Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischemia.

The bioactive lipid intermediate palmitoyl CoA (PCoA) can inhibit mitochondrial ADP/ATP transport, though the physiological relevance of this regulation remains unclear. We questioned whether myocardial ischemia provides a pathological setting in which PCoA regulation of ADP/ATP transport would be beneficial, and secondly, whether the chronically elevated lipid content within the diabetic heart could make mitochondria less sensitive to the effects of PCoA. PCoA acutely decreased ADP-stimulated state 3 respiration and increased the apparent Km for ADP twofold. The half maximal inhibitory concentration (IC50 ) of PCoA in control mitochondria was 22 µM. This inhibitory effect of PCoA on respiration was blunted in diabetic mitochondria, with no significant difference in the Km for ADP in the presence of PCoA, and an increase in the IC50 to 32 µM PCoA. The competitive inhibition by PCoA was localised to the phosphorylation apparatus, particularly the ADP/ATP carrier (AAC). During ischemia, the AAC imports ATP into the mitochondria, where it is hydrolysed by reversal of the ATP synthase, regenerating the membrane potential. Addition of PCoA dose-dependently prevented this wasteful ATP hydrolysis for membrane repolarisation during ischemia, however, this beneficial effect was blunted in diabetic mitochondria. Finally, using 31 P-magnetic resonance spectroscopy we demonstrated that diabetic hearts lose ATP more rapidly during ischemia, with a threefold higher ATP decay rate compared with control hearts. In conclusion, PCoA plays a role in protecting mitochondrial energetics during ischemia, by preventing wasteful ATP hydrolysis. However, this beneficial effect is blunted in diabetes, contributing to the impaired energy metabolism seen during myocardial ischemia in the diabetic heart.

A relevancy algorithm for curating earth science data around phenomenon.

Earth science data are being collected for various science needs and applications, processed using different algorithms at multiple resolutions and coverages, and then archived at different archiving centers for distribution and stewardship causing difficulty in data discovery. Curation, which typically occurs in museums, art galleries, and libraries, is traditionally defined as the process of collecting and organizing information around a common subject matter or a topic of interest. Curating data sets around topics or areas of interest addresses some of the data discovery needs in the field of Earth science, especially for unanticipated users of data. This paper describes a methodology to automate search and selection of data around specific phenomena. Different components of the methodology including the assumptions, the process, and the relevancy ranking algorithm are described. The paper makes two unique contributions to improving data search and discovery capabilities. First, the paper describes a novel methodology developed for automatically curating data around a topic using Earth science metadata records. Second, the methodology has been implemented as a stand-alone web service that is utilized to augment search and usability of data in a variety of tools.

Influence of Organic Amendment and Compaction on Nutrient Dynamics in a Saturated Saline-Sodic Soil from the Riparian Zone.

Cattle grazing in wet riparian pastures may influence nutrient dynamics due to nutrient deposition in feces and urine, soil compaction, and vegetation loss. We conducted a lab incubation study with a saline-sodic riparian soil to study nutrient (N, P, S, Fe, Mn, Cu, and Zn) dynamics in soil pore water using Plant Root Simulator (PRS) probes and release of nutrients into the overlying ponded water during flooding. The treatment factors were organic amendment (manure, roots, and unamended control), compaction (compacted, uncompacted), and burial time (3, 7, and 14 d). Amendment treatment had the greatest impact on nutrient dynamics, followed by burial time, whereas compaction had little impact. The findings generally supported our hypothesis that organic amendments should first increase nitrate loss, then increase Mn mobility, then Fe mobility and associated release of P, and finally increase sulfate loss. Declines in nitrate due to amendment addition were small because nitrate was at low levels in all treatments due to high denitrification potential instead of being released to soil pore water or overlying water. Addition of organic amendment strongly increased Mn and Fe concentrations in overlying water and of adsorbed Fe on PRS probes but only increased Mn on PRS probes on Day 3 due to subsequent displacement from ion exchange membranes. Transport of P to overlying water was increased by organic amendment addition but less so for manure than roots despite higher P on PRS probes. The findings showed that saline-sodic soils in riparian zones are generally a nutrient source for P and are a nutrient sink for N as measured using PRS probes after 3 to 7 d of flooding.

Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH).

The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by poor drug-like properties of lead compounds. Prodrugging temporarily masks undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin, exhibit significantly higher antimalarial potency than their parent compounds (1). However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH) is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum, where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a novel fluorogenic ester library, we characterize the structure activity relationship of APEH, and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a novel mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance (2-4). Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.

Transport of Residual Nitrogen and Carbon through Intact Soil Cores Amended with Stockpiled Feedlot Manure with Wood-Chip or Straw Bedding.

The environmental impact of using wood chips instead of straw bedding with feedlot manure on transport and leaching potential from feedlot manure is unknown. Our main objective was to determine if transport of total N, total organic N, NO-N, and nonpurgeable organic C (NPOC) to subsurface soil was lower for soils amended with feedlot manure if combined with wood chips compared with straw. A secondary objective was to compare transport of N and NPOC with organic amendments versus inorganic fertilizer. Stockpiled feedlot manure (SM) with wood chip (SM-WD) or barley straw (SM-ST) bedding at 39 Mg (dry wt.) ha, and inorganic fertilizer (IN) at 100 kg N ha, was applied annually for 13 yr to a clay loam soil in a replicated field experiment in southern Alberta, Canada. Intact soil cores were taken in fall 2011 (0-30 cm depth) from the three treatments, and the residual N and NPOC were eluted from the soil cores. Total N, total organic N, and NPOC were determined on filtered (1.0 µm) effluent samples that are primarily dissolved fraction but may contain some small particulate N and C. Peak concentrations, flow-weighted mean concentrations, and mass loss of total N, total organic N, NO-N, and NPOC were significantly ( ≤ 0.05) lower by 35 to 86% for SM-WD compared with SM-ST. Mean recoveries were also significantly lower for SM-WD than SM-ST by 0.07 to 8% (absolute difference). The transport behavior was similar for SM-WD and IN treatment, but solute transport was greater for SM-ST than for IN. Application of stockpiled feedlot manure with wood chips instead of straw bedding may be a beneficial management practice to reduce transport and leaching potential of N fractions and NPOC.

Pediatric reference intervals for endocrine markers in healthy children and adolescents on the Liaison XL (DiaSorin) immunoassay system.

OBJECTIVES: Prominent physiological changes occurring throughout childhood and adolescence necessitate the consideration of age and sex in biomarker interpretation. Critical gaps exist in pediatric reference intervals (RIs) for specialized endocrine markers, despite expected influence of growth and development. The current study aimed to establish and/or verify RIs for six specialized endocrine markers on a specialized immunoassay system. METHODS: Samples were collected from healthy children and adolescents (5 to <19 years) and apparently healthy outpatients (0 to <5 years) as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER). Serum samples were analysed for aldosterone, renin (plasma), thyroglobulin, anti-thyroglobulin, growth hormone, and insulin-like growth factor-1 (IGF-1) on the Liaison XL (DiaSorin) immunoassay platform. RIs (2.5th and 97.5th percentiles) were established for aldosterone, renin, thyroglobulin, anti-thyroglobulin, and growth hormone. Manufacturer-recommended pediatric RIs for IGF-1 were verified. RESULTS: Age-specific RIs were established for aldosterone, renin, and thyroglobulin, while no age-specific differences were observed for anti-thyroglobulin or growth hormone. IGF-1 was the only endocrine marker studied that demonstrated significant sex-specific differences. Manufacturer-recommended IGF-1 RIs were verified for children aged 6 to <19 years, while those for children aged 0 to <6 years did not verify. CONCLUSIONS: This study marks the first time that pediatric RIs for aldosterone and renin were established in the CALIPER cohort and highlights the dynamic changes that occur in water and sodium homeostasis during the first years of life. Overall, these data will assist pediatric clinical laboratories in test result interpretation and improve clinical decision-making for patients tested using Liaison immunoassays.

To skim or splice? Comparing the quantification of M-proteins using two peak-integration protocols across multiple electrophoresis platforms.

OBJECTIVES: M-protein quantification by peak integration in serum protein electrophoresis (SPE) plays a central role in diagnosing, prognosing and monitoring monoclonal gammopathies. The conventional perpendicular drop (PD) integration approach integrates M-spikes from the baseline, which performs acceptably when the M-protein concentration is relatively high compared to the amount of background proteins present. The alternative peak-integration protocol by tangential skim (TS), however, allows for more accurate M-protein estimations by excluding background proteins. Despite some guideline recommendations, TS has been poorly adopted, making an understanding of the differences between the two protocols and their potential impacts paramount when considering a change from PD to TS. DESIGN & METHODS: We conducted retrospective investigations of the differences in M-protein quantification over large concentration ranges between PD and TS on 3 of the most popular electrophoresis platforms. RESULTS: Compared to PD, TS gave consistently lower results; the differences between the two methods increased tremendously and became more sporadic as M-protein concentrations dropped below 15 g/L in all 3 platforms. At < 15 g/L, the average % difference ranged from -81 % to -95 %, while above 15 g/L, the average % difference was only -13 to -31 %. Medical decision point analyses using linear regression predicted statistically significant and platform-dependent differences, which could impact clinical interpretation. CONCLUSIONS: Careful consideration of the magnitude of concentration changes and the potential impacts on patient classification and management should be made when switching to TS for M-protein quantification.

Resistance of long-lived lymphocytes and plasma cells in rat lymph nodes to treatment with prednisone, cyclophosphamide, 6-mercaptopurine, and actinomycin D.

The cells of the popliteal lymph nodes of rats were labeled for 4 days after a secondary immunological stimulus. 31 days after the last dose of tritiated thymidine, groups of rats were started on courses of daily, intraperitoneal injections of prednisone, cyclophosphamide, 6-mercaptopurine, or actinomycin D. The initially low doses of these agents were doubled in successive weeks until either lymphoid hypoplasia or death occurred. Rats from each group were killed weekly, and the percentages of persisting, labeled small lymphocytes in the popliteal nodes were determined. Sections of these nodes were examined for persisting, labeled plasma cells. The per cent of lymphocytes labeled increased while the total number of lymphocytes decreased during treatment with prednisone and cyclophosphamide. Prednisone decreased the numbers of long-lived plasma cells, but these cells were preferentially resistant to cyclophosphamide. Neither 6-mercaptopurine nor actinomycin D had an appreciable effect on lymphoid tissues histologically nor on the proportions of labeled, long-lived lymphocytes and plasma cells before causing the deaths of the rats receiving them. These results indicate that long-lived lymphocytes and plasma cells survive treatment with the immunolytic drugs studied, and that long-lived lymphocytes are specifically resistant to prednisone and cyclophosphamide. We believe these results have an application to the attempts to find drugs useful in the treatment of immunologic rejections of organ transplants, and for therapy of autoimmune diseases.

Influence of streambank fencing on the environmental quality of cattle-excluded pastures.

Limited information exists on the effect of streambank fencing on riparian zone pastures. The objective of this study was to test the hypothesis that 4 to 6 yr of streambank fencing would improve the environmental quality of the cattle-excluded pasture compared with the grazed pasture and cause the fenced pasture to act as a buffer or filter strip. Rangeland health, vegetative and soil properties, and rainfall simulation runoff were measured in the cattle-excluded and adjacent grazed native pastures along the fenced reach of the Lower Little Bow River in southern Alberta, Canada, for 3 yr (2005-2007). Rangeland health was improved (health score increase from 55 to 72%); vegetation cover (13-21%) and standing litter (38-742%) were increased; and bare soil (72-93%) and soil bulk density (6-8%) were decreased under cattle exclusion, indicating an improvement in environmental quality from streambank fencing. In contrast, other vegetation (total and live basal area, fallen litter) and soil properties (soil water and soil C, N, and P) were not improved by cattle exclusion. Cattle exclusion significantly (P

Short-term legacy effects of feedlot manure application on soil mesofauna.

Little research exists on short-term legacy effects of feedlot manure application on soil mesofauna. This long-term (since 1998) study was on an irrigated clay loam soil in southern Alberta cropped to barley (Hordeum vulgare L.). We sampled the soil 3-4 yr (2017-2018) into the legacy period following 17 annual manure applications (1998-2014). The selected treatments sampled were stockpiled feedlot manure containing straw bedding applied at 0, 13, 39, and 77 Mg ha-1 (dry wt.). Intact soil cores were taken at three depth intervals (0-3, 3-6, and 6-9 cm) in the fall over 2 yr to determine the densities of Acari (mites) suborders and Collembola (springtails) families. Significant (P ≤ .05) application rate effects occurred on Oribatida and Astigmata after 3 yr (but not after 4 yr) into the legacy phase, whereas Prostigmata were unaffected. Densities of Astigmata after 3 yr were 3.2- to 4.1-fold greater at the 77 Mg ha-1 rate compared with three lower rates. Significant application rate effects occurred on Entomobryidae, Isotomidae, and Onychiuridae after 4 yr (but not after 3 yr), with no treatment effects on Neelidae. Densities of mesofauna were generally greater at higher than at lower rates, except for Entomobryidae in 2018, where the reverse trend occurred. Significant application rate effects were attributed to lower soil bulk density and greater volumetric soil water content and soil organic carbon. Therefore, legacy effects of feedlot manure application generally persisted on soil mesofauna 3-4 yr into the legacy phase but depended on mesofauna type, year, and depth.

Computed tomographic emphysema distribution: relationship to clinical features in a cohort of smokers.

Computed tomography (CT) scanning allows precise assessment of both the extent and distribution of emphysema. There has been little work on the relationship between the distribution of emphysema and clinical features of the disease. The current study investigated the association between clinical features and distribution of emphysema. A total of 129 patients with smoking-related chronic obstructive pulmonary disease underwent CT assessment of the extent and distribution of their emphysema (core/rind and upper/lower zone predominance). Emphysema was found predominantly in the upper/core zone and this distribution was related to the extent of disease. Core predominance was associated with lower forced expiratory volume in one second (FEV(1)), FEV(1)/forced vital capacity ratio and body mass index (BMI); and with higher BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) index and Medical Research Council dyspnoea score. Upper-zone predominance was associated with female sex and an increased total St George's Respiratory Questionnaire score. Using multiple linear regression age, sex and whole lung emphysema severity were independently associated with core/rind distribution, while sex and whole lung emphysema severity were independently related to upper/lower distribution. Distribution of emphysema related best to clinical features when divided into core/rind predominance. However, the effects were not independent of the extent of emphysema. Increased age and female sex were related to disease distribution independent of emphysema severity. These findings may be related to differences in development of emphysema.

Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with a 2-3-fold increase in the risk of ischaemic heart disease, stroke and sudden death. The mechanisms responsible for this association are not clear and appear to be independent of smoking history. OBJECTIVE: We test the hypothesis that patients with COPD have increased arterial stiffness and blood pressure in comparison with age and smoking matched controls. METHODS: In a prospective case control study, we recruited 102 patients with COPD and 103 healthy controls matched for age and smoking status. Patients were assessed by clinical history and spirometry, with arterial stiffness and blood pressure determined using radial artery applanation tonometry and sphygmomanometry. RESULTS: Patients with COPD had increased arterial stiffness compared with matched controls, with elevated augmentation pressure (17 (1) vs 14 (1) mm Hg; p = 0.005) and a reduced time to wave reflection (131 (1) vs 137 (2) ms; p = 0.004). These differences were associated with increases in both diastolic (82 (1) vs 78 (1) mm Hg; p = 0.005) and systolic blood pressure (147 (2) vs 132 (2) mm Hg; p<0.001). Serum C reactive protein concentrations were threefold higher in patients (6.1 (0.9) vs 2.3 (0.4) mg/l; p = 0.001). Data are presented as mean (SEM). CONCLUSIONS: Patients with COPD have increased arterial stiffness and blood pressure in comparison with controls matched for age and smoking status. We speculate that increased systemic inflammation and vascular dysfunction could potentially explain the excess cardiovascular morbidity and mortality associated with COPD.

Diagnosis and treatment of overactive bladder.

Overactive bladder is a very common condition, affecting an estimated 50 to 100 million people worldwide. More than 90% of women with overactive bladder have no recognizable pathology. Several risk factors have been recognized for overactive bladder syndrome and incontinence including age, diabetes, Caucasian race, and hormone replacement therapy. The gold standard for diagnosing detrusor overactivity is multichannel urethrocystometry, although single channel cystometry or even simple cystometry may be used. A variety of interventions are available for the treatment of the overactive bladder syndrome. These include behavioral interventions, pelvic floor electrical stimulation, electromagnetic innervation, neuromodulation, intravesical instillations and injections, operative bladder augmentation, and pharmacotherapy. In any therapy for overactive bladder symptoms, expectations play a pivotal role in success or failure, and communication between the healthcare provider and the patient is essential for setting and achieving treatment goals.

Comparison of plasma glucose, serum insulin, and C-peptide responses to three isocaloric breakfasts in non-insulin-dependent diabetic subjects.

While differences in glucose and insulin responses to specific carbohydrate foods have been reported, few data are available for mixed meals incorporating such foods. This study compared the plasma glucose (PG), serum insulin (SI), and C-peptide (CP) responses to three different isocaloric test breakfasts given in random order to eight insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) patients. The test meals were selected from a hospital food exchange list and contained similar quantities of carbohydrate, protein, fat, and dietary fiber. The postprandial PG, SI, and CP responses to two of the test breakfasts (meal A: eggs, toasted wholemeal bread, orange juice, margarine, and milk; meal B: wheatflake biscuits, toasted wholemeal bread, milk, and margarine) were similar (meal A: 104.3 +/- 23.0 mg X h X dl-1, 5996 +/- 1108 microU X min X ml-1, and 89.8 +/- 25.4 pmol X min X ml-1, respectively; meal B: 104.9 +/- 21.6 mg X h X dl-1, 6268 +/- 1161 microU X min X ml-1, and 99.8 +/- 26.4 pmol X min X ml-1, respectively). Meal C, consisting of toasted muesli and skim milk, produced smaller glycemic and insulin responses (46.8 +/- 8.8 mg X h X dl-1; P less than .02, and 4369 +/- 700 microU X min X ml-1; P less than .05, respectively) than meals A and B and less endogenous insulin secretion (CP response 62.8 +/- 19.9 pmol X min X ml-1; P less than .05 compared with meal A, NS compared with meal B).(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic effects of adding sucrose and aspartame to the diet of subjects with noninsulin-dependent diabetes mellitus.

This study compared the effects of adding sucrose and aspartame to the usual diet of individuals with well-controlled noninsulin-dependent diabetes mellitus (NIDDM). A double-blind, cross-over design was used with each 6-wk study period. During the sucrose period, 45 g sucrose (9% of total daily energy) was added, 10 g with each main meal and 5 g with each between-meal beverage. An equivalent sweetening quantity of aspartame (162 mg) was ingested during the aspartame period. The addition of sucrose did not have a deleterious effect on glycemic control, lipids, glucose tolerance, or insulin action. No differences were observed between sucrose and aspartame. Sucrose added as an integral part of the diabetic diet does not adversely affect metabolic control in well-controlled NIDDM subjects. Aspartame is an acceptable sugar substitute for diabetic individuals but no specific advantage over sucrose was demonstrated.

Blockade of tetanic- and calcium-induced long-term potentiation in the hippocampal slice preparation by neuroleptics.

The effect of neuroleptics which block calmodulin was studied on two forms of long-term potentiation of field responses evoked by stratum radiatum stimulation of the CA1 region in the in vitro preparation of hippocampal slices. Tetanic stimulation or brief exposure to 4 mM Ca2+ produced a long-lasting augmentation of the extracellular excitatory postsynaptic potentials EPSP) and of the responses of the population spikes. Both forms of potentiation were inhibited by perfusion of 10 microM trifluoperazine (TFP) or pimozide, an effect which is unlikely to involve interactions with dopamine or norepinephrine receptors, but rather a potent blockade of calmodulin-mediated events. The results suggest that induction of the "permanency" of both tetanic- and calcium-induced long term potentiation requires activation of calmodulin and involves some calmodulin-mediated mechanism(s).

Calcium-induced long-term potentiation in the hippocampus.

The effect of a transient increase in extracellular calcium concentration on the Schaffer collateral-commissural evoked excitatory postsynaptic potential and population spike responses of CAI pyramidal neurons was investigated using the rat in vitro hippocampal slice preparation. Brief exposure of slices (5-10 min) to twice the normal concentration of calcium (4 mM) induced a marked potentiation of both the excitatory postsynaptic potential and population spike that could persist for at least 3 h. No long-term changes were observed in either the presynaptic fiber volley of antidromically evoked CAI population spike, indicating that the potentiation could not be attributed to an increase in the number of fibers activated or a generalized increase in cellular excitability. The response of CAI pyramidal neurons to the iontophoretic application of L-glutamate in the apical dendritic zone was also unaffected after exposure to high calcium perfusate, suggesting a lack of alteration in membrane excitability or receptor sensitivity restricted to the region of synaptic input. In addition, total intracellular calcium content of individual slices, measured by atomic absorption spectrophotometry, was significantly increased for at least 1 h following return to the control medium. These data indicate that brief exposure of in vitro hippocampal slices to a high extracellular calcium concentration results in a long-term increase in synaptic efficacy which is similar in many respects to long-term potentiation induced by tetanic stimulation of hippocampal excitatory afferents. The results further suggest that the mechanisms underlying calcium-induced long-term potentiation may reside in presynaptic components and involve an enhanced transmitter release.

Prolonged use of large intravenous steroid pulses in the rheumatic diseases of children.

Nineteen children with rheumatic diseases refractory to standard treatment were given repeated large "pulses" of corticosteroid therapy. The pulses consisted of four repeated doses of 500 mg of hydrocortisone given intravenously over 20 to 30 minutes at six-hour intervals or of single intravenous injections of 30 mg/kg of methylprednisolone. All patients had temporary relief of signs or symptoms of inflammation. Complications were mild and only one child was removed from therapy because of a complication. Two children were judged to be treatment failures. Five patients have been weaned from all steroid treatment, and eight have required continued pulses at one- or two-week intervals as outpatients to maintain control. All of these have been able to reduce oral prednisone doses. Effects of the two forms of pulse appear similar. However, two children responded to the series of injections of hydrocortisone but not to single doses of methylprednisolone. Pulses have been given for periods up to three years without evident toxicity. Further work to define doses, schedules, and optimal drug is needed since this approach to steroid use appears effective and relatively nontoxic.

Behcet's disease presenting as chronic aphthous stomatitis in a child.

Behcet's disease is a chronic, recurrent, inflammatory disease of unknown cause that involves mucous surfaces, skin, eyes, joints, and the CNS. Although not reported in the pediatric literature, some cases start in childhood. This report describes a child whose chronic oral and genital ulcers preceded recognition of her gastrointestinal tract, eye, and CNS disease for nine years. The current knowledge of Behcet's disease in children is discussed.

Nephropathy in the Wiskott-Aldrich syndrome.

Nephropathy was detected in five of 32 patients with the Wiskott-Aldrich syndrome who were participating in a study of transfer factor (TF) therapy. In two patients, nephropathy was present before TF and did not appear changed by TF therapy. One of these patients subsequently developed progressive renal failure requiring dialysis beginning 5 1/2 years after TF therapy. In two patients, decreased renal function appeared very soon after the administration of TF. One patient showed gradually decreasing renal function beginning after two years of TF therapy. An additional patient was identified who died with renal failure without having received TF. The results suggest that renal failure occurs in the Wiskott-Aldrich syndrome more frequently than generally recognized and that administration of TF may precipitate or accelerate the renal disease in patients with this syndrome.