Optical detection of plasma chitotriosidase activity in healthy Chinese children using fluorescence spectrophotometry

BACKGROUND: Plasma chitotriosidase had been proposed as a biochemical marker of macrophage accumulation in several lysosomal storage disorders. The selection of wavelength and possible interferences and errors have not yet been explored in the assay of chitotriosidase activity. We evaluated the feasibility of measurement of plasma chitotriosidase activity by fluorescence spectrophotometry and established pediatric reference values for earlier diagnosis of related diseases. METHODS: We assayed plasma chitotriosidase activity in 104 healthy Chinese children by a fluorometric approach which combines 3-dimension scan spectra, wavelength scan spectra, time scan spectra and fluorescence intensity analysis. RESULTS: The optimal excitation wavelength and emission wavelength were 358 and 448 nm, respectively. A change of enzyme activity over time was observed fluorometrically, The reference value was 13.04+/-4.94 nmol/ml/h (12.45+/-4.37 nmol/ml/h for boys and 14.04+/-3.99 nmol/ml/h for girls). CONCLUSIONS: We present an integrated application of the fluorescence spectrophotometry as an ideal tool to determine enzymatic activity with 4-methylumbelliferyl triacetylchitotrioside as labeled substrates in clinical laboratory. The function of 3D scan was proved powerful in determination of plasma chitotriosidase activity. The establishment of plasma chitotriosidase activity reference pediatric values was potentially useful for the evaluation of all related diseases.     

Isotope dilution analysis of methylcitric acid in amniotic fluid for the prenatal diagnosis of propionic and methylmalonic acidemia

A stable isotope dilution assay for methylcitric acid in amniotic fluid was developed to provide rapid prenatal diagnosis of the inherited disorders propionic acidemia and methylmalonic acidemia. The method utilizes two ²H₃-labeled diastereoisomers of methylcitric acid as internal standards, isolation by liquid partition chromatography and quantitation of the trimethyl esters by chemical ionization selected ion monitoring gas chromatography-mass spectrometry. Methylcitric acid at a concentration of 0.38 ± 0.10 μmol/1 was detected in normal amniotic fluid. Highly elevated levels of 7.87 and 9.16 μmol were found in the fluids surrounding fetuses affected with propionic acidemia and levels of 1.79, 2.72 and 12.27 μmol were found for fetuses with methylmalonic acidemia. Methylcitric acid was not elevated in the amniotic fluid of a fetus heterozygous for propionic acidemia. In the five pregnancies at risk for propionic acidemia, and three pregnancies at risk for methylmalonic acidemia, the levels of methylcitric acid in amniotic fluid gave the diagnosis in all cases. Measurement of methylcitric acid in amniotic fluid therefore provides a rapid and reliable method for the prenatal diagnosis of these genetic disorders.     

Blood spot versus plasma chitotriosidase: A systematic clinical comparison

ObjectivesThis study aimed to evaluate the agreement between blood spot and plasma chitotriosidase using the economic substrate 4-methylumbelliferyl-β-D-N,N′,N″-triacetylchitotrioside, and to investigate the utility of the blood spot assay for the wide scale screening for lysosomal storage disorders among the clinically suspected.Design and methodsBlinded blood spot samples were compared with the corresponding plasma levels in 199 children (56 with confirmed diagnoses of ten different lysosomal storage disorders, 73 normal controls and 70 pathological controls). Several performance criteria (limit of detection, linearity, within-run and day-to-day precision and sample stability) were also evaluated.ResultsPlasma assay performed better by most criteria; however, blood spot performance was quite satisfactory. Quantitative values of the two methods can't be used interchangeably based on their 95% limits of agreement. Diagnostic sensitivity and specificity derived from ROC curves were 75.0 and 85.3% for the plasma assay and 71.4 and 79.0% for the blood spot assay, respectively. Cohen's kappa was 0.72 (95% CI: 0.616–0.821) denoting a good categorical agreement between the two methods.ConclusionThe clinical use of blood spot chitotriosidase for the screening of lysosomal storage disorders can be quite practical, provided proper cut-off values are determined for each lab.     

Plasma chitotriosidase and CCL18 as surrogate markers for granulomatous macrophages in sarcoidosis

BackgroundAccumulation of macrophages in multiple organs is a common feature of sarcoidosis and Gaucher disease. The vast number of storage macrophages in Gaucher patients has facilitated the discovery of suitable plasma markers like chitotriosidase and CCL18.MethodsPlasma specimens of patients with sarcoidosis were examined on chitotriosidase activity and CCL18 protein levels.ResultsChitotriosidase was markedly increased, being on average 13.7-fold elevated (range: 1.1–43.3). The sensitivity of demonstrating sarcoidosis using plasma chitotriosidase values exceeded that using serum angiotensin-converting enzyme values. A 3.5-fold (range: 1–15) increase in CCL18 was also observed. The relative changes in chitotriosidase and CCL18 during the course of disease closely mimicked each other, suggesting an identical cellular source. In situ hybridization analysis confirmed massive production of chitotriosidase by sarcoid macrophages. The increase in plasma chitotriosidase correlated with the stage of disease, being highest in active sarcoidosis with extrapulmonary involvement. Therapy with steroids resulted in clear reduction of plasma chitotriosidase and CCL18 and relapse of disease activity was preceded by increases in these parameters.ConclusionsSarcoid macrophages secrete high quantities of chitotriosidase and CCL18. Determination of plasma chitotriosidase and CCL18 may be useful to monitor changes in granulomatous macrophages during the course of sarcoidosis.     

Audit for IV fluid requirement in preterm babies in Sunderland Royal Hospital (SRH)

BackgroundPreterm infants are particularly vulnerable to the effects of fluid mismanagement due to shifts between intracellular, extracellular and vascular compartments; inappropriate fluid administration may lead to electrolyte imbalances, with the potential for serious morbidity.AimTo determine whether preterm babies are receiving the volume of IV fluid prescribed by a doctor, as indicated in the neonatal guidelines.Methods

• •A retrospective study of hospital notes was carried out using a pro forma to collect data.
• •The study sample (n = 35) consisted of all preterm babies <32 weeks admitted to ITU between July and December 2013.
• •Mean fluid intake, including and excluding lipids, was calculated and compared to volume prescribed. It was categorised as correct (±1.0 ml/kg/24 h prescribed volume), too much or too little.

Results

• •27/37 notes were available for analysis; 23 were suitable for the audit.
• •On average 22% (n = 5) babies received the correct volume of fluid, 22% (n = 5) received too much, 56% (n = 13) received too little (mean deficit: 3.89 ml/kg/24 h).
• •21 babies received lipids; with lipid inclusion 4% (n = 1) received the correct volume, 86% (n = 18) received too much (mean excess 5.51 ml/kg/24 h), 10% (n = 2) received too little.
• •There was no correlation between fluid accuracy and age of baby.

ConclusionMost babies receive total daily fluids within 6 ml of the volume prescribed yet few receive the correct volume to the nearest ml/kg/24 h. The inclusion of lipids in daily totals shifted the trend from under to over administration of fluid; clarification is required on whether this is significant enough to require lipid inclusion in daily totals.     

Lysosomal storage disorders: Novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe,Fabry, Gaucher and Hurler disease

ObjectivesDiagnosis of lysosomal storage disorders (LSDs) remains challenging due to wide clinical, biochemical and molecular heterogeneity. The study applies a combined biochemical and genetic approach to diagnose symptomatic Indian patients of Pompe, Fabry, Gaucher and Hurler disease to generate a comprehensive dataset of pathogenic variants for these disorders.Design & methodsSymptomatic patients were biochemically diagnosed by fluorometric methods and molecular confirmation was carried out by gene sequencing. Genetic variants were analyzed according to the ACMG/AMP 2015 variant interpretation guidelines.ResultsAmongst the 2181 suspected patients, 285 (13%) were biochemically diagnosed. Of these, 22.5% (64/285) diagnosed with Pompe disease harboured c.1933G>A, c.1A>G, c.1927G>A and c.2783G>C as common and 10 novel pathogenic variants while 7.4% (21/285) patients diagnosed with Fabry disease carried c.851T>C, c.902G>A, c.905A>C and c.1212_1234del as frequent disease-causing variants along with 7 novel pathogenic variants. As many as 48.4% (138/285) patients were diagnosed with Gaucher disease and had c.1448T>C as the most common pathogenic variant followed by c.1342G>C and c.754T>C with 7 previously unreported disease-causing variants and in the 21.7% (62/285) diagnosed cases of Hurler disease, c.1469T>C, c.754delC c.568_581del and c.1898C>T were identified as the most common causative variants along with 21 novel pathogenic variants.ConclusionThis comprehensive data set of disease-causing frequent and novel pathogenic variants reported for the first time in such a large patient cohort for each of these four LSDs from the Indian sub-continent, along with their biochemical and clinical spectrum will contribute towards providing definitive diagnosis and treatment, identifying carrier status, as well as in counselling prenatal cases to reduce the morbidity and mortality associated with these disorders.     

Pharmacological Chaperone Therapy: Preclinical Development,Clinical Translation,and Prospects for the Treatment of Lysosomal Storage Disorders

Lysosomal storage disorders (LSDs) are a group of inborn metabolic diseases caused by mutations in genes that encode proteins involved in different lysosomal functions, in most instances acidic hydrolases. Different therapeutic approaches have been developed to treat these disorders. Pharmacological chaperone therapy (PCT) is an emerging approach based on small-molecule ligands that selectively bind and stabilize mutant enzymes, increase their cellular levels, and improve lysosomal trafficking and activity. Compared to other approaches, PCT shows advantages, particularly in terms of oral administration, broad biodistribution, and positive impact on patients'' quality of life. After preclinical in vitro and in vivo studies, PCT is now being translated in the first clinical trials, either as monotherapy or in combination with enzyme replacement therapy, for some of the most prevalent LSDs. For some LSDs, the results of the first clinical trials are encouraging and warrant further development. Future research in the field of PCT will be directed toward the identification of novel chaperones, including new allosteric drugs, and the exploitation of synergies between chaperone treatment and other therapeutic approaches.     

Gene therapy for lysosomal storage disorders

Introduction: Lysosomal storage disorders (LSDs) encompass more than 50 distinct diseases, caused by defects in various aspects of lysosomal function. Neurodegeneration and/or dysmyelination are the hallmark of roughly 70% of LSDs. Gene therapy represents a promising approach for the treatment of CNS manifestations in LSDs, as it has the potential to provide a permanent source of the deficient enzyme, either by direct injection of vectors or by transplantation of gene-corrected cells. In this latter approach, the biology of neural stem/progenitor cells and hematopoietic cells might be exploited.

Areas covered: Based on an extensive literature search up until March 2011, the author reviews and discusses the progress, the crucial aspects and the major challenges towards the development of novel gene therapy strategies aimed to target the CNS, with particular attention to direct intracerebral gene delivery and transplantation of neural stem/progenitor cells.

Expert opinion: The implementation of viral vector delivery systems with specific tropism, regulated transgene expression, low immunogenicity and low genotoxic risk and the improvement in isolation and manipulation of relevant cell types to be transplanted, are fundamental challenges to the field. Also, combinatorial strategies might be required to achieve full correction in LSDs with neurological involvement.     

Newborn screening for Fabry disease by measuring GLA activity using tandem mass spectrometry

BackgroundFabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficiency of α-galactosidase A (GLA). We evaluated a tandem mass spectrometry method to measure GLA activity.MethodsOne 3.2 mm punch from a dried blood spot sample (DBS) was incubated with substrate and internal standard in the reaction buffer for 22 h. The resulting product was quantified against internal standard using MS/MS.ResultsThe median GLA activity of male newborn DBS (N = 5025) was 9.85 ± 6.4 µmol/h/l (CI 95% is 9.67–10.02 µmol/h/l); The median GLA activity of female newborns (N = 4677) was 10.2 ± 6.3 µmol/h/l (CI 95% is 10.02–10.38 µmol/h/l). The difference between the two subgroups is within assay analytical variation. The GLA activities in the DBS samples from 9 juvenile and adult males with previously identified FD were below 1.64 µmol/h/l. The GLA activities from 32 juvenile and adult females with confirmed FD were below 4.73 µmol/h/l. In 5 (16%) females GLA activities were above the 0.5th percentile of lower limit of CI 95% at 3.18 µmol/h/l.ConclusionsThe MS/MS method for Fabry disease newborn screening is robust and can be readily multiplexed with other lysosomal disorders such as Pompe, Gaucher, Niemann–Pick, and Krabbe diseases.     

Activity levels and properties of acid α-glucosidase from liver and neutral α-glucosidase from sera of cystic fibrosis patients and controls

The average activity levels of acid α-glucosidase are comparable in liver supernatant fluids for 15 cystic fibrosis patients and 12 controls (401 ± 131 and 347 ± 109 nmol/h/mg protein, respectively) and no significant differences were found for the cystic fibrosis and control liver acid α-glucosidases in their (a) apparent K_m values for the 4-methylumbelliferyl substrate (1.1 mmol/1), (b) pH optima (4.2) and thermostability curves and (c) isoelectric profiles (one form with an isoelectric point of 4.5 ± 0.2).In contrast, average neutral α-glucosidase activity levels were significantly increased (p < 0.0002) in sera from 21 cystic fibrosis patients compared to 15 controls (10.7 and 2.7 nmol/h/ml). This increased activity is not due to (a) different stability upon storage at ?20°C, (b) the presence of activators in cystic fibrosis sera or inhibitors in normal sera (as determined by mixing studies), (c) altered K_m values or (d) altered pH optima curves. Cystic fibrosis serum neutral α-glucosidase appears to be more thermostable and has a consistently altered isoelectric profile (greater percentage of activity above pI 4.8) when compared to the normal serum enzyme. This altered isoelectric composition may reflect changes in neutral α-glucosidase which contribute to its increased activity in cystic fibrosis sera.     

320层容积CT灌注成像诊断肺孤立性结节

目的 评价320层容积CT灌注成像鉴别诊断肺孤立性结节的价值。 方法 分析63例直径≤3 cm肺孤立性结节的容积CT灌注成像表现,其中恶性结节组30例,慢性炎性结节组17例,急性炎性结节组7例,良性结节组9例。采用320层容积CT灌注成像,用体部肿瘤灌注软件得到肺动脉灌注值(PP)、支气管动脉灌注值(BP)、灌注指数(PI)和时间-密度曲线(TDC),评价灌注参数的诊断效能。 结果 恶性结节组、良性结节组、慢性炎性结节组及活动性炎性结节组PP值分别为(67.50±21.78)ml/(100 ml·min)、(30.11±13.24)ml/(100 ml·min)、(81.11±21.11)ml/(100 ml·min)、(106.34±7.80) ml/(100 ml·min),BP分别为(80.40±20.96)ml/(100 ml·min)、(27.00±14.18)ml/(100 ml·min)、(50.75±21.89)ml/(100 ml·min)、(11.06±4.31)ml/(100 ml·min),PI分别为(45.87±7.60)%、(51.13±7.44)%、(48.09±13.12)%、(75.91±10.13)%。4组SPN的TDC类型不同,恶性结节组的TDC A型27例(27/30,90.00%),B型3例(3/30,10.00%);良性结节组的TDC为C型(9/9,100%);慢性炎症结节组的TDC共4种类型,B型7例(7/17,41.18%),C型1例(1/17,5.88%),D型4例(4/17,23.53%),B^-型5例(5/17,29.41%);急性炎症结节组的TDC为E型(7/7,100%)。BP在所得参数中鉴别各组最优。以PI>70%作为急性炎性结节的诊断阈值,敏感度100%(7/7),特异度100%(56/56);以PP<45 ml/(100 ml·min)且BP<50 ml/(100 ml·min)作为良性结节的诊断阈值,其敏感度、特异度、阳性预测值及阴性预测值分别为81.82%(9/11)、88.46%(46/52)、60.00%(9/15)、95.83%(46/48)。 结论 320层容积CT灌注成像对于在肺孤立性结节中鉴别恶性及良性结节,包括急性炎性、慢性炎性具有较高价值。     

An update on gene therapy for lysosomal storage disorders

Introduction: Gene therapies can be envisioned for many disorders where conventional therapies fall short. Lysosomal Storage Disorders (LSDs) are inherited, mostly monogenic, disorders resulting from deficient lysosomal enzyme or co-factor activity. Existing standard-of-care treatments for LSDs are expensive and can negatively impact quality-of-life. They also may not be sufficiently efficacious. LSDs are particularly amenable to gene therapy as modified cells can secrete functional enzyme that can also correct unmodified cells. Gene therapies may thus be able to provide sustained long-term correction for LSD patients.

Areas covered: We highlight recent advances and discuss advantages/disadvantages of gene therapies with a focus on lentiviral and adeno-associated virus vectors currently in clinical trials for LSDs. We also mention promising strategies that are close to clinical testing. We emphasize protocols using ex vivo hematopoietic stem cell-directed gene therapy, systemic/liver-directed gene therapy, and brain-directed gene therapy. We also discuss next-generation gene therapy approaches and how they may address emerging challenges in the field.

Expert opinion: Gene therapy is still in its infancy with respect to LSDs. However, efficacy and safety has been demonstrated in numerous pre-clinical studies, and promising clinical results suggest that gene therapy treatment for several LSDs is a real possibility.     

Gene therapy progress and prospects: gene therapy of lysosomal storage disorders

Despite disappointments with early clinical studies, there is continued interest in the development of gene therapy for the group of metabolic diseases referred to as lysosomal storage disorders (LSDs). The LSDs are monogenic and several small and large, representative animal models of the human diseases are available. Further, the successful reconstitution of only low and unregulated tissue levels of the affected lysosomal enzymes are expected to be sufficient to correct the disease at least in the case of some of the LSDs. For these reasons, they are perceived as good models for the evaluation of different gene delivery vectors and of different strategies for treating chronic genetic diseases by gene transfer. In this review, we will highlight the progress that has been made over the past 2 years in preclinical research for this group of disorders and speculate on future prospects.     

Plasma chitotriosidase activity in acute Plasmodium falciparum malaria

BACKGROUND: Chitotriosidase is a functional chitinase secreted by activated macrophages. It is encoded by a gene located on chromosome 1q31-32, whose mutations may be responsible for chitotriosidase deficiency, encountered in almost 6% of Caucasian population. OBJECTIVE: This study reports firstly plasma chitotriosidase activity in African children with acute Plasmodium falciparum malaria. The chitotriosidase activity was correlated to objective parameters reflecting the status of the disease and compared with those found in healthy African children. RESULTS: We found that plasma chitotriosidase levels are significantly increased in African children with acute malaria (185.0+/-141.0 nmol/h/ml; median 150; range 11-521) with respect to reference values obtained in age matched African children (84.4.5+/-72.8 nmol/ml/h; median 63; range 4-350) (P<0.001). Moreover the levels of chitotriosidase were higher in African children than in Caucasian children matched for age (28.86+/-18.7 nmol/h/ml; median 24; range 1-98) (P<0.0001). A remarkable significant correlation was found between plasma chitotriosidase and reticulo-endothelial activation, as judged by thrombocytopenia degree and serum ferritin level in children with acute malaria. CONCLUSION: Based on this study, it appears that genetic and environmental features might be responsible for diversity of plasma chitotriosidase activity in black children living in Burkina Faso.     

Gene therapy for the lysosomal storage disorders

The lysosomal storage disorders (LSD) are monogenic inborn errors of metabolism with heterogeneous pathophysiology and clinical manifestations. In recent decades, these disorders have been models for the development of molecular and cellular therapies for inherited metabolic diseases. Studies in preclinical in vitro systems and animal models have established proof-of-concept for the development of bone marrow transplantation (BMT) and enzyme-replacement therapy (ERT) as therapeutic options for several LSDs. BMT is limited by poor donor availability and high morbidity and mortality, and although ERT is a good treatment, it is not a life-long cure. Its high cost remains an impediment for developing countries. While substrate synthesis inhibition therapy is an important idea, its clinical use is far from certain. The neuropathology present in many LSDs has responded poorly to BMT or ERT, which makes gene therapy an attractive therapeutic alternative. Oncoretroviral vectors, and more recently adeno-associated and lentiviral vectors have been tested with some success. This review summarizes the main gene therapy strategies which have been employed or are under development for both non-neurological and neuronopathic LSDs. Some of the in vitro and in vivo preclinical studies presented herein have provided the rationale for gene therapy clinical trials for Gaucher disease Type 1.     

Gene therapy for lysosomal storage disorders

The lysosomal storage disorders (LSD) are monogenic inborn errors of metabolism with heterogeneous pathophysiology and clinical manifestations. In the last decades, these disorders have been models for the development of molecular and cellular therapies for inherited metabolic diseases. Studies in preclinical in vitro systems and animal models have allowed the successful development of bone marrow transplantation (BMT) and enzyme replacement therapy (ERT) as therapeutic options for several LSDs. However, BMT is limited by poor donor availability and high morbidity and mortality, and ERT is not a life-long cure. Moreover, the neuropathology present in many LSDs responded poorly, if at all, to these treatments. Therefore, gene therapy is an attractive therapeutic alternative. Gene therapy strategies for LSDs have employed ex vivo gene transduction of cellular targets with subsequent transplantation of the enzymatically corrected cells, or direct in vivo delivery of the viral vectors. Oncoretroviral vectors and more recently adeno associated vectors (AAV) and lentiviral vectors have been extensively tested, with some success. This review summarises the main gene therapy strategies which have been employed or are under development for both non-neurological and neuronopathic LSDs. Some of the in vitro and in vivo preclinical studies presented herein have provided the rationale for a gene therapy clinical trial for Gaucher disease Type I.     

Progress in gene and cell therapies for the neuronal ceroid lipofuscinoses

Introduction: The neuronal ceroid lipofuscinoses (NCLs) are a subset of lysosomal storage diseases (LSDs) that cause myoclonic epilepsy, loss of cognitive and motor function, degeneration of the retina leading to blindness, and early death. Most are caused by loss-of-function mutations in either lysosomal proteins or transmembrane proteins. Current therapies are supportive in nature. NCLs involving lysosomal enzymes are amenable to therapies that provide an exogenous source of protein, as has been used for other LSDs. Those that involve transmembrane proteins, however, require new approaches.

Areas covered: This review will discuss potential gene and cell therapy approaches that have been, are, or may be in development for these disorders and those that have entered clinical trials.

Expert opinion: In animal models, gene therapy approaches have produced remarkable improvements in neurological function and lifespan. However, a complete cure has not been reached for any NCL, and a better understanding of the limits of the current crop of vectors is needed to more fully address these diseases. The prospects for gene therapy, particularly those that can be delivered systemically and treat both the brain and peripheral tissue, are high. The future is beginning to look bright for NCL patients and their families.     

Biomarkers in Serbian patients with Gaucher disease

Objectives

The aim of the study was to evaluate the efficiency of the biomarkers chitotriosidase (Chito), total acid phosphatase (TACP), angiotensin converting enzyme (ACE) and ferritin in the diagnosis of Gaucher disease (GD) and to assess the utility of biomarkers for monitoring the effects of enzyme replacement therapy (ERT).

Design and methods

Forty treatment-naive Gaucher patients were studied. 27/40 GP were put on ERT and monitored every 6 months.

Results

The baseline median values of Chito, TACP, ACE and ferritin were highly elevated in GP: 10216 nmol/mL/h, 26.1 U/L, 253 U/L, 515 μg/L, and 555 μg/L, respectively. The only significant difference between mild and moderate GP subgroups is observed for Chito activity (p = 0.0116). During ERT, Chito showed the steepest decrease in regard to TACP and ACE, mainly within the first year (71.4%).

Conclusions

Among these biomarkers, Chito proved to be the most useful biomarker for diagnosing GD and monitoring the ERT.     

口服复方聚乙二醇-4000前吞服比沙可啶对简化CT结肠镜肠道清洁准备的作用

目的 探讨口服复方聚乙二醇-4000前吞服比沙可啶对简化CT结肠镜肠道清洁准备的作用。 方法 将40例接收CT结肠镜检查的患者随机均分成试验组、对照组。 检查前1天,试验组三餐前口服40% W/V硫酸钡20 ml,晚餐后将60%泛影葡胺20 ml溶于250 ml水并服完,口服2 L复方聚乙二醇-4000电解质液之前1 h吞服10 mg比沙可啶肠溶片;对照组不吞服比沙可啶,其余同试验组。统计分析两组结直肠存留肠液评分、存留肠液CT值及存留粪块评分。 结果 试验组存留肠液平均评分(1.50±0.06)低于对照组(1.78±0.08),差异有统计学意义(P=0.024)。试验组、对照组存留肠液平均CT值分别为(729±29)HU、(597±27)HU,差异无统计学意义(P>0.05)。试验组存留粪块评分(1.96±0.11)低于对照组(2.63±0.12),差异有统计学意义(P=0.001)。 结论 口服复方聚乙二醇-4000前吞服比沙可啶既可增强对肠液的清洁能力,又不影响存留肠液CT值,同时可增强对肠道粪块的清洁能力,较单独口服复方聚乙二醇-4000的肠道清洁效果好,是CT结肠镜前较好的简化肠道准备方法。     

Acquired lysosomal storage caused by frequent plasmapheresis procedures with hydroxyethyl starch

BACKGROUND: Hydroxyethyl starch (HES) solutions have largely replaced conventional plasma expanders such as human albumin and colloidal fluids. Only a few side effects have been reported and mainly concern pruritus or blood coagulation disorders. Excessive HES exposure can result in diffuse tissue storage and accumulation with foamy appearing macrophages which produce the enzyme chitotriosidase (CT). In case of massive tissue storage, this enzyme activity can reach levels comparable to those of Gaucher disease. STUDY DESIGN AND METHODS: In this single-center retrospective analysis of 11 consecutive patients receiving large amounts of HES for chronic plasmapheresis, plasma CT activity was investigated. Five patients receiving chronic intermittent plasmapheresis with conventional plasma expanders served as controls. Plasma CT activity was measured and plotted against creatinine clearance. Where available, marrow aspirate was analyzed with light microscopy to detect foamy macrophages. One patient developed a lysosomal storage disease and was examined extensively. RESULTS: Conventional plasma expanders did not alter plasma CT activity. In patients with impaired renal function, frequent plasma replacement with HES resulted in an increase in plasma CT activity. In the patient with the acquired lysosomal storage disease, massive tissue infiltration with activated foamy macrophages was observed. The phagocytic capacity in this patient, however, did not seem to be altered. CONCLUSION: Patients with impaired renal function receiving large amounts of HES exhibit an increase in plasma CT activity. Because excessive HES exposure can result in an acquired lysosomal storage disease, this should be avoided in chronic plasmapheresis procedures.