An aldose reductase inhibitor and aminoguanidine prevent vascular endothelial growth factor expression in rats with long-term galactosemia

OBJECTIVE: To study the effects of an aldose reductase inhibitor (ARI-509, Wyeth-Ayerst, Princeton, NJ) and aminoguanidine (AMG), agents that have been reported to prevent or delay diabetic retinopathy, on retinal vascular abnormalities and the immunocytochemical expression in the retina of vascular endothelial growth factor (VEGF) in rats maintained for up to 2 years on a 50% galactose diet. METHODS: Albino rats were placed on a control diet, a diet containing 50% galactose, or the 50% galactose diet containing either ARI-509 or AMG. Treatment with ARI-509 or AMG was initiated at the beginning of the experiment or after 12 months of galactose feeding. After 22 to 24 months, the rats were killed and the retinal vasculature from half of one eye was isolated by trypsin-elastase digestion for semiquantitative evaluation of retinal vascular lesions. The other half of the retina was prepared for immunocytochemistry and stained for the presence of VEGF, factor VIII, vimentin, and glial fibrillary acidic protein. Red blood cells, sciatic nerves, and a portion of the retina from the second eye were assayed for glucose, galactose, fructose, sorbitol, galactitol, and myo-inositol. Red blood cells were also assayed for galactosylated hemoglobin. RESULTS: Galactose-fed animals developed a vascular retinopathy characterized by severe cellular loss in the retinal capillaries and intensification of periodic acid-Schiff staining of the vascular basement membranes. Some animals also displayed dilation and hypercellularity of vessels in the posterior retina. These changes were substantially reduced in animals receiving ARI-509 from the beginning of the galactose diet, but were unaffected in all of the other treatment groups. None of the rats receiving ARI-509 or AMG treatment, whether initiated from the onset or after 12 months of galactosemia, demonstrated VEGF immunoreactivity. With the exception of the animals receiving ARI-509 from the beginning of the experiment, all of the galactose-fed animals developed dense cataracts within 6 weeks of the beginning of the galactose diet. Galactitol levels in animals receiving ARI-509 were 86% to 93% lower in red blood cells, retina, and sciatic nerve than those in the other galactose-fed groups. CONCLUSIONS: Although ARI-509 and AMG have different abilities to delay or prevent the diabetic-like retinopathy in galactosemic rats, even when substantial retinal microvascular acellularity occurs, both drugs prevent the immunocytochemical expression of VEGF. These results suggest that factors other than hypoxia may be responsible for VEGF expression in the retina, and that aldose reductase inhibitors and AMG have potential roles in preventing such expression and, thus, perhaps preventing retinal neovascularization.     

Stability of motor-unit force thresholds in the decerebrate cat

To further test the hypothesis that some fixed property of motoneurons determines their recruitment order, we quantified the variation in force threshold (FT) for motoneurons recruited in muscle stretch reflexes in the decerebrate cat. Motor axons supplying the medial gastrocnemius (MG) muscle were penetrated with micropipettes and physiological properties of the motoneuron and its muscle fibers, i.e., the motor unit, were measured. FT, defined as the amount of MG force produced when the isolated motor unit was recruited, was measured from 20 to 93 consecutive stretch trials for 29 motor units. Trials were selected for limited variation in base force and rate of rise of force, which have been shown to covary with FT, and in peak stretch force, which gives some index of motor-pool excitability. Under these restricted conditions, large variation in FT would have been inconsistent with the hypothesis. Analysis of the variation in FT employed the coefficient of variation (CV), because of the tendency for FT variance and mean to increase together. We found that CV was distributed with a median value of 10% and with only 2 of 29 units exceeding 36%. Some of this variation was associated with measurement error and with intertrial fluctuations in base, peak, and the rate of change of muscle force. CV was not significantly correlated with motor-unit axonal conduction velocity, contraction time, or force. In three cases FT was measured simultaneously from two motor units in the same stretch trials. Changes in recruitment order were rarely observed (5 of 121 stretch trials), even when FT ranges for units in a pair overlapped. We suggest that the large variation in recruitment threshold observed in some earlier studies resulted not from wide variation in the recruitment ranking of motoneurons within one muscle, but rather from variation in the relative activity of different pools of motoneurons. Our findings are consistent with the hypothesis that recruitment order is determined by some fixed property of alpha-motoneurons and/or by some unvarying combination of presynaptic inputs that fluctuate in parallel.     

A linkage map of human chromosome 21:43 PCR markers at average intervals of 2.5 cM

A genetic linkage map of human chromosome 21q (HC21q) containing 43 markers genotyped by the polymerase chain reaction in the CEPH pedigrees is presented. The markers placed on this map are highly polymorphic with an average heterozygosity of 61%. The average interval size of the markers localized at 1000:1 odds is 2.5 cM. The map has a total length of 65.5 cM, with male and female lengths of 47.7 and 83.3 cM, respectively. The genotypes used in the construction of this map were subjected to rigorous error checking, which is reflected in the shorter map length compared to previous maps; the estimated error rate in genotyping is less than 0.04%. As noted in previous linkage maps there is increased recombination in females on proximal HC 21q and in the male in a region near the telomere. This map of HC 21 represents a highly informative and dense meiotic linkage map and will be useful in linking disease phenotypes to loci on this chromosome.     

Colosplenic fistula in a patient treated with interleukin-2 for malignant melanoma

Interleukin-2 (IL-2) therapy often causes gastrointestinal side effects and at least 8 cases of bowel perforation have been reported. The patient reported here developed a colosplenic fistula, diagnosed by CT, with no neoplastic involvement of these organs. Awareness of these complications of IL-2 can help lead to earlier diagnosis.     

Childhood thyroid cancer. Characteristics and long-term outcome in children irradiated for benign conditions of the head and neck

OBJECTIVE: To determine the characteristics and long-term outcome of radiation-induced thyroid cancer in children. DESIGN: Retrospective review of a cohort of 4296 irradiated patients who received childhood radiation treatment to the head and neck area at the same hospital. PATIENTS: Forty-one children who were younger than 20 years when thyroid cancer developed in them and 77 adults in whom thyroid cancer developed. All 118 cases were diagnosed before 1974 and were followed up for a median of 19.4 years. RESULTS: Children presented with clinically palpable lymph nodes more often than adults (30.7% vs 15.1%, P = .05) and had more recurrences (39% vs 16%, P = .05). Despite these frequent recurrences, only one patient (an adult) died of thyroid cancer. Seventy percent of the recurrences occurred during the first 10 years of follow-up, but recurrences continued after 20 years. The adults had previously identified factors that predicted the risk of recurrences, but none could be identified in the children. CONCLUSION: The presentation and relatively good outcome of radiation-induced thyroid cancer in children is similar to that in nonirradiated children. Frequent and late recurrences call for lifelong follow-up.     

Early axon outgrowth of retinal ganglion cells in the fetal rhesus macaque

Employing retinal explants and retrograde transport techniques, we studied the formation of the arcuate fascicles by examining the growth of the central retina, the emergence of the adult fiber layer pattern, and the projections of retinal ganglion cells in the central and peripheral retina. Sixty days prior to foveal pit formation, the distance from the incipient fovea to the optic disk was equal to the adult, even though the retinal area was only 8% of the adult. Arcuate fibers, at this age, were observed to avoid the incipient fovea, with no fascicles and few axons projecting over this region. A small population of 15.2% of the ganglion cells located within 2 mm of the incipient fovea possessed an axon with an aberrant trajectory that wound around and projected 50 to several hundred microns away from the optic disk, compared to only 3% at other retinal locations. The incidence of disorder decreased with increasing fetal age, establishing mature values in late fetal periods. These findings suggest that the area of the central retina does not increase after embryonic day 60 and that guidance factors are present that allow outgrowing ganglion cell axons to distinguish and avoid that portion of the retina that will become the fovea.