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Gene therapy using adeno-associated virus (AAV) is a rapidly developing technology with widespread treatment potential. AAV2 vectors injected directly into the brain by stereotaxic brain surgery have shown good results in treating aromatic l- amino acid decarboxylase deficiency. Moreover, gene therapy using the AAV9 vector, which crosses the blood–brain barrier, has been performed in more than 2000 patients worldwide as a disease-modifying therapy for spinal muscular atrophy. AAV vectors have been applied to the development of gene therapies for various pediatric diseases. Gene therapy trials for hemophilia and ornithine transcarbamylase deficiency are underway. Clinical trials are planned for glucose transporter I deficiency, Niemann-Pick disease type C, and spinocerebellar ataxia type 1. The genome of AAV vectors is located in the episome and is rarely integrated into chromosomes, making the vectors safe. However, serious adverse events such as hepatic failure and thrombotic microangiopathy have been reported, and ongoing studies are focusing on developing more efficient vectors to reduce required dosages. [ABSTRACT FROM AUTHOR]

• Splenomegaly is the most common phenotype for Niemann-Pick disease type B (NPD-B). • Splenic rupture in NPD-B is rarely reported. • A NPD-B patient initially presenting with spontaneous splenic rupture is described. • Periodic assessment of spleen size for NPD-B patients is advised. Splenomegaly is the most common phenotype for Niemann-Pick disease type B (NPD-B), an autosomal recessive lipid storage disease caused by deficiency of the lysosomal enzyme acid sphingomyelinase. Although a spleen of massive volume is common in NPD-B, splenic rupture in this disease is rarely reported. We describe a patient with NPD-B who initially presented with spontaneous splenic rupture. Microscopic examination of the spleen specimen revealed expansion of the red pulp by abundant foamy histiocytes. A literature review revealed that splenic rupture resulting from latent splenomegaly may occur in middle adulthood in a mild form of NPD-B associated with SMPD1 variants of lower pathogenicity. We suggest that unexplained splenomegaly or splenic rupture should raise the possibility of a lysosomal storage disease, including NPD. For patients with NPD-B, spleen size should be evaluated periodically, and the risk of splenic rupture should always be considered. [ABSTRACT FROM AUTHOR]

Neurometabolic diseases are complex group of rare neurogenetic disorders, which are difficult to diagnose. Patients may have toxic metabolite accumulation, inadequate energy supply, or neurotransmitter deficiency, resulting in a variety of clinical manifestations and severity with enzyme activity or transporter function defects. Multiple organ involvement is frequently seen, among which neurological symptoms and signs are one of the most encountered problems. Ocular motor problems deserve special attention for it occurs in some inborn error of metabolism. Furthermore, some are early signs or characteristic findings of certain diseases, such as the gaze palsy in Niemann-Pick disease type C and Gaucher disease or oculogyric crisis in neurotransmitter diseases. Early recognition and intervention are important for better prognosis in treatable neurometabolic disorders. In addition, ways to evaluate and describe eye movement problems also help to demonstrate the severity or clinical progression for those diagnosed with certain neurometabolic diseases. However, the complexity of eye movement and ocular motor control renders our clinical observation, recording and even anatomic localization of abnormal eye movements. Clinicians are more likely to detect early signs and unravel problems by gaining awareness of abnormal eye movement. This study amied to approach neurometabolic diseases in children via eye motor manifestations. [ABSTRACT FROM AUTHOR]

• Atherogenic plasma lipid abnormalities are common in patients with ASMD. • The clinical experiences in lipid-lowering strategies are limited. • Olipudase alfa appears as the most promising candidate for improving lipid profile. Niemann-Pick disease (NPD) type A and type B are part of the spectrum disease of the acid sphingomyelinase deficiency (ASMD). Plasma lipid abnormalities are frequently associated with both NPD-A and NPD-B, and include decreased high-density lipoprotein cholesterol (HDL-C), increased low-density lipoprotein cholesterol (LDL-C), and hypertriglyceridemia. The atherogenic lipid profile has been associated to early atherosclerotic vascular disease and coronary artery disease in NPD-B patients. Thus, early treatment of dyslipidemia in these patients is advisable. We present here a pediatric case of NPD-B with an atherogenic lipid profile not responding to lifestyle changes, low fat diet, and daily supplementation with plant sterols. We reviewed the existing literature about the treatment strategies for dyslipidemia in ASMD patients, with a special focus on the pediatric age. Finally, we speculated on the mechanisms underlying dyslipidemia in this disorder. The clinical experiences in lipid-lowering strategies in NPD-B patients are limited, in particular in the pediatric age. Olipudase alfa appears as the most promising candidate for improving lipid profile. Since olipudase alfa is not yet approved and, due to its costs, it will probably not be available for all patients worldwide, further research is needed to broaden our knowledge on this clinical need and to evaluate the efficacy and the long-term effects of lipid-lowering agents in ASMD patients. A deep understanding of the pathophysiology of dyslipidemia in ASMD may promote the identification of new targets and support the identification of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective: To determine the utility of wearable technologies in physical activity assessment in three paediatric diseases, namely, Niemann-Pick C (NP-C), Juvenile Idiopathic Arthritis (JIA) and Duchenne Muscular Dystrophy (DMD). Design: Exploratory study Setting and Patients: Thirty children were recruited across three UK hospitals (Royal Manchester's Children Hospital, Great Ormond Street Children's Hospital, and the Great North Children's Hospital). Ten were diagnosed with NP-C, eight with DMD and twelve with JIA. Intervention: All participants completed the 6-min walk test (6MWT) at enrolment. Patients were provided with disease-specific smartphone apps paired with a wearable device via Bluetooth. Ambulation was recorded in 30-min epochs measuring average daily maximum (ADM), average daily steps (ADS) and average daily steps per 30-min epoch (ASE). Results: Median 6MWT results were 450 m, 325 m and 434.5 m for the NP-C, DMD and JIA cohorts, respectively. Wearable data capture was feasible in all three disease cohorts, although complete data capture was not sustained. A statistically significant between-cohort difference was identified for ADM, ADS and ASE. Statistically significant differences were found between DMD/JIA for ADM; NP-C/DMD for ADS and DMD/JIA for ASE. Discussion: Wearable sensor technologies have the potential to provide additional information for our understanding of ambulation in chronic paediatric disease. The wearable devices were easy to use and popular with patients although key features need to be addressed to appropriately meet study objectives. As the technology continues to evolve at a rapid pace, opportunities to implement child friendly solutions are already available. [ABSTRACT FROM AUTHOR]

Background: Niemann-Pick disease type C (NPC) is caused by the mutation of NPC genes, which leads to the abnormal accumulation of unesterified cholesterol and glycolipids in lysosomes. This autosomal recessive disease is characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration. Recently, the application of induced neural stem cells (iNSCs), converted from fibroblasts using specific transcription factors, to repair degenerated lesions has been considered a novel therapy. Objectives: The therapeutic effects on NPC by human iNSCs generated by our research group have not yet been studied in vivo; in this study, we investigate those effects. Methods: We used an NPC mouse model to efficiently evaluate the therapeutic effect of iNSCs, because neurodegeneration progress is rapid in NPC. In addition, application of human iNSCs from NPC patient-derived fibroblasts in an NPC model in vivo can give insight into the clinical usefulness of iNSC treatment. The iNSCs, generated from NPC patientderived fibroblasts using the SOX2 and HMGA2 reprogramming factors, were transplanted by intracerebral injection into NPC mice. Results: Transplantation of iNSCs showed positive results in survival and body weight change in vivo. Additionally, iNSC-treated mice showed improved learning and memory in behavior test results. Furthermore, through magnetic resonance imaging and histopathological assessments, we observed delayed neurodegeneration in NPC mouse brains. Conclusions: iNSCs converted from patient-derived fibroblasts can become another choice of treatment for neurodegenerative diseases such as NPC. [ABSTRACT FROM AUTHOR]

Niemann-Pick Type C disease (NPC) is a rare, incurable, autosomal-recessive, lysosomal storage disorder with protean and progressive neurovisceral manifestations characterized by accumulation of intracellular unesterified cholesterol. The investigational use of 2-hydroxypropyl-betacyclodextrin (HP-β-CD) in the treatment of NPC has shown promising results in improving life expectancy and reducing neurological damage in this patient population. This case report describes two children with the neurological form of NPC: a 5-year-old male patient in advanced stage of the disease and an 11-year-old female patient in moderately advanced stage. Despite treatment with the enzyme inhibitor, miglustat, both patients continued to exhibit severe neurodegeneration. High intrathecal (900mg) and low intravenous (350-500mg/kg) doses of HP-β-CD (Trappsol®Cyclo™) were administrated twice monthly to the patients in addition to miglustat therapy. The patients were monitored clinically as well as by imaging, laboratory, and biomarker (e.g., total tau protein [T-tau]; phosphorylated tau [P-tau]; neurofilament light [NFL], oxysterols) studies over a period of 16 to 22 months. The combination therapy of miglustat and HP-β-CD resulted in disease stabilization in both patients. The combination therapy demonstrated a good safety profile, and no adverse effects on hearing were observed. Additionally, CSF biomarkers appeared useful in monitoring neuronal damage. Large, randomized studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Objectives: Niemann-Pick diseases (NPD) is an autosomal recessive inherited lysosomal lipid storage disorder which occurs due to a defect in cellular cholesterol trafficking, leading to excess lipid accumulation in multiple organ systems such as the brain, lungs, spleen, and liver. SPMD1-associated disease includes classic infantile and visceral NPD type A and B respectively. Type C NPD is subacute or juvenile. Materials & Methods During 2012-2016, the patients who had the clinical and biochemical signs and symptoms of different types of NPD, underwent genetic analysis. All patients were collected from five provinces in Iran (Razavi Khorasan, South Khorasan, Khozaestan, Isfahan and Tehran province). Sanger sequencing of the candidate genes for NPD was performed followed by bioinformatics analysis to confirm the types of NPD and to identify novel mutations. All patients underwent full clinical assessment. Results: We present two cases with NPD type A, six cases with NPD type B, and 11 cases with type C with various enzymatic defects identified in these cases. Within these 19 patients, we present 9 previously reported mutations and 10 novel mutations causing NPD. Conclusion: This study is the largest Iranian study for NPD analysis ever. Our report demonstrates that NPD has a variable age of onset and can present early in life. We investigated the clinical and genetic manifestations of a large Iranian cohort. Understanding the variable presentation of NPD will allow for clinicians to have a high index of suspicion for the disease. [ABSTRACT FROM AUTHOR]

Acid sphingomyelinase deficiency (ASMD) is a severe lipid storage disorder caused by the diminished activity of the acid sphingomyelinase enzyme. ASMD is characterized by the accumulation of sphingomyelin in late endosomes and lysosomes leading to progressive neurological dysfunction and hepatosplenomegaly. Our objective was to investigate the utility of synthetic apolipoprotein A-I (ApoA-I) mimetics designed to act as lipid scavengers for the treatment of ASMD. We determined the lead peptide, 22A, could reduce sphingomyelin accumulation in ASMD patient skin fibroblasts in a dose dependent manner. Intraperitoneal administration of 22A formulated as a synthetic high-density lipoprotein (sHDL) nanodisc mobilized sphingomyelin from peripheral tissues into circulation and improved liver function in a mouse model of ASMD. Together, our data demonstrates that apolipoprotein mimetics could serve as a novel therapeutic strategy for modulating the pathology observed in ASMD. Synthetic high-density lipoprotein nanodiscs accept excess sphingomyelin from peripheral tissues in a mouse model of ASMD. Created with BioRender.com [Display omitted] [ABSTRACT FROM AUTHOR]

Olfactory impairment is the most common clinical manifestation among the elderly, and its prevalence increases sharply with age. Notably, growing evidence has shown that olfactory dysfunction is the first sign of neurodegeneration, indicating the importance of olfactory assessment as an early marker in the diagnosis of neurological disorders. In this review, we describe the nature of olfactory dysfunction and the advantage of using animal models in olfaction study, and we include a brief introduction to olfactory behavior tests widely used in this field. The contribution of microglia in the neurodegenerative processes including olfactory impairment is then discussed to provide a comprehensive description of the physiopathological role of interactions between neurons and microglia within the olfactory system. [ABSTRACT FROM AUTHOR]

Olfactory impairment is the most common clinical manifestation among the elderly, and its prevalence increases sharply with age. Notably, growing evidence has shown that olfactoiy dysfunction is the first sign of neurodegeneration, indicating the importance of olfactory assessment as an early marker in the diagnosis of neurological disorders. In this review, we describe the nature of olfactory dysfunction and the advantage of using animal models in olfaction study, and we include a brief introduction to olfactory behavior tests widely used in this field. The contribution of microglia in the neurodegenerative processes including olfactory impairment is then discussed to provide a comprehensive description of the physiopathological role of interactions between neurons and microglia within the olfactory system. [ABSTRACT FROM AUTHOR]

Many Inherited Metabolic Diseases (IMDs) have hepatic manifestations due to the highly metabolically active nature of the liver. IMDs are responsible for up to a third of acute liver failure in childhood. Manifestations include cholestatic jaundice, hepatomegaly and acute and chronic liver failure. It is important to consider and identify metabolic causes of liver disease early, particularly as some may present early for example with a self-limiting period of cholestasis before presenting in later childhood with irreversible disease, and in many early intervention improves outcomes. This review highlights features in the history and presentation which should raise suspicion for an IMD, and the specialist metabolic investigations to consider when evaluating the child with liver disease. The review also discusses the clinical course and management of specific IMDs including glycogen storage disorders, congenital disorders of glycosylation, cholesterol ester storage disease, galactosaemia, neonatal haemochromatosis, hereditary tyrosinemia, fatty acid oxidations disorders, urea cycle defects, Niemann Pick C, Wilson disease, citrin deficiency and disorders of bile acid synthesis. The role of liver transplantation is discussed briefly. [ABSTRACT FROM AUTHOR]

Objective: To analyze HRCT findings in patients with Niemann-Pick disease (NPD) type B, in order to determine the frequency of HRCT patterns and their distribution in the lung parenchyma, as well as the most common clinical characteristics. Methods: We studied 13 patients (3 males and 10 females) aged 5 to 56 years. HRCT images were independently evaluated by two observers, and disagreements were resolved by consensus. The inclusion criteria were presence of abnormal HRCT findings and diagnosis of NPD type B confirmed by histopathological examination of a bone marrow, lung, or liver biopsy specimen. Results: The most common clinical findings were hepatosplenomegaly and mild to moderate dyspnea. The most common HRCT patterns were smooth interlobular septal thickening and ground-glass opacities, which were both present in all patients. Intralobular lines were present in 12 patients (92.3%). A crazy-paving pattern was observed in 5 patients (38.4%), and areas of air trapping were identified in only 1 case (7.6%). Pulmonary involvement was bilateral in all cases, with the most affected area being the lower lung zone. Conclusions: Smooth interlobular septal thickening, with or without associated ground-glass opacities, in patients with hepatosplenomegaly is the most common finding in NPD type B. [ABSTRACT FROM AUTHOR]

Niemann-Pick Disease (NPD) is a group of rare inherited disorders that are both systemic and degenerative. Knowledge of the disease, its characteristics, and its progression are essential for the teacher and related service personnel to provide an appropriate educational experience for the student. For the teacher who has a student with NPC1 in his/her classroom, the focus is two-fold: first to provide a supportive academic environment for the student with NPC1 and her/his classroom peers; and, second, to provide emotional support for the student and the family. Included in this manuscript are suggested accommodations for the teacher and other therapists and related service personnel to use in providing an appropriate education for a student with NPC1. [ABSTRACT FROM AUTHOR]

Summary: A wild caught juvenile male raccoon with neurological disease was humanely destroyed due to poor prognosis. Necropsy examination revealed hepatomegaly, splenomegaly and multicentric lymphadenomegaly with diffuse hepatic pallor and pulmonary consolidation with pinpoint pale subpleural foci. Microscopically, there was marked pale cytoplasmic swelling of the central and peripheral neurons as well as the glial cells in the brain, accompanied by multiorgan infiltration by abundant foamy macrophages. Ultrastructural investigation revealed accumulation of concentrically arranged lamellar material within lysosomes of the affected neurons, macrophages and endothelial cells. Biochemical enzymatic analysis detected sphingomyelinase deficiency and lysosomal storage disease consistent with sphingomyelin lipidosis (Niemann–Pick disease [NPD]) was diagnosed. This is the first report of NPD in a raccoon. [ABSTRACT FROM AUTHOR]

Background: Impairment of acid sphingomyelinase (SMase) results in accumulation of sphingomyelin (SM) and cholesterol in late endosomes, the hallmarks of a lysosomal storage disease. Objective: We describe cellular lipid metabolism in fibroblasts from two patients with novel compound heterozygote mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene manifesting as Niemann-Pick disease type B (NPB) and demonstrate mechanisms to overcome the storage defect. Methods: Using biochemical assays and confocal microscopy, we provide evidence that accumulated lysosomal SM and cholesterol can be released by different treatments. Results: Defective SMase activity in these fibroblasts results in a 2.5-fold increased cellular mass of SM and cholesterol, increased de novo endogenous cholesterol synthesis, and decreased cholesterol esterification, demonstrating impaired intracellular cholesterol homeostasis. Depletion of exogenous addition of cholesterol for 24 hours or addition of the cholesterol acceptor apolipoprotein A-I are sufficient to restore normal homeostatic responses. In an effort to correct the lysosomal storage phenotype of NPB, we infected the fibroblasts with a lentivirus expressing the phosphotyrosine binding domain of the adapter protein GULP (PTB-GULP). We have previously shown that expression of PTB-GULP in Chinese hamster ovary cells promotes intracellular cholesterol trafficking and ABCA1-mediated cholesterol efflux. We find that expression of PTB-GULP in NPB fibroblasts results in increased ABCA1 expression, increased cellular cholesterol efflux and lysosomal cholesterol redistribution, independent of the impaired SMase and cholesterol presence. Conclusion: We provide extensive functional characterization of a novel compound heterozygote mutation and provide a novel functional mechanism to overcome lysosomal storage disease defects. [Copyright &y& Elsevier]

Background: Type A or B Niemann-Pick disease (NPD) is characterized by the accumulation of sphingomyelin in the lysosomes and cell membranes. This accumulation results because of a mutation in the sphingomyelin phosphodiesterase-1 (SMPD-1) gene that causes a deficit in the acid sphingomyelinase (ASM). Objective: Herein, we report on a new point mutation in the SMPD-1 gene that was discovered in a patient with type B NPD. Methods and Results: A culture of the patient’s fibroblasts demonstrated that the observed clinical symptoms and reduced plasma high-density lipoprotein cholesterol (HDL-C) were associated with a reduced efflux of cholesterol. Examination of the skin fibroblasts demonstrated that ASM activity was reduced to approximately 60% of that observed in control cells, and a newly identified point mutation was found in codon 494 [Gly (GGT) → Cys (TGT)] in the SMPD-1 gene. Furthermore, repeated measurements of the plasma HDL-C levels remained low (17.5-20.5 mg/dL), and the Apo A-I− or HDL−mediated cholesterol efflux from the patient’s fibroblasts was significantly reduced as compared with control fibroblasts. Conclusion: In summary, we identified a unique point mutation in a patient with type B NPD that was associated with various clinical findings, including a low plasma HDL-C level. This reduced cellular cholesterol efflux may be implicated, at least in part, in low plasma HDL levels. [Copyright &y& Elsevier]

Niemann-Pick type C disease (NPC) is a rare autosomal recessive lipid storage disorder caused by impaired cellular functions in processing and transporting low-density lipoprotein-cholesterol. In this report, we present magnetic resonance imaging (MRI), magnetic resonance spectrography (MRS) and 18-fluoro-2-deoxyglucose positron emission tomography (PET) imaging results for a 22-year-old male NPC patient. The patient''s two MRI studies (at age 19 years and 22 years) demonstrated progressive changes of brain atrophy that were more prominent at the frontal lobes, and hyperintense signals in bilateral parietal-occipital periventricular white matter. MRS (at age 19 years) revealed no significant decrease in N-acetyl aspartate/choline ratio in the left frontal central white matter. PET (at age 22 years) showed significant bilateral hypometabolism in the prefrontal cortex and dorsomedial thalamus, and hypermetabolism in the parietal-occipital white matter, lenticular nucleus of the basal ganglia, cerebellum and pons. The imaging findings noted by MRI, MRS and 18-fluoro-2-deoxyglucose PET offered a possible supplementary explanation for the clinical neurological symptoms of this NPC patient. [Copyright &y& Elsevier]

Background & Aims: Biliary cholesterol secretion helps maintain cholesterol homeostasis; it is regulated by the cholesterol exporter adenosine triphosphate–binding cassettes G5 and G8 (ABCG5/G8) and the cholesterol importer Niemann–Pick C1-like 1 (NPC1L1). We studied another putative regulator of cholesterol secretion into bile, Niemann–Pick C2 (NPC2)—a cholesterol-binding protein secreted by the biliary system—and determined its effects on transporter-mediated biliary secretion of cholesterol. Methods: Mice with hepatic knockdown of Npc2 or that overexpressed NPC2 were created using adenovirus-mediated gene transfer; biliary lipids were characterized. The effects of secreted NPC2 on cholesterol transporter activity were examined in vitro using cells that overexpressed ABCG5/G8 or NPC1L1. Results: Studies of mice with altered hepatic expression of NPC2 revealed that this expression positively regulates the biliary secretion of cholesterol, supported by the correlation between levels of NPC2 protein and cholesterol in human bile. In vitro analysis showed that secreted NPC2 stimulated ABCG5/G8-mediated cholesterol efflux but not NPC1L1-mediated cholesterol uptake. Consistent with these observations, no significant changes in biliary cholesterol secretion were observed on hepatic overexpression of NPC2 in ABCG5/G8-null mice, indicating that NPC2 requires ABCG5/G8 to stimulate cholesterol secretion. Analyses of NPC2 mutants showed that the stimulatory effect of biliary NPC2 was independent of the function of lysosomal NPC2 as a regulator of intracellular cholesterol trafficking. Conclusions: NPC2 is a positive regulator of biliary cholesterol secretion via stimulation of ABCG5/G8-mediated cholesterol transport. [Copyright &y& Elsevier]

Abstract: Cholesterol is always an issue because blood total cholesterol (TC) and low-density lipoprotein (LDL) correlate strongly with coronary heart disease. Cholesterol homeostasis is maintained by a complex mechanism of sterol absorption, anabolism, catabolism and excretion. Nutraceuticals and functional foods which lower TC must affect the genes which regulate cholesterol homeostasis. In general, cholesterol-lowering functional foods and nutraceuticals can be classified into seven types namely intestinal Niemann-Pick C1 like 1 (NPC1L1) competitors, intestinal acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors, 3-hydroxy-3-methylglutaryl (HMG-CoA) reductase inhibitors, LDL receptor up-regulators, bile acid reabsorption inhibitors, cholesterol-7α-hydroxylase (CYP7A1) activators, and plasma cholesteryl ester transporting protein (CETP) inhibitors. This mini-review classifies the popular cholesterol-lowering nutraceuticals and functional foods, and explores their underlying mechanisms. [Copyright &y& Elsevier]

Abstract: Cataplexy is the sudden muscle weakness brought on by strong emotions, particularly joking, laughter, or anger. Cataplexy may involve only certain group of muscles or the entire voluntary musculature. In rare cases, symptoms of cataplexy can be seen during the course of some inherited diseases (Niemann–Pick type C (NPC), Prader–Willi syndrome, myotonic dystrophy, Norrie disease). We report the successful use of miglustat, a reversible inhibitor of the enzyme glucosylceramide synthase, approved for use in Gaucher''s disease, and which catalyses the first step in the biosynthesis of most glycosphingolipid, in a boy with NPC with cataplexy. A 9-year-old boy was admitted for assessments of frequent “drop attacks” while laughing. The filipin fluorescence tests of cultured skin fibroblasts revealed massive accumulation of unesterified cholesterol, confirming the diagnosis of NPC disease. Molecular studies confirmed the diagnosis of NPC too. After approval from the bioethics committee, miglustat was initiated on the child at 100mg three times a day. Cataplectic attacks disappeared completely after 6 months on treatment, and patient continues to be in remission from the cataplectic attacks at 16 months follow-up. There was no further progression of neurological signs or symptoms or splenomegaly, with some improvement in cognitive function as well as social, affective and attention problems, up-gaze, and gait. Miglustat was well tolerated with no side effects observed. In summary, this is the first report of miglustat treatment of cataplexy in NPC. Long-term follow-up for continuing efficacy and tolerability in a larger cohort with NPC is needed to substantiate our observation. [Copyright &y& Elsevier]

Abstract: Background: The lipid metabolism of varicose veins (VVs) remains unknown. To elucidate the pathogenesis of VV, we utilized the novel technique of imaging mass spectrometry (IMS). Materials and methods: We obtained VV tissues from 10 limbs of 10 VV patients who underwent great saphenous vein stripping. As control vein samples, we harvested segmental vein tissues from 6 limbs of 6 patients with peripheral artery occlusive disease who underwent infra-inguinal bypass with reversed saphenous vein grafting. To identify the localisation of lipid molecules in the VV tissues, we performed matrix-assisted laser desorption/ionization IMS (MALDI-IMS). We also performed MS/MS analyses to identify the structure of each molecule. Results: We obtained mass spectra directly from control vein tissues and VV tissues and found a unique localisation of lipid molecules in the VV tissues. We localised lysophosphatidylcholine (LPC) (1-acyl 16:0), phosphatidylcholine (PC) (1-acyl 36:4) and sphingomyelin (SM) (d18:1/16:0) at the site of the VV valve. Conclusion: MALDI-IMS revealed the distribution of various lipid molecules in normal veins and VVs both. Accumulation of LPC (1-acyl 16:0), PC (1-acyl 36:4) and SM (d18:1/16:0) in the VV tissues suggested that inflammation associated with abnormal lipid metabolism may contribute to the development of VV. [ABSTRACT FROM AUTHOR]

In adults, elevated transaminases and hepatomegaly, often mild, with moderate to massive idiopathic splenomegaly might hint to a lysosomal storage disease (LSD). In most of these cases, hepatosplenomegaly does not eventually lead to cirrhosis, hepatocellular carcinoma or cholestasis. Nevertheless, the hepatic clinical findings might be the incentive for the patient to present at the physician’s office. Many of the currently known>50 lysosomal storage diseases might manifest in liver: out of these, the most important ones in adults are: Gaucher disease, cholesterol ester storage disease (CESD) and the Niemann-Pick diseases. An increase of plasma chitotriosidase should alert the physician for the presence of an LSD. For Gaucher’s disease, enzyme supplementation and substrate deprivation constitute effective therapeutic options. Fabry’s disease, the most prevalent lysosomal storage disease, does usually not affect the liver, but causes painful episodes of hands’ or feet pain (acroparesthesias), left ventricular hypertrophy, renal failure, early stroke and decreased life expectancy. The emerging advent of effective therapeutic options and the cumulative prevalence of lysosomal storage diseases urge the hepatologist to add these diagnostic pathways to the clinical repertoire. [ABSTRACT FROM AUTHOR]

Summary: Water-soluble Niemann-Pick C2 (NPC2) and membrane-bound NPC1 are cholesterol-binding lysosomal proteins required for export of lipoprotein-derived cholesterol from lysosomes. The binding site in NPC1 is located in its N-terminal domain (NTD), which projects into the lysosomal lumen. Here we perform alanine-scanning mutagenesis to identify residues in NPC2 that are essential for transfer of cholesterol to NPC1(NTD). Transfer requires three residues that form a patch on the surface of NPC2. We previously identified a patch of residues on the surface of NPC1(NTD) that are required for transfer. We present a model in which these two surface patches on NPC2 and NPC1(NTD) interact, thereby opening an entry pore on NPC1(NTD) and allowing cholesterol to transfer without passing through the water phase. We refer to this transfer as a hydrophobic handoff and hypothesize that this handoff is essential for cholesterol export from lysosomes. [ABSTRACT FROM AUTHOR]

The article presents a study that examined the effects of neural stem cell (NSC) Maudsley hippocampal clone 36 (MHP36) in the Niemann-Pick disease type C (NP-C) model mice to show that MHP36 transplantation improves the neuropathological features of the mice without acute immune response and promotes neuronal networks with functional synaptic transmission. Researchers found an increase in the number of surviving Purkinje neurons in MHP36 transplanted NP-C mice compared with sham-transplanted NP-C mice. They also observed that MHP36 did not induce significant immunological rejection in the host environment.

The article provides information on a study which evaluated the effects of direct intracerebral transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) on the progression of the Niemann-Pick type C (NP-C) disease, a devastating developmental disorder with progressive and fatal neurodegeneration, using a mouse model of NP-C disease. Results show that hUCB-MSCs transplantation into NP-C mice reduces the cholesterol accumulation level in neurons, prevents the loss of Purkinje neurons and inhibits cerebellar apoptotic cell death. The study findings provide evidence that hUCB-MSCs can improve neurological symptoms in NP-C disease and suggest that hUCB-MSCs is a potential therapeutic agent against neurodegenerative diseases.

Copyright of Journal of Ultrasound is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: Niemann-Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein that plays a critical role in cholesterol absorption. Ezetimibe, a hypocholesterolemic drug, has been reported to bind NPC1L1 and block cholesterol absorption. However, the molecular mechanism of NPC1L1-mediated cholesterol uptake and how ezetimibe inhibits this process are poorly defined. Here we find that cholesterol specifically promotes the internalization of NPC1L1 and that this process requires microfilaments and the clathrin/AP2 complex. Blocking NPC1L1 endocytosis dramatically decreases cholesterol internalization, indicating that NPC1L1 mediates cholesterol uptake via its vesicular endocytosis. Ezetimibe prevents NPC1L1 from incorporating into clathrin-coated vesicles and thus inhibits cholesterol uptake. Together, our data suggest a model wherein cholesterol is internalized into cells with NPC1L1 through clathrin/AP2-mediated endocytosis and ezetimibe inhibits cholesterol absorption by blocking the internalization of NPC1L1. [Copyright &y& Elsevier]

Abstract: Cholesterol is an important sterol in mammals. Defects in cholesterol synthesis or intracellular routing have devastating consequences already in utero: the Smith–Lemli–Opitz syndrome, desmosterolosis and Niemann–Pick C1 disease provide examples of severe human inherited diseases caused by mutations in cholesterol metabolism genes. On the other hand, elevated plasma cholesterol concentrations are associated with the development of atherosclerosis which represents a major health risk in Western societies. Moreover, several studies indicate that development of atherosclerosis may already start during fetal life. Hence, a carefully balanced regulation of cholesterol metabolism appears of critical importance for both the development of the fetus and health of the adult. In the adult, the liver X receptor is a key regulator of cholesterol metabolism. Its target genes regulate cellular cholesterol efflux and thereby modulate whole-body cholesterol fluxes. LXR and several of its target genes have recently been demonstrated to be expressed in the placenta, which would provide a means to control delivery of maternal cholesterol to the fetus. Here we discuss the potential role of the placenta in the regulation of fetal cholesterol homeostasis and strategies to influence maternal–fetal cholesterol transfer. [Copyright &y& Elsevier]

Copyright of Archivos de Bronconeumología (English Edition) is the property of Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Niemann-Pick C1-like 1 (NPC1L1) is a target for ezetimibe, a drug that blocks intestinal cholesterol absorption. A new study by in this issue of Cell Metabolism shows that non-lipoprotein-bound cholesterol induces endocytosis of NPC1L1 and that ezetimibe blocks the internalization of the NPC1L1/cholesterol complex. The in vivo significance of these findings is discussed. [Copyright &y& Elsevier]

Abstract: We present a 28-year-old woman with a diagnosis of Niemann–Pick type C disease which was initially diagnosed as Wilson disease due to low serum ceruloplasmin and elevated free copper. This report supports the hypothesis that NPC1 could play a role in copper metabolism. [Copyright &y& Elsevier]

The mechanisms of intracellular cholesterol transport are largely unknown. In this issue of Cell Metabolism, identify amino acid residues on the lumenal lysosomal protein Niemann-Pick C2 (NPC2) that are required for intralysosomal transfer of endocytosed cholesterol to membrane-bound NPC1 via a process that avoids movement of hydrophobic cholesterol through the aqueous phase. [ABSTRACT FROM AUTHOR]

Endocytosed cholesterol must be transferred from the environment (e.g., low-density lipoproteins) via the lysosomal system to the rest of the cell. In Niemann-Pick type C disease, this process fails. In a recent issue of Cell, suggest how this transpires mechanistically by crystallizing a domain of a protein defective in this syndrome. [Copyright &y& Elsevier]

Background & Aims: Some studies have indicated that dietary cholesterol has a role in the progression of liver fibrosis. We investigated the mechanisms by which dietary cholesterol might contribute to hepatic fibrogenesis. Methods: C57BL/6 mice were fed a high-cholesterol diet or a control diet for 4 weeks; liver fibrosis then was induced by bile-duct ligation or carbon tetrachloride administration. Hepatic stellate cells (HSCs) were isolated from mice fed high-cholesterol diets or from Niemann–Pick type C1-deficient mice, which accumulate intracellular free cholesterol. Results: After bile-duct ligation or carbon tetrachloride administration, mice fed high-cholesterol diets had significant increases in liver fibrosis and activation of HSCs compared with mice fed control diets. There were no significant differences in the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation, between mice fed high-cholesterol or control diets. Levels of free cholesterol were much higher in HSCs from mice fed high-cholesterol diets than those fed control diets. In cultured HSCs, accumulation of free cholesterol in HSCs increased levels of Toll-like receptor 4 (TLR4), leading to down-regulation of bone morphogenetic protein and activin membrane-bound inhibitor (a pseudoreceptor for transforming growth factor [TGF]β); the HSCs became sensitized to TGFβ-induced activation. Liver fibrosis was not aggravated by the high-cholesterol diet in C3H/HeJ mice, which express a mutant form of TLR4; HSCs that express mutant TLR4 were not activated by accumulation of free cholesterol. Conclusions: Dietary cholesterol aggravates liver fibrosis because free cholesterol accumulates in HSCs, leading to increased TLR4 signaling, down-regulation of bone morphogenetic protein and activin membrane-bound inhibitor, and sensitization of HSC to TGFβ. This pathway might be targeted by antifibrotic therapies. [Copyright &y& Elsevier]

Objective: The aim of this study was to determine whether sonographic fetal pulmonary artery flow velocity waveforms correlate with amniotic fluid biomarkers of fetal lung maturity. Study Design: We studied women with singleton pregnancies undergoing clinically indicated amniocentesis for fetal lung maturity at Yale-New Haven Hospital. Fetal pulmonary artery flow velocity measurements, including systolic/diastolic ratio, pulsatility index, resistance index, and acceleration-time/ejection-time ratio were obtained using spectral Doppler ultrasound. Pearson''s correlation coefficient was used to determine the association between fetal pulmonary artery flow velocity parameters and the lecithin/sphingomyelin ratio. Results: Twenty-nine subjects met study criteria. The acceleration-time/ejection-time ratio was inversely correlated with the lecithin/sphingomyelin ratio (r = −0.76; P ≤ .001). This relationship was maintained after controlling for potential confounders. Other fetal pulmonary artery flow velocity measurements were not associated with the lecithin/sphingomyelin ratio. Conclusion: There is an inverse correlation between the acceleration-time/ejection-time ratio in the fetal pulmonary artery and the amniotic fluid lecithin/sphingomyelin ratio. This suggests that ultrasound evaluation of fetal pulmonary artery blood flow may be a promising new noninvasive technique to evaluate fetal lung maturity. [Copyright &y& Elsevier]