Temperature-dependent autoactivation associated with clinical variability of PDGFRB Asn666 substitutions.

Ocular pterygium-digital keloid dysplasia (OPDKD) presents in childhood with ingrowth of vascularized connective tissue on the cornea leading to severely reduced vision. Later the patients develop keloids on digits but are otherwise healthy. The overgrowth in OPDKD affects body parts that typically have lower temperature than 37°C. We present evidence that OPDKD is associated with a temperature sensitive, activating substitution, p.(Asn666Tyr), in PDGFRB. Phosphorylation levels of PDGFRB and downstream targets were higher in OPDKD fibroblasts at 37°C but were further greatly increased at the average corneal temperature of 32°C. This suggests that the substitution cause significant constitutive autoactivation mainly at lower temperature. In contrast, a different substitution in the same codon, p.(Asn666Ser), is associated with Penttinen type of premature aging syndrome. This devastating condition is characterized by widespread tissue degeneration, including pronounced chronic ulcers and osteolytic resorption in distal limbs. In Penttinen syndrome fibroblasts, equal and high levels of phosphorylated PDGFRB was present at both 32°C and 37°C. This indicates that this substitution causes severe constitutive autoactivation of PDGFRB regardless of temperature. In line with this, most downstream targets were not affected by lower temperature. However, STAT1, important for tissue wasting, did show further increased phosphorylation at 32°C. Temperature-dependent autoactivation offers an explanation to the strikingly different clinical outcomes of substitutions in the Asn666 codon of PDGFRB.

A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome.

Missense variants located to the "molecular brake" in the tyrosine kinase hinge region of platelet-derived growth factor receptor-ß, encoded by PFGFRB, can cause Penttinen-type (Val665Ala) and Penttinen-like (Asn666His) premature ageing syndromes, as well as infantile myofibromatosis (Asn666Lys and Pro660Thr). We have found the same de novo PDGFRB c.1997A>G p.(Asn666Ser) variants in two patients with lipodystrophy, acro-osteolysis and severely reduced vision due to corneal neovascularisation, reminiscent of a severe form of Penttinen syndrome with more pronounced connective tissue destruction. In line with this phenotype, patient skin fibroblasts were prone to apoptosis. Both in patient fibroblasts and stably transduced HeLa and HEK293 cells, autophosphorylation of PDGFRß was observed, as well as increased phosphorylation of downstream signalling proteins such as STAT1, PLCγ1, PTPN11/SHP2-Tyr580 and AKT. Phosphorylation of MAPK3 (ERK1) and PTPN11/SHP2-Tyr542 appeared unaffected. This suggests that this missense change not only weakens tyrosine kinase autoinhibition, but also influences substrate binding, as both PTPN11 tyrosines (Tyr542 and Tyr580) usually are phosphorylated upon PDGFR activation. Imatinib was a strong inhibitor of phosphorylation of all these targets, suggesting an option for precision medicine based treatment.

Correlation between observation task performance and visual acuity, contrast sensitivity and environmental light in a simulated maritime study.

PURPOSE: To examine the relevance of visual acuity (VA) and index of contrast sensitivity (ICS) as predictors for visual observation task performance in a maritime environment. METHODS: Sixty naval cadets were recruited to a study on observation tasks in a simulated maritime environment under three different light settings. Their ICS were computed based on contrast sensitivity (CS) data recorded by Optec 6500 and CSV-1000E CS tests. The correlation between object identification distance and VA/ICS was examined by stepwise linear regression. RESULTS: The object detection distance was significantly correlated to the level of environmental light (p < 0.001), but not to the VA or ICS recorded in the test subjects. Female cadets had a significantly shorter target identification range than the male cadets. CONCLUSION: Neither CS nor VA were found to be significantly correlated to observation task performance. This apparent absence of proven predictive value of visual parameters for observation tasks in a maritime environment may presumably be ascribed to the normal and uniform visual capacity in all our study subjects.

Contrast sensitivity measured by two different test methods in healthy, young adults with normal visual acuity.

PURPOSE: This study reports contrast sensitivity (CS) reference values obtained by two different test methods in a strictly selected population of healthy, young adults with normal uncorrected visual acuity. Based on these results, the index of contrast sensitivity (ICS) is calculated, aiming to establish ICS reference values for this population and to evaluate the possible usefulness of ICS as a tool to compare the degree of agreement between different CS test methods. METHODS: Military recruits with best eye uncorrected visual acuity 0.00 LogMAR or better, normal colour vision and age 18-25 years were included in a study to record contrast sensitivity using Optec 6500 (FACT) at spatial frequencies of 1.5, 3, 6, 12 and 18 cpd in photopic and mesopic light and CSV-1000E at spatial frequencies of 3, 6, 12 and 18 cpd in photopic light. Index of contrast sensitivity was calculated based on data from the three tests, and the Bland-Altman technique was used to analyse the agreement between ICS obtained by the different test methods. RESULTS: A total of 180 recruits were included. Contrast sensitivity frequency data for all tests were highly skewed with a marked ceiling effect for the photopic tests. The median ICS for Optec 6500 at 85 cd/m2 was -0.15 (95% percentile 0.45), compared with -0.00 (95% percentile 1.62) for Optec at 3 cd/m2 and 0.30 (95% percentile 1.20) FOR CSV-1000E. The mean difference between ICSFACT 85 and ICSCSV was -0.43 (95% CI -0.56 to -0.30, p<0.00) with limits of agreement (LoA) within -2.10 and 1.22. The regression line on the difference of average was near to zero (R2=0.03). CONCLUSION: The results provide reference CS and ICS values in a young, adult population with normal visual acuity. The agreement between the photopic tests indicated that they may be used interchangeably. There was little agreement between the mesopic and photopic tests. The mesopic test seemed best suited to differentiate between candidates and may therefore possibly be useful for medical selection purposes.

Contrast sensitivity and the effect of 60-hour sleep deprivation.

PURPOSE: The study aimed to evaluate the possible influence of prolonged sleep deprivation on achromatic and chromatic (red-green and blue-yellow) contrast sensitivity (CS). METHODS: During 60-hr sleep deprivation, CS was measured in 11 naval officers every sixth hour using videographic (Vigra-C) sine-wave-generated stimuli. RESULTS: When comparing the CS measurements obtained in the first and last 24 hr of the study, no statistically significant mean changes of achromatic CS (2.0, 5.9 and 11.8 cpd) or yellow-blue CS (0.6, 2.0 and 4.7 cpd) were found, while a significantly increased mean red-green CS at 2.0 and 4.7 cpd was recorded in the last 24 hr (p = 0.003 in both). The variance of achromatic and chromatic CS measurements in the group did not differ significantly in the first and last 24 hr test periods. CONCLUSIONS: Prolonged sleep deprivation does apparently not cause clinically or occupationally significant changes of contrast sensitivity in otherwise healthy subjects with normal visual acuity.

Ocular pterygium--digital keloid dysplasia.

We describe an adolescent Peruvian male with marked, aggressive ingrowth of conjunctiva (pterygium-like) over the cornea associated with keloid formation on his distal limbs. He has in addition camptodactyly of all fingers and to some extent of his toes, and unusual skin pigmentations. He resembles an earlier described family from Norway in which a mother and two children showed a similar combination of signs. We present the follow-up of the Norwegian family. The entity resembles the Penttinen syndrome but can be differentiated due to the early aging in the latter, which is lacking in the presently reported entity. We suggest naming this entity ocular pterygium-digital keloid dysplasia. The condition follows likely an autosomal dominant pattern of inheritance.

Matching fundus photographs of classmates. An informal competition to promote learning and practice of direct ophthalmoscopy among medical students.

PURPOSE: To present a new approach for teaching direct ophthalmoscopy to medical students. METHODS: At the University of Bergen, four consecutive classes of fourth-year medical students complete a required 9-week ophthalmology course every year. In the present project, one fundus photograph was taken of each student. The photographs were randomly numbered, printed on A4 glossy photo paper, and displayed on the classroom wall. Each student was given a form to fill in the fellow students' names matching the number of the fundus photographs. They were encouraged to practise direct ophthalmoscopy on their classmates outside formal teaching hours. At the end of the course, they returned the filled-in forms, and those with the highest number of correct matches between the fundus photographs and fellow students received a reward. RESULTS: Between 2011 and 2013, 239 students completed their ophthalmology course. Of these, 220 students (92%) voluntarily participated in the project. The mean score was 70% correct matches between fundus photographs and fellow students (range 7 - 100%). The students' course evaluations were overall positive. CONCLUSIONS: We recommend the use of peer fundus photographs in the context of a learning competition as a simple, inexpensive, and effective way to improve teaching of direct ophthalmoscopy.

Acute bacterial conjunctivitis.

Acute bacterial conjunctivitis is the eye disease most commonly seen by general practitioners, and is estimated to represent approximately 1% of all consultations in primary care. This article gives a review of the epidemiology, aetiology, clinical picture, complications, differential diagnoses, in vitro examinations and therapy of acute bacterial conjunctivitis. Until now, topical antibacterial therapy has generally been preferred by both physicians and patients because this will usually shorten the course of the disease slightly and allow the early readmittance of children to their kindergarten or school. Recently, several reports from primary care have confirmed the well-known clinical experience that the disorder has an excellent prognosis with a high frequency of spontaneous remission. In accordance, an expectant attitude or delayed prescription policy are now frequently strongly recommended. However, these reports also emphasize the difficulty in making a correct clinical distinction between bacterial and viral conjunctivitis. The effect of a general non-prescription attitude on transmission rates of pathogens also remains to be clarified. This must be born in mind when deciding how these patients should be handled. The socioeconomic and medical pros and cons of different treatment policies are discussed, and a highly personal view on the optimal handling strategy for these patients is also presented.

Nordic research in ophthalmology.

Nordic ophthalmologists and vision scientists are active in many fields of eye research. This is most evident at the biannual Nordic Congress of Ophthalmology, most recently held in Malmö in June 2004. The authors here review some of the research in vision and ophthalmology presented at this meeting or published recently by Nordic scientists. This paper does not represent a comprehensive review of all Nordic research in the field, but attempts to give an overview of some of the activities underway in eye research in this part of the world.

The influence of donor age and cause of death on corneal endothelial cell density.

PURPOSE: To evaluate the joint effects of donor age and cause of death on the endothelial cell density of fresh human corneas. METHODS: The corneal endothelial cell density of 946 eyes from 946 donors was analysed. The donors were divided into three age groups: group 1 comprised those aged 50 years and less; group 2 those aged 51-75 years, and group 3 those aged over 75 years. They were also grouped according to the cause of death: group A included those who had died of cancer; group B those who had died of acute myocardial infarction, pulmonary embolism or intracerebral haemorrhage, and group C those who had died as a result of other diseases. RESULTS: There was a statistically significant negative correlation between donor age and mean corneal endothelial cell density, which was 2868 +/- 309 cells/mm(2) in group 1, 2716 +/- 335 cells/mm(2) in group 2, and 2670 +/- 368 cells/mm(2) in group 3. Among the various causes of death, the mean endothelial cell density was 2677 +/- 343 cells/mm(2) in group A, 2741 +/- 367 cells/mm(2) in group B, and 2713 +/- 337 cells/mm(2) in group C. The endothelial cell density was significantly lower in group A than in group B (p = 0.02). When the donors in the oldest age group (group 3) were analysed according to the various causes of death, the difference between group A (2603 +/- 342 cells/mm(2)) and group B (2729 +/- 338 cells/mm(2)) was even more significant (p = 0.0067). CONCLUSION: Longlasting, severe diseases like cancer, leading to cachexia and catabolism, reduce the number of endothelial cells to a greater degree than diseases that cause a more rapid death. This negative effect of cancer on endothelial cell density is aggravated by the general decline in endothelial cell density with advancing age.

[Can work-related eye injuries be avoided?]. / Kan arbeidsrelaterte øyeskader unngås?

BACKGROUND: The eyes are among the organs most frequently hurt in occupational injuries. The characteristics of eye injuries were studied in order to suggest preventive measures. MATERIAL AND METHODS: Analyses were performed on work-related eye injuries reported to the Norwegian Injury Surveillance System from a selection of emergency centres during the period 1990-2002, and on injuries reported by employers to the National Insurance Administration 1998-2001. RESULTS: The occurrence of injuries was stable over the period. Men sustained 94.4% of the injuries registered in injury surveillance system. The highest incidence was among those 20 to 24 years of age. Metal cutters and tools for polishing were involved in 25.7% of cases. Analyses of the injuries reported to the National Insurance Administration showed an odds ratio of 8.8 (95% CI 7.6-10.1) for injuries to workers in metal industry, 18.8 (95% CI 17.0-20.8) in automotive industry, and only 0.5 (95% CI 0.1-3.4) in oil refineries. Workers in oil refineries have a potentially hazardous work environment, but there, eye protection is mandatory. INTERPRETATION: There was no decline in the incidence of work-related eye injuries from 1990 to 2002. Workers in metal industry have a high risk of injuries and employers should consider requiring the use of eye protection.

[Acute bacterial conjunctivitis]. / Akutt bakteriell konjunktivitt.

Acute infectious conjunctivitis is the eye disease most commonly seen by general practitioners, and is estimated to represent 2-3% of their total number of consultations. The present paper gives a review of the epidemiology, etiology, clinical picture, complications, differential diagnoses and therapy of acute bacterial conjunctivitis. The condition has an excellent prognosis with a high frequency of spontaneous remission. However, topical antibacterial therapy should always be instituted, because this will shorten the course of the disease and reduce the risk of epidemic outbreaks, particularly in institutions for children.

[Ocular changes in Down syndrome]. / Øyeforandringer ved Downs syndrom.

BACKGROUND, MATERIAL AND METHODS: Down's syndrome is the most common cause of mental retardation with an incidence of about 1.5/1000 live births. Life expectancy and quality of life have improved substantially for this group over the last decades. The aim of this paper is to give an updated short survey of ocular changes present in Down's syndrome based on current international literature and the clinical experience of the authors. RESULTS AND INTERPRETATION: Ocular problems are common, mostly refractive errors, poor accommodation, strabismus, cataract, and keratoconus. Accommodation deficit is present in a majority of individuals with Down's syndrome, also in children and young people. Bifocal or progressive glasses should therefore be prescribed liberally. Because of the high frequency of ocular pathology, all individuals with Down's syndrome should be enrolled in a continuous visual screening programme from birth. We suggest the following screening guidelines: first examination at one month of age, then at one year of age, at 2-3 years of age, at 5-6 years of age (school start), and thereafter every five years. In case of positive findings (e.g. refractive errors, poor accommodation, strabismus) the frequency of examination should be increased and determined individually by the responsible ophthalmologist.