Central Nervous System Activity Research Articles

Skutki hamowania funkcji PCSK9 w obrębie wybranych tkanek*

Streszczenie Konwertazy probiałkowe (PCs, proprotein convertases) to rodzina 9 proteaz serynowych (PC1/3, PC2, furyna, PC4, PC5/6, PACE4, PC7, SKI-1), której przedstawicielem jest również konwertaza probiałkowa typu 9 o aktywności subtylizyny/keksyny (PCSK9). Poszczególni członkowie tej rodziny, są głównym elementem w potranslacyjnej obróbce białek prekursorowych, prowadzącej do powstania biologicznie czynnych cząsteczek, takich jak hormony, enzymy, czynniki transkrypcyjne oraz czynniki wzrostu. W związku ze zdolnością aktywacji dużej liczby substratów, PCs odgrywają znaczącą rolę w przebiegu procesów fizjologicznych, takich jak embriogeneza, aktywność ośrodkowego układu nerwowego, metabolizm lipidów, a także w stanach patofizjologicznych m.in. infekcjach wirusowych i bakteryjnych, osteoporozie, hiperglikemii, chorobach sercowo-naczyniowych, neurodegeneracyjnych oraz nowotworowych. Zahamowanie funkcji konwertazy proproteiny typu 9 o aktywności subtylizyny/keksyny (PCSK9, proprotein convertase subtilisin/kexin 9) przez przeciwciała, takie jak alirokumab czy ewolokumab zmniejsza tempo degradacji receptora LDL (lipoproteina o małej gęstości). Wiąże się to z redukcją stężenia cholesterolu LDL w osoczu, którego normalizacja jest jednym z głównych celów służących ograniczeniu ryzyka sercowo-naczyniowego. Inhibitory PCSK9 (alirokumab, ewolokumab, bococizumab) zostały stworzone m.in. z myślą o pacjentach, u których mimo stosowania optymalnych dawek dostępnych leków hipolipemizujących (statyn, ezetymibu) nie udało się uzyskać pożądanych wartości stężeń cholesterolu LDL we krwi. Wydaje się, że ze względu na dużą skuteczność, przyszłe zastosowanie inhibitorów PCSK9 (PCSK9i) w codziennej praktyce klinicznej będzie bardziej powszechne. Uwzględniając działania plejotropowe substancji dotychczas stosowanych w hiperlipidemii, takich jak statyny, omówiono piśmiennictwo pod kątem innych, poza hipolipemizującymi, możliwych skutków działania inhibitorów PCSK9 oraz oceniono ich potencjalne zalety lub wady.

Comparative Study of Intravenous Paracetamol Infusion versus Intramuscular Tramadol as an Intrapartum Labor Analgesia

Context: Paracetamol exerts its analgesic effect by inhibiting prostaglandin synthesis in the central nervous system and peripheral action by blocking the generation of pain impulses. It has also a serotonergic (5Ht) mechanism and a cannabinoid agonist mechanism. Aims: We planned this study to compare intravenous and intramuscular tramadol as labor analgesia. Settings and Design: This prospective single-blinded randomized study was conducted in primigravida labor patients at tertiary care hospital between January 2016 and December 2018 after getting the permission of the ethical committee. Methods: Patients were randomly divided into two groups using a computer-generated random table in the Paracetamol group (Group A) and Tramadol group (Group B). Group A (60 patients) received IV PCM 1000 mg in the active phase of labor single dose over 15 min. Group B, received intramuscular tramadol hydrochloride 100 mg. Labor was monitored using partograph, pain intensity was recorded before, 1 h, and 3 h of drug administration using the Mac Gill pain intensity scale. Statistical Analysis Used: We did statistical analysis using IBM SPSS version 22.0 software. We used an independent t-test to analyze the difference in continuous dependent variables in two groups. The MacGill's pain intensity scale score was examined using repeated measures of analysis of variance for mean scores on 3 outcome measures: Before drug delivery, 1 h after drug delivery and 3 h after drug delivery. Results: Overall paracetamol was well tolerated as compared to tramadol. Patients who received paracetamol experienced fewer side effects including nausea and vomiting. The difference was statistically significant (Chi-square = 8.091; df = 2; P = 0.018). In the paracetamol group, 8 (15%) patients had nausea and 1 (2%) experienced vomiting; while in the tramadol group, 6 (11%) patients had nausea and 10 (19%) patients experienced vomiting. Conclusions: Paracetamol is safe labor analgesic as compared to intramuscular tramadol. Further studies consisting of a greater number of patients are needed to validate the results of this study.

A Phase II study of nab-Paclitaxel (nab-P) in patients with advanced non-small cell lung cancer with EGFR mutations after frontline tyrosine kinase inhibitor therapy

BackgroundPatients with metastatic non-small cell lung cancer (NSCLC) harboring a sensitizing EGFR mutation have effective targeted therapy options initially but most patients eventually progress and receive cytotoxic chemotherapy. In this single-institution phase II study, we evaluated the role of nab-paclitaxel monotherapy in this patient population. Patients and MethodsPatients with metastatic NSCLC with an activating EGFR mutation whose disease progressed after frontline tyrosine kinase inhibitor therapy and who were chemotherapy naïve received nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint was response rate per RECIST 1.1 and secondary endpoints were duration of response, progression free survival, toxicity and overall survival. ResultsA total of 27 patients were enrolled and 21 patients were evaluable for response. Median age was 65 (range 52–81), 69% of patients were women, 42% of patients did not having a smoking history. 31% of patients had central nervous system (CNS) metastatic disease at baseline. Confirmed partial response was documented in 9 of 26 patients (35%, 95% CI 17–56) and disease control rate was 58% (95% CI 35–73). CNS was a common first site of progression. Median progression free survival was 4.0 months (95% CI 1.8–5.2). No new safety signals were observed. ConclusionSingle agent nab-paclitaxel showed modest antitumor activity in patients with EGFR mutation positive NSCLC and may be an option in patients who are platinum ineligible. Patients often progressed in the CNS and the results underscores the importance of CNS activity of systemic therapies in this patient population.

Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

Allopregnanolone, a positive modulator of GABAA receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED50, 5.6 mg/kg), picrotoxin (ED50, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a Tmax of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (Cmax, 16,000 ng/mg) whereas much lower levels (Cmax, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.

Analgesia in the intensive care unit

Background. Sedation is a technique of using drugs to put a patient in a condition in which he can tolerate unpleasant procedures, while maintaining cardiorespiratory function. The main problems associated with analgesia and sedation (AS) are associated with the development of hypoxia, vomiting and aspiration, hypotension and hemodynamic instability, apnea.
 Objective. To describe the features of the modern AS.
 Materials and methods. Analysis of literature data on this issue.
 Results and discussion. AS can be performed with the help of different drugs. Benzodiazepines (preferably midazolam) and/or propofol in combination with low doses of opioids should be used in patients with concomitant cardiac abnormalities. The use of propofol in this category of patients is carried out by fractional administration (on average, 50 mg) with an interval of 30-40 seconds until an adequate sedative effect is achieved. Dexmedetomidine has been suggested as an adjuvant. It should be kept in mind that benzodiazepines are not suitable for creating a long-lasting sedative effect, and can cause paradoxical agitation in the elderly. Features of sedation in patients at risk of obstructive sleep apnea syndrome are represented with the use of a minimum dose of hypnotics without the use of opioids. Dexmedetomidine is considered as an alternative. It is advisable to use continuous positive airways pressure by inhalation of oxygen through the nasal cannula. Patients with morbid obesity should avoid lying on their back. For the effective control of airway patency, it is advisable to use endotracheal intubation. It is recommended to avoid long-acting drugs and drugs that cause respiratory depression. The use of propofol in this group is often associated with respiratory complications, so the use of remifentanil and dexmedetomidine is recommended as an alternative. For patients with chronic renal failure, midazolam and/or fentanyl should be preferred, however, the cardiovascular and pulmonary side effects of any of these drugs are exacerbated when they are used concomitantly. In patients with hepatic dysfunction, midazolam may exacerbate symptoms, so propofol should be preferred. If the latter is used, the doctor should be near the patient throughout the procedure and monitor him exclusively. As for dexmedetomidine, this drug selectively binds and activates presynaptic α2-adrenoreceptors, inhibiting the release of norepinephrine. As a result, postsynaptic activation of adrenoceptors is inhibited, sympathetic activity is suppressed, leading to analgesia, sedation and decrease of anxiety. Under conditions of mild or moderate sedation caused by dexmedetomidine, patients respond to verbal stimulation and are able to communicate and cooperate with medical staff, and after awakening show high results in tests of central nervous system activity. Dexmedetomidine is less likely to cause postoperative delirium than midazolam (54 % vs. 76.6 %) and does not adversely affect sleep quality, unlike propofol. Dexmedetomidine can be used together with paracetamol. Intravenous paracetamol significantly reduces postoperative pain and the need for opioids.
 Conclusions. 1. AS can be performed with the use of benzodiazepines, propofol, dexmedetomidine. 2. Benzodiazepines are not suitable for creating a long-lasting sedative effect, and can cause paradoxical agitation in the elderly. 3. Patients with different comorbid conditions are characterized by different features of required AS. 4. Dexmedetomidine gives the patient the opportunity to communicate and cooperate with medical staff, rarely causes postoperative delirium and does not adversely affect the sleep quality. 5. Intravenous paracetamol significantly reduces postoperative pain and the need for opioids.

Surface Electromyography Meets Biomechanics: Correct Interpretation of sEMG-Signals in Neuro-Rehabilitation Needs Biomechanical Input.

Coordinated activation of muscles is the basis for human locomotion. Impaired muscular activation is related to poor movement performance and disability. To restore movement performance, information about the subject's individual muscular activation is of high relevance. Surface electromyography (sEMG) allows the pain-free assessment of muscular activation and many ready-to-use technologies are available. They enable the usage of sEMG measurements in several applications. However, due to the fact that in most rehabilitation applications dynamic conditions are analyzed, the correct interpretation of sEMG signals remains difficult which hinders the spread of sEMG in clinical applications. From biomechanics it is well-known that the sEMG signal depends on muscle fiber length, contraction velocity, contraction type and on the muscle's biomechanical moment. In non-isometric conditions these biomechanical factors have to be considered when analyzing sEMG signals. Additionally, the central nervous system control strategies used to activate synergistic and antagonistic muscles have to be taken into consideration. These central nervous system activation strategies are rarely known in physiology and are hard to manage in pathology. In this perspective report we discuss how the consideration of biomechanical factors leads to more reliable information extraction from sEMG signals and how the limitations of sEMG can be overcome in dynamic conditions. This is a prerequisite if the use of sEMG in rehabilitation applications is to extend. Examples will be given showing how the integration of biomechanical knowledge into the interpretation of sEMG helps to identify the central nervous system activation strategies involved and leads to relevant clinical information.

Normative data and correlation between dynamic knee valgus and neuromuscular response among healthy active males: a cross-sectional study

The dynamic knee valgus (DKV) during different sport maneuvers has been widely described as risk factor to develop an anterior cruciate ligament injury. Hip and knee muscles seem to have a crucial role to prevent the dynamic knee valgus. This study aimed to give normative and correlational data about DKV and hip and knee neuromuscular response (NMR) among healthy active males. The hypothesis is that DKV could be correlated with hip NMR. A cross-sectional correlational study. Research Anatomy Laboratory. The study was carried out among 50 active, non-injured males. Dynamic Knee-Valgus angle and lower limb posterior chain muscles Neuromuscular Response. DKV was measured using Kinovea software during a Single-Legged Drop Jump test and NMR was measured using tensiomyography and myotonometry for gluteus maximum, biceps femoris, semitendinosus, lateral and medial gastrocnemius. Right and left limbs were both performed and analyzed independently. No significant correlation was observed between DKV and hip and knee muscles NMR. This study shows normative and correlational data about dynamic knee valgus, tensiomyography and myotonometry for healthy and active males. The DKV control seems to be non-correlated with isolated hip and knee muscles NMR so this suggests it is more about Central Nervous System activity than about isolated muscles NMR.

A systematic review of caregiver-child physiological synchrony across systems: Associations with behavior and child functioning.

Extensive research has established a positive association between caregiver-child behavioral synchrony and child developmental functioning. Burgeoning research examining physiological synchrony has yet to elucidate its impact for children's developing self-regulation. The objectives of this systematic review were to: 1) determine whether there is evidence that caregiver-child physiological synchrony promotes positive child development, 2) examine developmental differences in physiological synchrony and its correlates, and 3) explore whether context, risk, and/or stress influence patterns of synchrony. Sixty-nine studies met the following criteria on PubMed and PsycINFO: 1) peer-reviewed empirical articles in English that 2) examine autonomic, hypothalamic-pituitary-adrenocortical, and/or central nervous system activity 3) for caregivers and children 4) in response to a task and 5) directly examine the association between caregiver and child physiology. Findings varied based on developmental period and current behavioral context. Functional differences may exist across physiological systems and contexts. Synchrony may have different developmental consequences for dyads with and without certain risk factors. Few studies examine physiological synchrony across multiple systems or contexts, nor do they measure child characteristics associated with synchrony. Statistical and methodological challenges impede interpretation. Findings generally support the idea that physiological synchrony may support children's developing self-regulation. Longitudinal research is needed to examine child developmental outcomes over time.

Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation.

This review highlights the pre-clinical and clinical work performed to use intranasal delivery of various compounds from growth factors to stem cells to reduce neuroimmune interactions. We introduce the concept of intranasal (IN) delivery and the variations of this delivery method based on the model used (i.e., rodents, non-human primates, and humans). We summarize the literature available on IN delivery of growth factors, vitamins and metabolites, cytokines, immunosuppressants, exosomes, and lastly stem cells. We focus on the improvement of neuroimmune interactions, such as the activation of resident central nervous system (CNS) immune cells, expression or release of cytokines, and detrimental effects of signaling processes. We highlight common diseases that are linked to dysregulations in neuroimmune interactions, such as Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, and traumatic brain injury.

Central Nervous System (CNS) Involvement in Adult Acute Lymphoblastic Leukemia (ALL) Assessed Solely By Flow Cytometry Has an Adverse Impact on Survival

Introduction: Several studies published in recent years dealing with the detection of Central Nervous System (CNS) disease in Acute Lymphoblastic Leukemia (ALL) have demonstrated superiority in terms of sensitivity of Flow Cytometry (FCM) over standard cytology (Tawfik et al, 2018). However, whether CNS activity detected by FCM has an impact on the clinical outcome of ALL adult patients, is still a matter of debate. (Del Principe et al, 2019) Methodology: We analyzed a retrospective cohort of newly diagnosed ALL adult patients in an oncologic center in Mexico, who had a CNS analysis by FCM and conventional cytology, diagnosed between 2017 and 2019. The primary endpoint was to assess the impact on the survival of patients with CNS disease detected by FCM. We defined positive FCM (FCM+) when the patient had >10 phenotypically pathologic events and positive cytology (Cyt+) when the patent had confirmed CNS-2 or CNS-3 activity as defined by NCCN and ESMO; double-negative (DN) patients were considered when neither FCM nor cytology demonstrated disease as described above. Baseline characteristics were grouped in tables and summarized as medians and ranges for quantitative variables or frequencies in qualitative variables. Basal characteristics and different outcomes were compared by the chi-square test for binary variables, and the Mann-Whitney U test for quantitative variables. Overall Survival (OS) and Disease-Free Survival (DFS) analysis were made by Kaplan-Meier curves. A comparison between groups was performed using the log-rank test, with a significant P value less than 0.05 and a 95% confidence interval (CI). We performed a Cox regression model to obtain an HR with a 95% confidence interval for survival to identify risk associations. Results: Of the 92 evaluable patients, the median age was 28 years. 88% of all ALL were ALL-B. The median count of leucocytes was 11.65 x109/L (range 4.71-38.24 x109/L); median LDH was 758 UI/L (range 314-1242 UI/L). 63% of patients had an unfavorable karyotype (hypodiploidy, complex karyotype, or KMT2A). At diagnosis, 27 (28%) were positive by FCM and negative by cytology. The median of the analyzed events was 14,733 (5,025-50,000) with a viability of 38.5% (22-61.75). Only 6 patients were positive by both techniques. 45% of patients with CNS involvement had neurological symptoms (mainly headache). The most used treatment was BFM in 56.7% of patients, followed by HyperCVAD in 37.8%. Patients with documented CNS infiltration by FCM or cytology were treated with triple intrathecal chemotherapy two times per week. Three patients had no response after two weeks of treatment, one received radiotherapy without any response and the other two were dead for chemotherapy toxicity. We found gender as the only statistically significant variable associated with a higher FCM+ (77% males vs 23% females, p<0.01). For the entire cohort, the complete remission (CR) after induction was 84% and 63% had a negative minimal residual disease (MRD) by FCM in the bone marrow. 15% of the patients were refractory. There were no differences between CR (73% versus 88%, p= 0.16), MRD negativity (46% versus 69%, p=0.11), refractory disease (26% versus 10%, p=0.13) or relapsed disease (50% versus 43%, p=0.65) between FCM(+) and ND groups. The OS for the entire cohort was 11.3 months. Patients with FCM+ had a lower survival of 5.6 months [CI95% (0.72-10.67)] compared with 11.8 months [CI95% (0.47-11.95)] in the DN group. The median DFS for the FCM+ patients was 4.6 months [CI95% (3.42-5.92)] versus 16.4 months [CI95% (6.21-26.75)] for DN group. In the Cox regression model, the HR for survival in patients with FCM+ was 1.85 (CI95% 1.004-3.421; p=0.04). Conclusions: Despite the retrospective nature of this study, the detection of CNS involvement was increased from 6% to 28% employing FCM compared with cytology. As mentioned previously, in other studies, FCM has greater sensitivity than cytology (Ranta et al. 2014). According to our results, the presence of CNS disease, detected by FCM has an adverse impact on OS in adult patients with newly diagnosed ALL. These results dictate consideration of FCM as a routine study in the diagnosis of ALL. Prospective studies are needed to evaluate more intensive treatment in these patients. Figure Disclosures No relevant conflicts of interest to declare.

Review of the Chemical Properties, Pharmacological Properties, and Development Studies of Cymbopogon sp.

Cymbopogon is a genus of aromatic plants that famed because of the essential oil production that has many benefit in industrial, daily life, or even for disease treatment. The Cymbopogon genus consists of about 180 plants, including different species, subspecies, varieties, and subvarieties. The aim of this review is to present chemical properties, pharmacological, and development of the Cymbopogon genus from books and research studies. There were many types of research that have been done to prove the benefits of the Cymbopogon genus, including studies about the extract, essential oil, the chemical compound biological activity, and development studies. Some pharmacological studies that have been confirmed are regarding the pharmacological effects of Cymbopogon in the central nervous system, anti-inflammatory, antimicrobial, antioxidant, and anticancer activity. In addition, there have been studied to improve Cymbopogon benefits.

Ensartinib as Treatment for ALK-Rearranged NSCLC

Ensartinib as Treatment for ALK-Rearranged NSCLC

Somatic embryogenesis and in vitro plant regeneration of Bacopa monnieri (Linn.) Wettst., a potential medicinal water hyssop plant.

Bacopa monnieri (Linn.) Wettst. commonly known as waterhyssop, Brahmi plant, traditionally used for memory enhancement, nerve tonic, epilepsy, central nervous system (CNS), antidepressant, anxiety, blood pressure and antioxidant activities. Due to pharmaceutical demands its lost natural habitat. At this juncture we describe a resourceful protocol for micropropagation of water hyssop plant. Surface sterilized leaf and nodal explants were inoculated on basal MS semi-solid medium added with PGRs; auxins, cytokinins. Highest calli formation from leaf explants was obtained on NAA (2.5 mg−1) and showed (94.22%) accompanied via 2,4-D showed (2.5 mg−1; 82.43%), maximum calli formation in nodal explants was obtained on 2,4-D showed (2.5 mg−1; 71.14%) followed by NAA (2.5 mg−1) showed (62.15%), in internodes explants uppermost calli formation was obtained from 2,4-D showed (2.5 mg−1; 65.21%) followed by NAA (2.5 mg−1) showed (52.14%). The maximum somatic embryogenic callus, calli induction and formation (84%) was observed on 2,4-D + KIN (2.0 + 1.5 mg−1) amended solid medium. Uppermost shoot formation was observed in combination of IAA + BAP (1.0 + 1.0 mg−1) showed (78.54%) shoot formation followed by IBA (2.0 mg−1) alone showed (75.37%). The maximum shoot elongation was noticed from NAA + BAP (3.0 + 3.0 mg−1) with 21.21 cm followed by NAA (2.0 mg−1) showed (15.22 cm) although, chief root formation was obtained from IBA (2.0 mg−1) with 83.75% root formation along higher number of roots (47.43%) per shoot. Followed by IAA (2.0 mg−1) showed root induction (73.43%) and no of roots (38.54%) per shoot. In hardening under pot condition plants survivability (100%) was observed under glass house conditions, the present in vitro PTC techniques is extremely significant to gratifying its natural conservation.

Synthesis and biological evaluation of imidazoline derivatives as potential CNS and CVS agents

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD50 activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD50 > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg).

Aspidosperma excelsum and its pharmacological potential: in silico studies of pharmacokinetic prediction, toxicological and biological activity

Based on ethnobotanical studies, the Aspidosperma excelsum was selected due to its highest claim of popular use for malaria and febrile diseases treatments. This species is rich in secondary metabolites as alkaloids and therefore, the aim of this study was to evaluate the pharmacokinetic, toxicological and biological activity of alkaloids isolated from Aspidosperma excelsum by in silico studies. All substances already isolated from this species were submitted to predictive studies of biological, toxicological and pharmacokinetic activities. Predictive studies of biological activities did not attribute the antimalarial activity to pure substances. However, other activities were found, such as: action on central nervous system and antineoplastic activity. In pharmacokinetic terms, many substances showed an inhibitory action on cytochrome P450 (CYP) and many adverse reactions, highlighting actions on the CNS. Also, several alkaloids, being nitrogenous substances, presented mutagenic or genotoxic activities. Thus, it is demonstrated the species potential for biological activities not yet studied, as well as the importance of investigating its pharmacokinetic and toxicological properties, justifying the accomplishment of the present study.

Strong Association between Serotonin Transporter 5-HTTVNTR Variant and Psychoactive Substance (Nicotine) Use in the Turkish Cypriot Population.

The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin transporter gene has been previously linked to psychological traits. A variable number of tandem repeats within the serotonin transporter-linked polymorphic gene region are believed to alter the transcriptional efficiency of the 5-HTT gene. Therefore, we aimed to investigate the association between this polymorphic site and smoking behavior in the Turkish Cypriot population. A total of 259 (100 smokers, 100 non-smokers and 59 ex-smokers) Turkish Cypriots were included in this population-based cross-sectional study. Genomic DNA was extracted from peripheral blood samples and the 5-HTTVNTR2 polymorphisms were determined by the PCR-RFLP. The allelic frequency and genotype distribution results of this study showed a strong association (P<0.0001) between smokers and non-smokers. No statistical significance was found between non-smokers and ex-smokers. This is the first genetic epidemiology study to investigate the allelic frequencies of 5-HTTVNTR2 polymorphisms associated with smoking behavior in the Turkish Cypriot population. Based on the results of this study, genome-wide association studies should be designed for preventive medicine in this population.

Blood-Brain Barrier Permeability of Asiaticoside, Madecassoside and Asiatic Acid in Porcine Brain Endothelial Cell Model.

Neurotherapeutic potentials of Centella asiatica and its reputation to boost memory, prevent cognitive deficits and improve brain functions are widely acknowledged. The plant's bioactive compounds, i.e. asiaticoside, madecassoside and asiatic acid were reported to have central nervous system (CNS) actions, particularly in protecting the brain against neurodegenerative disorders. Hence, it is important for these compounds to cross the blood-brain barrier (BBB) to be clinically effective therapeutics. This study aimed to explore the capability of asiaticoside, madecassoside and asiatic acid to cross the BBB using invitro BBB model from primary porcine brain endothelial cells (PBECs). Our findings showed that asiaticoside, madecassoside and asiatic acid are highly BBB permeable with apparent permeability (Papp) of 70.61±6.60, 53.31±12.55 and 50.94±10.91×10-6cm/s respectively. No evidence of cytotoxicity and tight junction disruption of the PBECs were observed in the presence of these compounds. Asiatic acid showed cytoprotective effect towards the PBECs against oxidative stress. This study reported for the first time that Centella asiatica compounds demonstrated high capability to cross the BBB, comparable to central nervous system drugs, and therefore warrant further development as therapeutics for the treatment of neurodegenerative diseases.

Differences in Activity of the Brain Networks During Voluntary Motor Tasks Engaging the Local and Global Muscular Systems of the Lower Trunk.

Low back pain constitutes a multidimensional problem of largely unknown origin. One of the recent theories explaining its frequent occurrence includes speculative statements on patterns of central nervous system activity associated with the control of so-called local and global muscles of the lower trunk. The objective of the study was to verify whether there is a difference in the activity of the brain during selective, voluntary contraction of the local and global abdominal muscles as assessed by functional MRI. Twenty healthy subjects participated. An experimental design was applied with repeated measurements of the blood-oxygen-level-dependent signal from the brain during voluntary contraction of the local and global abdominal muscles, performed in random order. Prior to registration, a 2-week training period was introduced, aiming to master the experimental motor tasks. The magnetic resonance imaging (MRI) data were processed using the FMRIB Software Library (Oxford, UK). Brain areas showing significant activations/deactivations were identified and averaged across all participants, and intercondition differential maps were computed. Areas of significant intercondition differences were linked to the corresponding anatomical structures and ascribed to the default mode functional brain network and to the sensorimotor network. Contraction of the local abdominal muscles elicited more pronounced activity of the brain cortex, basal ganglia, and cerebellum. This suggests that motor control of the abdominal musculature consists of two modes of brain activity and that control of the local muscles may be a more challenging task for the brain. Moreover, contraction of the local muscles elicited more distinct deactivation of the default mode network, which may have implications for diagnostics and therapy of low back pain.

Tyrosine Kinase Inhibitors as a Treatment of Symptomatic CNS Metastases in Oncogene-Driven NSCLC.

Central nervous system (CNS) metastases occur frequently in oncogene-driven non-small cell lung cancer (NSCLC). Standard treatment approaches can potentially delay systemic treatment (surgical intervention) or result in neurocognitive impairment (radiotherapy). Recently, next-generation tyrosine kinase inhibitors (TKIs) have demonstrated remarkable intracranial activity. However, most clinical trials did not enroll patients suffering neurological symptoms. Our study aimed to assess the CNS activity of targeted therapies in this patient population. We present a case series of nine NSCLC patients with either EGFR mutation or ALK rearrangement and symptomatic CNS metastases that were treated with TKIs. Clinicopathological characteristics, treatment, and outcomes were analyzed. Most patients presented with symptomatic CNS metastases at time of metastatic disease presentation (6/9). Additionally, the majority of patients had leptomeningeal disease (6/9) and multiple parenchymal metastases. Patients presented with a variety of CNS symptoms with the most common being nausea, vomiting, headache, and confusion. Most patients (6/9) responded rapidly both clinically and radiographically to the targeted treatment, with a marked correlation between systemic and intracranial radiographic response. In conclusion, upfront use of next-generation TKIs in patients with oncogene-driven NSCLC with symptomatic CNS metastases is associated with reasonable intracranial activity and represents a valuable treatment option.

Implications of Transient Receptor Potential Cation Channels in Migraine Pathophysiology.

Migraine is a common and debilitating headache disorder. Although its pathogenesis remains elusive, abnormal trigeminal and central nervous system activity is likely to play an important role. Transient receptor potential (TRP) channels, which transduce noxious stimuli into pain signals, are expressed in trigeminal ganglion neurons and brain regions closely associated with the pathophysiology of migraine. In the trigeminal ganglion, TRP channels co-localize with calcitonin gene-related peptide, a neuropeptide crucially implicated in migraine pathophysiology. Many preclinical and clinical data support the roles of TRP channels in migraine. In particular, activation of TRP cation channel V1 has been shown to regulate calcitonin gene-related peptide release from trigeminal nerves. Intriguingly, several effective anti-migraine therapies, including botulinum neurotoxin type A, affect the functions of TRP cation channels. Here, we discuss currently available data regarding the roles of major TRP cation channels in the pathophysiology of migraine and the therapeutic applicability thereof.