Set of Simulators of the Electrophysiology of the A-Type Potassium Current (IA) in Neurons / Conjunto de Simuladores de la Electrofisiología de la Corriente de Potasio Tipo-A (IA) en Neuronas

Abstract The A-type potassium current (IA) participates in important brain functions, including neuronal excitability, synaptic integration, and regulation of action potential patterns and firing frequency. Based on the characterization of its electrophysiological properties by current and voltage clamp techniques, mathematical models have been developed that reproduce IA function. For such models, it is necessary to numerically solve equations and utilize hardware with special speed and performance characteristics. Since specific software for studying IA is not found on the Internet, the aim of this work was to develop a set of simulators grouped into three computer programs: (1) IA Current, (2) IA Constant-V Curves and (3) IA AP Train. These simulators provide a virtual reproduction of experiments on neurons with the possibility of setting the current and voltage, which allows for the study of the electrophysiological and biophysical characteristics of IA and its effect on the train of action potentials. The mathematical models employed were derived from the work of Connor et al., giving rise to Hodgkin-Huxley type models. The programs were developed in Visual Basic® and the differential equation systems were simultaneously solved numerically. The resulting system represents a breakthrough in the ability to replicate IA activity in neurons.

Resumen La corriente de potasio tipo-A (IA) tiene importantes funciones cerebrales como: excitabilidad neuronal, integración sináptica y regulación de patrones de potenciales de acción y la frecuencia de disparo. Sus propiedades electrofisiológicas se han caracterizado mediante técnicas de fijación de corriente y de voltaje. A partir de estos conocimientos se desarrollaron modelos matemáticos que reproducen su función. La cantidad de ecuaciones a resolver hace que se requiera de hardware con velocidad y potencia especiales. Un software específico para el estudio propio de la corriente IA no se ha encontrado en Internet. En este trabajo se presenta un conjunto de simuladores agrupados en tres programas de cómputo: (1) Corriente IA, (2) Curvas Constante-V y (3) Tren-IA, que permiten reproducir los experimentos con técnicas de fijación de corriente y de voltaje para estudiar las características electrofisiológicas y biofísicas de la corriente IA, e investigar el efecto que tiene en el tren de potenciales de acción. Los modelos matemáticos utilizados fueron derivados de los trabajos de Connor et al., dando origen a modelos tipo Hodgkin y Huxley. Los programas fueron desarrollados en Visual Basic®. Los sistemas de ecuaciones diferenciales fueron resueltos simultáneamente de forma numérica. Los programas desarrollados contribuyen a solucionar la carencia de este tipo de programas.

Role of Multiple Choice Questions in Assessment of Competency of Knowledge in Anatomy

Objectives: The main objective of the current study is to examine the items using the item analysis to assess their competency of knowledge in human anatomy. Methods: This is a quantitative descriptive cross-sectional study conducted at the Najran University faculty of Medicine, in the department of anatomy. A 31-second year MBBS students of level three took the multiple-choice question exam comprising 100 questions in one session. Each item was analyzed by item analysis. The planned period of data collection is the first semester of the academic year 2019-2020. The data were analyzed using SPSS version 25, and Excel Software. All analyses were performed using the descriptive frequency, explore and correlation probabilities a p-value, p<0.01 (2-sided) was considered to indicate statistical significance. Results: The assessment of test items use the item analysis that is very difficult question: 25; 25%, difficult question: 8; 8%, average question: 46; 46%, easy questions; 9; 9% and very easy: 9; 9%. The discrimination indices, which are poor discrimination; 34; 34%, acceptable discrimination; 11; 11%,good discrimination; 6; 6%, very good discrimination; 4; 4% and excellent discrimination; 45; 45%. The performance of students in this test showing that a large number of items have a role in distinguishing students knowledge in the anatomy test, but in Simple parts of the scale that the items did not succeed in assessing students. Items of anatomy exams displayed a strong relationship of difficulty (P) and discrimination (D) indices. Conclusion: The MCQs items assess their competency of knowledge in human anatomy. The competence of students in the knowledge of anatomy measured at a high rate of A-type context-rich MCQs can be stem is case scenario, lead-in; question and options; distractors, and key. These items can differentiate good and poor accomplishment students..

β2-nicotinic acetylcholine receptor promotes development of GABA receptors in mouse hippocampal CA1 and CA3 pyramidal neurons / 南方医科大学学报

<p><b>OBJECTIVE</b>To explore the role of β2-nicotinic acetylcholine receptor (β2-nAChR) in the development of γ- aminobutyric acid A type receptors (GABA-Rs) in hippocampal CA1 and CA3 pyramidal neurons of mice.</p><p><b>METHODS</b>The hippocampal CA1 and CA3 pyramidal neurons were acutely isolated from β2-nAChR gene knockout (β2-KO group) mice. GABA currents in CA1 and CA3 pyramidal neurons were induced with the selective GABA-R agonist muscimol and recorded using perforated patch-clamp recording technique. The GABA currents of CA1 and CA3 pyramidal neurons were tested for their equilibrium potentials (Es) and kinetic parameters and were compared with the measurements in wild-type mice (WT group).</p><p><b>RESULTS</b>The mean E of CA1 neurons (=7) of β2-KO mice (=4) was -31.7±3.5 mV, showing an obvious depolarizing shift compared with the WT mice ( < 0.05); the mean E of CA3 neurons (=4) was -16.1±4.6 mV, also showing a depolarizing shift ( < 0.01). The difference in the Es between CA3 and CA1 neurons in β2-KO mice, but not in WT mice, was significant ( < 0.05). The GABA-R desensitization was significantly slowed down in both CA1 and CA3 neurons of β2-KO mice, with decay time of 2.2±0.2 s and 3.2±0.1 s, respectively, significantly longer than those in WT mice (1.6±0.1 s and 2.3±0.1 s, respectively; < 0.05).</p><p><b>CONCLUSIONS</b>β2-containing nAChRs may promote the functional maturation of GABA-R in CA1 and CA3 pyramidal cells in mouse hippocampus.</p>

Genetic characteristics of human enterovirus A type 71 in Qinghai province during 2016-2017 / 中华实验和临床病毒学杂志

Objective@#To investigate the genetic characteristics of enterovirus A 71 (EV-A71) and etiological features of hand, foot and mouth disease (HFMD) in Qinghai province from 2016 to 2017.@*Methods@#Specimens were collected from HFMD patients in Qinghai province, and detected by real-time reverse transcription-polymerase chain reaction (RT-PCR). For EV-A71 positive samples, virus was isolated and RNA was extracted, and then VP1 coding region was amplified by RT-PCR. The phylogenetic tree was constructed by comparing with other genotypes and sub-genotypes strains of EV-A71.@*Results@#It was shown that 114 strains of EV-A71 were isolated in Qinghai province from 2016 to 2017, which all belonged to genotype C4a, and could be divided to two different lineages by phylogenetic analysis. From 2016 to 2017, the epidemic strains of EV-A71 in the different transmission chains of Qinghai province was closely related to other provinces of China.@*Conclusions@#C4a was the dominant genotype of EV-A71 in Qinghai province from 2016 to 2017, and no other genotype was detected. In addition, EV-A71 isolated from Qinghai province co-evolved with EV-A71 in other provinces of China.

Potassium Channels: A Potential Therapeutic Target for Parkinson's Disease / 神经科学通报·英文版

The pathogenesis of the second major neurodegenerative disorder, Parkinson's disease (PD), is closely associated with the dysfunction of potassium (K) channels. Therefore, PD is also considered to be an ion channel disease or neuronal channelopathy. Mounting evidence has shown that K channels play crucial roles in the regulations of neurotransmitter release, neuronal excitability, and cell volume. Inhibition of K channels enhances the spontaneous firing frequency of nigral dopamine (DA) neurons, induces a transition from tonic firing to burst discharge, and promotes the release of DA in the striatum. Recently, three K channels have been identified to protect DA neurons and to improve the motor and non-motor symptoms in PD animal models: small conductance (SK) channels, A-type K channels, and K7/KCNQ channels. In this review, we summarize the physiological and pharmacological effects of the three K channels. We also describe in detail the laboratory investigations regarding K channels as a potential therapeutic target for PD.

Chronic Ca²⁺ influx through voltage-dependent Ca²⁺ channels enhance delayed rectifier K⁺ currents via activating Src family tyrosine kinase in rat hippocampal neurons

Excessive influx and the subsequent rapid cytosolic elevation of Ca²⁺ in neurons is the major cause to induce hyperexcitability and irreversible cell damage although it is an essential ion for cellular signalings. Therefore, most neurons exhibit several cellular mechanisms to homeostatically regulate cytosolic Ca²⁺ level in normal as well as pathological conditions. Delayed rectifier K⁺ channels (I(DR) channels) play a role to suppress membrane excitability by inducing K⁺ outflow in various conditions, indicating their potential role in preventing pathogenic conditions and cell damage under Ca²⁺-mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of IDR channels to hyperexcitable conditions induced by high Ca²⁺ pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high Ca²⁺-treatment significantly increased the amplitude of IDR without changes of gating kinetics. Nimodipine but not APV blocked Ca²⁺-induced IDR enhancement, confirming that the change of I(DR) might be targeted by Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated I(DR) enhancement was not affected by either Ca²⁺-induced Ca²⁺ release (CICR) or small conductance Ca²⁺-activated K⁺ channels (SK channels). Furthermore, PP2 but not H89 completely abolished I(DR) enhancement under high Ca²⁺ condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca²⁺-mediated I(DR) enhancement. Thus, SFKs may be sensitive to excessive Ca²⁺ influx through VDCCs and enhance I(DR) to activate a neuroprotective mechanism against Ca²⁺-mediated hyperexcitability in neurons.

Relationship among A-type behavior,job burnout and psychosomatic health in grassroots officers and soldiers stationed in Xinjiang / 中华行为医学与脑科学杂志

Objective To investigate the relationship among A-type behavior,job burnout and psychosomatic health in grassroots officers and soldiers stationed in Xinjiang, which provides the theoretical basis to maintain their psychosomatic health.Methods Evaluation was carried out with A-type behavior questionnaire, military job burnout scale and simple soldiers psychosomatic health scale in 1 939 grassroots officers and soldiers chosen by random cluster sampling method from army stationed in Xinjiang.Results ①The total scores and each factor scores of the scale had significant positive correlation among the physical scale, the job buruout scale and time hurry (TH) ,competitive and hostility (CH) (r=0.170-0.716, P＜0.01).②Job burnout entered into the physical and mental health regression equation and could explain 68.6％ of the variance(β=0.195, t=32.211, P＜0.01);TH, CH entered the regression equation of job burnout and could explain 29.5％ of the variance(t=4.925,4.427).③ TH indirectly affected physical and mental health through job burnout, the mediating effect of the amount was 0.27 ×0.83=0.2241;CH indirectly affected physical and mental health by job bumout,the mediating effect of the amount was 0.30×0.83 =0.2490.Conclusion Job burnout has fully mediated effect between TH, CH and physical and mental health.

The Downregulation of Somatic A-Type K+ Channels Requires the Activation of Synaptic NMDA Receptors in Young Hippocampal Neurons of Rats

The downregulation of A-type K+ channels (IA channels) accompanying enhanced somatic excitability can mediate epileptogenic conditions in mammalian central nervous system. As IA channels are dominantly targeted by dendritic and postsynaptic processings during synaptic plasticity, it is presumable that they may act as cellular linkers between synaptic responses and somatic processings under various excitable conditions. In the present study, we electrophysiologically tested if the downregulation of somatic IA channels was sensitive to synaptic activities in young hippocampal neurons. In primarily cultured hippocampal neurons (DIV 6~9), the peak of IA recorded by a whole-cell patch was significantly reduced by high KCl or exogenous glutamate treatment to enhance synaptic activities. However, the pretreatment of MK801 to block synaptic NMDA receptors abolished the glutamate-induced reduction of the IA peak, indicating the necessity of synaptic activation for the reduction of somatic IA. This was again confirmed by glycine treatment, showing a significant reduction of the somatic IA peak. Additionally, the gating property of IA channels was also sensitive to the activation of synaptic NMDA receptors, showing the hyperpolarizing shift in inactivation kinetics. These results suggest that synaptic LTP possibly potentiates somatic excitability via downregulating IA channels in expression and gating kinetics. The consequential changes of somatic excitability following the activity-dependent modulation of synaptic responses may be a series of processings for neuronal functions to determine outputs in memory mechanisms or pathogenic conditions.

Patrón de comportamiento tipo A, ira y enfermedades cardiovasculares (ECV) en población urbana chilena / Type A Behavior Pattern, Anger and Cardiovascular Disease (CVD) in Chilean Urban Population

Un aumento de las enfermedades cardiovasculares (ECV) mundialmente, la existencia de un porcentaje más alto que el promedio nacional de éstas para la región de Maule (Chile), y una atención incrementada en el análisis de factores psicológicos, motivan el análisis del Patrón de Comportamiento Tipo A (PCTA) y la ira respecto de las ECV. Se trabajó con 1007 participantes de 18 a 74 años (ciudadanos de Talca, Chile), mayoritariamente mujeres, quienes respondieron un cuestionario (información socio demográfica, hábitos alimentarios y de estilo de vida), la Escala Retiro de Patrón de Conducta tipo A (ERCTAa), y el Inventario de Ira de Novaco. Se les midió peso, masa corporal, presión arterial y sangre, como factores de riesgo cardiovascular. Los participantes son altamente sedentarios (79.9%), tabáquicos (53.6%), hipercolesterolémicos (44.5%), con sobrepeso (40.7%) y obesidad (32.6%), un cuarto de los cuales presenta hiperglicemia e hipertensión y con PCTA equirepartido según sexo. Es la ausencia de PCTA (ó presencia de PCTB) la que aparece asociada a factores tradicionales de riesgo cardiovascular (FRCV). La ira alta se presenta más en mujeres que en hombres (2.1% vs. 0.3%; c²(3) = 27.99, p<.0001), disminuyendo para ambos sexos con la edad, pero los infartos acaecen igualmente según sexo.

A worldwide raise in the number of cardiovascular disease (CVD) and the existence of a higher percentage in Maule (Chile) than the national media, and increased attention in the analysis of psychological factors motivate to analyze the Type A Behavior Pattern (TABP) and anger in relation to CVD. The sample was 1007 adults between 18 and 74 years old (citizens of Talca, Chile), mostly women. They provided information about their demographic details, eating habits and lifestyle, answered the Novaco's Anger Inventory and the Retiro Scale of Type A Behavior (RSTAB), and also were taken measurements like weight, body mass index and blood pressure and blood tests related to risk factors to traditional cardiovascular diseases. The results show Overall, that the participants appear highly sedentary (79.9%) with relatively high levels of tabaquism (53.6%), and hypercholesterolemia (44.5%), overweight (40.7%) and obesity (32.6%). A quarter of the sample also presents hyperglycemic indexes, hypertension and TABP unequally distributed by sex. The absence of PCTA (or PCTB presence) appeared mostly associated with traditional cardiovascular risk factors (CRF). Regarding anger, women present more high than men (2.1% against 0.3%; c²(3) = 27.99, p<.0001), decreasing for both sexes with age, while also befall stroke by sex.

Modulation of synaptic potentials and cell excitability by dendritic KIR and KAs channels in nucleus accumbens medium spiny neurons: A computational study.

The nucleus accumbens (NAc), a critical structure of the brain reward circuit, is implicated in normal goal-directed behaviour and learning as well as pathological conditions like schizophrenia and addiction. Its major cellular substrates, the medium spiny (MS) neurons, possess a wide variety of dendritic active conductances that may modulate the excitatory post synaptic potentials (EPSPs) and cell excitability. We examine this issue using a biophysically detailed 189-compartment stylized model of the NAc MS neuron, incorporating all the known active conductances. We find that, of all the active channels, inward rectifying K+ (KIR) channels play the primary role in modulating the resting membrane potential (RMP) and EPSPs in the down-state of the neuron. Reduction in the conductance of KIR channels evokes facilitatory effects on EPSPs accompanied by rises in local input resistance and membrane time constant. At depolarized membrane potentials closer to up-state levels, the slowly inactivating A-type potassium channel (KAs) conductance also plays a strong role in determining synaptic potential parameters and cell excitability. We discuss the implications of our results for the regulation of accumbal MS neuron biophysics and synaptic integration by intrinsic factors and extrinsic agents such as dopamine.

Develope Monoclonal Antibody against Foot-and-mouth Disease Virus A Type / 中国病毒学·英文版

In order to develop an anti-FMDV A Type monoclonal antibo by (mAb),BABL/c mice were immunized with FMDV A type.Monoclonal antibodies (mAbs) 7B11 and 8H4 against Foot-and-mouth disease virus (FMDV) serotype A were produced by fusing SP2/O myeloma cells with splenocyte from the mouse immunized with A/AV88.The microneutralization titer of the mAbs 7B11 and 8H4 were 1024 and 512,respectively.Both mAbs contain kappa light chains,the mAbs were IgG1.In order to define the mAbs binding epitopes,the reactivity of these mAbs against A Type FMDV,were examined using indirect ELISA,the result showed that both mAbs reacted with A Type FMDV.These mAbs may be used for further vaccine studies,diagnostic methods,prophylaxis,etiological and immunological research on FMDV.Characterization of these ncindicated that prepared anti-FMDV A mAbs had no cross-reactivity with Swine Vesicular Disease (SVD) or FMDV O,Asial and C Type antigens.Their titers in abdomen liquor were 1:5×106 and 1:2×106,respectively.7B11 was found to be of subtype IgG1,8H4 was classified as IgG2b subtype.The mAbs prepared in this study,are specific for detection of FMDV serotype A,and is potentially useful for pen-side diagnosis.

Analysis of risk factors of operation on 185 patients with acute type A aortic dissection / 中华急诊医学杂志

Objective To assess the risk factors of the in-hospital mortality of acute type A aortic dissection after operation. Method From January 2003 to June 2008,185 patients, 144 males and 41 females, with acute type A aortic dissection operated on were enrolled. The average age of patients was (49.46 ± 11.04 ) years old.The patients' demographics, history, clinical features, and some laboratory examinations were reviewed. Univariate and multivariate analysis followed by logistic regression analysis were carried out to identify the predictors of inhospital mortality. Results The in-hospital mortality rate was 9.1%. The results of univariate and multivariate analyses as follows: pre-operation positive neurological symptom (Univariate OR = 5.084,95%CI:1.792 -14.426, P = 0.002; Multivariate OR = 5.538,95%CI: 1.834 - 16.721, P = 0.002, respectively), hypotension (Univariate OR = 6.986,95%CI:1.510- 32.323,P =0.013; multivariate OR = 1.998,95%CI:0.315-12.679,P = 0.463, respectively) and renal failure (Univariate OR = 3.594,95%CI:1.237 - 10.438,P =0.019; Multivariate OR = 3.254,95%CI:1.034- 10.242, P= 0.044, respectively). Conclusions There are two predictors, pre-operation positive neurological symptom and renal failure, of pre-hospital mortality found in current analyses. Our results may improve the regimen made by cardiac surgeons and emergency doctors so as to help patients and their relatives to make correct decision.

Characterization of Ionic Currents in Human Neural Stem Cells

The profile of membrane currents was investigated in differentiated neuronal cells derived from human neural stem cells (hNSCs) that were obtained from aborted fetal cortex. Whole-cell voltage clamp recording revealed at least 4 different currents: a tetrodotoxin (TTX)-sensitive Na+ current, a hyperpolarization-activated inward current, and A-type and delayed rectifier-type K+ outward currents. Both types of K+ outward currents were blocked by either 5 mM tetraethylammonium (TEA) or 5 mM 4-aminopyridine (4-AP). The hyperpolarization-activated current resembled the classical K+ inward current in that it exhibited a voltage-dependent block in the presence of external Ba2+ (30micrometer) or Cs+ (3micrometer). However, the reversal potentials did not match well with the predicted K+ equilibrium potentials, suggesting that it was not a classical K+ inward rectifier current. The other Na+ inward current resembled the classical Na+ current observed in pharmacological studies. The expression of these channels may contribute to generation and repolarization of action potential and might be regarded as functional markers for hNSCs-derived neurons.

Correlation Between A-type Personality and Time Management Disposition of Normal College Students / 中国临床心理学杂志

Objective;To examine the correlation between A-type personality and time management disposition of normal college Students.Methods;Time Management Disposition Scale and the Scale of A-type Personality were administered to a sample of 526 college students.Results;Analysis showed significant positive correlation between A-type personality and time management disposition in college students(P

Exploration of relationship between the A type behavior and essential hypertension / 介入放射学杂志

Objective To evaluate the effectiveness of A type behavior in the development of essential hypertension.Methods The questionnaire of A type behavior were used to investigate 230 patients,divided into hypertension group (147) and no hypertension group (66). There are 89 patients and 14 patients of A type behavior in each group. 17 patients were eliminated. In some patients including A type (24 cases) and B type (26 cases), the level of norepinephrine (NE), renin (Ren) , angiotensin Ⅱ (AngⅡ), aldosterone (Ald) was tested. Results There were more A type behavior in hypertension group than no hypertension group, P 0.05).Conclusions The result confirmed that A type behavior has some influence on the development of essential hypetension and has some adverse effect on prognosis of patients.

Inhibition by Norfluoxetine, the Major Metabolite of Fluoxetine, of Voltage-Gated K+ Channels in Primary Cultured Rat Hippocampal Neurons / 대한마취과학회지

BACKGROUND: Fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has been shown to be effective in the treatment of depression. We investigated the effects of norfluoxetine, the major active metabolite of fluoxetine, on voltage-gated K+ currents in primary cultured hippocampal neurons, and determined the potency and modes of actions of norfluoxetine. METHODS: Voltage-gated K+ currents were studied in primary cultured rat hippocampal neurons using the whole-cell configuration of the patch-clamp technique. Electrophysiological recordings were done in hippocampal neurons between 5-10 days in culture. Transient A-type K+ currents (KA) and delayed-rectifier K+ (KDR) currents were isolated from whole-cell K+ currents using a pulse protocol. RESULTS: Norfluoxetine accelerated the decay rate of whole-cell K+ currents, and thus decreased the current amplitude at the end of a pulse in a concentration-dependent manner. Norfluoxetine inhibited KA and KDR currents in a concentration-dependent manner with IC50's of 0.93 and 0.70micro M, respectively. Norfluoxetine also reduced the areas of KA currents and the steady-state KDR current over the range of test potentials, and the reduction was voltage-dependent (greater increase at more positive potentials). From the onset of the fractional block of KA currents by norfluoxetine during the initial 40 ms of a clamp step, we calculated k1 = 53.26/micro M.s for the association rate constant, and k2 = 70.24/s for the dissociation rate constant. The resulting apparent KD was 1.32micro M, which is similar to the IC50 value obtained from the concentration-response curve. CONCLUSIONS: Our results indicate that norfluoxetine, the major metabolite of fluoxetine, at therapeutic levels, produces a concentration- and voltage-dependent inhibition of KA and KDR currents in primary cultured hippocampal neurons. These effects could perturb the neuronal excitability in the hippocampus, and may contribute to the therapeutic antidepressant action of fluoxetine.

Time Management Disposition and A-Type Personality in College Students / 中国临床心理学杂志

Objective: To investigate the relationship between college students' time management disposition and A-type personality. Methods: 320 college students were investigated by Time Management Disposition Scale and A-Type Personality Scale. Results: College students' personality types had positive correlation to their time management disposition.A-type students' time management disposition score was significantly higher than that of the B-type students'.Conclusion: College students' personality type had close relationship with their time management disposition.

A Case of Intramedullary Spinal Neurilemmoma

A rare case of intramedullary neurilemmoma of the spinal cord has been reported. A 23-year-old woman was admitted to our hospital, on 4th July, 1982, because of weakness of legs and difficulty of urination. Neurological examination revealed motor weakness of the both lower extremities with muscle atrophy. Sensory examination showed hypesthesia below the level of L3 dermatome of the right side and of L4 dermatome of the left. All deep tendon reflexes of the lower extremities were abolishes and Lasehue's sign was not appeared. Manometric Queckenstedt's test showed a complete block, with CSF protein of 460 mg/dl. Pantopaque myelogram demonstrated a complete block at the midportion of L1 spine. Total removal of the intramedullary tumor which was located in the dorsal column of the thoracolumbar segment was performed. The tumor was 4.0x1.5x1.0 cm in size and it proved to be an Antoni-A type neurilemmoma histologically. Only 20 similar cases have been published so far and summarized on Table 1, including our case. The relevant literature was reviewed.