Selective disruption of nuclear import by a functional mutant nuclear transport carrier.

p10/NTF2 is a nuclear transport carrier that mediates the uptake of cytoplasmic RanGDP into the nucleus. We constructed a point mutant of p10, D23A, that exhibited unexpected behavior both in digitonin-permeabilized and microinjected mammalian cells. D23A p10 was markedly more efficient than wild-type (wt) p10 at supporting Ran import, but simultaneously acted as a dominant-negative inhibitor of classical nuclear localization sequence (cNLS)-mediated nuclear import supported by karyopherins (Kaps) alpha and beta1. Binding studies indicated that these two nuclear transport carriers of different classes, p10 and Kap-beta1, compete for identical and/or overlapping binding sites at the nuclear pore complex (NPC) and that D23A p10 has an increased affinity relative to wt p10 and Kap-beta1 for these shared binding sites. Because of this increased affinity, D23A p10 is able to import its own cargo (RanGDP) more efficiently than wt p10, but Kap-beta1 can no longer compete efficiently for shared NPC docking sites, thus the import of cNLS cargo is inhibited. The competition of different nuclear carriers for shared NPC docking sites observed here predicts a dynamic equilibrium between multiple nuclear transport pathways inside the cell that could be easily shifted by a transient modification of one of the carriers.

A questionnaire survey on the management of Graves' orbitopathy in Europe.

OBJECTIVE: To determine management patterns among clinicians who treat patients with Graves' orbitopathy (GO) in Europe. DESIGN AND METHODS: Questionnaire survey including a case scenario of members of professional organisations representing endocrinologists, ophthalmologists and nuclear medicine physicians. RESULTS: A multidisciplinary approach to manage GO was valued by 96.3% of responders, although 31.5% did not participate or refer to a multidisciplinary team and 21.5% of patients with GO treated by responders were not managed in a multidisciplinary setting. Access to surgery for sight-threatening GO was available only within weeks or months according to 59.5% of responders. Reluctance to refer urgently to an ophthalmologist was noted by 32.7% of responders despite the presence of suspected optic neuropathy. The use of steroids was not influenced by the age of the patient, but fewer responders chose to use steroids in a diabetic patient (72.1 vs 90.5%, P<0.001). Development of cushingoid features resulted in a reduction in steroid use (90.5 vs 36.5%, P<0.001) and increase in the use of orbital irradiation (from 23.8% to 40.4%, P<0.05) and surgical decompression (from 20.9 to 52.9%, P<0.001). More ophthalmologists chose surgical decompression for patients with threatened vision due to optic neuropathy, who were intolerant to steroids than other specialists (70.3 vs 41.8%, P<0.01). CONCLUSION: Deficiencies in the management of patients with GO in Europe were identified by this survey. Further training of clinicians, easier access of patients to specialist multidisciplinary centres and the publication of practice guidelines may help improve the management of this condition in Europe.

Alteration of OBCAM conformation as a result of opioid receptor expression and opioid ligand treatment.

Several lines of evidence link the opioid binding cell adhesion molecule (OBCAM) to opioid function. When delta-opioid receptor cDNA (DOR-1) was expressed in CHO cells, OBCAM immunoreactivity (OBCAM-ir) was detected. Transfected cell lines which displayed high opioid binding also expressed high cell surface OBCAM-ir, while untransfected CHO and vector control cells did not. The positive control, neural cell adhesion molecule (NCAM), a protein with structural homology to OBCAM, displayed the same levels of immunofluorescence in transfected and nontransfected cell lines. Membranes from CHO cells transfected with and expressing a variety of muscarinic and dopamine receptors were tested for immunoreactivity. No significant OBCAM-ir was detected in any of these cell membranes. When anti-OBCAM peptide antibodies were used for immunoblots of CHO cells, untransfected, non-binding transfected, and high binding transfected cells revealed the same banding patterns with approximately equal intensity. These observations suggest that in untransfected cells OBCAM is either not present on the extracellular side of the CHO cell membrane or that it exists in an altered conformation which changes upon transfection with opioid receptors to allow recognition of the non-denatured protein by anti-OBCAM antibodies.

Orbital cellulitis caused by Fusobacterium necrophorum.

PURPOSE: To report the case of a previously healthy young female who developed orbital cellulitis caused by Fusobacterium necrophorum. We are unaware of previous reports of this condition caused by the same anaerobic, gram-negative, nonsporeforming bacterium and could find no reference to it in a computer search using MEDLINE. METHODS: Case report. RESULTS: In the case of orbital cellulitis presented here, the patient required 3 sinus debridement operations and 30 days of intravenous antibiotics. Despite this, her vision did not fully recover. CONCLUSION: F. necrophorum is capable of causing severe orbital disease that requires aggressive and prompt treatment to preserve sight.

Treatment of ptosis in chronic progressive external ophthalmoplegia.

Seventeen patients with ptosis as a feature of chronic progressive external ophthalmoplegia were managed in accordance with a new protocol. An anterior approach levator advancement was performed on seven patients (13 lids) with more than 4 mm of levator function and a brow suspension procedure on eight patients (14 lids) with minimal levator function, in whom the frontalis muscle was relatively spared. Ptosis props were prescribed for two patients with a very weak orbicularis and poor lid closure. Six patients required long term lubricants, and one developed a postoperative corneal abscess associated with a poor Bell's phenomenon. Satisfactory elevation of the lids was achieved in 16 patients (25 lids).

Primary myxoid liposarcoma of the orbit.

Orbital liposarcoma is a rare and usually unsuspected neoplasm. Over a five-year period three female patients aged 22, 71, and 77 years presented with primary myxoid liposarcoma of the orbit. The management of one patient was complicated by a history of orbital decompression for suspected thyroid eye disease. The tumour infiltrates locally beyond a deceptive pseudocapsule, and surgery has to be radical to be effective.

Delayed ciliochoroidal detachment following intraocular lens implantation.

Three patients who had extracapsular cataract extractions with intraocular lens implants developed delayed ciliochoroidal detachments, which responded to systemic steroid therapy. This rare complication may have been due to ciliary sulcus fixation of the implant. The possible mechanism and treatment are discussed.

Two brothers with trichiasis, entropion and corneal scarring, sensorineural hearing loss, progressive thinning of scalp hair, mild learning difficulties and distinct facial features. A new syndrome?

Two brothers with very similar phenotypes involving trichiasis (misdirected lashes), entropion with corneal abrasions, strabismus, progressive thinning of the scalp hair, sensorineural hearing impairment, mild learning difficulties, and inguinal hernias are described. They have similar, distinctive facial features with deep-set eyes, a high nasal bridge and a short philtrum. Both brothers are carriers of a maternally inherited apparently balanced translocation of chromosomes 11 and 18: 46,XY, t(11;18)(p13;q21)mat. However, this is thought to be coincidental, since their younger brother also carries this translocation and is phenotypically normal. Although they have many features that are found in the ectodermal dysplasia syndromes, their combination of features is distinct and has to our knowledge not been previously reported.

Reviews.

THE MANAGEMENT OF WOUNDS AND BURNS CHRONIC VENOUS DISEASES OF THE LEG FRAUD AND MISCONDUCT IN MEDICAL RESEARCH PSYCHOLOGY, PSYCHIATRY AND CHRONIC PAIN.

Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures.

AIM: To compare the outcome of various surgical approaches of orbital decompression in patients with Graves' orbitopathy (GO) receiving surgery for disfiguring proptosis. METHOD: Data forms and questionnaires from consecutive, euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis in 11 European centres were analysed. RESULTS: Eighteen different (combinations of) approaches were used, the swinging eyelid approach being the most popular followed by the coronal and transconjunctival approaches. The average proptosis reduction for all decompressions was 5.0 (SD 2.1) mm. After three-wall decompression the proptosis reduction was significantly greater than after two-wall decompression. Additional fat removal resulted in greater proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression. The average change in quality of life (QOL) in the appearance arm of the GO-QOL questionnaire was 20.5 (SD 24.8) points. CONCLUSIONS: In Europe, a wide range of surgical approaches is used to reduce disfiguring proptosis in patients with GO. The extent of proptosis reduction depends on the number of walls removed and whether or not fat is removed. Serious complications are infrequent. Worsening of ocular motility is still a major complication, but was rare in this series after the swinging eyelid approach.

Cosmetic orbital surgery.

PURPOSE: Current indications for orbital surgery primarily aimed at improving cosmesis are considered in the context of subspecialist orbital practice by an ophthalmologist. SCOPE: Thyroid eye disease, orbital vascular anomalies, and dermolipomas are common orbital diseases in which the symptoms can be purely cosmetic. Accurate anatomical awareness, preoperative scanning, control of medical factors including smoking and thyroid status, and endoscopic techniques have all contributed to the aesthetic outcome of orbital surgery. The threshold for performing reconstructive orbital surgery has also been lowered by public demand. CONCLUSIONS: Orbital surgeons can therefore offer the familiar techniques, such as orbital decompression, for pure cosmesis. Sensitive history taking and awareness of the psychological element are of paramount importance for the orbital surgeon who develops a cosmetic practice.

Optic disc swelling in sympathetic ophthalmitis and Harada's disease.

In sympathetic ophthalmitis and Harada's disease the fundus appearance is characterised by pale areas of elevated retina associated with a diffuse choroidal abnormality on fluorescein angiography. Optic disc swelling, though constant, is rarely prominent. Four patients, one with sympathetic ophthalmitis and three with Harada's disease, are described, in whom optic disc swelling with visual loss was the predominent sign at one stage of the disease.

Orbital dermoid cyst.

Over a thirteen year period forty patients underwent surgery to remove an orbital dermoid cyst. Cysts which became manifest after the age of three years were deeper and larger than most that were noted before that age. Three out of four epidermoid cysts appeared after the age of 17 years and had an intracranial component. The majority of cysts showed histological evidence of leakage and associated inflammation. It is our view that dermoid cysts should be totally excised because they gradually enlarge and cause inflammation and scarring in adjacent structures.

Ocular fundus lesions in sports divers using safe diving practices.

Ocular fundus fluorescein angiography was performed on 26 divers, who had used safe diving practices for at least 10 years, and on seven controls. There was no significant difference in the incidence of macular abnormalities between these groups and those of a previous study. Adherence to safe diving practice confers some protection against the macular abnormalities known to occur in divers with a history of decompression sickness.

MRI of idiopathic orbital inflammatory syndrome using fat saturation and Gd-DTPA.

Idiopathic orbital inflammatory syndrome encompasses a group of inflammatory conditions for which no systemic or local cause can be found, and is commonly referred to as orbital pseudotumour. On conventional MRI sequences subtle areas of inflammation or enhancing tissue can easily be masked by the high signal intensity of orbital fat and involvement of the fat itself may not be appreciated. We describe the MRI features of three patients with idiopathic orbital inflammation using frequency-selective fat saturation and Gd-DTPA.

Regulation of an opioid-binding protein in NG108-15 cells parallels regulation of delta-opioid receptors.

An opioid-binding protein has recently been purified from bovine brain and cloned, and its cDNA sequence has been obtained. Indirect evidence suggests that this protein has a role in opioid-receptor function. However, because direct testing of its function by expression of its cDNA has not yet been possible and because its structure bears no resemblance to G protein-coupled receptors, the role of this protein in opioid-receptor activity is still in question. An antibody raised to a portion of the predicted amino acid sequence of opioid-binding cell-adhesion molecule (OBCAM) specifically labeled the surface of NG108-15 cells, as visualized by immunofluorescence with confocal microscopy. Furthermore, chronic treatment of these cells with opioid agonist, which down-regulates opioid receptors, reduced OBCAM immunoreactivity (ir). Down-regulation of both opioid receptors and OBCAM-ir was greatest after chronic treatment of NG108-15 cells with delta-opioid agonists, as well as with nonselective agonists such as etorphine, whereas other agonists including [D-Ala2-N-MePhe4-Gly-ol]enkephalin, morphine, levorphanol, dynorphin A-(1-13), and U-50,488H were less effective or ineffective. Chronic treatment of NG108-15 cells with muscarinic agonists had no effect on OBCAM-ir. Furthermore, NG108-15 cells transfected with an antisense construct to OBCAM have a reduced density of opioid-binding sites as well as reduced OBCAM-ir. Taken together, these results strongly suggest that OBCAM has a role in opioid-receptor function in NG108-15 cells.

Thyroid lid surgery.

A retrospective study of 58 thyroid patients undergoing eyelid surgery for thyroid related lid malposition is reported. A treatment strategy is suggested, based on the results of this experience. The following points are stressed: (1) The importance of recognising and relieving the inferior rectus tethering component of upper lid retraction when present. (2) The usefulness of a scleral graft in lower lid retractor recession. (3) The inadequacy of lateral tarsorrhaphy in relieving lid retraction but its value in camouflage.