Top-down and bottom-up control of drug-induced sleep and anaesthesia

In recent decades, research has unravelled fascinating detail about the molecular mechanisms underpinning pharmacologic loss of consciousness (LOC). However, the systems-level mechanisms are far less clear. Recent genetic approaches, however, enable unprecedented dissection on neural pathways, and they are paving a way for this line of research. The focus of this thesis is to investigate the neuroanatomical substrates of commonly used drugs which reversibly render us unconscious. Zolpidem is a positive allosteric modulator (PAM) of the GABAA receptor which binds to the benzodiazepine (BZ) site. Because zolpidem binds 1-3,,2 containing GABAA receptors, which are widespread, it acts virtually everywhere. We do not know if zolpidem causes sleep by enhancing GABAergic inhibition throughout the entire brain, or if the therapeutic sleep-inducing property depends upon specific brain circuitry. 2I77 mice are devoid of zolpidem-sensitivity. But, zolpidem-sensitivity can be restored selectively in brain regions, enabling dissection of the circuitry involved in zolpidem’s effect. To isolate the therapeutic effect of zolpidem we deleted GABAA-2I77-subunits and replaced them with GABAA-2F77-subunits in HDC neurons or frontal-cortex in isolation. We were able to selectively restore zolpidem-sensitivity in target neurons. This conferred zolpidem-enhanced IPSCs locally. Compared with wild-type mice and zolpidem-insensitive 2I77lox mice, we found that GABAA-2F77 receptors in either HDC-neurons or frontal cortex alone were enough to rescue the majority of zolpidem-mediated sleep. The response in HDC-2F77 mice was similar to that of an H1-receptor antagonist. By producing a null effect in a negative-control area – the superior colliculus – we show that HDC neurons and the frontal cortex are both substrates involved in zolpidem-mediated sleep. We also investigated the role of synaptic-inhibition onto corticothalamic-neurons in anaesthetic-induced LOC and sleep-wake. To do this, we genetically ablated 2-subunits from layer-6 corticothalamic-cells by crossing Ntsr1-Cre mice with GABAA-2I77lox mice. We found this reduced isoflurane sensitivity, but left sleep-wake behaviours virtually unaffected.Open Acces

COMPONENT TECHNOLOGIES AND THEIR IMPACT UPON SOFTWARE DEVELOPMENT

Software development is beset with problems relating to development productivity, resulting in projects delivered late and over budget. While the term software engineering was first introduced in the late sixties, its current state reflects no other engineering discipline. Component-orientation has been proposed as a technique to address the problems of development productivity and much industrial literature extols the benefits of a component-oriented approach to software development. This research programme assesses the use of component technologies within industrial software development. From this assessment, consideration is given to how organisations can best adopt such techniques. Initial work focuses upon the nature of component-orientation, drawing from the considerable body of industrial literature in the area. Conventional wisdom regarding componentorientation is identified from the review. Academic literature relevant to the research programme focuses upon knowledge regarding the assessment of software technologies and models for the adoption of emergent technologies. The method pays particular attention to literature concerning practitioner focussed research, in particular case studies. The application of the case study method is demonstrated. The study of two industrial software development projects enables an examination of specific propositions related to the effect of using component technologies. Each case study is presented, and the impact of component-orientation is each case is demonstrated. Theories regarding the impact of component technologies upon software development are drawn from case study results. These theories are validated through a survey of practitioners. This enabled further examination of experience in component-based development and also understanding how developers learn about the techniques. A strategy for the transfer of research findings into organisational knowledge focuses upon the packaging of previous experience in the use of component-orientation in such a way that it was usable by other developers. This strategy returns to adoption theories in light of the research findings and identifies a pattern-based approach as the most suitable for the research aims. A pattern language, placed in the context of the research programme, is developed from this strategy. Research demonstrates that component-orientation undoubtedly does affect the development process, and it is necessary to challenge conventional wisdom regarding their use. While component-orientation provides the mechanisms for increased productivity in software development, these benefits cannot be exploited without a sound knowledge base around the domain

Acupuncture : a promising approach for Comorbid depression and insomnia in perimenopause

Comorbid depression and insomnia are ubiquitous mental complaints among women going through the perimenopausal stage of life and can result in major decline in quality of life. Antidepressive agents combined with/without hypnotics, and/or hormone therapy are currently the most common treatment for perimenopausal depression (PMD) and insomnia (PMI). Balancing the benefits of these pharmacotherapies against the risk of adverse events (AEs) is a difficult task for both clinicians and women. There has been a growing body of research regarding the utilization of acupuncture for treatment of PMD or PMI, whereas no studies of acupuncture for comorbid PMD and PMI have appeared. In this review, we summarize the clinical and preclinical evidence of acupuncture as a treatment for PMD or PMI, and then discuss the potential mechanisms involved and the role of acupuncture in helping women during this transition. Most clinical trials indicate that acupuncture ameliorates not only PMD/PMI but also climacteric symptoms with minimal AEs. It also regulates serum hormone levels. The reliability of trials is however limited due to methodological flaws in most studies. Rodent studies suggest that acupuncture prolongs total sleep time and reduces depression-like behavior in PMI and PMD models, respectively. These effects are possibly mediated through multiple mechanisms of action, including modulating sex hormones, neurotransmitters, hypothalamic-pituitary-adrenal axis/hypothalamic-pituitary-ovary axis, oxidative stress, signaling pathways, and other cellular events. In conclusion, acupuncture is a promising therapeutic strategy for comorbid depression and insomnia during perimenopause. Neuroendocrine modulation is likely to play a major role in mediating those effects. High-quality trials are required to further validate acupuncture’s effectiveness. © 2021 Zhao et al

ANTICONVULSANT AND PROCOGNITIVE EFFECT OF NONIMIDAZOLE HISTAMINE H3R RECEPTOR ANTAGONISTS /INVERSE AGONISTS IN EXPERIMENTAL ANIMAL MODELS

Epilepsy is a common chronic neurological disorder accompanied by cognitive impairment. Available antiepileptic drugs (AEDs) have not been reported to have ameliorative effects on epilepsy-associated memory impairment. The potential of histamine H3 receptors (H3R) in several neuropsychiatric diseases, including epilepsy and Alzheimer’s disease, is well recognized. In this study, a series of H3R antagonists (1-16) were screened for their in vivo anticonvulsant effect in several acute-induced seizures in rats. Moreover, the procognitive effect of the most promising H3R antagonist was investigated in dizocilpine (DIZ)-induced amnesic effect applying several behavioral memory tests. Furthermore, the most promising H3R antagonist was assessed for its simultaneous anticonvulsant and procognitive effect and its modulatory effect on levels of oxidative stress markers, several hippocampal neurotransmitters, and c-fos protein expression in the PTZ model. Finally, the promising H3R antagonist was examined for its anticonvulsant effect in PLC-induced SE and its ability to mitigate SE incidence. The Observed results indicated that H3R antagonist 4 (10 mg/kg i.p.) significantly exhibited high protection in maximum electroshock (MES)-induced seizures facilitated through histaminergic neurotransmission and activation of post-synaptically located H1R and full protection in the PTZ-acute induced seizures, Moreover, H3R antagonist 4 (5 mg/kg i.p.) showed a procognitive effect that was abrogated with RAM co-injection in all behavioral memory tests. Additionally, treatment with H3R antagonist 4 showed a simultaneous anticonvulsant and procognitive effect in addition to antioxidant effect in PTZ- acute and -chronic models. Furthermore, chronic treatment with H3R antagonist 4 (5 mg/kg i.p.) modified histamine, acetylcholine, and glutamate release, and reduced hippocampal c-fos activation. In addition, RAMadministration reversed the protective effects provided by H3R antagonist 4 in PTZ chronic model. Moreover, and in PLC-induced SE, systemic administration of H3R antagonist 4 (10 mg/kg i.p.) mitigated the severity of SE and exhibited antioxidant effect in the hippocampus of the treated rats, facilitated through the histaminergic neurotransmission. The observed findings recommend that the newly developed H3R antagonist 4 provides antiepileptic, memory-enhancing, and antioxidant properties in a PTZ-induced kindling model of epilepsy and provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the management of epilepsy with accompanied memory deficits

Acquisition, Distribution and Perspectives of Healthcare Information in Complementary and Alternative Medicines (CAM)

Merged with duplicate record 10026.1/2500 on 06.20.2017 by CS (TIS)From April 2001 until September 2005 1 worked as a Pilkington research fellow at the Department of Complementary Medicine, University of Exeter, which in 2002 was integrated as a unit of the Peninsula Medical School. All the publications presented here have been carried out during my time of employment in this post at the Complementary Medicine Unit of the Peninsula Medical School in Exeter, United Kingdom. During the first few months of my research post in 2001 1 recognized the importance of the Internet as a tool to obtain healthcare information. Under the supervision of Professor Edzard Ernst, director of CAM, I carried out five Internet surveys, of which I collected and summarized the data and drafted the first version of the manuscripts, which were then finalized by Professor Ernst's comments: * Health risks over the Internet: advice offered by'medical herbalists' to a pregnant woman. * Reflexologists' responses to a patient with abdominal pain -a survey on Internet advice. * Internet advice by acupuncturists -a risk factor for cardiovascular patients? * Are asthma sufferers at risk when consulting chiropractors over the Internet? * Aspects of MMR / MMR vaccination advice over the Internet