Phacoemulsification and intraocular lens placement in eyes with cataract and congenital coloboma: visual acuity and complications.

PURPOSE: To evaluate the safety and complications of phacoemulsification in a series of patients with congenital coloboma and cataract. SETTING: University-based hospital practice. METHODS: A retrospective review was conducted of consecutive patients who had coloboma and cataract and had phacoemulsification between January 1987 through December 1998. Complications and visual acuity 2 months postoperatively were assessed. RESULTS: Mean age of 7 cases at the time of surgery was 41.6 years +/- 11.1 (SD). Visual acuity improved in 6 of 7 eyes; 1 eye had no change. Six eyes had no serious complications. In 1 eye, a retinal detachment was observed postoperatively, but there was no loss in visual acuity. Another patient developed postoperative monocular diplopia from exposure of the intraocular lens (IOL) edge within the inferonasally located corectopia associated with the coloboma. Nonsurgical treatment was unsuccessful, but this symptom resolved after surgical pupilloplasty. CONCLUSIONS: The results of this small case series affirm that clinically significant cataract develops at a younger age in eyes with congenital coloboma than in eyes with typical age-related nuclear sclerotic cataract. Monocular diplopia, a potential complication after cataract surgery in these eyes, can be managed by pupilloplasty. The improved vision in this study indicates that phacoemulsification and IOL placement are safe and beneficial in patients with typical congenital coloboma and cataract.

Region-specific astrogliosis in brains of mice heterozygous for mutations in the neurofibromatosis type 1 (Nf1) tumor suppressor.

Brains from human neurofibromatosis type 1 (NF1) patients show increased expression of glial fibrillary acidic protein (GFAP), consistent with activation of astrocytes (M.L. Nordlund, T.A. Rizvi, C.I. Brannan, N. Ratner, Neurofibromin expression and astrogliosis in neurofibromatosis (type 1) brains, J. Neuropathol. Exp. Neurology 54 (1995) 588-600). We analyzed brains from transgenic mice in which the Nf1 gene was targeted by homologous recombination. We show here that, in all heterozygous mice analyzed, there are increased numbers of astrocytes expressing high levels of GFAP in medial regions of the periaqueductal gray and in the nucleus accumbens. More subtle, but significant, changes in the number of GFAP positive astrocytes were observed in the hippocampus in 60% of mutant mice analyzed. Astrocytes with elevated GFAP were present at 1 month, 2 months, 6 months and 12 months after birth. Most brain regions, including the cerebellum, basal ganglia, cerebral cortex, hypothalamus, thalamus, cortical amygdaloid area, and white matter tracts did not show any gliotic changes. No evidence of degenerating neurons was found using de Olmos' cupric silver stain. We conclude that Nf1/nf1 mice provide a model to study astrogliosis associated with neurofibromatosis type 1.

Neurofibromin expression and astrogliosis in neurofibromatosis (type 1) brains.

Patients with type 1 neurofibromatosis (NF1) have mutations in the gene encoding the protein neurofibromin. Immunocytochemistry on sections of cortex and cerebellum of unaffected and NF1 individuals and wild-type and NF1-deficient mice showed that the distribution of neurofibromin was similar to that reported for rat. However, dystrophic neurofibromin-expressing neurons were found in human but not rodent brain. Intensity of anti-neurofibromin reactivity was reduced in NF1-deficient mice but not in human brains. GFAP was upregulated in three NF1 brains studied by immunocytochemistry; a 4-18-fold increase in GFAP levels was documented by Western blot analysis in three brains. GFAP content/cell and the number of GFAP-immunoreactive astrocytes was increased in NF1 brains as compared to the controls. These results suggest that mutations in the NF1 gene do not grossly alter the pattern of neurofibromin expression, but activation of astrocytes may be common in NF1. Presence of degenerative debris in one of two brains using the cupric silver method suggests that degeneration is not always detectable in NF1 brains.

Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.

The neurofibromatosis (NF1) gene shows significant homology to mammalian GAP and is an important regulator of the ras signal transduction pathway. To study the function of NF1 in normal development and to try and develop a mouse model of NF1 disease, we have used gene targeting in ES cells to generate mice carrying a null mutation at the mouse Nf1 locus. Although heterozygous mutant mice, aged up to 10 months, likely attributable to a severe malformation of the heart. Interestingly, mutant embryos also display hyperplasia of neural crest-derived sympathetic ganglia. These results identify new roles for NF1 in development and indicate that some of the abnormal growth phenomena observed in NF1 patients can be recapitulated in neurofibromin-deficient mice.

Rapid induction of Thy-1 antigenic markers on keratinocytes and epidermal immune cells in the skin of mice following topical treatment with common preservatives used in topical medications and in foods.

Earlier experiments from our laboratory revealed that the medication most commonly used for depigmenting patients with vitiligo, monobenzyl ether of hydroquinone (MBEH), when applied to the skin of DBA/2 mice caused an increase in the population density (cells/mm2) of identifiable Ia+ and ATPase+ Langerhans cells. Further, this increase in Langerhans cell density could be correlated with an increase of contact hypersensitivity (CHS) reactivity to dinitrofluorobenzene (DNFB). The current experiments demonstrated that other compounds chemically similar to MBEH, such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), which are used as preservatives/antioxidants in many topical medications, cosmetics, food, and rubber products, can in five days significantly increase the population density of Thy-1+ dendritic epidermal cells. These compounds had no effects on Ia+ cells. This observation suggests that the Thy-1+ DEC cells may be more mobile and/or their surface markers may be readily expressed and are not a slowly mobile (trafficking) population of cells as suggested by the results of previous work. In addition, these parasubstituted phenolic compounds behaved like pertussis toxin and induced Thy-1 and Ia expression on keratinocytes. These changes in Thy-1 immune markers were not accompanied by functional alterations in the immune response to contact allergens as measured by the ear swelling technique.

Langerhans' cells in hair follicles of the depigmenting C57Bl/Ler-vit.vit mouse. A model for human vitiligo.

The C57Bl/Ler-vit.vit mouse grows a black pelage after birth. During successive hair molts, the fur loses its pigmentation. By 6 months of age, most of the fur of the animal is white. The epidermis of the ears and tail also loses its pigmentation. Histologic studies confirm that in the epidermis and hair follicles there is an absence of pigment cells identifiable by various histochemical or electron microscopic techniques. This mouse may be an excellent model in which to study the role of Langerhans' cells and the immune response in the pathogenesis of vitiligo, a study not easily done in humans. From results of prior studies, we postulated that if Langerhans' cells were involved in the destruction of melanocytes, they would be abnormal (either more or less numerous) in number during the active phase of depigmentation and normal in number after depigmentation was complete. To determine whether the Langerhans cell (Ia+/adenosine triphosphatase dendritic epidermal cell) might be involved in destruction of pigment cells, we quantified the number of Ia+ and adenosine triphosphatase dendritic cells in the hair follicles in skin from the ear, abdomen, back, and tail from male C57Bl/Ler-vit.vit mice while the fur and skin were depigmenting and after depigmentation was almost completed. We found that Langerhans' cells were normal in number during depigmentation and were most numerous after depigmentation. Previous studies indicate that Langerhans' cells in these mice are functionally defective and respond poorly to some contact allergens. From these morphologic and functional data, we conclude that Langerhans' cells probably are uninvolved in causing depigmentation in these mice. We also observed that the epithelium of hair follicles has a significantly higher (up to 1600/mm2) population density of Langerhans' cells than interfollicular skin.