Epilepsy and cannabidiol: a guide to treatment

The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis‐based products as an anti‐seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo‐controlled RCTs for patients with Lennox‐Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.     

Valproate causes reduction of the excitatory amino acid aspartate in nerve terminals

Valproate is well established in the treatment of epilepsy and psychiatric disorders, yet the main mechanism of action remains to be determined. Here we show that valproate may reduce neurotransmission of the excitatory amino acid, aspartate. By electron microscopic immunogold cytochemistry we demonstrate a 63–68% reduction in the level of aspartate in excitatory nerve terminals at 30 min after an acute dose of valproate. The level of glutamate in the same terminals was unchanged by valproate treatment. In inhibitory terminals, valproate caused a 65% decrease in the aspartate level, whereas the GABA level was not significantly changed. In summary, the present study shows that valproate reduces the nerve terminal content of the excitatory neurotransmitter aspartate. This points to a new mechanism of action for valproate: reduced neuronal excitation through reduced aspartergic neurotransmission.     

Effects of Selenomethionine on the Gene Expression Profile of Cloned Human Prostate Cancer Cells Representing a Phenotypic Continuum of Cancer Progression

The cutoff value of critical weight loss is still subject of discussion. In this pilot study, we investigated whether ≥5% weight loss in the past year predicts changes in nutritional status in patients with advanced cancer during treatment with palliative chemotherapy. In 20 patients with advanced cancer undergoing palliative (combination) chemotherapy, body weight, fat free mass (FFM), and cachexia were measured prior to the start and at 9 wk of treatment. History of weight loss was used to test differences in development of nutritional parameters during chemotherapy with use of independent sample t-tests. At baseline, 10 of 20 patients had lost ≥5% body weight during the past year and 5 patients were cachectic. The change in FFM in the first 9 wk of chemotherapy was significantly worse in patients with ≥5% weight loss compared to patients with <5% weight loss [mean difference: 3.5 kg (P = 0.001)]. Data also suggest that ≥5% weight loss predicts shorter survival (P = 0.03). We found that patients with ≥5% weight loss prior to chemotherapy have a deterioration in nutritional status during chemotherapy and may have a shorter survival. These results have to be confirmed in a larger study including a robust survival analysis.     

Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro

Twenty-four pesticides were tested for interactions with the estrogen receptor (ER) and the androgen receptor (AR) in transactivation assays. Estrogen-like effects on MCF-7 cell proliferation and effects on CYP19 aromatase activity in human placental microsomes were also investigated. Pesticides (endosulfan, methiocarb, methomyl, pirimicarb, propamocarb, deltamethrin, fenpropathrin, dimethoate, chlorpyriphos, dichlorvos, tolchlofos-methyl, vinclozolin, iprodion, fenarimol, prochloraz, fosetyl-aluminum, chlorothalonil, daminozid, paclobutrazol, chlormequat chlorid, and ethephon) were selected according to their frequent use in Danish greenhouses. In addition, the metabolite mercaptodimethur sulfoxide, the herbicide tribenuron-methyl, and the organochlorine dieldrin, were included. Several of the pesticides, dieldrin, endosulfan, methiocarb, and fenarimol, acted both as estrogen agonists and androgen antagonists. Prochloraz reacted as both an estrogen and an androgen antagonist. Furthermore, fenarimol and prochloraz were potent aromatase inhibitors while endosulfan was a weak inhibitor. Hence, these three pesticides possess at least three different ways to potentially disturb sex hormone actions. In addition, chlorpyrifos, deltamethrin, tolclofos-methyl, and tribenuron-methyl induced weak responses in one or both estrogenicity assays. Upon cotreatment with 17beta-estradiol, the response was potentiated by endosulfan in the proliferation assay and by pirimicarb, propamocarb, and daminozid in the ER transactivation assay. Vinclozolin reacted as a potent AR antagonist and dichlorvos as a very weak one. Methomyl, pirimicarb, propamocarb, and iprodion weakly stimulated aromatase activity. Although the potencies of the pesticides to react as hormone agonists or antagonists are low compared to the natural ligands, the integrated response in the organism might be amplified by the ability of the pesticides to act via several mechanism and the frequent simultaneous exposure to several pesticides.     

Language lateralization and cognitive control across the menstrual cycle assessed with a dichotic-listening paradigm

Lateralization has been shown to vary across the menstrual cycle, however, the underlying mechanisms are not fully understood, and results are inconsistent. Additionally, it has been suggested that estradiol enhances cognitive control. By modulating attention in a consonant-vowel dichotic listening test, the current study aims to investigate the effects of cycle-related changes on language lateralization (non-forced condition), as well as the effects of estradiol-modulated cognitive control (forced left condition) on the ear advantage. Fifteen women and fifteen men tested three times on the dichotic listening test, women once in menstrual, follicular, and luteal phase (verified by hormone assays). Whereas the results from the non-forced and forced-right condition remained stable, results from the forced left condition changed across the cycle, where women in the follicular phase compared to both menstrual and luteal phases showed a stronger left ear advantage, i.e. better cognitive control performance. The increase in performance from menstrual to follicular phase correlated negatively with increase in estradiol levels, indicating a shift from a stimulus-driven right ear advantage (indicating a left hemispheric asymmetry for language) when estradiol levels were low toward a cognitively controlled left ear advantage when estradiol levels were high. This finding strongly suggests an active role of estradiol on cognitive control. The study further suggests that the degree of cognitive control demands of a given task is important to consider when investigating lateralization across the menstrual cycle.     

Readiness to adopt a self-management approach to pain – Are profiles of subscale scores on the Pain Stages of Change Questionnaire useful?

The study evaluated the ability of the Pain Stages of Change Questionnaire (PSOCQ) to classify subjects into specific profiles of readiness to adopt a self‐management approach to pain. An analysis was made of whether the five earlier described PSOCQ‐profiles Precontemplation, Contemplation, Non‐contemplative Action, Participation and Ambivalent could be reproduced by two different methods, cluster analysis and visual analysis. The 184 included subjects completed the PSOCQ, the Hopkins Symptom Checklist (HSCL‐25), the Tampa scale of Kinesiophobia (TSK) and five self‐efficacy questions from the arthritis self‐efficacy questionnaire (ASES). Profiles were drawn based on the mean scores of the four subscales in PSOCQ. All the five predefined profiles were identified visually by two coders with an interrater agreement of Kappa 0.731. A 6‐cluster solution generated the four profiles Precontemplation, Contemplation, Non‐contemplative Action and Participation. Discriminant function analysis (DFA) on cluster analysis classified 83.5% of cases in the same group, and DFA on visual classification 72.1% of cases. Fifty‐three percent were classified in the same profile by cluster and visual analysis. The two profiles Precontemplation and Participation seem to identify distinct subgroups that differ in educational level, pain during activity and psychometric measures. Non‐contemplative Action share characteristics with Precontemplation, and the Contemplation group has scores in between. In conclusion, more research on the validity of the PSOCQ is needed. Outcome studies after pain treatment programmes could focus three main states that differ on measures for concurrent validity: Profiles that can be identified as Precontemplation or Non‐contemplative action, Contemplators, and subjects with Participation profiles.     

Incidence,characteristics, and outcome of solitary plasmacytoma and plasma cell leukemia. Population‐based data from the Swedish Myeloma Register

Solitary plasmacytoma (SP) and plasma cell leukemia (PCL) are uncommon (3‐6%) types of plasma cell disease. The risk of progression to symptomatic multiple myeloma (MM) is probably important for the outcome of SP. PCL is rare and has a dismal outcome. In this study, we report on incidence and survival in PCL/SP, and progression to MM in SP, using the prospective observational Swedish Multiple Myeloma Register designed to document all newly diagnosed plasma cell diseases in Sweden since 2008. Both solitary bone plasmacytoma (SBP) (n=124) and extramedullary plasmacytoma (EMP) (n=67) have better overall survival (OS) than MM (n=3549). Progression to MM was higher in SBP than in EMP (35% and 7% at 2 years, respectively), but this did not translate into better survival in EMP. In spite of treatment developments, the OS of primary PCL is still dismal (median of 11 months, 0% at 5 years). Hence, there is a great need for diagnostic and treatment guidelines as well as prospective studies addressing the role for alternative treatment options, such as allogeneic stem cell transplantation and monoclonal antibodies in the treatment of PCL.     

Association of physical activity with overall mortality among long-term testicular cancer survivors: A longitudinal study

Physical activity (PA) has been associated with reduced mortality among cancer survivors, but no study has focused on testicular cancer survivors (TCSs). We aimed to investigate the association of PA measured twice during survivorship with overall mortality in TCSs. TCSs treated during 1980 to 1994 participated in a nationwide longitudinal survey between 1998 to 2002 (S1: n = 1392) and 2007 to 2009 (S2: n = 1011). PA was self-reported by asking for the average hours per week of leisure-time PA in the past year. Responses were converted into metabolic equivalent task hours/week (MET-h/wk) and participants were categorized into: Inactives (0 MET-h/wk), Low-Actives (2-6 MET-h/wk), Actives (10-18 MET-h/wk) and High-Actives (20-48 MET-h/wk). Mortality from S1 and S2, respectively, was analyzed using the Kaplan-Meier estimator and Cox proportional hazards models until the End of Study (December 31, 2020). Mean age at S1 was 45 years (SD 10.2). Nineteen percent (n = 268) of TCSs died between S1 and EoS, with 138 dying after S2. Compared to Inactives at S1, the mortality risk among Actives was 51% lower (HR 0.49, 95% CI: 0.29-0.84) with no further mortality reduction among High-Actives. At S2, the mortality risk was at least 60% lower among the Actives, High-Actives and even the Low-Actives compared to the Inactives. Persistent Actives (≥10 MET-h/wk at S1 and S2) had a 51% lower mortality risk compared to Persistent Inactives (<10 MET-h/wk at S1 and S2; HR 0.49, 95% CI: 0.30-0.82). During long-term survivorship after TC treatment, regular and maintained PA were associated with an overall mortality risk reduction of at least 50%.