NONSURGICAL RESOLUTION OF FULL-THICKNESS MACULAR HOLES WITHOUT VITREOMACULAR TRACTION.

BACKGROUND/PURPOSE: The purpose of this study was to report a case series of full-thickness macular holes without vitreomacular traction that resolved without surgery. METHODS: This study is a retrospective case series of 11 patients who demonstrated closure of full-thickness macular holes without surgical intervention. RESULTS: All full-thickness macular holes closed, with all patients having improvement in visual acuity. All but one of the cases had visual acuity better than 20/40 at last recorded visit. Most cases presented with associated epiretinal membrane (73%), cystoid changes (64%), defects <150 µ m (80%), and resolved within 2 months (91%). Topical anti-inflammatory drops were used in 7 of 11 cases, and dorzolamide was used in one case. CONCLUSION: Full-thickness macular holes can develop in eyes without the presence of vitreomacular traction. Topical therapy without vitrectomy may be particularly helpful in closure of full-thickness macular holes with associated cystoid macular edema. Holes with a lamellar hole component may spontaneously resolve as part of a retinal remodeling process.

Targeting NLRP3 signaling by a novel-designed sulfonylurea compound for inhibition of microglial inflammation.

The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays an important role in microglia-mediated inflammation. Dysregulation of NLRP3 signaling results in microglial activation and triggers inflammatory responses contributing to the development of neurological disorders including ischemic stroke, schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Inhibition of the NLRP3-linked inflammatory pathways reduces microglia-induced inflammation and is considered as a promising therapeutic approach for neuro-inflammatory diseases. In the present study, we report the development of AMS-17, a rationally-designed tertiary sulfonylurea compound for inhibition of inflammation in microglia. AMS-17 inhibited expression of the NLRP3, and its downstream components and cytokines such as caspase-1, tumor necrosis factor-α (TNF-α), IL-1ß and inducible nitric oxide synthase (iNOS). It also suppressed lipopolysaccharide (LPS)-induced N9 microglial cell phagocytosis in vitro and activation of the microglia in mouse brain in vivo. Together, these results provide promising evidences for the inhibitory effects of AMS-17 in inflammation. This proof-of-concept study provides a new chemical scaffold, designed with the aid of pharmacophore modeling, with NLRP3 inhibitory activity which can be further developed for the treatment of inflammation-associated neurological disorders.

Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats.

Despite the crucial role of Polymyxin-B in treating life-threatening gram-negative infections, its clinical utility is limited due to the risk of acute kidney injury. In response, a novel formulation of polymyxin-B is being developed to mitigate drug-induced kidney injury. In this study, we have assessed the toxicity of four variants of that novel formulation (VRP034_F21-F24) in comparison with standard polymyxin-B using kidney injury biomarkers in rats. Sprague-Dawley rats were subcutaneously administered either polymyxin-B (control) or one of the four polymyxin-B formulations at a dose of 25 mg/kg/day (HED: 4 mg/kg/day) in four divided doses for two days. Serum samples were collected at baseline and at the end of day 2 for the determination of serum biomarkers. Necropsy was done on day 2 and kidney was collected for histopathological evaluation. In the control group, statistically significant increase (p < 0.0001) in all biomarkers was observed on day 2 as compared to baseline values [urea: 311%; creatinine: 700%; KIM-1: 180%; cystatin-C: 66%] and 50% of the animals died (one after the 7th dose and two after the 8th dose) before scheduled necropsy. In contrast, animals treated with novel formulations did not show a significant increase across any of the biomarkers and no mortality was observed. Histopathology of the control group kidney confirmed necrotic changes in tissues with congestion and vacuolization, whereas only minor tubular damage was noted in two formulation groups (VRP034_F21, F24) and no appreciable damage was detected in the other two groups (VRP034_F22-23). The novel formulation of polymyxin-B tested in this study significantly reduced the risk of polymyxin-induced kidney injury in rats.

In Situ Tremor in Vitreoretinal Surgery.

OBJECTIVE: Surgeon tremor was measured during vitreoretinal microscopic surgeries under different hand support conditions. BACKGROUND: While the ophthalmic surgeon's forearm is supported using a standard symmetric wrist rest when operating on the patient's same side as the dominant hand (SSD), the surgeon's hand is placed directly on the patient's forehead when operating on the contralateral side of the dominant hand (CSD). It was hypothesized that more tremor is associated with CSD surgeries than SSD surgeries and that, using an experimental asymmetric wrist rest where the contralateral wrist bar gradually rises and curves toward the patient's operative eye, there is no difference in tremor associated with CSD and SSD surgeries. METHODS: Seventy-six microscope videos, recorded from three surgeons performing macular membrane peeling operations, were analyzed using marker-less motion tracking, and movement data (instrument path length and acceleration) were recorded. Tremor acceleration frequency and magnitude were measured using spectral analysis. Following 47 surgeries using a conventional symmetric wrist support, surgeons incorporated the experimental asymmetric wrist rest into their surgical routine. RESULTS: There was 0.11 mm/s2 (22%) greater (p = .05) average tremor acceleration magnitude for CSD surgeries (0.62 mm/s2, SD = 0.08) than SSD surgeries (0.51 mm/s2, SD = 0.09) for the symmetric wrist rest, while no significant (p > .05) differences were observed (0.57 mm, SD = 0.13 for SSD and 0.58 mm, SD = 0.11 for CSD surgeries) for the experimental asymmetric wrist rest. CONCLUSION: The asymmetric wrist support reduced the difference in tremor acceleration between CSD and SSD surgeries.

Isatin Hybrids and Their Pharmacological Investigations.

Hybridization is an important strategy to design molecules that can be effectively used to treat fatal diseases known to mankind. Molecular hybrids and their pharmacological investigations aided in discovering several potent isatin (Indole 2, 3 dione) derivatives with anti-HIV, antimalarial, antitubercular, antibacterial, and anticancer activities. Indole-2,3-dione and their derivatives have diverse pharmacological properties and have a prominent role in the discovery of new drugs. To understand the various approaches for designing new molecules based on isatin nucleus analysis of various pharmacophore hybrids, spacers/linkers between pharmacophores and isatin for hybridization and their biological activities are important. This review discusses the progress in developing isatin hybrids as biologically effective agents and their crucial aspects of design and structure-activity relationships.

Cancer Control at the District Hospital Level in Sub-Saharan Africa: An Educational and Resource Needs Assessment of General Practitioners.

PURPOSE: The WHO framework for early cancer diagnosis highlights the need to improve health care capacity among primary care providers. In Rwanda, general practitioners (GPs) at district hospitals (DHs) play key roles in diagnosing, initiating management, and referring suspected patients with cancer. We sought to ascertain educational and resource needs of GPs to provide a blueprint that can inform future early cancer diagnosis capacity-building efforts. METHODS: We administered a cross-sectional survey study to GPs practicing in 42 Rwandan DHs to assess gaps in cancer-focused knowledge, skills, and resources, as well as delays in the referral process. Responses were aggregated and descriptive analysis was performed to identify trends. RESULTS: Survey response rate was 76% (73 of 96 GPs). Most responders were 25 to 29 years of age (n = 64 [88%]) and 100% had been practicing between 3 and 12 months. Significant gaps in cancer knowledge and physical exam skills were identified-88% of respondents were comfortable performing breast exams, but less than 10 (15%) GPs reported confidence in performing pelvic exams. The main educational resource requested by responders (n = 59 [81%]) was algorithms to guide clinical decision-making. Gaps in resource availability were identified, with only 39% of responders reporting breast ultrasound availability and 5.8% reporting core needle biopsy availability in DHs. Radiology and pathology resources were limited, with 52 (71%) reporting no availability of pathology services at the DH level. CONCLUSION: The current study reveals significant basic oncologic educational and resource gaps in Rwanda, such as physical examination skills and diagnostic tools. Capacity building for GPs in low- and middle-income countries should be a core component of national cancer control plans to improve accurate and timely diagnosis of cancer. Continuing professional development activities should address and focus on context-specific educational gaps, resource availability, and referral practice guidelines.

Inhibition of dengue virus by curcuminoids.

The dengue virus is considered to be a globally important human pathogen prevalent in tropical and subtropical regions of the world. According to a recent estimate, the disease burden due to DENV infections is ∼390 million infections per year globally in ∼100 countries including the southern US, Puerto Rico and Hawaii, resulting in nearly ∼25,000 deaths mostly among children. Despite the significant morbidity and mortality that results from DENV infections, there is currently no effective chemotherapeutic treatment for DENV infections. We identified curcumin as an inhibitor of DENV2 NS2B/NS3protease in a previous high-throughput screening (HTS) campaign. We synthesized four analogues of curcumin (curcuminoids) and tested the in vitro protease inhibition activity and inhibition of replication by cell-based assays. The results revealed that curcumin is a weak inhibitor of the viral protease. However, the analogues exhibited more potent inhibition of DENV infectivity in plaque assays suggesting that the cellular pathway(s) required for viral replication and/or assembly are targeted by these compounds. Further analysis shows that inhibition of genes involved in lipid biosynthesis, and of actin polymerization by curcuminoids, are likely to be involved as their mode of action in DENV2-infected cells. Three of the curcumin derivatives possess good selectivity indices (SI) (>10) when compared to the parent curcumin.

Propranolol for Proliferative Diabetic Retinopathy.

BACKGROUND AND OBJECTIVE: To determine the effect of propranolol on retinal neovascularization due to proliferative diabetic retinopathy (PDR). PATIENTS AND METHODS: For this prospective pilot, interventional, case series, patients with diabetes with PDR (n = 10 subjects; 12 eyes) were recruited at the ophthalmology clinic of the University of Wisconsin - Madison. Subjects were administered oral propranolol for 12 weeks and retinopathy and area of retinal neovascularization were monitored with fundus photography and fluorescein angiography (FA). The study's main outcome measures were photographic area of retinal neovascularization and degree of leakage on FA. RESULTS: All eyes demonstrated stable degrees of retinal neovascularization by the end of 12 weeks. CONCLUSION: This dose of oral propranolol during a period of 12 weeks did not demonstrate significant effect on retinal neovascularization due to PDR. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:35-40.].

Response to aflibercept as secondary therapy in patients with persistent retinal edema due to central retinal vein occlusion initially treated with bevacizumab or ranibizumab.

BACKGROUND: Recent advances have given practitioners options for the treatment of macular edema secondary to central retinal vein occlusion. These options include steroid injections and implants as well as anti-vascular endothelial growth factor medications. However, there is little in the medical literature to guide secondary therapy when an initial treatment strategy is insufficient. The authors present encouraging results from the treatment of six consecutive cases of central retinal vein occlusion treated with aflibercept as a secondary therapy for macular edema refractory to repeated intravitreal bevacizumab or ranibizumab injections. METHODS: A retrospective review of six consecutive cases of central retinal vein occlusion with persistent macular edema despite regular anti-vascular endothelial growth factor injections that were transitioned to aflibercept was conducted. Optical coherence tomography and visual acuity data were examined. RESULTS: All six eyes from the six patients included showed either complete or near complete resolution of macular edema with one or two injections of aflibercept. The improvement in edema was accompanied by lasting modest visual gains in three of the six patients and in subjective visual improvement in four of the six patients. CONCLUSION: The six eyes in this series all responded favorably to aflibercept as a secondary therapy. Although the sample size is too small to draw definitive conclusions, the results are encouraging.

Methyl 2-bromo-3-(4-chloro-benzene-sulfonamido)-benzoate.

In the crystal structure of the title compound, C(14)H(11)BrClNO(4)S, the mol-ecules form inversion dimers with R(2) (2)(8) motifs through pairs of N-H⋯O hydrogen bonds. The benzene rings are not coplanar and subtend a dihedral angle of 66.27 (8)°. The carbomethoxy group makes a dihedral angle of 75.1 (1)° with the ring to which it is attached.

Synthesis and biological evaluation of 2-(5-substituted-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-N-substituted-hydrazinecarbothioamides.

ABSTRACT: Various 5-substituted-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (4a, b) and 5-substituted-2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-N-(phenyl-4-substituted)hydrazinecarbothioamide (5a-h) derivatives were synthesized. The compounds were screened for cytotoxicity against human HeLa and CEM T-lymphocytes as well as murine L1210 cells. The compounds were also screened for ß-lactamase inhibitory activity, antiviral, antibacterial, and antifungal activity against various strains of microorganisms. Several of these compounds were endowed with low micromolar 50 %-cytostatic concentration (IC50) values, and some were virtually equally potent as melphalan. The most potent inhibitors against the murine leukemia cells (L1210) were also the most inhibitory against human T-lymphocyte (CEM) tumor cells. Derivative 2-(1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazinecarbothioamide 5c emerged as the most potent cytostatic compound among the tested compounds. Derivatives 4b, 5a, 5b, and 5d showed antiviral activity against HEL cell cultures (IC50 11-20 µM). Moderate antimicrobial activity was observed for all derivatives. The encouraging cytostatic and antiviral activity data provide an adequate rationale for further modification of these molecular scaffolds. GRAPHICAL ABSTRACT: Derivative 5c (1.9-4.4 µM) emerged as the most potent cytostatic compound among the tested compounds. Derivatives 4b, 5a, 5b, and 5d showed antiviral activity against HEL cell cultures (IC50 11-20 µM).

Polyketide decarboxylative chain termination preceded by o-sulfonation in curacin a biosynthesis.

Biosynthetic innovation in natural product systems is driven by the recruitment of new genes and enzymes into these complex pathways. Here, an unprecedented decarboxylative chain termination mechanism is described for the polyketide synthase of curacin A, an anticancer lead compound isolated from the marine cyanobacterium Lyngbya majuscula. The unusual chain termination module containing adjacent sulfotransferase (ST) and thioesterase (TE) catalytic domains embedded in CurM was biochemically characterized. The TE was proved to catalyze a hydrolytic chain release of the polyketide chain elongation intermediate. Moreover, a selective ST-mediated sulfonation of the (R)-beta-hydroxyl group was found to precede TE-mediated hydrolysis, triggering a successive decarboxylative elimination and resulting in the formation of a rare terminal olefin in the final metabolite.

Intratarsal epidermal inclusion cyst.

PURPOSE: To report 3 cases of epidermal inclusion cyst that arose within the tarsus, an unusual site of origin. METHODS: A retrospective review of medical records of patients undergoing excision of eyelid epidermal inclusion cysts by one surgeon (MJL) over a decade revealed 3 cases of intratarsal epidermal inclusion cyst. Initially, these lesions resembled chalazia and were first addressed with incision and curettage. There was recurrence of the cyst in all the 3 cases from 1 to 4 months, and subsequent complete excision was necessary. RESULTS: At surgery in each of these cases a cyst arising within the tarsus was encountered. Eventually, the tarsus containing the base of the cyst was excised to ensure complete removal. The cysts were approximately 8 mm to 10 mm in greatest dimension and had yellowish-white gelatinous contents. Histopathologic evaluation revealed keratin-filled cysts arising from tarsus and lined by stratified keratinized epithelium. In one of the cases the tarsal tissue around the cyst wall showed epidermal elements presumably derived from sebaceous gland. There have been no recurrences after complete excision (follow-up range, 9-60 months). CONCLUSIONS: Intratarsal epidermal inclusion cysts share some clinical features with chalazia. Lack of inflammation, lack of fluctuation in size, gradual continued slow growth, and delayed onset of recurrence may help to differentiate tarsal cyst from recurrent chalazion. Incision and curettage, however, is not effective long-term treatment for this entity. Total excision of the cyst including full-thickness excision of tarsus at the cyst's base of origin is suggested for definitive treatment.

A study of histopathological features of latanoprost-treated irides with or without darkening compared with non-latanoprost-treated irides.

OBJECTIVES: To study the histopathological features of latanoprost-treated irides with or without darkening, compared with non-latanoprost-treated irides. METHODS: Iridectomy specimens and patient history forms were independently examined by 3 ophthalmic pathologists in a masked fashion. Specimens were evaluated for premalignant changes and for differences in level of pigmentation and degrees of cellularity, inflammation, and vascular abnormalities. RESULTS: The specimens consisted of 22 latanoprost-treated darkened irides, 35 latanoprost-treated irides without darkening, and 35 non-latanoprost-treated irides. There was a statistically significant decrease in the number of nuclear invaginations and prominent nucleoli in latanoprost-treated darkened irides compared with the other 2 groups (P = .004 and P = .005, respectively). The average thickness and pigmentation of the anterior border layer was greater in the latanoprost-treated darkened irides than in the other 2 groups (P = .03 and P = .02, respectively). The latanoprost-treated darkened irides had increased pigmentation of the stroma (P < .001), stromal fibroblasts (P < .001), melanocytes (P = .005), vascular endothelium (P = .02), and adventitia (P < .001) relative to the other 2 groups. CONCLUSIONS: There is no histopathological evidence of premalignant changes in latanoprost-treated darkened irides. The latanoprost-induced iris color changes are due to a thickening of the anterior border layer and an increased amount of melanin in the anterior border layer and within the stromal melanocytes.

Resveratrol inhibits tumor growth of human neuroblastoma and mediates apoptosis by directly targeting mitochondria.

PURPOSE: Neuroblastoma is an aggressive childhood disease of the sympathetic nervous system. Treatments are often ineffective and have serious side effects. Because resveratrol, a natural plant product, has been reported to have limited toxicity at chemotherapeutic levels, we investigated its efficacy in the treatment of neuroblastoma as well as its underlying mechanism of action. EXPERIMENTAL DESIGN: Resveratrol was tested in mouse xenograft models of human neuroblastoma and in vitro using human cell lines. RESULTS: Resveratrol inhibited the outgrowth of tumors by as much as 80%. The bioavailability of the drug in serum was in the low micromolar range (2-10 micromol/L) and no accumulation was observed in tumor tissue. When resveratrol levels were increased by peritumor injection, rapid tumor regression occurred. Resveratrol decreased tumor cell viability in vitro by 75% to 90%, resulting from an inhibition of cell proliferation and an induction of apoptosis. Loss of mitochondrial membrane potential was an early response to resveratrol. In addition, resveratrol treatment of isolated mitochondria also led to depolarization, suggesting that the drug may target mitochondria directly. Following depolarization, resveratrol caused the release of cytochrome c and Smac/Diablo from the mitochondria and subsequently the activation of caspase-9 (4- to 8-fold) and caspase-3 (4- to 6-fold). CONCLUSIONS: These studies indicate that, despite low bioavailability, resveratrol is effective at inhibiting tumor growth. Elevated levels of resveratrol enhance its antitumor potency leading to tumor regression, associated with widespread tumor cell death, the underlying mechanism of which involves the direct activation of the mitochondrial intrinsic apoptotic pathway.

Clinicopathologic correlation of explanted AlphaCor artificial cornea after exposure of implant.

PURPOSE: To describe the clinical presentation and histopathologic findings in a case of explantation of an AlphaCor artificial cornea implant caused by exposure of the skirt. METHODS: We describe the case report of a 46-year-old man who suffered trauma to the right eye, resulting in 4 failed penetrating keratoplasties (PKPs). Subsequently, an AlphaCor implantation was performed with some visual improvement. Slightly more than 2 years after the implant, skirt exposure occurred, possibly secondary to infectious keratitis in an area of a ruptured bulla, and explantation was performed. Corneal stability was established with repeat corneal transplantation. RESULTS: Histopathologic evaluation of the surgical specimen revealed chronic nongranulomatous inflammation and fibrosis in the peripheral skirt, indicating that biointegration was maintained. However, peripheral corneal stromal melting led to skirt exposure. Focal calcification, as well as retroprosthetic membrane formation, was also identified. CONCLUSIONS: The AlphaCor implant is a viable method of treatment for multiple failed PKPs, but it may be associated with unique complications, including corneal stromal melting, focal calcification, and retroprosthetic membrane formation. Infectious keratitis may be a risk factor for corneal stromal melting and needs to be managed aggressively. Explantation of the implant is essential if the skirt is exposed.

1 alpha-Hydroxyvitamin D2 inhibits growth of human neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor in childhood. The poor outcomes of patients with high-risk neuroblastoma have encouraged the search for new therapies. In the current study, the effect of the vitamin D analog 1alpha-hydroxyvitamin D2 (1alpha-OH-D2, doxercalciferol) was assessed in a mouse xenograft model of human neuroblastoma. Vitamin D receptor (VDR) expression levels in seven neuroblastoma cell lines were compared using real-time PCR. SK-N-AS cells, which express relatively high levels of VDR, were injected into the flanks of 60 mice. The mice were treated daily via oral gavage for 5 weeks with vehicle (control), 0.15 microg, or 0.3 microg of 1alpha-OH-D2. The animals were then euthanized, and tumors, sera, and kidneys were collected and analyzed. End tumor volumes were significantly smaller in both the 0.15 microg group (712.07 mm3, P = 0.0121) and 0.3 microg group (772.97 mm3, P = 0.0209) when compared to controls (1,681.75 mm3). In terms of toxicity, serum calcium levels were increased but mortality was minimal in both treatment groups. These results were similar to those previously described in the transgenic (LHbeta-Tag) and human xenograft (Y-79) models of retinoblastoma, a related tumor. In vitro cell viability studies of SK-N-AS and NGP cells, which represent two major human neuroblastoma subtypes that differ in their genetic abnormalities as well as their VDR expression levels, show that both are sensitive to calcitriol, the active metabolite of vitamin D3. In conclusion, the present study shows that 1alpha-OH-D2 can inhibit human neuroblastoma growth in vivo with relatively low toxicity. The safety of 1alpha-OH-D2 has been extensively studied; the drug is FDA-approved for the treatment of adult kidney patients, and Phase I/II trials have been conducted in adult oncology patients. There should not be major obstacles to starting Phase I and II clinical trials with this drug in pediatric patients with high-risk neuroblastoma.