GAPDH inhibition mediated by thiol oxidation in human airway epithelial cells exposed to an environmental peroxide.

Intracellular redox homeostasis in the airway epithelium is closely regulated through adaptive signaling and metabolic pathways. However, inhalational exposure to xenobiotic stressors such as secondary organic aerosols (SOA) can alter intracellular redox homeostasis. Isoprene hydroxy hydroperoxide (ISOPOOH), a ubiquitous volatile organic compound derived from the atmospheric photooxidation of biogenic isoprene, is a major contributor to SOA. We have previously demonstrated that exposure of human airway epithelial cells (HAEC) to ISOPOOH induces oxidative stress through multiple mechanisms including lipid peroxidation, glutathione oxidation, and alterations of glycolytic metabolism. Using dimedone-based reagents and copper catalyzed azo-alkynyl cycloaddition to tag intracellular protein thiol oxidation, we demonstrate that exposure of HAEC to micromolar levels of ISOPOOH induces reversible oxidation of cysteinyl thiols in multiple intracellular proteins, including GAPDH, that was accompanied by a dose-dependent loss of GAPDH enzymatic activity. These results demonstrate that ISOPOOH induces an oxidative modification of intracellular proteins that results in loss of GAPDH activity, which ultimately impacts the dynamic regulation of the intracellular redox homeostatic landscape in HAEC.

Refractory Gastroparesis Following Duodenal Switch Treated With Laparoscopic Subtotal Gastrectomy With Roux-en-Y Reconstruction.

Gastroparesis following duodenal switch (DS) is a known but rare complication. Typically, patients are managed with prokinetic agents, with pyloromyotomy being the first-line surgical therapy. The literature is sparse regarding how to manage patients whose symptoms remain refractory to these first-line therapies. We present a patient who experienced gastroparesis following DS, who fell into this category. Her symptoms of prandial pain and regurgitation remained resistant to medical management and pyloromyotomy. She was successfully treated with subtotal gastrectomy with Roux-en-Y reconstruction with resolution of these symptoms. The literature suggests that bypassing or resecting the pylorus and removing overstretched aperistaltic gastric muscle could be the mechanism behind this treatment's effectiveness.

Real-time redox adaptations in human airway epithelial cells exposed to isoprene hydroxy hydroperoxide.

While redox processes play a vital role in maintaining intracellular homeostasis by regulating critical signaling and metabolic pathways, supra-physiological or sustained oxidative stress can lead to adverse responses or cytotoxicity. Inhalation of ambient air pollutants such as particulate matter and secondary organic aerosols (SOA) induces oxidative stress in the respiratory tract through mechanisms that remain poorly understood. We investigated the effect of isoprene hydroxy hydroperoxide (ISOPOOH), an atmospheric oxidation product of vegetation-derived isoprene and a constituent of SOA, on intracellular redox homeostasis in cultured human airway epithelial cells (HAEC). We used high-resolution live cell imaging of HAEC expressing the genetically encoded ratiometric biosensors Grx1-roGFP2, iNAP1, or HyPer, to assess changes in the cytoplasmic ratio of oxidized glutathione to reduced glutathione (GSSG:GSH), and the flux of NADPH and H2O2, respectively. Non-cytotoxic exposure to ISOPOOH resulted in a dose-dependent increase of GSSG:GSH in HAEC that was markedly potentiated by prior glucose deprivation. ISOPOOH-induced increase in glutathione oxidation were accompanied by concomitant decreases in intracellular NADPH. Following ISOPOOH exposure, the introduction of glucose resulted in a rapid restoration of GSH and NADPH, while the glucose analog 2-deoxyglucose resulted in inefficient restoration of baseline GSH and NADPH. To elucidate bioenergetic adaptations involved in combatting ISOPOOH-induced oxidative stress we investigated the regulatory role of glucose-6-phosphate dehydrogenase (G6PD). A knockout of G6PD markedly impaired glucose-mediated recovery of GSSG:GSH but not NADPH. These findings reveal rapid redox adaptations involved in the cellular response to ISOPOOH and provide a live view of the dynamic regulation of redox homeostasis in human airway cells as they are exposed to environmental oxidants.

BMI and HbA1c are metabolic markers for pancreatic cancer: Matched case-control study using a UK primary care database.

BACKGROUND: Weight loss, hyperglycaemia and diabetes are known features of pancreatic cancer. We quantified the timing and the amount of changes in body mass index (BMI) and glycated haemoglobin (HbA1c), and their association with pancreatic cancer from five years before diagnosis. METHODS: A matched case-control study was undertaken within 590 primary care practices in England, United Kingdom. 8,777 patients diagnosed with pancreatic cancer (cases) between 1st January 2007 and 31st August 2020 were matched to 34,979 controls by age, gender and diabetes. Longitudinal trends in BMI and HbA1c were visualised. Odds ratios adjusted for demographic and lifestyle factors (aOR) and 95% confidence intervals (CI) were calculated with conditional logistic regression. Subgroup analyses were undertaken according to the diabetes status. RESULTS: Changes in BMI and HbA1c observed for cases on longitudinal plots started one and two years (respectively) before diagnosis. In the year before diagnosis, a 1 kg/m2 decrease in BMI between cases and controls was associated with aOR for pancreatic cancer of 1.05 (95% CI 1.05 to 1.06), and a 1 mmol/mol increase in HbA1c was associated with aOR of 1.06 (1.06 to 1.07). ORs remained statistically significant (p < 0.001) for 2 years before pancreatic cancer diagnosis for BMI and 3 years for HbA1c. Subgroup analysis revealed that the decrease in BMI was associated with a higher pancreatic cancer risk for people with diabetes than for people without (aORs 1.08, 1.06 to 1.09 versus 1.04, 1.03 to 1.05), but the increase in HbA1c was associated with a higher risk for people without diabetes than for people with diabetes (aORs 1.09, 1.07 to 1.11 versus 1.04, 1.03 to 1.04). CONCLUSIONS: The statistically significant changes in weight and glycaemic control started three years before pancreatic cancer diagnosis but varied according to the diabetes status. The information from this study could be used to detect pancreatic cancer earlier than is currently achieved. However, regular BMI and HbA1c measurements are required to facilitate future research and implementation in clinical practice.

The impacts of donor transitions on health systems in middle-income countries: a scoping review.

As countries graduate from low-income to middle-income status, many face losses in development assistance for health and must 'transition' to greater domestic funding of their health response. If improperly managed, donor transitions in middle-income countries (MICs) could present significant challenges to global health progress. No prior knowledge synthesis has comprehensively surveyed how donor transitions can affect health systems in MICs. We conducted a scoping review using a structured search strategy across five academic databases and 37 global health donor and think tank websites for literature published between January 1990 and October 2018. We used the World Health Organization health system 'building blocks' framework to thematically synthesize and structure the analysis. Following independent screening, 89 publications out of 11 236 were included for data extraction and synthesis. Most of this evidence examines transitions related to human immunodeficiency virus/Acquired Immune Deficiency Syndrome (AIDS; n = 45, 50%) and immunization programmes (n = 14, 16%), with a focus on donors such as the Global Fund to Fight AIDS, Tuberculosis and Malaria (n = 26, 29%) and Gavi, the Vaccine Alliance (n = 15, 17%). Donor transitions are influenced by the actions of both donors and country governments, with impacts on every component of the health system. Successful transition experiences show that leadership, planning, and pre-transition investments in a country's financial, technical, and logistical capacity are vital to ensuring smooth transition. In the absence of such measures, shortages in financial resources, medical product and supply stock-outs, service disruptions, and shortages in human resources were common, with resulting implications not only for programme continuation, but also for population health. Donor transitions can affect different components of the health system in varying and interconnected ways. More rigorous evaluation of how donor transitions can affect health systems in MICs will create an improved understanding of the risks and opportunities posed by donor exits.

Use of Diaries for Family Members of Intensive Care Unit Patients to Reduce Long-Term PTSD: A Pilot Study.

Many family members whose loved ones stay in the intensive care unit (ICU) have post-traumatic stress disorder (PTSD) after the hospitalization. A mixed-methods longitudinal randomized trial studying family members of medical ICU (MICU) patients was conducted. Participants were randomized into 2 groups (intervention and control). Post-traumatic stress symptoms checklist-14 scores for the intervention group trended downward over time, but no differences were detected in PTSD risk between the intervention and control groups. The ICU experience for family members is traumatizing. A simple gesture of providing ICU diaries for them to use during the ICU stay may help reduce their emotional burden and requires further investigation.

Live cell imaging of oxidative stress in human airway epithelial cells exposed to isoprene hydroxyhydroperoxide.

Exposure to respirable air particulate matter (PM2.5) in ambient air is associated with morbidity and premature deaths. A major source of PM2.5 is the photooxidation of volatile plant-produced organic compounds such as isoprene. Photochemical oxidation of isoprene leads to the formation of hydroperoxides, environmental oxidants that lead to inflammatory (IL-8) and adaptive (HMOX1) gene expression in human airway epithelial cells (HAEC). To examine the mechanism through which these oxidants alter intracellular redox balance, we used live-cell imaging to monitor the effects of isoprene hydroxyhydroperoxides (ISOPOOH) in HAEC expressing roGFP2, a sensor of the glutathione redox potential (EGSH). Non-cytotoxic exposure of HAEC to ISOPOOH resulted in a rapid and robust increase in EGSH that was independent of the generation of intracellular or extracellular hydrogen peroxide. Our results point to oxidation of GSH through the redox relay initiated by glutathione peroxidase 4, directly by ISOPOOH or indirectly by ISOPOOH-generated lipid hydroperoxides. We did not find evidence for involvement of peroxiredoxin 6. Supplementation of HAEC with polyunsaturated fatty acids enhanced ISOPOOH-induced glutathione oxidation, providing additional evidence that ISOPOOH initiates lipid peroxidation of cellular membranes. These findings demonstrate that ISOPOOH is a potent environmental airborne hydroperoxide with the potential to contribute to oxidative burden of human airway posed by inhalation of secondary organic aerosols.

Using Primary Care Data to Report Real-World Pancreatic Cancer Survival and Symptomatology.

Pancreatic cancer is the 10th most common cancer diagnosed; despite recent advances in many areas of oncology, survival remains poor, in part owing to late diagnosis. Whilst primary care data are used widely for epidemiology and pharmacovigilance, they are less used for observing survival. In this study we extracted a pancreatic cancer cohort from a nationally representative English primary care database of electronic health records (EHRs) and reported on their symptom and mortality data. A total of 11, 649 cases were identified within the Oxford Royal College of General Practitioners (RCGP) Clinical Informatics Digital Hub network. All-cause mortality data was recorded for 4623 (39.69%). Mean age at recording of cancer diagnosis was 71.4 years (SD 12.0 years). 1-year and 5-year survival was 22.06% and 3.27% respectively. Within a multivariate model, age had a significant impact on survival; those diagnosed under the age of 60 had the longest survival, as compared to those age 60 - 79 (HR: 1.36, 95% CI: 1.20 - 1.54, p < 0.001) and 80+ (HR: 2.13, 95% CI: 1.86 - 2.44, p < 0.01). Symptomatology was examined; at any time point abdominal pain was the most commonly reported symptom present in 5271 cases (45.2%), but within the 12 months preceding diagnosis jaundice was the most common feature, present in 2587 patients (22.2%). Future studies clarifying other contributing factors on survival outcomes and patterns of symptomatology are needed; primary care EHRs provide an opportunity to evaluate real-world cancer patient cohort data.

Association between shunt-responsive idiopathic normal pressure hydrocephalus and alcohol.

OBJECTIVE Idiopathic normal pressure hydrocephalus (iNPH) is characterized by ventriculomegaly, gait difficulty, incontinence, and dementia. The symptoms can be ameliorated by CSF drainage. The object of this study was to identify factors associated with shunt-responsive iNPH. METHODS The authors reviewed the medical records of 529 patients who underwent shunt placement for iNPH at their institution between July 2001 and March 2015. Variables associated with shunt-responsive iNPH were identified using bivariate and multivariate analyses. Detailed alcohol consumption information was obtained for 328 patients and was used to examine the relationship between alcohol and shunt-responsive iNPH. A computerized patient registry from 2 academic medical centers was queried to determine the prevalence of alcohol abuse among 1665 iNPH patients. RESULTS Bivariate analysis identified associations between shunt-responsive iNPH and gait difficulty (OR 4.59, 95% CI 2.32-9.09; p < 0.0001), dementia (OR 1.79, 95% CI 1.14-2.80; p = 0.01), incontinence (OR 1.77, 95% CI 1.13-2.76; p = 0.01), and alcohol use (OR 1.98, 95% CI 1.23-3.16; p = 0.03). Borderline significance was observed for hyperlipidemia (OR 1.56, 95% CI 0.99-2.45; p = 0.054), a family history of hyperlipidemia (OR 3.09, 95% CI 0.93-10.26, p = 0.054), and diabetes (OR 1.83, 95% CI 0.96-3.51; p = 0.064). Multivariate analysis identified associations with gait difficulty (OR 3.98, 95% CI 1.81-8.77; p = 0.0006) and alcohol (OR 1.94, 95% CI 1.10-3.39; p = 0.04). Increased alcohol intake correlated with greater improvement after CSF drainage. Alcohol abuse was 2.5 times more prevalent among iNPH patients than matched controls. CONCLUSIONS Alcohol consumption is associated with the development of shunt-responsive iNPH.

Domestic violence in the Solomon Islands.

The Solomon Islands has one of the highest rates of family and sexual violence (FSV) in the world with 64% of women aged 15-49 have reported physical and/or sexual abuse by a partner. The National Referral Hospital (NRH) in the capital, Honiara, is the only tertiary hospital for the country. Our 4-week medical elective at the NRH was spent reflecting on healthcare challenges including FSV, with the aim of identifying cases of FSV and assessing on the current strategies to improve care for victims. Throughout our placement, we encountered many cases of probable FSV, particularly in the Emergency Department and Obstetrics and Gynecology. These patients were often not managed effectively, largely due to time pressures and overcrowding in the hospital. However, we identified a number of strategies, which have recently been implemented in order to help FSV victims in the Solomon Islands. These include strategies within the healthcare setting, in particular, the commencement of FSV reporting within the hospital, and the production of a manual to enable healthcare worker education on the issue. Strategies within the criminal justice system are also in place. These include recent changes in legislation and the work of the volunteer police force, Royal Assist Mission to the Solomon Islands, to improve attitudes toward FSV. These approaches to tackle the problem of FSV are currently in their early stages and have largely stemmed from Western policies and ideals. This report concludes that more time is needed to accurately assess the impact of the current changes before further recommendations are made.

Quantitative evaluation of changes in gait after extended cerebrospinal fluid drainage for normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait instability, urinary incontinence and cognitive dysfunction. These symptoms can be relieved by cerebrospinal fluid (CSF) drainage, but the time course and nature of the improvements are poorly characterized. Attempts to prospectively identify iNPH patients responsive to CSF drainage by evaluating presenting gait quality or via extended lumbar cerebrospinal fluid drainage (eLCD) trials are common, but the reliability of such approaches is unclear. Here we combine eLCD trials with computerized quantitative gait measurements to predict shunt responsiveness in patients undergoing evaluation for possible iNPH. In this prospective cohort study, 50 patients presenting with enlarged cerebral ventricles and gait, urinary, and/or cognitive difficulties were evaluated for iNPH using a computerized gait analysis system during a 3day trial of eLCD. Gait speed, stride length, cadence, and the Timed Up and Go test were quantified before and during eLCD. Qualitative assessments of incontinence and cognition were obtained throughout the eLCD trial. Patients who improved after eLCD underwent ventriculoperitoneal shunt placement, and symptoms were reassessed serially over the next 3 to 15months. There was no significant difference in presenting gait characteristics between patients who improved after drainage and those who did not. Gait improvement was not observed until 2 or more days of continuous drainage in most cases. Symptoms improved after eLCD in 60% of patients, and all patients who improved after eLCD also improved after shunt placement. The degree of improvement after eLCD correlated closely with that observed after shunt placement.

Variation in candidate genes CLOCK and ADCYAP1 does not consistently predict differences in migratory behavior in the songbird genus Junco.

Recent studies exploring the molecular genetic basis for migratory variation in animals have identified polymorphisms in two genes ( CLOCK and ADCYAP1) that are linked to circadian rhythms and correlate with migratory propensity and phenology among individuals and populations. Results from these initial studies are mixed, however, and additional data are needed to assess the generality and diversity of the molecular mechanisms that regulate the biology of migration. We sequenced CLOCK and ADCYAP1 in 15 populations across the two species of the avian genus Junco, a North American lineage in which multiple recently diverged subspecies and populations range from sedentary to long-distance migrants. We found no consistent associations between allele length and migratory status across the genus for either CLOCK or ADCYAP1. However, within two subspecies groups, populations that migrate longer distances have longer CLOCK alleles on average. Additionally, there was a positive relationship between ADCYAP1 allele length and migratory restlessness (zugunruhe) among individuals within one of two captive populations studied-a result similar to those reported previously within captive blackcaps ( Sylvia atricapilla). We conclude that, while both ADCYAP1 and CLOCK may correlate with migratory propensity within or among certain populations or species, previously identified relationships between migratory behavior and sequence variants cannot be easily generalized across taxa.

Using the photovoice method to advocate for change to a campus smoking policy.

OBJECTIVE: The authors used the photovoice method as a strategy for empowering students to advocate for change of a campus smoking policy. PARTICIPANTS: Participants included 49 college students and 160 photo-exhibit attendees during spring 2011. METHODS: Students were trained in the use of the photovoice method and a public exhibit was used to educate the campus community and advocate for change. RESULTS: The photovoice initiative resulted in an effective platform for students to successfully advocate for the relocation of ashtrays that were in violation of the policy and for the elicitation of future advocacy targets. CONCLUSIONS: The photovoice project provided a platform for students to have their views heard by campus community members and policymakers. The project served as a useful tool for grassroots student advocacy. Those interested in addressing campus health policy issues may want to consider conducting a photovoice project similar to the one described in this article.

Quantifying littered cigarette butts to measure effectiveness of smoking bans to building perimeters.

OBJECTIVE: The authors estimated the number of violations of a university policy that prohibited smoking within 25 ft of all campus buildings. PARTICIPANTS: The project was conducted by 13 student researchers from the university and a member of the local public health department. METHODS: Students quantified cigarette butts that were littered in a 30-day period inside the prohibited smoking area of 7 campus buildings (large residential hall, small residential hall, administrative building, 2 academic buildings, campus cafeteria, and student union). RESULTS: Investigators found a total of 7,861 cigarette butts (large residential hall: 1,198; small residential hall: 344; administrative building: 107; 2 academic buildings: 1,123 and 806; campus cafeteria: 2,651; and student union: 1,632). CONCLUSIONS: Findings suggest that there is low compliance with the university's smoking policy. The described project may be repeated by students at other universities as a method to advocate for policy change.

Deciphering information encoded in birdsong: male songbirds with fertile mates respond most strongly to complex, low-amplitude songs used in courtship.

Research on the function of acoustic signals has focused on high-amplitude long-range songs (LRS) and largely ignored low-amplitude songs produced by many species during close-proximity, conspecific interactions. Low-amplitude songs can be structurally identical to LRS (soft LRS), or they can be widely divergent, sharing few spectral and temporal attributes with LRS (short-range song [SRS]). SRS is often more complex than LRS and is frequently sung by males during courtship. To assess function, we performed two playback experiments on males of a socially monogamous songbird. We compared responses of males whose mates were fertile or nonfertile with differences in song structure (SRS vs. LRS and soft LRS), amplitude (SRS and soft LRS vs. LRS), and tempo (slow SRS vs. fast SRS). Males responded more strongly to SRS than to LRS or soft LRS, indicating that song structure had a greater effect on response than song amplitude. SRS tempo did not detectably affect male response. Importantly, males responded more strongly to SRS when their mates were fertile, presumably because hearing SRS can indicate that a male's mate is being courted by an intruding male and a strong response can deter extrapair competitors. We conclude that low-amplitude songs can function in both inter- and intrasexual communication and should receive greater attention in future studies of mate choice and male-male competition.

The effects of moxifloxacin ophthalmic solution 0.5% or gatifloxacin ophthalmic solution 0.3% treatment on corneal wound healing in pigmented rabbits following anterior keratectomy.

PURPOSE: These studies examined corneal healing rates, Type-IV collagen and zonula occludens membrane-associated protein (ZO-1) expression, as well as aqueous PGE(2) and IL-1 beta concentrations in pigmented rabbits treated with either moxifloxacin 0.5%, gatifloxacin 0.3% or BSS following anterior keratectomy. METHODS: Anterior keratectomy surgery was followed by topical administration with commercial ophthalmic formulations of either moxifloxacin or gatifloxacin or BSS (TID for 96 h). Images of the fluorescein-stained healing corneas were analyzed for wound area. At 48 or 96 h following surgery, aqueous humor samples were collected and analyzed for the inflammatory mediators PGE(2) and IL-1 beta using an ELISA. The corneas were subsequently evaluated using both scanning and transmission electron microscopy. In a second parallel study, corneas were evaluated at both 48 and 96 h for Type-IV collagen and ZO-1 expression using immunohistochemistry. RESULTS: Fluorescein-stained corneal images at 96 h postsurgery demonstrated that 90% +/- 8% re-epithelialization for moxifloxacin, 81% +/- 14% for gatifloxacin, and 88 +/- 6% for BSS((R)) (P > 0.05). PGE(2 )levels in the aqueous humor of fluoroquinolone treated eyes were reduced at 48 h compared to BSS treated eyes. IL-1 beta was undetectable in all samples. No differences in Type-IV collagen or ZO-1 expression were observed between any treatment groups. There were no differences between groups in histological appearance or in ultrastructural healing processes. CONCLUSIONS: These studies demonstrated that the commercial ophthalmic formulations of moxifloxacin and gatifloxacin were similar to each other in their effects on the levels of aqueous humor PGE(2) and rates of corneal wound re-epithelialization.

Corneal wound healing in New Zealand White Rabbits following anterior keratectomy and treatment with moxifloxacin ophthalmic solution 0.5% or gatifloxacin ophthalmic solution 0.3%.

PURPOSE: These studies examined corneal reepithelialization rates and type IV collagen expression in rabbits treated with either moxifloxacin HCl ophthalmic solution 0.5% as base or gatifloxacin 0.3% ophthalmic solution following anterior keratectomy. METHODS: Animals (n = 6 per group) underwent surgery to create an 8-mm anterior keratectomy in the right eye. Rabbits were subsequently dosed with 1 drop, 3 times per day for 4 days with either moxifloxacin, gatifloxacin, or a commercially available irrigating solution. Fluorescein images were collected daily for the duration of the study. Approximately 96 h following surgery, the eyes were processed and evaluated for the presence of type IV collagen using immunohistochemical techniques. In two similar parallel studies, epithelial tissues were collected after the 48-h slit-lamp examination for a quantitative comparison of type IV collagen using either Western blot or quantitative polymerase chain reaction (Q-RT-PCR) techniques. RESULTS: Analysis of fluorescein images demonstrated that there were no significant differences in reepithelialization rates between the groups at any time point. At 96 h, 87%+/- 8% reepithelialization for moxifloxacin-treated eyes was observed compared with 77%+/- 10% for gatifloxacin-treated eyes and 85%+/-14% for BSS-treated eyes. The wound healing rates for the parallel studies demonstrated similar levels of reepithelialization for all groups. No discernable differences in type IV collagen expression were observed between treatment groups in the animals. The Q-RT-PCR analysis yielded no significant quantifiable difference in type IV collagen expression between any of the treatment groups. Expression values for alpha1 type IV collagen relative to the 18 S ribosomal RNA control were 0.0306+/-0.005 for BSS, 0.0251+/-0.002 for moxifloxacin, and 0.0254+/-0.006 for gatifloxacin. CONCLUSIONS: These studies indicate that there are no significant differences in corneal reepithelialization rates and type IV collagen expression between moxifloxacin ophthalmic solution 0.5%, gatifloxacin ophthalmic solution 0.3%, and the commercially available irrigating solution in this anterior keratectomy model.

Safety of moxifloxacin as shown in animal and in vitro studies.

Topical treatment of ocular bacterial infection is practiced widely, and the choice of the antibacterial agent depends on the nature of the infection, including the susceptibility of the organism, the tissue affected, and the safety profile of the agent. Moxifloxacin is a fourth-generation fluoroquinolone approved for ophthalmic use as moxifloxacin ophthalmic solution 0.5% (VIGAMOX, Alcon, Fort Worth, TX). Moxifloxacin ophthalmic solution 0.5% is self-preserved at a near-neutral pH of 6.8. In treating ocular infection, the three important aspects of therapeutic control are potency, penetration of the drug to the target site, and safety of the drug and the drug product. Moxifloxacin ophthalmic solution 0.5% provides antibacterial potency and high penetration of target ocular tissues. The ocular and systemic safety profile of moxifloxacin compares favorably with those of other fluoroquinolone antimicrobial agents, with a low risk of recognized quinolone-related toxicity. In vitro studies of fluoroquinolones with human or rabbit corneal epithelial cells or keratocytes suggest that moxifloxacin is similar in cytotoxicity potential to other drugs of this family. Specialized in vivo corneal wound-healing studies draw little distinction between moxifloxacin-treated eyes and those treated with other fluoroquinolones. Repeated-dose topical ocular studies in rabbits and monkeys, with high concentrations (up to 3%) of moxifloxacin and at treatment durations and regimens well in excess of label-prescribed use, demonstrated a high safety margin for ocular and extraocular tissues. Cornea, the tissue with highest exposure, was found to be unaffected by these high exposures, with slit-lamp biomicroscopy, corneal thickness measurement, intraocular pressure, and specular microscopy of the corneal endothelium (monkeys only), and histologic evaluation showing no effects, as compared with controls. Moxifloxacin ophthalmic solution 0.5% affords superior efficacy and ocular tissue penetration, with a favorable safety profile.