Repeated injections of a ciliary neurotrophic factor analogue leading to long-term photoreceptor survival in hereditary retinal degeneration

PURPOSE: To determine whether ciliary neurotrophic factor (CNTF) or brain-derived neurotrophic factor (BDNF) treatment leads to long-term photoreceptor survival in hereditary retinal degeneration. METHODS: An autosomal dominant feline model of rod-cone dystrophy was used throughout the study with two normal animals. In the first experiment, intravitreal injections of a human CNTF analogue (Axokine; Regeneron Pharmaceuticals, Tarrytown, NY) were administered to one eye of each animal (n = 10) beginning on postnatal day 10 and were repeated every 4 weeks. Clinical and histopathologic examinations were performed at 5.5, 9.5, and 13.5 weeks. In the second experiment, animals (n = 17) were randomly assigned to receive intravitreal injections of either Axokine (at half the initial dose), human BDNF, or the vehicle for Axokine to one eye at 5.5 weeks. The same therapy was repeated every 4 weeks in each group. Clinical and histopathologic examinations were performed at 9.5, 13.5, and 17.5 weeks. Photoreceptor survival was assessed by cell counting. Apoptotic cells were identified by morphology and a modified TdT-dUTP terminal nick-end labeling (TUNEL) technique. In the third experiment, two normal animals were treated with Axokine as in the first experiment. Glial fibrillary acidic protein ((GFAP) immunohistochemistry was performed to assess glial cell reaction. RESULTS: In the first two experiments, Axokine significantly prolonged photoreceptor survival (P < 0.01) and reduced the presence of apoptotic cells (P < 0.05) and TUNEL-positive cells (P < 0.05). In the second experiment, results in the the BDNF- and sham-injected eyes were not significantly different from those in the untreated eyes. Minimal posterior subcapsular cataract and mild retinal folds were found in all Axokine-treated eyes in both dystrophic and normal animals. These complications were milder in the second experiment when injections were started later and at a reduced dose. GFAP immunolabeling was also increased in all Axokine-treated eyes. CONCLUSIONS: Axokine, but not BDNF, delays photoreceptor loss in this hereditary retinal degeneration. Repeated injections maintain the protective effect.     

Children of alcoholic parents in the community

The relationship between parental alcoholism and risk for maladjustment in the offspring was investigated in a community sample. Children of parents who met criteria for DIS/DSM-III alcohol abuse or dependence and children of parents who met criteria for ten other diagnoses were compared to children of "normal" parents. The data were obtained from the merging of the data banks of two major psychiatric epidemiology studies of the adult (17-64) and child (4-16) population of Puerto Rico. Results indicated that parental alcoholism in addition to creating an adverse family environment had an effect on the relative risk for maladjustment in the offspring (as measured by scores on the Child Behavior Checklist). Although previous studies have reported higher levels of externalizing behaviors in children of alcoholics, an increased risk for internalizing symptoms was observed in the children studied. Similar findings were obtained for the children of parents with other psychiatric disorders suggesting that the effects of parental alcoholism in children ages 4 to 16 may not be different from the consequences of parental mental illness per se.     

Analysis of cancers missed at screening mammography.

Analysis of 320 cancers found in a screened population between August 1985 and May 1990 revealed 77 cancers that were "missed" at screening mammography. The missed lesions consisted of cancers incorrectly diagnosed after mammography (false-negative results) but visible in retrospect (n = 19); cancers correctly diagnosed after mammography but visible in retrospect on an earlier mammogram (n = 47); and cancers that went undetected by the first of two readers (n = 11). Missed lesions were categorized according to type of miss, reason for the miss, breast density, lesion features, and lesion location. The missed lesion were compared with 121 cancers that were correctly diagnosed at screening mammography. The missed cancers occurred in women with denser breasts (P = .046), were less likely to demonstrate malignant microcalcifications, and were more likely to demonstrate a developing opacity as an indication of cancer (P = .005). An understanding of the characteristics of missed lesions may be a valuable aid in increasing the sensitivity of screening mammography.     

The Biosynthesis of Melanin-Concentrating Hormone in Trout Kept Under Different Conditions of Background Colour and Stress, as Determined by an in vitro Method

The aim of this study was to develop a method to monitor the synthetic activity of neurons which secrete the neurohypophysial melanin-concentrating hormone (MCH), a hormone implicated in two separate physiological roles in fish-pigmentary regulation and the response to stress. Trout hypothalamic fragments, containing the MCH neuronal cell bodies, were incubated in vitro in a medium including [(35) S]methionine. Labelled MCH-related products were separated by immunoprecipitation. Gel electrophoresis showed that radioactive methionine was incorporated into MCH precursors and into mature MCH, much as in vivo. Thus, de novo hormone synthesis continues in vitro. Trout reared at a fish-farm and adapted to black or white tanks for 39 days displayed nearly a 2-fold difference in their rate of methionine incorporation. Transferring fish from a black to a white background also doubled the rate of incorporation within 7 days and this rate increased only very slightly during the following 3 weeks. The rate of methionine incorporation by tissue from trout reared in black tanks was very depressed, and 4-fold lower than that of fish reared in white tanks, suggesting that very long-term adaptation to one or other background has increasingly marked effects on the activity and perhaps the number of synthetically active neurons. Stress also influenced the rate of methionine incorporation: a mild daily stress was stimulatory but more frequent stress had an inhibitory effect in many cases. The effects of daily dexamethasone administration were inconclusive. It is suggested that these differences in methionine incorporation reflect the relative rates of MCH synthesis in vivo, and that the method is useful to investigate conditions which modulate the biosynthesis of MCH in the trout.     

Effects of aminoglutethimide on delta 5-androstenediol metabolism in postmenopausal women with breast cancer

delta-5-Androstene-3 beta, 17 beta-diol has potential estrogenic activity because it is known to bind to receptors and translocate to the nucleus of certain estrogen target tissues. Its role in the biology of breast cancer is unclear. Aminoglutethimide plus hydrocortisone ("medical adrenalectomy") has been used to treat postmenopausal women with metastatic breast cancer. We studied delta 5-androstene-3 beta, 17 beta-diol metabolism in postmenopausal women with breast cancer before and during aminoglutethimide-plus-hydrocortisone therapy, utilizing the constant infusion technique. The metabolic clearance rate for five subjects was 799 +/- 89 liters/24 hr (470 +/- 47 liters/24 hr/sq m) before and 751 +/- 93 liters/24 hr (444 +/- 57 liters/24 hr/sq m) during therapy. Plasma delta 5-androstene-3 beta, 17 beta-diol and delta 5-androstene-3 beta, 17 beta-diol free index decreased despite absence of change in the metabolic clearance rate. Increased dehydroepiandrosterone/delta 5-androstene-3 beta, 17 beta-diol conversion ratios in individual patients suggested an increase in 17 beta-hydroxysteroid dehydrogenase activity during therapy. There were no alterations in the formation of the estrogen precursors testosterone and delta 4-androstene-3,17-dione.     

Myoclonus and the electroencephalogram, a review.

Myoclonus is a phenomenon which cuts through a considerable number of neurological conditions. It occurs in a variety of epileptic conditions (Primary generalized epilepsy, hypsarrhythmia, Lennox-Gastaut syndrome, also known as "petit mal variant"), in inborn errors of metabolism (Tay-Sachs disease, forms of ceroid lipofuscinosis), in neurobiochemically still poorly understood forms of degenerative processes such as Essential hereditary myoclonus epilepsy (Lafora-Unverricht-Lundborg), in benign heredo-degenerative disorders (Hartung's syndrome), in CNS infections (SSPE, Jakob-Creutzfeldt disease), in metabolic encephalopathies (renal failure, hypoglycemia), in CNS poisoning, in acute cerebral anoxia and in post-anoxic states. The EEG plays a crucial role in the differential diagnosis of these conditions by the demonstration of a) presence or absence of typical inter-ictal abnormalities, and b) various correlates of the myoclonic ictal event.