Author Correction: SciPy 1.0: fundamental algorithms for scientific computing in Python.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

SciPy 1.0: fundamental algorithms for scientific computing in Python.

SciPy is an open-source scientific computing library for the Python programming language. Since its initial release in 2001, SciPy has become a de facto standard for leveraging scientific algorithms in Python, with over 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories and millions of downloads per year. In this work, we provide an overview of the capabilities and development practices of SciPy 1.0 and highlight some recent technical developments.

Effect of oral anticoagulants on the outcome of faecal immunochemical test.

BACKGROUND: We aimed to evaluate whether oral anticoagulants (OACs) alter faecal immunochemical test (FIT) performance in average-risk colorectal cancer (CRC) screening. METHODS: Individuals aged 50-69 years were invited to receive one FIT sample (cutoff 75 ng ml(-1)) between November 2008 and June 2011. RESULTS: Faecal immunochemical test was positive in 9.3% (21 out of 224) of users of OAC and 6.2% (365 out of 5821) of non-users (P-trend=0.07). The positive predictive value (PPV) for advanced neoplasia (AN) in non-users was 50.4% vs 47.6% in users (odds ratio, 0.70; 95% CI, 0.3-1.8; P=0.5). The PPV for AN in OAC more antiplatelets (aspirin or clopidogrel) was 75% (odds ratio, 2; 95% CI, 0.4-10.8; P=0.4). CONCLUSIONS: Oral anticoagulant did not significantly modify the PPV for AN in this population-based colorectal screening program. The detection rate of advanced adenoma was higher in the combination OAC more antiplatelets.

Effects of acute and chronic methylphenidate on prepulse inhibition: A sex difference study in Wistar rats.

BACKGROUND: The utilization of methylphenidate (MPH) is experiencing a notable surge within the adult population. This growth can be attributed to two key factors: its recreational and cognitive enhancement purposes, as well as the rising prevalence of ADHD diagnoses within this population. This study examined acute and chronic oral MPH effects on attention in male and female Wistar rats. To this end, we used a prepulse inhibition (PPI) task, which is widely used to assess psychoactive drug effects in both humans and rodents. This task allowed us to evaluate changes in attention by analyzing sensorimotor gating associated with stimulus selection process. METHODS: Animals were administered a clinically relevant dose of MPH (5 mg/kg) daily for seven days. The estrous cycle phases of the female rats were measured during behavioral sessions. The PPI task was conducted 20 min after drug administration on day 1 (acute), day 7 (chronic), and 48 h post-treatment. RESULTS: Results indicated that both acute and chronic MPH treatment impaired PPI expression in male rats, but not in female rats, regardless of their estrous cycle phase. Furthermore, a differential effect of chronic MPH treatment on the PPI task was found in male rats. Specifically, on the seventh treatment day, the PPI effect was observed when animals undertook the PPI task for the first time but was impaired in those animals in which the initial PPI session occurred under the acute influence of the drug (day 1). CONCLUSIONS: These findings suggest that the impact of MPH on sensorimotor gating responses may vary based on sex and task experience, possibly leading to state-dependent effects in healthy individuals.

Clinical validation of the European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE) II criteria in an open-access unit: a prospective study.

BACKGROUND AND STUDY AIMS: The European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE I) criteria were recently updated (EPAGE II), but no prospective studies have used these criteria in clinical practice. The aim of the current study was to validate the EPAGE II criteria in an open-access endoscopy unit. PATIENTS AND METHODS: A prospective observational study was conducted in an open-access endoscopy unit at a tertiary care referral center. Consecutive outpatients (n = 1004; mean age 58.9 ±â€†13.1 years; 45 % men) were referred for diagnostic colonoscopy between September 2009 and February 2010. The appropriateness of colonoscopy was assessed based on EPAGE II criteria, and the relationship between appropriateness and both referral doctor and detection of significant lesions was examined. The effectiveness of EPAGE II criteria in assessing appropriateness was measured by means of sensitivity, specificity, and positive and negative predictive values for detecting significant lesions. RESULTS: Colonoscopic cecal intubation was achieved in 956 patients (95.2 %). Most referral doctors were gastroenterologists (58.0 %) and the most common indication was colorectal cancer (CRC) screening (35.2 %). EPAGE II criteria were applicable in 968 patients (96.4 %); of these patients, the indication was appropriate in 778 (80.4 %), inappropriate in 102 (10.5 %), and uncertain in 88 (9.1 %). Patients with appropriate or uncertain indications based on EPAGE II criteria had more relevant endoscopic findings than those with inappropriate indications (38.8 % vs. 24.5 %; OR 1.95, 95 %CI 1.22 - 3.13; P < 0.005). Sensitivity and negative predictive value of EPAGE II criteria for detecting significant lesions were 93.1 % (95 %CI 90 % - 96 %) and 75.5 % (95 %CI 67 % - 84 %), respectively, whereas for advanced neoplastic lesions these values were 98.0 % (95 %CI 95 % - 100 %) and 98.0 % (95 % CI 95 % - 100 %), respectively. Adherence to EPAGE II recommendations was an independent predictor of finding a significant lesion (OR 1.93, 95 %CI 1.20 - 3.11; P = 0.007). CONCLUSIONS: EPAGE II is a simple, valid score for detecting inappropriate colonoscopies in clinical practice.

Colon capsule endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

PillCam colon capsule endoscopy (CCE) is an innovative noninvasive, and painless ingestible capsule technique that allows exploration of the colon without the need for sedation and gas insufflation. Although it is already available in European and other countries, the clinical indications for CCE as well as the reporting and work-up of detected findings have not yet been standardized. The aim of this evidence-based and consensus-based guideline, commissioned by the European Society of Gastrointestinal Endoscopy (ESGE) is to furnish healthcare providers with a comprehensive framework for potential implementation of this technique in a clinical setting.

Public awareness of colorectal cancer and screening in a Spanish population.

OBJECTIVES: To investigate screening intentions and previous uptake of colorectal cancer (CRC) screening tests in a general population in Spain; and to determine knowledge about CRC, risk perceptions, major barriers to screening and perceived benefits of screening. STUDY DESIGN: Cross-sectional study. METHODS: Six hundred consecutive Spanish individuals over 50 years of age completed a questionnaire to determine their screening intentions, previous CRC diagnostic procedures, and knowledge about screening procedures, risk factors for CRC, 5-year prognosis, warning signs and symptoms, incidence, age-related risk and perceived barriers to screening. RESULTS: Although 78.8% of subjects reported that they were willing to participate in CRC screening, only 12% had ever undergone a screening test, and none with screening intention. Awareness of a breast cancer screening test [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.04-2.70; P = 0.035], visiting a general practitioner in the preceding year (OR 3.08, 95% CI 1.86-5.08; P < 0.0001), awareness of risk factors (OR 2.32, 95% CI 1.49-3.61; P < 0.001), awareness of CRC signs or symptoms (OR 1.65, 95% CI 1.03-2.64; P = 0.04) and belief in the efficacy of CRC screening (OR 8.85, 95% CI 1.53-51.3; P = 0.01) were independent predictors for intention to participate in CRC screening. The most common reasons given for refusing screening were 'CRC tests might be dangerous' (28.2%), 'CRC tests might be painful' (17.9%) and 'feeling healthy' (16.2%). CONCLUSION: Although reported willingness to undergo CRC screening was high, CRC knowledge and actual uptake of CRC screening were low. An educational intervention to reduce barriers and increase awareness could improve uptake of CRC screening.

Management of "stone pain" between the 18th and 19th centuries: A brief history of a medical prescription in the Viceroyalty of New Granada.

INTRODUCTION: The presence of stones in the urinary tract is a condition that has accompanied humans since ancient times. In colonial times, this condition was known as "stone pain" and its non-surgical management was based on the use of medicines derived from plants, animals and minerals. OBJECTIVE: To contextualize a medical prescription used to modulate stone pain in the 18th century in the New Kingdom of Granada. Additionally, to analyze its components and evaluate the basis of its possible phytotherapeutic effects on the disease and pain. MATERIAL AND METHOD: Document search in the Cipriano Rodríguez Santamaría Historical Archive of the Octavio Arizmendi Posada Library at Universidad de La Sabana. The document entitled "Prescription for bladder or kidney stone pain" was analyzed, and a complementary review of current scientific literature and original texts was performed with no time limits, in order to compare this prescription to related findings in the history of medicine. RESULTS: The transcription of the source document revealed several phytotherapeutic agents such as chamomile (Matricaria recutita), lilies (Lilium lancifolium), clover (Trifolium pratense), and mallow roots (Malva sylvestris), accompanied by a large amounts of water. CONCLUSIONS: There is scientific evidence that could explain the anti-inflammatory and antioxidant effects of all plant-derived medicines used in this prescription. Abundant water intake to increase urine volume was an essential part of treatment. However, the lack of more precise data related to the prescription and the evolution of the patients makes it difficult to analyze its therapeutic efficacy.

Blueberry supplementation attenuates microglial activation in hippocampal intraocular grafts to aged hosts.

Transplantation of central nervous tissue has been proposed as a therapeutic intervention for age-related neurodegenerative diseases and stroke. However, survival of embryonic neuronal cells is hampered by detrimental factors in the aged host brain such as circulating inflammatory cytokines and oxidative stress. We have previously found that supplementation with 2% blueberry in the diet increases graft growth and neuronal survival in intraocular hippocampal grafts to aged hosts. In the present study we explored possible biochemical mechanisms for this increased survival, and we here report decreased microglial activation and astrogliosis in intraocular hippocampal grafts to middle-aged hosts fed a 2% blueberry diet. Markers for astrocytes and for activated microglial cells were both decreased long-term after grafting to blueberry-treated hosts compared with age-matched rats on a control diet. Similar findings were obtained in the host brain, with a reduction in OX-6 immunoreactive microglial cells in the hippocampus of those recipients treated with blueberry. In addition, immunoreactivity for the pro-inflammatory cytokine IL-6 was found to be significantly attenuated in intraocular grafts by the 2% blueberry diet. These studies demonstrate direct effects of blueberry upon microglial activation both during isolated conditions and in the aged host brain and suggest that this nutraceutical can attenuate age-induced inflammation.

[Prevalence of osteoarticular infections by Enterobacteria producing extended-spectrum -lactamases]. / Prevalencia de infecciones osteoarticulares por enterobacterias productoras de -lactamasas de espectro extendido.

INTRODUCTION: Infections of enterobacteria producing extended-spectrum -lactamases place a heavy burden on health systems. Little is known in osteoarticular infections, so this work studied the prevalence of these infections in a third-level hospital. MATERIAL AND METHODS: Prevalence study in patients of a Traumatology Service during 2016, with infection criteria provided by the CDC in Atlanta, Georgia. The VITEK® 2 AST-N272 (bioMérieux) system was used for bacterial identification at the species level and for antimicrobial susceptibility tests. RESULTS: 7.85% (n = 86) were reported with osteoarticular infections; 22.09% (n = 19) were by enterobacteria BLEEs. An average of 77.1 days of hospitalization (SD 37.7) (46-200 days); isolation of the microorganism occurred 15 days after entry. Sixteen (84.2%) patients had osteomyelitis, three (15.8%) had a prosthetic knee or hip infection. The average number of treatment days was 60 days (21-129 days). Eighteen patients (94.7%) were discharged with resolution of their infectious picture; one patient died with infection over aggregated pneumonia due to carbapenem-resistant K. pneumoniae. DISCUSSION: The prevalence of osteoarticular infections by enterobacteria BLEEs could not be accurately calculated, but we consider it to be within what is expected, infection control measures require higher standards and there is a lack of development programs to use antimicrobials rationally to control the emergence of these pathologies.

INTRODUCCIÓN: Las infecciones por enterobacterias productoras de -lactamasas de espectro extendido (BLEEs) ocasionan una gran carga a los sistemas de salud. Poco se conoce de las infecciones osteoarticulares, por lo que este trabajo estudió la prevalencia de estas infecciones en un hospital de tercer nivel. MATERIAL Y MÉTODOS: Estudio de prevalencia en pacientes de un servicio de traumatología durante 2016, con criterios de infección proporcionados por el CDC de Atlanta, Georgia. Se utilizó el sistema VITEK® 2 AST-N272 (bioMérieux) para la identificación bacteriana a nivel de especie y para las pruebas de susceptibilidad antimicrobiana. RESULTADOS: Se reportaron 7.85% (n = 86) con infecciones osteoarticulares; 22.09% (n = 19) fueron por enterobacterias BLEEs. Con un promedio de 77.1 días de hospitalización (DE 37.7) (46-200 días); el aislamiento del microorganismo se produjo 15 días posteriores al ingreso; 16 (84.2%) pacientes presentaron osteomielitis, tres (15.8%) tuvieron infección protésica de rodilla o cadera. El promedio de días de tratamiento fue de 60 días (21-129 días); 18 pacientes (94.7%) fueron dados de alta con resolución de su cuadro infeccioso; un paciente falleció con infección sobreagregada por neumonía debida a K. pneumoniae resistente a carbapenémicos. DISCUSIÓN: La prevalencia de infecciones osteoarticulares por enterobacterias BLEEs no se pudo calcular con precisión, pero consideramos que se encuentra dentro de lo esperado, las medidas de control de infecciones requieren tener estándares más elevados y falta desarrollar programas de uso racional de antimicrobianos para controlar la aparición de estas patologías.

Variation among endoscopy units in the achievement of the standards of colonoscopic performance indicators.

BACKGROUND/AIMS: To assess the achievement of quality standards of colonoscopy at six endoscopy units. METHODOLOGY: Three indicators were used to assess the quality of 1056 colonoscopies performed at six hospitals: cecal intubation; adequate colon cleansing; and removal and recovery of all detected polyps. Analyses were performed on the total number of colonoscopies and on colonoscopies in which polyps were actually detected. The accomplishment of each indicator and a global compound index of all three indicators, named the Problem Rate, were analyzed. Results from each endoscopy unit were compared to previously established standards. RESULTS: Adequate colon cleansing was the most frequent problem for quality in all centers; adequate colon preparation was 67% (range 50 to 84%). The cecum was reached in 84% of all colonoscopies (range 76 to 90%). 75% of all patients (range 28. 79%) had all polyps excised and recovered. All centers had rates below standard for one or several indicators (p<0.01, all cases). Two of the participant hospitals had an overall problem rate above the estimated standard (p<0.01). CONCLUSIONS: There is a significant variation in the achievement of quality standards of colonoscopy between endoscopy units. Colon cleansing is the most frequent quality problem for colonoscopy.

Effects of long-term cyclo-oxygenase 2 selective and acid inhibition on Barrett's oesophagus.

BACKGROUND: There is an overexpression of cyclo-oxygenase 2 (COX-2) in Barrett's oesophagus (BO). AIM: To determine the long-term effect of a COX-2 inhibitor on cellular mechanisms involved in BO. METHODS: A randomized controlled trial was conducted in BO patients allocated to continue the usual proton pump inhibitor (PPI) alone treatment, or PPI combined with rofecoxib (25 mg/day) for 6 months. Cell proliferation index and COX-2 expression in BO glands was determined in biopsy specimens at baseline and after treatment. Cell apoptosis, cyclin D1, p53 and vascular endothelial growth factor (VEGF) expression was also explored in a subset of patients. Student-t test and the U-Mann-Whitney test were used for quantitative and ordinal variables. RESULTS: Of 62 patients, 58 completed the study. A higher proportion of patients on rofecoxib + PPI exhibited a decrease in COX-2 expression compared to those treated with PPI alone, but cell proliferation index was not affected. Unlike PPI alone, rofecoxib + PPI was associated with an increase in the apoptotic cell index, a decrease in p53 cell staining and VEGF expression in mucosal vessels. No effect on low-grade dysplasia or cyclin D1 was observed. CONCLUSIONS: The addition of rofecoxib to PPI therapy does not affect cell proliferation index in BO cells after 6 months of therapy, but does reduce COX-2 and VEGF expression and increases cell apoptosis.

An instrument to measure mechanical up-conversion phenomena in metals in the elastic regime.

Crystalline materials, such as metals, are known to exhibit deviation from a simple linear relation between strain and stress when the latter exceeds the yield stress. In addition, it has been shown that metals respond to varying external stress in a discontinuous way in this regime, exhibiting discrete releases of energy. This crackling noise has been extensively studied both experimentally and theoretically when the metals are operating in the plastic regime. In our study, we focus on the behavior of metals in the elastic regime, where the stresses are well below the yield stress. We describe an instrument that aims to characterize non-linear mechanical noise in metals when stressed in the elastic regime. In macroscopic systems, this phenomenon is expected to manifest as a non-stationary noise modulated by external disturbances applied to the material, a form of mechanical up-conversion of noise. The main motivation for this work is for the case of maraging steel components (cantilevers and wires) in the suspension systems of terrestrial gravitational wave detectors. Such instruments are planned to reach very ambitious displacement sensitivities, and therefore mechanical noise in the cantilevers could prove to be a limiting factor for the detectors' final sensitivities, mainly due to non-linear up-conversion of low frequency residual seismic motion to the frequencies of interest for the gravitational wave observations. We describe here the experimental setup, with a target sensitivity of 10(-15) m/Hz in the frequency range of 10-1000 Hz, a simple phenomenological model of the non-linear mechanical noise, and the analysis method that is inspired by this model.

Regulation of trophic factor expression by innervating target regions in intraocular double transplants.

Trophic factors have been found to play a significant role both in long-term survival processes and in more rapid and dynamic processes in the brain and spinal cord. However, little is known regarding the regulation of expression of growth factors, and how these proteins interact on a cell-to-cell basis. We have studied protein levels of one growth factor known to affect the noradrenergic innervation of the hippocampal formation, namely brain-derived neurotrophic factor (BDNF). The purpose of the present study was to determine if appropriate innervation or contact between the LC noradrenergic neurons and their target, the hippocampus, affects expression of this growth factor in either brain region. Fetal brain stem tissue, containing the LC, and hippocampal formation were dissected from embryonic day 17 rat fetuses and transplanted together or alone into the anterior chamber of the eye of adult Fisher 344 rats. The tissue was grown together for 6 weeks, after which the animals were sacrificed and ELISAs for BDNF were undertaken. Transplantation to the anterior chamber of the eye increased the expression of BDNF in the hippocampal but not the brain stem tissue, compared with levels observed in fetal and adult rats in vivo. In addition, double grafting with hippocampal tissue more than tripled BDNF levels in brain stem grafts and doubled BDNF levels in the hippocampal portion of double grafts compared with hippocampal single grafts. Triple grafts containing basal forebrain, hippocampus, and brain stem LC tissue increased brain stem and hippocampal BDNF levels even further. Colchicine treatment of LC-hippocampal double grafts gave rise to a significant decrease in hippocampal BDNF levels to levels seen in single hippocampal grafts, while only a partial reduction of BDNF levels was seen in the brain stem portion of the same double grafts treated with colchicine. The findings suggest that an appropriate hippocampal innervation or contact with its target tissues is essential for regulation of BDNF expression in the brain stem, and that retrograde transport of BDNF can occur between double grafted fetal tissues in oculo.

[Screening the at-risk population for squamous cell carcinoma of the esophagus]. / Cribado del carcinoma escamoso de esófago en población de riesgo.

Together with adenocarcinoma, epidermoid esophageal carcinoma is the most clinically important neoplasm of the esophagus. Because of the low incidence of epidermoid esophageal carcinoma in the general population, strategies for its early diagnosis are not a priority compared with other neoplasms. However, because survival is low when the disease is diagnosed in symptomatic patients (less than 20% at 5 years), methods for its early diagnosis should be investigated. The use of cytology or Lugol chromoendoscopy in countries with a high incidence of epidermoid carcinoma or in individuals at increased risk (mainly alcoholics and smokers) has allowed early diagnosis and potentially curative treatment, substantially increasing life expectancy in this group of patients. These results should stimulate the evaluation and eventual implementation of programs to achieve early diagnosis and therefore greater survival in patients with epidermoid esophageal carcinoma in Western countries.

Investigación médico-antropológica documental: prescripciones enfocadas al manejo del dolor / Medical-anthropological research: prescriptions focused on pain management

Introducción: Las recetas médicas o prescripciones históricas en el territorio de la Nueva Granada (hoy Colombia) revelan la evolución del manejo de la enfermedad en función de los efectos benéficos de administrar algún tipo de agente medicinal de origen vegetal, animal o mineral. Objetivo: Describir el tratamiento del reumatismo en los siglos XVIII y XIX, con base en dos recetas médicas de la época con base en la fundamentación contemporánea de su interacción fisiológica. Materiales y métodos: Búsqueda documental en el archivo Histórico de la Biblioteca Octavio Arizmendi Posada de la Universidad de La Sabana, donde se encontraron las recetas tituladas "Reumatismo" y "Rehumas". Resultados: Se describen cuatro clases de tratamientos para las enfermedades reumáticas utilizados en los siglos XVIII y XIX y orientados principalmente a la disminución del dolor. Este artículo presenta las bases fisiológicas de estos tratamientos, y cómo pudieron o no haber tenido algún efecto calmante al examinar su fisiología. Conclusiones: Estos medicamentos coloniales neogranadinos no ameritan su uso en el contexto actual de la medicina, pero pudieron representar una ayuda terapéutica en su momento.

Introduction: the medical prescriptions or historical prescriptions in the territory of New Granada (present-day Colombia) reveal the evolution of disease management given the beneficial effects of administering some type of medicinal agent of plant, animal or mineral origin. Objective: To describe the treatment of rheumatism in the 18th and 19th centuries based on two medical prescriptions of the time based on the contemporary rationale of their physiological interactions. Materials and methods: Documentary search in the Historical Archive of the Octavio Arizmendi Posada Library at Universidad de La Sabana in Colombia, where the prescriptions entitled "Reumatismo" and "Rehuma" were found. Results: Four classes of treatments for rheumatic diseases used in the 18th and 19th centuries and mainly oriented to pain reduction are described. This article presents the physiological basis of these treatments, and how they may or may not have had some calming effect when examining their physiology. Conclusions: These Neogranadian colonial drugs do not deserve their use in the current context of medicine, but they may have represented a therapeutic aid at the time.

Selective neurodegeneration, without neurofibrillary tangles, in a mouse model of Niemann-Pick C disease.

The BALB/c mouse model of Niemann-Pick type C (NPC) disease exhibits neuropathological similarities to the human condition. There is an age-related cerebral atrophy, demyelination of the corpus callosum, and degeneration of cerebellar Purkinje cells in the NPC mouse. In human NPC, many cortical and subcortical neurons contain neurofibrillary tangles, which are thought by some investigators to play an important role in the neurodegenerative process. The purpose of the present study was to determine whether neurodegeneration occurs in the NPC mouse, in brain regions other than the cerebellum and whether the degeneration is related to the presence of neurofibrillary tangles. Using light microscopic methods with immunohistochemistry, electron microscopy, and cell counting methods, 11-week-old NPC(+/+) and NPC(-/-) animals were examined. In the NPC(-/-) mice, there were 96% fewer Purkinje cells, 28% fewer neurons in the prefrontal cortex, 20% fewer neurons in the thalamus, and 63% fewer glial cells in the corpus callosum. On the other hand, previous studies indicate normal numbers of neurons and glial cells in these same neuroanatomical regions in young NPC(-/-) mice. There were normal numbers of cholinergic neurons in sections assessed in the striatum and basal forebrain in the 11-week-old animals and no evidence of neurofibrillary tangles within cells. The present data indicate that both neurons and glial cells die in the NPC mouse but that all cells are not equally vulnerable. There was no evidence for neurofibrillary tangles in the NPC mouse, and therefore the degenerative process in the mouse is unrelated to the neurofibrillary tangle.

Degeneration of neurons and glia in the Niemann-Pick C mouse is unrelated to the low-density lipoprotein receptor.

The BALB/c mouse model of Niemann-Pick type C disease exhibits similar neuropathological features to the human condition, including cerebral atrophy, demyelination of the corpus callosum, and degeneration of cerebellar Purkinje cells. The gene defect in Niemann-Pick C disease causes cholesterol to accumulate within the lysosomal compartment of neurons and glial cells. In order to determine whether cholesterol accumulation through the low-density lipoprotein receptor pathway plays an important role in the degenerative process, Niemann-Pick C mice were crossed with low-density lipoprotein receptor knockout mice. The purpose of the present study was to determine whether degeneration of neurons and glial cells is reduced in Niemann-Pick C animals lacking the low-density lipoprotein receptor. Using stereological counting methods, Purkinje cells were counted in the cerebellum and glial cell bodies were counted in the corpus callosum in mice at 3, 7.5 and 11 weeks of age. In the Niemann-Pick C animals, compared to wild-type control mice, there were 48% fewer glial cells at 3 weeks of age, and by 11 weeks of age there were 63% fewer glial cells. Purkinje cells were decreased in number by 13% at 3 weeks of age, and by 11 weeks of age there was a 96% loss. In the Niemann-Pick C animals lacking low-density lipoprotein receptors, there was no difference in the magnitude of glial cell or Purkinje cell loss compared to the Niemann-Pick C animals. These data indicate that both neurons and glia are vulnerable to degeneration in the Niemann-Pick C mouse, but that blocking the accumulation of cholesterol through the low-density lipoprotein receptor pathway does not alter the degenerative phenotype of Niemann-Pick C disease.

Glial cell line-derived neurotrophic factor is essential for neuronal survival in the locus coeruleus-hippocampal noradrenergic pathway.

It has been shown that the noradrenergic (NE) locus coeruleus (LC)-hippocampal pathway plays an important role in learning and memory processing, and that the development of this transmitter pathway is influenced by neurotrophic factors. Although some of these factors have been discovered, the regulatory mechanisms for this developmental event have not been fully elucidated. Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor influencing LC-NE neurons. We have utilized a GDNF knockout animal model to explore its function on the LC-NE transmitter system during development, particularly with respect to target innervation. By transplanting various combinations of brainstem (including LC) and hippocampal tissues from wildtype or GDNF knockout fetuses into the brains of adult wildtype mice, we demonstrate that normal postnatal development of brainstem LC-NE neurons is disrupted as a result of the GDNF null mutation. Tyrosine hydroxylase immunohistochemistry revealed that brainstem grafts had markedly reduced number and size of LC neurons in transplants from knockout fetuses. NE fiber innervation into the hippocampal co-transplant from an adjacent brainstem graft was also influenced by the presence of GDNF, with a significantly more robust innervation observed in transplants from wildtype fetuses. The most successful LC/hippocampal co-grafts were generated from fetuses expressing the wildtype GDNF background, whereas the most severely affected transplants were derived from double transplants from null-mutated fetuses. Our data suggest that development of the NE LC-hippocampal pathway is dependent on the presence of GDNF, most likely through a target-derived neurotrophic function.