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To help discern sites of focal activation during seizures of different phenotype, the numbers of Fos immunoreactive (FI) neurons in specific brain regions were analyzed following “brainstem-evoked,” “forebrain-evoked” and forebrain/brainstem combination seizures induced by a variety of methods. First, pentylenetetrazol (PTZ, 50 mg/kg) induced forebrain-type seizures in some rats, or forebrain seizures that progressed to tonic/clonic brainstem-type seizures in other rats. Second, minimal electroshock induced forebrain seizures whereas maximal electroshock (MES) induced tonic brainstem-type seizures in rats. Third, forebrain seizures were induced in genetically epilepsy-prone rats (GEPRs) by microinfusion of bicuculline into the area tempestas (AT), while brainstem seizures in GEPRs were induced by audiogenic stimulation. A final set was included in which AT bicuculline-induced forebrain seizures in GEPRs were transiently interrupted by audiogenic seizures (AGS) in the same animals. These animals exhibited a sequence combination of forebrain clonic seizure, brainstem tonic seizure and back to forebrain clonic seizures. Irrespective of the methods of induction, clonic forebrain- and tonic/clonic brainstem-type seizures were associated with considerable Fos immunoreactivity in several forebrain structures. Tonic/clonic brainstem seizures, irrespective of the methods of induction, were also associated with FI in consistent brainstem regions. Thus, based on Fos numerical densities (FND, numbers of Fos-stained profiles), forebrain structures appear to be highly activated during both forebrain and brainstem seizures; however, facial and forelimb clonus characteristic of forebrain seizures are not observable during a brainstem seizure. This observation suggests that forebrain-seizure behaviors may be behaviorally masked during the more severe tonic brainstem seizures induced either by MES, PTZ or AGS in GEPRs. This suggestion was corroborated using the sequential seizure paradigm. Similar to findings using MES and PTZ, forebrain regions activated by AT bicuculline were similar to those activated by AGS in the GEPR. However, in the combination seizure group, those areas that showed increased FND in the forebrain showed even greater FND in the combination trial. Likewise, those areas of the brainstem showing FI in the AGS model, showed an even greater effect in the combination paradigm. Finally, the medial amygdala, ventral hypothalamus and cortices of the inferior colliculi showed markedly increased FND that appeared dependent upon activation of both forebrain and brainstem seizure activity in the same animal. These findings suggest these latter areas may be transitional areas between forebrain and brainstem seizure interactions. Collectively, these data illustrate a generally consistent pattern of forebrain Fos staining associated with forebrain-type seizures and a consistent pattern of brainstem Fos staining associated with brainstem-type seizures. Additionally, these data are consistent with a notion that separate seizure circuitries in the forebrain and brainstem mutually interact to facilitate one another, possibly through involvement of specific “transition mediating” nuclei. [Copyright &y& Elsevier]

After methanol administration to monkeys, an accumulation of formate in blood occurs coincident with the development of metabolic acidosis and a depletion of blood bicarbonate. Formate metabolism in monkeys depends upon and is regulated by a folate-dependent system; therefore, the effect of folic acid pretreatment and 5-formyl tetrahydrofolic acid administration on methanol toxicity was investigated. Treatment of monkeys with repetitive doses of either sodium folate (48, 24, 12, and 4 hr prior to methanol) or 5-formyl tetrahydrofolic acid (2 mg/kg at 0, 4, 8, 12, and 18 hr after methanol) resulted in a marked decrease in the levels of blood formate and an absence of both metabolic acidosis and depletion of blood bicarbonate following methanol administration. Also, 5-formyl tetrahydrofolic acid reversed methanol toxicity once it was established in the monkey. The results indicate that folate compounds decrease formate accumulation after methanol by stimulating formate oxidation or utilization and suggest a possible use for folates in the treatment of certain cases of human methanol poisoning. [ABSTRACT FROM AUTHOR]

Mitochondria have long been known to participate in the process of cell injury associated with metabolic failure. Only recently, however, have we come to appreciate the role of mitochondria as primary intracellular targets in the initiation of cell dysfunction. In addition to ATP synthesis, mitochondria are also critical to modulation of cell redox status, osmotic regulation, pH control, and cytosolic calcium homeostasis and cell signaling. Mitochondria are susceptible to damage by oxidants, electrophiles, and lipophilic cations and weak acids. Chemical-induced mitochondrial dysfunction may be manifested as diverse bioenergetic disorders and considerable effort is required to distinguish between mechanisms involving critical mitochondrial targets and those in which mitochondrial dysfunction is secondary and plays only a modulatory role in cell injury. The following paragraphs review a few important examples of chemical-induced cytotoxic responses that are manifested as interference with mitochondrial metabolism and bioenergetics, gene regulation, or signal transduction in the form of apoptosis and altered cell cycle control. Greater understanding of the molecular mechanisms of mitochondrial bioenergetics, ion regulation, and genetics will lead to numerous additional examples of mitochondria-mediated cell injury, revealing important new insight regarding the prediction, prevention, diagnosis, and treatment of chemical-induced toxic tissue injury. [ABSTRACT FROM AUTHOR]

Le bimékizumab (BKZ) est un anticorps monoclonal IgG1 qui inhibe de manière sélective l'interleukine (IL)-17F et l'IL-17A et qui montré une efficacité clinique et d'un bon profil de tolérance chez les patients atteints de rhumatisme psoriasique (RP) actif [1,2]. Nous rapportons l'impact à long terme du traitement par BKZ, jusqu'à 3 ans, sur les critères patients (patient-reported outcomes [PRO]). Des patients avec un RP actif ont reçu le bimékizumab ou un placebo dans BE ACTIVE (phase 2b, NCT02969525) puis le bimekizumab à 160 mg toutes les 4 semaines dans l'étude d'extension en ouvert (NCT03347110)(S), quelle que soit la dose précédente reçue ; les résultats sont présentés pour tous les patients traités par le bimékizumab à S0/S48/S152. Les PRO rapportés (sur population totale d'analyse) incluaient : – les domaines individuels du questionnaire d'impact PsAID-9 analysés en variation par rapport à l'inclusion (Var) et en état acceptable (Patient Acceptable Symptom State [PASS] [acceptable pour un score ≤ 4]) ; – la fonction par HAQ analysé en différence minimale cliniquement importante (DMCI) du HAQI (DMCI ≥ 0,35 par rapport à l'inclusion) ; – Var pour : SF36, composantes physique et mentale du SF-36 (PCS/MCS) et douleur articulaire par échelle visuelle analogique (EVA). Les analyses étaient en imputation non-répondeur pour le PsAID et le HAQ. Sur les 206 patients randomisés à l'inclusion (BL) dans BE ACTIVE, 66,5 % avaient une surface corporelle atteinte par le psoriasis ≥ 3 %, 18,9 % avaient été précédemment traités par un anti-TNF et 63,6 % recevaient un traitement concomitant par le méthotrexate. À la S48/S152, les proportions de patients ayant un état PsAID acceptable (PASS) étaient de 74,2–76,8 %/63,7–67,1 % ; les proportions de patients ayant obtenu une DMCI du HAQ-DI étaient de 47,6–53,7 %/42,7–45,1 % (Fig. 1A–D). Tous les domaines du PsAID-9 et la majorité des 8 domaines de SF-36 se sont améliorés entre l'inclusion et S48 et S152, y compris la fatigue et la douleur. Sur cette même période, le SF-36-PCS s'est amélioré et le MCS est resté normal (Fig. 1E–F). Les patients ont montré une amélioration de la douleur durable (Var de douleur à S48 entre −26,8 et −34,7 en imputation multiple et à S152 entre −31,3 et −33,0 ; imputation multiple) (Fig. 1G). Le traitement par BKZ est associé à une amélioration prolongée des critères patients (PRO) concernant l'impact de la maladie et à des améliorations importantes et durables de la fonction physique et de la qualité de vie jusqu'à 3 ans. [ABSTRACT FROM AUTHOR]