Long-term visual outcomes and ocular complications in children with Marner's hereditary cataracts operated in the period 1940-2021.

PURPOSE: To investigate visual development and long-term complications after cataract surgery in childhood. METHODS: This cross-sectional study included patients from a family with Marner's hereditary cataracts who had cataract surgery before 18 years of age. The study was conducted from 1 January 2022 until 31 December 2022. The patients contributed to their medical files and participated in an updated ophthalmologic examination. RESULTS: We included 52 patients (101 eyes, 34 females). The median age at cataract surgery was 7 years (IQR: 5-10) and the age at examination was 40 years (IQR: 21-54). Primary and secondary intraocular lens implantation had been performed in 47.5% (25 patients, 48 eyes) and 16.8% (10 patients, 17 eyes). Visual acuity was ≤0.3 logMAR in 77% (78 eyes), and <0.5 logMAR in 8% (8 eyes). Glaucoma was present in 17% (9 patients, 12 eyes), ocular hypertension in 6% (3 patients, 4 eyes), and 10% (5 patients, 5 eyes) had prior retinal detachment. Mild visual field loss (2 < mean defect (MD) ≤ 6 dB) was found in 62% (63 eyes) and moderate to advanced visual field loss (MD > 6 dB) in 24% (24 eyes). Thirty-five patients (67%) held a driver's licence, and three were not allowed to drive due to low visual function. All patients were employed. CONCLUSION: After cataract surgery in childhood, many patients achieve normal visual acuity, but mild visual field loss is common. Long-term follow-up is important due to the high risk of glaucoma.

Anti-TNF Thioester Glucocorticoid Antibody-Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis Model.

We describe the discovery of a thioester-containing glucocorticoid receptor modulator (GRM) payload and the corresponding antibody-drug conjugate (ADC). Payload 6 was designed for rapid hepatic inactivation to minimize systemic exposure of nonconjugated GRM. Mouse PK indicated that 6 is cleared 10-fold more rapidly than a first-generation GRM payload, resulting in 10-fold lower exposure and 3-fold decrease in Cmax. The anti-mTNF conjugate ADC5 fully inhibited inflammation in mouse contact hypersensitivity with minimal effects on corticosterone, a biomarker for systemic GRM effects, at doses up to and including 100 mg/kg. Concomitant inhibition of P1NP suggests potential delivery to cells involved in the remodeling of bone, which may be a consequence of TNF-targeting or bystander payload effects. Furthermore, ADC5 fully suppressed inflammation in collagen-induced arthritis mouse model after one 10 mg/kg dose for 21 days. The properties of the anti-hTNF conjugate were suitable for liquid formulation and may enable subcutaneous dosing.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Long-term risk of glaucoma after cataract surgery in childhood.

PURPOSE: To examine the long-term risk of glaucoma after cataract surgery in childhood. METHODS: This study took place from January 2022 until December 2022 and included patients from a large family with hereditary childhood cataract who had cataract surgery before 18 years of age. Patients underwent an ophthalmologic examination to determine the presence of glaucoma or ocular hypertension (OHT). Patients who did not want to participate in the examination could contribute with a medical journal from their treating ophthalmologist. The risk of long-term glaucoma was determined using survival analysis, and risk factors were assessed using a Cox proportional hazards regression model. RESULTS: We included 68 patients (133 eyes) with a median age at cataract surgery of 7 years (IQR: 5-10). The median follow-up time after cataract surgery to glaucoma/OHT or the latest ophthalmologic examination was 35 years (IQR: 15-48). Twelve patients (18 eyes) had glaucoma, and five patients (eight eyes) had OHT, resulting in 15 patients with glaucoma/OHT. The long-term risk of glaucoma/OHT diagnosed in adulthood was 47.7% (CI: 21.8-70.9) at the age of 70 years of patients who were free of glaucoma before their 18th year. We could not confirm or dismiss an association between glaucoma/OHT and sex, age at surgery, number of ocular interventions before 18 years of age or glaucoma after cataract surgery in a first-degree relative. CONCLUSION: Cataract surgery in childhood is associated with a high risk of late-onset glaucoma. Regular lifelong follow-up is important to ensure early diagnosis and prevent extensive vision loss.

Prevalence and risk factors for hypothalamus-pituitary-adrenal axis suppression in infants receiving glucocorticoid eye drops after ocular surgery.

PURPOSE: To examine the prevalence and risk factors for hypothalamus-pituitary-adrenal axis suppression (HPA axis suppression) in infants receiving glucocorticoid (GC) eye drops after ocular surgery. METHODS: This was a clinical observational cohort study. Children under the age of two receiving GC eye drops after cataract or glaucoma surgery between 1 January 2017 and 31 December 2021 were included at one centre. Medical history and results of the adrenocorticotropic hormone (ACTH) stimulation tests were obtained through patient charts. RESULTS: Forty-nine infants were included in the study. Ten out of 22 patients (45.5%) tested during treatment and two out of 27 patients (7.4%) tested after treatment cessation were diagnosed with HPA axis suppression. The duration of HPA axis suppression extended beyond 3 months in 8 out of 12 patients. Logistic regression showed that infants with HPA axis suppression had received a higher GC dose/body weight/day before the first ACTH test (p < 0.001). There was a 79% (95% CI:1.28;2.50) increase in the odds of having HPA axis suppression for a 0.01 mg GC increase/kg/day corresponding to an additional daily eye drop for an infant weighing 5 kg. There was an association between HPA axis suppression and number of days from surgery to test (p = 0.003), age at surgery (p = 0.035) and cumulated GC dose (p = 0.005). Three infants with HPA axis suppression had affected growth and one had Cushing-like features, but there were no cases of Addisonian crisis. CONCLUSION: Infants are at risk of having hypothalamus-pituitary-adrenal axis suppression if they receive a high daily glucocorticoid dose per weight by topical ocular administration. Infants receiving glucocorticoids after ocular surgery should be monitored clinically or by ACTH testing.

Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure-activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

Cataract Surgery with or without Intraocular Lens Implantation in Pediatric Uveitis: A Systematic Review with Meta-Analyses.

PURPOSE: To systematically review the results of comparative studies of modern cataract surgery in pediatric uveitis with or without intraocular lens (IOL) implantation and to perform comparative meta-analyses to compare visual acuity outcomes and complication rates. METHODS: On 12 November 2020, we systematically searched the Cochrane Central, PubMed/MEDLINE, EMBASE, ClinicalTrials.gov, and all affiliated databases of the Web of Science. Two authors independently reviewed studies and extracted data. Studies were reviewed qualitatively in text and quantitatively with meta-analyses. Outcome measures were preoperative and postoperative best-corrected visual acuity (BCVA), inflammation control, and rates of postoperative complications. RESULTS: Ten studies of 288 eyes were eligible for review of which the majority were eyes with juvenile idiopathic arthritis-associated uveitis. Summary estimates revealed that the BCVA was better in pseudophakic eyes vs. aphakic eyes (1-year postoperative: -0.23 logMAR, 95% CI: -0.43 to -0.03 logMAR, P=0.027; 5-year postoperative: -0.35 logMAR, 95% CI: -0.51 to -0.18 logMAR, P=0.000036). Pseudophakic eyes had more visual axis opacification (OR 6.76, 95% CI: 2.73 to 16.8, P=0.000036) and less hypotony (OR 0.19, 95% CI: 0.04 to 0.95, P=0.044). CONCLUSIONS: In modern era cataract surgery on eyes with pediatric uveitis with IOL implantation leads to satisfactory and superior visual outcomes and no differences in complication rates apart from an increased prevalence of visual axis opacification and a decreased prevalence of hypotony when compared to aphakia. However, limitations of the retrospective design and the presence of selection bias necessitate a careful interpretation.

Pars plana vitrectomy combined with hyaloido-zonula-iridectomy in treatment of patients with chronic aqueous misdirection: A systematic literature review and case series.

PURPOSE: To evaluate the efficacy of vitrectomy combined with hyaloido-zonula-iridectomy from an anterior or a posterior approach in patients with treatment-resistant aqueous misdirection (chronic aqueous misdirection) by systematically reviewing existing literature in combination with presentation of a case series. METHODS: A systematic literature review was performed in PubMed, EMBASE and Cochrane Library databases using search terms: malignant glaucoma, ciliary block, ciliolenticular block and aqueous misdirection. A consecutive series of three pseudophakic patients (5 eyes) diagnosed with chronic aqueous misdirection after cataract surgery is presented. RESULTS: A literature search identified 31 articles describing treatment of chronic aqueous misdirection with vitrectomy and a hyaloido-zonula-iridectomy. Studies, where patients were treated with a complete vitrectomy from pars plana in combination with a hyaloido-zonula-iridectomy, reported low relapse rates. Studies describing a surgical approach with vitrectomy performed from the anterior chamber, followed by a hyaloido-zonula-iridectomy, also reported low relapse rates except for one reporting relapse in nearly half of the patients. In our case series, a complete vitrectomy combined with a hyaloido-zonula-iridectomy resolved the chronic aqueous misdirection in all five eyes after one procedure except one eye where the hyaloido-zonula-iridectomy was repeated due to an insufficient opening. Some of the eyes still needed antiglaucomatous treatment due to chronic angle closure. CONCLUSION: In treatment-resistant malignant glaucoma, vitrectomy combined with a hyaloido-zonula-iridectomy should be considered performed to ensure communication between the anterior chamber and the vitreous cavity. If the condition has been unresolved for a long time, extensive synechiae of the angle may decrease the success rate due to chronic angle closure.

Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study.

BACKGROUND: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity. METHODS: Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m2 on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX ≥ 4.0-9.9 µM, and severely delayed elimination was defined as 42-hour plasma MTX ≥ 10 µM. RESULTS: Median 42-hour plasma MTX was 0.61 µM (interquartile range, 0.4-1.06 µM). Of 1295 MTX infusions with 5 g/m2 (n = 140 patients) or 8 g/m2 (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m² (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 µM increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%-97%) and a specificity of 85% (95% CI, 83%-87%) for predicting 42-hour MTX ≥4.0 µM. CONCLUSIONS: A 25 µM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX.

Conversion of Human Fibroblasts to Stably Self-Renewing Neural Stem Cells with a Single Zinc-Finger Transcription Factor.

Direct conversion of somatic cells into neural stem cells (NSCs) by defined factors holds great promise for mechanistic studies, drug screening, and potential cell therapies for different neurodegenerative diseases. Here, we report that a single zinc-finger transcription factor, Zfp521, is sufficient for direct conversion of human fibroblasts into long-term self-renewable and multipotent NSCs. In vitro, Zfp521-induced NSCs maintained their characteristics in the absence of exogenous factor expression and exhibited morphological, molecular, developmental, and functional properties that were similar to control NSCs. In addition, the single-seeded induced NSCs were able to form NSC colonies with efficiency comparable with control NSCs and expressed NSC markers. The converted cells were capable of surviving, migrating, and attaining neural phenotypes after transplantation into neonatal mouse and adult rat brains, without forming tumors. Moreover, the Zfp521-induced NSCs predominantly expressed rostral genes. Our results suggest a facilitated approach for establishing human NSCs through Zfp521-driven conversion of fibroblasts.

ALLENE OXIDE CYCLASE (AOC) gene family members of Arabidopsis thaliana: tissue- and organ-specific promoter activities and in vivo heteromerization.

Jasmonates are important signals in plant stress responses and plant development. An essential step in the biosynthesis of jasmonic acid (JA) is catalysed by ALLENE OXIDE CYCLASE (AOC) which establishes the naturally occurring enantiomeric structure of jasmonates. In Arabidopsis thaliana, four genes encode four functional AOC polypeptides (AOC1, AOC2, AOC3, and AOC4) raising the question of functional redundancy or diversification. Analysis of transcript accumulation revealed an organ-specific expression pattern, whereas detailed inspection of transgenic lines expressing the GUS reporter gene under the control of individual AOC promoters showed partially redundant promoter activities during development: (i) In fully developed leaves, promoter activities of AOC1, AOC2, and AOC3 appeared throughout all leaf tissue, but AOC4 promoter activity was vascular bundle-specific; (ii) only AOC3 and AOC4 showed promoter activities in roots; and (iii) partially specific promoter activities were found for AOC1 and AOC4 in flower development. In situ hybridization of flower stalks confirmed the GUS activity data. Characterization of single and double AOC loss-of-function mutants further corroborates the hypothesis of functional redundancies among individual AOCs due to a lack of phenotypes indicative of JA deficiency (e.g. male sterility). To elucidate whether redundant AOC expression might contribute to regulation on AOC activity level, protein interaction studies using bimolecular fluorescence complementation (BiFC) were performed and showed that all AOCs can interact among each other. The data suggest a putative regulatory mechanism of temporal and spatial fine-tuning in JA formation by differential expression and via possible heteromerization of the four AOCs.

Fabricating pH-stable and swellable very thin hyperbranched poly(ethylene imine)-oligosaccharide films fabricated without precoating: first view on protein adsorption.

For using successful (ultra)thin dendritic macromolecule films in (bio)sensing and microfluidic devices and for obtaining reproducible film properties, alteration effects arising from precoatings have to be avoided. Here, oligosaccharide-modified hyperbranched poly(ethylene imine)s (PEI-OS) were used to fabricate very thin PEI-OS films (15-20 nm in dry state), cross-linked with citric acid under condensation, and vacuum condition. However, no reactive precoating is necessary to obtain stable films, which allows very simple film preparation and avoids alteration of the PEIS-OS film properties arising from precoating. Several methods [(in situ) ellipsometry, AFM, XPS, (in situ) ATR-IR, streaming potential measurements] were applied to characterize homogeneity, surface morphology, and stability of these PEI-OS films between pH 2 and pH 10, but also the low protein adsorption behavior.

Importance of EGF receptor, HER2/Neu and Erk1/2 kinase signalling for host cell elongation and scattering induced by the Helicobacter pylori CagA protein: antagonistic effects of the vacuolating cytotoxin VacA.

Helicobacter pylori is the causative agent of gastric pathologies ranging from chronic gastritis to peptic ulcers and even cancer. Virulent strains carrying both the cag pathogenicity island (cagPAI) and the vacuolating cytotoxin VacA are key players in disease development. The cagPAI encodes a type IV secretion system (T4SS) which forms a pilus for injection of the CagA protein into gastric epithelial cells. Injected CagA undergoes tyrosine phosphorylation and induces actin-cytoskeletal rearrangements involved in host cell scattering and elongation. We show here that the CagA-induced responses can be inhibited in strains expressing highly active VacA. Further investigations revealed that VacA does not interfere with known activities of phosphorylated CagA such as inactivation of Src kinase and cortactin dephosphorylation. Instead, we demonstrate that VacA exhibits inactivating activities on the epidermal growth factor receptor EGFR and HER2/Neu, and subsequently Erk1/2 MAP kinase which are important for cell scattering and elongation. Inactivation of vacA gene, downregulation of the VacA receptor RPTP-alpha, addition of EGF or expression of constitutive-active MEK1 kinase restored the capability of H. pylori to induce the latter phenotypes. These data demonstrate that VacA can downregulate CagA's effects on epithelial cells, a novel molecular mechanism showing how H. pylori can avoid excessive cellular damage.

Key clinical activities for quality asthma care. Recommendations of the National Asthma Education and Prevention Program.

In 1997, the National Asthma Education and Prevention Program (NAEPP), coordinated by the National Heart, Lung, and Blood Institute, published the second Expert Panel Report (EPR-2): Guidelines for the Diagnosis and Management of Asthma (National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the diagnosis and management of asthma. Bethesda MD: US Department of Health and Human Services, National Institutes of Health, 1997; publication no. 97-4051. Available at http://www.nhlbi.nih.gov/guidelines/ asthma/asthgdln.pdf). Subsequently, the NAEPP Expert Panel identified key questions regarding asthma management that were submitted to an evidence practice center of the Agency for Healthcare Research and Quality to conduct a systematic review of the evidence. The resulting evidence report was used by the Expert Panel to update recommendations for clinical practice on selected topics. These recommendations (EPR-Update 2002) were published in 2002. (National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma--update on selected topics 2002. J Allergy Clin Immunol 2002;110[November 2002, part 2]. Available at http://www.nhlbi.nih.gov/guidelines/asthma/index.htm). To improve the implementation of these guidelines, a working group of the Professional Education Subcommittee of the NAEPP extracted key clinical activities that should be considered as essential for quality asthma care in accordance with the EPR-2 guidelines and the EPR-Update 2002. The purpose was to develop a report that would help purchasers and planners of health care define the activities that are important to quality asthma care, particularly in reducing symptoms and preventing exacerbations, and subsequently reducing the overall national burden of illness and death from asthma. This report is intended to help employer health benefits managers and other health-care planners make decisions regarding delivery of health care for persons with asthma. Although this report is based on information directed to clinicians; it is not intended to substitute for recommended clinical practices for caring for persons with asthma, nor is it intended to replace the clinical decision-making required to meet individual patient needs. Readers are referred to the EPR-2 for the full asthma guidelines regarding diagnosis and management of asthma or to the abstracted Practical Guide (National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Practical guide for the diagnosis and management of asthma. Bethesda MD: US Department of Health and Human Services, National Institutes of Health, 1997; publication no. 97-4053. Available at http://www.nhlbi.nih.gov/health/prof/lung/asthma/practgde.htm) and to the EPR-Update 2002. The 1997 EPR-2 guidelines and EPR-Update 2002 were derived from a consensus of leading asthma researchers from academic, clinical, federal and voluntary institutions and based on scientific evidence supported by the literature. The 10 key activities highlighted here correspond to the four recommended-as-essential components of asthma management: assessment and monitoring, control of factors contributing to asthma severity, pharmacotherapy and education for a partnership in care. The key clinical activities are not intended for acute or hospital management of patients with asthma but rather for the preventive aspects of managing asthma long term. This report was developed as a collaborative activity between CDC and the NAEPP.

Stimulation of carotenoid metabolism in arbuscular mycorrhizal roots.

Development of arbuscular mycorrhizal roots is correlated with accumulation of various isoprenoids, i.e. acyclic C(14) polyene 'mycorradicin' and C(13) cyclohexenone derivatives. We present data indicating a strong stimulation of carotenoid metabolism in such roots. Carotenoid profiling revealed mycorrhiza-specific accumulation of zeta-carotene in Zea mays and Medicago truncatula. Precursor accumulation after inhibition of phytoene desaturase (Pds) activity by norflurazon indicated an increased phytoene biosynthetic capacity in mycorrhizal roots of all species analyzed. Nicotiana tabacum plants transformed with a PDS promoter- GUS construct showed a cell-specific induction of PDS promoter activity in root cells containing arbuscules. Mycorradicin biosynthesis and, partially, mycorrhization were impaired in maize mutants deficient in carotenoid biosynthesis. These data indicate that (1) mycorradicin is probably synthesized via a C(40) precursor carotenoid, (2) carotenoid biosynthesis is induced in mycorrhizal roots, (3) induction occurs, at least partially, at the transcriptional level, and (4) that this may play a functional role during mycorrhization.