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Item does not contain fulltext OBJECTIVES: To assess whether copper deficiency plays a role in the recently described cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, lysyl oxidase, and/or type I procollagen genes could be responsible for the occurrence of cysteamine toxicity in a small subset of patients with cystinosis. STUDY DESIGN: Thirty-six patients with cystinosis were included: 22 with Fanconi syndrome (including 7 with cysteamine toxicity), 12 after renal transplantation, 1 receiving hemodialysis, and 1 with ocular cystinosis. Serum copper and ceruloplasmin levels and urinary copper/creatinine ratio were measured. Genes ATP7A and CTR1 (encoding copper transporters), LOX (encoding lysyl oxidase), and COL1A1 and COL1A2 (encoding type I procollagen) were analyzed in patients with (n = 6) and without (n = 5) toxicity. Fibroblast (pro)collagen synthesis was compared in patients with (n = 3) and those without (n = 2) cysteamine toxicity. RESULTS: All 22 patients with Fanconi syndrome had increased urinary copper excretion. Serum copper and ceruloplasmin levels were decreased in 9 patients, including all 7 patients with cysteamine toxicity. No specific sequence variations were associated with toxicity. All fibroblasts exhibited normal (pro)collagen synthesis. CONCLUSION: Patients with cystinosis with cysteamine toxicity demonstrate copper deficiency. This can cause decreased activity of lysyl oxidase, the enzyme that generates the aldehydes required for collagen cross-linking. Thus, copper supplementation might prevent cysteamine toxicity.

Item does not contain fulltext Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.

Objective To report new adverse effects of cysteamine.Study design Detailed clinical information was obtained from the patients' physicians.Results New adverse events were reported in 8 of 550 patients with cystinosis treated with cysteamine in Europe during the last 5 years. Detailed clinical information was not available for 2 of these patients, 1 of whom died from cerebral ischemia. The 6 evaluable patients developed vascular elbow lesions (6/6), neurologic symptoms (1/6), bone and muscle pain (2/6), and/or skin striae (2/6). Analysis of biopsy specimens from the elbow lesions demonstrated angioendotheliomatosis with irregular collagen fibers. In 3 of the 6 patients, the daily cysteamine dose exceeded the recommended maximum of 1.95 g/m(2)/day. Dose reduction led to improvement of signs and symptoms in all 6 patients, suggesting a causal relationship with cysteamine administration.Conclusion Cysteamine administration can be complicated by the development of skin, vascular, neurologic, muscular, and bone lesions. These lesions improve after cysteamine dose reduction. Doses >1.95 g/m(2)/day should be prescribed with great caution, but underdosing is not advocated. (J Pediatr 2011;159:1004-11).

Objective Cystinosis causes renal and other organ failure. Treatment with 6-hourly cysteamine bitartrate (Cystagon, Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A recent study showed that an enteric-release cysteamine required less frequent daily dosing. This report describes the long-term use of enteric-coated (EC) cysteamine bitartrate (Cystagon) in children with cystinosis. Study design After a pharmacokinetic and pharmacodynamic study of EC-cysteamine in children with cystinosis, 5 patients remained on twice-daily treatment. White blood cell cystine levels were measured 12 hours after ingestion every 4 to 8 weeks. These levels were then compared with the patient's previous 6-h post-dose levels taken while on regular cysteamine bitartrate before entering the study. Blood chemistry was also measured. Results Five children with cystinosis (mean age, 9 years; range, 8 to 17 years) who previously took cysteamine bitartrate (mean dose, 47 mg/kg body wt), received EC-cysteamine for 10 to 27 months (mean dose, 25 mg/kg body wt) and had mean white blood cell cystine levels of 0.77 and 0.71 nmol half-cystine/mg protein, respectively. During the study period, patients maintained adequate growth and there was no significant deterioration in renal or thyroid function. Two children were required to restart acid suppression after 6 months on EC-cysteamine therapy. Conclusions Long-term, twice-daily EC-cysteamine, given at approximately 60% of the previous daily dose of cysteamine bitartrate, was effective at maintaining white blood cell cystine levels within a satisfactory range. There was no significant deterioration in renal or thyroid function.

To test the hypothesis that a controlled-release preparation of cysteamine, with fewer daily administrations, would improve the quality of life for patients with cystinosis.A specifically designed nasoenteric tube was used to administer cysteamine directly into the stomach, small intestine (SI) and colon and serial plasma cysteamine, serum gastrin and leukocyte cystine levels were measured.Eight control subjects (mean age 23.2 years) and 6 subjects with cystinosis (mean age 15.2 years) were studied. Cysteamine absorption (maximum concentration and area under the curve of the concentration-time gradient) was greater from the SI than stomach or cecum (P.01). Leukocyte cystine depletion was greater after delivery of cysteamine into the SI than stomach or cecum; this effect was associated with the plasma cysteamine maximum concentration and area under the curve (P.001 and.02, respectively). Gastrin levels were not affected by site of drug delivery and were elevated only in patients with cystinosis with gastrointestinal symptoms.The absorption of cysteamine and the effect of this agent on leukocyte cystine depletion are more profound after SI administration. Enteric-coated cysteamine, targeted for SI release, may require fewer daily dosages. Not all patients with cystinosis require acid-suppression therapy.

Aims Cysteamine is used to reduce tissue cystine content in patients suffering from nephropathic cystinosis. The objectives of the current study were to investigate pharmacokinetics and pharmacodynamics of cysteamine bitartrate in children and young adults with nephropathic cystinosis. Methods Cysteamine bitartrate was administered to 11 cystinosis patients at their regular dose level in a single-dose, open-label, steady-state study. Blood samples were collected and analysed for plasma cysteamine and white blood cell cystine content and pharmacokinetic and pharmacodynamic parameters estimated by NONMEM analysis using a linked pharmacokinetic–pharmacodynamic model. Results Cysteamine was rapidly cleared from the plasma (mean CL/F = 32.3 ml min−1 kg−1, range = 17.3–52.2), appeared to be extensively distributed (mean Vss/F = 15.1 l, range 2.7–32.3) and exhibited a mean Tmax of 1.4 h. White blood cell cystine content post-dosing was significantly decreased compared with pre- and post-dose values (average decrement approximately 47%). A counter-clockwise hysteresis was noted in all patients, suggestive of a lag time (mean Tlag = 0.44 h, range 0.22–0.92) between drug concentration and effect. Conclusions The results of this study establish that cysteamine is rapidly cleared from the plasma but that an every 6 h dosing interval adequately maintains white blood cell cystine content below the target of 1 nmol cystine per mg protein.

In this technical paper, the authors apply a cumulative genetic algorithm and a neural network to the transportation network design problem. Constraints of the problem must be addressed during the design process to determine the best feasible solution. After introducing the algorithm, it is demonstrated in examples of restrictions encountered in practice. Then, an analysis is made of alternative constraint processing methods and the optimization process is modified within the cumulative genetic algorithm. Two groups of constraints are defined for a test network to verify the applicability of the method. Results indicate that the search process yields the best feasible solutions, confirming the use of the cumulative genetic algorithm and neural network in processing constraints.

Three patients with nephropathic cystinosis and chronic renal disease, treated since early childhood with orally administered cysteamine, had an accelerated rate of rise of serum creatinine values after receiving recombinant human growth hormone. During 18 to 24 months of growth hormone treatment, each patient had a twofold to fourfold increase in growth velocity. The slope of the plot of reciprocal serum creatinine values versus age for each patient after growth hormone treatment was significantly steeper than the pretreatment slope. Growth hormone treatment had no effect on the rate of change of the uncorrected 24-hour renal creatinine clearance. We conclude that these patients gained body size but failed to compensate for their increased creatinine production with an increase in glomerular filtration rate. The result was an accelerated rate of rise of their serum creatinine values, hastening renal transplantation in one patient and the anticipated need for transplantation in another.

Sirs, We are concerned that the manner in which leukocytes are prepared for the determination of cystine levels may cause imprecise results which could adversely affect the treatment of patients with cystinosis. Leukocyte cystine levels are used to diagnose cystinosis, monitor Cystagon therapy, and for multiple purposes in research studies. The determination of cystine in leukocytes is performed only in a small number of laboratories worldwide, one of which is the Cystine Determination Laboratory at the University of California San Diego (UCSD). In the late 1970s, when the first cysteamine treatment trial was started, we evaluated ways to have blood shipped to the laboratory for the separation of leukocytes and the determination of intracellular cystine. It was determined that the leukocyte cystine level could only reliably be measured from samples that had been separated immediately after the blood was drawn. To ensure uniform preparation, our practice has been to ship reagents to point-of-care clinical laboratories, with precise instructions for sample preparation (http://biochemgen.ucsd.edu/cystinosis/), as in the published method [1]. Separated and lysed leukocyte samples are acidified, frozen and transported to our laboratory on dry ice for protein and cystine determinations. Other laboratories accept heparinized whole blood shipped on wet ice for the determination of leukocyte cystine levels. The leukocytes are separated from the sample upon arrival at the laboratory, typically 24–48 h after the blood was drawn. This frees the point-of-care laboratory from the task of preparing the leukocytes, a procedure which is not complicated but which is time consuming and may be seen as an inconvenience. Our laboratory therefore would naturally be interested in changing the procedure to accept whole blood. However, based on our experiences in the 1970s, we felt it was important to evaluate the stability of intracellular cystine in blood samples during storage and shipping. Until recently, the demanding cystine binding assay method used for the cystine assay made such an evaluation impractical, but a newer method using tandem mass spectrometry [3] has reduced sample analysis time drastically. The aim of our small study was to evaluate whether intracellular cystine levels would be reliable if leukocyte separation from heparinized whole blood were delayed for up to 24–48 h, as would be expected with express mail shipment. Three cystinotic patients were enrolled into the study. Patients on Cystagon therapy were asked to discontinue therapy 24 h before participating. Blood was drawn from each subject, with aliquots anticoagulated in Li-heparin or Na-heparin. Blood was divided into 3-mL samples, and leukocytes were prepared in triplicate by the ACD-dextran method immediately after collection (0 h, baseline) or after being stored for 24 ± 1 or 48 ± 1 h at either room temperature or 4°C. All reagents for the separation were prepared by the UCSD Cystine Determination Laboratory. Protein content was determined using the Lowry method [3], and cystine content was measured using tandem mass spectrometry [2, 4]. Leukocyte cystine content was calculated as nanomoles half-cystine per milligram protein and is presented in Table 1 as the percentage of baseline value. Samples stored for 48 h at room temperature and collected in Li- and Na-heparin, respectively, did not separate when mixed with ACD-dextran, and leukocytes could not be isolated from these samples. Leukocytes could be prepared from all other samples. Table 1 Leukocyte cystine levelsa after the storage of whole blood for 24 or 48 h in Li- and Na-heparin (results averaged together) at room temperature or 4°C before separation of leukocytes No differences were observed between Li- and Na-heparin, and the results for both anticoagulants were therefore combined. The levels determined at baseline and after storage for 24 and 48 h at 4°C and for 24 h at room temperature are shown in Table 1. Cystine levels in samples stored for 24 h at room temperature varied between 52 and 117% of baseline values. Even greater variations were measured when the samples were stored at 4°C for 24 h (37–214%). After 48 h, only samples stored at 4°C could be separated, and the cystine levels determined were between 52 and 240% of baseline values. Although we tested only a small number of samples, we believe these results clearly show that results will be imprecise if leukocytes are not prepared immediately after heparinized blood is drawn. Accordingly, we encourage nephrologists treating cystinosis patients to take into account the time involved in storing and shipping samples prior to separating leukocytes for cystine determination. We are hoping to expand this study and evaluate different agents which might stabilize leukocytes and obviate the need for immediate cell preparation, but we believe it important to share these results immediately with all pediatric nephrologists treating cystinosis patients.

Objective Cystinosis causes renal and other organ failure. Regular 6-hourly cysteamine bitartrate (Cystagon; Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A formulation of cysteamine requiring less frequent dosing may improve compliance and possibly patient outcome. Methods Enteric-release cysteamine was prepared. For a period of 1 month, patients received their regular cysteamine dose every 6 hours (stage I). The patients then underwent pharmacokinetic and pharmacodynamic studies following washout periods using single-doses of cysteamine and enteric-release cysteamine (stage II). Finally, the patients commenced regular enteric-release cysteamine therapy (stage III). Weekly trough white blood cell (WBC) cystine levels were recorded. Results Seven children with cystinosis (mean age, 11.8 years; range, 8-17 years) who received cysteamine and enteric-release cysteamine (mean dose, 45 and 28.8 mg/kg body weight/day, respectively) had mean WBC cystine levels of 0.7 ± 0.3 and 0.41 ± 0.22 nmol half-cystine/mg protein in study stages I and III, respectively. Study stage II showed that the mean time (Tmax) to reach the maximum plasma cysteamine level (Cmax) was longer for enteric-release cysteamine than for cysteamine (176 minutes vs 60 minutes; P = .001), but the mean Cmax at the same dose was similar. Mean serum gastrin levels were similar after ingestion of cysteamine and enteric-release cysteamine. Conclusions Twelve-hour enteric-release cysteamine, given at approximately 60% of the previous daily dose of cysteamine, was effective in maintaining trough WBC cystine levels within a satisfactory range.

The cystine that accumulates within cystinotic lysosomes comes primarily from proteins which have been degraded within this organelle. The individual amino acids have specific transport mechanisms to exit the lysosome. The lysosomal cystine transporter is defective in all types of cystinosis. When cells from patients with nephropathic and benign cystinosis were fused, the defect was not corrected and the cystine level remained elevated. This strongly indicates that the genetic defects are allelic (i.e., on the same chromosome). Cysteamine is a weak base which enters the cystinotic lysosome and reacts with cysteamine. forming a mixed disulfide of half-cystine and cysteamine. This mixed disulfide rapidly exits the lysosome via the transport system for cationic amino acids which is normal in cystinosis. Because of the success of renal transplantation, many cystinosis patients are alive in their twenties and even early thirties. Unfortunately, these patients have developed damage to other organs including thyroid, eye, central nervous system, pancreas, and muscle. Cysteamine and its analog, phosphocysteamine, are very beneficial to cystinosis patients, especially when started early in life. These drugs may prevent the need for transplantation. It is too early to know if they will prevent damage to other organs.

Consensus Statement First NIH/Office of Rare Diseases Conference on Cystinosis: past, present, and future Robert Kleta, Frederick Kaskel, Ranjan Dohil, Paul Goodyer, Lisa M. GuayWoodford, Erik Harms, Julie R. Ingelfinger, Vera H. Koch, Craig B. Langman, Mary B. Leonard, Roslyn B. Mannon, Minnie Sarwal, Jerry A. Schneider, Flemming Skovby, Barbara C. Sonies, Jess G. Thoene, Doris A. Trauner and William A. Gahl 19

Cysteamine prevents organ damage in children with cystinosis, but may cause gastrointestinal (GI) symptoms. In this study we evaluated the nature of GI disease, and the value of omeprazole in controlling GI symptoms in these children.Upper GI disease was evaluated with endoscopy, gastrin levels, and acid secretion studies after oral administration of cysteamine, before and after 16 weeks of therapy with omeprazole. A symptom score was devised.Eleven children (mean age, 5.7 years) were studied. After cysteamine ingestion, before and after omeprazole therapy, the mean maximum acid output was significantly higher than the mean basal acid output. The maximum acid output was measured within 60 minutes of cysteamine ingestion and was reduced by omeprazole therapy (P.01). The mean peak gastrin level was 30 minutes postcysteamine and was higher than baseline (P.01). The initial mean symptom score (maximum score, 14) was 6.9 and fell to 0.7 (P.0001) after 16 weeks of omeprazole therapy. At endoscopy, two children had diffuse gastric nodularity, and nearly all had cystine crystal deposits.GI symptoms in children with cystinosis receiving cysteamine are often acid-mediated and improve with omeprazole. Cystine crystals were detected in the GI tract and may signify inadequate treatment with cysteamine.

Aim: To evaluate the safety and efficacy of a new topical cysteamine formulation, stable at room temperature, for the treatment of corneal cystine crystals in cystinosis. Methods: 20 study subjects were enrolled in the safety study and 16 in the efficacy study. Both studies were randomised and double blind. The primary outcome for the safety study was the occurrence of predefined serious adverse reactions over 6 months and for the efficacy study the reduction of corneal cystine crystal score (CCCS) by 1.00 or more units on photographs graded by a reading centre using a standardised protocol. Results: No study subject developed any serious adverse reactions. In the efficacy study, 47% of eyes receiving the standard formulation experienced a reduction in the CCCS of ≥1.00 after 1 year, while 7% of eyes on the new formulation experienced such a decrease (p=0.04). Conclusion: Although no serious adverse reactions were observed with either formulation, the new formulation was not as effective as the standard formulation.

Objective. Cysteamine is a recently licensed orphan drug used to treat the inherited metabolic disease cystinosis. The drug delays the onset of renal failure in cystinotic patients and may provide many other significant health benefits. This study examined the cost-effectiveness of the administration of cysteamine to cystinotic patients prior to end-stage renal disease (ESRD). Method. Decision-tree analysis and cost-effectiveness analysis. Cost data were estimated from current clinical charges and Medicare public-access reports. Life expectancy outcomes were derived from both published and unpublished clinical studies and from the U.S. Renal Data System. Results. Cysteamine therapy can extend the life of kidneys and delay renal transplantation, thereby increasing life expectancy for patients with cystinosis. Patients receiving cysteamine therapy prior to renal failure have lifetime-treatment drug costs of $234,000, in comparison with $238,000 for those who are not medicated. Costs of cysteamine therapy are offset by savings associated with delaying transplantation and costs of dialysis. Conclusions. Use of the orphan drug cysteamine both improves health outcomes and reduces health care costs for patients with cystinosis. Key words: cystinosis; cysteamine ; decision analysis; cost-effectiveness. (Med Decis Making 1997;17:193-198)

Cysteamine bitartrate capsules (Cystagon) have been approved by the US Food and Drug Administration for use in patients with nephropathic cystinosis. Plasma cysteamine concentrations were virtually identical at various times following ingestion of either cysteamine hydrochloride or Cystagon capsules in 24 normal control subjects. A transfer study was done with eight cystinosis patients who had been receiving either cysteamine hydrochloride or phosphocysteamine for many years. The plasma cysteamine concentration was significantly higher 2h after Cystagon and the leukocyte cystine content was significantly lower at all times after Cystagon compared to older forms of the drug. These differences are probably the result of greater patient compliance in taking the capsules compared to the older, liquid forms of the drug. A new method for following the course of renal glomerular deterioration in diseases such as cystinosis has been published recently. This method was used to re-analyse data on the efficacy of cysteamine treatment and to re-analyse new data on treating cystinosis patients with either of two doses of cysteamine (1.30 g/m2 per day and 1.95 g/m2 per day). This new method agrees well with other methods and shows that both doses of drug are equally effective in maintaining glomerular function.

We report the case of a patient with infantile nephropathic cystinosis who required renal transplantation at age 30 months. Exhaustive evaluation did not identify a cause of progressive renal failure other than cystinosis. The patient's genetic lesion was allelic with those of other patients with cystinosis; fusion of this patient's fibroblasts with fibroblasts from another patient with infantile nephropathic cystinosis did not demonstrate complementation of the biochemical defect.

Cystinosis is an autosomal recessive metabolic disorder in which nonprotein cystine accumulates within most body tissues due to a defect in lysosomal cystine transport. Neurologic declarations are only recently being recognized. We studied 13 cystinotic subjects (aged 5 to 21 years old), determining median motor and sensory nerve conduction velocities, F waves, peroneal motor nerve conduction velocities, sural sensory nerve conduction velocities, median sympathetic skin response, electrocardiogram R-to-R variability, and blink reflex analysis. The results were normal. We conclude that neurophysiologic testing suggests relative sparing of the peripheral nervous system in nephropathic cystinosis.

The predicted reciprocal creatinine at age 10 years (PRC10), a parameter of renal function based upon the linear relationship between reciprocal serum creatinine and age, incorporates age, serum creatinine, and rate of renal deterioration into a single term. PRC10 measurements were employed to assess renal function in children with nephropathic cystinosis treated with oral cysteamine, a cystine-depleting agent. In 71 children receiving oral cysteamine for at least 1 year, PRC10 decreased linearly with initial serum creatinine concentration. This indicated that, although established renal damage in cystinosis was irreversible, early intervention with cysteamine therapy could favorably alter the rate of glomerular deterioration. In other analyses, mean PRC10 was shown to increase with duration of cysteamine therapy and extent of leukocyte cystine depletion. The predicted reciprocal creatinine value at a certain age can be useful in analyzing the effects of therapeutic intervention in a disease with a relatively uniform rate of renal deterioration.

Three patients with nephropathic cystinosis and chronic renal disease, treated since early childhood with orally administered cysteamine, had an accelerated rate of rise of serum creatinine values after receiving recombinant human growth hormone. During 18 to 24 months of growth hormone treatment, each patient had a twofold to fourfold increase in growth velocity. The slope of the plot of reciprocal serum creatinine values versus age for each patient after growth hormone treatment was significantly steeper than the pretreatment slope. Growth hormone treatment had no effect on the rate of change of the uncorrected 24-hour renal creatinine clearance. We conclude that these patients gained body size but failed to compensate for their increased creatinine production with an increase in glomerular filtration rate. The result was an accelerated rate of rise of their serum creatinine values, hastening renal transplantation in one patient and the anticipated need for transplantation in another.

Urine glyceraldehyde excretion is elevated in the renal Fanconi syndrome. We analyzed urinary constituents using GC/MS in 16 children with the renal Fanconi syndrome and 13 normal individuals. Urine glyceraldehyde levels were strikingly elevated in the renal Fanconi syndrome group (mean 5.1 ± 4.8 mg/mg creatinine) compared to levels in the normal group (mean 0.04 ± 0.04 mg/mg creatinine, P < 0.001). Urine lactate levels were also elevated in the renal Fanconi syndrome group (mean 2.3 ± 2.6 mg/mg creatinine) compared to normals (mean 0.01 ± 0.01 mg/mg creatinine, P < 0.003). Only small elevations of glyceraldehyde and lactate were found in urine from children with other renal disorders. Serum levels of glyceraldehyde and lactate were no greater in individuals with the Fanconi syndrome than in the normals. The fractional reabsorption of both glyceraldehyde and lactate was virtually complete in the normals, but was markedly impaired in the Fanconi syndrome patients where, in some cases, glyceraldehyde excretion greatly exceeded the excretion of creatinine. We conclude that marked glyceraldehyde excretion is a previously unrecognized feature of the renal Fanconi syndrome which may result from disordered proximal tubular glycolytic metabolism. Further studies will be required to determine the role of glyceraldehyde loss in the pathogenesis of this generalized disturbance of proximal tubular function.

Cystinosis is a recessively inherited metabolic disorder characterized biochemically by a high intracellular content of free (nonprotein) cystine which appears to be compartmentalized within lysosomes. This results in crystal deposition in the cornea, conjunctiva, bone marrow, lymph nodes, leukocytes, and internal organs. The primary metabolic defect which leads to cystine accumulation is unknown.

Boman, H. and Schneider, J. A. (Institute of Medical Genetics, University of Oslo, Oslo, Norway, and Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA). Prenatal diagnosis of nephropathic cystinosis: Pregnancy at risk ascertained through heterozygote diagnosis of parents. Acta Paediatr Scand, 70:389, 1981.–The biochemical diagnosis of cystinosis in a deceased girl was made indirectly through the demonstration of heterozygote values of free-cystine contents in leukocytes from both parents. Amniocentesis was performed on the mother in the 16th week of two subsequent pregnancies. Amniotic fluid cell lysate from the first fetus had 6–8 times normal levels of radioactivity in the cystine band determined by a 35S-cystine pulse labeling method followed by high voltage electrophoresis on paper. Values for the cystine contents in various organs of the affected fetus are given. The second fetus was found to be not affected, and this was subsequently confirmed by the birth of a healthy child. The results of the laboratory analyses in these two cases were available to the parents 21 and 23 days following amniocentesis, respectively. The interruption of the first pregnancy was performed in the 19th week. This was 4 and 6 weeks earlier, respectively, than in the two previously reported induced abortions of affected fetuses, and should increase the acceptability of the present method for prenatal diagnosis of nephrophatic cystinosis.

The prenatal diagnosis of cystinosis is currently based on the increased amount of free-cystine present in amniotic fluid cells. Amniocyte cultures must be grown for at least 2 weeks to obtain sufficient cells for such measurements. Thus, the diagnosis cannot be made until close to 20 weeks gestational age by this method. We report a case in which chorionic villi were used for direct cystine measurement resulting in the in utero diagnosis of cystinosis at 9 weeks gestational age. The diagnosis was confirmed by the study of cultured chorionic villus cells, and of the 10-week abortus.

A prototype man-computer system was developed for use in the design of urban bus transit systems. The Urban Transportation Analysis Section (UTRANS) permits design and evaluation of many alternatives within a relatively short period of time. UTRANS is currently limited to the design of transit systems that serve a many-to-one travel pattern, i.e., many trip origins having a common trip destination. The designer uses a graphics terminal to input design data for a bus transit system. A computerized behavioral model of mode split then predicts performance of the system design. A series of performance displays are provided for use in evaluation of the design. Repeated modifications of the original design permits the generation of many alternatives and eventual selection of a particular design that has best overall performance. An assessment of the utility of UTRANS in a real-world setting awaits the results of current efforts to apply the system in the design and evaluation of transit service to the University of Washington, Seattle, Wash.

Following renal transplantation in nephropathic cystinosis, an extension of retinopathy associated with a variety of subtle functional ocular abnormalities may occur. However, these abnormalities have not (except for photophobia) been of subjective significance to cystinotic patients. Our data, gathered from patients transplanted as long as nine years ago, indicate that cystinotic patients should not have renal transplant withheld because of the fear of subsequent progressive ocular deterioration.

Cysteamine (2-aminoethanethiol) has been given orally to 19 patients with nephropathic cystinosis for periods of 8-24 months in doses ranging from 50 to 70 mg base/kg/day. Adverse reactions were noted in 3 patients early in the study when a rapidly increasing dosage schedule was followed. The reactions included hyperthermia, lethargy and rash. These reactions were not seen when patients were started on a very low dosage which was increased gradually at 3-week intervals to a level which depleted leukocytes of about 90% of their free cystine. All three reactions resolved within 24 h or cessation of therapy and in these cases successful readministration of drug was achieved. Chronic cysteamine administration to pediatric patients with cystinosis is feasible. The efficacy of this therapy is still being evaluated.

As shown by the experiences gained in recent energy crises, transit agencies should prepare emergency contingency plans to deal with possible rapid and sharp increases in the demand for transit service. In this paper, contingency plans are developed for two suburban areas, Bellevue and Federal Way, in the Seattle, Washington metropolitan area. Bus transit system designs are developed for three emergency levels: 100, 75 and 50% of the work trips to be carried by buses. Altogether, 10 plans are developed. Six assume no vehicle availability constraints, and four assume only existing Metro and school buses are available. Results indicate that bus vehicle requirements for the 100 and 75% levels far exceed likely vehicle availability levels while the 50% level could be handled with currently available vehicles (Metro fleet combined with school buses). This design work was accomplished rapidly and effectively with an interactive graphic computer program called the Transit Network Optimization Program (TNOP). It would be impossible to do a similar study using conventional transit planning techniques.

The citations in this bibliography are presented by subject: airport planning and design, automobile design, citizen participation, downtown people-mover (dpm) systems planning and design, highway facilities, highway route planning, highway safety, human figure simulation, planning and design of ride sharing systems, rearload analysis and planning simulation of outer space and aircraft operations, simulation of traffic movements, traffic signal optimization, transit facilities and operations analysis and planning, transit system planning and design, transportation data display and editing, transportation education, transportation systems planning. (TRRL)

Graphics are a powerful but often costly means of communication. Computer-drawn graphics offer a new and relatively inexpensive way to assist the communication of complex technical information to both planners and non-technical people whose full potential is now beginning to be realized. This paper discusses the utility of graphics and introduces three computer-drawn graphic techniques which may be useful, both for analysis and presentation of results, in the transportation planning process. Cenvue(s) produces a three-dimensional, perspective-view map, on which virtually any type of transportation data or performance indicator can be displayed. Vap is designed to display origin-destination travel patterns in any region. Tdn transforms a physical-distance network into a time-distance network so that effects of different speeds in the transportation network can be readily seen. The cost-effectiveness of each technique is briefly discussed and some recommendations for evaluating computer graphics techniques are provided to aid the user in further assessing their utility in the transportation planning process. /Author/TRRL/

Utilisation des techniques de la conception assistee par ordinateur pour l'etude des interactions entre transports et occupation des sols. Presentation du logiciel UFOS (Urban form optimization system)

Five children with end-stage renal disease resulting from cystinosis received seven cadaver renal allografts. Four recipients have functioning grafts eight to 55 months after receiving the transplant and one recipient lost two grafts at 17 and 26 months after the transplant. There was no florid recurrence of the Fanconi syndrome although proximal renal tubular dysfunction developed in two patients, in one in association with chronic rejection and in one without apparent etiology. Free cystine content of white blood cells, cultured skin fibroblasts and allograft tissue was significantly increased. Cystine crystals were observed in the mesangium of two grafts and in the interstitial tissue of all grafts; however, no cystine crystals were found in the tubules. The location of the cystine crystals, as well as the fact that the highest free level of cystine of allograft tissue was observed in the graft undergoing chronic rejection, led to the hypothesis that recipient cells infiltrating the graft were the source of cystine deposition. The data indicate that successful cadaveric transplantation does not correct the primary metabolic defect in cystinosis, thereby explaining the persistence of the extrarenal clinical manifestations, such as photophobia and hypothyroidism, after renal transplantation in cystinosis.

Fasting plasma concentrations of cystine and of cysteine in six patients with cystinosis were not significantly different from that in four control children. Treatment with d-penicillamine or with a diet containing only the minimal requirement of cystine and methionine produced a substantial decrease in plasma cystine concentrations without affecting the appearance of the crystalline deposits in bone marrow or cornea. These findings suggest that plasma cystine is not in free equilibrium with the crystalline deposits of cystine and imply that the abnormality of cystine metabolism giving rise to cystine crystals is confined within the cells. Treatment with d-penicillamine caused a decrease in the urinary excretion of amino acid in only one of three patients, but in this patient there was continued progression of renal glomerular insufficiency.

A combined morning-glory spillway and gated outlet tower planned to operate both with submerged and unsubmerged outlet was designed with the aid of a hydraulic model. In this design, entrained air is permitted to rise to the soffit of the level discharge conduit, and is transported to the exit portal to the reservoir surface by means of a slotted device designed to maintain only small pressure differentials between it and the reservoir, so as to permit air to gradually escape.

The metabolic defect which results in the accumulation of cystine within tissues of children with the recessively inherited disease cystinosis has baffled investigators for almost half a century. Investigations by numerous laboratories have finally culminated in the delineation of the basic defect in this unusual disorder.

Many neurologic symptoms occur with coughing paroxysms in patients with CF. Few seek medical advice for these symptoms. Rarely, a patient who reports these symptoms should be evaluated further for more serious neurologic conditions, including brain abscess. 12 However, for most patients it seems reasonable to offer reassurance that, although the symptoms may be alarming, the incidence of irreversible sequelae appears small.

1. Noone P, Parsons TMC, Pattison JR, et al: Experience in monitoring gentamicin therapy during treatment of serious gram-negative sepsis, Br Med J 1:477, 1974. 2. Bootman JL, Wertheimer AI, Zaske DG, et al: Individualizing gentamicin .dosage regimens in burn patients with gram-negative septicemia: A cost-benefit analysis, J Pharm Sci 68:267, 1979. 3. Siber GR, Echeverria P, Smith AL, et al: Pharmacokinetics of gentamicin in children and adults, J Infect Dis 132:637, 1975. 4. Vogelstein B, Kowarski AA, and Lietman PS: The pharmacokinetics of amikacin in children, J PEDIATR 91:333, 1977. 5. Sawchuk RJ, and Zaske DE: Pharmacokinetics of dosing regimens which utilize multiple intravenous infusions: Gentamiein in burn patients. J Pharmacokin Biopharm 4:183, 1976. 6. Hoecker JL, Pickering LK, Swaney J, et al: Clinical pharmacology of tobramycin in children, J Infect Dis 137:592, 1978. 7. Yaffe S J, Gerbracht LM, Mosovich LL, Mattar ME, Danish M, and Jusko WJ: Pharmacokinetics of methieillin in patients with cystic fibrosis, J Infect Dis 135:828, 1977. 8. Lau WK, Young LS, Osher AB, and Dooley RR: Amikacin therapy of exacerbations of Pseudomonas aeruginosa infections in patients with cystic fibrosis, Pediatrics 60:372, 1977. 9. Zaske DE: Aminoglycosides, in Evans WE, Sehentag J J, and Jusko W J, editor: Applied pharmacokinetics: Principles of therapeutc drug monitoring, San Francisco, 1980, Applied Therapeutics inc., p 210. 10. Fishman AP: Chronic cor pulmonale: State of the art, Am Rev Respir Dis 114:775, 1976. 11. Wood RE, Boat TF, and Doershuk CF: Cystic fibrosis, Am Rev Resp Dis 113:833, 1976. 12. McCrae WM, Raeburn JA, and Hanson EJ: Tobramycin therapy of infections due to Pseudomonas aeruginosa in patients with cystic fibrosis: effect of dosage and concentration of antibiotic in sputum, J Infect Dis 134:1915, 1976.

Because high concentrations of ascorbic acid (0.57 mM) lower the free (nonprotein) cystine content of cultured cystinotic skin fibroblasts by over 50 per cent, we did a double-blind clinical trial to establish whether this drug would benefit cystinotic children. Sixty-four patients were randomized into the study; 32 received ascorbic acid (200 mg per kilogram of body weight per day), and 32 placebo. The study was terminated after approximately two years because there was no indication that vitamin C was beneficial and accumulating evidence that it might be harmful. Of 11 patients who left the study because of death or the requirement for dialysis or renal transplantation, eight were receiving ascorbic acid. The estimated relative risk (treatment vs. control) of an adverse event was R = 2.7, with a 90 per cent confidence interval of (0.8, 11.5). The serum creatinine concentration increased 0.53 mg per deciliter per year in patients receiving vitamin C and 0.24 mg per deciliter per year in patients receiving placebo (P = 0.08).

• Cystinosis is a rare metabolic disorder in which nonprotein cystine accumulates within lysosomes due to a defect in lysosomal cystine transport. Although cystine accumulates within most ocular tissues, patients with cystinosis generally complain only of photophobia and glare. We measured glare sensitivity in 12 patients with infantile cystinosis and compared their results with an age-matched control population. Ten of the 12 patients with cystinosis had demonstrable glare disability when compared with the control group. Glare disability scores in the patients with cystinosis ranged from 5% to 50%. Dazzle glare resulting from the accumulation of cystine crystals in ocular tissue may account for glare disability seen in these patients and contribute to their complaints of photophobia.

Important insights have recently been derived from studies of inborn human defects of sulfur metabolism. Metabolic lesions responsible for homocystinuria have been elucidated, with possible implications for understanding atherogenesis in the general population. The cause of cystinosis remains enigmatic, but important information has been gained on the origin of some stored cystine from degraded protein. Cysteamine and ascorbic acid deplete the cystine content of cystinotic fibroblasts in vitro, and clinical trials with these agents have been undertaken. Studies of patients with glutathione synthetase deficiency have provided new understanding of the roles of glutathione as in antioxidant and as a modulator of microtubule-related processes. Studies of patients with this disorder and glucose-6-phosphate dehydrogenase deficiency, in which the capacity to maintain glutathione in the reduced state is compromised, indicate that pharmacologic doses of vitamin E can correct certain functional consequences of an inadequate supply of reduced glutathione both in erythrocytes and polymorphonuclear leukocytes. Much remains to be learned about the mechanisms of membrane damage in these states of enhanced oxidative susceptibility.