An amino-terminal DAX1 (NROB1) missense mutation associated with isolated mineralocorticoid deficiency.

CONTEXT: Mutations in DAX1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome gene 1; NR0B1) cause X-linked adrenal hypoplasia congenita, a disease characterized by primary adrenal failure, testicular dysgenesis, and gonadotropin deficiency. Most DAX1 mutations are deletions, nonsense, or frameshift mutations that markedly impair its transcriptional activity. Missense mutations have been restricted to the carboxy-terminal domain and are associated with more variable clinical phenotypes. OBJECTIVE: The objective was to identify novel clinical phenotypes associated with DAX1 missense mutations. PATIENTS AND DESIGN: We investigated the genetic basis of isolated mineralocorticoid deficiency in a patient who carries a unique missense mutation (W105C) in the amino-terminal region of DAX1. RESULTS: The W105C DAX1 mutation in the proband was present in three asymptomatic hemizygous males, but it was not detected in the general population. Using in vitro studies of DAX1 expression and function in transfected cells, we demonstrate that the mutant DAX1 protein exhibits mild loss of function, whether studied for genes it represses or for genes it activates. Structure-function studies suggest that the W105C and other mutations in the aminoterminus are compensated by the presence of repeated LXXLL motifs that mediate DAX1 interactions with other proteins. CONCLUSIONS: We describe the first missense mutation in the aminoterminus of DAX1 and conclude that mutations in this region may be partially compensated by redundant functional domains. Mild DAX1 mutations may be a cause of isolated mineralocorticoid deficiency.

Modelling radiation loads to detectors in a SNAP mission.

In order to investigate the degradation of optical detectors of the Supernova Acceleration Project (SNAP) space mission because of irradiation, a three-dimensional model of the satellite has been developed. A realistic radiation environment at the satellite orbit, including both galactic cosmic rays and cosmic ray trapped in radiation belts, has been taken into account. The modelling has been performed with the MARS14 Monte Carlo code. In a current design, the main contribution to dose accumulated in the photo-detectors is shown to be due to trapped protons. The contribution of primary alpha particles is estimated. Predicted performance degradation for the photodetector for a four-year space mission is 40% and this can be reduced further by means of shielding optimisation.

Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry.

The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity.

Posterior retinal folds following vitreoretinal surgery.

The authors conducted a retrospective review of 32 patients with posterior retinal folds following retinal reattachment surgery. Twenty-eight of these patients underwent combined pars plana vitrectomy, fluid-air exchange with either internal drainage through a preexisting retinal break or external drainage of subretinal fluid, and scleral buckle. We believe these drainage techniques resulted in incomplete elimination of subretinal fluid, with resultant sequestration of fluid at the dependent border between attached and detached retina. Metamorphopsia and decreased visual acuity were noted in patients with folds involving the macula. The likelihood of fold formation may be greatly reduced by internal drainage through a posterior retinotomy combined with more complete removal of slowly gravitating fluid as it flows dependently to the drainage site.

The appearance of stippled retinal pigment epithelial detachments. A sign of occult choroidal neovascularization in age-related macular degeneration.

The clinical source of 62 eyes that had been coded for macular degeneration and fibrovascular retinal pigment epithelial (RPE) detachment on fluorescein angiography was reviewed; 17 eyes had signs of a choroidal neovascular membrane (CNVM) at initial examination, and 30 eyes developed a definite CNVM during follow-up examination. Thus, 47 of the 62 eyes (76%) developed a CNVM in association with fibrovascular RPE detachments. Features of fibrovascular RPE detachments include: 1) focal, tiny hyperfluorescent spots at the level of the RPE arising in the mid and late frames of the angiogram, which do not correspond to drusen or foci of depigmentation (stippled hyperfluorescence); 2) intensification of these spots in the later stages of the angiogram; 3) slight enlargement of the spots in the late frames of the angiogram; 4) occasional presence of scant overlying subretinal fluid; and 5) minimal elevation of the RPE. Fibrovascular RPE detachments appear to be a distinct form of an RPE detachment. It is concluded that this sign is associated with a high risk of developing a frank CNVM and is thus a reliable indicator of occult neovascularization.

Atypical healing of cytomegalovirus retinitis. Significance of persistent border opacification.

PURPOSE: To analyze a phenomenon seen in patients with acquired immune deficiency syndrome (AIDS) with cytomegalovirus (CMV) retinitis undergoing systemic antiviral treatment: a persistent white border opacification on the edge of healed CMV retinitis. PATIENTS AND METHODS: The authors prospectively evaluated a population of 137 patients with AIDS and CMV retinitis during a 44-month period. Eleven patients (12 eyes) who were undergoing maintenance antiviral treatment were identified with an atypical healing response--the persistence of a white flat border opacification that did not advance for many weeks to months. Patient records and photographs were reviewed. Results of one autopsy were analyzed with histopathology and special stains. RESULTS: The persistent white edge maintained (without advancement or smoldering) for an average of 11.6 weeks (range, 4 to 41 weeks). This border opacification was not affected by reinduction treatment in the six patients to whom reinduction was given. Results from histopathologic examination of one patient with a persistent white border are presented: these results show that dead cytomegalic cells formed stable structures within the retina, causing white opacification that could be confused with active lesions. Immunoperoxidase stains identified CMV antigens. CONCLUSION: This persistent white border opacification, which does not advance or smolder, represents an important clinical entity that should be recognized during antiviral treatment for CMV retinitis. It can often be observed. If it is not recognized as a stable configuration, patients may undergo unnecessary reinductions with potentially toxic doses of antiviral medications.

Cat scratch disease associated with neuroretinitis in a 6-year-old girl.

Cat scratch disease is a subacute regional lymphadenitis usually preceded by a history of being scratched by a cat or young kitten. The spectrum of illness ranges from mild self-limited adenopathy to severe systemic disease, including hepatosplenomegaly, encephalopathy, osteolytic lesions, splenic abscesses, mediastinal masses, and neuroretinitis. Vision loss is a rare complication of the disease. The authors report a patient with cat scratch disease associated with acute febrile illness, lymphocytic meningitis, and acute vision loss secondary to neuroretinitis. To their knowledge, this is the first ophthalmic case reported in which the diagnosis is supported by both a positive skin test and positive histopathology.

Use of the Life Purpose Questionnaire with an alcoholic population.

This paper examines the potential use of the Life Purpose Questionnaire (LPQ), which is an uncomplicated paper-and-pencil instrument designed to measure an individual's sense of life meaning. Sense of life meaning is an important focus of Crumbaugh's logotherapy for alcoholics. Correlations between scores of the LPQ and the more complicated Purpose-in-Life Test are significant for three separate alcoholic groups. Based on these results, it is concluded that the LPQ can be used with alcoholics in order to obtain a quick and readily understandable measure of the individual's sense of life meaning.