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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
There is an increase of serum levels of IgE during Plasmodium falciparum infections in individuals living in endemic areas. These IgEs either protect against malaria or increase malaria pathogenesis. To get an insight into the exact role played by IgE in the outcome of P. falciparum infection, total IgE levels and functional anti-parasite IgE response were studied in children and adults, from two different endemic areas Gabon and India, exhibiting either uncomplicated malaria, severe non cerebral malaria or cerebral malaria, in comparison with control individuals.
Blood samples were collected from controls and P. falciparum-infected patients before treatment on the day of hospitalization (day 0) in India and, in addition, on days 7 and 30 after treatment in Gabon. Total IgE levels were determined by ELISA and functional P. falciparum-specific IgE were estimated using a mast cell line RBL-2H3 transfected with a human Fcε RI α-chain that triggers degranulation upon human IgE cross-linking. Mann Whitney and Kruskall Wallis tests were used to compare groups and the Spearman test was used for correlations.
Total IgE levels were confirmed to increase upon infection and differ with level of transmission and age but were not directly related to the disease phenotype. All studied groups exhibited functional parasite-specific IgEs able to induce mast cell degranulation in vitro in the presence of P. falciparum antigens. Plasma IgE levels correlated with those of IL-10 in uncomplicated malaria patients from Gabon. In Indian patients, plasma IFN-γ , TNF and IL-10 levels were significantly correlated with IgE concentrations in all groups.
Circulating levels of total IgE do not appear to correlate with protection or pathology, or with anti-inflammatory cytokine pattern bias during malaria. On the contrary, the P. falciparum-specific IgE response seems to contribute to the control of parasites, since functional activity was higher in asymptomatic and uncomplicated malaria patients than in severe or cerebral malaria groups.
Malaria is a complex disease that kills between one and two million people every year. Most of those affected are children under five years of age, non-immune individuals and pregnant women [1]. The principal cause of death is infection by Plasmodium falciparum due to its ability to induce severe complications such as severe anaemia and/or cerebral malaria (CM) often associated with hypoglycaemia [2-4]. The physiopathology of malaria cannot be represented by a single scheme. For example, patients who develop CM present a range of acute neurological manifestations and the disease is characterized by a diffuse encephalopathy, altered levels of consciousness, deep coma and seizure leading to death. Even though during the last few years a lot of information has become available from clinical and experimental studies, the causes of CM remain to be determined. The clinical outcome of a P. falciparum infection depends on the genetic factors of the host and parasite, and also on host immune responses. Antibodies and T cells are among the immune factors thought to play a role in mediating protection and also pathology [2-5].
P. falciparum infection increases the serum levels of IgM and IgG antibodies but also IgE in individuals living in endemic areas [6-12]. IgEs may protect against or participate in malaria pathogenesis. The association of high anti-P. falciparum IgE levels with a reduced risk of developing clinical malaria suggests the involvement of IgE in protection [13,14]. The observation that circulating levels of IgE most often correlate with severe rather than uncomplicated disease suggests a pathogenic role of IgE [8,10-12], and the positive correlation between the levels of IgE/IgE immune complexes and the levels of TNF in CM patients provides supporting evidence [8,10-12]. The exact role played by IgE in malaria is still unclear.
IgE is an immunoglobulin isotype that only exists in mammals. It is present at very low concentrations in the serum of normal individuals, at levels ranging from 10 to 300 ng/ml [9]. Its functional effect has been shown to depends on Fc receptors expressed on mast cells and basophils both in mice and humans, as well as on eosinophils, monocytes/macrophages and platelets in humans [9]. IgEs positively regulate both of their receptors: the high affinity receptor (Fcε RI) and the low affinity receptor (Fcε RII or CD23) [15]. The Fcε RI is expressed only on mast cells and/or basophils in both mice and humans [9,16]. The binding of IgE to the high affinity receptor on the mast cell membrane and its subsequent aggregation with antigens results in degranulation and the release of mediators that further aggravate an ongoing allergic process [17]. On basophils, the cross-linking of Fcε RI-bound IgE rapidly induces the release of IL-4 and IL-13 [16], among other inflammatory mediators. The low affinity receptor (Fcε RII) is the second major and widely distributed IgE receptor. It is also known as CD23 and is constitutively expressed on B cells and is induced by IL-4 on macrophages, some T cells, human eosinophils and platelets [9,16]. The cross-linking of CD23 on macrophages or on other CD23-bearing effector cells by IgE-containing immune complexes is thought to play a pathogenic role in malaria via TNF-mediated pathways [16].
This study aimed to evaluate the total and functional P. falciparum-specific IgE responses, the association of these responses with plasma cytokine patterns and the phenotype of the disease in endemic controls and infected patients with different clinical forms of malaria. The infected patients originated from a low endemic area in India and a high endemic area in Gabon.
All the patients included in this study were children aged between 0.1 and 6 years (mean age = 2.6 years) recruited between 1996 and 2000 at the Owendo Pediatric Hospital (OPH) and the Libreville Hospital Center (LHC) in Gabon (see Table Table1).1). Informed parental consent had been obtained. Gabon has an equatorial climate that is hot and humid, with an endemic malaria transmission. The study design was approved by the local health office ethics committee. The patients were distributed into different groups according to World Health Organization (WHO) guidelines for the definition of uncomplicated and severe malaria [18]. A cohort of 135 P. falciparum-infected children was constituted and divided into three groups according to disease severity [[6], 67] 50patients with uncomplicated malaria (UM), 29 with severe non-cerebral malaria (SM) developing severe anaemia (haemoglobin level < 5 g/dl), or hypoglycaemia (glycaemia < 2.2 mmol/ml), and 17 with severe cerebral malaria (CM) with a Blantyre Coma Score < 2, or three convulsive episodes during 24 hours before admission with post-critical comatose > 15 minutes]. Two control groups were recruited: an uninfected group, also called endemic control (EC) group, comprising 17 children with P. falciparum-negative thin blood smear, and asymptomatic infected group (AI) comprising 22 children with no clinical manifestation of malaria but a P. falciparum-positive thin blood smear.
Malaria patients were recruited in the village of Gondia, an endemic region in the north-east of the Maharashtra State of India. The village is surrounded by forest. Gondia has been known as an endemic area for at least the last 20 years. P. falciparum appeared in Gondia over the last 10 years. It is transmitted during the rainy season in June, peaks in the winter season (November, December and January) and becomes rare as summer approaches (March, April and May). The studied groups consisted of 98 patients from four to 72 years of age, being predominantly adults (see Table Table1).1). Six cohorts were constituted according to WHO criteria for uncomplicated and severe malaria: two control groups of uninfected individuals from non-endemic (NEC) and endemic regions (EC) comprising nine and 14 patients respectively; three groups of infected patients, with 31 developing uncomplicated malaria (UM), 13 developing severe non-cerebral malaria (SM) and 26 developing cerebral malaria (CM); and one group of five patients that had recovered from CM (ex-cerebral malaria patients, Ex-CM). Between eight and 10% of the CM malaria cases died. UM cases were treated as outpatients. SM patients were admitted to hospital fully conscious and could respond well verbally to doctors' questions. CM cases were in coma. Drug treatment was paracetamol, quinine and arteether (E-mal®). Samples were collected after obtaining the consent of the patients, or of their families. Blood samples from endemic controls were collected from the relatives of malaria patients (brothers/sisters/parents) with their consent. These controls had not suffered from malaria during the previous two years. Non-endemic blood samples were collected from individuals who had not suffered from malaria during the previous five years.
Venous blood was collected on EDTA in sterile vacutainers from each patient on the day of hospitalization (day 0, before any treatment), and seven (day 7) and thirty days later (day 30). Plasma was obtained by centrifuging the blood samples at 5000 rpm for 15 min. Plasma samples were stored at -80°C until use.
Parasitaemia was assessed by counting asexual forms of P. falciparum on thin blood smears under a light microscope after Giemsa staining. Parasitaemia was expressed as the mean percentage of infected red blood cells.
Erythrocytic stages of the P. falciparum malaria parasite line FAN 5HS (source: NCCS, Pune, India) and 3D7 were cultured using candle jar dessicators as previously described [19]. The culture medium was RPMI 1640 (Gibco-BRL), supplemented with 0.5% AlbuMix (Gibco BRL). The cultures were maintained in six-well or 24-well tissue culture plates (NUNC). Parasitaemia was 5% at the start of culture and reached 25% after six days. Culture medium and fresh RBCs were added every other day.
Parasite soluble antigen was prepared from synchronous cultures containing more than 20% mature trophozoites; more than 6% rings and more than 5% schizonts were used. The cultures were pooled and centrifuged at 3,000 rpm at 4°C, and the pRBC pellet was kept and the supernatant discarded. The pRBC pellet was suspended in 10 ml sterile PBS 1 × (0.15 M, pH7.2) and then centrifuged. The parasitized red blood cell (pRBC) pellet was washed five times and then lysed by adding 15 ml of 0.1% saponin. The saponin treatment frees the parasites from the infected RBCs. This was centrifuged at 6,000 rpm for 30 min at 4°C. The supernatant was discarded and the parasite pellet was washed five or six times with sterile cold PBS. The parasite pellet was resuspended in 1 ml protein isolation buffer containing a cocktail of protease inhibitors. This was briefly sonicated and the tube was kept at 4°C for between four and five hours. The contents of the tube were agitated by cyclo-mixing and then centrifuged at 6,000 rpm for 30 min at 4°C. The clean supernatant was collected in a separate tube and the pellet was discarded. The contents were sterilized by passing through 0.22 μm-pore filters. Aliquots of the antigen were frozen at -70°C until use. Parasite proteins were quantified by the Bradford method. The concentration of the parasite line FAN 5HS and 3D7 were 1.2 and 2.6 mg/ml, respectively.
Normal red blood cell (RBC) extract was prepared from the same batch of RBCs used for culturing the parasites, and followed the same procedure as previously described for pRBCs. Briefly, the RBCs were washed with PBS and the buffy coat was removed. After centrifugation, the RBC pellet was suspended in 1 ml protein isolation buffer containing a cocktail of protease inhibitors. This was briefly sonicated and the tube was kept at 4°C for between four and five hours. The contents of the tube were agitated by cyclo-mixing and then centrifuged at 6000 rpm for 30 min at 4°C. The clean supernatant was collected in a separate tube and the pellet discarded. The protein contents were estimated using a protein determination kit (BCATM protein assay Kit, Pierce, France).
An ELISA method was used to detect total IgE plasma levels in samples corresponding to day 0, day 7 and day 30. ELISA plates (96 microwell plates, reacti-bind 96 EIA Plate 100/PKG, Pierce) were coated with 50 μl/well of purified sheep polyclonal anti-human IgE solution at 5 μg/ml (The Binding Site, Birmingham UK) by incubation overnight at 4°C. The plasma samples were diluted 1:5 and incubated for two hours at 37°C. Bound IgE was detected using a peroxydase-conjugated polyclonal anti-human-IgE (The Binding Site, Birmingham UK). Binding was revealed using the OPD substrate (Sigma) and the product was quantified from the optical density (OD) at 450 nm. Serial dilutions ranging from 2 μg/ml to 0.0019 μg/ml of IgE solution (human monoclonal IgE provided by Dr Thierry Batard – Stallergenes, Anthony, France) gave the standard curve. The median of each optical density value was fitted into the sigmoidal standard curve using a specific ELISA programme running in Igor version 3.16 (Wavemetrics, Lake Oswego, OR).
A new rat mast cell line RBL-2H3 transfected with a human Fcε RI α-chain that triggers degranulation upon human IgE cross-linking was used [20]. Cells were maintained in Dulbecco medium (Gibco BRL, Eragny, France) containing 10% foetal bovine serum (FCS), 100 U/ml penicillin and 100 U/ml streptomycin (GIBCO BRL, France). Cells were expanded by incubation at 37°C for three to four days in complete Dulbecco medium supplemented with G418 (GIBCO BRL, France).
β-Hexosaminidase is known as a component of the basophil and the mast cell specific granule, and is released during degranulation of these cells [21]. Degranulation was monitored after antigen stimulation by measuring the level of released β-hexosaminidase. Fcε RI α-chain RBL-2H3 transfected rat mast cell line cultures (5 × 105 cells per well) were incubated with the different serum samples at a non-cytotoxic dilution (previously determined) for 48 hours at 37°C in the absence of the G418 antibiotic. The upregulated receptors were saturated by incubation at 4°C for 30 minutes with the same samples diluted 1:10. The cells were then washed with PBS 1X, centrifuged and resuspended in 1 ml Tyrode buffer before being centrifuged again. Finally, the cell pellet was resuspended in 450 μl of D2O (50%) and Tyrode buffer (50%) solution and each culture sample was distributed to 10 ELISA plate wells. Different controls were carried out for each sample. Control cells on lane 1 and 2 were subjected to Triton disruption (Triton 5%) and represented 100% enzyme release. Cells on lanes 3 and 4 were incubated with 50 μl of complemented Dulbecco medium without serum and represented the background enzyme release. Lanes 5 and 6, 7 and 8, 9 and 10 were incubated with 50 μl of different duplicated concentrations of parasite extract (1,000, 100 and 10 ng/ml) for 30 minutes at 37°C. After centrifugation of each well sample, 50 μl of each supernatant was collected and incubated with 50 μl of PNAG substrate solution for 90 minutes at 37°C. The level of released β-hexosaminidase was estimated from the OD at 405 nm using a spectrophotometer. All results are expressed as the percentage of total β-hexosaminidase in the cells after correcting for spontaneous release in unstimulated cultures, calculated as following: (experimental β-hexosaminidase – background β-hexosaminidase)/(total β-hexosaminidase – background β-hexosaminidase) × 100.
FACS analysis was performed after incubating RBL-2H3-D12.8 cells with several dilutions of serum samples to follow the induction of the high affinity receptor (Fcε RI) expression after stimulation by IgEs in the patient's sera. Cells were incubated for 48 hours at 37°C with the different serum samples optimally diluted to avoid cytotoxicity. A saturation step with the same sera diluted 1:10 was done by incubation at 4°C for 30 minutes. Cells were washed with PBS 1X and incubated with FITC-labelled anti-IgE (Tebu, Le Perray en Yvelines, France) (1/100) for 30 minutes. Cells were washed again, centrifuged, resuspended in PBS 1X and analysed by cytofluorometry using Cellquest software (Beckton Dickinson, USA). 10,000 cells were acquired per tube.
The levels of cytokines in the plasma (IL-4, TNF, INF-γ, and IL-10) were estimated by Opti-ELISA kits (Pharmingen, San Diego, CA.USA) used following the manufacturer's instructions.
Due to a non-normal distribution of the scores in each group, non-parametric tests were performed, using the median to compare the different clinical groups. The Mann Whitney test was used for comparisons between two groups and the Kruskall Wallis test to compare three or more groups. Spearman's correlation was used to check for correlations between parameters. P values less than 0.05 were considered as significant. Chi-squared test was used to compare qualitative variables.
Total IgE levels were analysed in endemic controls and in cohorts of P. falciparum-infected patients with different clinical forms of malaria, ranging from asymptomatic to cerebral disease, from Gabonese and Indian endemic areas to study the association between the IgE response and disease severity. Total IgE levels were measured by ELISA in individual sera before drug administration (corresponding to day 0) and determined the general distribution in the studied populations from Gabon (Figure (Figure1A)1A) and India (Figure (Figure1B).1B). Total IgE concentrations were found to be much higher in patients from India (mainly adults) than in patients from Gabon (children). In both populations independent of the different levels of IgE in each population, the median IgE levels within each clinical group tended to increase upon infection (mainly in UM and SM groups), although the difference between the groups was only significant in the Indian population (Kruskall Wallis, p = 0.0005). As only Indian patients showed a significant difference, the Mann Whitney test was used to compare the different groups in this population only. There was a significant increase in IgE levels in the EC group compared to the NEC group (p = 0.042). The most significant increase in IgE levels (versus the EC group) occurred in the UM patients (p = 0.015) and in the SM patients (p = 0.013). No significant difference between the EC group and the CM and Ex-CM groups was observed.
A range of values of IgE levels was defined enabling the analysis of the frequency of normal, moderate and high IgE levels in each clinical group of patients. The so-called normal values were adjusted to the studied population because the Gabonese and Indian groups had different plasma total IgE ranges. Therefore, the normal value (N) was defined by the median IgE levels in the endemic controls of each study population. Consequently, all values between N and 2N were considered as low/moderate IgE levels and those between 2N and 3N as moderate/high IgE levels, with the highest levels being above 3N (Figures (Figures1C1C and and1D).1D). Even in Gabonese patients, for whom the increase of IgE in the disease groups was not significant, a higher percentage of patients with clinical disease had higher IgE levels than controls and asymptomatic patients. These differences were more marked in the UM, SM and CM Indian patients (Figure (Figure1D).1D). In the Indian population, the NEC group did not have moderate/high IgE levels, although a high percentage of patients exhibited normal IgE levels (Figure (Figure1D).1D). Also, no significant change was detected in IgE levels over time in the UM, SM and CM groups of the Gabonese cohorts when tested seven days and 30 days after treatment (Table (Table2).2). No significant association of malaria and IgE levels with sex in the two studied populations. However, a significant increase in IgE levels with age (p = 0.00034) was observed in the Gabonese subjects (Figure (Figure2A)2A) but not in the Indian subjects.
The correlation between IgE levels and the parasite load was tested. Although the general trend was different in the Indian and Gabonese population, there was no significant correlation between IgE concentration and parasite load for all groups together. In Gabonese cohorts, a negative correlation for all groups was observed, except for the UM patients where the correlation showed a positive tendency. In the Indian cohorts, a positive correlation was observed between IgE levels and parasite load, mainly in the UM and SM groups (Figure (Figure2B2B).
Previous studies have used ELISA to quantify specific IgE present in the serum [7,8,10,11]. The functionality of specific IgEs present in the serum was studied by evaluating the ability of these IgEs to induce mast cell degranulation in the presence of the parasite antigen. A rat mast cell line transfected with the human α-chain of Fcε RI was used [20]. Human Fcε RI expression was induced after incubation with all serum samples at non-cytotoxic dilutions. FACS was used to detect the presence of FcåRI receptors on the mast cells surface induced by IgE present in serum samples. Although the fluorescence intensity revealing human Fcε RI expression by the mast cells varied between patient samples, IgE receptors were upregulated in all the samples tested. No correlation between total IgE levels in the serum and the up-regulation of mast cell receptors was found. There was no significant correlation between IgE levels and receptor upregulation and the level of mast cell degranulation. Sensitized cells were then incubated with different concentrations of a P. falciparum blood-stage antigen extract. Mast cell degranulation was measured by quantifying the release of β-hexosaminidase. Control cells not exposed to any serum gave a maximum mast cell degranulation of 3%. Therefore, serum samples giving an enzyme release greater than 5% in the presence of at least one of the antigen concentrations were considered positive for functional IgE. In the Gabonese cohorts (Figure (Figure3A),3A), there were functional P. falciparum IgE in all clinical groups. However, the percentage of patients with functional specific anti-parasite IgE was higher in asymptomatic and uncomplicated malaria patients than in other groups. Also, the percentage of patients displaying parasite-specific IgE was lower in the group exhibiting severe disease. The distribution of patients per group releasing between 5 and 10%, 10 and 30% and above 30% β-hexosaminidase induced by specific anti-parasite IgE revealed that one patient in CM group had a degranulation level above 30%, being the highest induced response among all the tested individuals. The same assay was carried out on the Indian population. Although there was no significant difference between groups, the percentage of patients having functional IgE recognizing the parasite extract was slightly higher in EC and UM groups than in SM and CM groups (Figure (Figure3B).3B). All positive patients had an enzyme release of between 10 and 30%. No significant correlation was found between P. falciparum-specific IgE-induced mast cell degranulation levels and sex, age and parasitaemia.
IgE production is influenced by cytokines produced by activated T cells. These cytokines are also involved in pathophysiological mechanisms associated with severe malaria [4,22,23]. Therefore, the relationship between the cytokine profile, the IgE levels and the clinical manifestation was investigated. IFN-γ, TNF and IL-10 levels were measured in the sera of the Indian and Gabonese patients. IL-4 levels were measured only in Indian patients as it was not different between the Gabonese groups. IFNγ concentrations were highest in the Gabonese AI and CM groups (Table (Table3).3). This cytokine is significantly higher in the AI and CM groups than in EC (p = 0.02 and p = 0.009 respectively). The plasma TNF concentration was similar in the severe SM and CM groups and in disease-free EC and AI groups. TNF levels were clearly higher in SM and CM groups than in the UM group (p < 0.001). Surprisingly, EC and AI also exhibited higher TNF levels when compared to UM group. No association between IFN-γ or TNF and IgE levels were found. However, a significant positive correlation was found between the concentration of total IgE and IL-10 in the UM group (p = 0.02) and a significant negative correlation in the AI group (p = 0.02) (Figure (Figure4).4). The median levels of the different cytokines in the plasma of Indian patients are given in Table Table4.4. IL-10 and TNF levels were higher in CM patients than in controls and other P. falciparum-infected patients. The plasma concentrations of these cytokines were moderate in cured CM patients (ExCM). Their levels of IL-10 and TNF were slightly higher in endemic controls than in non-endemic controls. Levels of IFN- were lower in the CM group than in AI group. No difference was found for the levels of IFN-γ between the uncomplicated and severe disease. Although, there was a significant correlation between IgE levels and IFN-γ (Figure (Figure5A),5A), TNF (Figure (Figure5B)5B) and IL-10 (Figure (Figure5C)5C) levels when looking at all the groups combined. Most diseased groups had high cytokine levels, whereas control groups had lower levels (Figure 5A, B and and5C5C).
The main feature of this study is the comparison of total and functional P. falciparum-specific IgE responses in two populations of low and high malaria transmission levels, India and Gabon respectively and their relationship with disease severity. Several clinical groups were compared: endemic non-infected controls, asymptomatics and different clinical manifestations including uncomplicated, severe non-cerebral and cerebral malaria.
Indian and Gabonese individuals exhibited a different range of plasma levels of circulating IgE These cohorts had a different age range, with the Gabonese groups being children from 0 to 6 years of age, whereas Indian patients had a mean age of 30 years. In the two populations, irrespective of its concentration and also consistent with previously published data, the IgE distribution tended to increase upon parasite stimulation [8,10,11]. In the Indian population, circulating IgE levels were seven times higher in endemic controls than in non-endemic controls. This suggests that exposure to the parasite strongly influences the production of IgE, although this difference may also be due to other endemic factors [7]. Nevertheless, it was reported that IgE levels were greatest in patients developing severe disease than in CM group (Figure (Figure1A1A and and1B).1B). When considering the percentage of patients that produce high levels of IgE per group, it was shown that IgE levels are higher in UM and SM (Figure (Figure1C1C and and1D)1D) than in CM patients who had values similar to that of the controls [8,24]. In addition, the median levels of circulating IgE in the ExCM group were close to that of the CM group. Also, no significant correlation was found between both IgE and TNF levels in the CM group. These observations are contrary to published data describing increased IgE levels that correlate with high concentrations of circulating TNF, a cytokine associated with malaria severity and also with pRBC adherence on brain capillary endothelial cells [9,10,25,26]. The results suggest that either IgE does not play an important role in CM pathogenesis, or that these antibodies may participate in the parasite sequestration into the brain or other organ capillaries [24].
There was a significant increase in IgE levels with age in Gabonese children independent of the disease group (Figure (Figure2).2). This increase in IgE production between 0 and six years of age may also reflect an increase in the capacity of the immune system to respond to parasite infections [7,27]. Such a correlation was not found in Indian groups. This would be expected because the Indian groups comprised mainly adults, with the few children being older than five years. Although most of individuals in the Gabonese endemic control group had already been in contact with the parasite, as demonstrated by the high titres of specific antibody to P. falciparum-infected red blood cells observed in these children, the median plasma IgE concentrations were compared with those of the Indian NEC group. Although the median total IgE levels in the Indian NEC groups was higher than that of the Gabonese EC group, suggesting that age could be an important factor in IgE production, the higher IgE levels in the Indian population may also be interpreted as the result of either environmental factors, such as predominance of food allergies, of the genetic background, which may predispose to developing IgE responses [13,27,29-32] or of a co-infection with other parasites, such as helminths affecting the IgE responses in these patients [33,34]. In the Gabonese cohorts, IgE levels tended to correlate negatively to parasitaemia except in UM whereas all patient groups from India showed a positive correlation.
The pool of circulating IgE comprises both monomeric and complexed immunoglobulins [35,36]. A functional test was performed, based on the ability of the circulating IgE from the sera of different patient groups to induce degranulation of mast cells in the presence of pRBC antigens to better estimate the P. falciparum specific IgE response. This test does not provide specific IgE concentration within total IgE. It is based on the specific IgE induced percentage of mast cells degranulation. Degranulation was measured by quantifying β-hexosaminidase release. Functional P. falciparum-specific IgEs were detected in randomly chosen patients from all groups in both the Gabonese and Indian populations, except for ExCM Indian patients. The highest percentage of patients with functional anti-parasite IgEs was found in the Gabonese AI and UM and Indian EC and UM groups, which decreased in the SM and CM groups (Figure (Figure3A3A and and3B).3B). This suggests a protective role for P. falciparum-specific IgE, and is consistent with previous published data [13,14].
Although the CM group had a low percentage of patients able to induce degranulation, it was the only group where there was one patient serum inducing a mast cell degranulation above 30%. This intense response may be associated with the presence of IgE with higher affinity for P. falciparum antigens, as previously reported by Gonzalez-Espinosa et al. [37]. However, the level of degranulation can also be enhanced by the number of receptors involved in recognizing the antigen-IgE complex, which can strongly affect the size of the secretory response [37,38]. There was no evident correlation between the level of functional P. falciparum-specific IgE (percentage of enzyme release) and the level of total IgE per group within each population. This is unsurprising, given that both the monomeric and complexed forms of circulating parasite-specific IgE can affect the level of degranulation [39-41]. It is also acceptable that total IgE levels were not directly correlated to FcåRI upregulation levels [40,42]. The minimum level of receptors occupied by the parasite antigen-specific IgE complex required to induce a degranulation response is 10%. Consequently, this response will be independent of the total IgE levels [20]. An increase in specific IgE levels has been also seen in other parasitic infections, such as helminthiasis, in which the specific IgEs usually help to eliminate the pathogens either through hypersensitivity reactions resulting from mast cell degranulation or by inducing antibody-dependent cell-mediated responses [27].
High levels of IgE in P. falciparum-infected individuals have been shown to be due to an underlying imbalance in favour of IL-4 in the ratio of CD4+ T cell producers, which are responsible for the IgG/IgM isotype switching to IgE [10]. High levels of circulating IL-4 have also been associated with a greater parasite antigen-specific production of IgE in individuals less susceptible to malaria [13]. Also, Th1-type pro-inflammatory cytokines, such as IFN-γ and TNF are thought to play an important role in the both protecting against and increasing the pathogenesis of cerebral malaria [3,4,22]. Plasma TNF, IFN-γ and IL-10 levels were measured in both the Indian and Gabonese groups. In the Gabonese groups, no direct correlation was found between IgE and IFN-γ or TNF levels in the UM, SM and CM patients. However, the level of IgE production was correlated to IL-10 levels in UM and AI patients (Figure (Figure4).4). In this group, there was a positive association between IL-10 levels and parasite load, but not between IgE levels and parasitaemia. In the Indian groups, IFN-γ, TNF and IL-10 levels were all significantly correlated with IgE levels independent of the group (Figures 5A, B and and5C).5C). When looking for a correlation per group, no significant statistic value was found. IL-4 is the main cytokine responsible for IgE production, inducing antibody isotype switching from IgG and IgM to IgE [10]. Previous studies have shown an association between the IL-4/IFN-γ levels and IgE levels, suggesting an induced Th2-type switched response [43]. As IL-4 levels were different between groups only in Indians, a correlation was expected between this ratio and IgE levels, and surprisingly, the results showed an opposite correlation (p = 0,012). The levels of IL-4 remained almost constant across all groups as IgE levels increased. Therefore, this opposite correlation arises due to a parallel increase in both IFN-γ and IgE levels. This suggests that, in the Indian population, IL-4 does not seem to directly influence IgE levels. It has been shown experimentally that there are conditions under which alternative mechanisms may induce IgE production independent of IL-4 [44]. Regarding other cytokine ratios, like TNF/IL-10, no significant correlation was found with total IgE levels.
In conclusion, these results showed that total IgE levels increased in infected patients, mainly in UM and SM patients but not in CM patients. The decrease in total IgE levels in the CM group was associated with a higher intensity of mast cell degranulation induced in vitro by P. falciparum-specific IgE. In addition, no correlation was found between total and functional P. falciparum-specific IgE levels.
The results reported here show the high activity of functional circulating P. falciparum-specific IgE in asymptomatic malaria patients. However, no correlation was observed between plasma levels of total IgE, the disease phenotype and the cytokines pattern in the different groups of patients studied. The opposite association between pro- and anti-inflammatory cytokine ratios and IgE levels reveals the complexity of immune response disruption occurring during malaria in patients from low and high malaria endemic region.
Joana Duarte contributed to the acquisition, analysis, interpretation of data and manuscript drafting but not the design of the study. Prakash Deshpande and Vincent Guiyedi have highly contributed to conception and interpretation of data and manuscript revising. Salah Mécheri collaborated to the design and interpretation of IgE functional tests and manuscript drafting. Constantin Fesel contributed to the statistical analysis, interpretation of data and manuscript drafting.
Pierre-André Cazenave, Gyan C. Mishra and Maryvonne Kombila have contributed to conception of the study and manuscript revising. Sylviane Pied participated to conception, design, analysis and interpretation of data, the final approval of the version to be published.
This work was part of the Centre National de la Recherche Scientifique-Laboratoires Européens Associés "Génétique et developpement de la tolérance naturelle" program. It was supported by the PAL+ program of the French Ministry of Research. We thank the Indo-French Centre for the Promotion of Advanced Research (IFCPAR), New Delhi, India for providing financial assistance (project No.2103-3). C-F received a post-doctoral fellowship from the Fundaçâo para a Ciência e Tecnologia (Portugal). V-G holds a fellowship from the Agence Universitaire de la Francophonie (AUF).
We thank M. Bouyou-Akotet and M. Idrissa-Boubou for assistance with the collection of plasma samples. We are grateful to R.O. for critical reading of and his help in preparing the manuscript.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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** Comuse Travels is an affiliate of Tea Collection
Filed under: Travel Wear


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9637 Hollow SW Road, Pataskala, Ohio
$245,0003 Beds1+ BathsActive
$245,0003 Beds1+ BathsActive
9637 Hollow SW Road, Pataskala, Ohio 43062 - This home was built in 1850 and has been continually maintained and improved by a single family since 1964. The property is 1.88 acres and has a detached garage/barn that can be used for parking, working, and storage. It has a partial concrete basketball court and mature trees and lawn. The property is being sold in its AS-IS condition. It is located on the corner of SR310 and Hollow Road. The beauty and charm of the property are seen in the pictures provided with this listing.
Listing Courtesy of Connie J Klema (614) 847-1002 - Coughlin Realty, Inc. (614) 847-1002
"The Parrett Group was amazing to deal with. They always went above the call of duty and were helpful before we listed, durring the sales process and after closing to ensure that we were completely satisfied. Anyone buying or selling a home in The Parrett Group's territory that uses another agent is wasting their time and money."


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JACKSONVILLE, N.C. --- Schools -- including North Carolina -- are slowly discovering Jireh Wilson, a 6-foot-3, 188-pound athlete who led Northside High in both receiving and interceptions as it reached the state championship game.
Scouting Report
"Jireh is real athletic," Northside head coach Kendrick Pollock said. "He plays wide receiver for us [and] free safety. He has real big hands. He's only 16 years old, so he's still a baby. He's a humbled kid [and] doesn't show too much, but on Friday nights it comes out and it speaks on film -- he's just that quiet leader. As soon as football was over, he went over to basketball; after basketball he came right on out to track-- he's a hard-working kid. He's an excellent student. To be 6-3, 188 [pounds] and have the ability to stretch the field offensively, and then turnaround and play defense, and also special teams and return kicks is special."
Prep Career
Prior to his sophomore year, Wilson moved to Jacksonville from Florida. He immediately became an integral part of Northside High's offense and defense.
"This year, Jireh stepped up and made big plays for us on offense," Pollock said.
"As a safety, he's back there calling out the coverages for us. He's not afraid to come up and lay a hit. A couple of playoff games, we walked him down and put him on [the opponent's] tight end or whoever we thought their main guy was [and] he'd lock onto them man-to-man."
As Northside High marched its way into the NCHSAA 2AA title game, Wilson led the team in receiving yards (583) and receiving touchdowns (seven), with 31 receptions. Defensively, he was the team leader in interceptions with eight, while also making 41 tackles.
Wilson might be NC's greatest sleeper. At least initially, when college coaches visited Northside High during the Winter Evaluation Period they came to see Maurice McIntyre.
"When they first come in, everybody knew about Maurice," Pollock said. "And then I show them Jireh and Demetrius [Jones], because they're going to be big-time kids."
UNC, namely wide receivers coach Gunter Brewer, took a liking to Wilson.
"The first thing they like about Jireh is they like his size," Pollock said. "And then they shake his hands and they see he has big hands. They like his body frame. And then they see that he excels in the classroom. I think the light bulb went off, 'I have a student athlete that I don't need to worry about.'"
Clemson, Charlotte, Duke, Georgia Tech, NC State, Virginia, Virginia Tech, and Wake Forest have also taken an interest in Wilson. However, no school has offered.
UNC's interest in Wilson prompted an invitation to the Tar Heels' first junior day back in late January. He gladly accepted
"It was a great experience," Wilson said. "I loved the school; they gave me a tour of the facility. All the coaches approached me well. I just like the attitude and atmosphere of the school itself."
The experience provided Wilson his first conversation with Brewer.
"When I first met him, he asked me about my personal life -- how I grew up, who I live with," Wilson said. "And then he was telling me about how he likes my size and athleticism, and they're going to keep looking at me going into my senior season. And hopefully, they can offer me."
According to Wilson, Brewer is recruiting him as an athlete. Most other schools see Wilson as either a safety or receiver.
NC State is the only other school that Wilson has visited.
"My favorite is UNC, but I like NC State also," Wilson said. "They're both in-state and I kind of want to stay close to home, but also I just like the coaches and the environment."
Extra Points
Wilson's first name is pronounced JEYE-rah... With both parents in the military, Wilson has moved around a lot... Wilson maintains a 4.25 weighed GPA... Wilson has worked out with UNC wide receiver Josh Cabrera, during his breaks from school... As mentioned above, Wilson is also a member of the basketball team, which went undefeated and won the 2017 NCHSAA 2A Championship, and runs track. He plans to run in the 100-, 200-, and 400-meter dashes.


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Trailer sway occurs when an RV (recreational vehicle) or trailer (e.g., a cargo-carrying trailer or a boat) that is being towed by a car, truck or SUV begins to sway from side to side most likely at high speed down a freeway. Trailer sway (commonly known as "fishtailing) can also happen to the trailers of big-rig trucks, the semi-trailers that transport nearly all the consumer goods we use every day.
A Dangerous Phenomenon
Trailer sway is very dangerous, and it's more common than one might realize. According to the Recreational Vehicle Industry Association, there are more than nine million RVs on the road in the U.S.; nearly 10 percent of the vehicle-owning households in the U.S. have an RV. There are some five million trailer-trucks on our highways, according to the American Trucking Association.
How Trailer Sways Happen
A trailer sway accident may occur when:
when the vehicle/trailer combination is being passed by a large vehicle, the force of which moves the trailer
the trailer is hit by a sudden gust of wind
the driver of the trailer combination must make a quick evasive maneuver in traffic
the driver of the trailer combination is inexperienced and does not know how to control the trailer
the trailer driver is impaired by alcohol, drugs or fatigue and does not control the trailer
Trailer sway is dangerous to the driver of the vehicle towing the trailer, the occupants of the vehicle, and passengers in vehicles that are on the road at the same time and place. At times, the sway is severe enough for the trailer to hit another vehicle or to make the vehicle towing the trailer tip over.
Industry Awareness
The RV industry and trucking industry have known about the dangers of trailer sway for decades, but design and manufacturing defects in RVs, trailers and large trucks have often contributed to or caused accidents based on trailer sway. More needs to be done to prevent needless trailer sway accidents, injuries and fatalities.
Talk to a Plaintiffs' Attorney
If you've been in an accident that involved trailer sway, contact a law firm near you to discuss your circumstances. You may be eligible for financial compensation for your losses.
The federal government is under increasing pressure to impose tougher regulations on vehicle crashworthiness. In a long overdue effort, the National Highway Traffic Safety Administration...


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About Us
Lifeologia is an online pop magazine, where we share the latest and the most accurate news about your favourite hollywood stars. At lifeologia, we make sure that our readers get the freedom to share news and ideas with us, and we be publish the best ones on our website. So keep reading and sharing


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The Acne Opinions - Examine Them The following By Johnathan Cunn
Acne refers to a medical condition by which you will find a damaging deposition of sebium (essential oil) cures also comprises escalation on the microbes as well as inactive skin cells ensnared within the shell on the hair of our skin skin pores
. The fitness of acne is not a teenaged trouble only several people arrive at practical experience this trial at some point or any other how to get rid of acne. Before you be happy with any treatments for the acne predicament you will need to take into account the most efficient beyond many alternatives you will discover in current market though it may be also excellent to talk with all your health care practitioner or healthcare provider prior to tumble into any type of acne skin color treatment method.
Occasionally as a woman proceeding assumed the sensitive cycle of pregnancy stage you can receive amazed as to the reasons one's body takes that getaway backside your teen several years whenever you were required to encounter view of acne breakouts. The acne actuality will even now come specifically to girls encountering carrying a child. The rationale to the present is the fact that at pregnancy there is a heightened volume of hormonal manufacturing and this would increase the risk for skin oilier. An slimy pores and skin is a useful one reproduction soil for acne. In case you under no circumstances enjoyed possessing acne breakouts after you ended up being adolescent you can't would delight in having them now. So acne can be an trial at teenage and even if you are getting to be an adult.
Ahead of studying some top rated acne treatments be sure that keep in mind essentially will forever ought to consult with your health proper care provider before taking any drugs on your zits how to get rid of acne. The key reason why for this is we now have great shape of acne. Medicinal drugs like Zenmed and Acnezine are some of the prime alternatives for the management of the acne issue. Acne seriously isn't generis skin problem. You'll find styles of it which have been certain to some types of skin color consequently it will likely be recommended that you get expert assistance with what exactly is remedy of retreatment will suit your problem. The Zenmed acne option is generated and written by Warp speed Projects Ltd. This type is a superb acne procedure which was created to do the job both equally in house together with externally. The perfect solution is carries with it an state-of-the-art three action method that's collection to help remedy acne bacterial infections. The remedy will also regulate hormone creation and relieve. What also makes this alternative powerful is that it basins profound for the very cause and cause of the acne difficulty. This gives panic disorder get a grip on hormone imbalances instability and market a general purification from within.
Acnezine the other effective acne treatment methods you'll discover already in the market. Products is produced and retailed by Revitol Organization Inc . This place is an anti --acne method that's been aimed at provide alleviation for those skin variations. Why is this answer more beneficial is it can cope with any varieties of themes
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- Keeps cool for up to 3 days. DeepFreezeTM high performance insulation with radiant heat barrier.
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- Erected Dimensions: H 41.3 x W 35.6 x D 35.6 cm; Capacity: 23.7 US Quart (22.5 litres) / 60 x 335 ml cans; Weight: 4.2 kg
This Titan 22.5 Litre (23.7 US Quart) 60 Can Rolling Cooler holds ice up to 3 days! The interior is comprised of DeepFreezeTM high performance insulation with radiant heat barrier and triple layer Cold BlockTM base for superior cooling and features a seamless, leak proof liner that is removable for easy cleaning. The cooler's exterior is constructed of durable, water and stain resistant Rhino-Tech® and includes an easy access lid, expandable, insulated front compartment, 2 drink holders and a detachable bottle opener. The New Big Wheel All Terrain Cart can be used with or without the cooler, holds up to 45.4 kg and has oversized wheels and an expandable, extra wide base. If you want to use the cooler without the cart, the Backsaver® adjustable shoulder strap centres load weight to reduce contact pressure and muscle stress. Both the cooler and cart collapse for easy storage.


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Music retailers (you can change it depends on the essay)
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UK MUSIC RETAILERS Name Institution of Affiliation Course Date UK Music retailers 1. Businesses operating in any industry are bound to experience changing fortunes in so far as trade is concerned. There are several forces that play in the economy thus influencing the fate of each of the entities in a given sector…
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Music retailers (you can change it depends on the )
This includes carrying out professional analysis that entails identification service sector challenges and assessment of operations, evaluation of changes in the music industry and appraising measures of service quality. I further use interaction matrix to analyze how the business has changed over time. Finally, I conclude by comparing two players in this music sector and offer some appropriate recommendations. Just like in any other economy of the world, the UK economy also suffers from quite a number of challenges. Being an important component of the economy, the UK retailers have not been spared from the difficult moments that occasionally characterize the economy. Therefore, some traditional UK retailers such as music retailers who deal with the selling of music CD and VCD have been critically affected. In the past few years, some famous music retailers went bankrupt one after another. Cases in point include the Towers, KPS, and Virgin. Whilst some of the aforementioned retailers were troubled by the market changes, the likes of Find-CD, which is an online music company, were flourishing (Traynor, 2013). According to findings of Traynor (2013) in his research, nearly 140 music retailers are prone to perilous economic period in the near future. A case in point is the HMV music retailer. ...
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Guaranteed Bard Credit Greensboro Bend Vermont Payday Loans
Running out of cash in Greensboro Bend? Get the benefit of guaranteed bad credit Greensboro Bend VT loans. Filling of small online form would serve your purpose. Greensboro Bend company is offering online short-term fax free payday loans with least paper work. You have to just to comply with few of the company's requirements like, you must have full time Greensboro Bend job, attained 18 years of age and must have verifiable checking Vermont account. There are no further formalities required for getting the instant Greensboro Bend bad credit payday loans sanctioned. Other conventional Greensboro Bend Vermont loans call for collateral securities but guaranteed no fax payday loans are absolutely free from such bondages. Guaranteed no fax Greensboro Bend same day loans are flourishing, as the procedure is very simple and the company does all the Vermont formalities. The cash is deducted on the date of repayment from your VT checking account.
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Guaranteed no fax Greensboro Bend payday loans get approved within no time. The tenure for repayment is 30 days that can be extended as per your desires. The desired amount for instant no credit check loans may be $100 - $2000 or more depending on your Vermont requirements. Fee rates are only few dollars more than conventional loans but the Greensboro Bend same day loans render faster and better facilities. As soon as you fill the online form, the server substantiates all the relevant details and within one minute you receive the amount. The Greensboro Bend loan gets directly transferred in your Vermont checking account.
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Unformatted text preview: Chapter 10: Stress Management & Management Techniques
Introduction The Mind/Body Connection The Brain The Immune System Stress Prevalence Annual Cost Definition by Hans Selye Eustress Distress Chronic distress diseases Management of distress Stress, Health & Performance High Optimal performance and well-being Health and performance Eustress Low Low Optimal Stress Mental, emotional, and physiological limitations Distress High Fig. 10-1, p. 327 Physiological Response to Stress Stressor Individual perceives stress Hypothalamus Brain messages to Pituitary gland Activation of sympathetic nervous system Increase in: Heart rate Blood pressure Blood glucose Blood flow to active muscles and brain Oxygen uptake Strength General awareness Release of catecholamines from adrenal glands Stress release No stress release Body relaxation Decrease in health and performance Fig. 10-4, p. 336 Adapting to Stress Homeostasis General Adaptation Syndrome (Hans Selye) Resistance
E xh tion au s Homeostasis Alarm Stressor reaction Recovery Illness Exhaustion/ Recovery Fig. 10-2, p. 328 Perceptions & Health Explanatory Style Optimistic Pessimistic Self-Esteem A Fighting Spirit Sources of College Stress Alcohol use Time management Parental conflict Drug use Academic competition College red tape Religious conflicts Choice of major/ future job Sexual pressures Lack of privacy Illness and injury Love/ marriage decisions Family responsibilities
Loneliness Depression Anxiety Social alienation, anonymity Military obligations Money troubles Fig. 10-3, p. 330 Behavior Patterns (intro.) Type A Behavior Type B Behavior Type C Behavior Behavior Patterns (cont.) Structured Interview Vulnerability to Stress Time Management Distress if Poorly Done Five Steps Skills Coping with Stress (intro.) Recognize that a Problem Exists Identify the Stressor Remove the Stressor, or Respond Differently to the stressor Relaxation Techniques (intro.) Exercise Biofeedback Coping with Stress (cont.) Relaxation Techniques (cont.) Progressive Muscle Relaxation Breathing Exercises Visual Imagery Autogenic Training Meditation Yoga Which Relaxation Technique is Best? Individuals Vary in Responses The Environment is a Factor Experiment to Find Effective Choices ...
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- Fall '07
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If I Tell You I Have To Kill You
If I Tell You I Have To Kill You
No reviews
Morale Patch Armory's Description:
You have heard or maybe even said it to someone before, "If I Tell You, I Have To Kill You." Well now you can have it in Morale Patch form with this badge shaped Embroidered Morale Patch. With the dagger in the middle it's a surefire way to say, you live by the sword and other will die by the sword if they are on a need to know basis. Add this patch to your collection now!
Morale Patch Armory Specs
Design: Milspec Monkey
Material: Embroidered
Size: 2.25"x 2.75"


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Everything he does is awesome
Everything he does is awesome
a few of my favourite things ☆ (9/30) male characters: devon woodcomb
okay. okay. casey has some serious guns. is that creepy? yes. is that illegal? sadly, no.
CHUCK MEME: [1/8] characters - Devon 'Captain Awesome' Woodcomb
Well I've finally picked the perfect name and I don't want him to shoot it down. It's the most beautiful, unique, precious name for a girl…
"...Sometimes I know life isn't always awesome. What I'm trying to say is that, when things get rough I wanna face them together, the good times and the bad. I have a ring and I have the blessing of your brother, would you do me the honor becoming my wife Eleanor Faye Bartowski?"
↳ Young Blood- The Naked and Famous (4x13: Chuck vs. The Push Mix)
Everything he does is awesome. Climbing mountains, jumping out of planes, flossing.
Reblog if you are Team Ellie&Devon
4x13 - Chuck Versus the Push Mix


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Zevotek, Inc. (ZVTK.PK) Retains Services of Comptroller
Zevotek is focused on independently marketing and selling a range of distinct and independent lines of home care and household products. The company has entered into a license agreement to sell an energy saving compact fluorescent light bulb named the Ionic Bulb. Zevotek plans to market the Ionic Bulb through TV infomercials, websites, major US retail and specialty stores, catalogs and magazines.
Zevotek recently announced the addition of Chang Hun Kim who will act as the company's comptroller on a consultant basis. Mr. Kim has been an AICPA member since August of 2000. He is a graduate of Columbia University with a BS in 1988 and a MS completed in May 1989. Mr. Kim passed all four parts of the CPA exam in his first attempt.
Mr. Kim was brought to Zevotek's attention by Jason Ryu, the inventor of the Ionic Bulb. Mr. Ryu has been working diligently on the sales aspect of the business. In anticipation of contracts being completed, Mr. Ryu felt that this addition was much needed to ensure proper oversight measures.
Due to his long-standing relationship with Mr. Kim, Mr. Ryu was able to obtain his services at no cost to Zevotek at this current time. However, as the contracts are completed it was agreed that Mr. Kim will be fairly compensated.
Let us hear your thoughts: Zevotek, Inc. Message Board


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November 4, 2016
It's November, also known as National Diabetes Month, a time in our diabetes world when we in the United States raise awareness about diabetes and the importance of proper care and education. At AADE we proclaim the first full week of November National Diabetes Educator Week. It's November 6–12 in 2016.
August 31, 2016
Healthy Interactions' Conversation Map tools are the most deployed DSME/S curriculum in the world. The diabetes Map tools were developed in collaboration with the American Diabetes Association in the U.S.A. and the International Diabetes Federation outside of the USA. Over 80,000 diabetes educators have been trained to facilitate the Map sessions in over 120 countries. The effectiveness of the Map tools can vary from one cohort to the next due to cultural implications, although the program has been translated and made culturally relevant for each country in which it is used. Previous research assessing outcomes for specific cohorts of patients has been collected, but this is the first study to evaluate Map tools outcomes at the macro level.
August 18, 2016
Medicare requires that nine of 10 hours of DSME/S be administered via group sessions. The remaining one hour can be delivered individually, but it can also be delivered in a group setting if more appropriate. Healthy Interactions focuses mostly on group education sessions because one-on-one sessions have not proved as effective when it comes to patient program completion. Group sessions have been successful because the curriculum is totally centered on the participant and allows for individualization within a group environment. A group creates a support network, incentivizing patients to return for additional sessions.
June 16, 2016
WellDoc touts the value of PCMH collaboration in a new mHealth study involving diabetic patients. That's exactly what Healthy Interactions is looking for, as well.
June 16, 2016
Two health IT companies, Chicago-based Healthy Interactions and Toronto-based MedCurrent, have launched a new end-to-end clinical decision support (CDS) platform designed to manage chronic care conditions.
June 13, 2016
Over the past decade, Healthy Interactions "Diabetes Conversation Map" programs have improved the lives of over 30,000,000 people with diabetes, in 127 countries, and in 39 languages and cultures. The Healthy Interaction diabetes programs we developed in collaboration with the most recognized and important associations including: American Diabetes Association, Diabetes UK, International Diabetes Federation and the Canadian Diabetes Association. Over 50 independent clinical and behavioral studies validate the efficacy of the Healthy Interaction programs.
June 13, 2016
Healthy Interactions and MedCurrent recently introduced a first-of-its-kind clinical decision support (CDS) platform that merges evidence-based guidelines with clinical workflows at the point of care designed specifically to manage chronic care conditions.
June 13, 2016
Healthy Interactions and MedCurrent recently introduced a first-of-its-kind clinical decision support (CDS) platform that merges evidence-based guidelines with clinical workflows at the point of care designed specifically to manage chronic care conditions.
June 2, 2016
CDS system integrates into EHR, taps evidence-based guidelines for chronic conditions, and provides real-time, individualized care plans to save time and avoid unnecessary tests, treatments and procedures
November 6, 2015
Healthy Interactions lead facilitator, Barbara Eichorst, will be hosting a webinar on November 18th at 12pm CST entitled, "Empowering Behavior Change in People with Chronic Conditions: Utilizing Conversation Map® Tools and a Digital Platform."
June 2, 2016
September 2, 2015
October 17, 2015
July 27, 2015
July 23, 2015
July 22, 2015
March 23, 2015


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Carrie Bradshaw's Mac Gets Replaced in Sex and the City 2
Traded in for a HP.By Josh Duboff
Traded in for a HP.By Josh Duboff
Cause the Material Girl is going to sell a whole bunch more songs whatever you call it.By Willa Paskin
The agreement reportedly helped the lower-budget film get made.By Josh Duboff
Did you know the iPad will be in stores this weekend? If not, you definitely missed last night's episode of 'Modern Family.'By Lane Brown
Feel like buying Wonderbread/Diet Coke/Polaroid today?By Edith Zimmerman
Every time the movie gets attention, the Pixar hangout gets more business.By Carrie Bell
Beat that scripted TV!By Adam K. Raymond
Spam: It tastes better than people!By Lane Brown
Maybe if they charged everyone, our DVR wouldn't have cut off the last two minutes of the show!By Mark Graham
Since the show is set in the sixties, don't these companies risk seeming dated? We get schooled on the world of modern advertising.By Mike Vilensky
We think the answer is yes.By Mark Graham
Get your Encyclopedia Brown on, people!By Mark Graham
DJ Goldie May Have Just Confirmed the Identity of Banksy With a Slip of the Tongue
Johnny Depp Casually Jokes About Assassinating Donald Trump, References John Wilkes Booth
The Great Drake Bell–Josh Peck Feud Just Keeps Getting Pettier
As Brexit Talks Begin, the U.K. Has Few Cards to Play
Is Sex in Silicon Valley As Bad As Sex on Silicon Valley?
All the Different Reasons Jean-Claude Van Damme Was Allegedly Fired From Predator
Inside the 1950s LSD Therapy That Changed Cary Grant's Life
Orange Is the New Black Season Finale Recap: Unnecessary Force
The First Photos From the Versace Season of American Crime Story Are Out, and Damn, Ricky Martin


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June 16, 2016 — LaFrance "Joe" Clarke, a Principal's Multicultural Advisory Committee leadership team member, PMAC sponsor and language arts teacher at Pinellas Park High School has been selected to make a presentation at the state Education Commissioner's African American History Task Force Summer Institute.
June 15, 2016 — New this week on WPDS-TV14.
June 15, 2016 — Education Commissioner Pam Stewart honored the second class of Commissioner's Leadership Academy graduates at a ceremony yesterday.


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Rebecca J. Rosen is an associate editor at The Atlantic. She was previously an associate editor at The Wilson Quarterly, where she spearheaded the magazine's In Essence section.
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Venue: Palazzo Theater
3325 S. Las Vegas Blvd.
Las Vegas, NV
Show Dates: June 25, 2016 - March 31, 2018
Show Times: 7pm
Age Restriction: 5
Show Length: 90 minutes
Starting at $64.31
Do you want to take a look into the musical mind of filmmaker Baz Luhrmann? Well, "BAZ Star Crossed Love" is your opportunity. This unique entertainment experience combines theater, concert and nightclub experiences to create a high-energy journey that Vegas has yet to see.
BAZ was inspired by cinematic and musical films such as "Romeo + Juliet," "Moulin Rouge," "Strictly Ballroom," "Australia" and "The Great Gatsby." And backed by a six-member band, the show totally lives up to the hype. The show keeps an immersive feel thanks to the action taking place around the audience.
Brace yourself for an all-encompassing show that will leave you reminding your wild self that "A little party never killed nobody."


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Labour Reforms in India
Problems of Plantation Sector in India
February 15, 2016
In September and October 2015, there were agitations and strikes by the plantation workers in Kerala. In a major contrast, the agitations were initially led by women tea-leaf pickers under the collective name of 'Pombilai Orumai' in Munnar, Kerala. They challenged their own trade unions and simultaneously...
Various Issues Related to Labour in India
December 29, 2015
The Article 246 (with 7th schedule) of the Indian constitution puts the issues related to labour and labour welfare under the concurrent list. However, the exceptional matters related to labour and safety in mines and oilfields and industrial disputes concerning union employees come under Union List. The...
National Renewal Fund
October 17, 2015
The Government of India had announced to establish a National Renewal Fund (NRF) as a part of the slew of measures announced in New Industrial Policy of 1991. The Fund was later established in February, 1992 for a period of 10 years. Objectives of National Renewal Fund...
Current Issues in Labour Reforms in India
May 2, 2015
"Reform of the labour law is vital for the revival of manufacturing sector in India, without which the Make in India campaign is doomed to fail." Discuss critically.
Major Issues with Trade Union Act (1926)
May 2, 2015
Although there is a right to form an association or form a trade union; yet in our country, there is no nationwide law recognizing the trade union. For an employer, there is no compulsion to enter into a collective bargaining with laborers and it is also not...
Current Issues with Industrial Disputes Act (1947)
May 2, 2015
To what extent the Chapter V-B of the industrial disputes act is responsible for anomalies in the manufacturing sector in India. Discuss.


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£1,075 pcm Available: 4th July 2017
Sought after furnished flat in popular location comprising beautiful large lounge with fireplace and good quality furniture and fittings. Care has been taken to ensure this standard is maintained throughout and all three bedrooms(one single) are immaculate with neutral decor and soft furnishings.The property further benefits from a modern fitted kitchen and bathroom. Byres Road is only moments away with its bars, restaurants and shops, transport links and Hillhead Underground. This property will suit a young executive type looking for the west end lifestyle. A must view!! NO HMO LICENCE EPC BAND - D Landlord registration - to follow Tenant Suitability: Professionals - Yes Sharers - Yes Students - 3rd or 4th year minimum DSS - No HMO - No Pets - No Smokers - No **Please note restrictions are imposed by the landlord and may be based on mortgage or insurance conditions**
This house description is based upon information supplied by the owner, or on behalf of the owner. These property particulars are produced in good faith and do not constitute or form part of any contract. s1homes do not take any responsibility to the accuracy of the information contained in this document.


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Kingwood Nation
There is a company called TKO Sports that is calling Kingwood area businesses and claiming to be affiliated with Kingwood High School and Kingwood Athletics. They claim we have a deal with them to collect money for advertisement on t-shirts that will be given to Kingwood HS. This is absolutely false. Do not do business with these people. They have been taking money from Kingwood businesses without giving anything in return. This has been going on for almost 4 years now. So what I need is for you to forward this out to anyone you know that has business in the Kingwood area. I need to get the word out about these people. If businesses are interested in supporting Kingwood Athletics, they can contact me directly. Thank you in advance for helping me get this done and thank you for all the support you give to the Kingwood Athletic Programs. R. Barry CampbellAthletic Coordinator/Head Football CoachKingwood High SchoolHumble ISD


text: Nike had a big release event for the latest in Kevin Durant's line of footwear, the KD9. Afterwards, some of the top industry heads were treated to a presentation and a preview of the new line as well as the previous editions. The Swoosh released this video where Durant talks with Leo Chang, lead designer of all of KD's signature sneakers. The duo discuss Durant's evolution as a player and how it impacts the design of his latest offering. It's pretty dope, right down to the design renditions.


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Sixteen wins. It's what you'll need in order to hoist the Cup in NHL 18 for PlayStation 4. Go head-to-head against your favourite players and teams as you guide your team to the ultimate prize in this latest installment of the franchise.
Release date
September 12, 2017
EA Sports
EA Canada
PS4, Xbox One, PC
By Jon Scarr
Hockey fans, are you ready for the ultimate NHL experience? EA's NHL 18 is just around the corner and from what I have seen, it represents a major step forward for the franchise that hockey fans, like you and I, will love.
I am excited about NHL 18's new game modes, deeper customization, improved presentation, better A.I., and gameplay enhancements. There will also be a large variety of modes at your fingertips. I can't wait to get my hands on what is destined to be EA Canada's best outing yet.
Practically every piece of gameplay for NHL 18 has been refined and improved from skating, to shooting, to passing, to puck pickups. I'm happy to say, the end result is a hockey game that is tighter and more responsive than previous entries in the franchise.
Gameplay is so real, it's like you are playing on an NHL team in real life! I love the fact that you can push opposing players from shooting lanes, lift sticks, and tie up your opponent's body to ensure that the puck gets to the net. Just like in a real-world NHL game, your teammates now take greater risks and are more aggressive when the time calls for it.
EA Canada left no stone unturned, completing the true NHL experience, Goalies in NHL 18 are virtual replicas of their real-life counterparts. Goalies in NHL 18 react exactly as they would in a real NHL game right down to post-goal reactions. It is totally awesome, and you won't believe how life-like the players really are!
Each year EA Canada manages to improve the visuals on what is already a great looking game. NHL 18 once again ups the ante. With more noticeable improvements over previous years, including more authentic arenas, life-like jersey textures, more realistic player likenesses, and a crisper sheen to the ice that make this already highly realistic-looking sports game look even more so.
NHL 18 launches this fall on the PlayStation 4 and Xbox One. If you are a hockey fan, you won't want to miss NHL 18—I can honestly say it's the best installment that the series has seen thus far.
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At my Dad's workplace I straddle a hand rail going to his office. It has bumps on it and if I get one right between my legs I ride it until I tingle and shake, it's best when I wear ski pants because it presses my pants up me and I like the way my privates bulge, if I touch myself there it is hot and I spend all morning doing it until I shake and feel tight in my tummy.
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A Vintage-voiced Humbucker with Red-hot Output
The DiMarzio AT-1 pickup creates an exciting blend of precise definition and red-hot output that's sure to ignite your playing. The signature pickup of Andy Timmons, the AT-1 injects your licks with a balanced fusion of warmth and sweet-sounding clarity. When we first heard the AT-1 here at Sweetwater, our first impression was that of a late-'50s PAF-style humbucker - but much, much louder. The AT-1 is optimized for 25.5" scale, mahogany-bodied guitars, but it sounds great on just about everything, with enough lows to warm up brighter guitars and enough clarity to add articulation to darker ones. The DiMarzio AT-1 pickup is a vintage-voiced humbucker that rocks!DiMarzio AT-1 Pickup Features at a Glance:
- Andy Timmons signature pickup that blends precise definition and red-hot output
- Delivers vintage PAF-style sound with increased output that's great for rock
- Optimized for 25.5" scale, mahogany-bodied guitars, but sounds great on everything
- Warms up brighter guitars and adds articulation to darker ones


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The Tour
The Guides
Street Art Bike Tour
Street Art Walking Tours
El Borne & Gothic Street Art Tour
El Raval Street Art Tour
Maps & Departures
El Borne & Gothic Map
El Raval Map
Bike Tour Map and Departure
POBLE NOU Street Art Bike Tour
Jump on a bike with us and lets take a morning ride through Barcelona's ever developing industrial neighborhood of Poble Nou, where the remains of the industrial revolution meets the ever expanding digital revolution.
Apart from being home to the newest murals done by some of the Europe's top street artist, this blossoming district holds some of Barcelona's modern architectural treasures, and at the same time remains as a reminder of a booming textile industry with giant factories.
With wide streets and low car traffic, we cruise on our bikes comfortably as we uncover the the many large scale murals and the abundance of street art found around every corner in Poble Nou.
As we conclude our bike tour we take a scenic stroll along the beautiful beaches of Barcelona as we make our way back to the city center, where we conclude the tour in Plaça George Orwell and return our bikes.
This tour last approximately 3 hours, and operates Monday through Sunday, is by reservation only with a 24 hour advance notice, for a minimum of 2 people. This tour has a fee of €18.00 per person, bikes are included.
tours are subject to cancellation due to inclement weather
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Short Breaks
Book your Anantara experience now, with tempting benefits, room upgrade and late check out.
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Stay for 2 nights or more and benefit from daily breakfast, 20% savings on dining and spa throughout, as well as complimentary room upgrade. learn more
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Plan an amazing escape at least 21 days ahead to receive exclusive savings of 30%, as well as a delicious breakfast buffet for two every day. learn more
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Maldives Discovery
Why choose one when you can explore two of our four private island resorts? Stay six nights across your choice of two Anantara resorts in the Maldives and we'll enhance the indulgence even further wit... learn more
Anantara Dhigu Honeymoon and Romance
Enjoy a romantic Maldives hotel package for couples. Stay for 3 nights and receive return airport speedboat transfers, Champagne and chocolates on arrival, daily breakfast, 10% off spa treatments, a D... learn more
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Accommodations in RintelnSee All
Is Rinteln in Germany on your travel bucket list? This online travel guide is all you need to have before planning your trip. The nearest major city to Rinteln is Bremen. Bremen, is a worth visiting city owing to its prime attractions like Schnoor, Bremen Town Hall And Square, St. Peter's Cathedral. Popular vacation packages of Rinteln are of 1-2 days.
Don't just take a trip, let the trip take you! Have a enjoyable time at Rinteln.
Explore the best journey planner for your visit to Rinteln and create a flawless plan in few simple steps!


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In Reply to: RE: KT-150 ??? posted by Daverz on March 17, 2017 at 23:51:37
I don't have the M-180s but the Stereo 90. A very similar amp. I have tried many different power tubes in the amp including the Tung Sol KT120s. I do not care for the KT120 in my Rogue. I think the Preferred Series KT88 (I have the PentaLabs KT88SC which supposedly the same tube) is a much better sounding tube. So are the EI KT90 and the Gold Lion KT66. Probably the GL KT88 as well.
You would not be "downgrading" going to these tubes. Can't believe the Tung Sol KT120 is standard with all Rogue amps these days.
Follow Ups:
Thanks for you comments. The 90 uses 6SN7s, right? Not sure how this would effect comparisons with the M 180s.
Yes 6SN7 for drivers. I much prefer these to 12au7, more linear, more current, more variety in types.
My Stereo 90 began life as a Stereo 88 which had 12au7 for drivers. I rolled many different types but they all sounded mostly the same to me. Sent the amp back to Rogue for upgrade to Stereo 90 Magnum and was surprised by how much the choice of 6SN7 could alter the sound. I think Rogue took a step backwards when they went back to 12au7 for drivers.
The M-180s are gorgeous amps (I could really use the extra power!). Given the power they produce, unless you are running very difficult to drive speakers you could probably give up a little power to try another output tube.
I use KT120's in my Convergent Audio Technology JL1 mono's. The amps were upgraded to receive KT 120's by Ken Stevens. Ken feels KT120's sound best in his amps and I can't argue. I have have used KT88, 6550's and the KT 120's are by far the best.
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Dina will be organizing our adult membership campaigns, and has hit the ground running with her first project, working on the Census.
A little bit about Dina: Dina Omar is a Palestinian-American poet and graduate from the University California Berkeley in Middle Eastern Studies and Anthropology. At UCB Dina studied and taught in June Jordan's Poetry for the People Program and was an active organizer in Students For Justice in Palestine. Dina has published poems in various anthologies and her public readings include the Madrid PYN conference, the LGBTQ conference at CSUSB, Take Back the Night, MECA's Poetry for Gaza, and the Indian Treaty Council. Dina is currently submitting her first book to be reviewed for publication titled sabbar.


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Snow White and the Sic Punks T-shirt -Navy
Snow White and the Sic Punks " print t-shirt
Women fitted quality navy blue cotton shirt. With light blue contrast seams.
Stretch cotton fabric. Printed in white and pink ink
All our punk stuff is screenprinted by hand, by DEBDEN (original London punk!).There may be ink splats here and there as part of the design. Anarchy in the U.K...
Available Sizes and Measurements:
Chest: 42"/44"
Length: 24"
Sleeve Length: 1"


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Use our sturdy black vinyl tubing, which is FDA-approved and BPA-free, for your irrigation systems and tanks, and to complete your own hydroponic systems. The material is easy to cut to size, but will remain strong and reliable. Choose from six different 100-foot sizes, each in a convenient dispenser pack. Keep a roll on hand for instant access to repairs.
Price: $7.33 / each Estimate Shipping · Price Match
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— Ships from HF: OR, CA, CO, PA, TX, FL USA (not via USPS).


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"Excellent web site - easy to use and fab products and delivery. "
" Arrived in time. Unique gift. "
"Beautiful well made clocks. I could not believe how quickly they arrived. Ordered on Sunday, delivered.."
HTC phone case
A personal phone case is a great way to share your creativity with other people. Select your favourite photo or find a nice picture on internet. A famous quote or saying also looks very good on your HTC phone case! You can easily make your own phone case and add a professional design frame in our user friendly photo-editor!


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For ranges requiring a large broadhead target that will hold up to the abuse of the sharpest broadheads, the Range King answers your request. The large size is perfect for sighting in on, and broadheads pull with ease. Works well with both mechanical and fixed-blade heads.
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Note : Your Quotation Request will be directed to Vectron International.
The TFS140AE from Vectron International is a Band Pass Filter with Frequency 108 to 172 MHz, Bandwidth 32.00 MHz, Center Frequency 140 MHz, Insertion Loss 32.0 dB. Tags: RF SAW Filter. More details for TFS140AE can be seen below.
2437 MHz Bulk Acoustic Wave Filter
You can now find similar products from multiple companies on everything RF.


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Dancing Schools Near Me
One of the main factors that I consider when I am looking for dance schools near me is the proximity to my house. This is quite convenient since I can pass by the dance school for morning classes on my way to work or for an evening dance lesson after a long day.
Finding The Closest Dance School
If you're for the nearest dance school around then simply use the web application below and allow the browser to find your current location. Otherwise, simply enter an address to find the closest dance school to that single point.
Different Types of Dance Schools
Depending on the specialty of the instructors in a dance school, there will be a special type of dance that is common in the school. Most dance schools tend to identify with their dance of specialization. You will find that there are the following types of dance schools:
- Ballet Dance School
- Salsa Dance School
- Tap Dancing School
- Urban and Street Dance School
- Exotic Dance School
How Much Does Dance Schools Cost
Enrolling in most of the dance schools will cost between $20 and $50. This fee is because most of the dance schools require some form of membership and the enrolling fees are for member commitment and card processing. Once you have become a member, you pay a monthly fee which may range between $60 and $150 depending on the complexity of the class and the level of training you will be advancing to.
What to Expect with Dance Schools
In many of the dancing schools, a personal instructor is assigned and they adjust their schedule according to the student's availability. The dance schools are open all day and lessons can be scheduled for very early in the morning or late evening. Students are allowed to take classes at any level for as long as they want until they feel satisfied with their level of dance masterly. The introductory levels in the dance school are usually tough since the body might not be used to the vigorous physical exercises and the long periods of activity. After a couple of classes, the body gets used and the student can dance for a couple of hours comfortably.
What to Consider about Dance Schools
One of the most important thing to consider about dance schools is the instructors. The student needs to connect with the instructor and this happens when the instructors are concerned about the progress of the student. They review the improvements and they work on the areas that need polishing to make the student a better dancer. The diversity of a dance school should be considered too since it allows a student to learn different types of dances within the same establishment. A dance school that offers a wholesome experience is the best. This involves provision of emotional support in additional to the physical training. The student enjoys the learning process and the dances better when they are emotionally and physically connected to the moves they are making on the dance floor.
How to Get Started with Dance Schools
Dance schools take their students through various vigorous exercises and so for starters the student should have some sports gear for easy dancing. Sportswear is encouraged so that it can offer room for stretching muscles and it can also absorb sweat. Flat shoes are also encouraged to avoid twisting the ankles while learning some complicated moves unless the dance specifically requires a different type of shoe.
More Schools Around
If you're interested in learning more information about other schools and the various programs you can take, consider reading more about schools near me here.