Comparison of tolerability and adverse symptoms in oxcarbazepine and carbamazepine in the treatment of trigeminal neuralgia and neuralgiform headaches using the Liverpool Adverse Events Profile (AEP)

Background Adverse effects of drugs are poorly reported in the literature . The aim of this study was to examine the frequency of the adverse events of antiepileptic drugs (AEDs), in particular carbamazepine (CBZ) and oxcarbazepine (OXC) in patients with neuralgiform pain using the psychometrically tested Liverpool Adverse Events Profile (AEP) and provide clinicians with guidance as to when to change management. Methods The study was conducted as a clinical prospective observational exploratory survey of 161 patients with idiopathic trigeminal neuralgia and its variants of whom 79 were on montherapy who attended a specialist clinic in a London teaching hospital over a period of 2 years. At each consultation they completed the AEP questionnaire which provides scores of 19–76 with toxic levels being considered as scores >45. Results The most common significant side effects were: tiredness 31.3 %, sleepiness 18.2 %, memory problems 22.7 %, disturbed sleep 14.1 %, difficulty concentrating and unsteadiness 11.6 %. Females reported significantly more side effects than males. Potential toxic dose for females is approximately 1200 mg of OXC and 800 mg of CBZ and1800mg of OXC and 1200 mg of CBZ for males. Conclusions CBZ and OXC are associated with cognitive impairment. Pharmacokinetic and pharmacodynamic differences are likely to be the reason for gender differences in reporting side effects. Potentially, females need to be prescribed lower dosages in view of their tendency to reach toxic levels at lower dosages. Side effects associated with AED could be a major reason for changing drugs or to consider a referral for surgical management

Remobilization of inverted normal faults drives active extension in the axial zone of the southern Apennine mountain belt (Italy)

The Irpinia region is one of the most seismically active areas of Italy owing to ongoing, late-orogenic extension in the axial zone of the Apennine mountain belt. However, the 3D architecture and the nature of the faults that drive this extension are still uncertain, posing challenges to seismic hazard assessment. Here, we address these uncertainties by integrating a new catalogue of high-resolution micro-seismicity (ML < 3.5) complemented by earthquake focal mechanisms, with existing 3D seismic velocity models and geological data. We found that micro-seismicity is primarily taking place along a segmented, approximately 60 km long, deep-seated, Mesozoic normal fault that was inverted during the shortening stages of the Apennine orogeny and then extensionally reactivated during the Quaternary. These findings suggest that multiple events of reactivation of long-lived faults can weaken their strength, making them prone to co-seismic remobilization under newly imposed strain fields in active mountain belts

Comments on Inan’s Notions of Objectual and Propositional Curiosity

In this paper I comment on Inan’s notions of propositional and objectual curiosity. Even though Inan offers an interesting and intuitive distinction between propositional and objectual curiosity, I want to question two aspects of his theory of curiosity. One aspect concerns his thesis that propositional curiosity is interdependent on epistemic attitudes such as belief, certainty and interest. Another aspect of his theory that I discuss is his thesis that objectual curiosity is not reducible to propositional curiosity. In more detail, in the fi rst part, I start off by explaining what propositional curiosity is according to Inan and I bring up two worries that I call: (i) over-complexity as a result of subjectivity and (ii) overcomplexity as a result of dynamics for the above mentioned epistemic attitudes. Both worries stress the problem of over-complexity of Inan’s theory of propositional curiosity. In the second part, I argue that objectual curiosity is, contrary to Inan’s hypothesis, reducible to propositional curiosity. I further argue that the object of wh- questions that, according to Inan, express objectual curiosity can either be about the truth value of general or singular proposition. In addition, I suggest that only the reading where wh- questions express curiosity in a form of de re reading and have a singular proposition as their content is the one that is compatible with Inan’s notion of objectual curiosity

A systematic experimental neuropsychological investigation of the functional integrity of working memory circuits in major depression

Verbal and visuospatial working memory (WM) impairment is a well-documented finding in psychiatric patients suffering from major psychoses such as schizophrenia or bipolar affective disorder. However, in major depression (MDD) the literature on the presence and the extent of WM deficits is inconsistent. The use of a multitude of different WM tasks most of which lack process-specificity may have contributed to these inconsistencies. Eighteen MDD patients and 18 healthy controls matched with regard to age, gender and education were tested using process- and circuit-specific WM tasks for which clear brain-behaviour relationships had been established in prior functional neuroimaging studies. Patients suffering from acute MDD showed a selective impairment in articulatory rehearsal of verbal information in working memory. By contrast, visuospatial WM was unimpaired in this sample. There were no significant correlations between symptom severity and WM performance. These data indicate a dysfunction of a specific verbal WM system in acutely ill patients with MDD. As the observed functional deficit did not correlate with different symptom scores, further, longitudinal studies are required to clarify whether and how this deficit is related to illness acuity and clinical state of MDD patients

Inactivation of Cg10062, a cis-3-Chloroacrylic Acid Dehalogenase Homologue in Corynebacterium glutamicum, by (R)- and (S)-Oxirane-2-carboxylate: Analysis and Implications

ABSTRACT: (R)- and (S)-oxirane-2-carboxylate were determined to be active site-directed irreversible inhibitors of the cis-3-chloroacrylic acid dehalogenase (cis-CaaD) homologue Cg10062 found in Corynebacterium glutamicum. Kinetic analysis indicates that the (R) enantiomer binds more tightly and is the more potent inhibitor, likely reflecting more favorable interactions with active site residues. Pro-1 is the sole site of covalent modification by the (R) and (S) enantiomers. Pro-1, Arg-70, Arg-73, and Glu-114, previously identified as catalytic residues in Cg10062, have also been implicated in the inactivation mechanism. Pro-1, Arg-70, and Arg-73 are essential residues for the process as indicated by the observation that the enzymes with the corresponding alanine mutations are not covalently modified by either enantiomer. The E114Q mutant slows covalent modification of Cg10062 but does not prevent it. The results are comparable to those found for the irreversible inactivation of cis-CaaD by (R)-oxirane-2-carboxylate with two important distinctions: the alkylation of cis-CaaD is stereospecific, and Glu-114 does not take part in the cis-CaaD inactivation mechanism. Cg10062 exhibits low-level cis-CaaD and trans-3-chloroacrylic acid dehalogenase (CaaD) activities, with the cis-CaaD activity predominating. Hence, the preference of Cg10062 for the cis isomer correlates with the observation that the (R) enantiomer is the more potent inactivator. Moreover, the factors responsible for the relaxed substrate specificity of Cg10062 may accoun