Microcomputer-based recording system for clinical electrophysiology

We developed a personal computer-based system for clinical electrophysiologic measurements. The computer interfaced with a commercially available A/D converter, a low-noise isolation preamplifier, filter circuits, pattern and Ganzfeld stimulators, and a hardcopy unit. Separate programs were developed for electroretinography (ERG), pattern ERG and simultaneus visual evoked potential (VEP), flash and pattern-shift VEP, and electro-oculographic measurements. The complete control of the applied hardware (eg, stimulus control, automatic gain, and filter selection) is a common feature of the computer programs. These programs provide oscilloscopic functions, overload protection, artifact elimination, averaging, automatic peak latency and amplitude determination, baseline correction, smoothing, and digital filtering. The results can be presented on matrix, laser printers, or digital plotters. The hardware components and the features of the driver software are demonstrated on normal and pathologic signals.     

Effects of cyamemazine on hERG, INa, ICa, Ito, Isus and IK1 channel currents, and on the QTc interval in guinea pigs

The antipsychotic and anxiolytic phenothiazine, cyamemazine, was investigated for its effects on the hERG (human ether-à-go-go related gene) channel expressed in HEK 293 cells and on native INa, ICa, Ito, Isus, or IK1 of human atrial myocytes. Moreover, cyamemazine and terfenadine were compared for their effects on the QT interval in anesthetized guinea pigs. Cyamemazine reduced hERG current amplitude with an IC50 value of 470 nM. Cyamemazine 1 microM failed to significantly affect INa, Ito, Isus, or IK1 amplitudes and slightly decreased ICa (18%). For comparison, haloperidol (30 nM) and olanzapine (300 nM) reduced hERG current amplitude by 44.2+/-3.9% and 49.7+/-4.2%, respectively. The cardiac safety ratio of cyamemazine, calculated from the IC50/receptor affinity ratios, is 81 and 313 against dopamine D2 receptors and 5-HT2A receptors, respectively. In guinea pigs, QT and QTcBazett were not significantly modified by intravenous cyamemazine when compared to the effects produced by the vehicle. Conversely, terfenadine (5 mg/kg iv) increased significantly QTcBazett (+58 ms), QTcFrediricia (+83 ms) and QTcVan de Water (+78 ms). In conclusion, cyamemazine concentrations required to inhibit hERG current exceed substantially those necessary to achieve therapeutic activity in humans. Moreover, cyamemazine, in contrast to terfenadine, does not delay cardiac repolarization in the anesthetized guinea pig. These non-clinical findings confirm the excellent cardiac safety records of cyamemazine during its 30 years of extensive therapeutic use.     

A comparison of pattern and multifocal electroretinography in the evaluation of age-related macular degeneration and its treatment with photodynamic therapy

This study compares pattern electroretinography (PERG) and multifocal electroretinography (mfERG) measures in 13 patients with predominantly classic choroidal neovascularisation (CNV) associated with age-related macular degeneration (ARMD, 9/13 unilateral, 4/13 bilateral), assesses the usefulness of each test in monitoring disease progression, and identifies electrophysiological predictors of outcome following treatment with photodynamic therapy (PDT). PERG and mfERGs were recorded at presentation, 2 weeks post-treatment, and at 3 monthly intervals for 2 years. The PERG was detectable in 8/13 patients with unilateral disease; the mfERG was detectable in 12/13 patients. P50 and N95 amplitudes increased in 6/8 patients and mfERG p1 increased in 7/13 patients at 2 years. PERG amplitudes correlated strongly with mfERG amplitudes in patients with unilateral disease. PERG P50 and mfERG p1 amplitude correlated with visual acuity at 2 years (R = 0.68, R = 0.82, respectively). The largest PERG P50 and mfERG p1 amplitude difference between treated and fellow eyes of all the groups on initial visit was associated with a poor visual outcome (P50 64% difference; p1 29% difference) whereas those with the smallest P50 and p1 amplitude difference was associated with improved vision at 2 years (P50 30% difference; p1 21% difference). The PERG and mfERG provide an objective measure of central retinal function in the progression of ARMD. A detectable PERG on presentation was the single best indicator of improved function and visual acuity at 2 years. The mfERG demonstrated disease progression from central retina into the paramacular regions over 2 years. Patients with poor visual outcomes had the largest inter-ocular amplitude difference on presentation, suggesting that such patients may have a worse prognosis following treatment.In part presented at ARVO 2004 (Fort Lauderdale, USA) and ISCEV 2004 (Peurto Rico, USA).     

Early colour deprivation in the pigeon

When cats and monkeys are deprived of specific stimuli during an early sensitive period the development of their visual system is known to be affected. In pigeons, pattern discrimination learning has been shown to be affected by monocular deprivation [2]. Our study was set up to examine whether colour discrimination learning could be affected by colour deprivation. Young pigeons were reared under restricted colour illumination for at least 3 months after hatching so as to obtain a group bred under red illumination, one bred under blue illumination and a control group. After this period several psychophysical tests were used to test the pigeons' sense of colour. No significant difference was found between the ‘deprived’ birds and the controls. The spectral sensitivity, determined with the help of the ERG, did not differ for the three groups. We conclude that early colour deprivation does not affect visual development in the pigeon.     

LED-generated Multifocal ERG On- and Off-responses in Complete Congenital Stationary Night Blindness – A Case Report

We report on the application of a light emitting diode (LED) screen to elicit multifocal ERG on- and off-responses in a patient presenting with the complete type of congenital stationary night blindness (cCSNB): A 63-years old woman was diagnosed with cCSNB by means of standard ERG procedures and dark adaptometry. To confirm this diagnosis and to investigate topographical differences of on- and off-responses a multifocal approach employing long-duration stimuli was added. Results of mfERG-testing were averaged in three groups (a central area of 7.5°, a ring area of 7.5–21.9° and a peripheral ring of 21.9–31.1°). When compared to normal controls (n = 4) on-responses (P1-amplitudes) were severely reduced symmetrically at all eccentricities, while off-responses showed no reduction resulting in an increased off/on-ratio. Furthermore on-latencies of P1 were delayed symmetrically at all eccentricities, whereas off-latencies were normal. To our knowledge this is the first report of multifocal on- and off-responses in a CSNB-patient. Stimulus-generation with a LED-screen provides the advantage of a stable luminance during the long-duration on-phase. Presented in part at the 102^nd meeting of the German Academy of Ophthalmology, Berlin (Germany), 22–26 September 2004.     

Multifocal ERG in Subjects with a History of Retinopathy of Prematurity

Purpose: Investigate the function of the central retina in subjects with a history of retinopathy of prematurity (ROP). Methods: Multifocal electroretinogram (mfERG) responses to a scaled array of 103 hexagons were recorded in subjects, aged 11–23 years (N = 11), with a documented history of mild ROP. The amplitude and implicit time of the components (N₁, P₁, N₂) of the first order kernel for six concentric rings were compared to those of control subjects (N = 9). Results: The amplitude of each component varied significantly with eccentricity in both ROP and control subjects and was significantly smaller in the ROP subjects. The discrepancy between ROP and control subjects was greatest for central rings (1–3) and smaller for peripheral rings (4–6). The slopes of the functions summarizing log response density as a function of log eccentricity (degrees visual angle) were significantly shallower in ROP subjects. The implicit time of each component was longer in ROP subjects at all eccentricities. Conclusions: ROP associated alterations in neural retinal development may underlie the subtle macular dysfunction disclosed by the mfERG.     

Cytokeratin-positive epithelioid angiosarcoma presenting in the tonsil: a diagnostic challenge

Primary oral cavity sarcomas are exceedingly rare and may pose a great diagnostic challenge. A 71-year-old woman without history of malignancy or radiation to the head and neck presented with an antibiotic-refractory diffuse painful swelling of the right tonsil necessitating tonsillectomy. Histologic evaluation revealed subtotal replacement of the right tonsil by a high-grade epithelioid neoplasm displaying extensive ulceration, necrosis, and primitive vasoformation. Immunohistochemistry showed strong/diffuse expression of pancytokeratin antibodies KL-1 and Lu5, cytokeratin 8, cytokeratin 18, cytokeratin 19, vimentin, CD31, ERG, and Freund leukemia integration site 1 (FLI-1). High-molecular-weight cytokeratins (cytokeratin 5, 34β12), cytokeratin 7, cytokeratin 13, and cytokeratin 20 were not expressed. Within months, the patient underwent surgical resection of multiple bleeding intraoral and gastrointestinal metastases. She is currently alive with disease 9 months from diagnosis. To our knowledge, this case represents the first well-documented primary epithelioid angiosarcoma of the tonsil. The strong cytokeratin expression in epithelioid angiosarcomas represents a diagnostic pitfall. Thus, awareness of this rare and highly aggressive neoplasm is necessary for distinguishing it from poorly differentiated and acantholytic squamous cell carcinoma and diffuse large cell lymphoma.     

PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer

What’s known on the subject? and What does the study add? So far we know that ERG rearrangements and PTEN deletions interact to induce prostate cancer in transgenic mice. The study confirms that an association also exists between the two genetic aberrations in human prostate cancer, as there is increased incidence of PTEN deletions in cases with ERG rearrangements.

OBJECTIVE

To investigate the interaction between, and significance of, ERG gene rearrangements and PTEN genomic deletions in relation to the development and progression of prostate cancer (PCA).

PATIENTS AND METHODS

We interrogated an initial cohort of 220 men with localized PCA using fluorescence in situ hybridization for ERG rearrangements and PTEN genomic deletions.

RESULTS

The incidences of ERG rearrangements and PTEN deletions in PCA were significantly higher than in high‐grade prostatic intra‐epithelial neoplasia (HGPIN) and benign prostate tissue (P < 0.001). ERG rearrangements and PTEN deletions were detected in 41.9 and 42.6% of patients’ tumours, respectively. ERG rearrangements were never detected in benign prostate tissue, while PTEN aberrations were present at a basal level of 4.6%. PTEN hemizygous deletions showed higher frequency than homozygous deletions within each diagnostic category from benign prostate tissue to HGPIN and PCA (P ≤ 0.001). Furthermore, in 29 patients where all three tissues were available, PTEN genomic aberrations in PCA were significantly different from those in benign tissue (P = 0.005) and HGPIN (P = 0.02), reflecting the accumulation of genomic aberrations in the early stages of disease progression. Within this cohort, 71.4% of homozygous and 44.2% of hemizygous PTEN deletions occurred simultaneously with ERG rearrangements (P ≈ 0). Stratified according to Gleason score (GS), hemizygous PTEN deletions across various GS groups were observed at a higher frequency than homozygous deletions. However, PTEN homozygous deletions showed positive trends with higher GS, increasing in poorly differentiated PCA (GS 8–10) in comparison to moderately and well differentiated tumours (GS 6 and 7).

CONCLUSION

We show significant association between ERG gene rearrangements and PTEN genomic aberrations in subset of PCA. Our analysis also provides further support for the observation that homozygous PTEN deletions can occur within the subset of HGPIN lesions, and shows accumulating genetic aberrations with disease progression, evidenced by higher detection in PCA than in HGPIN and more PTEN homozygous deletions in GS 8–10 than in 6–7.     

Intrafamilial variability of the ocular phenotype in a Polish family with a missense mutation (A63D) in the Norrie disease gene

Purpose: To describe the phenotypic variability in a Polish Norrie disease (ND) family associated with the missense mutation A63D. Methods: A patient with spared vision from a Polish ND family underwent detailed ophthalmological examinations including slit-lamp biomicroscopy, ultrasound (USG), angiography, Goldmann kinetic visual field, and electroretinography (ERG). Mutation screening was carried out using the single-strand conformation polymorphism (SSCP) technique and subsequent DNA sequencing of the coding part of the ND gene. Results: A mutation was detected (exon 3, A63D) in a large Polish family with 12 affected males, all but one presenting with classical ND symptoms. In one male, partially preserved vision was observed up to 40 years of age (distance acuity of the right eye 1/50 and left eye 2/50). Slit-lamp examination revealed remnants of a persistent primary vitreous and hyaloid artery. Upon angiography, the retina was vascularized within the posterior pole but not in the periphery. The ERG revealed pathological changes characteristic for chorioretinal degenerations. Conclusion: Within one family, individuals with identical sequence alterations in the ND gene can show remarkable phenotypic variablity of the ocular symptoms. These findings indicate the involvement of additional factors (epigenetic or genetic) in ocular pathogenesis of ND.