Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P =.01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery

Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation.

Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease

Predicting Two Components of Career Maturity in School Based Adolescents

Three hundred and sixty-seven secondary school students across five year levels (8–12) were assessed for levels of career maturity (attitude and knowledge), work commitment, work value, career decidedness (indecision and certainty), career decision-making self-efficacy and self-esteem, and indicated their age, gender, socioeconomic status, school achievement and work experience. Using two multiple regression analyses, the predictor variables were able to account for 52% of the variance of career maturity attitude, and account for 41% of the variance of career maturity knowledge. Self-efficacy, age, career decidedness (certainty) and work commitment were the main predictors of career maturity attitude. Age, gender, career decidedness (certainty), work commitment and career decidedness (indecision) were the main predictors of career maturity knowledge. Results demonstrated the importance of examining two aspects of career maturity (attitude and knowledge), and were discussed in the context of Super’s (1957, 1990) theory of career development

Attenuation of fast neutrons in ilmenite concretes

Energy distributions of fast neutrons (> 0.5 MeV) transmitted through slabs of normal and high density ilmenite concretes, obtained by time of flight methods, are presented for concrete thicknesses increasing in steps of 7.6 cm from 0 to 46 cm. The incident spectrum consisted of a photoneutron continuum from aluminium irradiated with 35 MeV bremsstrahlung, and was thus of somewhat higher mean neutron energy than a typical fission spectrum. The measured distributions are in satisfactory agreement with the results of a Monte Carlo simulation, and results from the latter are used to extrapolate the measured data to greater thicknesses and other ilmenite concrete densities.NRC publication: Ye

Adolescent suicide due to inhalation of insect spray

A 17-year-old female who had been expressing suicidal ideation following domestic problems was found dead in her room next to a towel and an empty can of insect spray. There were no suspicious circumstances and it appeared that the deceased had inhaled insect spray using the towel to maintain the concentration of vapour around her nose and mouth. There was no history of recreational inhalation of volatile substances or other illicit drug use. Inhalation of insect spray is a rare method of suicide in keeping with the suggestion that young suicide victims utilize unusual methods of self-destruction determined to some degree by availability and accessibility.Å. Klitte, J.D. Gilbert, R. Lokan, R.W. Byar

Amphetamine derivative fatalities in South Australia : is "Ecstasy" the Culprit?

Objective: To analyze features of a series of fatalities caused by amphetamine-derivative designer drugs marketed as "Ecstasy" in South Australia, and to identify reasons for the recent marked increase in number of these deaths. Materials and methods: Following th death of a 26-year-old woman after alleged ingestion of Ecstasy tablets, a retrospective search of files at State Forensic Science, Adelaide and the South Australian State Coroner's Department was undertaken from February 1992 to January 1997 to identify similar cases. Results: Six fatalities were found, all of which have occurred since September 1995 (M:F ratio, 1:1; age range, 22 to 36 years; average age, 27.7 years). All individuals had histories of recent ingestion of illegal drugs thought to be Ecstasy (methylenedioxymethamphetamine, MDMA) at the time of purchase. Delay occurred in seeking medical attention, despite severe symptoms. Causes of death involved documented hyperthermia in 3 cases (temperatures of 415-46.1 degrees C), with features of hyperthermia in one other case, and intracranial hemorrhage in another. Drugs in toxic/lethal amounts identified at postmortem included paramethoxyamphetamine (PMA) in all cases, amphetamine/methamphetamine in 4 cases, and methylenedioxymethamphetamine (MDMA or Ecstasy) in only 2 cases. Interaction with a prescription medication (fluoxetine may have occurred in 1 case. Conclusions: The number of deaths due to amphetamine derivatives apparently due to substitution of PMA for MDMA(Ecstasy) have recently increased markedly in Adelaide. Potential users should be wraned tha tPMA has been associated with a much higher rate of lethal complications than other designer drugs, and that no guarantee can be made that tablets sold as Ecstasy are not PMA.R. W. Byard, J. Gilbert, R. James, R. J. Loka