The incidence of pediatric dacryocystitis among a population-based cohort of infants with congenital nasolacrimal duct obstruction.

PURPOSE: To report the incidence, clinical characteristics, and outcomes of acute dacryocystitis among a large, population-based cohort of children born with congenital nasolacrimal duct obstruction (CNLDO) over a 10-year period. METHODS: This multicenter retrospective, population-based cohort study included all patients diagnosed with acute dacryocystitis in a cohort of patients diagnosed with CNLDO before age 5 years in Olmsted County, Minnesota, United States of America from January 1, 1995, through December 31, 2004. RESULTS: Of 1,998 patients with CNLDO, there were 70 cases (36 female [(51%)]) of acute dacryocystitis during the study, yielding an incidence rate of 243 per 100,000 children (95% CI, 170-316). Mean age at diagnosis was 9.0 months. Patients who developed dacryocystitis were significantly less likely to be born via C-section (OR = 0.29, P = 0.009). Less than half of patients with dacryocystitis were treated with oral/intravenous antibiotics (46%), but whose who were had a significantly higher odds of requiring probing (OR = 8.50, P = 0.004). Spontaneous CNLDO resolution was significantly less likely to occur in patients diagnosed with acute dacryocystitis compared with those without (OR = 2.46, P = 0.001). The median age of spontaneous resolution in the dacryocystitis group (6.0 months) was significantly older than the uncomplicated CNLDO group (P = 0.012). CONCLUSIONS: Pediatric acute dacryocystitis is an uncommon complication of CNLDO and is associated with both a lower likelihood of and older age at spontaneous resolution of CNLDO symptoms.

Unilateral Glaucoma Without Facial Angioma in a Pediatric Patient: A Suspected Sturge-Weber Syndrome Variant.

The authors report a case of a 5-month-old full-term infant with chronic conjunctival redness and elevated intraocular pressure in the right eye. Magnetic resonance imaging ruled out leptomeningeal angiomatosis. Despite lacking a typical port-wine mark, the diagnosis of Sturge-Weber syndrome was established based on specific observations in the right eye that involved unilateral vascular glaucoma. These findings included Haab striae, a larger axial length measurement, an increased number of episcleral vessels with blood in Schlemm canal, and a thicker choroid in the macular region. This is the first reported pediatric case with these specific ocular manifestations in the absence of facial angioma, highlighting the need for awareness among clinicians to avoid misdiagnosis and facilitate proper management. [J Pediatr Ophthalmol Strabismus. 2024;61(3):e19-e22.].

Spontaneous resolution rates in congenital nasolacrimal duct obstruction managed with massage or topical antibiotics compared with observation alone.

BACKGROUND/AIMS: To determine if nasolacrimal massage or topical antibiotics are associated with higher rates of resolution compared with observation alone in a population-based cohort of infants with congenital nasolacrimal duct obstruction (CNLDO). METHODS: The medical records of all children <5 years diagnosed with CNLDO while residing in Olmsted County, Minnesota from 1 January 1995 through 31 December 2004 were retrospectively reviewed for type of management and non-surgical resolution of tearing. RESULTS: Among 1958 infants diagnosed and followed for CNLDO, 516 (26.4%) were merely observed, 506 (25.8%) were prescribed massage alone, 485 (24.8%) were prescribed at least one course of topical antibiotics, 397 (20.3%) were prescribed both topical antibiotics and massage, and 54 (2.8%) had no documented therapy. Non-surgical resolution, occurring in 1669 (85.2%) during a median follow-up of 3.1 months (range: 1 week-248 months), was 74.6% for the merely observed, 89.7% for those prescribed digital massage, 87.0% for those prescribed antibiotics and 90.7% for those treated with both. This comparison was significant in unadjusted (p<0.001) and multivariable comparisons (p<0.001). CONCLUSION: Prescribing topical antibiotics or digital massage for infants with CNLDO in this cohort, individually or in combination, was associated with a higher rate of spontaneous resolution than observation alone.

Reactivation of Epstein-Barr Virus by HIF-1α Requires p53.

We previously reported that the cellular transcription factor hypoxia-inducible factor 1α (HIF-1α) binds a hypoxia response element (HRE) located within the promoter of Epstein-Barr virus's (EBV's) latent-lytic switch BZLF1 gene, Zp, inducing viral reactivation. In this study, EBV-infected cell lines derived from gastric cancers and Burkitt lymphomas were incubated with HIF-1α-stabilizing drugs: the iron chelator deferoxamine (Desferal [DFO]), a neddylation inhibitor (pevonedistat [MLN-4924]), and a prolyl hydroxylase inhibitor (roxadustat [FG-4592]). DFO and MLN-4924, but not FG-4592, induced accumulation of both lytic EBV proteins and phosphorylated p53 in cell lines that contain a wild-type p53 gene. FG-4592 also failed to activate transcription from Zp in a reporter assay despite inducing accumulation of HIF-1α and transcription from another HRE-containing promoter. Unexpectedly, DFO failed to induce EBV reactivation in cell lines that express mutant or no p53 or when p53 expression was knocked down with short hairpin RNAs (shRNAs). Likewise, HIF-1α failed to activate transcription from Zp when p53 was knocked out by CRISPR-Cas9. Importantly, DFO induced binding of p53 as well as HIF-1α to Zp in chromatin immunoprecipitation (ChIP) assays, but only when the HRE was present. Nutlin-3, a drug known to induce accumulation of phosphorylated p53, synergized with DFO and MLN-4924 in inducing EBV reactivation. Conversely, KU-55933, a drug that inhibits ataxia telangiectasia mutated, thereby preventing p53 phosphorylation, inhibited DFO-induced EBV reactivation. Lastly, activation of Zp transcription by DFO and MLN-4924 mapped to its HRE. Thus, we conclude that induction of BZLF1 gene expression by HIF-1α requires phosphorylated, wild-type p53 as a coactivator, with HIF-1α binding recruiting p53 to Zp.IMPORTANCE EBV, a human herpesvirus, is latently present in most nasopharyngeal carcinomas, Burkitt lymphomas, and some gastric cancers. To develop a lytic-induction therapy for treating patients with EBV-associated cancers, we need a way to efficiently reactivate EBV into lytic replication. EBV's BZLF1 gene product, Zta, usually controls this reactivation switch. We previously showed that HIF-1α binds the BZLF1 gene promoter, inducing Zta synthesis, and HIF-1α-stabilizing drugs can induce EBV reactivation. In this study, we determined which EBV-positive cell lines are reactivated by classes of HIF-1α-stabilizing drugs. We found, unexpectedly, that HIF-1α-stabilizing drugs only induce reactivation when they also induce accumulation of phosphorylated, wild-type p53. Fortunately, p53 phosphorylation can also be provided by drugs such as nutlin-3, leading to synergistic reactivation of EBV. These findings indicate that some HIF-1α-stabilizing drugs may be helpful as part of a lytic-induction therapy for treating patients with EBV-positive malignancies that contain wild-type p53.

Incidence and clinical characteristics of congenital nasolacrimal duct obstruction.

BACKGROUND/AIMS: The literature on the prevalence and demographics of congenital nasolacrimal duct obstruction (CNLDO) is 30-70 years old and largely comprises small sample sizes. This study provides epidemiological findings of this common disorder from the largest cohort reported to date. METHODS: The medical records of all children (<5 years of age) residing in Olmsted County, Minnesota, when diagnosed with CNLDO from 1 January 1995 through 31 December 2004, were reviewed. RESULTS: Of 17 713 newborns born during the 10-year study period, 1998 were diagnosed with CNLDO, yielding a birth prevalence of one in nine live births. The diagnosis was made in approximately 90% by a primary care physician, at a median age of 5 weeks, with no gender predilection. Compared with the reference population, CNLDO was associated with premature birth (p=0.005) and was more prevalent among Caucasians (p<0.001). Two-thirds of patients initially presented with discharge alone, 18% with tearing alone and 15% with both discharge and tearing. CONCLUSIONS: In this large population-based cohort, CNLDO occurred in one in nine live births with no gender predilection. Prematurity and Caucasian race were associated with the development of CNLDO. Mucopurulent discharge was a much more common feature than tearing at initial presentation.

Spontaneous Resolution and Timing of Intervention in Congenital Nasolacrimal Duct Obstruction.

Importance: Although the overall rate of spontaneous resolution in congenital nasolacrimal duct obstruction (CNLDO) and efficacy of probing have been documented in the literature, the optimal timing of intervention has not been established. Objective: To report new findings regarding spontaneous resolution in a large cohort of children with CNLDO. Design, Setting, and Participants: The medical records of 1998 consecutive infants diagnosed with CNLDO from January 1, 1995, through December 31, 2004, while residing in Olmsted County, Minnesota, were retrospectively reviewed. Data were analyzed between January 1, 2015, and January 2017. Main Outcomes and Measures: Rate of spontaneous resolution over time and by sex. Results: The cohort, diagnosed at a median age of 1.2 months (interquartile range, 0.4-3.6), was 48% girls (n = 959) and 89% white (n = 1626; 173 were unreported). Among the 1998 cases, 1669 (83.5%) spontaneously resolved, 289 (14.5%) underwent treatment, and the remaining 40 (2.0%) were lost to follow-up. Of the 1958 infants followed up, CNLDO in 925 (47.3%) spontaneously resolved by age 3 months, in 1300 (66.4%) by 6 months, in 1472 (75.7%) by 9 months, and in 1516 (78.4%) by 12 months. The rate of resolution was 35% faster (95% CI, 23%-47%; P < .001) at less than 1 month vs 3 months, 43% faster (95% CI, 27%-64%; P < .001) at 3 months vs 6 months, 39% faster (95% CI, 16%-64%; P < .001) at 6 months vs 9 months, and 1% slower at 9 months vs 12 months (hazard ratio, 0.99; 95% CI, 0.80-1.22; P = .78). Congenital nasolacrimal duct obstruction resolved in boys 0.5 months (95% CI, 0.2-0.8; P < .001) faster than girls (median, 2.9 vs 3.4 months), and unilateral obstructions resolved 0.2 months (95% CI, 0.1-0.4; P = .002) faster than bilateral (median, 3.1 vs 3.3 months) ones. Children probed at 15 months or older had decreased odds of resolution after probing (odds ratio, 0.11; 95% CI, 0.01-0.89; P = .04) compared with children probed at age 12 to 14 months. Conclusions and Relevance: Based on this large cohort of children with CNLDO, probing between age 9 and 15 months may be reasonable given that the rate of spontaneous resolution plateaued after 9 months and initial probing success declined after 15 months. This time frame supports both an earlier and narrower range of ages for intervention compared with the current practice of probing after age 1 year.

Hypoxia-inducible factor-1α plays roles in Epstein-Barr virus's natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter.

When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV's natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a lytic-induction therapy for treating some EBV-associated malignancies.

The eye and tick-borne disease in the United States.

PURPOSE OF REVIEW: Tick-borne diseases are increasing in incidence and geographic distribution. Several diseases endemic to the United States have ophthalmic manifestations, including the most common tick-borne disease, Lyme borreliosis. As ocular complaints may lead a patient to seek medical evaluation, it is important to be aware of the systemic and ophthalmic manifestations of tick-borne diseases in order to make the correct diagnosis. RECENT FINDINGS: Vision-threatening ophthalmic manifestations are relatively common in Lyme disease and Rocky Mountain spotted fever. Ocular involvement is rare in babesiosis, tick-borne relapsing fever, Powassan encephalitis, ehrlichiosis, anaplasmosis, and Colorado tick fever.There are clear guidelines for diagnosis and treatment of Lyme disease; however, confusion and misinformation among the general public as well as controversy about chronic or late-stage Lyme disease can impact the evaluation of ophthalmic disease. Furthermore, there are many gaps in our knowledge regarding the pathophysiology of ocular borreliosis although it seems likely that Lyme uveitis is rare in the United States. SUMMARY: Knowledge of systemic and ophthalmic manifestations combined with an understanding of the epidemiology of disease vectors is crucial for the diagnosis of tick-borne diseases.