Effects of allopurinol on 6-mercaptopurine metabolism in unselected patients with pediatric acute lymphoblastic leukemia: a prospective phase II study.

Allopurinol can be used in maintenance therapy (MT) for pediatric acute lymphoblastic leukemia (ALL) to mitigate hepatic toxicity in patients with skewed 6- mercaptopurine metabolism. Allopurinol increases the erythrocyte levels of thioguanine nucleotides (e-TGN), which is the proposed main mediator of the antileukemic effect and decreases methyl mercaptopurine (e-MeMP) levels, associated with hepatotoxicity. We investigated the effects of allopurinol in thiopurine methyltransferase (TPMT) wild-type patients without previous clinical signs of skewed 6MP metabolism. Fifty-one patients from Sweden and Finland were enrolled in this prospective beforeafter trial during ALL MT. Mean e-TGN increased from 280 nmol/mmol Hb after 12 weeks of standard MT to 440 after 12 weeks of MT with addition of allopurinol 50 mg/m2 (p.

Measurement and stratification of nonsuicidal self-injury in adolescents.

BACKGROUND: Nonsuicidal self-injury (NSSI) is highly prevalent in adolescents. In survey and interview studies assessing NSSI, methods of assessment have been shown to influence prevalence estimates. However, knowledge of which groups of adolescents that are identified with different measurement methods is lacking, and the characteristics of identified groups are yet to be investigated. Further, only a handful of studies have been carried out using exploratory methods to identify subgroups among adolescents with NSSI. METHODS: The performance of two prevalence measures (single-item vs. behavioral checklist) in the same cross-sectional community sample (n = 266, age M = 14.21, 58.3% female) of adolescents was compared regarding prevalence estimates and also characterization of the identified groups with lifetime NSSI prevalence. A cluster analysis was carried out in the same sample. Identified clusters were compared to the two groups defined using the prevalence measures. RESULTS: A total of 118 (44.4%) participants acknowledged having engaged in NSSI at least once. Of these, a group of 55 (20.7%) adolescents confirmed NSSI on a single item and 63 (23.7%) adolescents confirmed NSSI only on a behavioral checklist, while denying NSSI on the single item. Groups differed significantly, with the single-item group being more severely affected and having higher mean scores on difficulties in emotion regulation, self-criticism, number of methods, higher frequency of NSSI, higher rates of suicidal ideation and suicidal behavior and lower mean score on health-related quality of life. All cases with higher severity were not identified by the single-item question. Cluster analysis identified three clusters, two of which fit well with the groups identified by single-item and behavioral checklist measures. CONCLUSIONS: When investigating NSSI prevalence in adolescents, findings are influenced by the researchers' choice of measures. The present study provides some directions toward what kind of influence to expect given the type of measure used, both with regards to the size of the identified group and its composition. Implications for future research as well as clinical and preventive work are discussed.

"You cannot just stop life for just that": a qualitative study on children's experiences on refugee journey to Sweden.

Children with refugee backgrounds are often exposed to violence and other adverse experiences with well-known detrimental consequences on mental health. However, the current group of approximately 40 million child refugees is heterogeneous, stressing the importance of first-person perspectives in understanding children's unique experiences and needs related to the migration process. Identifying contextual factors promoting health and resilience is also essential. For instance, the roles children play as active agents in constructing their own lives and adapting to different environments are poorly described in contemporary research on child refugees and their mental health. To address these knowledge gaps, we conducted qualitative interviews with a reflexive thematic analysis with eighteen children with refugee backgrounds in Sweden. This resulted in two main themes: Longing for a good life that cannot be taken for granted and Challenged agency and changing rights. The narratives indicate that children, although exposed to different challenges in different migration phases and based on gender and asylum status, have experiences of ordinary childhood with a desire for a good life with prospects. The results also show that children execute active and adaptable agency that is impacted by various factors. Reaching the full age appears to be a confusing and ambivalent transition due to changes in rights. The results pinpoint several possibilities to address factors that pose a risk to health and restrictions of rights among child refugees.

Early-life environment and the risk of eczema at 2 years-Meta-analyses of six Finnish birth cohorts.

BACKGROUND: Urban-related nature exposures are suggested to contribute to the rising prevalence of allergic diseases despite little supporting evidence. Our aim was to evaluate the impact of 12 land cover classes and two greenness indices around homes at birth on the development of doctor-diagnosed eczema by the age of 2 years, and the influence of birth season. METHODS: Data from 5085 children were obtained from six Finnish birth cohorts. Exposures were provided by the Coordination of Information on the Environment in three predefined grid sizes. Adjusted logistic regression was run in each cohort, and pooled effects across cohorts were estimated using fixed or random effect meta-analyses. RESULTS: In meta-analyses, neither greenness indices (NDVI or VCDI, 250 m × 250 m grid size) nor residential or industrial/commercial areas were associated with eczema by age of 2 years. Coniferous forest (adjusted odds ratio 1.19; 95% confidence interval 1.01-1.39 for the middle and 1.16; 0.98-1.28 for the highest vs. lowest tertile) and mixed forest (1.21; 1.02-1.42 middle vs. lowest tertile) were associated with elevated eczema risk. Higher coverage with agricultural areas tended to associate with elevated eczema risk (1.20; 0.98-1.48 vs. none). In contrast, transport infrastructure was inversely associated with eczema (0.77; 0.65-0.91 highest vs. lowest tertile). CONCLUSION: Greenness around the home during early childhood does not seem to protect from eczema. In contrast, nearby coniferous and mixed forests may increase eczema risk, as well as being born in spring close to forest or high-green areas.

Maternal prenatal psychological distress associates with offspring early-life wheezing - FinnBrain Birth Cohort.

BACKGROUND: Exposure to prenatal maternal psychological distress may contribute to the development of childhood atopic disorders. Little is known about the importance of distress severity and its duration for the risk. Our aim was to investigate how chronic maternal depressive and anxiety symptoms across gestation influence the risk of wheezing and eczema at child age 24 months. METHODS: The study population was drawn from the FinnBrain Birth Cohort Study, including 1305 mother-infant dyads followed across gestation until the child age of 24 months when the outcomes were mother-reported wheezing ever and doctor-diagnosed eczema. To investigate the risk of wheezing phenotypes, wheezing with and without eczema was separated. Maternal distress was assessed with the Edinburgh Postnatal Depression Scale for depressive and the Symptom Checklist-90 for anxiety symptoms three times during pregnancy, and the chronicity was demonstrated using symptom trajectories composed by latent growth mixture modeling. RESULTS: Of the children, 219/1305 (17%) had wheezing ever and 285/1276 (22%) had eczema. Risk of wheezing ever was elevated with maternal consistently high depressive symptoms (adjusted odds ratio 2.74; 95% confidence interval 1.37-5.50) or moderate and increasing anxiety symptoms (1.94; 1.06-3.54, respectively). Similarly, wheezing without eczema was associated with consistently high depressive (3.60; 1.63-7.94, respectively) and moderate and increasing anxiety symptoms (2.43; 1.21-4.91, respectively). CONCLUSIONS: Maternal chronic psychological distress across gestation was associated with toddler wheezing and especially wheezing without other atopic features (eczema). This finding supports the theory of intrauterine programming effect by maternal psychological distress on offspring immune system and respiratory morbidity.

Multi-professional and multi-agency model PLUSS to facilitate early detection and support of pre-school children with neurodevelopmental difficulties - a model description.

BACKGROUND: Neurodevelopmental difficulties, such as problems in social inter-relatedness, communication, motor coordination, and attention, are frequent in preschoolers and constitute a risk for later negative consequences. This article describes the development of a multi-professional and multi-agency model, PLUSS, to facilitate care and interventions for preschoolers with neurodevelopmental difficulties. METHODS: The PLUSS model was developed for children aged 1.5-5 years with a need for a further assessment of neurodevelopmental symptoms. The model is evaluated using a quasi-experimental study design along with qualitative interviews that study preschool teacher, and parent experiences of PLUSS. Outcomes of interest are a) implementation, b) effectiveness related to processes and multi-agency collaboration, c) capacity building among professionals, d) child-related outcomes with a longitudinal follow-up as well as d) parental wellbeing and satisfaction. RESULTS: The model was launched in 2019 and so far, approximately 130 children have been assessed. Results from a pilot study with 62 children (27-72 months; boys: girls 2.65:1) show that the total mean SDQ score in parental rating was 15 ± 6 and in preschool teacher ratings 14 ± 7, exceeding the Swedish cut-off of 12. 54 parents have participated in parental training and rate high levels of satisfaction (mean score 4.5, max 5.0). In addition, 74 pre-school professionals have been trained in early signs of neurodevelopmental difficulties to facilitate early detection. Feedback from participants indicates high satisfaction with educational activities (mean score 4.2, max 5.0 = very satisfied). CONCLUSIONS: The pilot study shows that the screening procedure can detect children with clinically significant problems. In addition, participant satisfaction is high in parent- and preschool teacher training. The longitudinal study approach enables both child follow-up and evaluation of interventions provided by the working model. TRIAL REGISTRATION: Clinical Trials 2021, PLUSS identifier, NCT04815889 . First registration 25/03/2021.

A systematic review of studies on resilience and risk and protective factors for health among refugee children in Nordic countries.

The Nordic welfare model is often used as an example for the promotion of health and wellbeing, even in vulnerable groups of children, such as refugees. Nonetheless, there are no published reviews on resilience and/or risk and protective factors for physical and mental health among refugee children living in Nordic countries. In this systematic review, we identified 5181 studies on the topic, screened titles, and abstracts, viewed 632, and finally included 26 studies. These studies described 18 samples with a total of 34,080 individuals ranging in ages 0-18 years. Overall, the studies were of good quality. Nearly all studies assessed adversity. Six studies reported physical health outcomes and all studies mental health outcomes, most often post-traumatic stress disorder and anxiety. None explicitly studied resilience. While we found that age and sex are the most frequently studied  risk- and protective factors, findings are inconclusive, since the direction of the associations was different in the different studies. This systematic review indicates that there is still a need for well-designed and -powered studies using clear definitions of key study concepts to examine health outcomes and resilience among refugee children in Nordic countries.

Experiences of paediatric emergence delirium - from parents' and a child's perspective.

BACKGROUND: Emergence delirium is a complex behaviour of perceptual disturbances that may occur after general anaesthesia in children. These children often exhibit delusions, confusion, restlessness and involuntary physical activity. They cry and are almost impossible to console. Research has mainly focused on comparing different medication agents in the occurrence of and dealing with emergence delirium. However, less is known about parents' experiences of emergence delirium during the recovery process, and there is hardly any research concerning the children's experiences. AIMS: The primary aim of this study was to describe parents' experiences and reflections during their child's emergence delirium behaviour when recovering from anaesthesia. A secondary aim was to describe children's experiences of having been in this condition. METHOD: A qualitative research approach with thematic analysis was applied. The study was conducted at two county hospitals in southern Sweden. A total of 16 parents and one child were interviewed. RESULTS: Watching their child demonstrate emergence delirium made parents feel as if they were encountering an incomprehensible scenario. They experienced fear and insecurity and had feelings of powerlessness and guilt. Information and previous experience turned out to offer relief, and being seen by the healthcare staff when they, in their vulnerability, failed to reach or console their child, gave hope and energy. The child confirmed the unexpected and uncontrolled behaviour described by parents. She clearly remembered being 'wild' and out of control. CONCLUSION: Emergence delirium must be extensively considered in children undergoing general anaesthesia. It is of great importance for healthcare staff to be aware of the parental difficulties it may cause and what is experienced as relieving, such as receiving information and staff members being available, responsive and supportive during the wake-up period.

Associations Between IFI44L Gene Variants and Rates of Respiratory Tract Infections During Early Childhood.

BACKGROUND: Genetic heterogeneity in type I interferon (IFN)-related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children. METHODS: In 2 prospective, population-based birth cohorts, the STEPS Study and the FinnBrain Birth Cohort Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until 1 or 2 years of age, respectively. At age 3 months, whole-blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children. RESULTS: In the STEPS Study (n = 1135), IFI44L minor/minor gene variants were associated with lower rates of acute otitis media episodes (adjusted incidence rate ratio, 0.77 [95% confidence interval, .61-.96] for rs273259 and 0.74 [.55-.99] for rs1333969) and courses of antibiotics for RTIs (0.76 [.62-.95] and 0.73 [.56-.97], respectively. In the FinnBrain cohort (n = 971), IFI44L variants were associated with lower rates of RTIs and courses of antibiotics for RTIs. In respiratory virus-positive 3-month-old children, IFI44L gene variants were associated with decreased expression levels of IFI44L and several other IFN-related genes. CONCLUSIONS: Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated IFN pathway activation by respiratory viruses.

Gut microbiota diversity but not composition is related to saliva cortisol stress response at the age of 2.5 months.

Human brain and intestinal microbes reportedly maintain a constant bidirectional connection through diverse neural, endocrine, immune, and metabolic pathways. Increasing evidence indicates that this communication system, referred to as microbiota-gut-brain axis, enables the gut microbes to influence several aspects of brain function and behavior, including hypothalamic-pituitary-adrenal (HPA) axis stress responses, and on the other hand, stress can affect gut microbiota. However, the role of gut microbiota in the HPA axis functioning in humans remains to be specified especially in early life. This study aimed at identifying the potential link between the cortisol stress response and the gut microbiota at the age of 2.5 months. Fecal microbiota profiles were acquired by 16S rRNA gene sequencing, while salivary cortisol responses after an exposure to a mild acute stressor represented the HPA axis reactivity. We observed that a blunted cortisol stress response was weakly associated with a diverse gut microbiota diversity at the age of 2.5 months. Gut microbiota composition was not associated with cortisol stress responsiveness, but rather with covariates, i.e. factors that influence gut microbiota composition and colonization.LAY SUMMARYThis exploratory study aimed at identifying possible links between cortisol stress responses and fecal microbiota composition in early infancy. In a well-characterized study population of 2.5-month-old infants, we observed that an attenuated cortisol stress responsiveness after a mild stressor was weakly associated with a diverse fecal microbiota. Our results suggest that the gut microbiota composition is associated with environmental factors, such as delivery mode and number of siblings, rather than with cortisol stress responsiveness, in this age group.

Association of different enteroviruses with atopy and allergic diseases in early childhood.

BACKGROUND: Enterovirus (EV) infections, being among the most prevalent viruses worldwide, have been associated with reduced risk of allergic diseases. We sought to determine the association between EVs and allergic sensitization and disease in early childhood. METHODS: The study was carried out in a nested case-control setting within a prospective birth cohort in Finland. We included 138 case children who had specific IgE (s-IgE) sensitization at the age of 5 years and 138 control children without s-IgE sensitization. Allergic disease was recorded at study visits and identified with the ISAAC questionnaire. We screened for the presence of serotype-specific antibodies against 41 EVs at 1-5 years of age and assessed their association with allergic sensitization and disease. RESULTS: The overall number of EV infections did not differ between s-IgE-sensitized children and non-sensitized control children. However, there was a tendency of case children with an allergic disease having less EV infections than their controls. This observation was statistically significant for species A EVs in case children with atopic dermatitis vs. control children: OR 0.6 (95% CI 0.36-0.99), p = .048. CONCLUSION: This study supports the evidence that EV exposure and development of allergic disease are inversely associated. Interestingly, the inverse association was not observed for bare atopic IgE sensitization, but for IgE sensitization coupled with clinical atopic disease. This suggests that environmental factors influencing IgE sensitization may differ from those influencing progression to clinical allergic disease.

Incidence and comorbidities of disruptive behavior disorders diagnosed in Finnish specialist psychiatric services.

PURPOSE: Disruptive behavior disorders (DBD), including oppositional defiant disorder (ODD) and conduct disorder (CD), are some of the most common psychiatric conditions in childhood. Despite this, there has been limited research on DBDs. We examined the incidence, comorbidity and gender differences of DBDs diagnosed by specialist services. METHOD: This was a nationwide register study of 570,815 children and adolescents born in 1996-2005. The 7050 individuals diagnosed with DBD by specialist healthcare services were matched to 26,804 controls. RESULTS: By the age of 15, the cumulative incidence of diagnosed DBDs was 3.5% for boys and 1.4% for girls. The yearly incidence rate increased for girls after 13 years of age, while the incidence for boys was relatively stable between 8 and 15 years of age. When we compared subjects born between 1996-1998 and 1999-2001, we found that by the age of 12, the cumulative incidence per 100 people had increased from 0.56 to 0.68 among girls and from 2.3 to 2.6 among boys. This indicated a minor increase in treated incidence. The parents of children diagnosed with DBDs had lower educational levels than the parents of controls. Children with DBD were also more likely to have been diagnosed with other psychiatric disorders. CONCLUSION: Although DBDs were 3.5 times more common among boys during the whole follow-up period, the yearly incidence during adolescence was fairly similar between boys and girls. DBD existed alongside various psychiatric disorders at a relatively young age and only a minor increase in treated incidence was found during childhood.

Management of Ocular Manifestations of Atopic Dermatitis: A Consensus Meeting Using a Modified Delphi Process.

There is a need for unified guidance on the management of ocular manifestations of atopic dermatitis and ocular manifestations associated with dupilumab in the Nordic region (Denmark, Finland, Norway and Sweden). This initiative gathered Nordic dermatologists and ophthalmologists to identify consensus in this area using a modified Delphi process. The initiative was led by a Nordic expert panel who developed a questionnaire that was circulated to a wider group. The results informed an agenda consisting of 24 statements to be voted on using a 5-point Likert scale at a meeting in Copenhagen on 24 April 2019. A facilitator moderated discussion and revised statements according to expert feedback for a second vote when required to reach consensus. Consensus was reached for 23 statements regarding the diagnosis, treatment and referral of these patients, which we hope will improve patient management in the Nordic region.

Clinical Management of Atopic Dermatitis in Adults: Mapping of Expert Opinion in 4 Nordic Countries using a Modified Delphi Process.

Similarities and differences in the everyday clinical management of moderate-to-severe atopic dermatitis in Nordic countries are unknown. Using a modified Delphi approach, 15 dermatologists from Denmark, Finland, Norway and Sweden completed face-to-face and online questionnaires and participated in summary discussions to map expert opinion on the clinical management of moderate-to-severe atopic dermatitis in these Nordic countries. Through discussions, 6 adult patient profiles, reflecting common disease presentations of atopic dermatitis, were identified. Using these case profiles, diagnostic work-up, treatment goals, patient education and treatment approaches were discussed. Patient education was identified as essential for effective management. A treatment sequence of moderate-to-potent topical glucocorticosteroids and emollients, followed by systemic treatment, was recommended, allowing 3 months to ascertain systemic treatment response before switching, if necessary. Consensus was not reached on systemic treatment choice, reflecting differences in clinical practice and reimbursement between countries. Practical, case-based clinical recommendations were developed for optimal patient care.

Prenatal Maternal Psychological Distress and Offspring Risk for Recurrent Respiratory Infections.

OBJECTIVE: To assess the relation between maternal prenatal psychological distress, comprising depression and anxiety symptoms and relationship quality, and the risk of recurrent respiratory infections (RRIs) in children up to 2 years of age. Children with RRIs frequently use health care services and antibiotics. Prenatal maternal psychological distress can be one, previously unidentified risk factor for RRIs. STUDY DESIGN: The study population was drawn from a population-based pregnancy cohort in Finland (www.finnbrain.fi). Children with RRIs (n = 204) and a comparison group (n = 1014) were identified by maternal reports at the child age of 12 or 24 months. The Edinburgh Postnatal Depression Scale, Symptom Checklist-90 anxiety subscale, the Pregnancy-Related Anxiety Questionnaire-Revised 2, and the Revised Dyadic Adjustment Scale were used to assess maternal symptoms and parental relationship quality at 34 weeks of gestation. Adjustment for maternal postnatal depressive and anxiety symptoms was performed. RESULTS: Maternal prenatal Edinburgh Postnatal Depression Scale (OR, 1.24; 95% CI, 1.08-1.44), Symptom Checklist-90/Anxiety (OR, 1.40; 95% CI, 1.01-1.76), Pregnancy-Related Anxiety Questionnaire-Revised 2 (OR, 1.28; 95% CI, 1.11-1.47), and Revised Dyadic Adjustment Scale (OR, 1.32; 95% CI, 1.01-1.58) total sum scores were associated with child RRIs by the age of 24 months. Greater number of siblings, shorter duration of breastfeeding, and the level of maternal education were also identified as risk factors for child RRIs. CONCLUSIONS: Maternal prenatal psychological distress is linked with a higher risk for child RRIs.

Rhinoviruses in infancy and risk of immunoglobulin E sensitization.

Previous data about the role of viruses in the development of allergic immunoglobulin E (IgE) sensitization are contradictory. The aim of this study was to determine the possible associations between exposure to different viruses (rhinovirus, enterovirus, norovirus, and parechovirus) during the first year of life and IgE sensitization. Viruses were analyzed from stool samples collected monthly from infants participating in a prospective birth cohort study. From that study, 244 IgE sensitized case children and 244 nonsensitized control children were identified based on their allergen-specific IgE antibody levels at the age of 6, 18, and 36 months. Stool samples (n = 4576) from the case and control children were screened for the presence of rhinovirus, enterovirus, norovirus, and parechovirus RNA by reverse transcription quantitative polymerase chain reaction. The study showed that rhinovirus was the most prevalent virus detected, present in 921 (20%) samples. None of the viruses were associated with IgE sensitization in the full cohort but after stratifying by sex, the number of rhinovirus positive samples was inversely associated with IgE sensitization in boys (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.69-0.94; P = 0.006). There was also a temporal relation between rhinoviruses and IgE sensitization, as rhinovirus exposure during the first 6 months of life was associated with a reduced risk of subsequent IgE sensitization in boys (OR: 0.76; 95% CI: 0.6-0.94; P = 0.016). In conclusion, early exposure to rhinoviruses was inversely associated with IgE sensitization but this protective association was restricted to boys.

Enterovirus infection during pregnancy is inversely associated with atopic disease in the offspring.

BACKGROUND: Prenatal environment has been shown to influence child's risk of atopic diseases. Laboratory-confirmed data about the role of maternal infections during pregnancy is scarce. OBJECTIVE: The aim of this study was to determine the associations between serologically confirmed maternal infections during pregnancy and atopic disease in the offspring. METHODS: This was a nested case-control study within a prospective birth cohort study. Altogether 202 atopic case children and 333 matched non-atopic control children were included. Atopic outcome was defined as having an atopic disease and IgE sensitization by the age of 5 years. We analysed serologically acute enterovirus (EV), influenza virus A (IAV) and Mycoplasma pneumoniae (M. pneumoniae) infections during pregnancy, and mother's seropositivity against human cytomegalovirus (CMV) and Helicobacter pylori. RESULTS: Maternal EV infection during pregnancy was inversely associated with atopic outcome in the offspring (odds ratio 0.43; 95% confidence interval: 0.23-0.80, P = 0.008). Acute IAV or M. pneumoniae infections or seropositivity against CMV or Helicobacter pylori were not associated with the atopic outcome. CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest that maternal EV infections during pregnancy are inversely associated with atopic disease in the offspring. Our finding provides further support to the previous studies suggesting an important role of the in utero environment in the development of atopic diseases.

p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3.

Nerve growth factor (NGF) influences the survival and differentiation of a specific population of neurons during development, but its role in non-neuronal cells has been less studied. We observed here that NGF and its pro-form, pro-NGF, are elevated in fatty livers from leptin-deficient mice compared with controls, concomitant with an increase in low density lipoprotein receptors (LDLRs). Stimulation of mouse primary hepatocytes with NGF or pro-NGF increased LDLR expression through the p75 neurotrophin receptor (p75NTR). Studies using Huh7 human hepatocyte cells showed that the neurotrophins activate the sterol regulatory element-binding protein-2 (SREBP2) that regulates genes involved in lipid metabolism. The mechanisms for this were related to stimulation of p38 mitogen-activated protein kinase (p38 MAPK) and activation of caspase-3 and SREBP2 cleavage following NGF and pro-NGF stimulations. Cell fractionation experiments showed that caspase-3 activity was increased particularly in the membrane fraction that harbors SREBP2 and caspase-2. Experiments showed further that caspase-2 interacts with pro-caspase-3 and that p38 MAPK reduced this interaction and caused caspase-3 activation. Because of the increased caspase-3 activity, the cells did not undergo cell death following p75NTR stimulation, possibly due to concomitant activation of nuclear factor-κB (NF-κB) pathway by the neurotrophins. These results identify a novel signaling pathway triggered by ligand-activated p75NTR that via p38 MAPK and caspase-3 mediate the activation of SREBP2. This pathway may regulate LDLRs and lipid uptake particularly after injury or during tissue inflammation accompanied by an increased production of growth factors, including NGF and pro-NGF.