Redox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate.

Neural stem cell (NSC) maintenance and functions are regulated by reactive oxygen species (ROS). However, the mechanisms by which ROS control NSC behavior remain unclear. Here we report that ROS-dependent Igfbp2 signaling controls DNA repair pathways which balance NSC self-renewal and lineage commitment. Ncf1 or Igfbp2 deficiency constrains NSCs to a self-renewing state and prevents neurosphere formation. Ncf1-dependent oxidation of Igfbp2 promotes neurogenesis by NSCs in vitro and in vivo while repressing Brca1 DNA damage response genes and inducing DNA double-strand breaks (DDSBs). By contrast, Ncf1-/- and Igfbp2-/- NSCs favor the formation of oligodendrocytes in vitro and in vivo. Notably, transient repression of Brca1 DNA repair pathway genes induces DDSBs and is sufficient to rescue the ability of Ncf1-/- and Igfbp2-/- NSCs to lineage-commit to form neurospheres and neurons. NSC lineage commitment is dependent on the oxidizable cysteine-43 residue of Igfbp2. Our study highlights the role of DNA damage/repair in orchestrating NSC fate decisions downstream of redox-regulated Igfbp2.

Closed-loop optogenetic control of the dynamics of neural activity in non-human primates.

Electrical neurostimulation is effective in the treatment of neurological disorders, but associated recording artefacts generally limit its applications to open-loop stimuli. Real-time and continuous closed-loop control of brain activity can, however, be achieved by pairing concurrent electrical recordings and optogenetics. Here we show that closed-loop optogenetic stimulation with excitatory opsins enables the precise manipulation of neural dynamics in brain slices from transgenic mice and in anaesthetized non-human primates. The approach generates oscillations in quiescent tissue, enhances or suppresses endogenous patterns in active tissue and modulates seizure-like bursts elicited by the convulsant 4-aminopyridine. A nonlinear model of the phase-dependent effects of optical stimulation reproduced the modulation of cycles of local-field potentials associated with seizure oscillations, as evidenced by the systematic changes in the variability and entropy of the phase-space trajectories of seizures, which correlated with changes in their duration and intensity. We also show that closed-loop optogenetic neurostimulation could be delivered using intracortical optrodes incorporating light-emitting diodes. Closed-loop optogenetic approaches may be translatable to therapeutic applications in humans.

Ferret Lung Transplantation Models Differential Lymphoid Aggregate Morphology Between Restrictive and Obstructive Forms of Chronic Lung Allograft Dysfunction.

BACKGROUND: Long-term survival after lung transplantation remains limited by chronic lung allograft dysfunction (CLAD). CLAD has 2 histologic phenotypes, namely obliterative bronchiolitis (OB) and restrictive alveolar fibroelastosis (AFE), which have distinct clinical presentations, pathologies, and outcomes. Understanding of OB versus AFE pathogenesis would improve with better animal models. METHODS: We utilized a ferret orthotopic single-lung transplantation model to characterize allograft fibrosis as a histologic measure of CLAD. Native lobes and "No CLAD" allografts lacking aberrant histology were used as controls. We used morphometric analysis to evaluate the size and abundance of B-cell aggregates and tertiary lymphoid organs (TLOs) and their cell composition. Quantitative RNA expression of 47 target genes was performed simultaneously using a custom QuantiGene Plex Assay. RESULTS: Ferret lung allografts develop the full spectrum of human CLAD histology including OB and AFE subtypes. While both OB and AFE allografts developed TLOs, TLO size and number were greater with AFE histology. More activated germinal center cells marked by B-cell lymphoma 6 Transcription Repressor, (B-cell lymphoma 6) expression and fewer cells expressing forkhead box P3 correlated with AFE, congruent with greater diffuse immunoglobulin, plasma cell abundance, and complement 4d staining. Furthermore, forkhead box P3 RNA induction was significant in OB allografts specifically. RNA expression changes were seen in native lobes of animals with AFE but not OB when compared with No CLAD native lobes. CONCLUSIONS: The orthotopic ferret single-lung transplant model provides unique opportunities to better understand factors that dispose allografts to OB versus AFE. This will help develop potential immunomodulatory therapies and antifibrotic approaches for lung transplant patients.

Ferret models of alpha-1 antitrypsin deficiency develop lung and liver disease.

Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause and risk factor for chronic obstructive pulmonary disease, but the field lacks a large-animal model that allows for longitudinal assessment of pulmonary function. We hypothesized that ferrets would model human AATD-related lung and hepatic disease. AAT-knockout (AAT-KO) and PiZZ (E342K, the most common mutation in humans) ferrets were generated and compared with matched controls using custom-designed flexiVent modules to perform pulmonary function tests, quantitative computed tomography (QCT), bronchoalveolar lavage (BAL) proteomics, and alveolar morphometry. Complete loss of AAT (AAT-KO) led to increased pulmonary compliance and expiratory airflow limitation, consistent with obstructive lung disease. QCT and morphometry confirmed emphysema and airspace enlargement, respectively. Pathway analysis of BAL proteomics data revealed inflammatory lung disease and impaired cellular migration. The PiZ mutation resulted in altered AAT protein folding in the liver, hepatic injury, and reduced plasma concentrations of AAT, and PiZZ ferrets developed obstructive lung disease. In summary, AAT-KO and PiZZ ferrets model the progressive obstructive pulmonary disease seen in AAT-deficient patients and may serve as a platform for preclinical testing of therapeutics including gene therapy.

Lack of CFTR alters the ferret pancreatic ductal epithelial secretome and cellular proteome: Implications for exocrine/endocrine signaling.

BACKGROUND: Cystic fibrosis (CF) related diabetes is the most common comorbidity for CF patients and associated with islet dysfunction. Exocrine pancreas remodeling in CF alters the microenvironment in which islets reside. Since CFTR is mainly expressed in pancreatic ductal epithelium, we hypothesized altered CF ductal secretions could impact islet function through paracrine signals. METHOD: We evaluated the secretome and cellular proteome of polarized WT and CF ferret ductal epithelia using quantitative ratiometric mass spectrometry. Differentially secreted proteins (DSPs) or expressed cellular proteins were used to mine pathways, upstream regulators and the CFTR interactome to map candidate CF-associated alterations in ductal signaling and phenotype. Candidate DSPs were evaluated for their in vivo pancreatic expression patterns and their functional impact on islet hormone secretion. RESULTS: The secretome and cellular proteome of CF ductal epithelia was significantly altered relative to WT and implicated dysregulated TGFß, WNT, and BMP signaling pathways. Cognate receptors of DSPs from CF epithelia were equally distributed among endocrine, exocrine, and stromal pancreatic cell types. IGFBP7 was a downregulated DSP in CF ductal epithelia in vitro and exhibited reduced CF ductal expression in vivo. IGFBP7 also altered WT islet insulin secretion in response to glucose. Many CFTR-associated proteins, including SLC9A3R1, were differentially expressed in the CF cellular proteome. Upstream regulators of the differential CF ductal proteome included TGFß, PDX1, AKT/PTEN, and INSR signaling. Data is available via ProteomeXchange with identifier PXD025126. CONCLUSION: These findings provide a proteomic roadmap for elucidating disturbances in autocrine and paracrine signals from CF pancreatic ducts and how they may alter islet function and maintenance.

Silicone encapsulation of thin-film SiOx, SiOxNyand SiC for modern electronic medical implants: a comparative long-term ageing study.

Objective.Ensuring the longevity of implantable devices is critical for their clinical usefulness. This is commonly achieved by hermetically sealing the sensitive electronics in a water impermeable housing, however, this method limits miniaturisation. Alternatively, silicone encapsulation has demonstrated long-term protection of implanted thick-film electronic devices. However, much of the current conformal packaging research is focused on more rigid coatings, such as parylene, liquid crystal polymers and novel inorganic layers. Here, we consider the potential of silicone to protect implants using thin-film technology with features 33 times smaller than thick-film counterparts.Approach.Aluminium interdigitated comb structures under plasma-enhanced chemical vapour deposited passivation (SiOx, SiOxNy, SiOxNy+ SiC) were encapsulated in medical grade silicones, with a total of six passivation/silicone combinations. Samples were aged in phosphate-buffered saline at 67 ∘C for up to 694 days under a continuous ±5 V biphasic waveform. Periodic electrochemical impedance spectroscopy measurements monitored for leakage currents and degradation of the metal traces. Fourier-transform infrared spectroscopy, x-ray photoelectron spectroscopy, focused-ion-beam and scanning-electron- microscopy were employed to determine any encapsulation material changes.Main results.No silicone delamination, passivation dissolution, or metal corrosion was observed during ageing. Impedances greater than 100 GΩ were maintained between the aluminium tracks for silicone encapsulation over SiOxNyand SiC passivations. For these samples the only observed failure mode was open-circuit wire bonds. In contrast, progressive hydration of the SiOxcaused its resistance to decrease by an order of magnitude.Significance.These results demonstrate silicone encapsulation offers excellent protection to thin-film conducting tracks when combined with appropriate inorganic thin films. This conclusion corresponds to previous reliability studies of silicone encapsulation in aqueous environments, but with a larger sample size. Therefore, we believe silicone encapsulation to be a realistic means of providing long-term protection for the circuits of implanted electronic medical devices.

Satisfactory outcomes after orthognathic surgery with surgically assisted rapid maxillary expansion using a hybrid device.

The self-reported functional outcomes, clinical findings, and results of dental cast analysis before and after orthognathic surgery with surgically assisted rapid maxillary expansion (SARME) using a hybrid rapid maxillary expander (RME) were evaluated. Data were collected from 43 patients who underwent orthognathic surgery with SARME using a hybrid RME between 2001 and 2013. The patients were recruited during a follow-up clinical examination and were required to complete a questionnaire about their opinions and self-reported functional outcomes. Dental casts were used to analyze posttreatment palatal expansion. The mean follow-up time was 68 months (range: 25-135 months). The most common indication for SARME was the presence of a crossbite. Of the 30 patients who underwent a follow-up clinical examination (69.8% answer rate), 4 (13.3%) had symptoms of temporomandibular disorder (TMD), 1 (3.3%) experienced myalgia, and 3 (10.0%) experienced arthralgia on clinical palpation. Cast analysis revealed significant palatal expansion. The intercanine distance, intermolar distance, and palatal height were increased by 3, 5, and 2 mm, respectively. Overall, the patients were satisfied with the preoperative information, improved functions, and aesthetic results. The prevalence of TMD symptoms and other side effects following orthognathic surgery with SARME using a hybrid RME was low, and significant palatal expansions were achieved.

Apparatus to investigate the insulation impedance and accelerated life-testing of neural interfaces.

OBJECTIVE: Neural interfaces and other implantable micro-devices that use polymer-encapsulated integrated circuits will only be allowed in medical devices when their lifetimes can be estimated from experimental data. An apparatus has been developed and tested that allows hundreds of insulated samples (interdigitated combs) to be aged under accelerated conditions of high temperature and voltage stress. Occasionally, aging is paused while the sample's impedance is measured; the impedance spectrogram may show degradation as it progresses before failure. APPROACH: The design was based on practical considerations which are reviewed. A Solartron Modulab provides the frequency response analyser and the femtoammeter. The apparatus can accommodate batches of samples at several temperatures and with different aging voltage waveforms. It is important to understand features of the spectra that are not due to comb-comb leakage, but come from other places (for example substrate-solution leakage); some have been observed and investigated using SPICE. MAIN RESULTS: The design is described in detail and test results show that it is capable of making measurements over long periods, at least up to 67 °C. Despite the size of the apparatus, background capacitance is about 1 pF and comb-comb capacitances of about 30 pF can be measured down to 10 mHz, an impedance of about 100 GΩ. An important discovery was the advantage of grounding the bathing solution, primarily in that it raises the measurement ceiling. Observation and SPICE simulation shows that leakage from the substrate to the bathing solution can give phase lags >90°, in contrast to comb-comb leakage which reduces phase lag to <90°. SIGNIFICANCE: The value of this paper is that it will facilitate research into the endurance of small implanted devices because, given a description of a proven apparatus, researchers can start building their own apparatus relatively quickly and with confidence.

The use of tungsten as a chronically implanted material.

This review paper shows that tungsten should not generally be used as a chronically implanted material. The metal has a long implant history, from neuroscience, vascular medicine, radiography, orthopaedics, prosthodontics, and various other fields, primarily as a result of its high density, radiopacity, tensile strength, and yield point. However, a crucial material criterion for chronically implanted metals is their long-term resistance to corrosion in body fluids, either by inherently noble metallic surfaces, or by protective passivation layers of metal oxide. The latter is often assumed for elemental tungsten, with references to its 'inertness' and 'stability' common in the literature. This review argues that in the body, metallic tungsten fails this criterion, and will eventually dissolve into the soluble hexavalent form W6+, typically represented by the orthotungstate [Formula: see text] (monomeric tungstate) anion. This paper outlines the metal's unfavourable corrosion thermodynamics in the human physiological environment, the chemical pathways to either metallic or metal oxide dissolution, the rate-limiting steps, and the corrosion-accelerating effects of reactive oxidising species that the immune system produces post-implantation. Multiple examples of implant corrosion have been reported, with failure by dissolution to varying extents up to total loss, with associated emission of tungstate ions and elevated blood serum levels measured. The possible toxicity of these corrosion products has also been explored. As the field of medical implants grows and designers explore novel solutions to medical implant problems, the authors recommend the use of alternative materials.

Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs.

Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-ß, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals.

Postentry processing of recombinant adeno-associated virus type 1 and transduction of the ferret lung are altered by a factor in airway secretions.

We recently created a cystic fibrosis ferret model that acquires neonatal lung infection. To develop lung gene therapies for this model, we evaluated recombinant adeno-associated virus (rAAV)-mediated gene transfer to the neonatal ferret lung. Unlike in vitro ferret airway epithelial (FAE) cells, in vivo infection of the ferret lung with rAAV1 required proteasome inhibitors to achieve efficient airway transduction. We hypothesized that differences in transduction between these two systems were because of an in vivo secreted factor that alter the transduction biology of rAAV1. Indeed, treatment of rAAV1 with ferret airway secretory fluid (ASF) strongly inhibited rAAV1, but not rAAV2, transduction of primary FAE and HeLa cells. Properties of the ASF inhibitory factor included a strong affinity for the AAV1 capsid, heat-stability, negative charge, and sensitivity to endoproteinase Glu-C. ASF-treated rAAV1 dramatically inhibited apical transduction of FAE ALI cultures (512-fold), while only reducing viral entry by 55-fold, suggesting that postentry processing of virus was influenced by the inhibitor factor. Proteasome inhibitors rescued transduction in the presence of ASF (~1600-fold) without effecting virus internalization, while proteasome inhibitors only enhanced transduction 45-fold in the absence of ASF. These findings demonstrate that a factor in lung secretions can influence intracellular processing of rAAV1 in a proteasome-dependent fashion.

The prevalence of blindness and low vision in older onset diabetes mellitus and associated factors: a community-based study.

PURPOSE: This community-based study was conducted to assess the prevalence and related factors of low vision and legal blindness in older onset diabetic patients (diagnosed at age 30 and older). METHODS: All known diabetic patients who live in the four primary health care center region Abidinpasa Ankara, Turkey (total population: 96,348) were included in this cross-sectional study. The prevalence of known diabetes mellitus is 2.2%, of which 96.6% are older onset and 3.4% are younger onset. RESULTS: In the older onset diabetes group (1289 cases), 10.8% of the population had low vision and only 2.7% had legal blindness. Diabetic retinopathy (DR) was observed in 23.6% of the patients with low vision (42% proliferative DR) and in 62.9% of the patients with legal blindness (90.1 % proliferative DR). CONCLUSIONS: In older onset diabetic patients with low vision, nonproliferative retinopathy was a more frequent cause of impaired vision than proliferative retinopathy. Low vision and legal blindness caused by retinopathy were significantly associated with sex, age at examination, age at diagnosis, duration of diabetes, type of diabetes treatment, and hypertension in univariate analysis. However, in logistic regression analysis, low vision and legal blindness caused by retinopathy were found to be associated with longer duration of diabetes (> or =15 years), use of insulin, and hypertension.

The prevalence of Behçet's disease above the age of 10 years. The results of a pilot study conducted at the Park Primary Health Care Center in Ankara, Turkey.

PURPOSE: The aim of this study was to determine the prevalence of Behçet's disease above the age of 10 years by means of a population-based study. METHODS: The epidemiological investigation (cross-sectional study) was made between May 1997 and May 1998 at the Park Primary Health Care Center, which is one of the education and research divisions of the Department of Public Health, Faculty of Medicine, Ankara University. The research aimed to cover all 17,256 (49.2% male, 50.8% female) inhabitants over 10 years of age living in this area. The screening team first surveyed and selected patients with recurrent aphthous stomatitis. These patients were further examined, free of charge, in the Preventive Ophthalmology Unit of the Public Health Center, at Ibni Sina Hospital's Behçet Center or in other clinics if necessary. In this study the International Study Group For Behçet's disease Criteria were used. RESULTS: As the final result of the screening, 11 female and 5 male patients with Behçet's disease were found (female/male = 2.2). These patients represented 9 already known and 7 newly diagnosed cases of Behçet's disease. The prevalence of Behçet's disease over 10 years of age is 0.11%. CONCLUSION: The existing regional prevalance studies conducted in Turkey have indicated that the real number of Behçet's patients in our country is markedly higher than the number of registered patients. Therefore the National Behçet's Disease Commity and Surveillance System was founded by our research group in December 1999.

A descriptive study on Behçet's disease.

This study was performed in order to evaluate the age, sex, geographical distribution, ocular involvement, age of onset, and attacks in Behçet's disease. We examined 540 Behçet patients between 1973-1993. Of the patients, 453 were male and 87 female (m/f: 5.2/1). The average age was 30.7 +/- 0.35. The disease mostly appeared in the third decade and it was statistically significant that sex affected the age at onset of the initial symptoms. The onset of symptoms was more frequent among males in the 25-29-year age group, and among females below 19 and above 35 years of age. The duration of the disease was 28.7 +/- 3.1 months. The state of ocular attacks were evaluated in 598 eyes of 303 patients who were followed regularly during the first year. The risk and frequency of attacks were greater in the eyes with poorer visual acuity, and in such eyes, the number of attacks was greater < or = 24 while smaller > or = 35 years of age.

Retinal and disc neovascularization in Behçet's disease and efficacy of laser photocoagulation.

BACKGROUND: The vaso-occlusive episodes resulting from Behçet's disease can cause capillary dropout and vascular remodeling. Retinal and disc neovascularizations, which occur as a result of occlusive vasculitis, can cause recurrent vitreal hemorrhages and neovascular glaucoma leading to severe visual impairment. METHODS: 1080 eyes of 540 patients with Behçet's disease were examined between 1973 and 1993. Of the 912 eyes with posterior segment involvement, laser photocoagulation could be performed in 13 of 25 eyes with disc neovascularization (NVD), 12 of 22 eyes with retinal neovascularization (NVE), and 4 of 6 eyes with NVD and NVE. Laser was directed at areas of NVE and retinal capillary nonperfusion. In cases of NVD, panretinal photocoagulation was performed. RESULTS: The rate of regression of NVD was significantly greater in laser-treated eyes than in the untreated group. The results were similar in cases of NVD with NVE. In eyes with NVE which underwent laser photocoagulation, the NVE regressed. None of the treated eyes developed neovascular glaucoma during the follow-up period. Vitreous hemorrhage occurred in two laser-treated eyes. CONCLUSION: Laser photocoagulation is successful in preventing complications of retinal and disc neovascularizations. Thus, in cases of occlusive vasculitis associated with Behçet's disease, laser photocoagulation should be considered for prevention of complications such as vitreous hemorrhage and neovascular glaucoma.

Early and late visual prognosis in solar retinopathy.

BACKGROUND: Solar retinopathy was observed in a total of 86 eyes of 58 patients following the solar eclipse over Turkey in April 1976. The visual prognosis and the presence of late complications were evaluated at the early and late periods. METHODS: Of the 58 patients, 34 (51 eyes) presented during the first week and came for follow-up examination in the succeeding week, also after 1, 3, 12, and 18 months. After that they were examined at yearly intervals (mean 4.2 years). Twenty-four patients (35 eyes) presented during the period between 1 and 11 years post-eclipse and were followed up for a mean period of 3.4 years. After a period of 15 years, all of the patients were invited for re-examination and nine patients (14 eyes) attended. RESULTS: The improvement in visual acuity was observed to have taken place mostly during the first 2 weeks to 1 month after the eclipse. Further improvement in visual acuity was not observed in any of the eyes after the 18-month examination. The improvement in visual acuity was more prominent and earlier in the eyes that had visual acuity of 0.2 or better initially. Only the eyes with initial visual acuity equal to or better than 0.4 had a chance to improve their acuity to 10/10. Having observed the 51 eyes for mean period of 4.2 years and the 35 eyes for 3.4 years, no change in visual acuity was observed. Among the total of 86 eyes, 9 were found to have pseudolamellar macular holes. CONCLUSION: Correlation was found between initial visual acuity and the funduscopic appearance after the 2nd week. Fluorescein angiography was not found to be a conclusive test in solar retinopathy. No late complications were observed.

Dye laser treatment in proliferative diabetic retinopathy and maculopathy.

The aim of this study was to compare the efficacy of various dye laser wavelengths in different forms of retinopathies. The study material consisted of 292 eyes of 210 diabetic retinopathy patients treated with dye laser photocoagulation between 1990 and 1992. All the patients were followed for at least 6 months after photocoagulation. Non-proliferative changes (maculopathy and/or preproliferative retinopathy) were present in 135 (46.3%) and proliferative retinopathy in 157 (53.7%) of the eyes undergoing photocoagulation. Of the 157 eyes with proliferative retinopathy, 60 (20.5%) had disc neovascularization, 71 (24.3%) had retinal neovascularization and 26 (8.9%) had retinitis proliferans. Yellow dye laser (580 nm) was applied in 92 (31.5%) eyes, red dye laser (630 nm) in 120 (41.1%) eyes and both yellow and red dye lasers in 80 (27.4%) eyes. There was no significant difference between the different wavelength groups with regard to visual acuity changes before and after treatment (p < 0.01). Overall, the visual acuity was maintained in 56.2% and improved in 25.0% of the eyes. After panretinal photocoagulation, disc neovascularization regressed partially or completely in 47 (78.3%) of the eyes. There was no significant difference among the various laser wavelengths with regard to treatment efficacy judged by the disappearance or regression of disc neovascularization (p < 0.01). All retinal neovascularizations regressed completely with laser treatment, but in 7 eyes (9.9%) new retinal neovascularizations in previously untreated areas developed. Dye laser has not resulted in any complications. It requires lower power settings compared to argon laser and thus facilitates photocoagulation. Another advantage of dye laser is the ability to use yellow and red wavelengths sequentially.

Medical and surgical aspects of congenital glaucoma.

During the years 1977-1986, 338 patients at the University Eye Clinic were diagnosed as having congenital glaucoma. This paper presents our experience of the management of 88 of these patients (161 eyes) who had a follow-up of at least 3 years. Medical therapy alone reduced the intraocular pressure to less than 21 mmHg in 17 eyes (11.8%) in the short-term and in 14 eyes (9.7%) in the long-term. Surgical intervention in 127 eyes (goniotomy: 9 eyes; trabeculotomy: 3 eyes; peripheral iridencleisis: 4 eyes; Elliott trephine; 23 eyes; trabeculectomy: 88 eyes), resulted in an immediate normalization of intraocular pressure in 98 eyes (77%, reducing to 66% at the final examination). Trabeculectomy normalized the intraocular pressure in 84% of eyes in the short-term and 76% in the long-term. Trabeculectomy is recommended as the surgical management of choice in congenital glaucoma in societies where presentation is late, or where individual surgeons may not be conversant with goniotomy.

Natural progression of age-related macular degeneration.

We planned to study the natural progression of age-related macular degeneration, not treated by laser photocoagulation, in 3172 eyes of 1642 patients seen by us between 1969 and 1989. The results were available in 1576 eyes of 811 patients followed for six to 180 months (median, 24 months). We came to the following conclusions: nonexudative lesions were more frequent (67%) and the incidence of exudative lesions increased in proportion to patient age and the duration of the disease, influencing the prognosis more adversely than do nonexudative ones.

Visualization of retinal vasculitis in Eales' disease.

Between 1970 and 1991 the authors examined 466 patients with Eales' disease. The mean age at diagnosis was 30, ranging between 14 and 55 years. The mean follow-up period was 43.5 months. At the initial examination, 356 cases were bilateral and 110 cases were unilateral (822 eyes). Vitreous hemorrhage was present in 257 of the 822 eyes. In the remaining 565 eyes, the major retinal lesions were retinal neovascularization (40.7%), vascular sheathing (20.7%), vascular sheathing and retinal hemorrhages (10.6%), retinitis proliferans (9.4%), disc neovascularization (9.0%), branch vein occlusion (3.2%), tractional retinal detachment (2.4%), central vein occlusion (1.8%), central vascular sheathing (1.1%), obliterated vessels (1.1%). Forty-nine out of the 110 initially unilateral cases eventually developed bilateral involvement after a mean period of 42 months. The percentage of eyes with a vision of 0.1 and better rose from 68.1% in the initial examination to 77.9% in the final examination. Fluorescein angiograms of the affected eyes show dye leakage with retinal staining, microaneurysms, capillary non-perfusion and neovascularization. Fundus changes are characteristic of Eales' disease. Unilateral cases should be closely followed because of the risk of involvement of the other eye. Fluorescein angiography is a requirement for early identification of vascular changes and for proper follow-up in Eales' disease.