A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFRC329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2V617F-positive clone in this PV patient harbors EGFRC329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2V617F disease clone in MPN.

BCR-ABL1 kinase domain mutations may persist at very low levels for many years and lead to subsequent TKI resistance.

BACKGROUND: BCR-ABL1 mutation analysis is recommended for chronic myeloid leukaemia patients. However, mutations may become undetectable after changing therapy, and it is unknown whether they have been eradicated. METHODS: We examined longitudinal data of patients with imatinib-resistant mutations, which became undetectable by Sanger sequencing to determine whether mutations could reappear, and the related circumstances. RESULTS: Identical imatinib- and nilotinib-resistant mutations reappeared following further therapy changes in five patients, and was associated with subsequent nilotinib resistance in four. CONCLUSION: The data suggest that some BCR-ABL1 mutations may persist at undetectable levels for many years after changing therapy, and can be reselected and confer resistance to subsequent inhibitors.

Long-term evolution of astigmatism following planned extracapsular cataract extraction.

Sixty-six eyes of 66 patients undergoing planned extracapsular cataract extraction with interrupted 10-0 nylon suture wound closure were followed up prospectively for three years following surgery to evaluate the long-term evolution of postoperative astigmatism. The study examined the period beginning three months postoperatively, well after all suture cutting was completed, a point often considered to represent "final postoperative astigmatism." For the group as a whole, the induced astigmatism measured at three months was not stable, but gradually shifted 0.69 diopter toward against-the-rule astigmatism. Three specific patterns of evolution of postoperative astigmatism were identified, depending on the amount of induced astigmatism found at three months. The data revealed that it was not possible to consistently induce with-the-rule astigmatism, although permanent against-the-rule induced astigmatism could be produced. The long-term evolution of postoperative cataract wounds toward more against-the-rule astigmatism seen in this study was not affected by the number of intact nylon sutures. Proper evaluation of any technique to modify postoperative astigmatism must consider the long-term evolution of the cataract wound.

Trends in hospital planning: tools for the next decade.

This article observes that the team of specialized professional disciplines needed to deal with the technical complexity in health care architecture has become fragmented. This has lead to an aesthetically boring and uninspiring architecture. The author's "dynamic" approach to the facility development process suggests a reintegration of disciplines as a first measure for improvement. As a second consideration he discusses technological advances in the state-of-the-art of pre-architecture (planning, programming) and design which could allow architects to more adequately address aesthetic and environmental needs of patients and workers in health care facilities.

Adjustment sensitivity of horizontal rectus muscles in adjustable strabismus surgery.

A "marking suture" was used in 12 consecutive cases of adjustable strabismus surgery to determine the relationship between ocular alignment and the amount of horizontal muscle adjustment. The average change in ocular alignment was 2.55 prism diopters for each millimeter of muscle adjustment. Regression analysis revealed the relationship to be linear over the range of adjustments studied. The sensitivity of adjustment was the same whether the adjusted muscle was advanced or further recessed and whether the adjusted muscle was the medial rectus or the lateral rectus. No relationship was found between the distance of a recessed muscle from its normal insertion and the subsequent adjustment sensitivity of that muscle. This information, when used clinically in conjunction with a marking suture, can facilitate the adjustment phase of adjustable strabismus surgery.

Use of Healon in eye muscle surgery with adjustable sutures.

Adhesions between the contacting surfaces of conjunctiva, Tenon's capsule, and muscle produce "tissue drag" which can complicate procedures with adjustable muscle sutures. The use of Healon is recommended to minimize this tissue drag and facilitate the "adjustment phase" of muscle surgery with adjustable muscle sutures. Data on 14 consecutive cases demonstrate the utility of Healon in adjustable strabismus surgery.

Night blindness after jejunoileal bypass surgery.

A 53-year-old woman developed night blindness 9 years after jejunoileal bypass surgery. Abnormal rod function was confirmed by dark-adapted electroretinography, and vitamin A deficiency was confirmed by low serum levels of vitamin A and carotene. Administration of oral vitamin A supplementation resulted in complete resolution of the patient's symptom and return of the electroretinogram to normal. Based on this case and the four previously reported cases, we suggest that jejunoileal bypass patients be routinely questioned about decreased night vision. Patients with this complaint should undergo thorough ophthalmic evaluation. Dark-adapted electroretinography or dark adaptation testing should be done to establish the presence of abnormal rod function, and serum levels of vitamin A or carotene should be obtained to identify the cause. It is important to identify vitamin A-deficient patients because of their potential to develop permanent impairment of night vision.

Marked intraocular pressure rise following Nd:YAG laser capsulotomy.

A Nd:YAG laser was used to perform a posterior capsulotomy on a patient one and a half years after phacoemulsification. Within 24 hours the intraocular pressure had increased to 67 mm Hg despite pre-treatment with timolol and acetazolamide. Intraocular pressure eventually returned to pre-capsulotomy levels after several days. A mechanism is postulated for the particularly high pressures encountered in this case.

The natural and modified course of post-cataract astigmatism.

We performed sequential central keratometry on 52 cataract patients for six months. We found no statistically significant difference in the induced postoperative astigmatism between wound closure with interrupted and double shoelace running closure with 10-0 monofilament nylon. In 31 patients, the postoperative astigmatism was always with-the-rule. In 21 patients who underwent wound closure with 8-0 polyglactin suture, we documented a postoperative shift in induced astigmatism from with- to against-the-rule which took place between the fourth and fifth postoperative week. Based on our present study of the natural and modified course of post-cataract astigmatism and based upon previous research, we feel the cataract surgeon now has the appropriate means to reduce and/or control post-cataract astigmatism.

Gentian violet keratoconjunctivitis.

A case of bilateral keratoconjunctivitis caused by self-instillation of a 1% aqueous solution of gentian violet was complicated by a secondary uveitis and gram-negative conjunctivitis. The patient was treated with cycloplegics and specific antibiotics and after resolution of the bacterial infection, a mild topical corticosteroid was used. After six months the patient had completely recovered from the keratitis, but bilateral corneal vascularization, had unilateral posterior synechiae, corneal scarring, and cataract formation were present. Cationic dyes such as gentian violet appear to be toxic to the ocular surfaces and tend to produce severe intraocular inflammation.