Inherent seizure susceptibility in patients with antihistamine-induced acute symptomatic seizure: a resting-state EEG analysis.

We compared neural activities and network properties between the antihistamine-induced seizures (AIS) and seizure-free groups, with the hypothesis that patients with AIS might have inherently increased neural activities and network properties that are easily synchronized. Resting-state electroencephalography (EEG) data were collected from 27 AIS patients and 30 healthy adults who had never had a seizure. Power spectral density analysis was used to compare neural activities in each localized region. Functional connectivity (FC) was measured using coherence, and graph theoretical analyses were performed to compare network properties between the groups. Machine learning algorithms were applied using measurements found to be different between the groups in the EEG analyses as input features. Compared with the seizure-free group, the AIS group showed a higher spectral power in the entire regions of the delta, theta, and beta bands, as well as in the frontal areas of the alpha band. The AIS group had a higher overall FC strength, as well as a shorter characteristic path length in the theta band and higher global efficiency, local efficiency, and clustering coefficient in the beta band than the seizure-free group. The Support Vector Machine, k-Nearest Neighbor, and Random Forest models distinguished the AIS group from the seizure-free group with a high accuracy of more than 99%. The AIS group had seizure susceptibility considering both regional neural activities and functional network properties. Our findings provide insights into the underlying pathophysiological mechanisms of AIS and may be useful for the differential diagnosis of new-onset seizures in the clinical setting.

Modulation of Long-Term Potentiation by Gamma Frequency Transcranial Alternating Current Stimulation in Transgenic Mouse Models of Alzheimer's Disease.

Transcranial alternating current stimulation (tACS) is a neuromodulation procedure that is currently studied for the purpose of improving cognitive function in various diseases. A few studies have shown positive effects of tACS in Alzheimer's disease (AD). However, the mechanism underlying tACS has not been established. The purpose of this study was to investigate the mechanism of tACS in five familial AD mutation (5xFAD) mouse models. We prepared twenty 4-month-old mice and divided them into four groups: wild-type mice without stimulation (WT-NT group), wild-type mice with tACS (WT-T group), 5xFAD mice without stimulation (AD-NT group), and 5xFAD mice with tACS (AD-T group). The protocol implemented was as follows: gamma frequency 200 µA over the bilateral frontal lobe for 20 min over 2 weeks. The following tests were conducted: excitatory postsynaptic potential (EPSP) recording, Western blot analysis (cyclic AMP response element-binding (CREB) proteins, phosphorylated CREB proteins, brain-derived neurotrophic factor, and parvalbumin) to examine the synaptic plasticity. The EPSP was remarkably increased in the AD-T group compared with in the AD-NT group. In the Western blot analysis, the differences among the groups were not significant. Hence, tACS can affect the long-lasting enhancement of synaptic transmission in mice models of AD.

Cognitive Function Improvement in Mouse Model of Alzheimer's Disease Following Transcranial Direct Current Stimulation.

Anodal transcranial direct current stimulation (tDCS) is a painless noninvasive method that reportedly improves cognitive function in Alzheimer's disease (AD) by stimulating the brain. However, its underlying mechanism remains unclear. Thus, the present study investigates the cognitive effects in a 5xFAD AD mouse model using electrophysiological and pathological methods. We used male 5xFAD C57BL/6J and male C57BL/6J wild-type mice; the dementia model was confirmed through DNA sequencing. The verified AD and wild-type mice were randomly assigned into four groups of five mice each: an induced AD group receiving tDCS treatment (Stim-AD), an induced AD group not receiving tDCS (noStim-AD), a non-induction group receiving tDCS (Stim-WT), and a non-induction group not receiving tDCS (noStim-WT). In the Stim group, mice received tDCS in the frontal bregma areas at an intensity of 200 µA for 20 min. After 2 weeks of treatment, we decapitated the mice, removed the hippocampus from the brain, confirmed its neuronal activation through excitatory postsynaptic potential (EPSP) recording, and performed molecular experiments on the remaining tissue using western blots. EPSP significantly increased in the Stim-AD group compared to that in the noStim-AD, which was comparable to that in the non-induced groups, Stim-WT and noStim-WT. There were no significant differences in cyclic amp-response element binding protein (CREB), phosphorylated CREB (pCREB), and Brain-derived neurotrophic factor (BDNF) levels in the Stim-AD group compared to those in the noStim-AD group. This study demonstrated that a tDCS in both frontal lobes of a transgenic 5xFAD mouse model affects long-term potentiation, indicating possible enhancement of cognitive function.

Regulation of gene expression after combined scalp acupuncture and transcranial magnetic stimulation in middle cerebral artery occlusion mice.

BACKGROUND: The effect of combined repetitive transcranial magnetic stimulation (rTMS) and scalp acupuncture stimulation (SAS) on middle cerebral artery occlusion (MCAO) mice has not yet been reported. The regulation of gene expression after combined stimulation remains unclear. OBJECTIVE: To analyze gene expression patterns through ribonucleic acid (RNA) sequencing. METHODS: Thirty-six 8-weeks-old C57BL/6J male mice weighing 50-60 grams were used for this experiment. The MCAO was induced with 60-min occlusion and subsequent reperfusion of the middle cerebral artery. Experimental mice were randomly assigned to four groups, with nine mice in each group, as follows: control group (no treatment), SAS group (10 minutes SAS), rTMS group (1 Hz rTMS), and combined group (1 Hz rTMS and SAS). Stimulation was performed from the 3rd day to the 7th day after the induction of MCAO. All mice were sacrificed, and brain tissues were taken from the motor area of the MCAO lesion. We analyzed their gene expression profiles using RNA sequencing technology. RESULTS: After stimulation, the grip strength increased in the SAS and rTMS group compared to the control and combined group. The nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) was the key up-regulated protein in the SAS group while src homologus and collagene gene (SHC) and p90 ribosomal protein S6 kinases (p90RSK) were key up-regulated proteins in the rTMS group. However, the C-terminal src kinase-homologous kinase (CHK) was down-regulated whereas p90RSK was up-regulated in the combined group based on the RNA sequencing analysis. CONCLUSIONS: Each stimulation method showed different patterns with neurotrophin signaling pathway including NFκB, SHC, p90RSK, and CHK. These can be used in further mechanistic studies about gene expression related to neurorecovery.

Identification of Plant Extracts that Inhibit the Formation of Diabetes-Linked IAPP Amyloid.

The extracts of 27 vegetables, spices and herbs were screened for their functional ability to inhibit the aggregation of islet amyloid polypeptide (IAPP, amylin) into toxic amyloid aggregates. The aggregation of IAPP has been directly linked to the death of pancreatic ß-islet cells in type 2 diabetes. Inhibiting the aggregation of IAPP is believed to have the potential to slow, if not prevent entirely, the progression of this disease. As vegetables, spices and herbs are known to possess many different positive health effects, the extracts of 27 plants (abundant within the United States and spanning several plant families) were screened for their ability to inhibit the formation of toxic IAPP aggregates. Their anti-amyloid activities were assessed through (1) thioflavin T binding assays, (2) visualization of amyloid fibers using atomic force microscopy and (3) cell rescue studies. From this research, mint, peppermint, red bell pepper and thyme emerged as possessing the greatest anti-amyloid activity.

Anti-solvent co-crystallization of carbamazepine and saccharin.

The co-crystal approach has been investigated extensively over the past decade as one of the most promising methods to enhance the dissolution properties of insoluble drug substances. Co-crystal powders are typically produced by mechanical grinding (neat or wet) or a solution method (evaporation or cooling). In this study, high-purity carbamazepine-saccharin (CBZ-SAC) co-crystals were manufactured by a novel method, anti-solvent addition. Among various solvents, methanol was found to perform well with water as the anti-solvent for the co-crystallization of CBZ and SAC. When water was added to the methanol solution of CBZ and SAC at room temperature under agitation, nucleation of CBZ-SAC co-crystals occurred within 2-3 min. Co-crystallization was complete after 30 min, giving a solid yield as high as 84.5% on a CBZ basis. The effects of initial concentrations, focusing on the SAC/CBZ ratio, were examined to establish optimal conditions. The whole anti-solvent co-crystallization process was monitored at-line via ATR-FTIR analysis of regularly sampled solutions. The nucleation and crystal growth of CBZ-SAC co-crystals were detected by a significant increase in absorption in the range of 2400-2260 cm(-1), associated with the formation of hydrogen bonds between the carbonyl group in CBZ and the N-H of SAC. When CBZ hydrates were formed as impurities during anti-solvent co-crystallization, the hydrogen bonding between methanol and water was reduced greatly, primarily due to the incorporation of water molecules into the CBZ crystal lattice. In conclusion, an anti-solvent approach can be used to produce highly pure CBZ-SAC co-crystal powders with a high solid yield.

Characteristics of indomethacin-saccharin (IMC-SAC) co-crystals prepared by an anti-solvent crystallization process.

The creation of co-crystals of various insoluble drug substances has been extensively investigated as a promising approach to improve their pharmaceutical performance. In this study, co-crystal powders of indomethacin and saccharin (IMC-SAC) were prepared by an anti-solvent (water) addition and compared with co-crystals by evaporation method. No successful synthesis of a pharmaceutical co-crystal powder via an anti-solvent approach has been reported. Among solvents examined, methanol was practically the only one that resulted in the formation of highly pure IMC-SAC co-crystal powders by anti-solvent approach. The mechanism of a preferential formation of IMC-SAC co-crystal to IMC was explained with two aspects: phase solubility diagram and solution complexation concept. Accordingly, the anti-solvent approach can be considered as a competitive route for producing pharmaceutical co-crystal powders with acceptable properties.

Quantitative in-line monitoring of solvent-mediated polymorphic transformation of sulfamerazine by near-infrared spectroscopy.

The in-line monitoring of pharmaceutical processes with high risk, such as crystallization, has been one of the most popular research topics in recent years. Sulfamerazine (SMZ), a well-known sulfonamide antibacterial agent was investigated to examine the mechanism of polymorphic conversion by solvent-mediated polymorphic transformation (SMPT). The primary purpose of this study is to monitor the polymorphic transformation through in-line near-infrared (NIR) measurements and concurrently interpret the whole process quantitatively with off-line characterizations. Samples taken at every hour during SMPT were analyzed by X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). NIR spectra in the range of 7500-4900 cm(-1) were taken into account for multivariate analysis, which included partial least square (PLS) regression and principal component analysis (PCA). In brief, the form II content was estimated very accurately and reproducibly during the SMPT process not only by XRD but also by the DSC measurements. In addition, the form II content values were predicted very accurately by separate experiments at two designated time points. In a separate study, it was demonstrated that PCA could be employed to explain a complicated process such as SMPT mechanistically by several stages.

Polymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process.

The reliable in-line monitoring of pharmaceutical processes has been regarded as a key tool toward the full implementation of process analytical technology. In this study, near-infrared (NIR) spectroscopy was examined for use as an in-line monitoring method of the paracetamol cooling crystallization process. The drug powder was dissolved in ethanol-based cosolvent at 60°C and was cooled by 1°C/min for crystallization. NIR spectra acquired by in-line measurement were interpreted by principal component analysis combined with off-line characterizations via X-ray diffraction, optical microscopy, and transmission electron microscopy. The whole crystallization process appeared to take place in three steps. A metastable form II polymorph of paracetamol was formed and transformed into the stable form I polymorph on the way to the growth of pure form I by cooling crystallization. These observations are consistent with a previous focused beam reflectance method-based study (Barthe et al., Cryst Growth Des 8:3316-3322, 2008).

In line NIR quantification of film thickness on pharmaceutical pellets during a fluid bed coating process.

Along with the risk-based approach, process analytical technology (PAT) has emerged as one of the key elements to fully implement QbD (quality-by-design). Near-infrared (NIR) spectroscopy has been extensively applied as an in-line/on-line analytical tool in biomedical and chemical industries. In this study, the film thickness on pharmaceutical pellets was examined for quantification using in-line NIR spectroscopy during a fluid-bed coating process. A precise monitoring of coating thickness and its prediction with a suitable control strategy is crucial to the quality assurance of solid dosage forms including dissolution characteristics. Pellets of a test formulation were manufactured and coated in a fluid-bed by spraying a hydroxypropyl methylcellulose (HPMC) coating solution. NIR spectra were acquired via a fiber-optic probe during the coating process, followed by multivariate analysis utilizing partial least squares (PLS) calibration models. The actual coating thickness of pellets was measured by two separate methods, confocal laser scanning microscopy (CLSM) and laser diffraction particle size analysis (LD-PSA). Both characterization methods gave superb correlation results, and all determination coefficient (R(2)) values exceeded 0.995. In addition, a prediction coating experiment for 70min demonstrated that the end-point can be accurately designated via NIR in-line monitoring with appropriate calibration models. In conclusion, our approach combining in-line NIR monitoring with CLSM and LD-PSA can be applied as an effective PAT tool for fluid-bed pellet coating processes.

Optimality models in the age of experimental evolution and genomics.

Optimality models have been used to predict evolution of many properties of organisms. They typically neglect genetic details, whether by necessity or design. This omission is a common source of criticism, and although this limitation of optimality is widely acknowledged, it has mostly been defended rather than evaluated for its impact. Experimental adaptation of model organisms provides a new arena for testing optimality models and for simultaneously integrating genetics. First, an experimental context with a well-researched organism allows dissection of the evolutionary process to identify causes of model failure--whether the model is wrong about genetics or selection. Second, optimality models provide a meaningful context for the process and mechanics of evolution, and thus may be used to elicit realistic genetic bases of adaptation--an especially useful augmentation to well-researched genetic systems. A few studies of microbes have begun to pioneer this new direction. Incompatibility between the assumed and actual genetics has been demonstrated to be the cause of model failure in some cases. More interestingly, evolution at the phenotypic level has sometimes matched prediction even though the adaptive mutations defy mechanisms established by decades of classic genetic studies. Integration of experimental evolutionary tests with genetics heralds a new wave for optimality models and their extensions that does not merely emphasize the forces driving evolution.

Pythiogeton zizaniae, a new species causing basal stalk rot of water bamboo in Taiwan.

A new species, Pythiogeton zizaniae, was isolated from diseased water bamboo (Zizania latifolia) in central Taiwan. The organism formed a colony with scanty mycelia and mycelial aggregates on rye-water bamboo medium. Special treatments were required for production of sporangia which were terminal, noncaducous and mostly ovoid. Chlamydospores were absent. The fungus was homothallic. Oogonia produced on V-8 water bamboo medium in water were mostly globose to subglobose and each was attached with a club-shaped, monoclinous antheridium by the base of the oogonium stalk. Oospores were plerotic and globose to subglobose. Py. zizaniae caused death of water bamboo suckers but did not infect seedlings of corn, rice, wheat, sorghum, cucumber, tomato, soybean or water spinach. It also did not affect cucumber and tomato fruit, carrot roots or potato tubers.