IGF-1 infusion increases growth in fetal sheep when euinsulinemia is maintained.

Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late-gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for 1 week. The fetus underwent a metabolic study immediately prior to infusion start and after 1 week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P = 0.0081) and had heavier heart, liver, and adrenal glands than IGF and CON (P < 0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P < 0.0001) and lower final amino acid concentrations than CON (P = 0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P < 0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P < 0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

Mitochondrial respiration is lower in the intrauterine growth-restricted fetal sheep heart.

Fetuses affected by intrauterine growth restriction have an increased risk of developing heart disease and failure in adulthood. Compared with controls, late gestation intrauterine growth-restricted (IUGR) fetal sheep have fewer binucleated cardiomyocytes, reflecting a more immature heart, which may reduce mitochondrial capacity to oxidize substrates. We hypothesized that the late gestation IUGR fetal heart has a lower capacity for mitochondrial oxidative phosphorylation. Left (LV) and right (RV) ventricles from IUGR and control (CON) fetal sheep at 90% gestation were harvested. Mitochondrial respiration (states 1-3, LeakOmy, and maximal respiration) in response to carbohydrates and lipids, citrate synthase (CS) activity, protein expression levels of mitochondrial oxidative phosphorylation complexes (CI-CV), and mRNA expression levels of mitochondrial biosynthesis regulators were measured. The carbohydrate and lipid state 3 respiration rates were lower in IUGR than CON, and CS activity was lower in IUGR LV than CON LV. However, relative CII and CV protein levels were higher in IUGR than CON; CV expression level was higher in IUGR than CON. Genes involved in lipid metabolism had lower expression in IUGR than CON. In addition, the LV and RV demonstrated distinct differences in oxygen flux and gene expression levels, which were independent from CON and IUGR status. Low mitochondrial respiration and CS activity in the IUGR heart compared with CON are consistent with delayed cardiomyocyte maturation, and CII and CV protein expression levels may be upregulated to support ATP production. These insights will provide a better understanding of fetal heart development in an adverse in utero environment. KEY POINTS: Growth-restricted fetuses have a higher risk of developing and dying from cardiovascular diseases in adulthood. Mitochondria are the main supplier of energy for the heart. As the heart matures, the substrate preference of the mitochondria switches from carbohydrates to lipids. We used a sheep model of intrauterine growth restriction to study the capacity of the mitochondria in the heart to produce energy using either carbohydrate or lipid substrates by measuring how much oxygen was consumed. Our data show that the mitochondria respiration levels in the growth-restricted fetal heart were lower than in the normally growing fetuses, and the expression levels of genes involved in lipid metabolism were also lower. Differences between the right and left ventricles that are independent of the fetal growth restriction condition were identified. These results indicate an impaired metabolic maturation of the growth-restricted fetal heart associated with a decreased capacity to oxidize lipids postnatally.

Pathway to Independence Awards (K99/R00): Funding Dynamics and Prediction of Future National Institutes of Health Research Project Funding.

PURPOSE: The authors used the National Institutes of Health (NIH) RePORTER (Research Portfolio Online Reporting Tools) to evaluate funding trends and historic NIH investment increase in the K99 award pathway and examine whether R00 to R01 or R21 achievement time correlated with the future success of an early-stage NIH-funded investigator. METHOD: All K99 awards and funding data in this study were limited to all clinical departments. The authors identified all researchers and awards through a K99 search from fiscal years (FYs) 2007 to 2022 across all clinical departments and investigated trends in K99 awards and funding from NIH FYs 2007 to 2022. They generated an R00 data set and analyzed the K99 to R00 achievement statistics from FYs 2007 to 2022. The authors aggregated NIH annual data files for FYs 2007 to 2021 to generate a master data file of all R01 and R21 awards. They linked R01 and R21 award data to the researcher previously identified through the K99 search and focused on the connection between K99/R00 awardees and subsequent R01 or R21 awards. RESULTS: From FY 2008 to FY 2022, the NIH K99 budget increased 127.0%, whereas the NIH program-level budget increased 17.3%. A principal investigator's mean funding per year significantly decreased as time from R00 to R01 or R21 increased ( P < .001); 7 of 15 comparisons differed significantly (2 at P < .01 and 5 at P < .001). CONCLUSIONS: NIH investment in the K99 award pathway has substantially outpaced the NIH program-level budget increase, and there is a strong association between mean funding per year since the start of the R00 phase and time from R00 to R01 or R21. This analysis may be useful to clinical departments as they evaluate selecting new and retaining current biomedical scientists for independent research positions.

National Institutes of Health Funding Gaps for Principal Investigators.

Importance: Early-stage and established investigators compete for a limited supply of funds from the National Institutes of Health (NIH). Regardless of their previous funding success, many principal investigators (PIs) encounter a funding gap in which they no longer receive ongoing funding from the NIH. Objective: To determine incidence rates of PI-level funding gaps, the mean funding gap length, and whether these 2 metrics are associated with previous funding success. Design, Setting, and Participants: This study was conducted using data from NIH RePORTER. Historical datafiles for fiscal year (FY) 2011 to FY 2021 were aggregated to generate 2 master datafiles for this period: all NIH awards and only R01 awards. PIs with no funding in FY 2011 or FY 2021 were removed. PIs were sorted by FY 2011 total funding amounts and grouped by quarter of amount. Results: A total of 39 944 unique researchers were awarded 220 131 NIH awards, of which 103 753 were R01 awards. For all NIH awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (from 27% to 75%), percentage of these gap PIs who had at least 2 consecutive years without funding (from 56% to 68%), and mean maximum consecutive years without funding for gap PIs (2.2 years to 3.1 years). For only R01 awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (50% to 74%), percentage of gap PIs who had at least 2 consecutive years without funding (59% to 71%), and mean maximum consecutive years without funding for gap PIs (2.4 years to 3.1 years). Conclusions and Relevance: In this cohort study of NIH-funded investigators, PIs with higher NIH funding were less likely to experience a funding gap. Additionally, when these PIs encountered a funding gap, this period without funding was shorter; however, among all PIs, funding gaps typically lasted 2 to 3 years. These associations were found inclusive of all NIH awards and when analysis was limited to only R01 awards. These findings may be useful to PIs and academic institutions as they prepare, structure, and project research resource allocations.

Analyzing the demographics of patients with uveitis in an indigent, urban population.

PURPOSE: To study the types of uveitis examined in a hospital serving indigent populations in need of low-cost care. METHODS: A retrospective chart review examined the electronic medical records of all patients with uveitis-related at Drexel Eye Physicians. Data collected included demographics, anatomic location of the uveitis, systemic disease associations, treatment modalities and insurance. Statistical analysis was performed using χ² or Fischer exact tests. RESULTS: 270 patients (366 eyes) were included for analysis, 67% of patients identified as African American. Most eyes (95.3%, N = 349) were treated with topical corticosteroid drops, and only 6 (1.6%) received an intravitreal implant. Immunosuppressive medications were started in 24 patients (8.9%). Nearly 80% depended to some extent on Medicare or Medicaid Assistance for treatment coverage. There was no association between insurance type and use of biologics or difluprednate. CONCLUSION: We found no association between insurance type and the prescription of medications for uveitis that should be used at home. There was a minimal number of patients prescribed medications for implantation in the office. The adherence of use of medications at home should be investigated.

Chronic Fetal Leucine Infusion Increases Rate of Leucine Oxidation but Not of Protein Synthesis in Late Gestation Fetal Sheep.

BACKGROUND: Leucine increases protein synthesis rates in postnatal animals and adults. Whether supplemental leucine has similar effects in the fetus has not been determined. OBJECTIVE: To determine the effect of a chronic leucine infusion on whole-body leucine oxidation and protein metabolic rates, muscle mass, and regulators of muscle protein synthesis in late gestation fetal sheep. METHODS: Catheterized fetal sheep at ∼126 d of gestation (term = 147 d) received infusions of saline (CON, n = 11) or leucine (LEU; n = 9) adjusted to increase fetal plasma leucine concentrations by 50%-100% for 9 d. Umbilical substrate net uptake rates and protein metabolic rates were determined using a 1-13C leucine tracer. Myofiber myosin heavy chain (MHC) type and area, expression of amino acid transporters, and abundance of protein synthesis regulators were measured in fetal skeletal muscle. Groups were compared using unpaired t tests. RESULTS: Plasma leucine concentrations were 75% higher in LEU fetuses compared with CON by the end of the infusion period (P < 0.0001). Umbilical blood flow and uptake rates of most amino acids, lactate, and oxygen were similar between groups. Fetal whole-body leucine oxidation was 90% higher in LEU (P < 0.0005) but protein synthesis and breakdown rates were similar. Fetal and muscle weights and myofiber areas were similar between groups, however, there were fewer MHC type IIa fibers (P < 0.05), greater mRNA expression levels of amino acid transporters (P < 0.01), and a higher abundance of signaling proteins that regulate protein synthesis (P < 0.05) in muscle from LEU fetuses. CONCLUSIONS: A direct leucine infusion for 9 d in late gestation fetal sheep does not increase protein synthesis rates but results in higher leucine oxidation rates and fewer glycolytic myofibers. Increasing leucine concentrations in the fetus stimulates its own oxidation but also increases amino acid transporter expression and primes protein synthetic pathways in skeletal muscle.

A Novel Hands-on Approach Towards Teaching Diagnostic Radiology Residents MRI Scanning and Physics.

RATIONALE AND OBJECTIVES: Traditional approaches towards teaching magnetic resonance imaging (MRI) scanning and physics have limitations that a hands-on course may help overcome. A dedicated week of MRI instruction may help improve radiology resident confidence and competence. Additional benefits may include improved physician-technologist communication and accelerated mastery of MRI safety. MATERIALS AND METHODS: Surveys and tests were approved by our Program Evaluation Committee and administered at the beginning and at the end of this one-week course. The course consisted of protected reading time as well as practice scanning with a research magnet and assisting with clinical scanning under the close supervision of a licensed MRI technologist. Eighteen senior residents (nine third-year and nine fourth-year) participated in this course during its first year. RESULTS: Few residents had previous experience with MRI physics, scanning, or research prior to residency. After this course, mean resident confidence increased by 0.47 points (3.33 vs 2.86; p=0.01) on a five-point Likert scale. Understanding of MRI physics, as measured by pre- and post-tests, increased by 22% (0.72 vs 0.50; p<0.01), corresponding to a large effect size of 1.29 (p<0.001). Resident feedback reported that this course was efficacious (5/5), engaging (4.9/5), and had optimal faculty oversight. The most highly rated component of the course was the opportunity to experiment with the research MR scanner (5/5). CONCLUSION: A dedicated week of MRI education was highly rated by residents and associated with improvements in confidence and understanding, suggesting a positive correlation between confidence and competence. Additional metrics, such as trends in scores on the American Board of Radiology's Core Examination over the next several years, may further support the apparent benefits of this hands-on MR course.

Local versus Systemic Therapy for Noninfectious Uveitis (NIU).

The mainstay of treatment for noninfectious uveitis (NIU) is immunosuppressant therapy. This may come in a localized form that is administered specifically to the eye or a systemic form that penetrates ocular tissues. Over the last twenty years, both local and systemic treatments have undergone advancements in pharmaceutical development. In this review, we will discuss new therapies and analyze the risks and benefits for all existing NIU therapies. Some of these therapies include topical, intravitreal, periocular, and systemic steroids, as well as systemic antimetabolites, tumor necrosis factor-α inhibitors, T-cell inhibitors, anti-CD 20 agents, interleukin-6 inhibitors, alkylating agents, and intravenous immunoglobulin.

Large Hyphema following Femtosecond Laser-assisted Cataract Surgery (FLACS) and Trabectome Resulting in Endocapsular Hematoma.

Aim: To report a large hyphema following femtosecond laser-assisted cataract surgery (FLACS) and trabectome resulting in endocapsular hematoma. Background: Hyphema has previously been described following trabectome, however, no cases have been reported following FLACS or FLACS combined with microinvasive glaucoma surgery (MIGS). We report a case of a large hyphema following FLACS combined with MIGS that resulted in an endocapsular hematoma. Case description: A 63-year-old myopic female with exfoliation glaucoma underwent FLACS with a trifocal intraocular lens implant and Trabectome in the right eye. Significant intraoperative bleeding ensued following the trabectome and was treated with viscoelastic tamponade, anterior chamber (AC) washout, and cautery. The patient developed a large hyphema with intraocular pressure (IOP) rise that was treated with multiple AC taps, paracentesis, and eye drops. The hyphema took approximately 1 month to completely clear, leaving an endocapsular hematoma. This was treated successfully with Neodymium:Yttrium-Aluminum-Garnet (Nd:YAG) laser posterior capsulotomy. Conclusion: Hyphema may occur with angle-based MIGS in combination with FLACS and may cause endocapsular hematoma. An increase in episcleral venous pressure during the docking and suction phase of the laser may predispose to bleeding. Endocapsular hematoma is an uncommon finding after cataract surgery and may be treated with Nd:YAG posterior capsulotomy. How to cite this article: Chang EL, Apostolopoulos N, Mir TA, et al. Large Hyphema following Femtosecond Laser-assisted Cataract Surgery (FLACS) and Trabectome Resulting in Endocapsular Hematoma. J Curr Glaucoma Pract 2022;16(3):195-198.

Fetal Sex Does Not Impact Placental Blood Flow or Placental Amino Acid Transfer in Late Gestation Pregnant Sheep With or Without Placental Insufficiency.

Pregnant sheep have been used to model complications of human pregnancies including placental insufficiency and intrauterine growth restriction. Some of the hallmarks of placental insufficiency are slower uterine and umbilical blood flow rates, impaired placental transport of oxygen and amino acids, and lower fetal arterial concentrations of anabolic growth factors. An impact of fetal sex on these outcomes has not been identified in either human or sheep pregnancies. This is likely because most studies measuring these outcomes have used small numbers of subjects or animals. We undertook a secondary analysis of previously published data generated by our laboratory in late-gestation (gestational age of 133 ± 0 days gestational age) control sheep (n = 29 male fetuses; n = 26 female fetuses; n = 3 sex not recorded) and sheep exposed to elevated ambient temperatures to cause experimental placental insufficiency (n = 23 male fetuses; n = 17 female fetuses; n = 1 sex not recorded). The primary goal was to determine how fetal sex modifies the effect of the experimental insult on outcomes related to placental blood flow, amino acid and oxygen transport, and fetal hormones. Of the 112 outcomes measured, we only found an interaction between fetal sex and experimental insult for the uterine uptake rates of isoleucine, phenylalanine, and arginine. Additionally, most outcomes measured did not show a difference based on fetal sex when adjusting for the impact of placental insufficiency. Exceptions included fetal norepinephrine and cortisol concentrations, which were higher in female compared to male fetuses. For the parameters measured in the current analysis, the impact of fetal sex was not widespread.

Anterior Subcapsular Cataract Formation With Long-term Topical Netarsudil Treatment for Glaucoma.

PURPOSE: The purpose of this study was to describe anterior subcapsular cataract development in patients on long-term topical netarsudil use. PATIENTS AND METHODS: This clinical observational study summarizes a similar cataract pattern demonstrated in a series of patients from a single physician practice and a university-based outpatient clinic during their routine clinical follow-up visits from October 2020 to August 2021. All patients have been using topical netarsudil once daily for at least 15 months. No anterior capsular changes have been observed in any patient at the time when netarsudil was initiated. RESULTS: Five eyes from 4 patients between the ages of 41 and 61 and 1 eye from a patient aged 84 were found to develop anterior subcapsular opacities 15 to 37 months after beginning netarsudil. These cataracts were overall small, 1 to 3 mm, round, oval or ring-shaped, central or paracentral with mild density. No other risk factors for cataract development apart from age were found in these patients. CONCLUSION: Patients on long-term netarsudil should be monitored for potential development of anterior subcapsular cataracts.

Quantitative evaluation of brain iron accumulation in different stages of Parkinson's disease.

BACKGROUND AND PURPOSE: Excessive brain iron deposition is involved in Parkinson's disease (PD) pathogenesis. However, the correlation of iron accumulation in various brain nuclei is not well-established in different stages of the disease. This cross-sectional study aims to evaluate quantitative susceptibility mapping (QSM) as an imaging technique to measure brain iron accumulation in PD patients in different stages compared to healthy controls. METHODS: Ninety-six PD patients grouped by their Hoehn and Yahr (H&Y) stages and 31 healthy controls were included in this analysis. The magnetic susceptibility values of the substantia nigra (SN), red nucleus (RN), caudate, putamen, and globus pallidus were obtained and compared. RESULTS: Iron level was increased in the SN of PD patients in all stages versus controls (p < .001), with no significant difference within stages. Iron in the RN was significantly increased in stage II versus controls (p = .013) and combined stages III and IV versus controls (p < .001). The iron levels in caudate, putamen, and globus pallidus were not different between any groups. CONCLUSIONS: Our data suggest iron accumulation occurs early in the disease course and only in the SN and RN of these patients. This is a large cross-sectional study of brain iron deposition in PD patients according to H&Y staging. Prospective studies are warranted to further validate QSM as a method to follow brain iron, which could serve as a disease biomarker and a therapeutic target.

Lower citrate synthase activity, mitochondrial complex expression, and fewer oxidative myofibers characterize skeletal muscle from growth-restricted fetal sheep.

Skeletal muscle from the late gestation sheep fetus with intrauterine growth restriction (IUGR) has evidence of reduced oxidative metabolism. Using a sheep model of placental insufficiency and IUGR, we tested the hypothesis that by late gestation, IUGR fetal skeletal muscle has reduced capacity for oxidative phosphorylation because of intrinsic deficits in mitochondrial respiration. We measured mitochondrial respiration in permeabilized muscle fibers from biceps femoris (BF) and soleus (SOL) from control and IUGR fetal sheep. Using muscles including BF, SOL, tibialis anterior (TA), and flexor digitorum superficialis (FDS), we measured citrate synthase (CS) activity, mitochondrial complex subunit abundance, fiber type distribution, and gene expression of regulators of mitochondrial biosynthesis. Ex vivo mitochondrial respiration was similar in control and IUGR muscle. However, CS activity was lower in IUGR BF and TA, indicating lower mitochondrial content, and protein expression of individual mitochondrial complex subunits was lower in IUGR TA and BF in a muscle-specific pattern. IUGR TA, BF, and FDS also had lower expression of type I oxidative fibers. Fiber-type shifts that support glycolytic instead of oxidative metabolism may be advantageous for the IUGR fetus in a hypoxic and nutrient-deficient environment, whereas these adaptions may be maladaptive in postnatal life.

A Two-Week Insulin Infusion in Intrauterine Growth Restricted Fetal Sheep at 75% Gestation Increases Skeletal Myoblast Replication but Did Not Restore Muscle Mass or Increase Fiber Number.

Intrauterine growth restricted (IUGR) fetuses are born with lower skeletal muscle mass, fewer proliferating myoblasts, and fewer myofibers compared to normally growing fetuses. Plasma concentrations of insulin, a myogenic growth factor, are lower in IUGR fetuses. We hypothesized that a two-week insulin infusion at 75% gestation would increase myoblast proliferation and fiber number in IUGR fetal sheep. Catheterized control fetuses received saline (CON-S, n=6), and the IUGR fetuses received either saline (IUGR-S, n=7) or insulin (IUGR-I, 0.014 ± 0.001 units/kg/hr, n=11) for 14 days. Fetal arterial blood gases and plasma amino acid levels were measured. Fetal skeletal muscles (biceps femoris, BF; and flexor digitorum superficialis, FDS) and pancreases were collected at necropsy (126 ± 2 dGA) for immunochemistry analysis, real-time qPCR, or flow cytometry. Insulin concentrations in IUGR-I and IUGR-S were lower vs. CON-S (P ≤ 0.05, group). Fetal arterial PaO2, O2 content, and glucose concentrations were lower in IUGR-I vs. CON-S (P ≤ 0.01) throughout the infusion period. IGF-1 concentrations tended to be higher in IUGR-I vs. IUGR-S (P=0.06), but both were lower vs. CON-S (P ≤ 0.0001, group). More myoblasts were in S/G2 cell cycle stage in IUGR-I vs. both IUGR-S and CON-S (145% and 113%, respectively, P ≤ 0.01). IUGR-I FDS muscle weighed 40% less and had 40% lower fiber number vs. CON-S (P ≤ 0.05) but were not different from IUGR-S. Myonuclear number per fiber and the mRNA expression levels of muscle regulatory factors were not different between groups. While the pancreatic ß-cell mass was lower in both IUGR-I and IUGR-S compared to CON-S, the IUGR groups were not different from each other indicating that feedback inhibition by endogenous insulin did not reduce ß-cell mass. A two-week insulin infusion at 75% gestation promoted myoblast proliferation in the IUGR fetus but did not increase fiber or myonuclear number. Myoblasts in the IUGR fetus retain the capacity to proliferate in response to mitogenic stimuli, but intrinsic defects in the fetal myoblast by 75% gestation may limit the capacity to restore fiber number.

Reduced glucose-stimulated insulin secretion following a 1-wk IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defect.

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, n = 8), an analog of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n = 9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n = 8; CON, n = 7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n = 8; CON, n = 7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared with CON (P = 0.0135 and P = 0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared with CON (P = 0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P = 0.0447). In summary, IGF-1 LR3 infusion for 1 wk into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for 1 wk. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in ß-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.NEW & NOTEWORTHY After a 1-wk infusion of IGF-1 LR3, late gestation fetal sheep had lower plasma insulin and glucose concentrations, reduced fetal glucose-stimulated insulin secretion, and decreased fractional insulin secretion from isolated fetal islets without differences in pancreatic insulin content.

Nocardia keratitis mimicking superior limbic keratoconjunctivitis and herpes simplex virus.

PURPOSE: Nocardia keratitis is a rare type of infectious keratitis and may mimic other corneal diseases and lead to delay in diagnosis. This case illustrates how Nocardia often escapes accurate diagnosis due to its insidious onset, variable clinical manifestations, and unusual characteristics on cultures. OBSERVATION: The patient presented with an epithelial defect and superior pannus and scarring, which was misdiagnosed as superior limbic keratoconjunctivitis (SLK) and herpes simplex virus (HSV) keratitis. Repeat corneal scraping cultures, smears, and conjunctival biopsy were necessary to elucidate the diagnosis. It can be effectively treated with the intravenous preparation of trimethoprim-sulfamethoxazole 80 mg/mL (brand name SEPTRA) used topically as eye drops. CONCLUSION: The diagnosis of Nocardia keratitis relies on a high clinical suspicion and a prompt corneal scraping with culture. Due to its potential for rapid resolution with early therapy, it is important to isolate Nocardia early in its disease course. IMPORTANCE: Topical amikacin had been the standard of care for Nocardia keratitis for many years. However, recently there is increasing resistance of Nocardia to amikacin. SEPTRA offers an alternative therapy. Nocardia keratitis mimics other infectious and inflammatory etiologies so rapid diagnosis and treatment is critical in the prevention of long-term complications.

IGF-1 infusion to fetal sheep increases organ growth but not by stimulating nutrient transfer to the fetus.

Insulin-like growth factor-1 (IGF-1) is an important fetal growth factor. However, the role of fetal IGF-1 in increasing placental blood flow, nutrient transfer, and nutrient availability to support fetal growth and protein accretion is not well understood. Catheterized fetuses from late gestation pregnant sheep received an intravenous infusion of LR3 IGF-1 (LR3 IGF-1; n = 8) or saline (SAL; n = 8) for 1 wk. Sheep then underwent a metabolic study to measure uterine and umbilical blood flow, nutrient uptake rates, and fetal protein kinetic rates. By the end of the infusion, fetal weights were not statistically different between groups (SAL: 3.260 ± 0.211 kg, LR3 IGF-1: 3.682 ± 0.183; P = 0.15). Fetal heart, adrenal gland, and spleen weights were higher (P < 0.05), and insulin was lower in LR3 IGF-1 (P < 0.05). Uterine and umbilical blood flow and umbilical uptake rates of glucose, lactate, and oxygen were similar between groups. Umbilical amino acid uptake rates were lower in LR3 IGF-1 (P < 0.05) as were fetal concentrations of multiple amino acids. Fetal protein kinetic rates were similar. LR3 IGF-1 skeletal muscle had higher myoblast proliferation (P < 0.05). In summary, LR3 IGF-1 infusion for 1 wk into late gestation fetal sheep increased the weight of some fetal organs. However, because umbilical amino acid uptake rates and fetal plasma amino acid concentrations were lower in the LR3 IGF-1 group, we speculate that animals treated with LR3 IGF-1 can efficiently utilize available nutrients to support organ-specific growth in the fetus rather than by stimulating placental blood flow or nutrient transfer to the fetus.NEW & NOTEWORTHY After a 1-wk infusion of LR3 IGF-1, late gestation fetal sheep had lower umbilical uptake rates of amino acids, lower fetal arterial amino acid and insulin concentrations, and lower fetal oxygen content; however, LR-3 IGF-1-treated fetuses were still able to effectively utilize the available nutrients and oxygen to support organ growth and myoblast proliferation.

Adult zebrafish ventricular electrical gradients as tissue mechanisms of ECG patterns under baseline vs. oxidative stress.

AIMS: In mammalian ventricles, electrical gradients establish electrical heterogeneities as essential tissue mechanisms to optimize mechanical efficiency and safeguard electrical stability. Electrical gradients shape mammalian electrocardiographic patterns; disturbance of electrical gradients is proarrhythmic. The zebrafish heart is a popular surrogate model for human cardiac electrophysiology thanks to its remarkable recapitulation of human electrocardiogram and ventricular action potential features. Yet, zebrafish ventricular electrical gradients are largely unexplored. The goal of this study is to define the zebrafish ventricular electrical gradients that shape the QRS complex and T wave patterns at baseline and under oxidative stress. METHODS AND RESULTS: We performed in vivo electrocardiography and ex vivo voltage-sensitive fluorescent epicardial and transmural optical mapping of adult zebrafish hearts at baseline and during acute H2O2 exposure. At baseline, apicobasal activation and basoapical repolarization gradients accounted for the polarity concordance between the QRS complex and T wave. During H2O2 exposure, differential regional impairment of activation and repolarization at the apex and base disrupted prior to baseline electrical gradients, resulting in either reversal or loss of polarity concordance between the QRS complex and T wave. KN-93, a specific calcium/calmodulin-dependent protein kinase II inhibitor (CaMKII), protected zebrafish hearts from H2O2 disruption of electrical gradients. The protection was complete if administered prior to oxidative stress exposure. CONCLUSIONS: Despite remarkable apparent similarities, zebrafish and human ventricular electrocardiographic patterns are mirror images supported by opposite electrical gradients. Like mammalian ventricles, zebrafish ventricles are also susceptible to H2O2 proarrhythmic perturbation via CaMKII activation. Our findings suggest that the adult zebrafish heart may constitute a clinically relevant model to investigate ventricular arrhythmias induced by oxidative stress. However, the fundamental ventricular activation and repolarization differences between the two species that we demonstrated in this study highlight the potential limitations when extrapolating results from zebrafish experiments to human cardiac electrophysiology, arrhythmias, and drug toxicities.

Importance of thorough examination in foreign body exposure: An impressive case of asphyxiation with foam sealant.

Foreign body exposure requires a systematic exploration. There are no specific guidelines regarding cancer screening with prior toxin exposure. More research about the pathophysiology and management may further our knowledge and improve morbidity.