HUPA-UCM diabetes dataset.

This dataset provides a collection of Continuous Glucose Monitoring (CGM) data, insulin dose administration, meal ingestion counted in carbohydrate grams, steps, calories burned, heart rate, and sleep quality and quantity assessment ac- quired from 25 people with type 1 diabetes mellitus (T1DM). CGM data was acquired by FreeStyle Libre 2 CGMs, and Fitbit Ionic smartwatches were used to obtain steps, calories, heart rate, and sleep data for at least 14 days. This dataset could be utilized to obtain glucose prediction models, hypoglycemia and hyperglycemia prediction models, and research on the relationships among sleep, CGM values, and the rest of the mentioned variables. This dataset could be used directly from the preprocessed version or customized from raw data. The data set has been used previously with different machine learning algorithms to predict glucose values, hypo, and hyperglycemia and to analyze influences among the features and the quality and quantity of sleep in people with T1DM.

Outcomes and Associated Extracardiac Malformations in Neonates from Colombia with Severe Congenital Heart Disease.

Congenital heart disease (CHD) is a common structural anomaly, affecting ~ 1% of live births worldwide. Advancements in medical and surgical management have significantly improved survival for children with CHD, however, extracardiac malformations (ECM) continue to be a significant cause of morbidity and mortality. Despite clinical significance, there is limited literature available on ECM in neonates with CHD, especially from Latin America. A cross-sectional study of neonates with severe CHD evaluated by the medical-surgical board team at Fundación Cardiovascular de Colombia from 2014 to 2019 was completed to characterize morbidity, mortality, surgical outcomes, and ECM. Demographics and surgical outcomes were compared between neonates with and without ECM. Medical record data were abstracted and descriptive statistical analysis was performed. Of 378 neonates with CHD, 262 had isolated CHD (69.3%) and 116 had ECM (30.7%). The most common ECM was gastrointestinal (n = 18, 15.5%) followed by central nervous system (n = 14, 12%). Most neonates required a biventricular surgical approach (n = 220, 58.2%). Genetic testing was performed more often for neonates with ECM (n = 65, 56%) than neonates with isolated CHD (n = 14, 5.3%). Neonates with ECM had lower birth weight, longer hospital stays, and higher postsurgical complications rates. There was no difference in survival between groups. Overall, Screening for ECM in neonates with CHD is important and identification of ECM can guide clinical decision-making. These findings have important implications for pediatric healthcare providers, especially in low- and middle-income countries, where the burden of CHD is high and resources for managing CHD and extracardiac malformations may be limited.

[Critical points to implement an antibiotic form for management of surgical wound infection]. / Puntos críticos para implementar un formulario de antibióticos para el manejo de infección de herida quirúrgica.

Background: Surgical site infection (SSI) is a major complication of surgical procedures and contributes to morbidity, mortality, and healthcare costs. It is commonly caused by Gram-negative bacteria and should be monitored in hospital units. Objective: To identify critical points to implement an antibiotic form for surgical wound infection management. Material and methods: Descriptive observational study in 100 cultures of wounds with SSI. The most common diagnosis, the microorganism involved, sensitivity to antibiotics and prescription consistency were identified. In addition, demographic variables were assessed and a questionnaire was applied to surgeons in order to identify the critical points to implement a local formulary of antibiotics. Results: 37% of cultures came from female patients. The most common diagnosis was hollow viscus perforation in 31%. The most common microorganism was Escherichia coli ESBL in 20% and 55% of these were sensitive to imipenem. The critical points observed were consistency in the prescription of antimicrobials, which reached only 29%, and that surgeons did not actively participate in strategies for the rational use of antibiotics. Conclusions: As a critical point to implement the antibiotic form, little involvement of surgeons with the hospital infection control team was found. The incidence of SSI was 2.4%, predominantly in emergency surgery. The presence of E. coli ESBL is frequent, with resistance to broad-spectrum antimicrobials.

Introducción: las infecciones del sitio quirúrgico (ISQ) son una complicación importante de los procedimientos quirúrgicos y contribuyen a la morbilidad, la mortalidad y los costos sanitarios. Comúnmente son causadas por bacterias Gram-negativas y deben ser monitoreadas en las unidades hospitalarias. Objetivo: identificar puntos críticos para implementar un formulario de antibióticos para el manejo de infección de herida quirúrgica. Material y métodos: estudio observacional descriptivo en 100 cultivos de heridas con ISQ. Se identificó el diagnóstico más común, el microorganismo involucrado, la sensibilidad a los antibióticos y la congruencia de la prescripción. Además, se evaluaron variables demográficas y se aplicó un cuestionario a cirujanos para identificar los puntos críticos para implementar un formulario local de antibióticos. Resultados: el 37% de los cultivos procedieron de pacientes mujeres. El diagnóstico más común fue perforación de víscera hueca en el 31%. El microrganismo más común fue Escherichia coli BLEE en el 20% y el 55% de estos fueron sensibles a imipenem. Los puntos críticos observados fueron la congruencia en la prescripción de antimicrobianos que alcanzó solo 29% y que los cirujanos no participaron activamente en las estrategias del uso razonado de antibióticos. Conclusiones: como punto crítico para implementar el formulario de antibióticos se encontró poca participación de los cirujanos con el equipo hospitalario de control de infecciones. La incidencia de ISQ fue del 2.4% y preedominaron en la cirugía de urgencia. La presencia de E. coli BLEE es frecuente, con resistencia en antimicrobianos de amplio espectro.

Somatic Support with Veno-venous ECMO in a Pregnant Woman with Brain Death: A Case Report.

Supporting homeostasis in a pregnant woman with brain death to achieve fetal viability is called somatic support. We present a case of young pregnant woman at 21 weeks' gestation who developed acute respiratory distress syndrome secondary to influenza A H2N3 infection requiring veno-venous extracorporeal membrane oxygenation (VV ECMO) support for refractory hypoxemia. The clinical course was complicated by intracranial hemorrhage and subsequent brain death. After multidisciplinary team discussion with her family, consensus was reached to continue somatic support with VV ECMO to enable fetal development to attain extrauterine viability. The challenging clinical, ethical, and legal concerns are discussed.

Implication of coughing dynamics on safe social distancing in an indoor environment-A numerical perspective.

Coughing is a primary symptomatic pathway of respiratory or air-borne disease transmission, including COVID-19. Several parameters such as cougher's age, gender, and posture affect particle dispersion indoors. This study numerically investigates the transient cough evolution, contamination range, particle reach probability, and deposition fraction for different age groups of males and females in standing and sitting postures in a ventilated room. The efficacy of a cloth mask has also been studied with and without the influence of air ventilation. Validated Computational Fluid Dynamics methodology has been implemented to model complex physics such as turbulent buoyant cloud, particle-air interaction, particle collision/breakup, and droplet evaporation. Our results show that overall, the contamination range is slightly lower for females due to lower cough velocities and particle counts. Moreover, a significant fraction of particles crosses the two meters social distancing guideline threshold with an unhindered cough. Besides, wearing a cloth mask reduces the average contamination range by approximately two-third of the distance compared to coughing without the mask. However, aerosolized particles reach longer streamwise distances and drift for extended durations beyond thirty seconds. This study can be used to improve the heating, ventilation, and air conditioning recommendations and distancing guidelines in indoor settings.

Optogenetic Modulation of Intraocular Pressure in a Glucocorticoid-Induced Ocular Hypertension Mouse Model.

Purpose: Steroid-induced glaucoma is a common form of secondary open angle glaucoma characterized by ocular hypertension (elevated intraocular pressure [IOP]) in response to prolonged glucocorticoid exposure. Elevated IOP occurs with increased outflow resistance and altered trabecular meshwork (TM) function. Recently, we used an optogenetic approach in TM to regulate the 5-phosphatase, OCRL, which contributes to regulating PI(4,5)P2 levels. Here, we applied this system with the aim of reversing compromised outflow function in a steroid-induced ocular hypertension mouse model. Methods: Elevated IOP was induced by chronic subconjunctival dexamethasone injections in wild-type C57Bl/6j mice. AAV2 viruses containing optogenetic modules of cryptochrome 2 (Cry2)-OCRL-5ptase and CIBN-GFP were injected into the anterior chamber. Four weeks after viral expression and dexamethasone exposure, IOP was measured by tonometer and outflow facility was measured by perfusion apparatus. Human TM cells were treated with dexamethasone, stimulated by light and treated with rhodamine-phalloidin to analyze actin structure. Results: Dexamethasone treatment elevated IOP and decreased outflow facility in wild-type mice. Optogenetic constructs were expressed in the TM of mouse eyes. Light stimulation caused CRY2-OCRL-5ptase to translocate to plasma membrane (CIBN-CAAX-GFP) and cilia (CIBN-SSTR3-GFP) in TM cells, which rescued the IOP and outflow facility. In addition, aberrant actin structures formed by dexamethasone treatment were reduced by optogenetic stimulation in human TM cells in culture. Conclusions: Subcellular targeting of inositol phosphatases to remove PIP2 represents a promising strategy to reverse defective TM function in steroid-induced ocular hypertension. Translational Relevance: Targeted modulation of OCRL may be used to decrease steroid-induced elevated IOP.

OCRL regulates lysosome positioning and mTORC1 activity through SSX2IP-mediated microtubule anchoring.

Lysosomal positioning and mTOR (mammalian target of rapamycin) signaling coordinate cellular responses to nutrient levels. Inadequate nutrient sensing can result in growth delays, a hallmark of Lowe syndrome. OCRL mutations cause Lowe syndrome, but the role of OCRL in nutrient sensing is unknown. Here, we show that OCRL is localized to the centrosome by its ASH domain and that it recruits microtubule-anchoring factor SSX2IP to the centrosome, which is important in the formation of the microtubule-organizing center. Deficiency of OCRL in human and mouse cells results in loss of microtubule-organizing centers and impaired microtubule-based lysosome movement, which in turn leads to mTORC1 inactivation and abnormal nutrient sensing. Centrosome-targeted PACT-SSX2IP can restore microtubule anchoring and mTOR activity. Importantly, boosting the activity of mTORC1 restores the nutrient sensing ability of Lowe patients' cells. Our findings highlight mTORC1 as a novel therapeutic target for Lowe syndrome.

A molecular subtype of colorectal cancers initiates independently of epidermal growth factor receptor and has an accelerated growth rate mediated by IL10-dependent anergy.

Although epidermal growth factor receptor (EGFR)-targeted therapies are approved for colorectal cancer (CRC) treatment, only 15% of CRC patients respond to EGFR inhibition. Here, we show that colorectal cancers (CRC) can initiate and grow faster through an EGFR-independent mechanism, irrespective of the presence of EGFR, in two different mouse models using tissue-specific ablation of Egfr. The growth benefit in the absence of EGFR is also independent of Kras status. An EGFR-independent gene expression signature, also observed in human CRCs, revealed that anergy-inducing genes are overexpressed in EGFR-independent polyps, suggesting increased infiltration of anergic lymphocytes promotes an accelerated growth rate that is partially caused by escape from cell-mediated immune responses. Many genes in the EGFR-independent gene expression signature are downstream targets of interleukin 10 receptor alpha (IL10RA). We further show that IL10 is detectable in serum from mice with EGFR-independent colon polyps. Using organoids in vitro and Src ablation in vivo, we show that IL10 contributes to growth of EGFR-independent CRCs, potentially mediated by the well-documented role of SRC in IL10 signaling. Based on these data, we show that the combination of an EGFR inhibitor with an anti-IL10 neutralizing antibody results in decreased cell proliferation in organoids and in decreased polyp size in pre-clinical models harboring EGFR-independent CRCs, providing a new therapeutic intervention for CRCs resistant to EGFR inhibitor therapies.

Factors associated with dehiscence of intestinal anastomosis.

OBJETIVO: Identificar los factores asociados a dehiscencia de anastomosis de intestino delgado y grueso. MÉTODO: Se incluyeron 92 anastomosis de intestino delgado y grueso, en mayores de 18 años, realizadas en 2012-2016. Se evaluaron factores asociados en el preoperatorio, el transoperatorio y el posoperatorio. RESULTADOS: Se presentó dehiscencia de anastomosis en el 13% de los casos. Se encontró una asociación significativa con ingesta previa de medicamentos (p = 0.05; odds ratio [OR]: 1.17; IC 95%) y con anastomosis primaria (p = 0.05; OR: 3.6; 0.92-14.5). En los pacientes con dehiscencia se incrementó la estancia intrahospitalaria. CONCLUSIÓN: La presencia de dehiscencia de anastomosis fue similar a lo reportado en la literatura. Los factores asociados fueron la ingesta previa de medicamentos y la anastomosis primaria. OBJECTIVE: To identify the factors associated with dehiscence of anastomosis of the small and large intestine. METHOD: 92 anastomoses of the small and large intestine were included in patients over 18 years of age, performed in 2012-2016. Associated factors were evaluated in pre, trans and postoperative. RESULTS: Anastomosis dehiscence was presented in 13%. A significant association was found for previous medication intake (p = 0.05; odds ratio [OR]: 1.17; 1.024-1.33) and primary anastomosis (p = 0.05, OR: 3.6; 0.92-14.5). In patients with dehiscence, the hospital stay was increased. CONCLUSION: The presence of dehiscence of anastomosis was similar to that reported in the literature. The associated factors were previous medication intake, and primary anastomosis.

Defective INPP5E distribution in NPHP1-related Senior-Loken syndrome.

BACKGROUND: Senior-Loken syndrome is a rare genetic disorder that presents with nephronophthisis and retinal degeneration, leading to end-stage renal disease and progressive blindness. The most frequent cause of juvenile nephronophthisis is a mutation in the nephronophthisis type 1 (NPHP1) gene. NPHP1 encodes the protein nephrocystin-1, which functions at the transition zone (TZ) of primary cilia. METHODS: We report a 9-year-old Senior-Loken syndrome boy with NPHP1 deletion, who presents with bilateral vision decrease and cystic renal disease. Renal function deteriorated to require bilateral nephrectomy and renal transplant. We performed immunohistochemistry, H&E staining, and electron microscopy on the renal sample to determine the subcellular distribution of ciliary proteins in the absence of NPHP1. RESULTS: Immunohistochemistry and electron microscopy of the resected kidney showed disorganized cystic structures with loss of cilia in renal tubules. Phosphoinositides have been recently recognized as critical components of the ciliary membrane and immunostaining of kidney sections for phosphoinositide 5-phosphatase, INPP5E, showed loss of staining compared to healthy control. Ophthalmic examination showed decreased electroretinogram consistent with early retinal degeneration. CONCLUSION: The decreased expression of INPP5E specifically in the primary cilium, coupled with disorganized cilia morphology, suggests a novel role of NPHP1 that it is involved in regulating ciliary phosphoinositide composition in the ciliary membrane of renal tubular cells.

Developmental distribution of primary cilia in the retinofugal visual pathway.

The mammalian visual system is composed of circuitry connecting sensory input from the retina to the processing core of the visual cortex. The two main retinorecipient brain targets, the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN), bridge retinal input and visual output. The primary cilium is a conserved organelle increasingly viewed as a critical sensor for the regulation of developmental and homeostatic pathways in most mammalian cell types. Moreover, cilia have been described as crucial for neurogenesis, neuronal maturation, and survival in the cortex and retina. However, cilia in the visual relay center remain to be fully described. In this study, we characterized the ciliation profile of the SC and dLGN and found that the overall number of ciliated cells declined during development. Interestingly, shorter ciliated cells in both regions were identified as neurons, whose numbers remained stable over time, suggesting that cilia retention is a critical feature for optimal neuronal function in SC and dLGN. Our study suggests that primary cilia are important for neuronal maturation and function in cells of the SC and dLGN.

Optogenetic stimulation of phosphoinositides reveals a critical role of primary cilia in eye pressure regulation.

Glaucoma is a group of progressive optic neuropathies that cause irreversible vision loss. Although elevated intraocular pressure (IOP) is associated with the development and progression of glaucoma, the mechanisms for its regulation are not well understood. Here, we have designed CIBN/CRY2-based optogenetic constructs to study phosphoinositide regulation within distinct subcellular compartments. We show that stimulation of CRY2-OCRL, an inositol 5-phosphatase, increases aqueous humor outflow and lowers IOP in vivo, which is caused by a calcium-dependent actin rearrangement of the trabecular meshwork cells. Phosphoinositide stimulation also rescues defective aqueous outflow and IOP in a Lowe syndrome mouse model but not in IFT88fl/fl mice that lack functional cilia. Thus, our study is the first to use optogenetics to regulate eye pressure and demonstrate that tight regulation of phosphoinositides is critical for aqueous humor homeostasis in both normal and diseased eyes.

Funcionamiento del ciclo de Krebs durante la sepsis y el choque séptico. Una mirada al metabolismo intermediario durante condiciones de hipoxia / The krebs cycle during sepsis and septic shock: a look at intermediate metabolism in hypoxia

El choque séptico es una patología que involucra alteraciones hemodinámicas y compromiso de la microvasculatura que derivan en una disfunción celular que conlleva a la falla orgánica múltiple propia de esta enfermedad. Los protocolos de manejo actuales se centran en la normalización de variables macrohemodinámicas y biomarcadores relacionados con la hipoxia tisular, convirtiéndose en un desafío clínico que requiere el reconocimiento temprano, el control de la infección y la optimización del estado hemodinámico del paciente. En los últimos años se ha identificado que la disfunción multiorgánica que se observa en el choque séptico se encuentra relacionada con el desarrollo de disfunción mitocondrial. Se han planteado dos posibilidades para explicar el surgimiento de esta disfunción mitocondrial, que son el convectivo e inmunometabólico. Dentro del contexto metabólico se observa que el ciclo de Krebs puede funcionar en un entorno de hipoxia mediante la fragmentación y reorientación de sus reacciones enzimáticas, permitiendo la adaptación al metabolismo intermediario a la noxa séptica.

Septic shock is a condition involving hemodynamic alterations and microvascular dysfunction which lead to cellular dysfunction which is typically linked with multiple organ failure. Current management guidelines focus in reestablishing normal macro hemodynamics and biomarkers related with tissue hypoxia. This poses a clinical challenge requiring early recognition, effective infection control and optimization of hemodynamic status in the septic patient. Over the last years multiple organ involvement in septic shock has been correlated with impairment of mitochondrial function. Convective transport and immune cell metabolism have been proposed as two possible reasons for mitochondrial dysfunction during sepsis. Within the metabolic context it is evidenced that the Krebs cycle remains operational even in hypoxic environments by means of fragmentation and reprogramming of enzyme-mediated reactions, activating intermediate metabolism adaptation mechanisms in response to a septic noxa.

Endoscopic Cyclophotocoagulation and Other Cyclodestructive Methods: Histopathologic Comparison of In Vivo Treatment in Humans and Monkeys.

PURPOSE: To compare the histologic effects of endoscopic cyclophotocoagulation (ECP) with other ciliary body ablative procedures. A secondary aim was to correlate these findings with historical clinical success and complication rates. DESIGN: Prospective, qualitative comparison of histopathologic tissue analysis. PARTICIPANTS: Two eyes of two patients who had undergone ECP for open-angle glaucoma were studied. Two eyes from a healthy monkey were treated with ECP and studied. For comparison, 1 eye each of patients who had undergone contact and noncontact neodymium:yttrium-aluminum-garnet transscleral cyclophotocoagulation (TCP) for open-angle glaucoma were analyzed. METHODS: The human globes were enucleated and submitted for analysis by gross examination and light and electron microscopy. Monkey eyes were studied by gross examination and light microscopy 1 week, 2 weeks, and 1 month after ECP. MAIN OUTCOME MEASURES: Gross and histopathologic specimens of all eyes were analyzed with respect to location and type of tissue effects and degree of collateral damage. RESULTS: The gross analysis of all ECP specimens showed a uniform anterior-to-posterior whitening of each treated ciliary process. This correlated with microscopic evidence of loss of pigmentation from the pigmented ciliary epithelial cells seen with mostly preserved architecture and vasculature of the ciliary processes. By comparison, the TCP specimens showed erratic treatment of the ciliary processes with overlap into the pars plicata of the ciliary body. Microscopic analysis revealed significant disruption of the cells throughout the ciliary processes and loss of vessels within the stroma. CONCLUSIONS: Treatment with ECP results in less overall tissue destruction and a targeted effect on the pigmented ciliary epithelium of the ciliary processes when compared with TCP.

Reorganization and clinical management for hypertension control at primary healthcare / Reorganización y manejo clínico para el control de la hipertensión en el primer nivel

Background: In Mexico, 40% of hypertensive patients see their blood pressure under control. The evidence to keep hypertension (HT) under control is scarce, particularly in older adults who have the highest prevalence and require more health services. The objective was to determine the impact of a double intervention to increase the percentage of hypertensive patients with blood pressure levels under control and estimate differences among adults and older adults. Methods: Quasi-experimental design including reorganization and training to physicians using clinical guidelines in four primary healthcare units at the Instituto Mexicano del Seguro Social (IMSS). We included adults who participated whether in the intervention group (IG) or in the control group without equivalence (CGNE). We used regression models for longitudinal data for systolic pressure (SP) and diastolic pressure (DP) variables and proportion of patients with hypertension under control. Results: 530 participants, 272 in the IG; 57.5% were ≥ 60 years. In the IG decreased the SP, ß= −5.93 (95%CI −9.59, −2.28) and increased the proportion with blood pressure under control in young adults (OR 1.48, 95%CI 1.02, 2.14). In the elderly the intervention decreased the DP among those with HT and other comorbidities, ß= −3.57(95%CI −6.72, −0.41), p < 0.05. Conclusion: The interventions reduced SP among adults and DP among older adults with hypertension and other comorbidities. Actions of secondary prevention addressed to each group of age are needed to achieve the control of hypertension at IMSS.

Introducción: en México, 40% de hipertensos observan la tensión arterial (TA) bajo control. La evidencia de intervenciones para controlar la hipertensión (HTA) es aún escasa, particularmente en adultos mayores que tienen mayor prevalencia y uso de servicios de salud. El objetivo fue determinar el impacto de una doble intervención para incrementar la proporción de pacientes con cifras de TA controladas y estimar las diferencias en el control de la TA entre adultos y adultos mayores. Métodos: estudio cuasi experimental que incluyó reorganización gerencial y capacitación clínica a médicos de cuatro unidades del IMSS. Se incluyeron adultos y adultos mayores que participaron en el grupo intervención (GI) o en el grupo control no equivalente (GCNE). Se usaron modelos de regresión para datos longitudinales para las variables de tensión arterial sistólica y diastólica y proporción con cifras TA controladas. Resultados: hubo 530 participantes, 272 en el GI y 258 en GCNE, 57.5% mayores de 60 años. En el GI disminuyó la TAS, ß = −5.93 (IC al 95% entre −9.59 y −2.28) e incrementó la proporción con TA en control entre los adultos jóvenes RM 1.48 (IC al 95% 1.02-2.14); en el grupo de adultos mayores, la intervención redujó niveles de TA diastólica de aquellos con HTA y otras comorbilidades, ß = −3.57(IC 95% entre −6.72 y −0.41), p < 0.05. Conclusión: las intervenciones redujeron la TA sistólica en adultos jóvenes y la TA diastólica en ancianos con HTA y otras comorbilidades. Son necesarias acciones de prevención secundaria para cada grupo de edad a fin de lograr el control de la HTA en el IMSS.

Intraluminal Deposits Found in Glaucoma Tube Shunts Via Anterior Segment Ocular Coherence Tomography.

PURPOSE: To describe and characterize a novel observation of intraluminal deposits of glaucoma tube shunts (TS) using spectral domain (SD) ocular coherence topography (OCT). PATIENTS AND METHODS: Fifteen TS in 11 patients diagnosed with primary open-angle, neovascular, aphakic, and uveitic glaucomas. Both Ahmed (n=11) and Baerveldt (n=4) TS were examined with 5-line raster anterior segment SD-OCT imaging. RESULTS: The exposed tubes of 2 patients had highly reflective intraluminal deposits in the corresponding exposed areas. Seven tubes without exposure had a thin rim of highly reflective material. Six tubes were clear of luminal deposits. The most common diagnosis in the study was uveitic glaucoma which occurred in 5 of the 15 eyes (33%). The next most common diagnosis was primary open-angle glaucoma which occurred in 4 of the 15 eyes (25%). There were 2 nonvalved Baerveldt tubes in each group. The mean duration of TS implantation was 15.0 months in the deposit group and 33.7 months in the group without luminal deposits. The majority of patients in each group were using eye drops at presentation (88.9% deposit, 83.3% clear), and the average intraocular pressure was 20.2 mm Hg in the deposit group and 19.0 mm Hg in the clear group. CONCLUSIONS: Anterior segment OCT imaging may be used to evaluate TS integrity. Intraluminal deposits in TS may occur as a natural response to implanted drainage device, possibly as an inflammatory response.

Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome.

Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P2, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane is poorly understood. Here, we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in Ocrl-null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P2 in Lowe patient cells. Accumulation of sonic hedgehog protein in response to hedgehog agonist was decreased in MEFs derived from a Lowe syndrome mouse model. Together, our findings show for the first time an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome.