KAAACI Allergic Rhinitis Guidelines: Part 1. Update in pharmacotherapy

The prevalence of allergic rhinitis (AR) and the socioeconomic burden associated with the medical cost and quality of life of AR have progressively increased. Therefore, practical guidelines for the appropriate management of AR need to be developed based on scientific evidence considering the real-world environment, values, and preferences of patients and physicians. The Korean Academy of Asthma, Allergy and Clinical Immunology revised clinical guidelines for AR to address key clinical questions of the management of AR. Part 1 of the revised guideline covers the pharmacological management of patients with AR in Korea. Through a meta-analysis and a systematic review, we made 4 recommendations for AR pharmacotherapy, including intranasal corticosteroid (INCS)/intranasal antihistamine combination therapy, oral antihistamine/INCS combination therapy, leukotriene receptor antagonist treatment in AR patients with asthma, and prophylactic treatment for patients with pollen-induced AR. However, all recommendations are conditional because of the low or very low evidence of certainty. Well-designed and strictly executed randomized controlled trials are needed to measure and report appropriate outcomes.

KAAACI Allergic Rhinitis Guidelines: Part 2. Update in nonpharmacotherapy

Allergic rhinitis is the most common chronic disease worldwide. Various upper airway symptoms lower quality of life, and due to the recurrent symptoms, multiple treatments are usually attempted rather than one definitive treatment. There are alternatives to medical (medication-based) and nonmedical treatments. A guideline is needed to understand allergic rhinitis and develop an appropriate treatment plan. We have developed guidelines for medical treatment based on previous reports. The current guidelines herein are associated with the “KAAACI Evidence-Based Guidelines for Allergic Rhinitis in Korea, Part 1: Update in pharmacotherapy” in which we aimed to provide evidence-based recommendations for the medical treatment of allergic rhinitis. Part 2 focuses on nonpharmacological management, including allergen-specific immunotherapy, subcutaneous or sublingual immunotherapy, nasal saline irrigation, environmental management strategies, companion animal management, and nasal turbinate surgery. The evidence to support the treatment efficacy, safety, and selection has been systematically reviewed. However, larger controlled studies are needed to elevate the level of evidence to select rational non-medical therapeutic options for patients with allergic rhinitis.

Understanding the Mouse Model of Respiratory Allergic Diseases / 대한이비인후과학회지

Respiratory allergic diseases, represented by allergic rhinitis and asthma, show various features due to their complex pathophysiology. Mouse models of respiratory allergic diseases replicate the characteristics of human allergic rhinitis and asthma, including airway inflammation airway hyperresponsiveness. Different phenotypes and immunologic features are shown according to the various strain of mouse; C57BL/6 strain and BALB/c strain are commonly used in allergic rhinitis and asthma. Ovalbumin as well as pathophysiologically relevant allergen, including house dust mite and fungus are generally used. The mouse model protocols usually include allergen sensitization period followed by allergen provocation period. Allergens possibly combined with adjuvant are introduced into mouse via intraperitoneal, subcutaneous, or intranasal route (sensitization period). Then, mouse repetitively inhales allergen by intranasal, intratracheal, or nebulized formation (aerosol), resulting in a robust influx of inflammatory cells in the airways (provocation period). We can evaluate several parameters including nasal rubbing and sneezing count, airway hyperresponsiveness, histological assessment, cellular composition, cytokine expression of nasal and lung tissue, and allergenspecific immunoglobulin of serum. These examinations provide useful information to understand the pathogenesis of allergic rhinitis and asthma and to test the safety and efficacy of new therapeutic agents. The present review analyzes several protocols and considerations as well as similarities and differences of mouse model of allergic rhinitis and asthma in detail.

An Alternative Dendritic Cell-Induced Murine Model of Asthma Exhibiting a Robust Th2/Th17-Skewed Response

PURPOSE: Simple and reliable animal models of human diseases contribute to the understanding of disease pathogenesis as well as the development of therapeutic interventions. Although several murine models to mimic human asthma have been established, most of them require anesthesia, resulting in variability among test individuals, and do not mimic asthmatic responses accompanied by T-helper (Th) 17 and neutrophils. As dendritic cells (DCs) are known to play an important role in initiating and maintaining asthmatic inflammation, we developed an asthma model via adoptive transfer of allergen-loaded DCs.METHODS: Ovalbumin (OVA)-loaded bone marrow-derived DCs (BMDCs) (OVA-BMDCs) were injected intravenously 3 times into non-anesthetized C57BL/6 mice after intraperitoneal OVA-sensitization.RESULTS: OVA-BMDC-transferred mice developed severe asthmatic immune responses when compared with mice receiving conventional OVA challenge intranasally. Notably, remarkable increases in systemic immunoglobulin (Ig) E and IgG1 responses, Th2/Th17-associated cytokines (interleukin [IL]-5, IL-13 and IL-17), Th2/Th17-skewed T-cell responses, and cellular components, including eosinophils, neutrophils, and goblet cells, were observed in the lungs of OVA-BMDC-transferred mice. Moreover, the asthmatic immune responses and severity of inflammation were correlated with the number of OVA-BMDCs transferred, indicating that the disease severity and asthma type may be adjusted according to the experimental purpose by this method. Furthermore, this model exhibited less variation among the test individuals than the conventional model. In addition, this DCs-based asthma model was partially resistant to steroid treatment.CONCLUSIONS: A reliable murine model of asthma by intravenous (i.v.) transfer of OVA-BMDCs was successfully established without anesthesia. This model more accurately reflects heterogeneous human asthma, exhibiting a robust Th2/Th17-skewed response and eosinophilic/neutrophilic infiltration with good reproducibility and low variation among individuals. This model will be useful for understanding the pathogenesis of asthma and would serve as an alternative tool for immunological studies on the function of DCs, T-cell responses and new drugs.

Survive or thrive: tradeoff strategy for cellular senescence

Aging-dependent cellular behaviors toward extrinsic stress are characterized by the confined localization of certain molecules to either nuclear or perinuclear regions. Although most growth factors can activate downstream signaling in aging cells, they do not in fact have any impact on the cells because the signals cannot reach their genetic targets in the nucleus. For the same reason, varying apoptotic stress factors cannot stimulate the apoptotic pathway in senescent cells. Thus, the operation of a functional nuclear barrier in an aging-dependent manner has been investigated. To elucidate the mechanism for this process, the housekeeping transcription factor Sp1 was identified as a general regulator of nucleocytoplasmic trafficking (NCT) genes, including various nucleoporins, importins, exportins and Ran GTPase cycle-related genes. Interestingly, the posttranslational modification of Sp1 is readily influenced by extrinsic stress, including oxidative and metabolic stress. The decrease in SP1 O-GlcNAcylation under oxidative stress or during replicative senescence makes it susceptible to proteosomal degradation, resulting in defective NCT functions and leading to nuclear barrier formation. The operation of the nuclear barrier in aging provides a fundamental mechanism for cellular protection against stress and promotes survival at the expense of growth via stress-sensitive transcriptional control.

Clinical Comparison of 3D Endoscopic Sinonasal Surgery Between ‘Insect Eye’ 3D and ‘Twin Lens’ 3D Endoscopes

BACKGROUND AND OBJECTIVES: Three-dimensional (3D) imaging is gaining popularity and has been partially used in robotic surgery but not in sinonasal surgery owing to technical problems. This is not only the first pilot study to evaluate the usefulness of newly-developed ‘twin lens’ HD-3D endoscope (Machida), but also the first clinical study to compare this instrument with the pre-existing ‘insect eye’ 3D endoscope (Visionsense). MATERIALS AND METHOD: A total of 45 surgeries for cerebrospinal fluid leakage, angiofibroma, or sinonasal malignancy were performed using a 3D endoscope between November 2011 and October 2013 (‘insect eye’ Visionsense VSII 3D: 29 cases, ‘twin lens’ Machida HD-3D: 16 cases). RESULTS: Depth perception and recognition of anatomical structures were all excellent in the two 3D methods. The ‘twin lens’ HD-3D endoscope provided better image resolution and naturalness of color and showed less unfavorable phenomena such as image blurring and blackout than the ‘insect eye’ 3D endoscope. CONCLUSION: If the technical limitations are solved, the 3D endoscope will be used as a substitute and a standard tool in endoscopic sinonasal surgery rather than as supplement to the two-dimensional (2D) endoscope in the near future.

Canine adipose tissue-derived mesenchymal stem cells ameliorate severe acute pancreatitis by regulating T cells in rats

Severe acute pancreatitis (SAP) is associated with systemic complications and high mortality rate in dogs. Mesenchymal stem cells (MSCs) have been investigated for their therapeutic potential in several inflammation models. In the present study, the effects of canine adipose tissue-derived (cAT)-MSCs in a rat model of SAP induced by retrograde injection of 3% sodium taurocholate solution into the pancreatic duct were investigated. cAT-MSCs labeled with dioctadecyl-3,3,3′-tetramethylindo-carbocyanine perchlorate (1 × 10⁷ cells/kg) were systemically administered to rats and pancreatic tissue was collected three days later for histopathological, quantitative real-time polymerase chain reaction, and immunocytochemical analyses. Greater numbers of infused cAT-MSCs were detected in the pancreas of SAP relative to sham-operated rats. cAT-MSC infusion reduced pancreatic edema, inflammatory cell infiltration, and acinar cell necrosis, and decreased pancreatic expression of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, -6, -12, -17, and -23 and interferon-γ, while stimulating expression of the anti-inflammatory cytokines IL-4 and IL-10 in SAP rats. Moreover, cAT-MSCs decreased the number of clusters of differentiation 3-positive T cells and increased that of forkhead box P3-positive T cells in the injured pancreas. These results indicate that cAT-MSCs can be effective as a cell-based therapeutic strategy for treatment of SAP in dogs.

The Prevalence and Risk Factors of Tinnitus in Korean Adolescents / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Tinnitus is the perception of sound in the absence of any outside acoustic stimulus with high prevalence. Multiple risk factors for tinnitus have been identified. So far, most of studies have concentrated on prevalence and associated chronic disease of tinnitus in adults. In the present study, we focused on tinnitus in adolescents which has not been adequately evaluated. The main goal of this study was to assess the prevalence and associated risk factors of tinnitus in adolescents. SUBJECTS AND METHOD: This study was a retrospectively designed analysis of data from the 5th Korea National Health and Nutrition Examination Survey conducted in 2011-2012. We used tinnitus related interview data, the results of physical and audiological evaluation by ENT specialists, the results of daily intake of vitamin using a 24-hour dietary recall method, and blood samples in 1370 subjects. RESULTS: The prevalence of tinnitus was 22.2% in the age range of 12 and 19 years old. Logistic regression is a statistical method used to assess the association between tinnitus and independent variables. The following factors were independently and positively associated with tinnitus; sex (adjusted OR=1.531, CI=1.097-2.137), excessive earphone use (adjusted OR=1.422, CI=1.026-1.970), Non-occupational noise (adjusted OR=4.096, CI=1.702-9.859), explosive noise (adjusted OR=4.100, CI=1.703-9.872), niacin intake (adjusted OR=0.966, CI=0.940-0.993), vitamin (vit.). D serum concentration (adjusted OR=0.959, CI=0.925-0.994). CONCLUSION: This study showed an association between tinnitus prevalence in adolescents and gender, noise exposure, and vit. D supplement. Tinnitic patients are recommended to reduce excessive noise and use hearing protection devices such as earplugs or earmuffs; they are also recommended to obtain a supply vit. D from adequate sun exposure and outside activities.

Cervical Sympathetic Chain Schwannoma Mimicking Carotid Body Tumor / 대한이비인후과학회지

Schwannoma arising from cervical sympathetic chain is relatively uncommon and can be occasionally misdiagnosed as carotid body tumor. On MR images, schwannoma shows generally hypointense features on the T1-weighted images and hyperintense features on the T2-weighted images. Occasionally, however, contrast administration, which lets schwannoma show marked enhancement, may make it difficult to differentiate schwannoma from carotid body tumor. A 41-year-old woman presented a neck mass on the left. MR images of the neck and carotid angiography revealed a well-enhancing ovoid tumor, which separated the internal carptod arteries from the external carotid arteries at the level of carotid bifurcation. Complete tumor resection was performed and histopathology findings confirmed a schwannoma originating from the sympathetic chain. Postoperatively, miosis and facial anhydrosis of the left side were noted without ptosis, enophthalmos or other neurologic deficits. We report this case with a review of the literatures.

Investigation on Influencing Environmental Factors on Health Status of Korean Septuagenarians Dwelling in Longevity Region in Jeonla Province / 대한지역사회영양학회지

OBJECTIVES: To evaluate the critical environmental factors on healthy-aging of Korean people, we investigated the significant factors influencing health status of septuagenarians living in rural area of Jeonla province, known to be one of the representative longevity regions in Korea. METHODS: We divided subjects into healthy group (36M/25F) or poor-health group (26M/73F) based on self-reported health status, body mass index, a number of prescription, and blood test data. General characteristics, physical measurements, lifestyle, dietary behavior and nutrient intake, physical health and mental health data were statistically compared between the two groups. RESULTS: Average age was not different between healthy group and poor-health group in men and women, respectively. In men, significantly favorable factors to health were observed to be higher education, regular exercise, higher grip strength and walking function, body mass index (> or = 18.5 kg/m2), moderate frequency of drinking and eating-out, non-smoking, normal red blood cell (RBC) count, higher serum dehydroepiandrosterone-sulfate (DHEAS) level, good digestive function and appetite, normal hearing function, regular meals, adequate vegetable and fruit intake, diverse food intake, adequate energy and nutrients (protein, vitamin B1, B6, C and E, folate, niacin, P, Zn and K) intake, higher mini-nutrient status assessment (MNA) score and low level of depression. On the other hand, in women, those were literacy, living arrangement, moderate frequency of drinking, healthy teeth, higher grip strength and walking function, bone mineral density, normal RBC and white blood cell (WBC) count, higher DHEAS concentration, higher MNA score, normal cognition and memory function, having snack and adequate fruit intake. CONCLUSIONS: These results could be useful to plan effective strategies to increase health-life expectancy of Korean old people living in rural areas.

Hearing Outcome According to the Timing of Intratympanic Dexamethasone Injection in Idiopathic Sudden Sensorineural Hearing Loss / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Oral systemic steroids are the most commonly accepted treatment for idiopathic sudden sensorineural hearing loss (SSNHL) despite pathophysiological uncertainty. Recently, intratympanic dexamethasone (ITD) has been proposed as an effective, alternative method for patients in whom oral steroids either fail to respond or are contraindicated. The authors compared the efficacy of ITD according to the duration of hearing loss prior to first dose of ITD. SUBJECTS AND METHOD: We retrospectively reviewed the medical records and audiologic data of 86 SSNHL patients who received ITD from May 2009 to April 2012. Injections were repeated 5 times for 2 weeks and the favorable recovery was defined as complete or partial recovery using Siegel's criteria. We compared the hearing outcomes between pre-ITD and post-ITD with respect to the duration of hearing loss. RESULTS: The mean pure-tone audiograms before and after ITD were 57.91+/-25.52 dB and 50.81+/-24.28 dB (p<0.01), respectively. According to Siegel's criteria, the overall rate of hearing improvement after ITD was 22.1% (19/86). Favorable hearing recovery was observed in 8 of 18 (44.4%) patients within 10 days, 7 out of 41 (17.1%) between 10 days and 20 days, 2 of 18 (11.1%) between 20 days and 30 days, 2 of 7 (28.6%) over 30 days. CONCLUSION: ITD is a useful method as primary or salvage treatment of SSNHL. The results of this study suggest that early ITD after hearing loss increase the probability of hearing recovery.

A Case of Lemierre Syndrome Following Oropharyngeal Infection / 대한이비인후과학회지

Lemierre syndrome is characterized by a history of recent oropharyngeal infection, clinical or radiological evidence of internal jugular vein thrombosis, and isolation of pathogens, mainly Fusobacterium necrophorum. Septic emboli resulting from infected thrombophlebitis of the internal jugular vein leads to metastatic infections involving lung, liver, kidney, bone and central nervous system. Before the advent of antibiotics, the disease used to be common, incurring a high mortality rate. The disease is less frequently seen nowadays, but it is still a life-threatening disease, requiring a high index of suspicion and prompt treatment. We report a case of Lemierre syndrome, which showed oropharyngeal infection, and internal jugular vein thrombosis.

Application of Revised Nursing Work Index to Hospital Nurses of South Korea

PURPOSE: Based on the Revised Nursing Work Index (NWI-R), this research aimed to develop a Korean Hospital General Inpatient Unite-Nursing Work Index (KGU-NWI). This study also aimed to compare the common points and differences between the subfactors of the KGU-NWI and the subfactors from previous studies. METHODS: Based on opinions from 3,151 nurses in Korean hospital general inpatient unit, this research used 57 items of NWI-R and the principal axis factor analysis for deriving subfactors. We evaluated the convergent validity through factor analysis and the content validity of KGU-NWI in terms of the association between nurses' job outcome and the subfactors derived. RESULTS: Six subfactors and 26 items for KGU-NWI were derived from NWI-R. Among them, 'physician-nurse relationship', 'adequate nurse staffing' and 'organizational support and management of hospital' were the same with results from previous studies. In addition, two subfactors, 'participation of decision-making processes' and 'education for improving quality of care', which were similar with results from previous Korean studies, were newly added by using Korean hospital cases. In contrast to previous Korean studies, a unique subfactor this study found was 'nursing processes'. This research confirmed that the six subfactors were highly correlated with job satisfaction, intention to leave, and quality of health care, which represented a nurse's job outcome. CONCLUSION: KGU-NWI including six subfactors and 26 items is an applicable instrument to investigate nurse work environment in Korean hospital general inpatient unit.

A Case of Cerebellar Hemangioblastoma Mimicking Benign Paroxysmal Positional Vertigo / 대한이비인후과학회지

The most common cause of positional vertigo is benign paroxysmal positional vertigo (BPPV). BPPV is characterized by brief recurrent spells of vertigo often brought about by certain head position changes that occur when looking up, turning over in bed, or straightening up after bending over. Its diagnosis relies on a thorough history and physical examination, including Dix-Hallpike maneuver. BPPV usually resolves spontaneously, but treatment of persistent cases with canalolith repositioning maneuvers and exercise therapy has been relatively successful. Those patients with atypical findings or whose symptoms fail to respond to medical therapy and otolith repositioning maneuver, however, require further evaluation to rule out intracranial pathologic conditions. We report here on an unusual case of cerebellar hemangioblatoma showing paroxysmal positional vertigo with a review of the related literature.

Anthropometric Index, Dietary Habits and Nutrient Intake of the Oldest-old Population Aged 95 and Over Living in Seoul / 대한지역사회영양학회지

The population aged 95 years and older in Seoul approximately increased to five-fold over the past 10 years, while nationwide rates increased to three-fold. In order to examine the dietary habit and nutritional status of oldest-old population living in Seoul, we recruited 87 subjects (25 males and 62 females) aged 95 years and older. The prevalence of underweight (BMI or = 25 kg/m2) were 18.2% and 18.2% in males, and 20.8% and 9.4% in females, respectively. In self-assessment of health, only 25.3% answered to be unhealthy. More males exercised regularly and reported a wide range of activities than females. The average of %Kcal from carbohydrate, protein and fat (C : P : F) was 64.9 : 13.8 : 21.2 in males and 68.1 : 14.2 : 17.7 in females. The average daily energy intake was 1,307 kcal in males and 1,304 kcal in females. More than 75% of subjects were taking under estimated average requirements (EAR) for vitamin B1, B2 & C and Ca. The average of mean adequacy ratio (MAR) was 0.66 in males and 0.70 in females, and 28.8% of males and 12.9% of females were in MAR < 0.50. Based on MAR, 32.0% of males and 14.5% females were classified as normal and 16.0% of males and 25.8% of females were classified as malnourished. Our subjects were taking more animal food, especially milk and its products, compared to those living, in rural areas. However, a significant proportion did not meet the EAR for vitamin B1, B2 & C and Ca.

Revision of subjects of the Korean Optometrist Licensing Examination suggested by optometrists / 보건의료교육평가

No abstract available.

Biliverdin reductase A in the prevention of cellular senescence against oxidative stress

Biliverdin reductase A (BLVRA), an enzyme that converts biliverdin to bilirubin, has recently emerged as a key regulator of the cellular redox cycle. However, the role of BLVRA in the aging process remains unclear. To study the role of BLVRA in the aging process, we compared the stress responses of young and senescent human diploid fibroblasts (HDFs) to the reactive oxygen species (ROS) inducer, hydrogen peroxide (H2O2). H2O2 markedly induced BLVRA activity in young HDFs, but not in senescent HDFs. Additionally, depletion of BLVRA reduced the H2O2-dependent induction of heme oxygenase-1 (HO-1) in young HDFs, but not in senescent cells, suggesting an aging-dependent differential modulation of responses to oxidative stress. The role of BLVRA in the regulation of cellular senescence was confirmed when lentiviral RNAitransfected stable primary HDFs with reduced BLVRA expression showed upregulation of the CDK inhibitor family members p16, p53, and p21, followed by cell cycle arrest in G0-G1 phase with high expression of senescence-associated beta-galactosidase. Taken together, these data support the notion that BLVRA contributes significantly to modulation of the aging process by adjusting the cellular oxidative status.

Protective effect of 4,4'-diaminodiphenylsulfone against paraquat-induced mouse lung injury

Although 4,4'-diaminodiphenylsulfone (DDS, dapsone) has been used to treat several dermatologic conditions, including Hansen disease, for the past several decades, its mode of action has remained a topic of debate. We recently reported that DDS treatment significantly extends the lifespan of the nematode C. elegans by decreasing the generation of reactive oxygen species. Additionally, in in vitro experiments using non-phagocytic human fibroblasts, we found that DDS effectively counteracted the toxicity of paraquat (PQ). In the present study, we extended our work to test the protective effect of DDS against PQ in vivo using a mouse lung injury model. Oral administration of DDS to mice significantly attenuated the lung tissue damage caused by subsequent administration of PQ. Moreover, DDS reduced the local expression of mRNA transcripts encoding inflammation-related molecules, including endothelin-1 (ET-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and transforming growth factor-beta (TGF-beta). In addition, DDS decreased the PQ-induced expression of NADPH oxidase mRNA and activation of protein kinase Cmicro (PKCmicro). DDS treatment also decreased the PQ-induced generation of superoxide anions in mouse lung fibroblasts. Taken together, these data suggest the novel efficacy of DDS as an effective protective agent against oxidative stress-induced tissue damages.

A Case of Acute Endophthalmitis After 23-gauge Transconjunctival Sutureless Vitrectomy

PURPOSE: To report a case of acute endophthalmitis associated with 23-gauge transconjunctival sutureless vitrectomy and gas tamponade for macular hole surgery. CASE SUMMARY: A 66-year-old female patient who presented with a macular hole in the left eye was treated with 23-gauge transconjunctival sutureless vitrectomy. On postoperative day 2, the patient developed acute endophthalmitis and was treated with gas-fluid exchange, lensectomy and intravitreal antibiotic injection. Staphylococcus epidermidis was detected in the vitreous fluid of the operated eye. Intraoperative fundus findings showed severe retinal hemorrhage, vascular occlusion and fibrous membranes due to inflammatory response. After treatment, the patient's fundus findings markedly improved and the inflammatory response was controlled. CONCLUSIONS: Acute endophthalmitis after sutureless vitrectomy performed via intraocular gas injection may quickly result in inflammation and disease due to infection. Immediate reoperation and intravitreal antibiotic injections are recommended in such cases.

Suppression of ROS generation by 4,4'-diaminodiphenylsulfone in non-phagocytic human diploid fibroblasts

The action mode of 4,4'-diaminodiphenylsulfone (DDS) is still under debate, although it has long been used in treatment of several dermatologic diseases including Hansen's disease. In this study, we tested the effect of DDS as an antioxidant on paraquat-induced oxidative stress in non-phagocytic human diploid fibroblasts (HDFs). Overall, preincubation of HDFs with DDS prevented the oxidative stress and the resulting cytotoxic damages caused by paraquat in these cells. The specific effects of DDS in paraquat-treated HDFs are summarized as follows: a) reducing the expression of NADPH oxidase 4 (NOX4) by inhibiting paraquat-induced activation of PKC; b) inhibiting paraquat-induced decreases in mitochondrial complex protein levels as well as in membrane potentials; c) consequently, inhibiting the generation of cytosolic and mitochondrial superoxide anions. Taken together, these findings suggest that DDS would suppress the radical generation in non-phagocytic HDFs during oxidative stress, and that DDS might have the extended potential to be used further in prevention of other oxidative stress-related pathologies.