This study aims to investigate the cost-effectiveness of the add-on exenatide to conventional pharmacotherapy in patients with Parkinson's disease (PD) when considering the coexistence of diabetes ...mellitus (DM). We used the Keelung and Community-based Integrated Screening databases to understand the medical utilisation in the Hoehn and Yahr stages of patients with PD. A Markov model with 1-year cycle length and 50-year time horizon was used to assess the cost-effectiveness of add-on exenatide to conventional pharmacotherapy compared to conventional pharmacotherapy alone. All costs were adjusted to the value of the new Taiwanese dollar (NT$) as of the year 2020. One-way sensitivity and probability analyses were performed to test the robustness of the results. From a societal perspective, the add-on exenatide brought an average of 0.39 quality-adjusted life years (QALYs) gained, and a cost increment of NT$104,744 per person in a 50-year horizon compared to conventional pharmacotherapy. The incremental cost-effectiveness ratio (ICER) was NT$268,333 per QALY gained. As the ICER was less than the gross domestic product per capita (NT$839,558), the add-on exenatide was considered to be very cost-effective in the two models, according to the World Health Organization recommendation. Add-on exenatide had a 96.9% probability of being cost-effective in patients with PD, and a 100% probability of being cost-effective in patients with PD and DM. Add-on exenatide is cost-effective in PD combined with DM. Considering that DM may be a risk factor for neurodegenerative diseases, exenatide provides both clinical benefits and cost-effectiveness when considering both PD and DM.
There are limited therapeutic options for patients with Dravet syndrome (DS). The equilibrative nucleoside transporters 1 (ENT1) mediate both the influx and efflux of adenosine across the cell ...membrane exerted beneficial effects in the treatment of epilepsy. This study aimed to evaluate the anticonvulsant effect of the ENT1 inhibitor in an animal model of DS (Scn1a
mice). J7 (5 mg/kg) treatment was efficacious in elevating seizure threshold in Scn1a
mice after hyperthermia exposure. Moreover, the J7 treatment significantly reduced the frequency of spontaneous excitatory post-synaptic currents (sEPSCs, ~35% reduction) without affecting the amplitude in dentate gyrus (DG) granule cells. Pretreatment with the adenosine A1 receptor (A1R) antagonist, DPCPX, abolished the J7 effects on sEPSCs. These observations suggest that the J7 shows an anticonvulsant effect in hyperthermia-induced seizures in Scn1a
mice. This effect possibly acts on presynaptic A1R-mediated signaling modulation in granule cells.
This study aimed to determine whether a cognitive test the Mini-Mental State Examination (MMSE) and the Ascertain Dementia 8 (AD8) instrument applied in combination could improve the accuracy of ...dementia detection in a community setting.
Study participants were recruited from a community-based integrated screening program in Tainan, Taiwan. Participants completed the AD8 and were administered the Chinese version of the MMSE by psychologists. In addition, the presence of dementia was determined by neurologists based on the 2011 National Institute on Aging–Alzheimer's Association guidelines. Logistic regression analysis determined whether the combination of these two tests provided any additional information for dementia detection than either test alone. Receiver operating characteristic (ROC) curve analyses were conducted to explore the performances of different screening modalities in detecting dementia.
In total, 282 participants with an average age of 69.31 ± 10.27 years were enrolled. The prevalence of dementia among participants aged ≥65 years was 9.29 %. The sensitivity and specificity of the AD8 applied alone for detecting dementia were 64.71 % and 87.89 %, respectively, and of the MMSE applied alone, after adjusting for education level, were 41.18 % and 84.50 %, respectively. Using a cutoff score of 21 for the MMSE resulted in sensitivity of 77.78 % and specificity of 73.58 %. The AD8 and MMSE when combined in parallel yielded 88.89 % sensitivity and 70.16 % specificity. The serial use of the AD8 followed by the MMSE yielded 50 % sensitivity and 93.02 % specificity. Except for when an MMSE cutoff value of 26 was applied, the sensitivity of all examined modalities was poor and specificity was moderate for detecting mild cognitive impairment. ROC curve analysis revealed that the parallel application of the MMSE and AD8 (area under the ROC curve AUC: 82.3 % 75.1 %–89.4 %) resulted in better dementia detection accuracy than the AD8 alone (AUC: 73.3 % 60.7 %–85.9 %), the MMSE alone (AUC: 77.4 % 67.6 %–87.3 %), or serial test administration (AUC: 67.6 % 53.4 %–81.8 %).
This study successfully demonstrated that the MMSE and AD8 combination for dementia screening could improve detection accuracy in a community setting.
•MMSE combined with AD8 increased dementia detection sensitivity and specificity.•The two tests provided different and additive information for dementia screening.•Under the rule-in accuracy, parallel testing is preferable for dementia detection.•Under the rule-out accuracy, serial testing is preferable for dementia evaluation.
Mutation of DJ-1 (PARK7) has been linked to the development of early-onset Parkinson's disease (PD). However, the underlying molecular mechanism is still unclear. This study is aimed to compare the ...sensitivity of nigrostriatal dopaminergic neurons to lipopolysaccharide (LPS) challenge between DJ-1 knockout (KO) and wild-type (WT) mice, and explore the underlying cellular and molecular mechanisms. Our results found that the basal levels of interferon (IFN)-γ (the hub cytokine) and interferon-inducible T-cell alpha chemoattractant (I-TAC) (a downstream mediator) were elevated in the substantia nigra of DJ-1 KO mice and in microglia cells with DJ-1 deficiency, and the release of cytokine/chemokine was greatly enhanced following LPS administration in the DJ-1 deficient conditions. In addition, direct intranigral LPS challenge caused a greater loss of nigrostriatal dopaminergic neurons and striatal dopamine content in DJ-1 KO mice than in WT mice. Furthermore, the sensitization of microglia cells to LPS challenge to release IFN-γ and I-TAC was via the enhancement of NF-κB signaling, which was antagonized by NF-κB inhibitors. LPS-induced increase in neuronal death in the neuron-glia co-culture was enhanced by DJ-1 deficiency in microglia, which was antagonized by the neutralizing antibodies against IFN-γ or I-TAC. These results indicate that DJ-1 deficiency sensitizes microglia cells to release IFN-γ and I-TAC and causes inflammatory damage to dopaminergic neurons. The interaction between the genetic defect (i.e. DJ-1) and inflammatory factors (e.g. LPS) may contribute to the development of PD.
This article presents a support vector machine (SVM) processor that supports both seizure detection and on-chip model adaptation for epileptic seizure control. Alternating direction method of ...multipliers (ADMM) is utilized for highly parallel computing for SVM training. From the algorithm aspect, minimum redundancy maximum relevance (mRMR) and low-rank approximation are exploited to reduce overall computational complexity by 99.4% while also reducing memory storage by 90.4%. For hardware optimization, overall hardware complexity is reduced by 87% through a hardware-shared configurable coordinate rotation digital computer (CORDIC)-based processing element array. Parallel rotations and folded structure for the approximate Jacobi method reduce overall training latency by 98.6%. The chip achieves a detection performance with a 96.6% accuracy and a 0.28/h false alarm rate within 0.71 s with the power dissipation of 1.9 mW. The proposed SVM processor achieves the shortest detection latency compared with the state-of-the-art seizure detectors. It also supports real-time model adaptation with a latency of 0.78 s. Compared with previous designs, this work achieves a 22× higher throughput and a 162× higher energy efficiency for SVM training.
Background and purpose: Levetiracetam is an effective anti‐epileptic drug in the treatment of partial and generalized seizure. The purpose of the present study was to investigate whether ...levetiracetam regulates AMPA and NMDA receptor‐mediated excitatory synaptic transmission and to determine its site of action in the dentate gyrus (DG), the area of the hippocampus that regulates seizure activities.
Experimental approach: Whole‐cell patch‐clamp method was used to record the AMPA and NMDA receptor‐mediated excitatory postsynaptic currents (EPSCAMPA and EPSCNMDA) in the presence of specific antagonists, from the granule cells in the DG in brain slice preparations from young Wistar rats (60–120 g).
Key results: Levetiracetam (100 µM) inhibited both evoked EPSCAMPA and EPSCNMDA to an equal extent (80%), altered the paired‐pulse ratio (from 1.39 to 1.25), decreased the frequency of asynchronous EPSC and prolonged the inter‐event interval of miniature EPSCAMPA (from 2.7 to 4.6 s) without changing the amplitude, suggesting a presynaptic action of levetiracetam. The inhibitory effect of levetiracetam on evoked EPSCAMPA was blocked by ω‐agatoxin TK (100 nM), a selective P/Q‐type voltage‐dependent calcium channel blocker, but not by nimodipine (10 µM) or ω‐conotoxin (400 nM).
Conclusions and implications: These results suggest that levetiracetam modulated the presynaptic P/Q‐type voltage‐dependent calcium channel to reduce glutamate release and inhibited the amplitude of EPSC in DG. This effect is most likely to contribute to the anti‐epileptic action of levetiracetam in patients.
J. Neurochem. (2010) 114, 717-727. The cellular localization of organic cation transporter (OCT) 1 and OCT2 in isolated brain microvessel endothelial cells from humans, rats, and mice and in cultured ...adult rat brain endothelial cells was examined by confocal microscopy and in isolated luminal and abluminal membrane fractions by Western blot analysis. Cellular uptake of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was measured with or without OCT1/OCT2 silencing. The interaction between MPTP and amantadine was studied by in vitro kinetic analysis and in vivo brain microdialysis. MPTP-induced dopaminergic toxicity was examined by measuring dopamine levels in the brain striatum and by positron emission tomography scanning. The results showed that both OCT1 and OCT2 were mainly expressed on the luminal side of brain microvessel endothelial cells and adult rat brain endothelial cells. Cellular uptake of MPTP was significantly (p < 0.05) decreased by about 53%, 60%, or 91% following silencing of OCT1, OCT2, or both, respectively. Amantadine competitively inhibited MPTP uptake in vitro and significantly (p < 0.05) reduced the area under the time-concentration curve for MPTP and MPP⁺ in the brain extracellular fluid in rats and mice by 65-70% and 35-85%, respectively. MPTP-induced dopaminergic toxicity in mice was ameliorated by amantadine without stimulating dopamine turnover. In conclusion, OCT1 and OCT2 are important for MPTP transfer across the blood-brain barrier and amantadine reduces the blood-brain barrier transfer of MPTP and MPTP-induced dopaminergic toxicity in rodents.
Ischemic stroke is a devastating disease with limited therapeutic options. It is very urgent to find a new target for drug development. Here we found that the blood level of MIF in ischemic stroke ...patients is upregulated. To figure out the pathological role of MIF in ischemic stroke, both in vitro and in vivo studies were conducted. For in vitro studies, primary cortical neuron cultures and adult rat brain endothelial cells (ARBECs) were subjected to oxygen-glucose deprivation (OGD)/reoxygenation. Middle cerebral artery occlusion (MCAo) rodent models were used for in vivo studies. The results show that MIF exerts no direct neuronal toxicity in primary culture but disrupts tight junction in ARBECs. Furthermore, administration of MIF following MCAo shows the deleterious influence on stroke-induced injury by destroying the tight junction of blood-brain barrier and increasing the infarct size. In contrast, administration of MIF antagonist ISO-1 has the profound neuroprotective effect. Our results demonstrate that MIF might be a good drug target for the therapy of stroke.
Aims
To evaluate polypharmacy‐related problems in the elderly people who live in rural through a proactive pharmaceutical care project under a novel remote medical service infrastructure (the ...Houston‐Apollo polypharmacy project).
Methods
It is a prospectively cross‐sectional study. The elderly aged 65 years old lived in communities executed the congregate meal service and joined the Houston‐Apollo project were included. During March and July on 2020, the pharmaceutical care team of Houston‐Apollo polypharmacy project interviewed old people and collected their medications by remote video. Polypharmacy situation and drug‐related problems, including potentially inappropriate medications (PIMs), anticholinergic burden (ACB) and risk of sarcopaenia, were evaluated by clinical pharmacists. In addition, we analysed the categories of the prescription types between polypharmacy and non‐polypharmacy users, polypharmacy users with and without PIMs or ACB. A patient‐specific integrated pharmacist's note for medication education and a dear doctor letter (as needed) were generated and delivered within 2‐weeks postinterviewed. Age‐ and sex‐adjusted logistic regression model was used to evaluate the association between polypharmacy and these potential medication problems.
Results
There were 87 older people (mean age = 75.9) and 536 long‐term medications were collected. Among them, 52% were defined as polypharmacy users. Polypharmacy was significantly associated with higher risk of PIMs and ACB. The adjusted odd ratio was 5.31 (95% CI: 2.02‐13.9) and 10.1 (95% CI: 3.4‐29.7), respectively. Among polypharmacy users, there were nearly double the prescriptions for the nervous system and musculoskeletal system among patients with PIMs compared with those without PIMs. Besides, polypharmacy users with ACB showed higher rate of prescriptions for the nervous system and the alimentary tract and metabolism system compared with those without ACB.
Conclusion
Polypharmacy was significantly associated with negative impact of medication safety among the elderly people in rural area. A persistent remote pharmaceutical care intervention was crucial for improving this problem.
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