition, LMP1 leads to the activation of c-Jun N-terminal kinase 2 (JNK2) followed by JNK1 in the effected tissue. Specific AP1 family members FosB, Fra-1 and JunB are constitutively induced and serum response factor, AP1 and nuclear factor kappaB (incorporating p65) are activated in the transgenic tissue compared with wild-type. This system allows the analysis of early events resulting from the expression of a viral oncogene with broad impact in the signalling milieu and the attempts at homeostasis in the responding tissue. It reveals what regulatory circuits are in place in a normal tissue, thus facilitating further prediction of causative events in carcinogenic progression.     

Epstein-Barr virus latent membrane protein 1 (CAO) up-regulates VEGF and TGF alpha concomitant with hyperlasia, with subsequent up-regulation of p16 and MMP9

EBV latent membrane protein 1 (LMP1) is an oncoprotein frequently expressed in nasopharyngeal carcinoma. We have generated transgenic mice expressing the nasopharyngeal carcinoma-derived CAO strain of LMP1 and LMP1 of the B95-8 strain, using the viral ED-L2 promoter for epithelial expression. LMP1(CAO) and LMP1(B95-8) induce transforming growth factor alpha expression and epidermal hyperplasia. However, levels of total epidermal growth factor receptor (EGFR) decline with the appearance of phosphorylated EGFR products, suggesting that the negative feedback loop upon EGFR expression is intact or that there is faster turnover at these early stages of carcinogenesis. In the L2LMP1(CAO) mice, increased levels of vascular endothelial growth factor are also seen at an early stage in the skin. As the phenotype worsens, with increasing hyperplasia and vascularization leading to keratoacanthoma, p16(INK4a) and matrix metalloproteinase 9 expression is induced. The lesions can progress spontaneously to carcinoma. Carcinoma cell lines developed from these mice show high levels of total and phosphorylated EGFR. These data show that the induction of signaling through EGFR by LMP1 is an early event in carcinogenesis and that any inhibition upon EGFR expression is lifted during progression. Furthermore, expression of LMP1 is not sufficient to inhibit induction of p16(INK4a) in response to abnormal proliferation. These data are consistent with the cooperative effects seen between LMP1 and loss of the INK4a locus in transgenic mice and with the frequency of loss of this locus in EBV-associated nasopharyngeal carcinoma.     

Vertical and Orovestibular Forces Generated by Beta-Titanium and Stainless-Steel Rectangular Wires in Labial and Fully Customized Lingual Bracket Systems

This study aimed to investigate the force values exerted from rectangular wires when combined with conventional labial and fully customized lingual appliances under predefined, idealized activation. Fully customized lingual brackets of two brands Incognito™ (3M Unitek, Monrovia, CA, USA) and WIN (DW Lingual Systems, Bad Essen, Germany) and labial brackets of another brand, discovery^® MIM and discovery^® smart systems (Dentaurum, Ispringen, Germany), were chosen. Stainless-steel and beta-titanium wires of 0.018” × 0.025” were examined. For Incognito^TM, 0.0182” × 0.025” beta-titanium wires were tested. Intrusion/extrusion and orovestibular movements were performed in a range of 0.2 mm, and the forces were recorded for each 0.1 mm of the movement. Mean values and standard deviations were calculated for all measurements, and ANOVA was performed for statistical analysis. Slight differences were observed between the forces generated from beta-titanium and stainless-steel wires. The same wire generated in some cases 5–53% higher forces with the lingual appliance due to the vertical orientation of the long walls during intrusion/extrusion and increased wire stiffness at the anterior region. Beta-titanium and stainless-steel 0.018” × 0.025” wires can generate similar force values during the final stages of the orthodontic therapy; thus, possibly only one of the two alloys could be used in each orthodontic wire sequence.     

Atypical fibroxanthoma in an HIV-infected individual

Atypical fibroxanthoma is a neoplasm primarily occurring in older patients, with a predilection for photo-damaged skin of the head and neck. Compared to the immunocompetent population, patients infected with HIV have a higher risk of certain malignancies including non-Hodgkin lymphoma, Kaposi's sarcoma and skin cancer. Although atypical fibroxanthoma has been reported in another immunocompromised group, namely organ transplant recipients, there are no previous reports in the published literature of this tumour arising in patients infected with HIV. We report a case of an atypical fibroxanthoma arising in a 71- year old HIV-positive male.