Does response to vagus nerve stimulation for drug-resistant epilepsy differ in patients with and without Lennox–Gastaut syndrome?

Introduction: Literature on outcomes of patients with Lennox–Gastaut syndrome (LGS) receiving adjunctive vagus nerve stimulation (VNS) lacks information on seizure types and the time course of therapeutic effects. We have therefore performed what is to our knowledge the largest and most in-depth analysis of the effectiveness of VNS in LGS patients paying special attention to the impact of VNS Therapy on individual seizure types. Methods: The VNS Therapy Outcomes Registry includes over 7000 patients. A propensity score matching method was employed to match patients with LGS to non-LGS patients with drug-resistant epilepsy (DRE). Overall seizure frequencies were assessed prior to implantation and at 3-, 6-, 12-, 18-, and 24-month follow-ups to derive the main study outcomes: response rates and time to first response.Results: A total of 564 LGS patients with sufficient data were identified in the registry and matched 2:1 to 1128 non-LGS patients. Responder rates at 24 months were 57.5% in the LGS group and 61.5% in the non-LGS group. Median seizure frequency reduction at 24 months was 64.3% versus 66.7% in the LGS versus non-LGS group, respectively. In both groups, VNS was most effective at reducing focal aware seizures, “other” seizures, generalized-onset non-motor seizures, and drop attacks with relative reduction rates for these seizure types at 24 months exceeding 90% in both groups. Time-to-first response did not differ between the groups; however, there was a significantly higher proportion of patients who regressed from bilateral tonic–clonic (BTC) seizure response in the LGS group versus the non-LGS group at 24 months: 22.4% versus 6.7%; p =.015. Conclusions: Although limited by its retrospective design, the study shows that the effectiveness of VNS is comparable in DRE patients with and without LGS; however, LGS patients may be more prone to fluctuating control of BTCs.</p

Вклад региональных и глобальных факторов в межгодовую изменчивость гидрометеорологических условий прибрежной зоны Черного моря

Выполнен факторный анализ рядов среднегодовых и среднепятилетних значений метеорологических и гидрологических параметров по данным измерений на береговых гидрометстанциях. Получены количественные оценки вклада глобальных и региональных факторов в межгодовую и декадную изменчивость показателей гидрометеорологического режима черноморской прибрежной зоны Украины.Виконано факторний аналіз рядів середньорічних і середньоп’ятирічних значень метеорологічних і гідрологічних величин за даними вимірювань на берегових гідрометстанціях. Отримані кількісні оцінки внеску глобальних і регіональних факторів у міжрічну та декадну мінливість показників гідрометеорологічного режиму чорноморської прибережної смуги України.Factor analysis of the time-series of annual and five-year averaged meteorological and hydrological values measured on shore hydrometeorological stations was performed. Quantitative estimations were obtained for the global and regional factors input to the interannual and decadal variability of the Ukrainian Black Sea coastal zone hydrometeorological regimen indices

Radiobiology of Radiosurgery for the Central Nervous System

According to Leksell radiosurgery is defined as &quot;the delivery of a single, high dose of irradiation to a small and critically located intracranial volume through the intact skull.&quot; Before its birth in the early 60s and its introduction in clinical therapeutic protocols in late the 80s dose application in radiation therapy of the brain for benign and malignant lesions was based on the administration of cumulative dose into a variable number of fractions. The rationale of dose fractionation is to lessen the risk of injury of normal tissue surrounding the target volume. Radiobiological studies of cell culture lines of malignant tumors and clinical experience with patients treated with conventional fractionated radiotherapy helped establishing this radiobiological principle. Radiosurgery provides a single high dose of radiation which translates into a specific toxic radiobiological response. Radiobiological investigations to study the effect of high dose focused radiation on the central nervous system began in late the 50s. It is well known currently that radiobiological principles applied for dose fractionation are not reproducible when single high dose of ionizing radiation is delivered. A review of the literature about radiobiology of radiosurgery for the central nervous system is presented

Proposed Definition of Experimental Secondary Ischemia for Mouse Subarachnoid Hemorrhage.

Inconsistency in outcome parameters for delayed cerebral ischemia (DCI) makes it difficult to compare results between mouse studies, in the same way inconsistency in outcome parameters in human studies has for long obstructed adequate comparison. The absence of an established definition may in part be responsible for the failed translational results. The present article proposes a standardized definition for DCI in experimental mouse models, which can be used as outcome measure in future animal studies. We used a consensus-building approach to propose a definition for "experimental secondary ischemia" (ESI) in experimental mouse subarachnoid hemorrhage that can be used as an outcome measure in preclinical studies. We propose that the outcome measure should be as follows: occurrence of focal neurological impairment or a general neurological impairment compared with a control group and that neurological impairment should occur secondarily following subarachnoid hemorrhage (SAH) induction compared with an initial assessment following SAH induction. ESI should not be used if the condition can be explained by general anesthesia or if other means of assessments sufficiently explain function impairment. If neurological impairment cannot reliably be evaluated, due to scientific setup. Verification of a significant secondary impairment of the cerebral perfusion compared with a control group is mandatory. This requires longitudinal examination in the same animal. The primary aim is that ESI should be distinguished from intervention-related ischemia or neurological deficits, in order establish a uniform definition for experimental SAH in mice that is in alignment with outcome measures in human studies

Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide.

Glioblastoma (GBM) is a lethal disease with limited clinical treatment options available. Recently, a new inhibitor targeting the prominent cancer signaling pathway mTOR was discovered (Rapalink-1), but its therapeutic potential on stem cell populations of GBM is unknown. We applied a collection of physiological relevant organoid-like stem cell models of GBM and studied the effect of RL1 exposure on various cellular features as well as on the expression of mTOR signaling targets and stem cell molecules. We also undertook combination treatments with this agent and clinical GBM treatments tumor treating fields (TTFields) and the standard-of-care drug temozolomide, TMZ. Low nanomolar (nM) RL1 treatment significantly reduced cell growth, proliferation, migration, and clonogenic potential of our stem cell models. It acted synergistically to reduce cell growth when applied in combination with TMZ and TTFields. We performed an in silico analysis from the molecular data of diverse patient samples to probe for a relationship between the expression of mTOR genes, and mesenchymal markers in different GBM cohorts. We supported the in silico results with correlative protein data retrieved from tumor specimens. Our study further validates mTOR signaling as a druggable target in GBM and supports RL1, representing a promising therapeutic target in brain oncology

Defining activities in neurovascular microsurgery training : entrustable professional activities for vascular neurosurgery

Background Entrustable professional activities (EPAs) represent an assessment framework with an increased focus on competency-based assessment. Originally developed and adopted for undergraduate medical education, concerns over resident ability to practice effectively after graduation have led to its implementation in residency training but yet not in vascular neurosurgery. Subjective assessment of resident or fellow performance can be problematic, and thus, we aim to define core EPAs for neurosurgical vascular training. Methods We used a nominal group technique in a multistep interaction between a team of experienced neurovascular specialists and a medical educator to identify relevant EPAs. Panel members provided feedback on the EPAs until they reached consent. Results The process produced seven core procedural EPAs for vascular residency and fellowship training, non-complex aneurysm surgery, complex aneurysm surgery, bypass surgery, arteriovenous malformation resection, spinal dural fistula surgery, perioperative management, and clinical decision-making. Conclusion These seven EPAs for vascular neurosurgical training may support and guide the neurosurgical society in the development and implementation of EPAs as an evaluation tool and incorporate entrustment decisions in their training programs.Peer reviewe

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

Abstract: Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply of macromolecular precursors by targeting enzymes involved in biosynthesis is a promising strategy in cancer therapy. Several tumors excessively metabolize glutamine to generate precursors for nonessential amino acids, nucleotides, and lipids, in a process called glutaminolysis. Here we show that pharmacological inhibition of glutaminase (GLS) eradicates glioblastoma stem-like cells (GSCs), a small cell subpopulation in glioblastoma (GBM) responsible for therapy resistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolic studies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared with neural stem cells (NSC). Moreover, our study demonstrates the usefulness of in vitro pharmaco-metabolomics to score target specificity of compounds thereby refining drug development and risk assessment

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

Abstract: Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply of macromolecular precursors by targeting enzymes involved in biosynthesis is a promising strategy in cancer therapy. Several tumors excessively metabolize glutamine to generate precursors for nonessential amino acids, nucleotides, and lipids, in a process called glutaminolysis. Here we show that pharmacological inhibition of glutaminase (GLS) eradicates glioblastoma stem-like cells (GSCs), a small cell subpopulation in glioblastoma (GBM) responsible for therapy resistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolic studies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared with neural stem cells (NSC). Moreover, our study demonstrates the usefulness of in vitro pharmaco-metabolomics to score target specificity of compounds thereby refining drug development and risk assessment

Bursts of vertex activation and epidemics in evolving networks

The dynamic nature of contact patterns creates diverse temporal structures. In particular, empirical studies have shown that contact patterns follow heterogeneous inter-event time intervals, meaning that periods of high activity are followed by long periods of inactivity. To investigate the impact of these heterogeneities in the spread of infection from a theoretical perspective, we propose a stochastic model to generate temporal networks where vertices make instantaneous contacts following heterogeneous inter-event intervals, and may leave and enter the system. We study how these properties affect the prevalence of an infection and estimate , the number of secondary infections of an infectious individual in a completely susceptible population, by modeling simulated infections (SI and SIR) that co-evolve with the network structure. We find that heterogeneous contact patterns cause earlier and larger epidemics in the SIR model in comparison to homogeneous scenarios for a vast range of parameter values, while smaller epidemics may happen in some combinations of parameters. In the case of SI and heterogeneous patterns, the epidemics develop faster in the earlier stages followed by a slowdown in the asymptotic limit. For increasing vertex turnover rates, heterogeneous patterns generally cause higher prevalence in comparison to homogeneous scenarios with the same average inter-event interval. We find that is generally higher for heterogeneous patterns, except for sufficiently large infection duration and transmission probability