Isolation of DNA fragments from chromosome 13

A number of patients with retinoblastoma have a deletion of chromosome 13. Comparison of the deleted segments from different individuals reveals that all deletions involve chromosome band 13q14. This observation has lead to the hypothesis that in this region is a gene of genes important in the etiology of retinoblastoma. As a first step toward understanding those genes, the authors successfully isolated five DNA fragments from chromosome 13 using recombinant DNA techniques. The DNA fragments from chromosome 13 will be useful in identifying DNA polymorphic sites that are linked to the retinoblastoma locus tentatively assigned to 13q14. Such DNA polymorphisms will be important in the genetic counselling of families with retinoblastoma. These chromosome 13q14 fragments also may be useful in searching for microdeletions of 13q14.     

A superantigen hypothesis for the pathogenesis of chronic hyperplastic sinusitis with massive nasal polyposis

BACKGROUND: The pathogenesis of chronic hyperplastic sinusitis with massive nasal polyposis is still an enigma; however, the molecular biology of this disease is beginning to become unraveled and the proinflammatory cytokines and the message and the product of these cytokines have all been identified in nasal polyps. However, the initial trigger that causes inflammation of the lateral wall of the nose to up-regulate lymphocytes and eosinophils is still unknown. METHODS: Thirteen patients with massive polyposis were studied. The mucus of the nasal cavities surrounding the nasal polyps was studied for both bacterial and fungal species. The lymphocytes of the nasal polyps were extracted and evaluated for the T-cell receptor, particularly, the variable beta region of this receptor. Enterotoxins (superantigens) of the bacteria were studied. Finally, the histopathology of nasal polyps was studied. RESULTS: Fifty-five percent of the patients had toxin-producing Staphylococcus aureus in the nasal mucus adjacent to the polyps. Three different enterotoxins were isolated, including Staphylococcus enterotoxin A, Staphylococcus enterotoxin B, and toxic shock syndrome toxin 1. The variable B specificity for these superantigens was identified also in the polyp lymphocyte T-cell receptor. CONCLUSION: A superantigen hypothesis for massive polyposis is suggested because the most common bacterial species found in the nasal mucus is Staphylococcus aureus. These bacteria produce enterotoxins in all of the cases studied and the corresponding variable beta region of the T-cell receptor also was up-regulated in the polyp lymphocytes in cases studied thus far. These data taken together suggest that the initial injury to the lateral wall of the nose may be the result of toxin-producing Staphylococci. Superantigens (enterotoxins) may up-regulate lymphocytes to produce cytokines that are responsible for the massive up-regulation of lymphocytes, eosinophils, and macrophages, the three most common inflammatory cells found in massive nasal polyposis.     

Novel mutations in the KCNV2 gene in patients with cone dystrophy and a supernormal rod electroretinogram

PURPOSE: To identify mutations in KCNV2 in patients with a form of cone dystrophy characterized by a supernormal rod electroretinogram (ERG). METHODS: The 2 exons and flanking intron DNA of KCNV2 from 8 unrelated patients were PCR amplified and sequenced. RESULTS: We found 1 frameshift, 2 nonsense, 1 non-stop, and 6 missense mutations. Every patient had one or two mutations identified. Of the missense mutations, 4 affected residues were in the amino terminal region of the protein, and two in the pore region. CONCLUSIONS: KCNV2 mutations account for most if not all cases of cone dystrophy with a supernormal rod ERG.     

Conjunctival non-caseating granulomas in a human immunodeficiency virus (HIV) positive patient attributed to sarcoidosis

PURPOSE: To report a rare case of isolated ocular sarcoidosis in an HIV positive patient. DESIGN: Case report. METHODS: A 47-year-old HIV+ Caucasian male was referred for chronic bilateral follicular conjunctivitis. RESULTS: A conjunctival biopsy that was performed on the right eye showed sarcoidosis. General medical evaluation including a spiral thin cut chest CT scan revealed no systemic involvement. The ocular signs and symptoms resolved completely with topical corticosteroid treatment. CONCLUSIONS: HIV infection and sarcoidosis rarely coexist, presumably because their immunopathogenesis mechanisms diverge. In the absence of systemic involvement, a definite diagnosis can only be made by biopsy of the ocular tissues.     

Molecular genetics of Oguchi disease, fundus albipunctatus, and other forms of stationary night blindness: LVII Edward Jackson Memorial Lecture

PURPOSE: To compare the clinical findings of the various forms of stationary night blindness caused by mutations in identified genes encoding proteins of photoreceptors or the retinal pigment epithelium. METHODS: Review of the visual acuities, visual fields, fundi, dark-adaptation curves, and electroretinograms from patients with stationary night blindness caused by mutations in the genes RHO, GNAT1, PDE6B, RHOK, SAG, RDH5, and CACNA1F, respectively encoding rhodopsin, the alpha subunit of rod transducin, the beta subunit of rod cGMP-phosphodiesterase, rhodopsin kinase, arrestin, 11-cis retinol dehydrogenase, and a retinal L-type calcium channel. RESULTS: In the evaluated forms of stationary night blindness, the time course of dark adaptation and the characteristics of the electroretinogram indicate that rod photoreceptors are present and that they function, although abnormally. In night blindness resulting from defects in rhodopsin, the alpha subunit of rod transducin, or the beta subunit of rod cGMP phosphodiesterase, rod photoreceptors respond only to light intensities far brighter than normal, and the sensitivity of rods to light is similar to that of normal individuals who are not dark adapted. In fundus albipunctatus and in Oguchi disease, the rod photoreceptors can achieve normal sensitivity to dim light but only after 2 or more hours of dark adaptation, compared with approximately 0.5 hours for normal individuals. In each of these forms of stationary night blindness, the poor rod sensitivity and the time course of dark adaptation correlate with the known or presumed physiologic abnormalities caused by the identified gene defects. Patients with some forms of stationary night blindness, such as fundus albipunctatus and Oguchi disease, may develop degeneration of the retina leading to severe loss of vision in later life. CONCLUSIONS: The identification of the mutant genes causing forms of stationary night blindness refines the classification of these diseases and enhances our understanding of the underlying physiologic defects. Ophthalmologists must be aware that although these diseases are traditionally categorized as "stationary," some of them lead to reduced visual acuity or constricted visual fields, especially in older patients. Efforts to develop therapies for these diseases should concentrate on these more severe forms.     

Clinical Phenotype in a Swedish Family with a Mutation in the IMPDH1 Gene

Purpose: Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) have recently been discovered to cause a form of autosomal dominant retinitis pigmentosa (adRP). Such mutations are estimated to account for approximately 2–5% of the adRP cases among Americans of European origin and Europeans. Aiming towards an understanding of the molecular background of retinitis pigmentosa, this paper describes the phenotype of a Swedish family with a mutation in IMPDH1. Methods: Venous blood samples were obtained from 12 family members and screened for mutations in IMPDH1. Six individuals with the mutation were examined clinically and with full-field electroretinography (ERG), dark adaptometry, multifocal electroretinography (mfERG), and optical coherence tomography (OCT). Also reviewed were the clinical findings and ERGs obtained 14 years earlier. Results: The proband and eight other relatives from three generations were found to harbor the Asp226Asn mutation in IMPDH1. These individuals, from three generations, showed clinical and electrophysiological signs of retinitis pigmentosa. The cone responses to the full-field, 30-Hz flicker ERG demonstrated an unusual pattern, with implicit times within normal limits or only slightly prolonged. Rod ERG responses, however, were undetectable. OCT showed intraretinal fluid and swelling, changes that were more pronounced in younger individuals. mfERG showed residual preserved central function. The older the individual, the smaller the area of preserved central function. Conclusion: In this family with a mutation in IMPDH1, we found a specific phenotype with rod function affected more than cone function, foveal edema, and central retinal function preserved for a long period of time. Foveal edema could be a pathogenic feature in this form of retinal degeneration.     

Effect of a single dose of captopril on left-ventricular function in patients with chronic congestive cardiomyopathy

In 15 patients with mild, chronic congestive heart failure the effect of a single dose of captopril (25 mg/m2 b.s.) on heart rate, systolic and diastolic blood pressure as well as on left ventricular function was studied at rest and after a submaximal physical effort. Preejection period (PEP), left ventricular ejection time (LVET) and the contractility index PEP/LVET were polycardiographically determined++. Left ventricular end diastolic volume (DVol), and systolic volume (SVol), ejection fraction (EF), stroke volume index (SVI) and cardiac index (CI) were estimated using two-dimensional echocardiography. Obtained data indicate, that in patients with chronic, congestive heart failure, a single dose of captopril lowers blood pressure at rest without significant changes of hemodynamic parameters, but improves left ventricular function during physical effort.     

Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa.

Mutations in the gene encoding the beta subunit of rod cGMP phosphodiesterase are known causes of photoreceptor degeneration in two animal models of retinitis pigmentosa, the rd (retinal degeneration) mouse and the Irish setter dog with rod/cone dysplasia. Here we report a screen of 92 unrelated patients with autosomal recessive retinitis pigmentosa for defects in the human homologue of this gene. We identified seven different mutations that cosegregate with the disease. They were found among four patients with each patient heterozygously carrying two mutations. All of these mutations are predicted to affect the putative catalytic domain, probably leading to a decrease in phosphodiesterase activity and an increase in cGMP levels within rod photoreceptors. Mutations in the gene encoding the beta subunit of rod phosphodiesterase are the most common identified cause of autosomal recessive retinitis pigmentosa, accounting for approximately 4% of cases in North America.