Comparison of erythrocyte uridine sugar nucleotide levels in normals, classic galactosemics, and patients with other metabolic disorders

By limiting galactosylation mechanisms, a cellular deficiency of the uridine sugar nucleotide, UDPgalactose, has been implicated as a cause of the long-term complications seen in patients with classic galactosemia despite dietary treatment. As a result, great interest has been generated in the accurate assessment of UDPgalactose, as well as UDPglucose, from which UDPgalactose may be derived by the function of a ubiquitous, active UDPgalactose-4-epimerase. Since several series of values for the concentration of these compounds in red blood cells (RBCs) of galactosemics have been flawed by the use of methods subsequently shown to be unsuitable, we have quantified erythrocyte UDPgalactose and UDPglucose levels by an accurate high-performance liquid chromatography (HPLC) assay in 116 normals, 76 galactosemics, and 39 patients with other metabolic disorders. These large groups have permitted the evaluation of age, diet, and genotype as influential factors in the steady-state RBC levels of the sugar nucleotides. The data show that age is an important determinant of RBC levels, with children younger than 10 years having higher values than individuals older than 10 years. Mean UDPgalactose levels in galactosemic children younger than 10 years and those older than 10 years were 30% and 18% lower, respectively, than levels in comparable normals. Although the mean differences were highly significant, there was considerable overlap of individual values. There was no difference in UDPglucose levels between galactosemics and normals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the retinal nerve fiber layer

In normal eyes, the retinal nerve fiber layer (RNFL) is usually best visible in the inferior temporal part of the fundus, followed by the superior temporal region, the nasal superior region and the nasal inferior region. This distribution correlates with the configuration of the neuroretinal rim, the diameter of the retinal arterioles, the location of the foveola, and the lamina cribrosa morphology. With increasing age, the RNFL visibility decreases diffusely without preferring special fundus regions and without the development of localized defects. With all optic nerve diseases, the visibility of the RNFL is decreased in addition to the age-related loss, in a diffuse and/or a localized manner. The localized defects are wedge-shaped and not spindle-like defects, running toward or touching the optic disk border. Typically occurring in about 20% of all glaucoma eyes, they can be found also in other ocular diseases, such as optic disk drusen, toxoplasmotic retinochoroidal scars, longstanding papilledema or optic neuritis due to multiple sclerosis. Since they are not present in normal eyes, they almost always signify an abnormality. RNFL evaluation is especially helpful for early glaucoma diagnosis and in glaucoma eyes with small optic disks. In advanced optic nerve atrophy, other examination techniques, such as perimetry, may be more helpful for following optic nerve damage. Considering its great importance in the assessment of optic nerve anomalies and diseases and taking into account the feasibility of its ophthalmoscopic evaluation using green light, the retinal nerve fiber layer should be examined during any routine ophthalmoscopy.     

Antitumor activity of tricyclic pyrone analogs, a new synthetic class of microtubule de-stabilizing agents, in the murine EMT-6 mammary tumor cell line in vitro

Methods of both linkage analysis and association analysis may be model-based or model-free. The former are useful for initial exploratory analysis, the latter for more detailed multivariate genometric analysis. Linkage leads to an association, but that association may be solely intrafamilial. Allelic association may be due to pleiotropy, linkage disequilibrium, meiotic drive, selection, or population stratification. Using non-transmitted parental alleles as controls for alleles transmitted to cases, in conjunction with a McNemar-type test, does not detect association in the absence of linkage. Model-based analyses should use models that approximate the complexity of the disease being studied in order to be both robust and powerful.     

Biomarkers in Barrett''s esophagus (review)

Lens major intrinsic protein (MIP) is the founding member of the MIP family of membrane channel proteins. Its isolation from ovine lens fibre cell membranes and its two-dimensional crystallization are described. Membranes were solubilized with N-octyl-beta-D-glucoside and proteins fractionated by sucrose gradient centrifugation containing decyl-beta-D-maltoside. MIP was purified by cation exchange chromatography, and homogeneity was assessed by mass analysis in the scanning transmission electron microscope. Purified MIP reconstituted into a lipid bilayer at a low lipid-to-protein ratio formed highly ordered tetragonal two-dimensional crystals. The square unit cell had a side length of 6.4 nm, and exhibited in negative stain four stain-excluding elongated domains surrounding a central stain-filled depression. Projection maps of freeze-dried crystals exhibited a resolution of 9 A, and revealed a monomer structure of MIP consisting of distinct densities. Despite significant differences in the packing of tetramers in the crystals, the projection map of the MIP monomer was similar to that of aquaporin-1 (AQP1), the first member of the MIP family which had its structure resolved to 6 A. Our protocols for the purification and reconstitution of MIP establish the feasibility for future work to visualize structure elements which determine the diverse functional properties of the MIP family members.     

Motor neuron syndromes in cancer patients

Previous reports indicate that motor neuron disease (MND) may rarely be associated with systemic cancer. We have encountered 14 patients with MND and cancer who formed three distinct groups. Group 1: Three patients developed a rapidly progressive MND, less prominent symptoms of involvement of other areas of the nervous system, and anti-Hu antibodies. Group 2: Five women developed signs of upper motor neuron (UMN) disease, initially resembling primary lateral sclerosis (PLS), and breast cancer. In 4, symptoms of UMN occurred within 3 months of cancer diagnosis or tumor recurrence. They had no metastases or spinal cord compression. Serum anti-neuronal antibodies were negative. Three patients are alive (follow-up of 156, 15, and 12 months), and 2 remain without lower motor neuron signs. Group 3: Six patients developed MND resembling amyotrophic lateral sclerosis between 47 months before and 48 months after their cancer diagnosis. In group 1, the MND associated with the anti-Hu antibody is unequivocally paraneoplastic. In group 2, the proximate onset of MND with the diagnosis of cancer or its recurrence, its pure or long-lasting UMN signs, and its association with breast cancer, suggest that the disorder may be paraneoplastic. Although for most cancer patients who develop MND the occurrence of both disorders is probably coincidental, in some patients with MND a careful search for an underlying cancer is warranted (ie, patients in groups 1 and 2).