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.     

Osteitis condensans ilii: prevalence and characteristics of a neglected mimic of sacroiliitis

Clinical Rheumatology - Osteitis condensans ilii (OCI) is a benign condition characterised by triangular sclerosis of the iliac bone which may mimic radiographic sacroiliitis. Prevalence is...     

Evidence for fusion between cardiac and skeletal muscle cells

Cardiomyoplasty with skeletal myoblasts may benefit cardiac function after infarction. Recent reports indicate that adult stem cells can fuse with other cell types. Because myoblasts are "fusigenic" cells by nature, we hypothesized they might be particularly likely to fuse with cardiomyocytes. To test this, neonatal rat cardiomyocytes labeled with LacZ and green fluorescent protein (GFP) were cocultured with unlabeled C2C12 myoblasts. After 3 days, we observed a small population of skeletal myotubes that expressed LacZ and GFP, indicating cell fusion. To test whether such fusion occurred in vivo, LacZ-expressing C2C12 myoblasts were grafted into normal nude mouse hearts. At 2 weeks after grafting, cells at the graft-host interface expressed both LacZ and cardiac-specific myosin light chain 2v (MLC2v). To test more definitively whether fusion between skeletal and cardiac muscle could occur, we used a Cre/lox reporter system that activated LacZ only upon cell fusion. When neonatal cardiomyocytes from -myosin heavy chain promoter (-MHC)-Cre mice were cocultured with myoblasts from floxed-lacZ reporter mice, LacZ was activated in a subset of cells, indicating cell fusion occurred in vitro. Finally, we grafted the floxed-lacZ myoblasts into normal hearts of -MHC-Cre+ and -MHC-Cre- mice (n=5 each). Hearts analyzed at 4 days and 1 week after transplantation demonstrated activation of LacZ when the skeletal muscle cells were implanted into hearts of -MHC-Cre+ mice, but not after implantation into -MHC-Cre- mice. These data indicate that skeletal muscle cell grafting gives rise to a subpopulation of skeletal-cardiac hybrid cells with a currently unknown phenotype. The full text of this article is available online at http://circres.ahajournals.org.     

Fifty years of newborn screening

Newborn screening has evolved fast following recent advances in diagnosis and treatment of disease, particularly the development of multiplex testing and applications of molecular testing. Formal evidence of benefit from newborn screening has been largely lacking, due to the rarity of individual disorders. There are wide international differences in the choice of disorders screened, and ethical issues in both screening and not screening are apparent. More evidence is needed about benefit and harm of screening for specific disorders and renewed discussion about the basic aims of newborn screening must be undertaken.     

Gene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice

Complications of dopamine replacement for Parkinson’s disease (PD) can limit therapeutic options, leading to interest in identifying novel pathways that can be exploited to improve treatment. p11 (S100A10) is a cellular scaffold protein that binds to and potentiates the activity of various ion channels and neurotransmitter receptors. We have previously reported that p11 can influence ventral striatal function in models of depression and drug addiction, and thus we hypothesized that dorsal striatal p11 might mediate motor function and drug responses in parkinsonian mice. To focally inhibit p11 expression in the dorsal striatum, we injected an adeno-associated virus (AAV) vector producing a short hairpin RNA (AAV.sh.p11). This intervention reduced the impairment in motor function on forced tasks, such as rotarod and treadmill tests, caused by substantia nigra lesioning in mice. Measures of spontaneous movement and gait in an open-field test declined as expected in control lesioned mice, whereas AAV.sh.p11 mice remained at or near normal baseline. Mice with unilateral lesions were then challenged with l-dopa (levodopa) and various dopamine receptor agonists, and resulting rotational behaviors were significantly reduced after ipsilateral inhibition of dorsal striatal p11 expression. Finally, p11 knockdown in the dorsal striatum dramatically reduced l-dopa–induced abnormal involuntary movements compared with control mice. These data indicate that focal inhibition of p11 action in the dorsal striatum could be a promising PD therapeutic target to improve motor function while reducing l-dopa–induced dyskinesias.Pharmacologic replacement of depleted dopamine is the primary therapeutic approach to treating Parkinson’s disease (PD). Although this usually improves the major motor problems of this disorder, complications of medical therapy can often limit both dosing and effectiveness. Among the most common adverse effects limiting dopamine replacement therapy for PD is the development of abnormal involuntary movements (AIMs), also known as levodopa-induced dyskinesia (LID) (1). Treatment of LID usually requires reducing the dosage of dopaminergic medications to below the threshold for major complications, although certain pharmacotherapies or surgeries can improve LID as well (1). Understanding both the anatomic location and molecular pathways underlying dyskinesia responses to dopamine replacement therapy is necessary to develop improved therapies, which can reduce motor symptoms without this debilitating problem.Previous studies have identified certain signaling pathways that may influence the development of dyskinesia. The primary site of action of l-dopa (levodopa) on PD motor symptoms after conversion to dopamine is the dorsal striatum, owing to the loss of the normal dopaminergic inputs from the substantia nigra pars compacta (2). This same region has also been shown to be responsible for motor complications of l-dopa therapy, including LID. Specifically, neurons harboring the D1 dopamine receptor appear to be primarily involved in these responses (3–5). Furthermore, other signaling pathways, including the serotonin 5-HT1B receptor, seem to modulate the response of these neurons to dopamine replacement therapy (6, 7). Nonetheless, it has been difficult to identify potential therapeutic targets that both improve motor function and reduce dyskinesia.Here we demonstrate that dorsal striatal p11 is a key regulator of dopamine responses in PD. We previously reported that p11, a small adaptor protein also known as S100A10, binds to specific serotonin receptor subtypes, including 5-HT1B (8–10). Because activation of the 5-HT1B serotonin receptor (5-HT1BR) reduces dyskinesia, and p11 binds to 5-HT1BR and potentiates 5-HT1B activity, we hypothesized that dorsal striatal p11 may influence the response to dopamine replacement therapy. We found that inhibition of p11 expression in the dorsal striatum improved motor function in parkinsonian mice. Surprisingly, blockade of dorsal striatal p11 expression profoundly inhibited dyskinesias in response to chronic l-dopa treatment, to a greater extent than pharmacologic activation of 5-HT1B in controls. This indicates that inhibition of striatal p11 is a promising potential target to block dyskinesias while improving motor function in PD, and that these effects likely occur through a mechanism other than 5-HT1B.     

Heterozygous Mutations in Natriuretic Peptide Receptor‐B (NPR2) Gene as a Cause of Short Stature

Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor‐B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family. Nine additional rare nonsynonymous NPR2 variants were found in three additional cohorts. Functional studies identified eight loss‐of‐function mutations in short individuals and one gain‐of‐function mutation in tall individuals. With these data, we were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature. We estimate a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in people with ISS. We suggest that NPR2 gain of function may be a more common cause of tall stature than previously recognized.