Arylesterase activity is associated with antioxidant intake and paraoxonase-1 (PON1) gene methylation in metabolic syndrome patients following an energy restricted diet

The arylesterase (ARE) activity linked to the paraoxonase-1 (PON1) gene is known to protect lipoproteins from oxidation and provide defense against metabolic syndrome (MetS) and cardiovascular diseases. The epigenetic regulation of enzymatic activities is gaining importance nowadays. This research aimed to assess the potential relationships between the ARE activity with the methylation levels of the PON1 gene transcriptional regulatory region, anthropometrics, biochemical markers and antioxidant dietary components. Forty-seven subjects (47 ± 10 y.o; BMI 36.2 ± 3.8 kg/m2; 46.8 % female) with MetS features, who followed a sixmonth energy-restricted dietary weight-loss intervention, were included in this study (www.clinicaltrials.gov; NCT01087086). Anthropometric, biochemical, enzymatic and dietary data were assessed using validated procedures. PON1 transcriptional regulatory region methylation was analyzed by a microarray technical approach. Volunteers reduced ARE activity in parallel with body weight (p = 0.005), BMI (p = 0.006), total fat mass (p = 0.020), diastolic blood pressure (p = 0.018), mean blood pressure (p = 0.022) and triglycerides (p = 0.014). Methylation levels of some CpG sites of the PON1 gene correlated negatively with ARE activity (p < 0.05). Interestingly, dietary vitamin C (p = 0.001), tocopherols (p = 0.009) and lycopene (p = 0.038) were positively associated with ARE activity and showed an inverse correlation (p = 0.004, p = 0.029 and p = 0.021, respectively) with the methylation of some selected CpG sites of the PON1 gene. In conclusion, ARE activity decreased in parallel with MetS-related markers associated to the energy restriction, while dietary antioxidants might enhance the ARE activity by lowering the PON1 gene methylation in patients with MetS features

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study

BACKGROUND: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. METHODS: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. FINDINGS: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8-8·8]; p<0·0001) and upper-middle-income (1·6 [1·2-2·2]; p=0·0024) country status; age 15-18 years (1·6 [1·1-2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8-3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm3 (1·8 [1·3-2·4]; p=0·0001), and intensive treatment (1·8 [1·3-2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3-0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3-0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3-2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1-2·3]; p=0·020). INTERPRETATION: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness. FUNDING: American Lebanese Syrian Associated Charities and the National Cancer Institute

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. Findings: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8–8·8]; p<0·0001) and upper-middle-income (1·6 [1·2–2·2]; p=0·0024) country status; age 15–18 years (1·6 [1·1–2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8–3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm3 (1·8 [1·3–2·4]; p=0·0001), and intensive treatment (1·8 [1·3–2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3–0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3–0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3–2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1–2·3]; p=0·020). Interpretation: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness. Funding: American Lebanese Syrian Associated Charities and the National Cancer Institute.Fil: Mukkada, Sheena. St Jude Children's Research Hospital; Estados UnidosFil: Bhakta, Nickhill. St Jude Children's Research Hospital; Estados UnidosFil: Chantada, Guillermo Luis. Hospital Sant Joan de Déu Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chen, Yichen. St Jude Children's Research Hospital; Estados UnidosFil: Vedaraju, Yuvanesh. St Jude Children's Research Hospital; Estados UnidosFil: Faughnan, Lane. St Jude Children's Research Hospital; Estados UnidosFil: Homsi, Maysam R. St Jude Children's Research Hospital; Estados UnidosFil: Muniz Talavera, Hilmarie. St Jude Children's Research Hospital; Estados UnidosFil: Ranadive, Radhikesh. St Jude Children's Research Hospital; Estados UnidosFil: Metzger, Monika. St Jude Children's Research Hospital; Estados UnidosFil: Friedrich, Paola. St Jude Children's Research Hospital; Estados UnidosFil: Agulnik, Asya. St Jude Children's Research Hospital; Estados UnidosFil: Jeha, Sima. St Jude Children's Research Hospital; Estados UnidosFil: Lam, Catherine G.. St Jude Children's Research Hospital; Estados UnidosFil: Dalvi, Rashmi. Bombay Hospital And Medical Research Centre; IndiaFil: Hessissen, Laila. Universite Mohammed V. Rabat; Otros paises de ÁfricaFil: Moreira, Daniela. St Jude Children's Research Hospital; Estados UnidosFil: Santana, Victor M. St Jude Children's Research Hospital; Estados UnidosFil: Sullivan, Michael. University of Melbourne; AustraliaFil: Bouffet, Eric. University Of Toronto. Hospital For Sick Children; CanadáFil: Caniza, Miguela A.. St Jude Children's Research Hospital; Estados UnidosFil: Devidas, Meenakshi. St Jude Children's Research Hospital; Estados UnidosFil: Pritchard Jones, Kathy. UCL Great Ormond Street Institute of Child Health; Reino UnidoFil: Rodriguez Galindo, Carlos. St Jude Children's Research Hospital; Estados Unido

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. Findings: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8–8·8]; p<0·0001) and upper-middle-income (1·6 [1·2–2·2]; p=0·0024) country status; age 15–18 years (1·6 [1·1–2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8–3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm3 (1·8 [1·3–2·4]; p=0·0001), and intensive treatment (1·8 [1·3–2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3–0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3–0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3–2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1–2·3]; p=0·020). Interpretation: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness. Funding: American Lebanese Syrian Associated Charities and the National Cancer Institute.Fil: Mukkada, Sheena. St Jude Children's Research Hospital; Estados UnidosFil: Bhakta, Nickhill. St Jude Children's Research Hospital; Estados UnidosFil: Chantada, Guillermo Luis. Hospital Sant Joan de Déu Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chen, Yichen. St Jude Children's Research Hospital; Estados UnidosFil: Vedaraju, Yuvanesh. St Jude Children's Research Hospital; Estados UnidosFil: Faughnan, Lane. St Jude Children's Research Hospital; Estados UnidosFil: Homsi, Maysam R. St Jude Children's Research Hospital; Estados UnidosFil: Muniz Talavera, Hilmarie. St Jude Children's Research Hospital; Estados UnidosFil: Ranadive, Radhikesh. St Jude Children's Research Hospital; Estados UnidosFil: Metzger, Monika. St Jude Children's Research Hospital; Estados UnidosFil: Friedrich, Paola. St Jude Children's Research Hospital; Estados UnidosFil: Agulnik, Asya. St Jude Children's Research Hospital; Estados UnidosFil: Jeha, Sima. St Jude Children's Research Hospital; Estados UnidosFil: Lam, Catherine G.. St Jude Children's Research Hospital; Estados UnidosFil: Dalvi, Rashmi. Bombay Hospital And Medical Research Centre; IndiaFil: Hessissen, Laila. Universite Mohammed V. Rabat; Otros paises de ÁfricaFil: Moreira, Daniela. St Jude Children's Research Hospital; Estados UnidosFil: Santana, Victor M. St Jude Children's Research Hospital; Estados UnidosFil: Sullivan, Michael. University of Melbourne; AustraliaFil: Bouffet, Eric. University Of Toronto. Hospital For Sick Children; CanadáFil: Caniza, Miguela A.. St Jude Children's Research Hospital; Estados UnidosFil: Devidas, Meenakshi. St Jude Children's Research Hospital; Estados UnidosFil: Pritchard Jones, Kathy. UCL Great Ormond Street Institute of Child Health; Reino UnidoFil: Rodriguez Galindo, Carlos. St Jude Children's Research Hospital; Estados Unido

Improving the Timing of Insulin Administration in Adult Acute Care Patients

Background: The correct timing of insulin administration in diabetic patients admitted to the hospital is important for the prevention of transient and serious glycemic deviations that could lead to negative patient outcomes. In November 2021, a South Florida Hospital identified an area of opportunity for quality improvement related to the process of subcutaneous insulin administration. In addition to bar code scanning, manual verification of the insulin dose by the primary nurse and another nurse was required prior to administration. Patients were experiencing delays in the timing of their insulin dose and nurses were reporting frustration with the process. Methods: The project followed the Plan-Do-Study-Act (PDSA) cycle for performance improvement. Results: The change in medication administration workflow resulted in achievement of administering insulin within 30 minutes of the scheduled time. Ninety percent of the nurses surveyed reported improvement in their workflow when giving subcutaneous insulin to their patients (n=112). Conclusion: Interdisciplinary collaboration, innovation in education of the nursing staff, monitoring adherence to the process, and sustaining engagement among stakeholders contributed to the success of this initiative, resulting in improved workflow in subcutaneous insulin administration. Keywords: Bar code medication administration, insulin, safety, quality improvemen

Olfactory and trigeminal interaction of menthol and nicotine in humans

The purpose of the study was to investigate the interactions between two stimuli—menthol and nicotine—both of which activate the olfactory and the trigeminal system. More specifically, we wanted to know whether menthol at different concentrations modulates the perception of burning and stinging pain induced by nicotine stimuli in the human nose. The study followed an eightfold randomized, double-blind, cross-over design including 20 participants. Thirty phasic nicotine stimuli at one of the two concentrations (99 and 134 ng/mL) were applied during the entire experiment every 1.5 min for 1 s; tonic menthol stimulation at one of the three concentrations (0.8, 1.5 and 3.4 μg/mL) or no-menthol (placebo control conditions) was introduced after the 15th nicotine stimulus. The perceived intensities of nicotine’s burning and stinging pain sensations, as well as perceived intensities of menthol’s odor, cooling and pain sensations, were estimated using visual analog scales. Recorded estimates of stinging and burning sensations induced by nicotine initially decreased (first half of the experiment) probably due to adaptation/habituation. Tonic menthol stimulation did not change steady-state nicotine pain intensity estimates, neither for burning nor for stinging pain. Menthol-induced odor and cooling sensations were concentration dependent when combined with low-intensity nicotine stimuli. Surprisingly, this dose dependency was eliminated when combining menthol stimuli with high-intensity nicotine stimuli. There was no such nicotine effect on menthol’s pain sensation. In summary, we detected interactions caused by nicotine on menthol perception for odor and cooling but no effect was elicited by menthol on nicotine pain sensation

Impact of hospital characteristics on implementation of a Pediatric Early Warning System in resource-limited cancer hospitals

BackgroundPediatric Early Warning Systems (PEWS) aid in identification of deterioration in hospitalized children with cancer but are underutilized in resource-limited settings. Proyecto EVAT is a multicenter quality improvement (QI) collaborative in Latin America to implement PEWS. This study investigates the relationship between hospital characteristics and time required for PEWS implementation.MethodsThis convergent mixed-methods study included 23 Proyecto EVAT childhood cancer centers; 5 hospitals representing quick and slow implementers were selected for qualitative analysis. Semi-structured interviews were conducted with 71 stakeholders involved in PEWS implementation. Interviews were recorded, transcribed and translated to English, then coded using a priori and novel codes. Thematic content analysis explored the impact of hospital characteristics and QI experience on time required for PEWS implementation and was supplemented by quantitative analysis exploring the relationship between hospital characteristics and implementation time.ResultsIn both quantitative and qualitative analysis, material and human resources to support PEWS significantly impacted time to implementation. Lack of resources produced various obstacles that extended time necessary for centers to achieve successful implementation. Hospital characteristics, such as funding structure and type, influenced PEWS implementation time by determining their resource-availability. Prior hospital or implementation leader experience with QI, however, helped facilitate implementation by assisting implementers predict and overcome resource-related challenges.ConclusionsHospital characteristics impact time required to implement PEWS in resource-limited childhood cancer centers; however, prior QI experience helps anticipate and adapt to resource challenges and more quickly implement PEWS. QI training should be a component of strategies to scale-up use of evidence-based interventions like PEWS in resource-limited settings

Defining the Role of the Mouse Jhy Gene in the Ependyma and Choroid Plexus

The cerebrospinal fluid (CSF) is produced by the choroid plexus and is contained within the brain ventricular system (Damkier et al., 2013). CSF flows from the lateral ventricles to the third ventricle, where it then enters the fourth ventricle through the cerebral aqueduct (Brinker et al., 2014). The composition of the CSF is derived from passive filtration of plasma and membrane secretion and it has three mains functions: 1) protect the brain by serving as a cushion against mechanical shock, 2) serve as a route for nutrient delivery and signaling factors, and 3) carry waste products and toxins away from the brain (Lun et al., 2015; Spector et al., 2015). CSF production and circulation should be carefully regulated to allow proper brain development (Gato et al., 2014; Mohammad Nabiuni, 2015). Increased CSF volume causes ventricular dilation and it can lead to the development of a neurological condition known as hydrocephalus. Congenital hydrocephalus is the most common form of the disease, which is present at birth and it affects 1-2/1000 children in the United States (Kahle et al., 2015). Hydrocephalus can result from abnormalities in the production, flow or absorption of the CSF, and if untreated it can lead to death. The ventricles of the brain are lined by a monolayer of ciliated squamous epithelia known as the ependymal cells. The ependyma carry motile cilia (9+2), which coordinately beat to produce a laminar flow and promote CSF circulation throughout the ventricles (Spassky, 2013). The choroid plexus is composed of a monolayer of modified ependymal cells though these cells have developed a unique polarization of membrane associated proteins, along with other secretory properties that allow choroid plexus (CP) cells to function in CSF secretion (Damkier et al., 2013; Dziegielewska et al., 2001). Hydrocephalus can result from the disruption of ependymal cells and/or the choroid plexus by the loss of CSF flow and CSF overproduction, respectively (Baas et al., 2006a; Banizs et al., 2005). Despite the undeniable importance of the ependyma and the CP in CSF homeostasis, the mechanisms and factors involved in their differentiation are largely unknown. The work presented here aimed to further characterize the structure and function of the ependymal cells and the specialized ependymal cells of the CP. The JhylacZ mouse line carries an insertional mutation in the Jhy gene (formerly 4931429I11Rik), and homozygous JhylacZ/lacZ mice develop a rapidly progressive juvenile hydrocephalus (Appelbe et al., 2013). Molecular analysis of the ependymal cells in JhylacZ/lacZ mice was performed using a cell-type specific marker approach to assess the expression of markers involved in vital cellular processes of these cells. JhylacZ/lacZ mice display abnormal ependymal cell differentiation with ventricular ependyma retaining an unorganized and multi-layered morphology, representative of immature ependymal cells. Morphological and molecular analysis of the ependyma demonstrated a delay rather than a block in differentiation. Additionally, JhylacZ/lacZ ependymal cells manifest disruptions in adherens junction formation. Ultrastructural analysis of postnatal JhylacZ/lacZ mice found abnormal organization of the motile cilia lining the lateral ventricles of the brain, structures believed to be required for proper CSF flow. JhylacZ/lacZ ependymal cells have defects in the polarized organization of the apically located cilia. The latter resulted in severely reduced motility, a likely cause for the development of hydrocephalus. A second Jhy mutant model (i.e. JhylacZNeo ) was generated upon the availability of Jhy targeted embryonic stem cells from the Knockout mouse consortium (KOMP). We sought to identify the role of Jhy in the specialized ependymal cells of the choroid plexus in the JhylacZNeo mouse line. Our analysis indicates that JhylacZNeo/lacZNeo develop early onset hydrocephalus, with mice rarely surviving past 3 weeks of age. JhylacZNeo/lacZNeo CP also displays disruptions in adherens junction formation, with abnormal localization of the key adherens junction protein, E-cadherin. TEM analysis of the CP in JhylacZNeo/lacZNeo demonstrated defects in ciliary ultrastructure, along with altered microvilli distribution. Together, this data identifies Jhy as a gene required for proper adherens junction formation and cilia ultrastructure, in the ependyma and the specialized ependyma of the choroid plexus

Delayed differentiation of medial ventricular wall ependymal cells in <i>Jhy</i>^{<i>lacZ/lacZ</i>} mice.

<p>(A, B) IF detection of S-100β in P5 coronal sections from <i>Jhy</i>^<i>+/+</i> (A) and <i>Jhy</i>^{<i>lacZ/lacZ</i>} (B) brains. The boxed region in each large image shows the region of the inset, and the white bracket denotes the width of the cell layers marked by S-100β expression. A) <i>Jhy</i>^<i>+/+</i> medial wall cells display a flattened, single cell-layered differentiated ependyma, while B) <i>Jhy</i>^{<i>lacZ/lacZ</i>} medial wall cells retain a pseudostratified undifferentiated appearance. (C) Schematic of lateral ventricle showing regions designated as medial wall and lateral wall, dorsal and ventral. (D-G) H&E staining of sections of P5 <i>Jhy</i>^<i>+/+</i> (D, E) and <i>Jhy</i>^{<i>lacZ/lacZ</i>} (F, G) lateral ventricle medial ependymal walls. <i>Jhy</i>^<i>+/+</i> ependyma has a differentiated appearance in both dorsal and ventral regions (D, E), while <i>Jhy</i>^{<i>lacZ/lacZ</i>} remains undifferentiated dorsally, but is largely differentiated ventrally (F, G). MW, medial wall; LW, lateral wall; LV, lateral ventricle; D, dorsal; V, ventral; L, lateral. Scale bars: 50μm (A-B); 20μm (D-G).</p

The mouse <i>Jhy</i> gene regulates ependymal cell differentiation and ciliogenesis

<div><p>During the first postnatal week of mouse development, radial glial cells lining the ventricles of the brain differentiate into ependymal cells, undergoing a morphological change from pseudostratified cuboidal cells to a flattened monolayer. Concomitant with this change, multiple motile cilia are generated and aligned on each nascent ependymal cell. Proper ependymal cell development is crucial to forming the brain tissue:CSF barrier, and to the establishment of ciliary CSF flow, but the mechanisms that regulate this differentiation event are poorly understood. The <i>Jhy</i>^<i>lacZ</i> mouse line carries an insertional mutation in the <i>Jhy</i> gene (formerly <i>4931429I11Rik</i>), and homozygous <i>Jhy</i>^{<i>lacZ/lacZ</i>} mice develop a rapidly progressive juvenile hydrocephalus, with defects in ependymal cilia morphology and ultrastructure. Here we show that beyond just defective motile cilia, <i>Jhy</i>^{<i>lacZ/lacZ</i>} mice display abnormal ependymal cell differentiation. Ventricular ependyma in <i>Jhy</i>^{<i>lacZ/lacZ</i>} mice retain an unorganized and multi-layered morphology, representative of undifferentiated ependymal (radial glial) cells, and they show altered expression of differentiation markers. Most <i>Jhy</i>^{<i>lacZ/lacZ</i>} ependymal cells do eventually acquire some differentiated ependymal characteristics, suggesting a delay, rather than a block, in the differentiation process, but ciliogenesis remains perturbed. <i>Jhy</i>^{<i>lacZ/lacZ</i>} ependymal cells also manifest disruptions in adherens junction formation, with altered N-cadherin localization, and have defects in the polarized organization of the apical motile cilia that do form. Functional studies showed that cilia of <i>Jhy</i>^{<i>lacZ/lacZ</i>} mice have severely reduced motility, a potential cause for the development of hydrocephalus. This work shows that JHY does not only control ciliogenesis, but is a crucial component of the ependymal differentiation process, with ciliary defects likely a consequence of altered ependymal differentiation.</p></div