In-vivo NMR spectroscopy in patients with phenylketonuria: changes of cerebral phenylalanine levels under dietary treatment.

Localized proton magnetic resonance spectroscopy at short echo times was used to measure phenylalanine (Phe) in parieto-occipital periventricular brain. Six treated adult patients with phenylketonuria were investigated repeatedly following reinstitution of a Phe-restricted diet. Difference spectroscopy clearly enabled the identification of elevated cerebral Phe levels by subtracting spectra obtained from healthy volunteers.

Luminal transport system for H+/organic cations in the rat proximal tubule. Kinetics, dependence on pH; specificity as compared with the contraluminal organic cation-transport system.

The efflux of radiolabelled organic cations from the tubular lumen into proximal tubular cells was investigated by using the stop-flow microperfusion method. The efflux rate increased in the sequence: N1-methylnicotinamide (NMeN+) < cimetidine < tetraethylammonium (TEA+) < N-methyl-4-phenylpyridinium (MPP+). Preloading the animals by i.

Transport interactions of different organic cations during their excretion by the intact rat kidney.

Organic cations, in addition to being filtrated, are secreted or reabsorbed in the proximal renal tubule whereby they have to pass the contraluminal and the luminal cell membrane. Interactions with the transport of other organic cations can occur at either cell side, leading to inhibition or stimulation of net secretion or net reabsorption. A qualitative evaluation of such processes is possible by using the in vivo bolus injection of an organic cation as test substance.

Ultrastructural, immunocytochemical and stereological investigation of hepatocytes in a patient with the mutation of the ornithine transcarbamylase gene.

We studied a male newborn suffering from deficiency of ornithine transcarbamylase (OTC) that is due to a G-to-A substitution in codon 269 of the OTC gene. This study intends to define the cell biological mechanisms in this naturally occurring OTC mutation which may explain the mild clinical course in spite of the very low residual enzyme activity. Using immunogold labeling of thawed thin frozen sections of liver from this patient and a control liver, we analyzed the quantitative distribution of several mitochondrial proteins in the cytosol and the mitochondria of hepatocytes.

Neurological findings in early treated phenylketonuria.

Twenty early treated, normal intelligent patients (IQ: mean 101.4, SD 10.0; age: mean 10.

Smith-Lemli-Opitz syndrome diagnosed by using time-of-flight secondary-ion mass spectrometry.

We describe a rapid and sensitive method involving time-of-flight secondary-ion mass spectrometry (TOF-SIMS) for specific laboratory diagnosis of the Smith-Lemli-Opitz syndrome, which is characterized by massive (approximately 1000-fold) accumulation of the biosynthetic cholesterol precursor 7-dehydrocholesterol. Minute amounts of blood (1-50 microL) were extracted with n-hexane, and aliquots were analyzed by TOF-SIMS. 7-Dehydrocholesterol and its isomers were detected at 491.

Carbohydrate-deficient glycoprotein syndrome (CDGS)--glycosylation, folding and intracellular transport of newly synthesized glycoproteins.

Carbohydrate-deficient glycoprotein syndrome (CDGS) is a hereditary glycosylation disorder of unknown origin. In this study we used skin fibroblasts from patients with CDGS to study the glycosylation of three well characterized glycoproteins using gel mobility analysis, endoglycosidase treatments and protein folding studies. We show that glycoprotein transport along the secretory pathway was delayed.

In vivo study of brain metabolism in galactosemia by 1H and 31P magnetic resonance spectroscopy.

In order to further evaluate different hypotheses concerning brain metabolism in galactosemia, six adult patients aged 18-29 years with classical galactosemia under dietary treatment underwent localized 1H and 31P magnetic resonance spectroscopy (MRS) in addition to conventional T1- and T2-weighted MRI. Galactose-1-phosphate levels in erythrocytes were 1.1-3.

White matter abnormalities in phenylketonuria: results of magnetic resonance measurements.

In adolescents and adults with PKU, blood phenylalanine levels above 10 mg/dl are generally associated with white matter changes in MRI. The grade of these changes is correlated to most recent blood phenylalanine levels. Based on studies using T2 relaxometry the MRI changes seem to be the consequence of a reversible dysmyelination.

Assessment of tubular reabsorption of sodium, glucose, phosphate and amino acids based on spot urine samples.

Reference values for tubular transport of sodium, phosphate, glucose and amino acids are generally based on inulin or creatinine short-term clearances, which are difficult to obtain in children. Hence, quantitative assessment of tubular transport capacities is rarely performed. For a simplified procedure, reference values for fractional sodium excretion, phosphate reabsorption related to glomerular filtration rate, percent glucose and percent amino acid reabsorption were established in 62 children from spot urine and simultaneously obtained blood samples.

Cranial MRI in PKU: evaluation of a critical threshold for blood phenylalanine.

A group of 15 adolescent patients with PKU and good life time blood phenylalanine control was tested for white matter abnormalities on MRI. Five of the patients presented mild to moderate abnormalities in association with blood phenylalanine levels above 5.0 mg/dl.

Polysubstrates: substances that interact with renal contraluminal PAH, sulfate, and NMeN transport: sulfamoyl-, sulfonylurea-, thiazide- and benzeneamino-carboxylate (nicotinate) compounds.

Some N-containing xenobiotics were recently shown to behave as bisubstrates; that is, they interact with and are transported by both the contraluminal transport system for organic anions (PAH) and the contraluminal transport system for organic cations (NMeN). Thus we determined whether other classes of N-containing substrates, such as sulfamoyl-, sulfonylurea-, thiazide- and benzeneamino-carboxylate (nicotinate) compounds, amongst them diuretics and other drugs, also interact with both transporters. To test this, we applied the stop-flow peritubular capillary perfusion method with initial flux measurements and determined app.

Simple device for continuous measurement of fluorescent anions and cations in the rat kidney in situ.

A simple device for fluorescence measurements on kidney surface in situ (FKS) is described. The device consists of (1) an illuminating unit, (2) a detector, (3) an evaluation unit. The device was developed for measurement of tissue content of anionic sulfofluorescein and cationic 4(4-dimethylaminostyryl)-N-methylpyridinium (ASP) during its secretion by proximal renal tubular cells.

The use of dichloroacetate in the treatment of overwhelming hypoxic acidosis.

Overwhelming hypoxic acidosis due to poor tissue oxygen delivery from low cardiac output, pulmonary failure, and other causes has devastating effects postoperatively on patient outcome. Whereas conventional therapeutics often can not reverse the downward spiral of these patients, dichloroacetate (DCA) has been shown to be beneficial. This study investigated the metabolic and hemodynamic effects of DCA given after the onset of overwhelming hypoxic acidosis in a canine model.

Ifosfamide-induced subclinical nephrotoxicity and its potentiation by cisplatinum.

Renal function was assessed in 72 children and adolescents 3.5 to 123 months after completion of chemotherapy employing ifosfamide (n = 39) or ifosfamide plus cisplatinum (n = 33). No patient had preexisting renal parenchymal disease.

Screening for lysosomal disorders.

Patients at any age who develop regression of learned skills, onset of dementia, loss of motor control and organ enlargement should be considered for lysosomal screening. Morphological and biochemical screening methods may reinforce the clinical suspicion, but they are not diagnostic. A widespread use of enzyme assays that appear to be related to the clinical problems is recommended.

A splice junction mutation causes deletion of a 72-base exon from the mRNA for lysosomal acid lipase in a patient with cholesteryl ester storage disease.

The genetic defect leading to cholesteryl ester storage disease (CESD) has been determined in a 12-yr-old patient. Lysosomal acid lipase (LAL) activity in cultured skin fibroblasts was reduced to approximately 9% of control fibroblasts. Plasma cholesterol (255 mg/dl) and LDL-cholesterol (215 mg/dl) were elevated whereas HDL-cholesterol was reduced (19 mg/dl).

White matter abnormalities in patients with treated hyperphenylalaninaemia: magnetic resonance relaxometry and proton spectroscopy findings.

In order to further clarify the pathogenesis and clinical significance of MRI white matter abnormalities in treated hyperphenylalaninaemia (HPA), ten patients (seven type I HPA, two type II and one type III) underwent T2 relaxometry (n = 8) and/or 1H spectroscopy (n = 7) in addition to conventional MR spin-echo imaging at 1.5 T. Two patients with severe MRI abnormalities had repeat examinations during and after a 6- to 8-month period of strict diet control.