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A better understanding of the determinants of placental growth is needed. Our primary aim was to explore associations between maternal ethnic origin and cardio-metabolic factors during pregnancy, and placental weight, surface area, shape and thickness. A multi-ethnic population-based cohort study of 474 pregnant women examined at mean 15 and 28 weeks' gestation. Placentas were inspected after birth by a placental pathologist. Outcome measures were trimmed placental weight and three uncorrelated placental components; surface area, shape (oval vs round) and thickness, created through a principal components analysis. Multivariate linear regression models were used to explore the associations with maternal factors. Compared with ethnic European women, mothers with South- and East Asian ethnicity had placentas with lower weight (−51 g (95% CI: 75, −27) and −55 g (−95, −14) respectively), primarily due to a smaller surface area. The association between South Asian ethnicity and placental surface area was still significant after adjusting for maternal characteristics and cardio-metabolic factors. Fat mass index in early pregnancy was associated with higher placental weight and thickness. Placental surface area was positively associated with mid-gestational increases in fat mass, fasting glucose and triglycerides and with the 2-h glucose value at the 28 week oral glucose tolerance test, and inversely with a mid-gestational increase in HDL-cholesterol. Mid-gestational changes in fat mass, glucose, triglycerides and cholesterol were associated with, but only partly explained ethnic differences in placental surface area, while maternal fat mass in early pregnancy was associated with placental thickness. • We report placental characteristics from a multi-ethnic, population-based cohort. • Mothers with Asian ethnic origin had smaller placental surface area. • Placental thickness was associated with maternal fat mass in early pregnancy. • Placental surface area was related to mid-gestational cardio-metabolic changes. [ABSTRACT FROM AUTHOR]

Physiological transformation with remodeling of the uteroplacental spiral arteries is key to a successful placentation and normal placental function. It is an intricate process that involves, but is not restricted to, complex interactions between maternal decidual immune cells and invasive trophoblasts in the uterine wall. In normal pregnancy, the smooth muscle cells of the arterial tunica media of uteroplacental spiral arteries are replaced by invading trophoblasts and fibrinoid, and the arterial diameter increases 5- to 10-fold. Poor remodeling of the uteroplacental spiral arteries is linked to early-onset preeclampsia and several other major obstetrical syndromes, including fetal growth restriction, placental abruption, and spontaneous preterm premature rupture of membranes. Extravillous endoglandular and endovenous trophoblast invasions have recently been put forth as potential contributors to these syndromes as well. The well-acknowledged disturbed extravillous invasion of maternal spiral arteries in preeclampsia is summarized, as are briefly novel concepts of disturbed extravillous endoglandular and endovenous trophoblast invasions. Acute atherosis is a foam cell lesion of the uteroplacental spiral arteries associated with poor remodeling. It shares some morphologic features with early stages of atherosclerosis, but several molecular differences between these lesions have also recently been revealed. Acute atherosis is most prevalent at the maternal-fetal interface, at the tip of the spiral arteries. The localization of acute atherosis downstream of poorly remodeled arteries suggests that alterations in blood flow may trigger inflammation and foam cell development. Acute atherosis within the decidua basalis is not, however, confined to unremodeled areas of spiral arteries or to hypertensive disorders of pregnancy and may even be present in some clinically uneventful pregnancies. Given that foam cells of atherosclerotic lesions are known to arise from smooth muscle cells or macrophages activated by multiple types of inflammatory stimulation, we have proposed that multiple forms of decidual vascular inflammation may cause acute atherosis, with or without poor remodeling and/or preeclampsia. Furthermore, we propose that acute atherosis may develop at different gestational ages, depending on the type and degree of the inflammatory insult. This review summarizes the current knowledge of spiral artery remodeling defects and acute atherosis in preeclampsia. Some controversies will be presented, including endovascular and interstitial trophoblast invasion depths, the concept of 2-stage trophoblast invasion, and whether the replacement of maternal spiral artery endothelium by fetal endovascular trophoblasts is permanent. We will discuss the role of acute atherosis in the pathophysiology of preeclampsia and short- and long-term health correlates. Finally, we suggest future opportunities for research on this intriguing uteroplacental interface between the mother and fetus. [ABSTRACT FROM AUTHOR]

Introduction: Maternal alloimmunization against human platelet antigen (HPA)-1a has been implied to mediate both reduced birth weight and chronic placental inflammation. Fetal growth restriction is associated with different types of chronic inflammation in the placenta, mainly chronic histiocytic intervillositis and chronic villitis. The aim of this prospective study was to do a systematic examination of placentas from HPA-1a alloimmunized pregnancies, with focus on the histopathological and immunohistochemical diagnosis of variants of chronic inflammation.Material and Methods: In a Polish-Norwegian study, 48 placentas were examined. The histopathology of placentas from 27 HPA-1a immunized women was compared with 21 placentas from non-immunized HPA-1a negative women (controls). In the group of alloimmunized women, ten received antenatal intravenous immunoglobulin G (IVIg). Tissue sections from formalin fixed paraffin embedded placental tissue were stained with hematoxylin and eosin and microscopically examined with focus on various types of chronic placental inflammations.Results: Chronic histiocytic intervillositis was observed in 40.7% of placentas from HPA-1a alloimmunized pregnancies, compared to none in the control group (p = 0.001). Chronic villitis of unknown etiology was more frequently found in the alloimmunized group, however this difference was not statistically significant. Maternal administration of IVIg did not seem to protect against chronic inflammatory lesions.Discussion: Placentas with detectable maternal anti-HPA-1a antibodies are associated with highly increased risk of low-grade chronic histiocytic intervillositis. [ABSTRACT FROM AUTHOR]

Introduction: The objectives of this study were to describe the histo-morphology of post-date placentas in clinically uncomplicated pregnancies without adverse delivery outcomes and the association with maternal circulating pre-delivery Placental Growth Factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), as well as the sFlt-1/PlGF ratio.Methods: Post-date placentas (gestational week ≥40+2, n = 87) were macroscopically and histo-morphologically assessed according to the international, standardized Amsterdam Workshop Consensus Group criteria. Inter-rater agreement was evaluated by percentage of agreement. PlGF and sFlt-1 concentrations were available from maternal serum sampled close to delivery, and were compared by Mann-Whitney U test. Linear regression analyses were adjusted for predefined potential confounders.Results: The majority of the post-date placentas showed morphological signs of delayed maturation. About half of the placentas showed increased syncytial knotting and fibrin. In placentas with increased presence of intervillous fibrin, median maternal PlGF level was significantly lower (p = 0.004), median sFlt-1 level higher and sFlt-1/PlGF ratio significantly higher (p = 0.002) compared to those with normal fibrin amounts. Increased placental syncytial knotting was associated with lower levels of PlGF, higher sFlt-1 and higher sFlt-1/PlGF ratio compared to those with normal knotting.Discussion: Our standardized morphological study of post-date placentas in clinically healthy women with uncomplicated pregnancies and delivery outcomes revealed delayed maturation in the majority of placentas. Increased pre-delivery circulating anti-angiogenic profile was associated with increased intervillous fibrin and syncytial knotting. We propose that circulating maternal angiogenic biomarkers may be of future use in clinical post-date pregnancy assessment, as they reflect important aspects of placental health and function. [ABSTRACT FROM AUTHOR]

Objective: Due to the small size of the murine knee joint, extracting the chondrocyte transcriptome from articular cartilage (AC) is a major technical challenge. In this study, we demonstrate a new pragmatic approach of combining bulk RNA-sequencing (RNA-seq) and single cell (sc)RNA-seq to address this problem.Design: We propose a new cutting strategy for the murine femur which produces three segments with a predictable mixed cell population, where one segment contains AC and growth plate (GP) chondrocytes, another GP chondrocytes, and the last segment only bone and bone marrow. We analysed the bulk RNA-seq of the different segments to find distinct genes between the segments. The segment containing AC chondrocytes was digested and analysed via scRNA-seq.Results: Differential expression analysis using bulk RNA-seq identified 350 candidate chondrocyte gene in the AC segment. Gene set enrichment analysis of these genes revealed biological processes related- and non-related to chondrocytes, including, cartilage development (adj. P-value: 3.45E-17) and endochondral bone growth (adj. P-value 1.22E-4), respectively. ScRNA-seq of the AC segment found a cluster of 131 cells containing mainly chondrocytes. This cluster had 759 differentially expressed genes which enriched for extracellular matrix organisation (adj. P-value 7.76E-40) and other joint development processes. The intersection of the gene sets of bulk- and scRNA-seq contained 75 genes.Conclusions: Based on our results, we conclude that the combination of the two RNA-seq methods is necessary to precisely delineate the chondrocyte transcriptome and to study the disease phenotypes of chondrocytes in murine OA models in the future. [ABSTRACT FROM AUTHOR]

Continuous spikes and waves during sleep (CSWS) is an epileptic encephalopathy characterized by generalised epileptiform activity and neurocognitive dysfunction. Causes and outcome are diverse and treatment is mainly empirical. Retrospective descriptive analysis of clinical and EEG data of children with CSWS diagnosed between 1998 and 2018 at the University Hospital Heidelberg. Ninety-five children were included with a median age at diagnosis of 5.4 years. A structural/metabolic aetiology was found in 43.2%, genetic alterations in 17.9%, while it remained unknown in 38.9%. The proportion of patients with genetic aetiology increased from 10.3% (1998–2007) to 22.8% (2008–2018). On average, each patient received 5 different treatments. CSWS was refractory in >70% of cases, steroids and neurosurgery were most effective. No difference was observed between children with CSWS or Near-CSWS (Spike-Wave-Index 40–85%). Our cohort confirms CSWS as an age-dependent epileptic encephalopathy. Structural brain abnormalities were most frequent, but genetic causes are increasingly identified. More specific criteria for the diagnosis and treatment goals should be elaborated and implemented based on evidence. This study is the largest monocentric observational study on treatment effects in children with CSWS, providing data for diagnostic and therapeutic decisions. • Age at CSWS occurrence is earlier in children with identifiable etiology. • Significant better treatment effects were found for the treatment with steroids or neurosurgery. • No difference between patients with CSWS (SWI >85%) and Near-CSWS (SWI 40–85%) apart from applied treatments was found [ABSTRACT FROM AUTHOR]

Background Exercise is considered an effective treatment strategy for non-specific chronic low back pain (NSCLBP).background In spite of the wide use of exercise protocols, it is not clear what type of exercise is more effective in decreasing pain, disability and normalizing muscle activation patterns in people with chronic low back pain. Objectives To assess the effects of two exercise protocols (stabilization vs movement control) on pain and disability scores and the flexion relaxation ratio (FRR) of lumbar multifidus (LM) and iliocostalis lumbarum pars thoracic (ICLT) in people with extension related non-specific chronic low back pain. Study design Pilot randomized control trial. Methods 32 subjects with active extension pattern chronic low back pain (stabilization group = 16, movement control group = 16) participated in this study. Treatment groups received 4 weeks of exercise therapy. Outcomes were based on pain score (Numeric rating Scale-NRS), disability (Oswestry Disability Index- ODI) and FRR of the LM and ICLT. Results Four people dropped out of the study in each group for reasons unrelated to the protocols of the study. Pain and disability reduced in both groups, with no significant difference between the groups. The FRR of LM did not change in either treatment group after treatment. However, the FRR of ICLT was significantly increased after treatment in the movement control group. Conclusion Both movement control and stabilization exercises reduced pain and disability in the short-term among people with extension pattern NSCLBP, with no difference in effectiveness between the groups. However, movement control exercises were more effective in normalizing back muscle activation patterns than stabilization exercises. [ABSTRACT FROM AUTHOR]

Urban tree risk assessment and mitigation is a process that is strongly influenced by professional experience, risk perception, and risk tolerance. While arborists and other tree risk assessors document all of the risk factors they see in an effort to provide their clients a comprehensive assessment of a tree and its surroundings, the homeowner or property manager ultimately determines what mitigation measures are adopted. Using photographed urban tree scenarios and conjoint analysis, we assessed the level in which seven commonly taught risk factors related to target, likelihood of failure, and consequences of failure contributed to risk ratings given by non-professionals, professionals, and advanced professionals. While risk ratings from all three respondent groups were influenced by the presence and severity of a tree defect and proximity to target, defect severity accounted for approximately half of the risk rating decision (48.5–55.3%). Some risk factors (e.g., tree size, tree species) had little influence on risk ratings. Findings from this research highlight the need to educate both the public and tree care professionals regarding the importance of risk factors beyond tree condition. [ABSTRACT FROM AUTHOR]

Summary Rationale Biomarkers for monitoring response to anti-tuberculosis treatment are needed. We explored immune markers previously published as having predictive capability for 8 week culture status in 39 adults enrolled in a clinical trial in Kampala, Uganda. Methods We consecutively selected 20 HIV-negative pulmonary TB subjects with positive cultures, and 19 subjects with negative cultures at the end of intensive phase therapy. At baseline and after 8 weeks, serum was assayed for nine cytokines and soluble cytokine receptors using multiplexed platforms or ELISA. We evaluated their association with week 8 culture status first using single-variable logistic models, then using cross-validated estimates of the C-statistic, a measure of discrimination, of candidate models including 2 or 3 analytes in addition to age. Results All but one analyte decreased from baseline to week 8 (all p < 0.01). Individual biomarkers were not associated with 8 week culture status. Logistic models including increasing age, higher baseline soluble tumor necrosis factor receptor alpha 1 (sTNF-R1), and higher week 8 C-reactive protein (CRP) concentration classified subjects by culture status with up to 85% accuracy and acceptable discrimination (cross-validated C-statistic 0.76) and calibration (Hosmer–Lemeshow P > 0.2). Conclusion Exploratory post-hoc models including sTNF-R1, CRP, and age, classified 8 week culture status with promising accuracy. [ABSTRACT FROM AUTHOR]

Summary: Phase 2 clinical trials for tuberculosis (TB) treatment require reliable culture methods to determine presence or absence of Mycobacterium tuberculosis (Mtb) over the course of therapy, as these trials are based primarily on bacteriological endpoints. We evaluate which of 5 solid media is most reliable: Lowenstein–Jensen (LJ) egg-base medium and 4 Middlebrook agar media (nonselective 7H10 and 7H11 and selective 7H10 and 7H11). We analyze 393 specimens from 50 HIV-negative Ugandan adults with newly-diagnosed, pulmonary TB and high acid-fast bacillus smear grade. Specimens were collected every 2–4 weeks during the first 12 weeks of therapy. We compare the results for each culture to 2 composite reference standards—one that was deemed positive if any solid culture was positive for Mtb and another based on latent-class analysis. Both reference standards established that the 2 selective Middlebrook media most reliably determine the presence or absence of Mtb (P < 0.003), largely because of their lower contamination rates. We also showed that results on Middlebrook media were similar to each other, while LJ was most frequently discordant. Contaminated results appeared more likely to be truly negative than to harbor undetected Mtb. [Copyright &y& Elsevier]

Summary: We conducted a prospective study to determine which solid medium is the most reliable overall and after two months of therapy to detect Mycobacterium tuberculosis complex (MTB). MTB isolation and contamination rates on LJ and Middlebrook 7H10 and 7H11 agar with and without selective antibiotics were examined in a single laboratory and compared against a constructed reference standard and MGIT 960 results. Of 50 smear positive adults with pulmonary TB enrolled, 45 successfully completed standard treatment. Two spot sputum specimens were collected before treatment and at week 8 and one spot specimen each at weeks 2, 4, 6, and 12. The MTB recovery rate among all solid media for pre-treatment specimens was similar. After 8 weeks, selective (S) 7H11 had the highest positivity rate. Latent class analysis was used to construct the primary reference standard. The 98.7% sensitivity of 7H11S (95% Wilson confidence interval 96.4%–99.6%) was highest among the 5 solid media (P = 0.003 by bootstrap); the 82.6% specificity of 7H10S (95% CI 75.7%–87.8%) was highest (P = 0.098). Our results support 7H11S as the medium of choice. Further studies in different areas where recovery and contamination are likely to vary, are recommended. [Copyright &y& Elsevier]

Abstract: The Karamzinist-Shishkovite polemic exhibits Karamzinolatry and epigonism in their positive and negative manifestations. Karamzinolatry is characterized by intensity, a tendency to create martyria, and epigonism. Epigonism is examined as specific to this era and as a theoretical phenomenon in a close analysis of its nature and its function in Shishkovite texts. Ideas from, e.g., Tynianov, Ginzburg, Maiofis, and Proskurin are extended. Shishkov's Rassuzhdenie and Shakhovskoi's plays exemplify a major function of epigones: they serve as proxies for the target, Karamzin. Epigonic texts, indeed hierarchies of them, are interwoven with lines from Karamzin to discredit him and his aim of modernizing Russian literature. Epigonism becomes a potent weapon against Karamzin personally and against the central tenets of Sentimentalism. It gains in complexity as Karamzinists themselves professed (at least rhetorical) epigonism: the stylistic imitation of women. [Copyright &y& Elsevier]

Summary: Conventional sports training emphasizes adequate training of muscle fibres, of cardiovascular conditioning and/or neuromuscular coordination. Most sports-associated overload injuries however occur within elements of the body wide fascial net, which are then loaded beyond their prepared capacity. This tensional network of fibrous tissues includes dense sheets such as muscle envelopes, aponeuroses, as well as specific local adaptations, such as ligaments or tendons. Fibroblasts continually but slowly adapt the morphology of these tissues to repeatedly applied challenging loading stimulations. Principles of a fascia oriented training approach are introduced. These include utilization of elastic recoil, preparatory counter movement, slow and dynamic stretching, as well as rehydration practices and proprioceptive refinement. Such training should be practiced once or twice a week in order to yield in a more resilient fascial body suit within a time frame of 6–24 months. Some practical examples of fascia oriented exercises are presented. [Copyright &y& Elsevier]

Background & Aims: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to the development of AIP and new therapeutic strategies. Methods: We used quantitative polymerase chain reaction, immunohistochemical, and enzyme-linked immunosorbent analyses to measure the expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing lymphotoxin (LT)α and β specifically in acinar cells (Ela1-LTab mice). Results: Messenger RNA levels of LTα and β were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines (CXCL13, CCL19, CCL21, CCL1, and B-cell–activating factor) was increased in pancreatic and serum samples from patients. Up-regulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LTαβ (Ela1-LTαβ) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LTαβ did not cause autoimmunity in mice without lymphocytes (Ela1-LTab/Rag1 −/− ); moreover, lack of proinflammatory monocytes (Ela1-LTab/Ccr2−/− ) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as antipancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTβR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. Conclusions: Overexpression of LTαβ specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LTβR ligands might be used to treat patients with AIP. [Copyright &y& Elsevier]

Background: A minimum of six electroconvulsive therapy (ECT) treatments has to be delivered to achieve sustained improvement in major depression. However, the mechanisms of the therapeutic actions of ECT are still debated. Objective: We aimed to study the time course and duration of increased Kv7.2 and Kv11.1 mRNA expression in the hippocampus and piriform cortex (Pir) after electroconvulsive stimulation (ECS). Methods: Adult male Sprague-Dawley rats received three ECS per week over 1, 2, or 3 weeks and were decapitated 3 days after the last stimulus. Additional groups of rats receiving nine ECS were sacrificed 7 or 28 days after the last ECS. In situ hybridization was used to measure Kv channel mRNA expression after ECS. Results: Kv7.2 mRNA was increased in the hippocampus and Pir 3 days after both six and nine, but not after three ECS. This was also seen for Kv11.1 mRNA in Pir. These changes lasted for at least 7 days. Conclusions: These results indicate that the changes in Kv7.2 and Kv11.1 channels may contribute to the therapeutic effect of ECT. However, further research needs to be undertaken in this area to extend these findings. [Copyright &y& Elsevier]

Abstract: The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression that displays characteristics similar to those of depressed patients including lower body weight, decreased appetite and reduced REM sleep latency. Hypothalamic neuropeptides such as orexin/hypocretin, melanin-concentrating hormone (MCH) and cocaine and amphetamine regulated transcript (CART), that are involved in the regulation of both energy metabolism and sleep, have recently been implicated also in depression. We therefore hypothesized that alterations in these neuropeptide systems may play a role in the development of the FSL phenotype with both depressive like behavior, metabolic abnormalities and sleep disturbances. In this study, we first confirmed that the FSL rats displayed increased immobility in the Porsolt forced swim test compared to their control strain, the Flinders Resistant Line (FRL), which is indicative of depressive-like behavior. We then examined the number of orexin-, MCH- and CART-immunopositive neurons in the hypothalamus using stereological analyses. We found that the total number of orexin-positive neurons was higher in the hypothalamus of female FSL rats compared to female FRL rats, whereas no changes in the MCH or CART populations could be detected between the strains. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram reduced immobility only in the FRL rats where it also increased the number of MCH positive neurons compared to untreated rats. These findings support the view that orexin may be involved in depression and strengthen the notion that the “depressed” brain responds differently to pharmacological interventions than the normal brain. [Copyright &y& Elsevier]

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This article reviews the role of imaging in the diagnosis of sinonasal tumors, illustrating the diversity of tumors affecting this region. The symptoms of sinonasal tumors are nonspecific; imaging plays a critical role in distinguishing benign and malignant disease and may occasionally illustrate characteristic radiological features of specific tumors. The patterns of local and distant spread of sinonasal malignancy are demonstrated and the respective roles of computed tomography and magnetic resonance imaging are explained. Critical imaging review areas are discussed together with accurate staging, including orbital and intracranial involvement, which determine the appropriate surgical approach. The sites and patterns of tumor recurrence and the imaging features of recurrent tumor are also discussed. [Copyright &y& Elsevier]

This article summarizes the imaging features that aid in distinguishing inflammatory from neoplastic disease and benign from malignant conditions. Diagnostic pitfalls are highlighted. [Copyright &y& Elsevier]

Inflammatory sinus disease is ubiquitous. Patients with recurrent or unilateral disease and those who do not respond to treatment require imaging. Computed tomographic scanning is the mainstay of investigation; magnetic resonance imaging is used as a problem-solving tool. The imaging characteristics of sinonasal inflammatory conditions are varied. The role of imaging is to identify patterns of disease, provide a roadmap for the endoscopist, identify anatomical variants that impact on drainage, and exclude aggressive pathology. [Copyright &y& Elsevier]

Anatomy is the foundation on which the understanding of pathological processes in radiology is based. This article describes the anatomy of the sinonasal region and the clinically relevant anatomical variants, highlighting the need for multiplanar reconstructions as a routine part of the examination when reviewing this region. [Copyright &y& Elsevier]

This article reviews the role of imaging in the management of tumors of the salivary glands, discussing tumor localization, extent, and, where possible, characterization. The relative benefits of the different modalities and the typical features of benign and malignant lesions are discussed for each modality. Characteristic appearances of specific tumors are highlighted. [Copyright &y& Elsevier]

Inflammatory conditions are the most common pathology to affect the salivary glands, of which sialolithiasis is the most frequent etiology. This article reviews the role of all imaging modalities in the management of inflammatory salivary disease. The technique for performing salivary gland ultrasound is described with some common pitfalls. The typical features of a comprehensive range of pathology including obstructive and infective sialadenitis, Sjogren’s syndrome, sarcoidosis, HIV sialopathy, and their complications are described. [Copyright &y& Elsevier]

This article describes the anatomy of the salivary glands highlighting those anatomical features that are relevant to the radiologist. Magnetic resonance images with superimposed line illustrations have been used to aid the understanding of the anatomy of this region. [Copyright &y& Elsevier]

Background: Atopic dermatitis (AD) is a common dermatosis that highly impairs a patient's quality of life. The recent discovery that epidermal barrier defects caused by an aberrant differentiation process of keratinocytes are comparably important to the well-characterized changes in immune response patterns attributed a crucial role to the keratinocytes. Fibroblasts are able to alter proliferation and differentiation of keratinocytes, but their role in AD is not yet fully understood. Objective: We sought to determine the role of fibroblasts in skin proliferation and differentiation in patients with AD. Methods: We used human 3-dimensional organotypic skin cultures consisting of atopic fibroblasts and healthy keratinocytes, as well as healthy fibroblasts and atopic keratinocytes, and compared them with their controls. The expression of differentiation markers in these organotypic cultures were analyzed by using immunohistology and quantitative RT-PCR. Furthermore, the fundamental role of fibroblast-secreted leukemia inhibitory factor was assessed by using small interfering RNA–mediated knockdown cultures. Results: We observed that atopic fibroblasts influence the proliferation of keratinocytes and the terminal differentiation process, resulting in an in vivo–like morphology of AD. Subsequently, healthy fibroblasts were able to restore the structural deficits of the epidermis consisting of atopic keratinocytes. Partially, these effects were due to a reduced expression of the differentiation-associated cytokine leukemia inhibitory factor by atopic fibroblasts. Conclusion: These data demonstrate that fibroblasts and the modulation of fibroblast-derived factors might be new therapeutic targets for the alleviation of AD. [Copyright &y& Elsevier]