Central Nervous System Excitability Research Articles

Acute effects of weighted plyometric exercise on sprint, agility and jump performance in university football players

Background: Conditioning activities such as resistance training can cause excitation of central nervous system resulting in Post-activation Potentiation phenomenon. Plyometric exercise also has an important role to develop Post-activation Potentiation following a resistance stimulus. So the purpose the study was to investigate the immediate effects of weighted plyometric exercise on sprint, agility and jump performance. Materials and methods: Twenty male university football players (age=21.3±1.5 years, body mass=63.3±9.5 kg, height=169.8±6.4 m) participated in this Single group pre-test post-test study. Agility Time (AT), Sprint Time (ST) and Counter-Movement Jump (CMJ) height were measured prior to and 1st and 5th minutes following plyometric exercise. Results: A repeated measures ANOVA employed at baseline (T0), 1 minute (T1), and 5 minutes (T5) post intervention showed significant effect for all the three outcome measures (p<0.001). Post-hoc Bonferroni pairwise comparison showed a significant decrease in both AT and ST from baseline to assessments at both T1 (p<0.001) and T5 (p<0.001), whereas there was a significant increase in the CMJ height. However, no statistical difference was found between T1 and T5 (p=0.058) in ST, but AT was significantly lower at T5 than at T1 (p=0.008), and CMJ height showed significant increase from T1 to T5 (p=0.001). Conclusion: Our results suggest that weighted plyometric exercises have an acute response on sprint, agility and counter movement jump (CMJ Height) following Post-Activation Potentiation (PAP) effect developed after plyometric exercises.

Effects of lactate and carbon monoxide interactions on neuroprotection and neuropreservation.

Lactate, historically considered a waste product of anerobic metabolism, is a metabolite in whole-body metabolism needed for normal central nervous system (CNS) functions and a potent signaling molecule and hormone in the CNS. Neuronal activity signals normally induce its formation primarily in astrocytes and production is dependent on anerobic and aerobic metabolisms. Functions are dependent on normal dynamic, expansive, and evolving CNS functions. Levels can change under normal physiologic conditions and with CNS pathology. A readily combusted fuel that is sshuttled throughout the body, lactate is used as an energy source and is needed for CNS hemostasis, plasticity, memory, and excitability. Diffusion beyond the neuron active zone impacts activity of neurons and astrocytes in other areas of the brain. Barriergenesis, function of the blood-brain barrier, and buffering between oxidative metabolism and glycolysis and brain metabolism are affected by lactate. Important to neuroprotection, presence or absence is associated with L-lactate and heme oxygenase/carbon monoxide (a gasotransmitter) neuroprotective systems. Effects of carbon monoxide on L-lactate affect neuroprotection – interactions of the gasotransmitter with L-lactate are important to CNS stability, which will be reviewed in this article.

Differences between paediatric and adult suspected neuropsychiatric adverse drug reactions of Melatonin reported to the European Medicines Agency

Melatonin has been approved as a sleep medication in Europe since 2007. The pharmacological dosages of this substance are much higher than the physiological ones, so it is no surprise that it has potential for many adverse effects. In children melatonin has been used for many years off-label, but in 2018 the Committee for Medicinal Products for Human Use (CHMP) granted paediatric-use marketing authorization for melatonin. We used the European Medicines Agency (EMA) database to compare the distribution of melatonin adverse drug reaction (ADRs) between the pediatric and the adult population. The results will serve as a basis for future research involving melatonin use in specific populations. All ADR reports received in EMA up to 23.03.2019 were analyzed for overall numbers, age and gender. The nature of the ADRs and the most frequently reported drug substances and drug event combinations were evaluated using MedDRA 21.0. As of 27th March 2019, EudraVigilance contained 1061 spontaneous reports. After excluding all the cases with other suspected or concomitant drugs, we are left with 177 cases. In children ADRs were generally associated with central nervous system (CNS) excitability, whereas in adults there was mainly inhibition. The present study focused on the ADR reports of melatonin in one of the largest databases. Future research of melatonin in the pediatric population is needed, because the current SmPCs lack such information, and in the cases of melatonin use in children are increasing in recent years.

Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory mediators in the central nervous system (CNS). GABAARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABAARs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABAARs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABAARs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABAARs.

Singultus, paper-bag ventilation, and hypercapnia

ABSTRACT Sir Louis Francis Knuthsen (1869–1957), the physician who painstakingly listed almost all treatments known for obstinate hiccough, ascribes the holding of breath method to Philip Henry Pye-Smith, FRS (1840–1914), consultant at Guy’s Hospital in London. In fact, the strategy is much older and was mentioned by greats such as Francis Bacon (1561–1626), Aristoteles (384–322 BC), and Eryximachus (late-fifth century bce). Hypoventilation to reduce central nervous system excitability was used in antiquity as evidenced by Cyriacus’ treatment of Artemia, the daughter of Emperor Diocletian (≈ 244–311). She was suffering from (among others) seizures that Cyriacus was apparently controlling by tightening a scarf around her neck, as depicted by Mathias Grünewald (1460–1528) on a wing of the so-called Heller Altar now on display at the Historical Museum, Frankfurt, Germany. In modern times, around 1920, inducing hypercapnia by CO2 inhalation as therapy for hiccups was suggested and tried by a number of anesthetists, such as Americans Russel Firth Sheldon (1885–1960) and Brian Collins Sword (1889–1956) in Boston; Briton Christopher Langton Hewer (1896–1986) at St. Bartholomew’s Hospital in London; Austrian Karl Doppler (1887–1947) in Vienna; and the German/Polish Arthur Dzialoszynski (1893–1977) in Berlin. Although various authors assign the scientific primate to any of them, the first mention of carbon dioxide inhalation as treatment of singultus in the scientific literature is of French origin and was made by Paris pharmacist Henri Bocquillon-Limousin (1856–1917) in his 1892 Formulaire des médicaments nouveaux et des médications nouvelles.

Initial Evaluation of Pain Intensity Among Depressed Patients as a Possible Mediator Between Depression and Pain Complaints.

Pain complaints are frequently described by depressed patients, and are mostly attributed to abnormal pain perception and modulation. The present study aimed to assess whether a unique pain processing profile differentiates depressed patients from healthy controls. Participants were 25 patients suffering from a moderate-severe unipolar depressive episode and 25 age and sex-matched healthy controls. Thermal stimuli were used to assess sensory threshold and pain threshold. Pain-60 temperature (temperature that induces pain ratings of 60 out of 100) was the first noxious stimuli to be administered during the experimental session. Central pain inhibition was assessed via conditioned pain modulation (CPM) and the degree of central nervous system excitability was assessed via mechanical temporal summation. Depressed patients reported higher levels of pain compared with healthy controls, and a significantly higher perceived pain during the last month. Additionally, they displayed significantly lower pain-60 temperature values compared with healthy controls (p = 0.01). Otherwise, no significant group differences were found in measures of pain perception and modulation. Our results suggest that the initial evaluation of pain intensity among depressed patients, as validated by pain-60 temperature values, is increased compared with healthy controls, and might be the mediator between depression and pain complaints. Possibly, depressed patients' negative bias in the processing of pain is similar to their processing pattern of facial expression or future events. Further studies are necessary in order to establish the mechanisms underlying the excessive pain complaints reported by patients with unipolar depression.

Noncompetitive antagonists induce cooperative AMPA receptor channel gating.

Glutamate is released from presynaptic nerve terminals in the central nervous system (CNS) and spreads excitation by binding to and activating postsynaptic iGluRs. Of the potential glutamate targets, tetrameric AMPA receptors mediate fast, transient CNS signaling. Each of the four AMPA subunits in the receptor channel complex is capable of binding glutamate at its ligand-binding domains and transmitting the energy of activation to the pore domain. Homotetrameric AMPA receptor channels open in a stepwise manner, consistent with independent activation of individual subunits, and they exhibit complex kinetic behavior that manifests as temporal shifts between four different conductance levels. Here, we investigate how two AMPA receptor-selective noncompetitive antagonists, GYKI-52466 and GYKI-53655, disrupt the intrinsic step-like gating patterns of maximally activated homotetrameric GluA3 receptors using single-channel recordings from cell-attached patches. Interactions of these 2,3-benzodiazepines with residues in the boundary between the extracellular linkers and transmembrane helical domains reorganize the gating behavior of channels. Low concentrations of modulators stabilize open and closed states to different degrees and coordinate the activation of subunits so that channels open directly from closed to higher conductance levels. Using kinetic and structural models, we provide insight into how the altered gating patterns might arise from molecular contacts within the extracellular linker-channel boundary. Our results suggest that this region may be a tunable locus for AMPA receptor channel gating.

Central contributions to torque depression: an antagonist perspective.

Torque depression (TD) is the reduction in steady-state isometric torque following active muscle shortening when compared to an isometric reference contraction at the same muscle length and activation level. Central nervous system excitability differs in the TD state. While torque production about a joint is influenced by both agonist and antagonist muscle activation, investigations of corticospinal excitability have focused on agonist muscle groups. Hence, it is unknown how the TD state affects spinal and supraspinal excitability of an antagonist muscle. Eight participants (~ 24y, three female) performed 14 submaximal dorsiflexion contractions at the intensity needed to maintain a level of integrated electromyographic activity in the soleus equivalent to 15% of that recorded during a maximum plantar flexion contraction. The seven contractions of the TD protocol included a 2s isometric phase at an ankle angle of 140°, a 1s shortening phase at 40°/s, and a 7s isometric phase at an angle of 100°. The seven isometric reference contractions were performed at an ankle angle of 100° for 10s. Motor evoked potentials (MEPs), cervicomedullary motor evoked potentials (CMEPs), and maximal M-waves (Mmax) were recorded from the soleus in both conditions. In the TD compared to isometric reference state, a 13% reduction in dorsiflexor torque was accompanied by 10% lower spinal excitability (normalized CMEP amplitude; CMEP/Mmax), and 17% greater supraspinal excitability (normalized MEP amplitude; MEP/CMEP) for the soleus muscle. These findings demonstrate a neuromechanical coupling following active muscle shortening and indicate that the underlying mechanisms of TD influence antagonist activation during voluntary force production.

Thyroid Storm: Emergency Care for Thyrotoxicosis

Thyroid hormones affect all organ systems and, in excess, can cause increased metabolic rate, heart rate, ventricle contractility, and gastrointestinal motility as well as muscle and central nervous system excitability. Thyroid storm is the extreme manifestation of thyrotoxicosis with an estimated incidence of 0.20 per 100,000 per year among hospitalized patients in Japan. The mortality of thyroid storm without treatment ranges from 80% to 100%; but with treatment, the mortality rate is between 10% and 50%. The diagnostic strategy for thyroid storm may take into consideration Burch–Wartofsky scoring or Akamizu's diagnostic criteria. Multiple treatment aims need to be addressed in managing thyroid storm effectively. This paper puts together all aspects to be considered for the management of hyperthyroidism and thyroid storm during the acute and emergency phase as well as consideration of special populations.

Exercise-induced pain and analgesia? Underlying mechanisms and clinical translation.

An acute bout of physical activity and exercise can increase pain in individuals with chronic pain, but regular exercise is an effective treatment. This review will discuss these two dichotomous findings by summarizing studies in human and animal subjects. We will provide the data that supports the role of physical activity in modulating central nervous system excitability and inhibition, immune system function, and psychological constructs associated with pain. We show evidence that the sedentary condition is associated with greater excitability and less inhibition in both the central nervous system (brainstem inhibitory/facilitatory sites) and the immune system. We further show that exercise and regular physical activity decreases excitability and improves inhibition in both the central nervous system (brainstem inhibitory/facilitatory sites) and the immune system. We will then discuss the clinical implications of these findings, make recommendations for clinical application of exercise, and suggest future research directions.

Toxicity of muscimol and ibotenic acid containing mushrooms reported to a regional poison control center from 2002–2016

Background: Amanita muscaria (AM) and A. pantherina (AP) contain ibotenic acid and muscimol and may cause both excitatory and sedating symptoms. Gastrointestinal (GI) symptoms are not classically described but have been reported. There are relatively few reported cases of poisoning with these mushrooms in North America.Methods: This is a retrospective review of ingestions of ibotenic acid and muscimol containing mushrooms reported to a United States regional poison center from 2002–2016. Cases were included if identification was made by a mycologist or if AM was clearly described.Results: Thirty-four cases met inclusion criteria. There were 23 cases of AM, 10 AP, and 1 A. aprica. Reason for ingestion included foraging (12), recreational (6), accidental (12), therapeutic (1), self-harm (1), and unknown (2). Of the accidental pediatric ingestions 4 (25%) were symptomatic. None of the children with a symptomatic ingestion of AM required admission. A 3-year-old male who ingested AP had vomiting, agitation, and lethargy and received benzodiazepines. He was intubated and had a 3-day ICU stay. There were 25 symptomatic patients. All but one patient developed symptoms within 6 h. Six patients had symptoms for less than 6 h while 15 had symptoms lasting less than 24 h. Ingestions of AP were more symptomatic than AM with regard to the presence of any GI symptoms (80% vs. 35%), central nervous system (CNS) depression (70% vs. 35%), and CNS excitation (70% vs. 35%) respectively. Five patients were intubated. No patients experienced hypotension, seizures, acute kidney injury, or hepatotoxicity. No deaths were reported.Discussion: Ingestion of ibotenic acid/muscimol containing mushrooms often produces a syndrome with GI upset, CNS excitation, and CNS depression either alone or in combination. Ingestion of AP was associated with a higher rate of symptoms compared to AM.

The influence of residual force enhancement on spinal and supraspinal excitability.

BackgroundFollowing active muscle lengthening, there is an increase in steady-state isometric force as compared with a purely isometric contraction at the same muscle length and level of activation. This fundamental property of skeletal muscle is known as residual force enhancement (RFE). While the basic mechanisms contributing to this increase in steady-state isometric force have been well documented, changes in central nervous system (CNS) excitability for submaximal contractions during RFE are unclear. The purpose of this study was to investigate spinal and supraspinal excitability in the RFE isometric steady-state following active lengthening of the ankle dorsiflexor muscles.MethodsA total of 11 male participants (20–28 years) performed dorsiflexions at a constant level of electromyographic activity (40% of maximum). Half of the contractions were purely isometric (8 s at an ankle angle of 130°), and the other half were during the RFE isometric steady-state following active lengthening (2 s isometric at 90°, a 1 s lengthening phase at 40°/s, and 5 s at 130°). Motor evoked potentials (MEPs), cervicomedullary motor evoked potentials (CMEPs), and compound muscle action potentials (M-waves) were recorded from the tibialis anterior during the purely isometric contraction and RFE isometric steady-state.ResultsCompared to the purely isometric condition, following active lengthening, there was 10% RFE (p < 0.05), with a 17% decrease in normalized CMEP amplitude (CMEP/Mmax) (p < 0.05) and no change in normalized MEP amplitude (MEP/CMEP) (p > 0.05).DiscussionThese results indicate that spinal excitability is reduced during submaximal voluntary contractions in the RFE state with no change in supraspinal excitability. These findings may have further implications to everyday life offering insight into how the CNS optimizes control of skeletal muscle following submaximal active muscle lengthening.

Altered Brain Excitability and Increased Anxiety in Mice With Experimental Colitis: Consideration of Hyperalgesia and Sex Differences.

Crohn’s disease (CD) and ulcerative colitis (UC) are incurable lifelong inflammatory bowel diseases (IBD) with a rising worldwide incidence. IBD is characterized by diarrhea, rectal bleeding, severe cramping and weight loss. However, there is a growing evidence that IBD is also associated with anxiety- and depression-related disorders, which further increase the societal burden of these diseases. Given the limited knowledge of central nervous system (CNS) changes in IBD, we investigated CNS-related comorbidities in a mouse model of experimental colitis induced by dextran sulfate sodium (DSS) administration in drinking water for 5 days. In male and female C57BL6J mice, DSS treatment caused increased brain excitability, revealed by a decrease in seizure onset times after intraperitoneal administration of kainic acid. Moreover, both sexes showed increased anxiety-related behavior in the elevated plus-maze (EPM) and open field (OF) paradigms. We assessed somatic pain levels, because they may influence behavioral responses. Only male mice were hyperalgesic when tested with calibrated von Frey hairs and on the hotplate for mechanical and thermal pain sensitivity respectively. Administration of diazepam (DZP; ip, 1 mg/kg) 30 min before EPM rescued the anxious phenotype and improved locomotion, even though it significantly increased thermal sensitivity in both sexes. This indicates that the altered behavioral response is unlikely attributable to an interference with movement due to somatic pain in females. We show that experimental colitis increases CNS excitability in response to administration of kainic acid, and increases anxiety-related behavior as revealed using the EPM and OF tests.

GIRK1-mediated inwardly rectifying potassium current suppresses the epileptiform burst activities and the potential antiepileptic effect of ML297

G protein-gated inwardly rectifying potassium (GIRK) channels are important inhibitory regulators of neuronal excitability in central nervous system, and the impairment of GIRK channel function has been reported to be associated with the susceptibility of epilepsy. However, the dynamics of GIRK channels in the pathogenesis of epilepsy are still unclear. In this study, our results showed that cyclothiazide, a potent convulsant, dose dependently increased the epileptiform bursting activities and suppressed the baclofen induced GIRK currents. In addition, TPQ, a selective GIRK antagonist, significantly decreased the total inwardly rectifying potassium (Kir) current, and increased the neuronal epileptiform activities. In contrast, ML297, a potent and selective GIRK channel agonist, reversed the cyclothiazide induced decrease of GIRK currents and the increase of neuronal excitability in cultured hippocampal neurons. Further investigation revealed that GIRK1, but not GIRK2, played a key role in suppressing epileptic activities. Finally, in pilocarpine mice seizure model, we demonstrated that ML297 significantly suppressed the seizure behavior. In summary, our current results indicate that GIRK channels, especially GIRK1-containing channels, are involved in epileptic activities and ML297 has a potential antiepileptic effect.

Dynamic Adaptation in Neurosteroid Networks in Response to Alcohol.

The term neurosteroid refers to rapid membrane actions of steroid hormones and their derivatives that can modulate physiological functions and behavior via their interactions with ligand-gated ion channels. This chapter will highlight recent advances pertaining to the modulatory effects of a select group of neurosteroids that are primarily potent positive allosteric modulators of γ-aminobutyric acidA receptors (GABAARs). Nanomolar concentrations of neurosteroids, which occur in vivo, potentiate phasic and tonic forms of GABAAR-mediated inhibition, indicating that both synaptic and extrasynaptic GABAARs possess sensitivity to neurosteroids and contribute to the overall ability of neurosteroids to modulate central nervous system excitability. Common effects of alcohol and neurosteroids at GABAARs have stimulated research on the ability of neurosteroids to modulate alcohol's acute and chronic effects. Background on neurosteroid pharmacology and biosynthetic enzymes will be provided as it relates to experimental findings. Data will be summarized on alcohol and neurosteroid interactions across neuroanatomical regions and models of intoxication, consumption, dependence, and withdrawal. Evidence supports independent regulation of neurosteroid synthesis between periphery and brain as well as across brain regions following acute alcohol administration and during withdrawal. Local mechanisms for fine-tuning neuronal excitability via manipulation of neurosteroid synthesis exert predicted behavioral and electrophysiological responses on GABAAR-mediated inhibition. Collectively, targeting neurosteroidogenesis may be a beneficial treatment strategy for alcohol use disorders.

An Acute Exposure to Muscle Vibration Decreases Knee Extensors Force Production and Modulates Associated Central Nervous System Excitability.

Local vibration (LV) has been recently validated as an efficient training method to improve muscle strength. Understanding the acute effects may help elucidate the mechanism(s). This study aimed to investigate the effects of a single bout of prolonged LV on knee extensor force production and corticospinal responsiveness of vastus lateralis (VL) and rectus femoris (RF) muscles in healthy young and old adults. Across two visits, 23 adult subjects (20–75 years old) performed pre- and post-test measurements, separated by 30-min of either rest (control; CON) or LV. Maximal voluntary contraction (MVC) force was assessed and transcranial magnetic stimulation (TMS) was used to evaluate cortical voluntary activation (VATMS) as well as the motor evoked potential (MEP) and silent period (SP). In 11 young adults, thoracic electrical stimulation was used to assess the thoracic motor evoked potential (TMEP). Although MVC decreased after both CON (−6.3 ± 4.4%, p = 0.01) and LV (−12.9 ± 7.7%, p < 0.001), the MVC loss was greater after LV (p = 0.001). Normalized maximal electromyographic (EMG) activity decreased after LV for both VL (−25.1 ± 10.7%) and RF (−20.9 ± 16.5%; p < 0.001), while it was unchanged after CON (p = 0.32). For RF, the TMEP and MEP/TMEP ratio decreased (p = 0.01) and increased (p = 0.01) after LV, respectively. Both measures were unchanged for VL (p = 0.27 and p = 0.15, respectively). No changes were reported for TMS-related parameters. These results confirm our hypothesis that modulations within the central nervous system would accompany the significant reduction of maximal voluntary force. A reduced motoneuron excitability seems to explain the decreased MVC after prolonged LV, as suggested by reductions in maximal EMG (all subjects) and TMEP area (data from 11 young subjects). A concomitant increased cortical excitability seems to compensate for lower excitability at the spinal level.

Direct current stimulation modulates the excitability of the sensory and motor fibres in the human posterior tibial nerve, with a long-lasting effect on the H-reflex.

Several studies demonstrated that transcutaneous direct current stimulation (DCS) may modulate central nervous system excitability. However, much less is known about how DC affects peripheral nerve fibres. We investigated the action of DCS on motor and sensory fibres of the human posterior tibial nerve, with supplementary analysis in acute experiments on rats. In forty human subjects, electric pulses at the popliteal fossa were used to elicit either M-waves or H-reflexes in the Soleus, before (15min), during (10min) and after (30min) DCS. Cathodal or anodal current (2mA) was applied to the same nerve. Cathodal DCS significantly increased the H-reflex amplitude; the post-polarization effect lasted up to ~25min after the termination of DCS. Anodal DCS instead significantly decreased the reflex amplitude for up to ~5min after DCS end. DCS effects on M-wave showed the same polarity dependence but with considerably shorter after-effects, which never exceeded 5min. DCS changed the excitability of both motor and sensory fibres. These effects and especially the long-lasting modulation of the H-reflex suggest a possible rehabilitative application of DCS that could be applied either to compensate an altered peripheral excitability or to modulate the afferent transmission to spinal and supraspinal structures. In animal experiments, DCS was applied, under anaesthesia, to either the exposed peroneus nerve or its Dorsal Root, and its effects closely resembled those found in human subjects. They validate therefore the use of the animal models for future investigations on the DCS mechanisms.

Neurophysiology of the "Celiac Brain": Disentangling Gut-Brain Connections.

Celiac disease (CD) can be considered a complex multi-organ disorder with highly variable extra-intestinal, including neurological, involvement. Cerebellar ataxia, peripheral neuropathy, seizures, headache, cognitive impairment, and neuropsychiatric diseases are complications frequently reported. These manifestations may be present at the onset of the typical disease or become clinically evident during its course. However, CD subjects with subclinical neurological involvement have also been described, as well as patients with clear central and/or peripheral nervous system and intestinal histopathological disease features in the absence of typical CD manifestations. Based on these considerations, a sensitive and specific diagnostic method that is able to detect early disease process, progression, and complications is desirable. In this context, neurophysiological techniques play a crucial role in the non-invasive assessment of central nervous system (CNS) excitability and conductivity. Moreover, some of these tools are known for their valuable role in early diagnosis and follow-up of several neurological diseases or systemic disorders, such as CD with nervous system involvement, even at the subclinical level. This review provides an up-to-date summary of the neurophysiological basis of CD using electroencephalography (EEG), multimodal evoked potentials, and transcranial magnetic stimulation (TMS). The evidence examined here seems to converge on an overall profile of “hyperexcitable celiac brain,” which partially recovers after institution of a gluten-free diet (GFD). The main translational correlate is that in case of subclinical neurological involvement or overt unexplained symptoms, neurophysiology could contribute to the diagnosis, assessment, and monitoring of a potentially underlying CD.

Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal.

Endogenous γ-aminobutyric acidA receptor (GABAAR)-active neurosteroids (e.g., allopregnanolone) regulate central nervous system excitability and many physiological functions, so fluctuations are implicated in several neuropsychiatric disorders. Pertinently, evidence supports an inverse relationship between endogenous GABAAR-active neurosteroid levels and behavioral changes in excitability during ethanol withdrawal (WD). The present studies determined mouse genotype differences in ten neurosteroid levels in plasma, cortex, and hippocampus over the time course of ethanol WD in the WD Seizure-Prone (WSP) and WD Seizure-Resistant (WSR) selected lines and in the DBA/2J (DBA) inbred strain. Gas chromatography-mass spectrometry was utilized to simultaneously quantify neurosteroid levels from control-treated male WSP-1, WSR-1, and DBA mice and during 8 and 48h of WD. Combined with our prior work, there was a consistent decrease in plasma allopregnanolone levels at 8h WD in all three genotypes, an effect that persisted at 48h WD only in DBA mice. WSR-1 and WSP-1 mice exhibited unexpected divergent changes in cortical neurosteroids at 8h WD, with the majority of neurosteroids (including allopregnanolone) being significantly decreased in WSR-1 mice, but unaffected or significantly increased in WSP-1 mice. In DBA mice, hippocampal allopregnanolone and tetrahydrodeoxycorticosterone were significantly decreased at 8h WD. The pattern of significant correlations between allopregnanolone and other GABAAR-active neurosteroid levels differed between controls and withdrawing mice. Ethanol WD dysregulated neurosteroid synthesis. Results in WSP-1 mice suggest that diminished GABAAR function is more important for their high WD phenotype than fluctuations in neurosteroid levels.

Assessment of Use of Drugs at Elderly With out-of Hospital Pneumonia

One of the most important tasks of Clinical Pharmacology - strict adherence to the principles of Rational use of drugs in geriatrics to increase the efficiency and safety of pharmacotherapy. The purpose of research - pharmacoepidemiology drugs in the elderly. -Retrospective pharmacoepidemiological. Analysis of medical history data 632 elderly patients with out-of hospital pneumonia. Assessment indicators: the interaction effect of drugs, impact on efficacy and safety, risks of clinically significant interaction effects. Valuation techniques using reference sources - Swedish Physicians Desk Reference, Beers Criteria, The American Geriatric Association. 33.5% of patients receiving drug potentially recommended list Beers, of which 24.5% with a high security risk. 632 patients treated with 414 drug combinations, drug interactions safety profile analysis demonstrates their irrationality. Most often – 29.2% of the drug combination found cephalosporins+NSAIDs. In 107 cases, we used a combination of ceftriaxone+ furosemide, which enhances the nephrotoxic effects of cephalosporins. The 1.8% (3) simultaneously combined drugs of the group of cephalosporins, aminoglycosides plus furosemide, each of which has nephrotoxicity and ototoxic action. 3% of the drug combinations include the fluoroquinolones + NSAIDs, trombokard + levofloxacin that increase the risk of central nervous system excitation and convulsions. Total of 72 combinations of drugs have been reported which comprises a drug-type “C”. Potentially clinically significant drug interactions have been - 22 furosemide + enalapril, 34 digoxin+furosemide, 16 digoxin + spironolactone. Inclusion of drugs “type C” the combination increases the risk of potentially clinically significant adverse drug reactions, for the prevention of which may require dose adjustment. The pharmacotherapy of elderly is characterized by the high level (76,1%) of an irrational combination of drugs, frequent appointment (33,5%) of the drugs which aren’t recommended elderly, not compliance of clinical need in case of VP (18%) that leads to decrease in efficiency and safety of therapy.