Metyrapone abolishes spike-wave discharge seizures in genetic absence epilepsy rats from Strasbourg by reducing stress hormones.

OBJECTIVE: Stress is one of the most commonly reported triggers for seizures in patients with epilepsy, although the mechanisms that mediate this effect are not established. The clinical evidence supporting this is derived from patients' subjective experience of stress, and how this influences their own seizures. Animal models can be used to explore this phenomenon in controlled environments, free from subjective bias. Here, we used genetic absence epilepsy rats from Strasbourg (GAERS), a genetic rat model of absence epilepsy, to explore the influence of stress and stress hormones on spontaneous seizures. METHODS: Adult male GAERS (n = 38) and nonepileptic control (NEC) rats (n = 4) were used. First, rats were subjected to 30-min restraint stress to assess hypothalamic-pituitary-adrenal axis function. Next, we assessed the effects of 30-min noise stress, and cage tilt stress, on spike-wave discharge seizures in GAERS. We then performed pharmacological experiments to assess the direct effects of stress hormones on seizures, including corticosterone, metyrapone, and deoxycorticosterone. RESULTS: GAERS exhibited elevated baseline corticosterone levels, compared to NEC rats. Noise stress and cage tilt stress significantly enhanced seizure incidence (p < .05), but only during stress periods. Exogenous corticosterone administration also significantly increased seizure occurrence (p < .05). Metyrapone, an inhibitor of corticosterone synthesis, completely abolished seizures in GAERS, and seizures remained suppressed for >2 h. However, deoxycorticosterone, the precursor of corticosterone, increased seizures. SIGNIFICANCE: These results suggest that GAERS exhibit elevations in stress hormones, and this may contribute to seizures. Inhibiting corticosterone synthesis with metyrapone prevents seizures in GAERS, and shows potential for repurposing this drug as a future antiseizure medication.

A scoping review of home-produced heroin and amphetamine-type stimulant substitutes: implications for prevention, treatment, and policy.

Several home-produced substances such as krokodil and boltushka are prevalent in many Eastern European countries. Anecdotal reports of its use have been circulating in Germany and Norway; however, this has not been confirmed. Its use has also been reported by the media in the USA, although only one confirmed report of its use exists. Home-produced drugs are associated with high levels of morbidity and a number of complex health issues such as the spread of blood borne viruses, gangrene, and internal organ damage. The high incidence of HIV rates amongst people who inject home-produced substances is a public health concern. The resulting physical health consequences of injecting these crude substances are very severe in comparison to heroin or amphetamine acquired in black markets. Due to this fact and the increased mortality associated with these substances, professionals in the area of prevention, treatment, and policy development need to be cognisant of the presentation, harms, and the dangers associated with home-produced substances globally. This scoping review aimed to examine existing literature on the subject of home-produced heroin and amphetamine-type stimulant substitutes. The review discussed the many implications such research may have in the areas of policy and practice. Data were gathered through the use of qualitative secondary resources such as journal articles, reports, reviews, case studies, and media reports. The home production of these substances relies on the utilisation of precursor drugs such as less potent stimulants, tranquillizers, analgesics, and sedatives or natural plant ingredients. The Internet underpins the facilitation of this practice as recipes, and diverted pharmaceutical sales are available widely online, and currently, ease of access to the Internet is evident worldwide. This review highlights the necessity of prevention, education, and also harm reduction related to home-produced drugs and also recommends consistent monitoring of online drug fora, online drug marketplaces, and unregulated pharmacies.

Rev1 is essential in generating G to C transversions downstream of the Ung2 pathway but not the Msh2+Ung2 hybrid pathway.

Somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes are initiated by the enzymatic deamination of cytosine (C) to uracil (U). Uracil-DNA-glycosylase (Ung2) converts uracils into apyrimidinic (AP) sites, which is essential for the generation of transversions (TVs) at G/C basepairs during SHM and for efficient DNA break formation during CSR. Besides Ung2, the mismatch repair protein Msh2 and the translesion synthesis (TLS) DNA polymerase (Pol) Rev1 are implicated in SHM and CSR. To further unravel the role of Rev1, we studied WT, Rev1-deficient, Msh2-deficient, and Rev1, Msh2 double-deficient B cells. Loss of Rev1 only slightly reduced CSR. During SHM G/C to C/G TVs are generated in both Ung2- and Ung+Msh2-dependent fashions. We found that Rev1 is essential for the Msh2-independent generation of these TVs downstream of Ung2-induced AP sites. In the Ung+Msh2 hybrid pathway, Rev1 is not essential and can be substituted by an alternative TLS Pol, especially when Rev1 is lacking.