Non-prescription treatments for childhood infections: an Austrian, monocentric, cross-sectional questionnaire study.

BACKGROUND: Infectious diseases like the common cold, otitis media, or gastroenteritis frequently occur in childhood. In addition to prescription drugs, parents often use supplementary over-the-counter (OTC) products recommended by pharmacists and other non-medical professionals to relieve their children's symptoms. However, the efficacy of such alternative treatments lacks conclusive evidence. The objective of this study was to investigate the use of OTC products and related active ingredients in children, and the motivations behind this choice. METHODS: The present study included 215 children aged between 1 and 14 years with an acute respiratory tract infection, e.g., common cold, bronchitis, otitis media, tonsillitis, or gastroenteritis. During their visit to the pediatric practice, parents filled in a self-administered questionnaire about their child's diagnosis, additional treatment options, and motivations to integrate supplementary medicinal products after their first visit for acute infection or follow-up examination. Children with chronic illnesses and patients visiting for a routine maternal and child health program check-up were excluded. RESULTS: The study included 111 (51.6%) males and 104 (48.4%) females. Median age was 3.00 (IQR 2.0 - 5.0) years. The most common reason for a visit was a respiratory tract infection (78.6%). Out of 215 parents, 182 (84.7%) resorted to non-prescription remedies to alleviate their child's symptoms. Teas (45.1%), and home remedies (43.3%) were the most popular. At total 133 (74.3%) followed recommendations from friends and family regarding additional medications usage. Parents with previous experience with complementary medicine tended to prefer this approach to treat their children (p.adjust = 0.08). CONCLUSION: The use of non-prescription medicine is increasing as well as the range of related information sources. Evidence-based recommendations in this field might improve pediatric care.

A cross-sectional, exploratory survey on health-relevant free-time activities and body mass index in preschool children in urban and rural settings of Austria.

BACKGROUND: The increasing prevalence of obesity is among the most relevant healthcare issues in Europe. The number of overweight people rises due to lifestyle changes, increased sitting activities, and less physical activity. Prevention in early childhood is paramount to stop this alarming trend. AIM: This study primarily aimed to evaluate the average time children (3-5 years) from rural and urban Austrian regions spent engaging in physical activity and sedentary behaviors in their free-time. Additionally, we investigated the potential correlation between duration and habits of free-time activity or place of residence and age- and sex-specific body mass index (BMI). The potential impact of socio-economic factors on BMI was examined. METHODS: Urban (Vienna) and rural (Carinthia) regions of Austria were chosen for this observational cross-sectional study. Preschool children (n=130) attending nurseries in these regions were included. Weight and height were measured and BMI calculated. Free-time activity and socio-economic data were asked using a self-administered questionnaire. Data on sedentary behavior time (sedentary activity and media consumption) and physical activity time (defined as organized or spontaneous exercise) were analyzed using non-parametric tests. RESULTS: Preschool children spent approximately as many hours of their free-time engaged in physical activity as in sedentary behaviors. Time trend in media consumption amounts to one-third of the cumulative time spent engaging in sedentary behaviors. Preschoolers from the urban area spent fewer hours practicing organized exercise and more in sedentary behaviors than peers in the rural area. In the selected areas, 7 % of preschoolers were overweight, 3.9 % were obese. BMI was not associated with free-time activities but showed a trendwise negative correlation with organized exercise. A positive correlation of age and organized exercise was observed but not with physical activity per se. CONCLUSIONS: Our results confirm the necessity of preventive interventions among Austrian preschoolers and lead to a better understanding of their free-time activities. Further investigations with larger study populations are needed to promote effective childhood obesity prevention and examine the differences regarding obesity prevalence and leisure-time activity between rural and urban areas.

Drug-Drug Interactions Between Lithium and Cardiovascular as Well as Anti-Inflammatory Drugs.

INTRODUCTION: Lithium is the gold standard in treating bipolar affective disorders. As patients become increasingly older, drug-drug interactions leading to decreased excretion of lithium represent a key issue in lithium safety. As no study considered the effect of comedications on lithium serum concentration in combination, we aimed to quantify the impact of drugs affecting renal blood flow and function and thus potentially interacting drugs (diuretics, ACE inhibitors, AT1 antagonists, and non-steroidal anti-inflammatory drugs) on lithium serum levels in addition to age, sex, and sodium and potassium serum levels as well as renal function. METHODS: Retrospective data of lithium serum levels were analyzed in 501 psychiatric inpatients (2008-2015) by means of linear regression modelling. RESULTS: The number of potentially interacting drugs was significantly associated with increasing serum levels of lithium in addition to the established factors of age, renal function, and sodium concentration. Additionally, absolute lithium levels were dependent on sex, with higher values in females. However, only NSAIDs were identified to increase lithium levels independently. DISCUSSION: Routine clinical practice needs to focus on drugs affecting renal blood flow and function, especially on NSAIDs as over-the-counter medication that may lead to an increase in lithium serum concentration. To prevent intoxications, clinicians should carefully monitor the comedications, and they should inform patients about possible intoxications due to NSAIDs.

Characterisation of RSV infections in children without chronic diseases aged 0-36 months during the post-COVID-19 winter season 2022/2023.

Background: Respiratory syncytial virus (RSV) is one of the leading causes of hospitalisation, morbidity, and mortality due to respiratory infection in the first years of life. This longitudinal prospective study outlines the 2022/23 season's viral patterns in Austria after the epidemiological changes determined by public health measures. We aimed to highlight differences within the RSV subtypes and genotypes in 0-36-month-old children without chronic diseases in the outpatient setting. Methods: From November 2022 to March 2023 children younger than 36 months admitted to Vienna's largest paediatric primary healthcare centre with an acute respiratory infection were enrolled in this study. Nasal swabs and multiplex PCR panels detected 20 viruses including RSV subtypes and genotypes. Clinical presentation, features, and treatment of the participants were documented and analysed using the Modified Tal Score (MTS). Patients were scheduled for a telemedical follow-up one week after the initial appointment. Analysis was done using descriptive statistics, including Cramér V and binominal logarithmic regression. Results: Among the 345 samples from 329 children, RSV was the most common virus (31.9%), followed by influenza (17.5%) and rhinovirus infections (20.58%). Of the RSV positive samples, only 13 cases were RSV subtype A (11.8%), whereas 97 were of subtype B (87.3%); ON1 and BA9 were the only detectable RSV genotypes (ON1: BA9 = 1:9.25). RSV was the main predictor of hospitalisation (OR: 7.5, 95% CI: (1.46-38.40), and age had a significant but smaller effect (OR: 0.89, 95% CI: (0.81-0.99). Almost all patients' clinical status improved within the first days. Conclusion: RSV cases showed a rapid onset in late November 2022, and subtype B was predominant throughout the season. RSV infection was associated with higher hospitalisation rates, even after excluding high-risk patients (preterm and severe chronic diseases population).Further testing in the upcoming winter seasons will improve our knowledge of the dominant subtype and its association with disease severity, especially with the development of novel RSV vaccine candidates.

The surge of RSV and other respiratory viruses among children during the second COVID-19 pandemic winter season.

Background: The non-pharmaceutical measures in the first Covid-19 winter season significantly impacted respiratory pathogens such as RSV, influenza, or metapneumovirus, which cause respiratory infections, especially in infants and young children. This longitudinal prospective study aimed to determine how less strict measures affect the pathogen profile in the second winter season. Methods: From September 2021 till the end of March 2022, 678 children (0-36 months) admitted to Vienna's largest pediatric center with an acute respiratory infection were enrolled in this study. The researchers performed nasal swabs and tested them by multiplex PCR for 23 respiratory pathogens, chronicled clinical features and treatment, and analyzed the effect of lockdown on the pathogen prevalence. Results: The 815 smears of 678 children revealed the most common pathogens to be rhino-/enterovirus (38.5%), RSV (26.7%), and metapneumovirus (7.2%). The lockdown interrupted the early RSV onset in September [RR 0.367, CI (0.184-0.767), p = 0.003], while no effects on the other pathogens were found. Metapneumovirus started circulating in January. Influenza was only sporadically detected. The hospitalization rate was significantly higher than last season due to RSV [OR 4.089, 95%CI (1.414-11.827), p-adj = 0.05]. Conclusion: With more flexible non-pharmaceutical measures, children aged 0-36 months started presenting again with viral pathogens, such as RSV and metapneumovirus. RSV, associated with a high hospitalization rate, had a very early onset with an abrupt interruption due to the only lockdown.

Effective German and English Language mHealth Apps for Self-management of Bronchial Asthma in Children and Adolescents: Comparison Study.

BACKGROUND: Mobile health (mHealth) apps hold great potential for asthma self-management. Data on the suitability of asthma apps intended for children are insufficient, and the availability of German language apps is still inadequate compared with English language apps. OBJECTIVE: This study aims to identify functional asthma apps for children in German and to compare them with English language apps. In line with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, the Google Play Store and Apple App Store are systematically searched to preselect the most efficient apps, which are then compared according to a self-compiled criteria catalog. METHODS: Both app stores were screened for the term asthma. Following a PRISMA preselection process, the apps that met the inclusion criteria (ie, available free of charge, German or English language, and suitable for children) were rated by 3 independent persons following a criteria catalog consisting of 9 categories, some conceived for this purpose (availability, child-friendly, learning factor, and range of functions) and some adopted from existing validated catalogs (functionality and design, ease of use, potential for improving asthma self-management, fun factor and incentives, and information management and medical accuracy). The highest rated apps in German and English were compared. RESULTS: A total of 403 apps were identified on the Google Play Store and the Apple App Store. Finally, 24 apps that met the inclusion criteria were analyzed. In the first step of the quality assessment, only 4 available German language asthma apps were compared with 20 English language asthma apps. The 4 German language apps were then compared with the 4 highest rated English language apps. All selected apps, independent of the language, were comparable in the following categories: availability, functionality and design, ease of use, and information management and medical accuracy. The English language apps scored significantly higher in the following categories: potential for improving self-management, child-friendly, fun factor, learning factor, and range of function. English language apps (mean total points 34.164, SD 1.09) performed significantly better than German language asthma apps (mean total points 22.91, SD 2.898; P=.003). The best rated English language app was Kiss my asthma (36/42 points), whereas the best rated German language app Kata achieved only 27.33 points. CONCLUSIONS: The recommended English language apps are Kiss my asthma, AsthmaXcel, AsthmaAustralia, and Ask Me, AsthMe!, whereas the only recommended German language app is Kata. The use of apps plays an increasingly important role in patients' lives and in the medical field, making mHealth a staple in the future of asthma treatment plans. Although validated recommendations on rating mHealth apps have been published, it remains a challenging task for physicians and patients to choose a suitable app for each case, especially in non-English-speaking countries.

Respiratory Infections in Children During a Covid-19 Pandemic Winter.

Background: The Covid-19 pandemic compelled the implementation of measures to curb the SARS CoV-2 spread, such as social distancing, wearing FFP2 masks, and frequent hand hygiene. One anticipated ramification of these measures was the containment of other pathogens. This prospective, longitudinal study aimed to investigate the spread of 22 common seasonal non-SARS-CoV-2 pathogens, such as RSV and influenza, among children with an acute respiratory infection during a pandemic. Methods: Three hundred ninety children (0-24 months) admitted to Vienna's largest pediatric center with acute respiratory infection (November 2020-April 2021) were included in this study. The researchers tested nasal swabs for 22 respiratory pathogens by Multiplex PCR, documented clinical features and treatment, and evaluated data for a potential connection with the lockdown measures then in force. Results: The 448 smears revealed the most common pathogens to be rhino-/enterovirus (41.4%), adenovirus (2.2%), and coronavirus NL63 (13.6%). While the first two were active throughout the entire season, coronaviruses peaked in the first trimester of 2021 in conjunction with the lift of the lockdown period (OR 4.371, 95%CI 2.34-8.136, P < 0.001). RSV, metapneumovirus, and influenza were absent. Conclusion: This prospective, longitudinal study shows that Covid-19 measures suppressed the seasonal activity of influenza, RSV, and metapneumovirus among very young children, but not of rhino-/enterovirus and adenovirus. The 0-24 month-olds are considered the lowest risk group and were only indirectly affected by the public health measures. Lockdowns were negatively associated with coronaviruses infections.

Emotional and learning behaviour in mice overexpressing heat shock protein 70.

The effects of inducible heat shock protein 70 (HSP70) on emotional and learning behaviour as well as hippocampal long-term potentiation was investigated in transgenic HSP70 overexpressing mice. In active two-way avoidance learning (shuttle box) as well as spatial 8-arm radial maze learning, the HSP70 overexpressing mice showed diminished learning performance. In several tests there was no indication of differences in anxiety behaviour between transgenic mice and wild-type mice. This suggests that impairment in learning behaviour is unrelated to the learning task and motivational aspects of behaviour. To investigate the neurophysiological correlate of learning, long-term potentiation experiments were performed. In transversal hippocampal slices, an enhanced amplitude of the population spike was found in HSP70 overexpressing mice. It was hypothesised that enhanced potentiation in conjunction with potentiation effects due to learning led to learning impairment.

Differential effects of mu-opioid receptor agonists in a hippocampal hypoxia/hypoglycemia model.

BACKGROUND: In rat hippocampal slices, a short hypoxia/hypoglycemia causes immediate loss of evoked potentials (population spike amplitude) in the CA1 region and the extent of electrophysiological restoration during reperfusion can serve as a parameter for cell function. Previous experiments using this model revealed that exposure to morphine aggravates the neurotoxic effects of a subsequent hypoxia/hypoglycemia in a concentration-dependent manner. Therefore, the aim of the present study was to evaluate the effects of additional mu-opioid receptor (MOPr) agonists on the electrophysiological restoration after hypoxia/hypoglycemia. METHODS: Rat hippocampal slices were exposed to either morphine (10 microM), pethidine (10 microM), fentanyl (100 nM/1 microM) or to the synthetic peptide [d-Ala2, N-Me-Phe4, Glycinol5]-enkephalin (DAMGO, 10 microM) for 60 min; thereafter, slices underwent a brief hypoxic/hypoglycemic episode followed by reperfusion (drug-free) for 2.5 h. Electrophysiological recording consisted of determination of population spike amplitude in CA1 in response to constant stimulation of Schäffer's collaterals. RESULTS: Exposure to morphine prior to hypoxia/hypoglycemia resulted in a significantly impaired electrophysiological recovery during reperfusion when compared to controls. Following exposure to pethidine, the electrophysiological recovery was slightly reduced, whereas fentanyl or DAMGO did not affect restoration of population spike amplitude during reperfusion. CONCLUSIONS: The results of the present study demonstrate that different MOPr agonists differentially influence the electrophysiological recovery of hippocampal slices following a brief hypoxia/hypoglycemia. It is speculated that known receptor-internalizing opioids such as fentanyl or DAMGO may have less neurotoxic effect in hypoxia/hypoglycemia than the non-internalizing drug morphine.

Pentylenetetrazol-kindling in mice overexpressing heat shock protein 70.

Kindling induced by the convulsant pentylenetetrazol (PTZ) is an accepted model of primary generalized epilepsy. Because seizures represent a strong distressing stimulus, stress-induced proteins such as heat shock proteins might counteract the pathology of increased neuronal excitation. Therefore, the aim of the present study was to determine whether PTZ kindling outcome parameters are influenced by heat shock protein 70 (Hsp70) overexpression in Hsp70 transgenic mice as compared to the respective wild-type mice. Kindling was performed by nine intraperitoneal injections of PTZ (ED(16) for induction of clonic-tonic seizures, every 48 h); control animals received saline instead of PTZ. Seven days after the final injection, all mice received a PTZ challenge dose. Outcome parameters included evaluation of seizure stages and overall survival rates. In addition, histopathological findings such as cell number in hippocampal subfields CA1 and CA3 were determined. The onset of the highest convulsion stage was delayed in Hsp70 transgenic mice as compared to wild-type mice, and overall survival during kindling was improved in Hsp70 transgenic mice as compared to wild-type mice. In addition, a challenge dose after termination of kindling produced less severe seizures in Hsp70 transgenic mice than in wild-type mice. PTZ kindling did not result in significant subsequent neuronal cell loss in CA1 or CA3 neither in wild-type mice nor in the Hsp70 transgenic mice. The results of the present experiments clearly demonstrate that overexpression of Hsp70 exerts protective effects regarding seizure severity and overall survival during PTZ kindling. In addition, the decreased seizure severity in Hsp70 transgenic mice after a challenge dose suggests an interference of Hsp70 with the developmental component of kindling.

p110γ/δ Double-Deficiency Induces Eosinophilia and IgE Production but Protects from OVA-Induced Airway Inflammation.

The catalytical isoforms p110γ and p110δ of phosphatidylinositide 3-kinase γ (PI3Kγ) and PI3Kδ play an important role in the pathogenesis of asthma. Two key elements in allergic asthma are increased levels of eosinophils and IgE. Dual pharmacological inhibition of p110γ and p110δ reduces asthma-associated eosinophilic lung infiltration and ameliorates disease symptoms, whereas the absence of enzymatic activity in p110γKOδD910A mice increases IgE and basal eosinophil counts. This suggests that long-term inhibition of p110γ and p110δ might exacerbate asthma. Here, we analysed mice genetically deficient for both catalytical subunits (p110γ/δ-/-) and determined basal IgE and eosinophil levels and the immune response to ovalbumin-induced asthma. Serum concentrations of IgE, IL-5 and eosinophil numbers were significantly increased in p110γ/δ-/- mice compared to single knock-out and wildtype mice. However, p110γ/δ-/- mice were protected against OVA-induced infiltration of eosinophils, neutrophils, T and B cells into lung tissue and bronchoalveolar space. Moreover, p110γ/δ-/- mice, but not single knock-out mice, showed a reduced bronchial hyperresponsiveness. We conclude that increased levels of eosinophils and IgE in p110γ/δ-/- mice do not abolish the protective effect of p110γ/δ-deficiency against OVA-induced allergic airway inflammation.

Correction: p110γ/δ Double-Deficiency Induces Eosinophilia and IgE Production but Protects from OVA-Induced Airway Inflammation.

[This corrects the article DOI: 10.1371/journal.pone.0159310.].

Rapid, transient, and dose-dependent expression of hsp70 messenger RNA in the rat brain after morphine treatment.

Induction of Hsp70 in the brain has been reported after intake of drugs of abuse like amphetamine and lysergic acid diethylamide. In this investigation, gene expression of Hsp70 and other heat shock genes in the rat brain was studied in response to morphine. Twenty milligrams per kilogram morphine intraperitoneally resulted in a marked induction of Hsp70 messenger RNA (mRNA) expression in the frontal cortex with a maximum increase of 13.2-fold after 2 hours. A moderate increase of Hsp27 mRNA expression (6.7-fold) could be observed after 4 hours, whereas mRNA expression of Hsp90 and of the constitutive Hsc70 did not exceed a mean factor of 1.8-fold during the 24 hours interval. The increase in Hsp70 mRNA was dose dependent, showing a significant elevation after doses ranging from 10 to 50 mg/kg morphine. In situ hybridization revealed enhanced Hsp70 mRNA expression mainly in cortical areas, in the hippocampus, in the paraventricular and supraoptic nuclei of the hypothalamus, in the locus coeruleus, as well in the pineal body. The double in situ hybridization technique revealed increased Hsp70 mRNA expression mainly in VGLUT1-positive neurons and to a lesser extent in olig1-positive oligodendroglia. Immunohistochemistry revealed a marked increase of Hsp70 protein in neuronal cells and blood vessels after 12 hours. In contrast to animal experiments, morphine did not increase Hsp70 mRNA expression in vitro in micro-opioid receptor (MOR1)-expressing human embryonic kidney 293 cells, suggesting no direct MOR1-mediated cellular effect. To exclude a body temperature-related morphine effect on Hsp70 mRNA expression, the temperature was recorded. Five to 20 mg/kg resulted in hyperthermia (maximum 40.6 degrees), whereas a high dose (50 mg/kg) that produced the highest mRNA induction, showed a clear hypothermia (minimum 37.2 degrees C). These findings argue against the possibility that Hsp70 induction by morphine is caused by its effect on body temperature. It may be speculated that increased expression of Hsp70 after morphine application protects brain structures against potentially hazardous effects of opiates.

Modified Foxp3 mRNA protects against asthma through an IL-10-dependent mechanism.

Chemically modified mRNA is capable of inducing therapeutic levels of protein expression while circumventing the threat of genomic integration often associated with viral vectors. We utilized this novel therapeutic tool to express the regulatory T cell transcription factor, FOXP3, in a time- and site-specific fashion in murine lung, in order to prevent allergic asthma in vivo. We show that modified Foxp3 mRNA rebalanced pulmonary T helper cell responses and protected from allergen-induced tissue inflammation, airway hyperresponsiveness, and goblet cell metaplasia in 2 asthma models. This protection was conferred following delivery of modified mRNA either before or after the onset of allergen challenge, demonstrating its potential as both a preventive and a therapeutic agent. Mechanistically, FOXP3 induction controlled Th2 and Th17 inflammation by regulating innate immune cell recruitment through an IL-10-dependent pathway. The protective effects of FOXP3 could be reversed by depletion of IL-10 or administration of recombinant IL-17A or IL-23. Delivery of Foxp3 mRNA to sites of inflammation may offer a novel, safe therapeutic tool for the treatment of allergic asthma and other diseases driven by an imbalance in helper T cell responses.

Tissue slice model of human lung cancer to investigate telomerase inhibition by nanoparticle delivery of antisense 2'-O-methyl-RNA.

Nanoparticles delivery of oligonucleotides represents a potential approach for cancer treatment. However, most of the experiments were based on established cancer cell lines and may not reflect the original solid tumor in vivo. Both, tumor microenvironment and tumor cell biological properties in the tumor can influence the delivery efficiency of oligonucleotides. Therefore, it is important to understand the effect of nanoparticles delivery of oligonucleotides on tumor response in intact tissue architecture of individual tumors. We used freshly isolated human tumor tissue slices and primary lung cancer cells from non-small cell lung cancer patients to evaluate this nanocarrier system. Chitosan-coated poly(lactide-co-glycolide) (PLGA) nanoparticles were used to form oligonucleotide-nanoparticle-complexes (nanoplexes) with antisense 2'-O-methyl-RNA (OMR) that can inhibit telomerase activity by binding to the RNA component of telomerase. OMR cellular uptake was strongly enhanced by nanoplexes mediated delivery in both, primary cells and tissue slices. More than 80% of primary cancer cells and 50% of cells in tissue slices showed OMR uptake. Telomerase activity was inhibited by approximately 45% in primary cancer cells and about 40% in tissue slices. Nanoplexes could penetrate into tumor tissue without influencing tissue architecture and the delivered OMR was able to inhibit telomerase activity with relatively low cytotoxicity.

Morphine-induced changes of gene expression in the brain.

Repeated opiate administration alters gene expression in different brain regions of rodents, an effect which may contribute to plastic changes associated with addictive behaviour. There is increasing evidence that multiple transcription factors are induced in morphine tolerance, sensitization and during morphine withdrawal. Whereas morphine treatment does not lead to major alterations in the expression of mu-opioid receptors (MOR), there is transcriptional regulation of proteins involved in MOR trafficking such as GRK2 or beta arrestin 2 as well as altered expression of other receptors such as dopamine receptors, NMDA receptors, GABA(A) receptor and alpha(2A) adrenoceptor. Recent gene expression profiling studies reveal additional clusters of morphine-responsive genes: whereas single dose administration has been shown to predominantly reduce expression of genes involved in metabolic function, ascending morphine doses leading to morphine tolerance revealed induction of genes which alter patterns of synaptic connectivity such as arc or ania-3. These genes remained elevated after precipitated withdrawal, which also triggered the expression of several transcriptional activators and repressors. In addition, morphine has been shown to be a strong inducer of heat shock protein 70, a cell protective protein which might counter-regulate opiate-induced neurotoxicity. Temporal expression profiles during a chronic morphine application schedule revealed discrete and fluctuating expression of gene clusters such as transcription factors, G-protein-coupled receptors and neuropeptides. Prolonged abstinence seems to be characterized by up-regulation of several transcription factors and persistent down-regulation of ligand gated ion channels such as glutamatergic and GABA-ergic receptor subunits. These long-term changes in receptor expression suggest a persistent alteration of synaptic signalling after morphine treatment.

Gene expression of transcription factors in the rat brain after morphine withdrawal.

Multiple approaches have been performed to elucidate the molecular mechanisms underlying drug withdrawal in opioid-dependent animals. Opiate withdrawal represents a state of neuronal hyperexcitability in the brain that leads to alterations in a number of second-messenger systems which, in turn, induce expression of transcription factors. Whereas earlier studies have primarily demonstrated an early and transient transcriptional activation of members of the Fos, Jun, and Krox families, recent microarray studies investigating the delayed response could additionally identify several transcriptional repressors such as cAMP response element modulator (CREM), IkappaB, silencer factor B, helix-loop-helix proteins, or glucocorticoid-induced leucine zipper, indicating the attempt of the brain to re-establish homeostasis after withdrawal-induced excitation.