Randomized, Controlled, Double-Masked, Multicenter, Pilot Study Evaluating Safety and Efficacy of Intranasal Neurostimulation for Dry Eye Disease.

Purpose: We assess the safety and effectiveness of intranasal neurostimulation to promote tear production via the nasolacrimal pathway in subjects with dry eye disease. Methods: A multicenter, randomized, controlled, double-masked pilot study was conducted in adults with dry eye diagnosis and at least one eye with corneal fluorescein staining ≥2 in at least one region or a sum of all regions ≥5 (National Eye Institute grading), basal Schirmer test score ≤10 mm, a cotton-swab stimulated Schirmer score ≥7 mm higher, and an Ocular Surface Disease Index score ≥23. Subjects were randomized to receive active intranasal neurostimulation or sham control intranasal stimulation 4 to 8 times per day. Assessments were scheduled before (unstimulated) and during (stimulated) device application at days 0, 7, 14, 30, and 90. The primary effectiveness endpoint was stimulation-induced change in Schirmer test (with anesthesia) score. Primary safety measure was incidence of device-related adverse events (AEs). Results: Fifty-eight subjects were randomized at nine sites in Australia and New Zealand; 56 completed the 90-day study. Stimulation-induced change in Schirmer score was significantly greater with active intranasal (mean ± SEM, 9.0 ± 2.0) than sham control intranasal stimulation (0.4 ± 0.6; P < 0.001) at day 90. Similar results were observed at days 0, 7, 14, and 30 (P < 0.001). No serious device-related AEs were observed. Mild nosebleed, the most common device-related AE, was reported in five (16.7%) subjects. Conclusions: Intranasal neurostimulation was effective in inducing acute tear production after 90 days of use and generally was well tolerated in subjects with dry eye disease.

The collagen matrix of the human trabecular meshwork is an extension of the novel pre-Descemet's layer (Dua's layer).

BACKGROUND: The trabecular meshwork (TM) located at the angle of the anterior chamber of the eye contributes to aqueous drainage. A novel layer in the posterior part of the human cornea has recently been reported (the pre-Descemet's layer (Dua's layer (PDL)). We examined the peripheral part of this layer in relation to the origin of the TM. METHODS: The PDL and TM of 19 human donor eyes and one exenterated sample were studied. Samples were examined by light and electron microscopy (EM) for tissue architecture and by immunohistology for four matricellular proteins, five collagen types and CD34. RESULTS: EM revealed that beams of collagen emerged from the periphery of PDL on the anterior surface of the Descemet's membrane and divided and subdivided to continue as the beams of the TM. Long-spacing collagen was seen in the PDL and TM. Trabecular cells (CD34-ve) associated with basement membrane were seen in the peripheral part of the PDL and corresponded to the start of the separation of the collagen lamellae of PDL. Collagen VI was present continuously in PDL and extended into the TM. Matricellular proteins were seen predominantly in the TM with only laminin extending into the periphery of PDL. CONCLUSIONS: This study provides an insight into the origins of the collagen core of the TM as an extension of the PDL of the cornea. This finding adds to the knowledge base of the TM and cornea and has the potential to impact future research into the TM and glaucoma.

Human corneal anatomy redefined: a novel pre-Descemet's layer (Dua's layer).

PURPOSE: To define and characterize a novel pre-Descemet's layer in the human cornea. DESIGN: Clinical and experimental study. PARTICIPANTS: We included 31 human donor sclerocorneal discs, including 6 controls (mean age, 77.7 years). METHODS: Air was injected into the stroma of donor whole globes (n = 4) and sclerocorneal discs (n = 21) as in the clinical deep anterior lamellar keratoplasty procedure with the big bubble (BB) technique. The following experiments were performed: (1) creation of BB followed by peeling of the Descemet's membrane (DM); (2) peeling off of the DM followed by creation of the BB, and (3) creation of the BB and continued inflation until the bubble popped to measure the popping pressure. Tissue obtained from these experiments was subjected to histologic examination. MAIN OUTCOME MEASURES: Demonstration of a novel pre-Descemet's layer (Dua's layer) in the human cornea. RESULTS: Three types of BB were obtained. Type-1, is a well-circumscribed, central dome-shaped elevation up to 8.5 mm in diameter (n = 14). Type-2, is a thin-walled, large BB of maximum 10.5 mm diameter, which always started at the periphery, enlarging centrally to form a large BB (n = 5), and a mixed type (n = 3). With type-1 BB, unlike type-2 BB, it was possible to peel off DM completely without deflating the BB, indicating the presence of an additional layer of tissue. A type-1 BB could be created after first peeling off the DM (n = 5), confirming that DM was not essential to create a type-1 BB. The popping pressure was 1.45 bar and 0.6 bar for type-1 BB and type-2 BB, respectively. Histology confirmed that the cleavage occurred beyond the last row of keratocytes. This layer was acellular, measured 10.15 ± 3.6 microns composed of 5 to 8 lamellae of predominantly type-1 collagen bundles arranged in transverse, longitudinal, and oblique directions. CONCLUSIONS: There exists a novel, well-defined, acellular, strong layer in the pre-Descemet's cornea. This separates along the last row of keratocytes in most cases performed with the BB technique. Its recognition will have considerable impact on posterior corneal surgery and the understanding of corneal biomechanics and posterior corneal pathology such as acute hydrops, Descematocele and pre-Descemet's dystrophies. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Good Medical Practice or CanMEDS for education?

BACKGROUND: The medical regulator in the UK, the General Medical Council, requires curricula and assessments for postgraduate training to be blueprinted to its regulatory statement, Good Medical Practice. A similar document, Tomorrow's Doctors (2009), covers undergraduate education and training. Good Medical Practice, originally designed to regulate medical practice, is not optimally worded as an educational document. The Royal College of Physicians and Surgeons of Canada's physician competency framework known as CanMEDS is designed with education more centrally in mind. METHODS: The wordings of Good Medical Practice and Tomorrow's Doctors (2009) were compared with CanMEDS using 'word clouds', a textual analysis tool which provides a display of word frequency, revealing the emphasis in the wording of documents. RESULTS: Good Medical Practice places much greater emphasis on the regulatory rather than the educational aspects of medical practice when compared with CanMEDS and is therefore less suitable for blueprinting curricula, especially in disciplines with high science content such as pathology. CONCLUSIONS: Good Medical Practice is less suitable for an educational role and the General Medical Council should consider developing a more specific educational document around these principles.

Histological and confocal microscopy changes in chronic corneal edema: implications for endothelial transplantation.

PURPOSE: To report in vivo confocal microscopic (IVCM) features in corneal edema supported by histopathologic correlation. METHODS: This was an observational study with evaluation of diagnostic technology. Twenty patients with clinically diagnosed corneal edema were involved, including 11 with Fuchs' endothelial dystrophy (FED). All cases, in addition to a control group of six normal eyes, were examined with IVCM before keratoplasty. Four eyes were examined after surgery. Thirteen corneal samples obtained by penetrating keratoplasty were examined by light and/or electron microscopy. IVCM and histopathologic sections were then analyzed for correlation and proper interpretation. Seven patients underwent Descemet's stripping endothelial keratoplasty (DSEK). RESULTS: Subepithelial fibroblasts were seen histologically and with IVCM in 7 (53.8%) of 13 full-thickness corneal samples. IVCM alone detected these changes in 11 (55%) subjects before surgery, as well as after postoperative clinical improvement. Other IVCM features included absent (30%) or reduced (70%) subbasal corneal nerves, expanded hyperreflective keratocyte cell bodies, and processes with small vacuoles and large extracellular lacunae (95%), seen on IVCM only. Endothelial changes with polymegathism and reduced cell density were seen in non-FED cases. CONCLUSIONS: This is the first study in which IVCM features of corneal edema have been compared in detail with histopathologic findings. Subepithelial fibroblasts, reduced subbasal corneal nerves, and stromal keratocyte morphology were well documented in this study. With increasing popularity of DSEK this work supports the role of IVCM in quantitative evaluation of corneal edema in early preoperative stages, as well as after surgery, when the cornea appear clinically, but not histologically, normal.

Early-onset type 2 diabetes: high risk for premature diabetic retinopathy.

AIM: To examine the relationship between early-onset type 2 diabetes (T2D) and retinopathy in relation to the burden, severity, the extent of its premature development and associated predictive risk factors. METHODS: A cross sectional study using the hospital diabetes register and eye screening database to identify T2D subjects and to ascertain retinopathy severity. Early and later-onset cohort were defined as age of diagnosis <40 and >40 years respectively. RESULTS: 2516 subjects were identified of which 455 were diagnosed below 40 years. After 10 years of diagnosis, the prevalence of overall retinopathy was significantly higher in the early-onset cohort (p < 0.05). For significant retinopathy (SigDR), there was a non-significant trend of higher prevalence with increasing diabetes duration in the early-onset cohort. The rate of increase for SigDR was greater in the early-onset cohort who experienced similar burden of SigDR up to 20 years earlier than the later-onset cohort. Hypertension (p < 0.05), suboptimal glycaemic control (p < 0.05) and long diabetes duration (p < 0.05) were associated with risk of retinopathy whilst lower age of diagnosis and dyslipidaemia were not significant predictive factors. CONCLUSIONS: Early-onset T2D subjects are at risk of developing premature retinopathy driven predominantly by hypertension and prolonged exposure to suboptimal diabetes control.

Early intensive cardiovascular risk management in young people with type 2 diabetes.

This study assessed the adequacy of cardiovascular risk management among recently diagnosed early-onset T2D. Despite the presence of adverse cardiovascular risk profile, intensive treatment to prevent cardiovascular disease remained suboptimal in these young subjects.

Pseudoactinomyces in cervical mucus.

Actinomyces israelii are gram-positive filamentous bacteria forming yellow sulfur granules. They are the most well known complication of intrauterine contraceptive devices (IUCD). Healthcare staff dealing with reporting cervical smears should be aware of pseudoactinomyces entity in a cervical smears and biopsies as it may raise a false alarm to the clinician and may lead to unnecessary removal of IUCD and/or medical treatment.

"It's not rocket science, what I do": Self-directed harm reduction strategies among drug using ethno-racially diverse gay and bisexual men.

BACKGROUND: Research on harm reduction has typically focused on broad-based or organisational strategies such as needle exchange and opiate substitute programmes. Less attention has been paid to the self-directed harm reduction practices of substance users themselves. Few studies have focused on sexual minority populations such as gay and bisexual men and fewer still on the marginalised groups that constitute these populations. This paper identifies self-directed harm reduction strategies among substance using ethno-racially diverse gay and bisexual men. METHODS: This article presents findings from the Party Drugs Study in Toronto's gay dance club scene, a community-based qualitative study in Toronto, Canada. We present a thematic analysis of interviews with 43 gay and bisexual men from diverse ethno-racial backgrounds about their substance use in the gay dance club scene. FINDINGS: We identify five self-directed harm reduction strategies: rationing, controlling or avoiding mixing, controlling quality, maintaining a healthy lifestyle, and following guidelines during substance use. CONCLUSIONS: We discuss our findings in relation to prior research and to critical theory. We suggest that drug users' awareness of possible harm, and their personal investment in harm reduction, constitute a viable platform from which community-based and public health organisations may promote and strengthen harm reduction among gay and bisexual men from ethno-racially diverse backgrounds.

Toric implantable collamer lens for patients with moderate to severe myopic astigmatism: 12-month follow-up.

PURPOSE: To report on the 12-month follow-up of 77 eyes with moderate to high myopic astigmatism implanted with toric implantable collamer lenses (ICLs). METHODS: Retrospective case-note review of 77 eyes from 42 patients undergoing toric ICL placement by one surgeon. Preoperative mean spherical equivalent -2.50 dioptres (D) to -15.00 D myopia and 1.00 D to 7.00 D astigmatism. RESULTS: At 12 months, mean manifest refractive cylinder (MRC) decreased 81% from 2.38 D to 0.44 D. MRC within 1.00 D occurred in 99% (76/77) of eyes, whereas 86% (66/77) had MRC within 0.75 D. 99% (76/77) had postoperative best-corrected visual acuity (BCVA) better than or equal to preoperative values, whereas 78% (60/77) gained up to one line BCVA and 1% (1/77) lost one line BCVA. Uncorrected binocular vision of 6/6 or better occurred in 90% (38/42) of patients compared with binocular BCVA of 6/6 or better in 67% (28/42) preoperatively. One ICL was replaced due to low vaulting. Two eyes with astigmatism of 3.25 D and 3.50 D received subsequent laser in situ keratomileusis (LASIK) to reduce residual small refractive errors. Indications for ICL were: myopia too high for LASIK (73%), cornea too thin for LASIK (44%) and contact lens intolerance (33%). Night halos were reported in 10% (8/77) of eyes at 12 months. One ICL was removed due to unrecognized preoperative glaucoma. There were no cases of cataract formation, or endophthalmitis. CONCLUSION: This study is the largest reported series of toric ICL implantation in New Zealand. It supports the safety, efficacy and predictability of toric ICLs to treat myopic astigmatism.

Spherical implantable collamer lenses for myopia and hyperopia: 126 eyes with 1-year follow up.

BACKGROUND: To report on 1-year follow up of a series of 126 eyes implanted with a spherical implantable collamer lens (ICL). METHODS: Retrospective case note review of 126 eyes (68 patients) undergoing ICL placement by a single surgeon (TG) to correct preoperative mean spherical equivalents between +8.88 and -20.50 D. Main outcome measures included uncorrected visual acuity (UCVA), refraction, best spectacle-corrected VA, unaided binocular vision, adverse events, operative/postoperative complications and patient symptoms. RESULTS: Complete data were available at 1 year on 121 of the 126 eyes (65 out of 68 patients). At 12 months 86% (104/121) had postoperative UCVA better than or equal to preoperative best spectacle-corrected VA, and 98% (118/121) had UCVA within one line of preoperative best spectacle-corrected VA. Ninety-six per cent (116/121) had postoperative UCVA of 6/9 or better, and 100% had postoperative best-corrected visual acuity of 6/12 or better. Ninety-eight per cent (64/65) patients had unaided binocular vision at 1 year of 6/7.5 or better. Average myopia treated was -8.83 D (116 patients), and average hyperopia +7.14 D (10 patients). Two ICLs were replaced because of high vaulting; one eye had increased intraocular pressure that resolved with smaller ICL placement. Four patients had visually insignificant pigment deposits on the ICL at 3/12, but no pigmentary glaucoma. Five patients noticed haloes around lights at night, none preventing driving. CONCLUSIONS: One-year results from this study, the largest reported clinical investigation of the use of ICLs in New Zealand, support the safety, efficacy and predictability of ICL to treat both hyperopic and myopic spherical refractive errors.

Hypocupremia: an under recognized cause of subacute combined degeneration.

It is increasingly evident that a multitude of etiologies can give rise to signal abnormality in the dorsal and lateral columns of the spinal cord, apart from pernicious anemia. We report a case of dorsal and lateral columns signal abnormality related to hypocupremia resulting in progressive sensory ataxia and weakness in the lower and upper limbs, compounded by a recent diagnosis of Sjögren's syndrome.

Histologic features of transplanted amniotic membrane: implications for corneal wound healing.

PURPOSE: To evaluate the histologic changes occurring in the transplanted amniotic membrane in human eyes. DESIGN: Observational consecutive case series. PARTICIPANTS: Seven consecutive patients who underwent amniotic membrane transplantation (AMT) for bullous keratopathy and subsequently had a penetrating keratoplasty (PK). METHODS: Corneal buttons obtained at PK were examined by light and electron microscopy and by immunohistology with antibodies against CD34 (keratocytes), alpha smooth muscle actin and vimentin (myofibroblasts and fibroblasts respectively). Time from AMT to PK ranged from 2 to 32 months. MAIN OUTCOME MEASURES: Immunophenotypic characteristics of cells populating transplanted amniotic stroma. RESULTS: Amniotic tissue was covered with stratified corneal epithelium with well-defined desmosomes and hemidesmosomes. Transformed corneal stroma-derived cells (CSDCs) could be seen migrating from the anterior stroma, through breaks in the Bowman's zone, into connective tissue of the amniotic membrane. Immunohistology showed that the cells populating amniotic stroma were CD34 negative but positive for vimentin and alpha smooth muscle actin. In 2 samples in which corneal transplants were performed approximately 1 year or more after AMT, some cells in the amniotic stroma showed CD34+ staining. Features of increased metabolic activity and formation of new collagen were seen on electron microscopy. In 2 cases, epithelial cell nests were seen in the amniotic stroma. CONCLUSIONS: The amniotic basement membrane facilitates epithelial cell migration and adhesion. The amniotic stroma supports CSDCs and epithelial cells. Repopulation of the amniotic stroma by CSDCs migrating through breaks in Bowman's zone integrates the amnion with corneal tissue and allows for rebuilding of corneal stroma. Over time, some CSDCs may revert to the resting keratocyte immunophenotype.

Optimization of amniotic membrane (AM) denuding for tissue engineering.

INTRODUCTION: Amniotic membrane (AM) has gained increasing popularity as a useful carrier for ex vivo-expanded cells for tissue engineering, particularly in ocular surface reconstruction. However, current methods employed for denuding AM are highly variable, and the consequent effects on the structural and molecular composition of the AM basement membrane (BM) are ambiguous. We compare the effects of the main denuding procedures, and propose a highly effective standardized alternative. METHODS: AMs preserved for transplantation were denuded using published ethylenediaminetetraacetic acid (EDTA)- and dispase-based methodologies and our novel thermolysin-based procedure. Scanning and transmission electron microscopy and immunohistochemistry, for BM components (collagens IV and VII, laminin 5, and integrins alpha6 and beta4), were used to assess effectiveness of denuding epithelium, whilst maintaining the integrity of the BM. RESULTS: EDTA- and dispase-based denuding techniques resulted in the disaggregation and even destruction of the BM structure and molecular composition. Employing thermolysin effectively denuded epithelium whilst maintaining BM structural and molecular integrity. CONCLUSION: Current procedures for preparing AM are variable and often ineffective, resulting in nonstandard membranes. Our novel thermolysin-based technique effectively denudes the AM whilst preserving an essentially intact and consistent BM. Therefore, we propose that this novel thermolysin procedure may potentially improve overall generation of tissue-engineered constructs using AM.

Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies.

Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and alpha-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.

Outbreak of diffuse lamellar keratitis caused by marking-pen toxicity.

PURPOSE: To examine the evidence that a series of cases of diffuse lamellar keratitis (DLK) after laser in situ keratomileusis (LASIK) was caused by a type of marker pen. SETTING: Eye Institute, Auckland, New Zealand. METHODS: During a 10-week period, 522 consecutive LASIK procedures were performed using a 60 Hz IntraLase femtosecond laser (IntraLase Corp.) to create the LASIK flap and a 217Z 100 Hz excimer laser (Bausch & Lomb) to perform the refractive ablation. As standard practice, a marking pen was used to enable accurate flap realignment. Three weeks after a sudden increase in the incidence of DLK was identified, one of the 5 surgeons performed 5 consecutive bilateral cases using the marking pen in the right eyes but not in the left eyes. RESULTS: Of the 522 LASIK cases (119 without marking pen, 403 with marking pen), DLK developed in 49 (9.4%). No eye treated without the marking pen developed DLK; of those in which the marking pen was used, 49 (12.2%) developed DLK (P<0.0001, Fischer exact test; odds ratio, 27). In the 5 consecutive bilateral cases in which the marking pen was used in the right eye but not the left eye, 4 right eyes and no left eye developed DLK (P=0.03). Forty-five of the 49 eyes with DLK quickly recovered. The other 4 developed central toxic keratopathy. CONCLUSION: There is strong statistical evidence that the marking pen was a factor in the occurrence of DLK.