Central Nervous System Activity Research Articles

Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07).

TPS1096 Background: HER2-targeted therapies have improved survival in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) but challenges remain, including resistance to current HER2-targeted therapies. Also, additional treatment options are needed in pts with brain metastases (BM). In the phase 2 DESTINY-Breast01 trial, T-DXd demonstrated efficacy, with an objective response rate (ORR) of 61.4% and median progression-free survival (mPFS) of 19.4 mo in pts with previously treated HER2+ advanced/mBC (Modi SABCS 2020); data from an earlier cutoff of this trial supported approval of T-DXd in the US, Europe, and Japan. In a subgroup analysis of 24 pts with stable BM, T-DXd showed preliminary efficacy, with mPFS of 18.1 mo (Jerusalem ESMO Breast Cancer 2020). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC, including pts with stable and active BM. Methods: DESTINY-Breast07 (NCT04538742) is a global, multicenter, open-label, phase 1b/2 trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC. This study consists of a T-DXd monotherapy module (module 0) and 5 combination modules of T-DXd plus (1) durvalumab, (2) pertuzumab, (3) paclitaxel, (4) durvalumab + paclitaxel, or (5) tucatinib, all in pts with no or stable BM. Two additional modules consisting of (6) T-DXd + tucatinib and (7) T-DXd monotherapy will include pts with untreated BM not requiring local therapy or previously treated BM that have progressed since local therapy (active BM). The need for chronic steroids or local therapy to manage BM symptoms is exclusionary. Modules 2 to 5 will each consist of 2 parts: dose finding (part 1) and dose expansion (part 2). Modules 0, 1, 6, and 7 will include part 2 only. Part 1 of individual modules will enroll pts who have had disease progression while receiving ≥1 prior line of therapy in the metastatic setting. In part 2, pts who have received no prior therapy (modules 0 to 5) or ≤1 prior therapy (modules 6 to 7) for metastatic disease will be randomized to receive a T-DXd combination regimen or monotherapy. The primary endpoints are determination of the recommended phase 2 doses (part 1 only) and safety and tolerability of T-DXd and combinations (parts 1 and 2). Secondary endpoints include ORR, PFS, PFS2, duration of response (DoR), and overall survival (all assessed in part 2 only) and pharmacokinetics and immunogenicity (parts 1 and 2). To assess central nervous system (CNS) activity, exploratory endpoints were added, including CNS-ORR, CNS-DoR, and CNS-PFS (by RECIST version 1.1 and RANO-BM criteria) as well as cognitive and symptom assessment using CANTAB, MDASI-BT, and NANO. Clinical trial information: NCT04538742 .

Effects of urethane and isoflurane on the sensory evoked response and local blood flow in the early postnatal rat somatosensory cortex

Functional studies in the central nervous system are often conducted using anesthesia. While the dose-dependent effects of anesthesia on neuronal activity have been extensively characterized in adults, little is known about the effects of anesthesia on cortical activity and cerebral blood flow in the immature central nervous system. Substitution of electrophysiological recordings with the less-invasive technique of optical intrinsic signal imaging (OIS) in vivo allowed simultaneous recordings of sensory-evoked functional response and local blood flow changes in the neonatal rat barrel cortex. Using OIS we characterize the effects of two widely used anesthetics—urethane and isoflurane. We found that both anesthetics suppressed the sensory-evoked optical intrinsic signal in a dose-dependent manner. Dependence of the cortical response suppression matched the exponential decay model. At experimental levels of anesthesia, urethane affected the evoked cortical response less than isoflurane, which is in agreement with the results of electrophysiological recordings demonstrated by other authors. Changes in oxygenation and local blood flow also showed negative correlation with both anesthetics. The high similarity in immature patterns of activity recorded in different regions of the developing cortex suggested similar principles of development regardless of the cortical region. Therefore the indicated results should be taken into account during functional explorations in the entire developing cortex. Our results also point to urethane as the anesthetic of choice in non-survival experimental recordings in the developing brain as it produces less prominent impairment of cortical neuronal activity in neonatal animals.

023 Sleep in a Brainless Animal - The Relationship Between Centralization and Sleep in the Upside-down Jellyfish

Abstract Introduction Though sleep is pervasive in animals, its fundamental roles, and the processes involved in generating the behavior, remain poorly understood. A key outstanding question in sleep regulation is whether sleep is controlled strictly by a top-down mechanism via activity of specific central nervous system (CNS) neurons or is controlled partially by bottom-up signals from neural and non-neural tissue. Recently, we showed that the upside-down jellyfish Cassiopea sleeps, providing an opportunity to study sleep control, regulation, and function in an animal without a CNS. Methods Cassiopea have a decentralized nervous system (DNS) of radially spaced interconnected ganglia called rhopalia along their bell margin that control muscle contractions. The signal to contract is sent to muscle fibers local to the initiating ganglion, and the contraction propagates outwards as a point source wave. We have developed computer programs to detect the controlling ganglion, which allows us to non-invasively determine ganglia activity, and to understand how a simple network of ganglia controls behavior. We are also using immunofluorescence, in situ hybridization, qPCR, and RNAseq to characterize the effect of sleep deprivation (SD) on the jellyfish nervous system. Results We have discovered a temporally centralized form of behavioral control that changes between day and night, and during SD. A subset of ganglia share behavioral control—while some almost never initiate contractions, others are active both day and night, or are mostly day-active or night-active, and SD drastically changes ganglia usage. Regions that increase activity at night are less active the following day, perhaps evidence of homeostatic regulation. Using RNAseq we found that during SD, one nAChRα subunit increases expression ~3.8-fold and we are studying its role in arousal and sleep. Conclusion We are investigating a different kind of nervous system, one that is morphologically decentralized (a network of discrete ganglia), and yet temporally centralized (a subset of ganglia dominate activity control). Wake, sleep, and SD involve different ganglia activity patterns, different levels of centralization, and different gene expression. Thus, temporal centralization could provide a mechanism to explain how local sleep, via a bottom-up mechanism, can result in organismal sleep behavior. Support (if any) UC Berkeley Miller Postdoctoral Fellowship

Limited brain metastases: a narrative review.

Limited brain metastases refer to an oligometastatic state in the brain for which focal therapy with stereotactic radiosurgery (SRS) is appropriate. The definition of what is considered "limited" for brain metastases, however, is not well defined. Multiple recent randomized trials show that metastasis-directed therapy with surgery or stereotactic radiation can prolong survival for patients with 1-5 metastases from various primary tumors, but patients with untreated brain metastases were largely excluded from these trials. Stereotactic radiosurgery allows for the treatment of multiple brain metastases while avoiding whole brain radiation (WBRT), which has a known negative impact on neurocognitive function. Randomized trials have shown that stereotactic radiation alone is effective for the treatment of up to 4 brain metastases with decreased neurocognitive side effects and no detriment to overall survival (OS). These data have led to our current definition of "limited" brain metastases. However, more recent data suggests that patients with up to 10 brain metastases can benefit from SRS. Ongoing trials are investigating if patients with up to 15-20 brain metastases may similarly benefit from SRS alone. Advances in systemic therapies which penetrate the blood-brain barrier and have greater activity in central nervous system (CNS) may also expand the population for whom radiosurgery is an appropriate treatment. Immunotherapy may also be synergistic with radiosurgery in some cases. This narrative review will discuss the evolving definition and management of limited brain metastases.

Method of evaluation of the minimal sample size for acoustical signal therapy monitored via electroencephalographic activity of human brain

The aim of the study. Improvement of the preparation to the acoustical signal therapy test or experiment of electroencephalographic activity of human brain and validation of the specified test results.
 The problem to be solved. Estimation of the minimal possible sample size for maintaining needed research accuracy in the research field of the electroencephalographic activity of human brain via monitoring of the brainwave patterns during exposure to the musical signal.
 Main scientific results. New method for selection minimal passable sample size for brainwave pattern studies is presented. Example of application of method for one rhythm of the brainwaves (delta-rhythm) is shown. Perspective way of obtaining clinically valuable differences between test group results was acquired. Differences between mean values for groups of results of different types of music and stress factor exposure are presented.
 The area of practical use of the research results. Research facilities dedicated to the study of electroencephalographic activity of human brain and medical facilities and institutions, dedicated to the treatment of pathologies of the central nervous system, brain damage, stress, and progressive post-stress action psychological state restoration.
 An innovative technological product. Dedicated method for quick estimation of minimal passable sample size for brainwave pattern studies, which is recommended for usage in the studies of the implementation of music therapy.
 The area of application of an innovative technological product. Electroencephalographic activity of human brain study via brainwave pattern research. Clinical practice of application of a music therapy.

Dopamine D2 receptor agonist, bromocriptine, remodels adipose tissue dopaminergic signalling and upregulates catabolic pathways, improving metabolic profile in type 2 diabetes

Background and objectivesThe therapeutic effects of the dopamine D2 receptor (D2R) agonist, bromocriptine, in type 2 diabetes (T2D) have been attributed to central nervous system actions. However, peripheral dopamine directly modulates glucose uptake in insulin-sensitive tissues and lipid metabolism in adipose tissue (AT). We hypothesized that the dopaminergic system may be impaired in the adipose tissue of patients with T2D and that the therapeutic actions of bromocriptine could involve the modulation of metabolism in this tissue. MethodsThe expression of dopamine receptors was evaluated in visceral AT samples from patients with obesity and stratified in several groups: insulin sensitive (IS); insulin resistance (IR) normoglycaemic; insulin resistant prediabetic; insulin resistant diabetic, according to Ox-HOMA2IR, fasting glycaemia and HbA1c levels. T2D Goto-Kakizaki rats (GK) were fed a high-caloric diet (HCD) for five months and treated with bromocriptine (10 mg/kg/day, i.p.) in the last month. The levels of dopaminergic system mediators and markers of insulin sensitivity and glucose and lipid metabolism were assessed in the peri-epididymal adipose tissue (pEWAT) and brown (BAT) adipose tissues, liver, and skeletal muscle. ResultsPatients with IR presented a decreasing trend of DRD1 expression in the visceral adipose tissue, being correlated with the expression of UCP1, PPARA, and insulin receptor (INSR) independently of insulin resistance and body mass index. Although no differences were observed in DRD2, DRD4 expression was significantly decreased in patients with prediabetes and T2D. In HCD-fed diabetic rats, bromocriptine increased D1R and tyrosine hydroxylase (TH) levels in pEWAT and the liver. Besides reducing adiposity, bromocriptine restored GLUT4 and PPARγ levels in pEWAT, as well as postprandial InsR activation and postabsorptive activation of lipid oxidation pathways. A reduction of liver fat, GLUT2 levels and postprandial InsR and AMPK activation in the liver was observed. Increased insulin sensitivity and GLUT4 levels in BAT and an improvement of the overall metabolic status were observed. ConclusionsBromocriptine treatment remodels adipose tissue and the liver dopaminergic system, with increased D1R and TH levels, resulting in higher insulin sensitivity and catabolic function. Such effects may be involved in bromocriptine therapeutic effects, given the impaired expression of dopamine receptors in the visceral adipose tissue of IR patients, as well as the correlation of D1R expression with InsR and metabolic mediators.

Ambient air pollutants are associated with morning serum cortisol in overweight and obese Latino youth in Los Angeles

BackgroundHypothalamic-pituitary-adrenal (HPA)-axis dysfunction has been associated with a variety of mental health and cardio-metabolic disorders. While causal models of HPA-axis dysregulation have been largely focused on either pre-existing health conditions or psychosocial stress factors, recent evidence suggests a possible role for central nervous system activation via air pollutants, such as nitrogen dioxide (NO2), ozone (O3) and particulate matter (PM). Therefore, in an observational study of Latino youth, we investigated if monthly ambient NO2, O3, and PM with aerodynamic diameter ≤ 2.5 (PM2.5) exposure were associated with morning serum cortisol levels.MethodsIn this cross-sectional study, morning serum cortisol level was assessed after a supervised overnight fast in 203 overweight and obese Latino children and adolescents (female/male: 88/115; mean age: 11.1 ± 1.7 years; pre-pubertal/pubertal/post-pubertal: 85/101/17; BMI z-score: 2.1 ± 0.4). Cumulative concentrations of NO2, O3 and PM2.5 were spatially interpolated at the residential addresses based on measurements from community monitors up to 12 months prior to testing. Single and multi-pollutant linear effects models were used to test the cumulative monthly lag effects of NO2, O3, and PM2.5 on morning serum cortisol levels after adjusting for age, sex, seasonality, social position, pubertal status, and body fat percent by DEXA.ResultsSingle and multi-pollutant models showed that higher O3 exposure (derived from maximum 8-h exposure windows) in the prior 1–7 months was associated with higher serum morning cortisol (p < 0.05) and longer term PM2.5 exposure (4–10 months) was associated with lower serum morning cortisol levels (p < 0.05). Stratification by pubertal status showed associations in pre-pubertal children compared to pubertal and post-pubertal children. Single, but not multi-pollutant, models showed that higher NO2 over the 4–10 month exposure period associated with lower morning serum cortisol (p < 0.05).ConclusionsChronic ambient NO2, O3 and PM2.5 differentially associate with HPA-axis dysfunction, a mechanism that may serve as an explanatory pathway in the relationship between ambient air pollution and metabolic health of youth living in polluted urban environments. Further research that uncovers how ambient air pollutants may differentially contribute to HPA-axis dysfunction are warranted.

Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity.

Multiple sclerosis (MS)-related inflammation can be divided into lesional activity, mediated by immune cells migrating from the periphery to the central nervous system (CNS) and non-lesional activity, mediated by inflammation compartmentalized to CNS tissue. Lesional inflammatory activity, reflected by contrast-enhancing lesions (CELs) on the magnetic resonance imaging (MRI), is effectively inhibited by current disease modifying therapies (DMTs). While, the effect of DMTs on non-lesional inflammatory activity is currently unknown. Reliable and simultaneous measurements of both lesional and non-lesional MS activity is necessary to understand their contribution to CNS tissue destruction in individual patients. We previously demonstrated that CNS compartmentalized inflammation can be measured by combined quantification of cerebrospinal fluid (CSF) immune cells and cell-specific soluble markers. The goal of this study is to develop and validate a CSF-biomarker-based molecular surrogate of MS lesional activity. The training cohort was dichotomized into active (CELs > 1 or clinical relapse) and inactive lesional activity (no CELs or relapse) groups. Matched CSF and serum samples were analyzed for 20 inflammatory and axonal damage biomarkers in a blinded fashion. Only the findings from the training cohort with less than 0.1% probability of false positive (i.e., p < 0.001) were validated in an independent validation cohort. MS patients with lesional activity have elevated IL-12p40, CHI3L1, TNFα, TNFβ, and IL-10, with the first two having the strongest effects and validated statistically-significant association with lesional activity in an independent validation cohort. Marker of axonal damage, neurofilament light (NfL), measured in CSF (cNfL) was also significantly elevated in MS patients with active lesions. NfL measured in serum (sNfL) did not differentiate the two MS subgroups with pre-determined significance, (p = 0.0690) even though cCSF and sNfL correlated (Rho = 0.66, p < 0.0001). Finally, the additive model of IL12p40 and CHI3L1 outperforms any biomarker discretely. IL12p40 and CHI3L1, released predominantly by immune cells of myeloid lineage are reproducibly the best CSF biomarkers of MS lesional activity. The residuals from the IL12p40/CHI3L1-cNfL correlations may identify MS patients with more destructive inflammation or contributing neurodegeneration.

The features of temperament and levels of activation of central nervous system of female students with various condition of reproductive health

The article demonstrates the relationship between temperamental features and functional state of central nervous system in female students various regimen of reproductive system functioning. The sampling included 115 female students of Krasnoyarsk with different status of menstrual function, including 51 female students with normal gonadotropic and prolactin type of anovulation and 64 female students with ovulatory menstrual cycle. The questionnaire DOTS-R was applied to establish the temperament characteristics. The functional condition of the central nervous system was studied using method of simple and complex visual-motor reaction by means of device "Psychophysiologist". The results of the study demonstrated that girls with "calm" and "rigid" types of temperament have features of functional state of the central nervous system that can condition predisposition to menstrual cycle disorders. The particular features of functional state of the central nervous system in female students with anovulatory cycle were established: decreasing of level of activation of the central nervous system in individuals with "intense" and "unstable" types of temperament and workability of girls of "adequate" type. The application of complex reproductive health evaluation to female students to establish personalty temperamental features will input into forming of risk groups relating to development of menstrual cycle disorders in female students.

Endosomal escape cell-penetrating peptides significantly enhance pharmacological effectiveness and CNS activity of systemically administered antisense oligonucleotides

Antisense oligonucleotides (ASOs) are an emerging class of gene-specific therapeutics for diseases associated with the central nervous system (CNS). However, ASO delivery across the blood–brain barrier (BBB) to their CNS target cells remains a major challenge. Since ASOs are mainly taken up into the brain capillary endothelial cells interface through endosomal routes, entrapment in the endosomal compartment is a major obstacle for efficient CNS delivery of ASOs. Therefore, we evaluated the effectiveness of a panel of cell-penetrating peptides (CPPs) bearing several endosomal escape domains for the intracellular delivery, endosomal release and antisense activity of FDA-approved Spinraza (Nusinersen), an ASO used to treat spinal muscular atrophy (SMA). We identified a CPP, HA2-ApoE(131–150), which, when conjugated to Nusinersen, showed efficient endosomal escape capability and significantly increased the level of full-length functional mRNA of the survival motor neuron 2 (SMN2) gene in SMA patient-derived fibroblasts. Treatment of SMN2 transgenic adult mice with this CPP-PMO conjugate resulted in a significant increase in the level of full-length SMN2 in the brain and spinal cord. This work provides proof-of-principle that integration of endosomal escape domains with CPPs enables higher cytosolic delivery of ASOs, and more importantly enhances the efficiency of BBB-permeability and CNS activity of systemically administered ASOs.

CAPE and Neuroprotection: A Review.

Propolis, a product of the honey bee, has been used in traditional medicine for many years. A hydrophobic bioactive polyphenolic ester, caffeic acid phenethyl ester (CAPE), is one of the most extensively investigated active components of propolis. Several studies have indicated that CAPE has a broad spectrum of pharmacological activities as anti-oxidant, anti-inflammatory, anti-viral, anti-fungal, anti-proliferative, and anti-neoplastic properties. This review largely describes CAPE neuroprotective effects in many different conditions and summarizes its molecular mechanisms of action. CAPE was found to have a neuroprotective effect on different neurodegenerative disorders. At the basis of these effects, CAPE has the ability to protect neurons from several underlying causes of various human neurologic diseases, such as oxidative stress, apoptosis dysregulation, and brain inflammation. CAPE can also protect the nervous system from some diseases which negatively affect it, such as diabetes, septic shock, and hepatic encephalopathy, while numerous studies have demonstrated the neuroprotective effects of CAPE against adverse reactions induced by different neurotoxic substances. The potential role of CAPE in protecting the central nervous system (CNS) from secondary injury following various CNS ischemic conditions and CAPE anti-cancer activity in CNS is also reviewed. The structure–activity relationship of CAPE synthetic derivatives is discussed as well.

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

BackgroundFollicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear.MethodsTo determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells.ResultsMice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE.ConclusionsBlimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

Toward a unified model of stress recovery and cognitive restoration in nature

There is abundant evidence for both cognitive and affective improvements stemming from spending time in nature; however, the mechanism underlying these effects are still under debate. Frameworks such as Attention Restoration Theory (ART; Kaplan 1995) and Stress Recovery Theory (SRT; Ulrich et al. 1991) have been helpful in understanding how restoration is achieved. Using the neurovisceral integration model (NIVM; Thayer and Lane 2000, 2002), we suggest that cognitive restoration and stress recovery co-occur and that they are bidirectional manifestations of activity in the vagus nerve, which links the peripheral nervous system (PNS) to the central nervous system (CNS). Future research should examine both PNS and CNS activity simultaneously to provide a better understanding of the changes in the body and brain associated with immersion in nature. This research program will provide the scientific evidence to help inform public policy related to human health, urban design, and environmental protection.

A Comparison Between First-, Second- and Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non-Small-Cell Lung Cancer and Brain Metastases

Patients with non-small-cell lung cancer (NSCLC), harboring Epidermal Growth Factor Receptor (EGFR) mutations, are more susceptible to brain metastases (BM). Comparisons of the efficacy of different-generation EGFR-tyrosine kinase inhibitors (TKI) on BMs from NSCLC are currently limited. We identified studies comparing different EGFR-TKIs for NSCLC through Pubmed literature search and selected those with neurological outcome data. By two retrospective analyses, Erlotinib showed longer neurological time-to-progression (30 months vs. 15.8 months, P = 0.024) and reduced the risk of central nervous system (CNS) progression (Hazard Ratio (HR) 0.25; 95% CI, 0.08–0.81; P = 0.021) compared to Gefitinib. In a phase 2b randomized trial, 16% of patients with BMs had a similar Progression Free Survival (PFS) (HR 0.76, 95% CI 0.41–1.44) or Overall Survival (OS) (HR 1.16, 95% CI 0.61–2.21) with Afatinib versus Gefitinib; a lower risk of developing subsequent BMs with Afatinib than Gefitinib (HR 0.49; 95% CI 0.34–0.71; P &lt; 0.001) was reported by a retrospective study. A randomized phase 3 trial proved that patients with BMs treated with Osimertinib had longer PFS (HR 0.47, 95% CI 0.30–0.74) and OS (HR 0.79, 95% CI 0.61–1.01) than with Gefitinib, and lower incidence of CNS progression (6% vs. 15%, respectively). Although there is limited evidence, differences in CNS activity may exist between EGFR-TKIs.

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.

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.&#x0D; Objective. To describe the features of the modern AS.&#x0D; Materials and methods. Analysis of literature data on this issue.&#x0D; 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.&#x0D; 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.