Infectious neutrophil deployment is regulated by resolvin D4.

Neutrophils reside in the bone marrow (BM), ready for deployment to sites of injury/infection, initiating inflammation and its resolution. Here, we report that distal infections signal to the BM via resolvins to regulate granulopoiesis and BM neutrophil deployment. Emergency granulopoiesis during peritonitis evoked changes in BM resolvin D1 (RvD1) and BM RvD4. We found that leukotriene B4 stimulates neutrophil deployment. RvD1 and RvD4 each limited neutrophilic infiltration to infections, and differently regulated BM myeloid populations: RvD1 increased reparative monocytes, and RvD4 regulated granulocytes. RvD4 disengaged emergency granulopoiesis, prevented excess BM neutrophil deployment, and acted on granulocyte progenitors. RvD4 also stimulated exudate neutrophil, monocyte, and macrophage phagocytosis, and enhanced bacterial clearance. This mediator accelerated both neutrophil apoptosis and clearance by macrophages, thus expediting the resolution phase of inflammation. RvD4 stimulated phosphorylation of ERK1/2 and STAT3 in human BM-aspirate-derived granulocytes. RvD4 in the 1 to 100 nM range stimulated whole-blood neutrophil phagocytosis of Escherichia coli. RvD4 increased BM macrophage efferocytosis of neutrophils. Together, these results demonstrate the novel functions of resolvins in granulopoiesis and neutrophil deployment, contributing to the resolution of infectious inflammation.

Recovery From Homonymous Hemianopia in Hyperglycemia-Induced Occipital Lobe Electroclinical Seizures Following Glycemic Control.

BACKGROUND: Visual changes due to hyperglycemia in diabetes are not uncommon. While blurred vision is a well-established sequela of chronic hyperglycemia, homonymous hemianopia with or without electroclinical seizures is much rarer and can be mistaken for migraine, temporal arteritis, or ischemia of the central nervous system. METHODS: This article analyzed case studies for 3 patients (67M, 68M, 52F) presenting with complex visual phenomena, from 3 to 42 days duration, including pathogenesis, clinical findings, management, and follow-up. RESULTS: Examinations demonstrated dense left homonymous hemianopias in 2 patients and a left inferior homonymous quadrantanopia in one, with no other abnormalities. Patients described vivid, nonstereotyped intermittent hallucinations in the affected fields. Blood glucose levels ranged from 13.5 to 35.0 mmol/L (243-630 mg/dL) without ketosis and HbA1c from 14.6% to 16.8%. Computed tomography of the brain showed no acute intracranial pathology. MRI of the brain either detected no abnormalities or demonstrated changes consistent with seizure activity. Electroencephalogram (EEG) demonstrated seizures over the right occipital region in each patient. EEG seizures coincided with patients' hallucinations, while they remained otherwise conscious. Oral hypoglycemic and antiepileptic medications were commenced with rapid and complete reversal of the seizures and visual field deficits, confirmed by repeat Automated 30-2 and MRI. CONCLUSIONS: Hyperglycemia-induced occipital lobe seizures with visual hallucinations and interictal homonymous visual field defects represent a rare but clinically important diagnosis. This article highlights the importance of prompt recognition and treatment to facilitate recovery.

Potency boost of a Mycobacterium tuberculosis dihydrofolate reductase inhibitor by multienzyme F420H2-dependent reduction.

Triaza-coumarin (TA-C) is a Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitor with an IC50 (half maximal inhibitory concentration) of ∼1 µM against the enzyme. Despite this moderate target inhibition, TA-C shows exquisite antimycobacterial activity (MIC50, concentration inhibiting growth by 50% = 10 to 20 nM). Here, we investigated the mechanism underlying this potency disconnect. To confirm that TA-C targets DHFR and investigate its unusual potency pattern, we focused on resistance mechanisms. In Mtb, resistance to DHFR inhibitors is frequently associated with mutations in thymidylate synthase thyA, which sensitizes Mtb to DHFR inhibition, rather than in DHFR itself. We observed thyA mutations, consistent with TA-C interfering with the folate pathway. A second resistance mechanism involved biosynthesis of the redox coenzyme F420 Thus, we hypothesized that TA-C may be metabolized by Mtb F420-dependent oxidoreductases (FDORs). By chemically blocking the putative site of FDOR-mediated reduction in TA-C, we reproduced the F420-dependent resistance phenotype, suggesting that F420H2-dependent reduction is required for TA-C to exert its potent antibacterial activity. Indeed, chemically synthesized TA-C-Acid, the putative product of TA-C reduction, displayed a 100-fold lower IC50 against DHFR. Screening seven recombinant Mtb FDORs revealed that at least two of these enzymes reduce TA-C. This redundancy in activation explains why no mutations in the activating enzymes were identified in the resistance screen. Analysis of the reaction products confirmed that FDORs reduce TA-C at the predicted site, yielding TA-C-Acid. This work demonstrates that intrabacterial metabolism converts TA-C, a moderately active "prodrug," into a 100-fold-more-potent DHFR inhibitor, thus explaining the disconnect between enzymatic and whole-cell activity.

Closed globe and adnexal eye injuries: Epidemiology, clinical and surgical outcomes, and an economic cost analysis.

BACKGROUND: To examine the epidemiology, visual outcomes, surgical interventions, and socioeconomic costs of closed globe (CGI) and adnexal injuries. METHODS: A retrospective 11-year tertiary-trauma centre study of 529 consecutive CGI was conducted using the Revised Globe and Adnexal Trauma Terminology classification in individuals aged ≥16 years. Outcome measures included best-corrected visual acuity (BCVA), operating theatre visits, and socioeconomic costs. RESULTS: CGI disproportionately impacted young males during work (89.1%) and sports (92.2%), with eye protection only worn in 11.9% and 2.0%, respectively. Home was the most prevalent location (32.5%) due to falls (52.3%) in older females (57.9%). Concomitant adnexal injuries occurred frequently (71.5%), particularly in assaults (88.1%), and included eyelid lacerations (20.8%), orbital injuries (12.5%), and facial fractures (10.2%). Final median BCVA improved to 0.2 logMAR [6/9] (IQR 0-0.2) from 0.5 logMAR [6/18] (IQR 0-0.5) (p < 0.001). Surgery was required in 89 CGI (16.8%) in 123 theatre visits. In multivariable logistical regression modelling, presenting BCVA was predictive of final BCVA (odds ratio [OR] 8.4, 95% confidence interval [95%CI] 2.6-27.8, p < 0.001), while involvement of the lids (OR 2.6, 95%CI 1.3-5.3, p = 0.006), nasolacrimal apparatus (OR 74.9, 95%CI 7.9-707.4, p < 0.001), orbit (OR 5.0, 95%CI 2.2-11.2, p < 0.001), and lens (OR 8.4, 95%CI 2.4-29.7, p < 0.001) predicted for operating theatre visits. Economic costs totalled AUD20.8-32.1 million (USD16.2-25.0 million) and were estimated at AUD44.5-77.0 million (USD34.7-60.1 million) annually for Australia. CONCLUSIONS: CGI is a prevalent and preventable burden on patients and the economy. To mitigate this burden, cost-effective public health strategies should target at-risk populations.

Predicting nitroimidazole antibiotic resistance mutations in Mycobacterium tuberculosis with protein engineering.

Our inability to predict which mutations could result in antibiotic resistance has made it difficult to rapidly identify the emergence of resistance, identify pre-existing resistant populations, and manage our use of antibiotics to effectively treat patients and prevent or slow the spread of resistance. Here we investigated the potential for resistance against the new antitubercular nitroimidazole prodrugs pretomanid and delamanid to emerge in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn) is the only identified enzyme within M. tuberculosis that activates these prodrugs, via an F420H2-dependent reaction. We show that the native menaquinone-reductase activity of Ddn is essential for emergence from hypoxia, which suggests that for resistance to spread and pose a threat to human health, the native activity of Ddn must be at least partially retained. We tested 75 unique mutations, including all known sequence polymorphisms identified among ~15,000 sequenced M. tuberculosis genomes. Several mutations abolished pretomanid and delamanid activation in vitro, without causing complete loss of the native activity. We confirmed that a transmissible M. tuberculosis isolate from the hypervirulent Beijing family already possesses one such mutation and is resistant to pretomanid, before being exposed to the drug. Notably, delamanid was still effective against this strain, which is consistent with structural analysis that indicates delamanid and pretomanid bind to Ddn differently. We suggest that the mutations identified in this work be monitored for informed use of delamanid and pretomanid treatment and to slow the emergence of resistance.

Taxonomic re-appraisal for toothfish (Dissostichus: Notothenioidea) across the Antarctic Polar Front using genomic and morphological studies.

The Patagonian toothfish, Dissostichus eleginoides, is one of the largest predatory fishes inhabiting Southern Ocean waters spanning the Antarctic Polar Front (APF), a prominent biogeographic boundary restricting gene flow and driving species divergence between Antarctic and sub-Antarctic waters. In the light of emerging threats to toothfish conservation and sustainability, this study investigated genetic [mtDNA sequences and genome wide nuclear single nucleotide polymorphisms (SNPs)] and morphological data to critically evaluate the taxonomic status of toothfish north (Chile and Patagonian shelf) and south (South Georgia and South Sandwich Islands) of the APF. mtDNA revealed reciprocally monophyletic lineages on either side of the APF with coalescent analysis indicating these diverged during the Pleistocene. Integration with data from other sources suggests the Chilean/Patagonian lineage is endemic. SNP analysis confirmed restricted nuclear gene flow between both groups and revealed a consensus suite of positive outlier SNPs compatible with adaptive divergence between these groups. Finally, several morphological features permit unequivocal assignment of individuals to either of the clades. Based on the genetic, phenotypic and ecological divergence, the authors propose that toothfish on either side of the APF be recognised as distinct species, with the name D. eleginoides used for toothfish occurring in South American waters north of the APF and toothfish south of the APF being classified using the new name D. australis reflecting their southern distribution.

Open globe injuries: Epidemiology, visual and surgical predictive variables, prognostic models, and economic cost analysis.

BACKGROUND: Open globe injuries (OGI) represent a visually and economically devastating cause of vision loss. We examined the epidemiology, predictive variables, prognostic models, and economic cost of surgically managed OGI. METHODS: A retrospective tertiary centre study from 2008 to 2018 of 155 consecutive OGI in individuals aged 16 and older was performed. Medical records review, application of Ocular Trauma Score (OTS) and Classification and Regression Tree Analysis (CART) and cost analysis were undertaken. Key outcomes measured were visual acuity, number of operating theatre visits, prognostication using OTS and CART and estimated costs. RESULTS: Younger males at work with inadequate protective eyewear (89.1%) and falls in the elderly were overrepresented. Inferior visual outcomes were associated with a more severe OTS score, a larger injury zone, increasing age, the presence of retinal detachment, extraocular muscle involvement, intraocular foreign body, and globe rupture (R2  = 0.723, p < 0.001). Multiple operating theatre visits were required in the presence of retinal detachment, lens or orbit involvement, work-related injury, globe rupture, and a history of previous intraocular surgery (R2  = 0.0423, p < 0.001). Both OTS and CART prognosticated outcomes (p < 0.001). The OTS predicted for no vision (no light perception/enucleation/evisceration) and profound visual loss (worse than 6/120; specificity: both 100%, sensitivity: 88.2% and 88%) whereas the CART predicted for visual survival (light perception or better) and minimal-to-severe visual loss (6/120 or better; specificity: 88.5% and 81.7% , sensitivity: 97.7% and 100%). Estimated annual OGI cost for Australia was AUD48.1-60.5 million (USD37.3-47.0 million). CONCLUSIONS: The total cost of OGI is immense with young males and the elderly being disproportionately affected. Implementation of targeted government legislation and public health preventative measures may be cost-effective in ameliorating the significant burden.

Retrospective chart review to assess domains of quality of death (recognition of dying, appropriate limitations, symptom monitoring, anticipatory prescribing) of patients dying in the acute hospital under the care of a nephrology service with renal supportive care support over time.

AIM: To explore the quality of deaths in an acute hospital under a nephrology service at two teaching hospitals in Sydney with renal supportive care services over time. METHODS: Retrospective chart review of all deaths in the years 2004, 2009 and 2014 at St George Hospital (SGH) and in 2014 at the Concord Repatriation General Hospital. Domains assessed were recognition of dying, invasive interventions, symptom assessment, anticipatory prescribing, documentation of spiritual needs and bereavement information for families. End-of-life care plan (EOLCP) use was also evaluated at SGH. RESULTS: Over 90% of patients were recognized to be dying in all 3 years at SGH. Rates of interventions in the last week of life were low and did not differ across the 3 years. There was a significant increase in the prescription of anti-psychotic, anti-emetic and anti-cholinergic medication over the years at SGH. Use of EOLCP was significantly higher at SGH, and their use improved several quality domains. Of all deaths, 68% were referred to palliative care at SGH and 33% at Concord Repatriation General Hospital (not significant). Cessation of observations and non-essential medications and documentation of bereavement information given to families was low across both sites in all years, although this significantly improved when EOLCP were used. CONCLUSION: While acute teams are good at recognizing dying, they need support to care for dying patients. The use of EOLCP in acute services can facilitate improvements in caring for the dying. Renal supportive care services need time to become embedded in the culture of the acute hospital.

The Redox Cofactor F420 Protects Mycobacteria from Diverse Antimicrobial Compounds and Mediates a Reductive Detoxification System.

A defining feature of mycobacterial redox metabolism is the use of an unusual deazaflavin cofactor, F420 This cofactor enhances the persistence of environmental and pathogenic mycobacteria, including after antimicrobial treatment, although the molecular basis for this remains to be understood. In this work, we explored our hypothesis that F420 enhances persistence by serving as a cofactor in antimicrobial-detoxifying enzymes. To test this, we performed a series of phenotypic, biochemical, and analytical chemistry studies in relation to the model soil bacterium Mycobacterium smegmatis Mutant strains unable to synthesize or reduce F420 were found to be more susceptible to a wide range of antibiotic and xenobiotic compounds. Compounds from three classes of antimicrobial compounds traditionally resisted by mycobacteria inhibited the growth of F420 mutant strains at subnanomolar concentrations, namely, furanocoumarins (e.g., methoxsalen), arylmethanes (e.g., malachite green), and quinone analogues (e.g., menadione). We demonstrated that promiscuous F420H2-dependent reductases directly reduce these compounds by a mechanism consistent with hydride transfer. Moreover, M. smegmatis strains unable to make F420H2 lost the capacity to reduce and detoxify representatives of the furanocoumarin and arylmethane compound classes in whole-cell assays. In contrast, mutant strains were only slightly more susceptible to clinical antimycobacterials, and this appeared to be due to indirect effects of F420 loss of function (e.g., redox imbalance) rather than loss of a detoxification system. Together, these data show that F420 enhances antimicrobial resistance in mycobacteria and suggest that one function of the F420H2-dependent reductases is to broaden the range of natural products that mycobacteria and possibly other environmental actinobacteria can reductively detoxify.IMPORTANCE This study reveals that a unique microbial cofactor, F420, is critical for antimicrobial resistance in the environmental actinobacterium Mycobacterium smegmatis We show that a superfamily of redox enzymes, the F420H2-dependent reductases, can reduce diverse antimicrobials in vitro and in vivoM. smegmatis strains unable to make or reduce F420 become sensitive to inhibition by these antimicrobial compounds. This suggests that mycobacteria have harnessed the unique properties of F420 to reduce structurally diverse antimicrobials as part of the antibiotic arms race. The F420H2-dependent reductases that facilitate this process represent a new class of antimicrobial-detoxifying enzymes with potential applications in bioremediation and biocatalysis.

High-Resolution Ocular Surface Imaging: Real-Time Visualization of Tear Film Dysfunction.

PURPOSE: Recent advancements in infrared sensing technology have made it possible to visualize tear film dynamics in real time, enabling evaluation of tear film quality during blinking. A retrospective clinical evaluation was conducted to explore this by grading videos of the tear film and comparing grading data with dry eye diagnostic results using the OCULUS keratograph (K5M). METHODS: Videos were used to grade patients' tear film perturbations as compared with healthy control subjects. The grading was then correlated with the ocular surface disease index (OSDI) scores, tear film breakup time (TFBUT), tear meniscus height (TMH), corneal staining, redness, and meibography data. RESULTS: Infrared imaging of the ocular surface revealed instantaneous and recurring dynamic characteristics of the tear film, allowing for the differentiation between normal and abnormal tear films. Abnormal features included a complete absence of a spreading tear film, hindered spreading of the tear film after blinking, areas of tear film instability, or a combination of the latter 2. Some of these features show a resemblance to the tear film appearance after fluorescein staining. The grading of these features correlated with TFBUT and, to a lesser extent, with TMH but did not show significant correlation with any other diagnostic data from the K5M. Furthermore, the speed of tear film spreading after blinking showed a positive correlation with TMH. CONCLUSIONS: Direct visualization of the tear film across the entire palpebral aperture using infrared sensing offers a noninvasive, reproducible, and rapid method for assessing the health and quality of the tear film.

A systematic review on the effects of ROCK inhibitors on proliferation and/or differentiation in human somatic stem cells: A hypothesis that ROCK inhibitors support corneal endothelial healing via acting on the limbal stem cell niche.

Rho kinase inhibitors (ROCKi) have attracted growing multidisciplinary interest, particularly in Ophthalmology where the question as to how they promote corneal endothelial healing remains unresolved. Concurrently, stem cell biology has rapidly progressed in unravelling drivers of stem cell (SC) proliferation and differentiation, where mechanical niche factors and the actin cytoskeleton are increasingly recognized as key players. There is mounting evidence from the study of the peripheral corneal endothelium that supports the likelihood of an internal limbal stem cell niche. The possibility that ROCKi stimulate the endothelial SC niche has not been addressed. Furthermore, there is currently a paucity of data that directly evaluates whether ROCKi promotes corneal endothelial healing by acting on this limbal SC niche located near the transition zone. Therefore, we performed a systematic review examining the effects ROCKi on the proliferation and differentiation of human somatic SC, to provide insight into its effects on various human SC populations. An appraisal of electronic searches of four databases identified 1 in vivo and 58 in vitro studies (36 evaluated proliferation while 53 examined differentiation). Types of SC studied included mesenchymal (n = 32), epithelial (n = 11), epidermal (n = 8), hematopoietic and other (n = 8). The ROCK 1/2 selective inhibitor Y-27632 was used in almost all studies (n = 58), while several studies evaluated ≥2 ROCKi (n = 4) including fasudil, H-1152, and KD025. ROCKi significantly influenced human somatic SC proliferation in 81% of studies (29/36) and SC differentiation in 94% of studies (50/53). The present systemic review highlights that ROCKi are influential in regulating human SC proliferation and differentiation, and provides evidence to support the hypothesis that ROCKi promotes corneal endothelial division and maintenance via acting on the inner limbal SC niche.

Modified Limbal-Conjunctival Autograft Surgical Technique: Long-Term Results of Recurrence and Complications.

PURPOSE: The aim of this study was to report the recurrence and complication rates of a modified limbal-conjunctival autograft surgical technique for pterygium excision. METHODS: This was a retrospective, single-surgeon, single-operating environment, consecutive case series of 176 eyes in 163 patients with a biopsy-proven diagnosis of pterygium. All patients underwent excision using a 23-gauge needle to "behead" the pterygium head, followed by a limbal-conjunctival autograft including ∼50% of the palisades of Vogt. Outcomes measured included recurrence, defined as any conjunctival fibrovascular growth, and complication rates. Correlations between preoperative patient characteristics, pterygium morphology, and intraoperative factors (width of corneal extension, conjunctival defect, and graft) with postoperative recurrence were examined using logistic regression models. RESULTS: The median age was 59.5 years and 122 eyes (69.3%) had primary pterygium (type I: 17%, II: 37.5%, and III: 45.5%). Kaplan-Meier analysis demonstrated the median pterygium-free follow-up period to be 723 days (range 46-7230 days). Recurrence was observed in 3 eyes of 2 patients (1.7%). No postoperative graft-related complications were observed. Postoperative symptomatology was transient. Age demonstrated a negative correlation with recurrence (odds ratio 0.888, 95% CI, 0.789-0.998, P = 0.046). However, no other correlations with preoperative or intraoperative factors, including whether pterygium was primary or recurrent, were identified (all P > 0.05). CONCLUSIONS: This modified limbal-conjunctival autograft technique represents an effective alternative that offers a very low recurrence rate and avoids extensive dissection or antimetabolites, with minimal complications and transient postoperative symptomatology, over a long-term follow-up period. This technique is relatively simple and successful for both primary and recurrent pterygia. Future comparative studies with other surgical techniques may determine which are superior.

Minimally invasive, indirect corneal neurotization using an ipsilateral sural nerve graft for early neurotrophic keratopathy.

Purpose: Neurotrophic keratopathy is a degenerative disease characterized by damage to the corneal nerves leading to corneal hypoesthesia and anaesthesia. The resultant progressive visual deterioration is refractory to existing conventional treatment options. Corneal neurotization is a novel and effective surgical procedure that directly targets the underlying pathology of nerve loss by stimulating new corneal nerve growth. This study reports the outcomes and the pre- and postoperative in vivo confocal microscopy findings of the first published Australian case of indirect, minimally invasive, corneal neurotization using an ipsilateral sural nerve autograft. Observations: An 11-year-old boy developed corneal hypoesthesia in the left eye following surgical debulking of a cerebellopontine angle arachnoid cyst. He was diagnosed with Mackie Stage 1 neurotrophic keratopathy. Due to his hypoesthesia, he had developed recurrent microbial keratitis and corneal ulceration secondary to foreign bodies sustained during contact sports. At presentation, he reported photophobia and dry eye symptoms, corrected-distance visual acuity was 6/18, Cochet-Bonnet aesthesiometer demonstrated reduced corneal sensation (5-15mm), Schirmer's I test was 15mm, and in vivo confocal microscopy showed a complete absence of a subepithelial corneal plexus. He underwent indirect, minimally invasive, corneal neurotization using the ipsilateral supratrochlear nerve and a sural nerve autograft. Subjective improvement in corneal sensation was noticed by the patient at 2 months. Objective improvement, measured on Cochet-Bonnet aesthesiometer, was first observed at 6 months with steady stepwise improvement to 20-35mm at 21 months. Importantly, due to the increase in corneal sensation, the patient did not develop any further corneal complications. At 12 months, dry eye symptoms resolved and Schirmer's I test improved to 30mm. At 15 months, corrected-distance visual acuity improved to 6/5 and in vivo confocal microscopy demonstrated evidence of corneal reinnervation with nerves running through the subepithelial space surrounded by healthy and active keratocytes. Conclusions and importance: Corneal neurotization represents an exciting development in the armamentarium for the treatment of neurotrophic keratopathy and can be considered for younger patients with early-stage disease.

Ocular Distribution of the Renin-Angiotensin-Aldosterone System in the Context of the SARS-CoV-2 Pandemic.

The COVID-19 pandemic has resulted in an unprecedented impact on global health, economy, and way of life. SARS-CoV-2, the virus responsible for the disease, utilizes the ACE2 receptor found on host cells to mediate entry, replication, and infection. Numerous studies have elucidated the presence of many components of the renin-angiotensin-aldosterone system (RAAS) in the eye, including the ACE2 receptor. Considering this, and the anatomical vulnerability that the exposed ocular surface offers with its interconnectedness to the respiratory system, there is a theoretical risk of pathogen entry from the ocular route as well as the development of COVID-19-associated eye disease. Despite this, the actual epidemiological data demonstrates low ocular symptoms, possibly due to differing ACE2 receptor expression across age, ethnicity, and sex coupled with the protective properties of tears. We summarize the current literature on ocular RAAS with specific focus on the ACE2 receptor and its interplay with the SARS-CoV-2 virus.

5-Fluorouracil in primary, impending recurrent and recurrent pterygium: Systematic review of the efficacy and safety of a surgical adjuvant and intralesional antimetabolite.

Pterygium is an ultraviolet-related disease characterized by an aberrant, wing-shaped and active wound-healing process. There is nothing quite as disheartening for the surgeon or patient as the recurrence of pterygium, and various adjuvants have been studied to ameliorate this. This systematic review provides a comprehensive summary of the efficacy and safety of 5-Fluorouracil (5-FU) as an antimetabolite agent for pterygium management. An appraisal of electronic searches of six databases identified 34 clinical studies reporting recurrence outcomes of 5-FU use in primary, impending recurrent and recurrent pterygia. In vitro and in vivo studies of 5-FU showed dose- and duration-dependent cytostatic and cytotoxic effects in human cells. 5-FU is relatively inexpensive, available, and easy to administer, making it attractive for resource-limited scenarios. However, the published evidence demonstrates a recurrence rate of 11.4-60% with the bare scleral technique, 3.5-35.8% with conjunctival rotational flaps, 3.7-9.6% with conjunctival autografts for intraoperative topical 5-FU, and 14-35.8% for preoperative and intraoperative injections. This suboptimal efficacy brings the role of 5-FU as an adjuvant for pterygium surgery into question and the authors do not recommend its use. In contrast, postoperative intralesional injections of 5-FU to arrest progression in impending recurrent pterygium and true recurrent pterygia were more promising, with success rates of 87.2-100% and 75-100%, respectively. Furthermore, 5-FU as a treatment modality, without surgery, effectively arrested progression in 81.3-96% of primary and recurrent pterygia. Other treatments such as topical and intralesional corticosteroids, cyclosporine and anti-VEGF agents are discussed. Complications of 5-FU increase with higher doses and range from transient and reversible to severe and sight-threatening. For pterygium, 5-FU has a predilection for causing scleral thinning, corneal toxicity, and graft-related complications. Additional study with extended follow-up is needed to elucidate the optimal dose, frequency, duration, and long-term safety of 5-FU injections. If 5-FU is used in the management of pterygium, it should be with caution, in selected patients and with vigilant long-term monitoring.

Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection.

Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the in vitro and in vivo profiles of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones, against mycobacteria and Trypanosoma cruzi. Derivatives with monocyclic side chains were selective against Mycobacterium tuberculosis and were able to reduce the bacterial load when dosed orally in mice. We demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in M. tuberculosis. Oral administration of compounds with extended biaryl side chains (73 and 74) was effective in suppressing infection in an acute T. cruzi-infected murine model. These findings demonstrate that active nitroimidazopyrazinones have potential to be developed as orally available clinical candidates against both tuberculosis and Chagas disease.

Successful surgical management of interlenticular membrane by vitreoretinal interlenticular membranectomy (VIM).

The formation of a light scattering interlenticular membrane (ILM) is a known complication of polypseudophakia and has been particularly noted with the use of dual intracapsular Alcon AcrylSof intraocular lenses (IOLs). The treatment options for this condition have largely been restricted to either Nd:YAG laser membranotomy or explantation of the dual IOL complex. In this case report, we describe an unusual case of ILM in a 76-year-old woman whose ILM had formed between her primary intracapsular IOL and her piggyback sulcal IOL. Furthermore, we describe vitreoretinal interlenticular membranectomy (VIM), a novel technique involving a translimbal anterior interlenticular membranectomy using vitreoretinal instrumentation. There were no intraoperative or postoperative complications. Postoperative best-corrected visual acuity was 6/4, maintained for 3 years of follow-up. VIM is offered as a management option for surgeons to address ILM when Nd:YAG laser therapy fails, and the IOLs cannot be safely explanted.