Changes in glutamate concentration, glucose metabolism, and cerebral blood flow during focal brain cooling of the epileptogenic cortex in humans.

OBJECTIVE: Recently, focal brain cooling (FBC) was proposed as a method for treating refractory epilepsy. However, the precise influence of cooling on the molecular basis of epilepsy has not been elucidated. Thus the aim of this study was to assess the effect of FBC on glutamate (Glu) concentration, cerebral blood flow (CBF), and glucose metabolism in patients with intractable epilepsy. METHODS: Nine patients underwent FBC at 15°C for 30 min prior to cortical resection (n = 6) or hippocampectomy (n = 3). Measurement of metabolites and CBF, as well as electrocorticography (ECoG), was performed. RESULTS: Epileptic discharge (ED), as observed by ECoG, disappeared in the cooling period and reappeared in the rewarming period. Glu concentrations were high during the precooling period and were reduced to 51.2% during the cooling period (p = 0.025). Glycerol levels showed a similar decrease (p = 0.028). Lactate concentration was high during the precooling period and was reduced during the cooling period (21.3% decrease; p = 0.005). Glucose and pyruvate levels were maintained throughout the procedure. Changes in CBF were parallel to those observed by ECoG. SIGNIFICANCE: FBC reduced EDs and concentrations of Glu and glycerol. This demonstrates the neuroprotective effect of FBC. Our findings confirm that FBC is a reasonable and optimal treatment option for patients with intractable epilepsy.

Cooling of the epileptic focus suppresses seizures with minimal influence on neurologic functions.

PURPOSE: Focal brain cooling is effective for suppression of epileptic seizures, but it is unclear if seizures can be suppressed without a substantial influence on normal neurologic function. To address the issue, a thermoelectrically driven cooling system was developed and applied in free-moving rat models of focal seizure and epilepsy. METHODS: Focal seizures limited to the unilateral forelimb were induced by local application of a penicillin G solution or cobalt powder to the unilateral sensorimotor cortex. A proportional integration and differentiation (PID)-controlled, thermoelectrically driven cooling device (weight of 11 g) and bipolar electrodes were chronically implanted on the eloquent area (on the epileptic focus) and the effects of cooling (20, 15, and 10°C) on electrocorticography, seizure frequency, and neurologic changes were investigated. KEY FINDINGS: Cooling was associated with a distinct reduction of the epileptic discharges. In both models, cooling of epileptic foci significantly improved both seizure frequency and neurologic functions from 20°C down to 15°C. Cooling to 10°C also suppressed seizures, but with no further improvement in neurologic function. Subsequent investigation of sensorimotor function revealed significant deterioration in foot-fault tests and the receptive field size at 15°C. SIGNIFICANCE: Despite the beneficial effects in ictal rats, sensorimotor functions deteriorated at 15°C, thereby suggesting a lower limit for the therapeutic temperature. These results provide important evidence of a therapeutic effect of temperatures from 20 to 15°C using an implantable, hypothermal device for focal epilepsy.

Safety and efficacy of uninterrupted treatment with edoxaban or warfarin during the peri-procedural period of catheter ablation for atrial fibrillation.

BACKGROUND: The real-world safety and efficacy of uninterrupted anticoagulation treatment with edoxaban (EDX) or warfarin (WFR) during the peri-procedural period of catheter ablation (CA) for atrial fibrillation (AF) are yet to be investigated. METHODS: We conducted a two-center experience, observational study to retrospectively investigate consecutive patients who underwent CA for AF and received EDX or WFR. We examined the incidence of thromboembolic and bleeding complications during the peri-procedural period. RESULTS: The EDX and WFR groups included 153 and 103 patients, respectively (total: 256 patients). Demise or thromboembolic events did not occur in either of the groups. The incidence of major bleeding in the EDX and WFR groups was 0.7% and 2.9%, respectively. The total incidence of major/minor bleeding in the EDX and WFR groups was 7.8% and 8.7%, respectively. Of note, the incidence of bleeding complications in the uninterrupted WFR strategy group was markedly high in patients with an estimated glomerular filtration rate (eGFR) <30 (75%) or a HAS-BLED score ≥3 (60%). Patients with eGFR ≥30 and a HAS-BLED score ≤2 had a lower incidence of bleeding (<10%), regardless of the administered anticoagulation drug (EDX or WFR). CONCLUSIONS: This study confirmed the safety and efficacy of uninterrupted anticoagulation therapy using EDX or WFR in real-world patients undergoing CA for AF. Patients with severely impaired renal function and/or a higher bleeding risk during uninterrupted therapy with WFR were at a prominent risk of bleeding. Therefore, particular attention should be paid in the treatment of these patients.

Remote Management of Pacemaker Patients With Biennial In-Clinic Evaluation: Continuous Home Monitoring in the Japanese At-Home Study: A Randomized Clinical Trial.

BACKGROUND: Current expert consensus recommends remote monitoring for cardiac implantable electronic devices, with at least annual in-office follow-up. We studied safety and resource consumption of exclusive remote follow-up (RFU) in pacemaker patients for 2 years. METHODS: In Japan, consecutive pacemaker patients committed to remote monitoring were randomized to either RFU or conventional in-office follow-up (conventional follow-up) at twice yearly intervals. RFU patients were only seen if indicated by remote monitoring. All returned to hospital after 2 years. The primary end point was a composite of death, stroke, or cardiovascular events requiring surgery, and the primary hypothesis was noninferiority with 5% margin. RESULTS: Of 1274 randomized patients (50.4% female, age 77±10 years), 558 (RFU) and 550 (Conventional follow-up) patients reached either the primary end point or 24 months follow-up. The primary end point occurred in 10.9% and 11.8%, respectively (P=0.0012 for noninferiority). The median (interquartile range) number of in-office follow-ups was 0.50 (0.50-0.63) in RFU and 2.01 (1.93-2.05) in conventional follow-up per patient-year (P<0.001). Insurance claims for follow-ups and directly related diagnostic procedures were 18 800 Yen (16 500-20 700 Yen) in RFU and 21 400 Yen (16 700-25 900 Yen) in conventional follow-up (P<0.001). Only 1.4% of remote follow-ups triggered an unscheduled in-office follow-up, and only 1.5% of scheduled in-office follow-ups were considered actionable. CONCLUSIONS: Replacing periodic in-office follow-ups with remote follow-ups for 2 years in pacemaker patients committed to remote monitoring does not increase the occurrence of major cardiovascular events and reduces resource consumption. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01523704.

A microfluidic dual capillary probe to collect messenger RNA from adherent cells and spheroids.

Collection of bioanalytes from single cells is still a challenging technology despite the recent progress in many integrated microfluidic devices. A microfluidic dual capillary probe was prepared from a theta (theta)-shaped glass capillary to analyze messenger RNA (mRNA) from adherent cells and spheroids. The cell lysis buffer solution was introduced from the injection aperture, and the cell-lysed solution from the aspiration aperture was collected for further mRNA analysis based on reverse transcription real-time PCR. The cell lysis buffer can be introduced at any targeted cells and never spilled out of the targeted area by using the microfluidic dual capillary probe because laminar flow was locally formed near the probe under the optimized injection/aspiration flow rates. This method realizes the sensitivity of mRNA at the single cell level and the identification of the cell types on the basis of the relative gene expression profiles.

Radiation exposure to patients' skin during cardiac resynchronization therapy.

AIMS: The purpose of the current study is to evaluate the patients' entrance skin dose (ESD) during cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Entrance skin doses were assessed during 16 CRT procedures. Seven of the 16 patients were upgrade of conventional pacemaker to CRT. The patients wore jackets which had 100 radiosensitive indicators placed on the back during the procedures. After the procedure, the patients' ESDs were calculated from the colour difference of the indicators. Eleven of the 16 patients were implanted devices with a defibrillator, and three patients those without a defibrillator. In the other two, the procedures failed. The average total fluoroscopic time (TFT), total numbers of cine frames, and the maximum ESDs were 56.7 +/- 28.0 min, 674 +/- 342 frames, and 1.0 +/- 0.6 Gy, respectively. Of the 16 patients, six received ESDs exceeding 1 Gy, TFT, total number of cine frames, and the maximum ESD tended to decrease as the operator experience increased. CONCLUSION: The patients' ESDs during CRT procedures can exceed the thresholds for radiation skin injuries due to prolonged fluoroscopic times. Therefore, interventionalists should estimate the doses.

Relationship between decrease in ambulatory blood pressure and heart rate variability due to the effects of taking olmesartan medoxomil.

UNLABELLED: BACKGROUNDS AND METHODS: A higher degree of clinical efficacy with olmesartan compared with other angiotensin receptor blockers, has been reported by several sources. In this study of 31 examples of cases of essential hypertension, Holter electrocardiogram, ambulatory blood pressure monitoring and pulse wave velocity (PWV) measurements were performed before and after substituting olmesartan 20 mg for candesartan 8 mg antihypertensive drug therapy. RESULTS: Following the therapeutic change, daily average systolic and diastolic blood pressures were decreased by 6.7 +/- 9.3 mmHg and 3.6 +/- 8.3 mmHg, respectively, with olmesartan 20 mg; PWV was also significantly decreased. Holter electrocardiogram heart rate variability spectral analysis demonstrated that none of the very low frequency (VLF), high frequency (HF) and low frequency (LF)/HF components were significantly altered. However, a significant correlation was observed between the LF/HF component and blood pressure difference, when blood pressure and heart rate variability components in each individual case were studied. CONCLUSION: This study shows that olmesartan has a stronger antihypertensive effect in comparison to candesartan, and does not generate reflex sympathoexcitatory activity.

A Palm-Sized Cryoprobe System With a Built-In Thermocouple and Its Application in an Animal Model of Epilepsy.

OBJECTIVE: The purpose of this study is to propose a palm-sized cryoprobe system with a built-in thermocouple (TC) for highly accurate and sensitive temperature measurements, and to verify the effectiveness of the system. METHODS: Conventional cryoprobe systems based on the boiling effect of a refrigerant have triple coaxial tubes. In the proposed system, the outer and middle coaxial tubes are made of two different metals that are welded only at the probe tip, thereby forming a TC. The thermoelectric properties of the built-in TC and measurement accuracy were investigated in agar in a constant-temperature chamber. The system was also applied in a penicillin G-induced rat brain epilepsy model. RESULTS: We verified that the built-in TC has appropriate thermoelectric properties and that the system more accurately and sensitively measured transient temperature changes at the probe tip wall compared to conventional systems, showing the cooling performance of the system. In the rat model, epileptiform activities disappeared on freezing, and reliable cell necrosis was achieved at an end temperature of -45.2 ± 1.6 °C. CONCLUSIONS: The proposed system is suitable for reliable cryosurgery. SIGNIFICANCE: The system is probably to be valuable for clarifying the relationship between freezing temperature and cell necrosis in vivo.

High-speed microparticle isolation unlimited by Poisson statistics.

High-speed isolation of microparticles (e.g., microplastics, heavy metal particles, microbes, cells) from heterogeneous populations is the key element of high-throughput sorting instruments for chemical, biological, industrial and medical applications. Unfortunately, the performance of continuous microparticle isolation or so-called sorting is fundamentally limited by the trade-off between throughput, purity, and yield. For example, at a given throughput, high-purity sorting needs to sacrifice yield, or vice versa. This is due to Poisson statistics of events (i.e., microparticles, microparticle clusters, microparticle debris) in which the interval between successive events is stochastic and can be very short. Here we demonstrate an on-chip microparticle sorter with an ultrashort switching window in both time (10 µs) and space (10 µm) at a high flow speed of 1 m s-1, thereby overcoming the Poisson trade-off. This is made possible by using femtosecond laser pulses that can produce highly localized transient cavitation bubbles in a microchannel to kick target microparticles from an acoustically focused, densely aligned, bumper-to-bumper stream of microparticles. Our method is important for rare-microparticle sorting applications where both high purity and high yield are required to avoid missing rare microparticles.

Detailed spectral profile analysis of electrocorticograms during freezing against penicillin-induced epileptiform discharges in the anesthetized rat.

OBJECTIVES: Cryosurgery is an alternative technique for minimally invasive treatment of lesions. We have recently examined cryosurgery for epilepsy in animal models, and found that penicillin G (PG)-induced epileptiform discharges (EDs) mostly vanished after freezing. However, EDs were provoked again after insufficient freezing. Inadequate freezing is not visually detectable during and just after freezing and is not predictable beforehand. To manage this problem, we examined whether intraoperative monitoring of electrocorticograms (ECoGs) can predict recurrence of EDs after cryosurgery. METHODS: A palm-sized cryoprobe system was applied to focal seizures in a Wistar rat model in which EDs were induced in advance by intracerebral injection of PG. During stable induction of EDs, the cryoprobe was carefully inserted into the epileptic region and this region was immediately frozen. After the series of prefreezing, freezing, and postfreezing, rats in which PG-induced EDs relapsed within 3 h were defined as the ED-relapsed (EDR) group, and other rats were defined as the ED-vanished (EDV) group. Time-frequency analysis was conducted on the ECoGs in each group through each freezing series. RESULTS: Relapse of PG-induced EDs on ECoG after the freezing series was associated with the remaining power of the delta band in the freezing period more strongly in the EDR group than in the EDV group. CONCLUSIONS: Success or failure of the freezing procedure can be predicted by the specificity of the delta band of the ECoG obtained intraoperatively.

Epidural focal brain cooling abolishes neocortical seizures in cats and non-human primates.

Focal brain cooling (FBC) is under investigation in preclinical trials of intractable epilepsy (IE), including status epilepticus (SE). This method has been studied in rodents as a possible treatment for epileptic disorders, but more evidence from large animal studies is required. To provide evidence that FBC is a safe and effective therapy for IE, we investigated if FBC using a titanium cooling plate can reduce or terminate focal neocortical seizures without having a significant impact on brain tissue. Two cats and two macaque monkeys were chronically implanted with an epidural FBC device over the somatosensory and motor cortex. Penicillin G was delivered via the intracranial cannula for induction of local seizures. Repetitive FBC was performed using a cooling device implanted for a medium-term period (FBC for 30min at least twice every week; 3 months total) in three of the four animals. The animals exhibited seizures with repetitive epileptiform discharges (EDs) after administration of penicillin G, and these discharges decreased at less than 20°C cooling with no adverse histological effects. The results of this study suggest that epidural FBC is a safe and effective potential treatment for IE and SE.

The Self-Organizing Relationship (SOR) network employing fuzzy inference based heuristic evaluation.

When human beings acquire a new skill, this usually is accomplished by the summarization of numerous experiences based on their own evaluation criteria. Usually these experiences are obtained by trial and error. The criteria for success and failure are based on our own knowledge or advice given by others. The Self-Organizing Relationship (SOR) network has been inspired by this process and has been proposed to emulate this process computationally. In the previous applications of the SOR network for controller design, the evaluation criteria have been assigned by using mathematical expressions. Generally, however, mathematical expressions of the evaluation criteria become difficult as the complexity of a target system increases. On the other hand, human beings can contrive to express their knowledge for evaluation by using heuristic expressions, although a target system is complicated. In this study, we employ fuzzy inference in order to realize heuristic expressions of the evaluation criteria.

Iron-catalyzed directed C2-alkylation and alkenylation of indole with vinylarenes and alkynes.

An iron-N-heterocyclic carbene catalyst generated from an iron(III) salt, an imidazolinium salt, and a Grignard reagent promotes alkylation and alkenylation reactions at the indole C2-position with vinylarenes and internal alkynes, respectively, via imine-directed C-H activation. The former reaction affords 1,1-diarylalkane derivatives with exclusive regioselectivity. Deuterium-labeling experiments suggest that these reactions involve oxidative addition of the C-H bond to the iron center, insertion of the unsaturated bond into the Fe-H bond, and C-C reductive elimination.

The Palm-Sized Cryoprobe System Based on Refrigerant Expansion and Boiling and Its Application to an Animal Model of Epilepsy.

GOAL: The purpose of this study is to propose the palm-sized cryoprobe system based on a new concept and to suggest that the freezing technique could be used for treatment of epilepsy. METHODS: We propose herein a cryoprobe system based on the boiling effect that uses a specific refrigerants with a boiling point higher than that of liquid nitrogen yet low enough to result in cell necrosis. To evaluate and verify the effectiveness of the proposed system, cooling characteristics are investigated in agar. In addition, the system is applied to a Wistar rat brain-model, in which the epileptic activities are induced in advance by a potent epileptogenic substance. RESULTS: The design concept yielded the following benefits: 1) the selected refrigerant promotes sealing in the tank; 2) the tank can be made as compact as possible, limited only by the volume required for the refrigerant; 3) because the tank and probe units can be separated by a nonconducting, flexible, and high-pressure tube, the tank unit can be manipulated without disturbing the probe tip with mechanical vibrations and electrical noise. Although the agar experiments, we verified that the proposed system can uniquely and reproducibly create an ice ball. Moreover, in the rat experiments in vivo, it was confirmed that penicillin G-induced epileptic activities disappeared on freezing with the proposed system. CONCLUSIONS: The palm-sized system has desired characteristics and can apply for an animal model of epilepsy. SIGNIFICANCE: Results of in vivo experiments suggest that cryosurgery may be an effective treatment for epilepsy.

Alkene isomerization-hydroarylation tandem catalysis: indole C2-alkylation with aryl-substituted alkenes leading to 1,1-diarylalkanes.

A cobalt-N-heterocyclic carbene catalyst generated from CoBr2 , imidazolium salt, and cyclohexylmagnesium bromide was found to promote the imine-directed C2-alkylation of indoles with nonconjugated arylalkenes through a tandem alkene isomerization-hydroarylation process, affording 1,1-diarylalkanes with exclusive regioselectivity. The feasibility of the tandem catalysis was demonstrated for allyl-, homoallyl-, and bishomoallylbenzene derivatives. The catalytic system is also applicable to a variety of ß-substituted styrene derivatives. Mechanistic experiments using deuterium-labeled indole substrate and Grignard reagent provided insight into the cobalt-mediated C-H activation step, which likely involves exchange of the C2-hydrogen atom of the former and the ß-hydrogen atoms of the latter.

Annulation of α,ß-unsaturated imines and alkynes via cobalt-catalyzed olefinic C-H activation.

A cobalt-triarylphosphine catalyst promotes an annulation reaction of an α,ß-unsaturated imine and an internal alkyne to afford a polysubstituted dihydropyridine derivative in good yield under mild conditions. The reaction likely involves alkenylation of the olefinic C-H bond via cobalt-mediated nitrogen-assisted C-H activation followed by facile 6π electrocyclization of the resulting azatriene intermediate.

Penicillin-induced epileptiform activity elevates focal brain temperature in anesthetized rats.

To elucidate a relationship between changes in focal brain temperature and severity of abnormal brain activity, epileptiform discharges and behavioral seizures were induced by Penicillin G in anesthetized rats, and focal brain-temperature was measured. Penicillin G was injected into the right primary sensorimotor cortex (400IU/µl). After the injection, epileptiform discharges induced a temperature increase gradually by 0.65±0.24°C. Moreover, when behavioral seizures were induced by reducing the anesthesia level, the temperature was raised by 0.26±0.22°C. These results suggest that elevation of the focal brain temperature is associated with the severity of epileptic activity.

Neuroprotective effects of focal brain cooling on photochemically-induced cerebral infarction in rats: analysis from a neurophysiological perspective.

Although systemic hypothermia provides favorable outcomes in stroke patients, it has only been adopted in a limited number of patients because of fatal complications. To resolve these issues, focal brain cooling (FBC) has recently drawn attention as a less-invasive treatment for brain injuries. Therefore, we investigated whether FBC has a favorable effect on focal cerebral ischemia (FCI). Male-adult-Wistar rats were used. Under general anesthesia, a small burr hole was made and FCI was induced in the primary sensorimotor area (SI-MI) using photothrombosis. An additional craniotomy was made over the SI-MI and FBC was performed at a temperature of 15°C for 5h. Electrocorticograms (ECoG) were recorded on the border cortex of the ischemic focus. Thereafter, rats were sacrificed and the infarct area was measured. In another experiment, rats were allowed to recover for 5 days after cooling and neurobehavioral function was evaluated. FBC suppressed all ECoG frequency bands during and after cooling (p<0.05), except for the delta frequency band in the precooling versus rewarming periods. The injured areas in the cooling and non-cooling groups were 0.99±0.30 and 1.71±0.54 mm(2), respectively (p<0.03). The grip strength at 2 days after surgery was preserved in the cooling group (p<0.05). We report the novel finding that epileptiform discharges were suppressed in the ischemic border, the infarct area was reduced and neurobehaviour was preserved by FBC. These results indicate that FBC is neuroprotective in the ischemic brain and has demonstrated therapeutic potential for cerebral infarction.

Investigating oral health-related quality of life and self-perceived satisfaction with partial dentures.

AIM: To investigate the prevalence and severity of oral health-related quality of life in patients treated with removable partial dentures at a publicly-funded dental hospital. The association between patients' demographic profiles, denture-related, variables and oral health-related quality of life was also investigated. METHODS: A questionnaire was designed to investigate the use and satisfaction of removable partial dentures, and oral health-related quality of life of removable partial denture wearers using the Oral Health Impact Profile-14. The questionnaire was administered to 740 randomly-selected patients who received removable partial dentures during 2005-2008. The response rate was 31.35%. Non-parametric tests and a logistic regression model were used to analyze the association between denture-related variables and oral health-related quality of life. A question on symptoms unrelated to dentures was also analyzed. RESULTS: The Oral Health Impact Profile-14 prevalence calculated was 43.1%. The removable partial denture experience and frequency of use was inversely associated with Oral Health Impact Profile-14 scores. Metal-based removable partial dentures were associated with lower Oral Health Impact Profile prevalence and severity scores. No significant association was found between demographic profile, circumstance for provision of removable partial dentures and Oral Health Impact Profile-14 score. CONCLUSION: The participants of this study indicated that perceived denture performance, removable partial dentures material, experience, and frequency of use are associated with oral health-related quality of life.