Antiepileptogenic effects of trilostane in the kainic acid model of temporal lobe epilepsy

Objective: Epileptogenesis after status epilepticus (SE) has a faster onset in rats treated to reduce brain levels of the anticonvulsant neurosteroid allopregnanolone with the 5α-reductase inhibitor finasteride; however, it still has to be evaluated whether treatments aimed at increasing allopregnanolone levels could result in the opposite effect of delaying epileptogenesis. This possibility could be tested using the peripherally active inhibitor of 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase trilostane, which has been shown repeatedly to increase allopregnanolone levels in the brain. Methods: Trilostane (50 mg/kg) was administered subcutaneously once daily for up to six consecutive days, starting 10 min after intraperitoneal administration of kainic acid (15 mg/kg). Seizures were evaluated by video-electrocorticographic recordings for 70 days maximum, and endogenous neurosteroid levels were assessed by liquid chromatography–electrospray tandem mass spectrometry. Immunohistochemical staining was performed to evaluate the presence of brain lesions. Results: Trilostane did not alter the latency of kainic acid-induced SE onset or its overall duration. When compared to the vehicle-treated group, rats receiving six daily trilostane injections presented a remarkable delay of the first spontaneous electrocorticographic seizure and subsequent tonic–clonic spontaneous recurrent seizures (SRSs). Conversely, rats treated with only the first trilostane injection during SE did not differ from vehicle-treated rats in developing the SRSs. Notably, trilostane did not modify neuronal cell densities or the overall damage in the hippocampus. In comparison to the vehicle group, repeated administration of trilostane significantly decreased the activated microglia morphology in the subiculum. As expected, allopregnanolone and other neurosteroid levels were remarkably increased in the hippocampus and neocortex of rats treated for 6 days with trilostane, but pregnanolone was barely detectable. Neurosteroids returned to basal levels after a week of trilostane washout.. Significance: Overall, these results suggest that trilostane led to a remarkable increase in allopregnanolone brain levels, which was associated with protracted effects on epileptogenesis

Facile multi-components one-pot synthesis of dipyrazolo[1,5-a:3',4'-d]pyrimidine as potent bioactive scaffolds

An efficient, three-component, catalyst free synthesis of dipyrazolo[1,5-a:3',4'-d]pyramid scaffolds has been carried out using 3-methyl-1H-pyrazol-5(4H)-one (1), 5-amino pyarazole (2a-b) and substituted aromatic aldehydes. The reaction underwent cyclocondensation reaction in reflux condition with moderate to good (62%–90 %) yields. The twenty newly prepared molecules were analyzed by means of 1H & 13C NMR, Mass, and IR spectroscopies and their activities against the bacterial and fungal strains were screened. Some of tested compounds have shown excellent antibacterial activities while another four were found to have good antifungal activity

The importance of contextual aspects in the care for patients with functional somatic symptoms

Functional somatic symptoms refer to physical symptoms that cannot be (bio) medically explained. The pattern or clustering of such symptoms may lead to functional syndromes like chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, among many others. Since the underlying pathophysiology remains unknown, several explanatory models have been proposed, nearly all including social and psychological parameters. These models have stimulated effectiveness studies of several psychological and psychopharmacological therapies. While the evidence for their effectiveness is steadily growing, effect-sizes are at most moderate and many patients do not benefit. We hypothesize that the context in which interventions for functional somatic symptoms are delivered substantially influences their effectiveness. Although this hypothesis is in line with explanatory models of functional somatic symptoms, to our knowledge, studies primarily focusing on the influence of contextual aspects on treatment outcome are scarce. Contextual research in the field of somatic symptoms has (irrespective whether these symptoms can be medically explained or not), however, just begun and already yielded some valuable results. These findings can be organized according to Duranti's and Goodwin's theoretical approach to context in order to substantiate our hypothesis. Based on this approach, we categorized empirical findings in three contextual aspects, i.e. 1) the setting, 2) the behavioural environment, and 3) the language environment. Collectively, some support is found for the fact that early identification of patients with functional somatic symptoms, starting treatment as soon as possible, having a neat appearance and an organized office interior, a warm and friendly nonverbal approach and a language use without defensiveness are contextual parameters which enhance the assessment by the patient of the physician's competence to help. Nonetheless, in vivo studies addressing the most aspects, i.e. nonverbal behaviour and language, are needed for better understanding of these contextual aspect. Moreover, future research should address to what extent optimizing contextual aspects improve care for functional somatic symptoms

"One time I fell, but I didn't have to cry." A qualitative study on everyday physical complaints in children

OBJECTIVE: Young children experience physical complaints, like abdominal pain or minor injuries from playing, almost every day. These experiences may shape how they deal with health issues later in life. While models exist to explain illness perception in adults, information is lacking on the perspective of young children. This qualitative study aimed to explore important themes in the experience of everyday physical complaints in four- and five-year-old children, using children as informants. STUDY DESIGN: 30 semi-structured interviews were performed in which four- and five-year-old children were questioned about their experiences with everyday physical complaints. The interviews were double coded using Atlas.ti and subsequently qualitative content analysis was used to define themes. RESULTS: All participating children were able to elaborate on their experiences with physical complaints. Three themes emerged from the interviews: causes of complaints, appraisal of complaints, and implications of complaints. In their appraisal of complaints, four- and five-year-old children made a distinction between visible and invisible complaints and real or pretended complaints. CONCLUSION: Four- and five-year-old children can already give details about their experiences with everyday physical complaints. They have developed ideas about the causes and implications of complaints and try to make an appraisal

Crowdworking: Nurturing Expert-Centric Absorptive Capacity

Absorptive capacity, or the organizational capability to identify, assimilate, and apply new knowledge for commercial ends, is a key determinant of how organizations successfully generate value from external sources of knowledge and sustain a competitive advantage. Crowdworking—a novel form of digitally mediated work—allows organizations to hire on-demand highly skilled external experts to leverage their knowledge, skills, and networks. The approach of integrating crowdworking into organizations is increasingly gaining traction among large corporations seeking to harness the knowledge in external communities for value generation. Building on an in-depth embedded case study in a large organization that relies on two established crowdwork platforms, we explore how the organization developed its crowdworking-related absorptive capacity to generate value from external experts. We find that the crowdworking-related absorptive capacity phenomenon is a particular instance of expert-centric absorptive capacity that organizations develop by retaining on-demand external experts. We also find that this capacity can be developed through two idiosyncratic configurations of orchestrated and distributed routines that integrate external experts and utilize their knowledge in the host organization. These findings offer new insights into the prevailing modus operandi related to harnessing external knowledge in today’s organizations

Cyber-physical systems design for runtime trustworthiness maintenance supported by tools

The trustworthiness of cyber-physical systems is a critical factor for establishing wide-spread adoption of these systems. Hence, especially the behavior of safety-critical software components needs to be monitored and managed during system operation. Runtime trustworthiness maintenance should be planned and prepared in early requirements and design phases. This involves the identification of threats that may occur and affect user’s trust at runtime, as well as related controls that can be executed to mitigate the threats. Furthermore, observable and measureable system quality properties have to be identified as indicators of threats, and interfaces for reporting these properties as well as for executing controls have to be designed and implemented. This paper presents a process model for preparing and designing systems for runtime trustworthiness maintenance, which is supported by several tools that facilitate the tasks to be performed by requirements engineers and system designer