Probiotic Lactobacillus spp. improves Drosophila memory by increasing lactate dehydrogenase levels in the brain mushroom body neurons.

Probiotics are live microorganisms that offer potential benefits to their hosts and can occasionally influence behavioral responses. However, the detailed mechanisms by which probiotics affect the behavior of their hosts and the underlying biogenic effects remain unclear. Lactic acid bacteria, specifically Lactobacillus spp. are known probiotics. Drosophila melanogaster, commonly known as the fruit fly, is a well-established model organism for investigating the interaction between the host and gut microbiota in translational research. Herein, we showed that 5-day administration of Lactobacillus acidophilus (termed GMNL-185) or Lacticaseibacillus rhamnosus (termed GMNL-680) enhances olfactory-associative memory in Drosophila. Moreover, a combined diet of GMNL-185 and GMNL-680 demonstrated synergistic effects on memory functions. Live brain imaging revealed a significant increase in calcium responses to the training odor in the mushroom body ß and γ lobes of flies that underwent mixed feeding with GMNL-185 and GMNL-680. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and whole-mount brain immunohistochemistry revealed significant upregulation of lactate dehydrogenase (LDH) expression in the fly brain following the mixed feeding. Notably, the genetic knockdown of Ldh in neurons, specifically in mushroom body, ameliorated the beneficial effects of mixed feeding with GMNL-185 and GMNL-680 on memory improvement. Altogether, our results demonstrate that supplementation with L. acidophilus and L. rhamnosus enhances memory functions in flies by increasing brain LDH levels.

Thrombolysis induced by intravenous administration of plasminogen activator in magnetoliposomes: dual targeting by magnetic and thermal manipulation.

In previously published studies, intra-arterial (i.a.), but not intravenous (i.v.) delivery of recombinant tissue-type plasminogen activator (rtPA) immobilized on the surface of magnetic nanoparticles induces thrombolysis by magnetic targeting. We asked whether i.v. delivery of protected rtPA in a thermosensitive magnetoliposome (TML@rtPA) may achieve target thrombolysis. PEGylated TML@rtPA was optimized and characterized; controlled release of rtPA was achieved by thermodynamic and magnetic manipulation in vitro. The lysis index of TML@rtPA incubated with blood at 43 °C vs. 37 °C was 53 ±â€¯11% vs. 81 ±â€¯3% in thromboelastograms, suggesting thermosensitive thrombolysis of TML@rtPA. In a rat embolic model with superfusion of 43 °C saline on a focal spot on the iliac artery with clot lodging, release of rtPA equivalent to 20% regular dose from TML@rtPA administered i.a. vs. i.v. significantly restored iliac blood flow 15 vs. 55 min after clot lodging, respectively. TML@rtPA with magnetic guiding and focal hyperthermia may be potentially amendable to target thrombolysis.

Electrical cortical stimulation for refractory focal epilepsy: A long-term follow-up study.

OBJECTIVE: To report the long-term seizure control and safety of open-loop electrical cortical stimulation in patients with refractory focal epilepsy of diverse etiologies. METHODS: Six patients who received a therapeutic trial of cortical stimulation were included retrospectively. The frequency of seizures was recorded before and after implantation. Surgical procedure- and stimulation-related adverse effects were also recorded. RESULTS: The mean reductions in seizures were 61% at 1 year, 68% at 2 years, and 80% at 3-7 years post-implantation. The median follow-up time was 54 months (range 36-156 months). The etiologies of epilepsy included polymicrogyria in two patients, post-traumatic in one patient, and periventricular heterotopia, post-encephalitis, and familial lateral temporal lobe epilepsy in the remaining three patients. Status epilepticus stopped immediately after stimulation in three patients with focal status epilepticus or epilepsia partialis continua at baseline, with a long-term reduction in seizures of more than 90% and improvements in conscious level. Tissue incompatibility with the connection wire was noted in one patient, which subsided after the system was removed. CONCLUSIONS: Open-loop cortical stimulation of epileptic foci improved seizure control in our patients with refractory focal epilepsy of diverse etiologies. Electrical cortical stimulation stopped epilepsia partialis continua/focal status epilepticus immediately after the intervention and exhibited a sustained effect in reducing seizures. No procedure-related complications were observed. Further case cohort studies are needed to clarify which patients respond to open-loop cortical stimulation.

Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians.

OBJECTIVE: To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in Asian populations (Chinese and Thai). METHODS: We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)-induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database. RESULTS: We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10-10; odds ratio 27.90; 95% confidence interval [CI] 7.84-99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077-0.584). CONCLUSIONS: Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.

Duration of electroencephalographic recordings in patients with epilepsy.

PURPOSE: Previous studies have demonstrated different diagnostic yields with electroencephalography (EEG). Due to the small sample sizes or different patient populations (outpatients or inpatients only) in these previous studies, the clinical use of routine EEG and outpatient/inpatient video-EEG monitoring (VEM) needs further clarification. In this study, we investigated EEGs obtained from patients referred by epileptologists; by comparing the results of different EEG methods, we sought to determine the optimal durations and specific types of EEG recordings for different clinical situations. METHODS: The data from 335 routine EEGs, 281 3 h outpatient VEMs, and 247 inpatient VEMs (>48 h) were reviewed. We analyzed the latency to the first epileptiform discharge or clinical event. RESULTS: In patients undergoing outpatient VEMs, 48% of the first epileptiform discharges appeared within 20 min, and 64% appeared within 30 min. In patients undergoing inpatient VEMs, 21.2% had their first attack within 3h. The second peak of event occurrence was during the 33rd-36th h. Only 3.5% of the seizures were recorded after 57 h. The detection rate of epileptiform discharges was higher for 3h outpatient VEM than for routine EEG (54.1% versus 16.4%, p<0.01). Epileptic and/or nonepileptic events were recorded in 45.8% of the inpatient VEMs, the diagnostic yield of which was higher than for outpatient VEMs (p<0.01). Since the patients in this study had been selected to limit the bias between each group, the diagnostic yield of EEGs in this study are likely to have been higher than those found in routine practice. Patients with generalized epilepsy had a shorter latency to the first epileptiform discharge compared to patients with localization-related epilepsy (mean, 22.1 min versus 33.9 min, p<0.05). CONCLUSIONS: Two-thirds of epileptiform discharges were detected within 30 min of VEM. A 30-min recording is recommended for routine EEG examinations that aim to detect epileptiform discharges. A 3h outpatient VEM is a reasonable option when a routine EEG fails to detect epileptiform discharges. The latency to the first epileptiform discharge was shorter in patients with generalized epilepsy than in patients with localization-related epilepsy. 48 h of inpatient VEM might be adequate for detecting the target events.

Significant thalamocortical coherence of sleep spindle, theta, delta, and slow oscillations in NREM sleep: recordings from the human thalamus.

The electrophysiological studies of thalamocortical oscillations were mostly done in animal models. Placement of stimulation electrodes at the anterior nucleus of the thalamus (ANT) for seizure reduction enables the study of the thalamocortical interplay in human subjects. Nocturnal sleep electroencephalograms (EEGs) and local field potentials (LFPs) of the left and right thalamus (LT, RT) were recorded in three subjects receiving ANT stimulation. Sleep stages were scored according to American Academy of Sleep Medicine criteria. The whole-night time-frequency coherence maps between EEG (C3, C4) and LFP (LT, RT) showed specific coherence patterns during non-rapid eye movement (NREM) sleep. Pooled coherence in the NREM stage was significant in slow, delta, theta and spindle frequency ranges. The spindle oscillations had the highest coherence (0.17-0.58) in the homolateral hemisphere. Together, these observations indicate that the oscillations were related to thalamocortical circuitry.

Long-term anterior thalamus stimulation for intractable epilepsy.

BACKGROUND: Deep brain stimulation (DBS) has re-emerged as an alternative therapy for intractable epilepsy. In this study, we investigated the feasibility, efficacy and safety of long-term anterior thalamic nucleus (ATN) stimulation for intractable epilepsy. METHODS: In this open-label pilot study of electrical stimulation of the ATN, we investigated four cases of intractable epilepsy (one man with generalized seizure, and three woman with partial seizure and secondary generalization; age range, 18-45 years), with a follow up of 2 years. Under the indication of bilateral or nonlocalized epileptic foci, each patient underwent stereotactic implantation of a quadripolar stimulating electrode in the bilateral ATN, guided by single-unit microelectrode recording. The stimulator was turned on after a sham period of 2-4 weeks. Seizure frequency was monitored and compared with the pre-implantation baseline. Twenty-one similar cases reported in the literature during the past 20 years were reviewed. RESULTS: Insertion into and stimulation through electrodes implanted in the ATN decreased seizure frequency, with a mean reduction rate of 49.6% in the current series. Two patients had seizure reductions of > or = 60%, with complete remission achieved in one patient. These findings were consistent with those in four other investigations of intractable epilepsy, which showed an overall rate of 45-55% in seizure reduction. One of our patients suffered a small frontal hemorrhage, and a second patient had extension erosion over the scalp; however, no resultant major or permanent neurological deficits were observed. CONCLUSIONS: Based on our study results and literature review, it appears reasonable to conclude that long-term ATN stimulation is a safe and effective treatment for seizure reduction in patients with intractable epilepsy.

Pallidotomy effect on the cortical excitability in patients with severe Parkinson's disease.

Surgical lesions in the medial pallidum have been shown to ameliorate motor deficits in patients with Parkinson's disease (PD). It is believed that interruption of the pallidothalamocortical projections to the motor cortex is required for the satisfactory results. In this report, we adopt cortico-cortical inhibition as the tool to assess the pallidotomy effect on cortical excitability in PD. Interstimulus interval between 1 and 15 msec were investigated. The average peak-to-peak amplitude was measured and calculated at each delay. A total of 8 patients (M:F = 4:4) 54.9 years of age (SD = 9.6) and 10 controls were recruited for the study. In the controls, the inhibitory phenomenon was observed from the 1-msec to the 4-msec delay points and the maximal inhibition was at the 3-msec delay point (33.69% +/- 6.50% of the control response). Mild facilitation was noticed since the 5-msec delay point and thereafter. In patients before operation, a similar trend of inhibition was also observed in the initial 4 msec with the maximal inhibition also at the 3-msec delay point (64.66 +/- 6.77% of the control response). In the postoperative group, the short interstimulus interval inhibition can no longer be observed and the conditioned response was 95.06 +/- 23.68% of the control at the 3-msec delay point. The suppression was gone at and after the 7-msec delay point. Results of repeated-measures analysis of variance show a significant difference among the controls and PD patients before and 3 months after pallidotomy (F = 3.40, P = 0.05). Post hoc examination revealed a significant difference between the controls and PD patients 3 months after pallidotomy at the 3-msec delay point (P = 0.004). However, no correlation was observed between the 3-msec inhibition and the Unified Parkinson's Disease Rating Scale Motor score or the dyskinesia score. The results suggest that pallidotomy can modulate the cortical inhibitory circuitry in patients with PD.

Short-term effect of bilateral subthalamic stimulation for advanced Parkinson's disease.

BACKGROUND: Subthalamic nucleus (STN) hyperactivity is a pathophysiological phenomenon of Parkinson's disease (PD). Inhibition of this hyperactivity by chronic deep brain stimulation (DBS) can possibly reset the aberrant function of the cortico-striato-thalamal circuit and improve the parkinsonian symptoms. DBS was introduced as a safe and alternative way of performing functional stereotaxic surgery for treating PD. METHODS: Seven advanced PD patients with complicated motor fluctuations and dyskinesia were enrolled in the study. A quadripolar electrode was bilaterally installed in the STN. Patients were evaluated before and 6 months after implantation using a battery of clinical assessments, including the motor score of the unified Parkinson's disease rating scale (UPDRS), modified Hoehn and Yahr (HY) staging, and the Schwab and England activities of daily living scale (SEADL). Preoperative baseline evaluations included both "off-medication" periods and "on-medication" periods, while postoperative evaluations included a cross-over of the above 2 periods with and without DBS. RESULTS: The motor disability, HY staging, and SEADL all significantly improved in both the off- and on-medication periods 6 months after STN DBS. Compared to the baseline off-medication score, a significant improvement was found in the UPDRS motor and other subscores including tremors, rigidity, and bradykinesia. The SEADL score showed a great improvement of 205.6%. Ballism/chorea, mood changes, and blepharospasm may have been induced by DBS. Neither serious nor permanent side effects appeared. CONCLUSIONS: Bilateral STN DBS improved the motor symptoms in advanced PD patients in both the off- and on-medication periods. They showed improvements not only in motor disabilities of tremors, rigidity, bradykinesia, and postural and gait instability, but also in levodopa-related dyskinesia and psychosis.