Systemic investigations in dry eye disease.

The incidence of dry eye disease has increased manifold in the past few years with more patients presenting with these complaints to our clinics every day. In the more severe forms of disease, it is important to evaluate for any systemic association which could be driving the disease such as in Sjogren's syndrome. Understanding the possible varied etiopathogenesis and knowing when to evaluate, form an important part of treating this condition effectively. In addition, it is sometimes confusing as to which investigations to order and how to prognosticate the disease in these situations. This article simplifies this into an algorithmic approach with insights from the ocular and systemic point of view.

Modulation of mucin secretion using combined polyethylene glycol-propylene glycol topical formulation in a hyperosmotic stress-based explant model.

Purpose: Ocular surface discomfort and dry eye disease are caused by a dysfunctional tear film. The efficacy of lubricating eye drops on the human eye is known, but the compositions may show differential effects on rescuing the tear film. Mucins form a critical layer of the tear film, a reduction of which may be causative for ocular surface conditions. Therefore, it is essential to develop relevant human-derived models to test mucin production. Methods: Human corneoscleral rims were obtained from a healthy donor (n = 8) post-corneal keratoplasty and cultured in DMEM/F12 media. Hyperosmolar stress mimicking dry eye disease was induced by exposing the corneoscleral rim tissues to +200 mOsml NaCl-containing media. The corneoscleral rims were treated with polyethylene glycol-propylene glycol (PEG-PG)-based topical formulation. Gene expression analysis was performed for NFAT5, MUC5AC, and MUC16. Secreted mucins were measured by enzyme-linked immunosorbent assay (ELISA) (Elabscience, Houston, TX, USA) for MUC5AC and MUC16. Results: The corneoscleral rims responded to hyperosmolar stress by upregulating NFAT5, a marker for increased osmolarity, as observed in the case of dry eye disease. The expression of MUC5AC and MUC16 was reduced upon an increase in hyperosmotic stress. The corneoscleral rim tissues showed induction of MUC5AC and MUC16 expression upon treatment with PEG-PG topical formulation but did not show significant changes in the presence of hyperosmolar treatments. Conclusion: Our findings showed that PEG-PG-based topical formulation slightly alleviated hyperosmolar stress-induced decrease in MUC5AC and MUC16 gene expression that is encountered in DED.

A randomized controlled study evaluating outcomes of intense pulsed light and low-level light therapy for treating meibomian gland dysfunction and evaporative dry eye.

Purpose: This randomized, controlled, blinded study evaluates the efficacy of intense pulsed light (IPL) therapy with low-level light therapy (LLLT) in the treatment of meibomian gland dysfunction (MGD) and evaporative dry eye (EDE) compared to a control group. Methods: Hundred patients with MGD and EDE were randomized into control (50 subjects, 100 eyes) and study group (50 subjects, 100 eyes). The study group underwent three sittings of IPL with LLLT 15 days apart and were followed up 1 month and 2 months after the last treatment sitting. The control group underwent sham treatment and was followed up at the same intervals. The patients were evaluated at baseline and 1 month and 3 months (post 1st treatment) for dry eye. Schirmer's test and tear breakup time (TBUT), OSDI, meibomian gland expression, and meibography. Results: The study group showed significant improvement in OSDI scores (P < 0.0001) compared to the control group and a significant improvement in TBUT (P < 0.005) compared to the control group. There was no change in schirmer's test and an improvement in the meibomian gland expression but not significant. Conclusion: The results show that a combined therapy of IPL with LLT is effective in treating MGD with EDE compared to controls, and repeated treatment sessions have a cumulative effect on the disease outcomes.

Statin adherence in patients with high cardiovascular risk: a cross-sectional study.

OBJECTIVES: Statin adherence is an essential problem although lifetime medication is recommended especially in patients with high cardiovascular risk. The importance of perceived risk as a predictor of adherence among cardiology patients has not been fully explored. This study aimed to test the importance of perceived risk as a predictor of statin adherence amongst hypercholesterolemic patients to identify predictors associated with poor adherence. METHODS: This cross-sectional study was conducted at cardiology outpatient clinics of the University hospital in Ankara, Turkey. A total of 327 consecutive patients with high CV risk were recruited. Self-reported Morisky Green Levine Medication Adherence Scale was used to assess statin adherence. RESULTS: Of the patients studied, 34.5% had concerns about side effects. Also, the mean age was 63.85 ± 11.29 years, 66.1% were men, 32.4% applied non-drug alternative therapies, 53.2% had a Mediterranean-style diet and 20.8% checked their lipid values irregularly. Participants reported 50.2% high, 30% moderate, and 19.9% low statin medication adherence. Low-density lipoprotein cholesterol (LDL-C), Total Cholesterol (TC), Triglyceride (TG) and high-density lipoprotein (HDL) control rates were 44.6%, 74.3%, 61.5% and 41.6%. On multiple logistic regression, concern about side effects was associated with a statistically significant quadruple elevation of odds of non-adherence. Also, being male, former smokers, not having complementary interventions, having regular visits, being educated for more than 5 years, having low depressive symptom scores, living in a rural, being never or former smokers, employee were significant predictors of high medication adherence scores. CONCLUSION: Approximately half of the patients reported high medication adherence. Proper strategies to improve adherence would include patient education efforts focused on patients with concerns about side effects and those who are female, less educated, current smokers, interested in complementary interventions, have irregular follow-up visits, and have depressive symptoms. Brief medication adherence scales may facilitate the assessment of patients' adherence.

Evaluating the safety and efficacy of compression sutures with intracameral perfluoropropane (C3F8) in the management of acute corneal hydrops.

BACKGROUND: To evaluate the safety and efficacy of using corneal compression sutures with intracameral perfluoropropane (C3F8) in patients presenting with acute corneal hydrops in ectatic disorders. METHODS: A retrospective analysis was done for 43 eyes of patients of acute corneal hydrops, managed using a combination of intracameral 14% C3F8 and full-thickness compression sutures. Time for resolution of edema, corneal thickness (CT) change on anterior segment ocular coherence tomography (ASOCT), and visual outcomes were assessed. RESULTS: Corneal edema resolved with a mean duration of 14.8 ± 3.5 days (range 10-21). The mean CT on ASOCT decreased from a mean of 1437 µm (689-2770 µm) preoperatively to 543 µm (434 -66 µm) on the complete resolution of corneal edema. CONCLUSION: Our results suggest that full-thickness compression sutures and intracameral C3F8 injection can restore the imperviousness of posterior stroma. This technique appears to be a safe and effective technique for faster resolution of corneal edema post hydrops.

Review of current status of refractive lens exchange and role of dysfunctional lens index as its new indication.

Advances in phacodynamics and intraocular lenses (IOLs) has given second life to clear lens extraction (CLE) or refractive lens exchange (RLE) in recent years for the treatment of patients with high degrees of myopia, hyperopia, and astigmatism who are unsuitable for laser surgery. Furthermore, presbyopia treatment with RLE supplemented with multifocal or accommodating IOLs gives the dual benefit of correcting refractive errors with eliminating the need for cataract surgery. RLE should be consistent and effective for a good refractive outcome along with safety during the surgical procedure and in the postoperative period. Therefore, proper patient selection and accurate preoperative protocols for IOL power calculations and selection are important along with an appropriate choice of surgical procedure. Dysfunctional lens index is a new objective tool that helps surgeon to aid in diagnosing, counseling, and educating patients with dysfunctional clear lens. In this article, we give a brief overview about the application of RLE for individuals with presbyopia and refractive errors like myopia, hyperopia, and astigmatism who are not suitable for laser correction.

Algorithmic approach to diagnosis and management of post-refractive surgery dry eye disease.

Dry eye disease (DED) is a condition that is fast reaching epidemic proportions around the world. Dry eye post-refractive surgery is the leading cause of iatrogenically induced DED. The wide variety of presentations and the disparity between signs and symptoms in many patients make this a very challenging aspect of our clinical practice. There has been a paradigm shift in the way we approach and treat this condition. The International Dry eye workshop has added new knowledge and focus to our management of dry eye. A wide range of newer diagnostic modalities are available for the diagnosis of DED. Dry eye is one of the most common side effects of refractive surgery and can have a bearing the patient's perception of surgical outcomes as well. A thorough understanding of the possible underlying etiopathologies of this disease and the difference in etiopathogenesis of postrefractive dry eye is essential for optimal outcomes. It is important to approach each case in a unique fashion and customize the therapy to the patient presentation. This review article compiles all these aspects of management of dry eye in general, and postrefractive surgery dry eye in particular; from the ones commonly practiced in the clinic to the newer modalities of therapy with insights into the disease from a more practical point of view.

Screening and prophylaxis of retinal degenerations prior to refractive surgery.

The need and demand for surgical correction of refractive errors, particularly myopia, has been increasing. Degenerations involving the peripheral retina are common in myopes and can result in a rhegmatogenous retinal detachment. There are no clear guidelines for retinal screening and management of asymptomatic retinal degenerations prior to refractive surgery or for follow-up of these patients. This article aims to provide a set of guidelines for the management of retinal degenerations in eyes undergoing refractive surgeries.

Multimodal imaging of an idiopathic florid vascularised epiretinal membrane: Course, treatment, and outcome.

Idiopathic vascular epiretinal membrane is an extremely rare entity and the pathogenesis and clinical course is not clearly understood. A 53-year-old hypertensive female patient presented with complaints of altered vision in the right eye. On examination, her vision was 20/30 and fundoscopy showed a vascularized epiretinal membrane (ERM), which was confirmed on spectral-domain optical coherence tomography. No primary cause was found after investigations. The symptoms and ERM showed slow progression over the next three years with a visual acuity of 20/60. She underwent surgery for removal of the ERM, which was subjected to histopathological evaluation. This is a unique case of a florid proliferative vascularisation of an ERM in the absence of any identifiable cause, which had a good visual outcome following surgery.

Does the trait anxiety affect the dental fear?

The aims of the present study were to evaluate possible associations between trait anxiety, dental fear and the predictors of these interactions including demographic characteristics and dental history of patients applied to the dental care center in Ankara, Turkey. A sample of 607 participants (mean age: 21.02 ± 2.32) responded to a Turkish version of the Modified Dental Fear Survey (MDFS), the State-Trait Anxiety Inventory (STAI-T) and a questionnaire regarding previous negative dental experience. Multiple logistic regression analysis was used to identify the association between dental fear and the independent variables including trait anxiety, age groups, education level, dental visit frequency, experience and the source of dental knowledge. There was a trend for increasing in trait anxiety scores with greater levels of dental fear in a medium level of the dental fear group (OR = 1.055, 95%CI [1.025-1.086]; p < 0.001) and in a high level of the dental fear group (OR = 1.090 [1.057-1.124]; p < 0.001). Comparing to the low level of dental fear group; participants of medium dental fear level intended more likely to go to the dentist when they have a complaint instead of regularly going (odds ratio; OR = 3.177, 95%CI [1.304-7.741]; p = 0.011). Participants of high dental fear level tended to be less likely to have experienced no problem (OR = 0.476, 95%CI [0.284-0.795]; p = 0.005) than the low level of the dental fear group. We strongly indicate that higher dental fear scores have a predisposition of having high trait anxiety scores. Unpleasant dental experiences increased the risk for high dental fear levels. Patients with dental fear tended only to visit a dentist when necessary, avoiding regular visits.

Description of Califorctenus (Cteninae, Ctenidae, Araneae), a new spider genus from Mexico.

Califorctenus gen. nov. (Araneae: Ctenidae) a new genus and a new species (Califorctenus cacachilensis sp. nov.) from the Baja California Peninsula in Mexico are described and illustrated. Califorctenus gen. nov. can be diagnosed by the morphology of the male palp, with embolus cylindrical and elongated, locking lobes of embolus positioned retrolaterally and the cup-shaped and elongated median apophysis.

Does the trait anxiety affect the dental fear?

Abstract The aims of the present study were to evaluate possible associations between trait anxiety, dental fear and the predictors of these interactions including demographic characteristics and dental history of patients applied to the dental care center in Ankara, Turkey. A sample of 607 participants (mean age: 21.02 ± 2.32) responded to a Turkish version of the Modified Dental Fear Survey (MDFS), the State–Trait Anxiety Inventory (STAI-T) and a questionnaire regarding previous negative dental experience. Multiple logistic regression analysis was used to identify the association between dental fear and the independent variables including trait anxiety, age groups, education level, dental visit frequency, experience and the source of dental knowledge. There was a trend for increasing in trait anxiety scores with greater levels of dental fear in a medium level of the dental fear group (OR = 1.055, 95%CI [1.025–1.086]; p < 0.001) and in a high level of the dental fear group (OR = 1.090 [1.057–1.124]; p < 0.001). Comparing to the low level of dental fear group; participants of medium dental fear level intended more likely to go to the dentist when they have a complaint instead of regularly going (odds ratio; OR = 3.177, 95%CI [1.304–7.741]; p = 0.011). Participants of high dental fear level tended to be less likely to have experienced no problem (OR = 0.476, 95%CI [0.284–0.795]; p = 0.005) than the low level of the dental fear group. We strongly indicate that higher dental fear scores have a predisposition of having high trait anxiety scores. Unpleasant dental experiences increased the risk for high dental fear levels. Patients with dental fear tended only to visit a dentist when necessary, avoiding regular visits.

Comparison of estimated GFR equations based on serum cystatin C alone and in combination with serum creatinine in patients with coronary artery disease.

OBJECTIVE: Several new equations (GFRCKD-EPI-cr, GFRCKD-EPI-CysC, GFRCKD-EPI Cr+CysC) are used for the calculation of estimated GFR (eGFR) to evaluate renal function. These equations explicitly demonstrate the association of coronary artery disease (CAD) and severe renal impairment cases. However, these equations are considered insufficient to explain the relation with normal or mildly impaired eGFR and CAD. Our hypothesis was to indicate the inversely proportional relationship of eGFR values, calculated by the different equations, with the presence of CAD in patients with normal or mildly impaired renal function. METHODS: Eighty-eight patients who underwent elective coronary angiographic intervention were enrolled into the study. The study population was divided into two groups based on angiographic documents: patients with normal coronary arteries (CAD-) and patients with CAD (CAD +). These patients were stable and decided to implement angiography for the purpose of suspicion about CAD and control. Since it is thought that eGFR equations based on creatinine are inadequate to determine chronic kidney disease (CKD) and overestimate CKD diagnosis, cystatin C-based equations are considered an alternative. Due to the potential effects of inflammatory events of the markers used in equations, patients with diabetes mellitus, severe CKD, and inflammatory bowel disease were excluded from the study. RESULTS: The average age of all participants was 51.93±9.31 (32-65 years); 80.7% (n=71) was male. A statistical difference was found between the CAD (-) group and the CAD (+) group in terms of the variables of age (45.46±8.48 vs. 54.95±8.11, p<0.001), gender (67.9% vs. 86.7%, male, p=0.037), cystatin C values (1.37±0.34 vs. 0.85±0.39, p<0.001), and GFR equations defined by the Chronic Kidney Disease Epidemiology: GFRCKD-EPI-cr (85.86±14.20 vs. 79.45±10.25, p=0.018), GFRCKD-EPI-CysC (58.61±21.87 vs. 100.82±32.00, p<0.001), and GFRCKD-EPI Cr+CysC (68.29±13.49 vs. 90.75±18.34, p<0.001). After adjustment of the variables in multiple regression analyses, only age (OR, 1.199; 95% CI, 1.077 to 1.335, p=0.001), gender (OR, 8.252; 95% CI, 0.223 to 55.659, p=0.030), and the GFRCKD-EPI-CysC equation (OR, 1.059; 95% CI, 1.028 to 1.090, p<0.001) were detected as predictors for presence of CAD. CONCLUSION: GFR equations based on cystatin C or combined with creatinine may have superiority to GFR equations based on creatinine alone in CAD patients. However, the impact of different variables on the GFRCKD-EPI-CysC equation should not be ignored in specific groups, such as CAD.

Targeting prolyl endopeptidase with valproic acid as a potential modulator of neutrophilic inflammation.

A novel neutrophil chemoattractant derived from collagen, proline-glycine-proline (PGP), has been recently characterized in chronic obstructive pulmonary disease (COPD). This peptide is derived via the proteolytic activity of matrix metalloproteases (MMP's)-8/9 and PE, enzymes produced by neutrophils and present in COPD serum and sputum. Valproic acid (VPA) is an inhibitor of PE and could possibly have an effect on the severity of chronic inflammation. Here the interaction site of VPA to PE and the resulting effect on the secondary structure of PE is investigated. Also, the potential inhibition of PGP-generation by VPA was examined in vitro and in vivo to improve our understanding of the biological role of VPA. UV-visible, fluorescence spectroscopy, CD and NMR were used to determine kinetic information and structural interactions between VPA and PE. In vitro, PGP generation was significantly inhibited by VPA. In vivo, VPA significantly reduced cigarette-smoke induced neutrophil influx. Investigating the molecular interaction between VPA and PE showed that VPA modified the secondary structure of PE, making substrate binding at the catalytic side of PE impossible. Revealing the molecular interaction VPA to PE may lead to a better understanding of the involvement of PE and PGP in inflammatory conditions. In addition, the model of VPA interaction with PE suggests that PE inhibitors have a great potential to serve as therapeutics in inflammatory disorders.

CYP1A1 and CYP1B1-mediated biotransformation of the antitrypanosomal methamidoxime prodrug DB844 forms novel metabolites through intramolecular rearrangement.

DB844 (CPD-594-12), N-methoxy-6-{5-[4-(N-methoxyamidino)phenyl]-furan-2-yl}-nicotinamidine, is an oral prodrug that has shown promising efficacy in both mouse and monkey models of second stage human African trypanosomiasis. However, gastrointestinal (GI) toxicity was observed with high doses in a vervet monkey safety study. In the current study, we compared the metabolism of DB844 by hepatic and extrahepatic cytochrome P450s to determine whether differences in metabolite formation underlie the observed GI toxicity. DB844 undergoes sequential O-demethylation and N-dehydroxylation in the liver to form the active compound DB820 (CPD-593-12). However, extrahepatic CYP1A1 and CYP1B1 produced two new metabolites, MX and MY. Accurate mass and collision-induced dissociation mass spectrometry analyses of the metabolites supported proposed structures of MX and MY. In addition, MY was confirmed with a synthetic standard and detection of nitric oxide (NO) release when DB844 was incubated with CYP1A1. Taken altogether, we propose that MX is formed by insertion of oxygen into the amidine CN to form an oxaziridine, which is followed by intramolecular rearrangement of the adjacent O-methyl group and subsequent release of NO. The resulting imine ester, MX, is further hydrolyzed to form MY. These findings may contribute to furthering the understanding of toxicities associated with benzamidoxime- and benzmethamidoxime-containing molecules.

Safety, pharmacokinetic, and efficacy studies of oral DB868 in a first stage vervet monkey model of human African trypanosomiasis.

There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD). In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868; CPD-007-10), in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase) were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median C(max) (dosing regimen) that was 12-fold (3 mg/kg/day for 7 days), 15-fold (10 mg/kg/day for 7 days), and 31-fold (20 mg/kg/day for 5 days) greater than the IC50 (14 nmol/L) against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5-7 days), oral regimen for first stage HAT.

Cigarette smoke enhances chemotaxis via acetylation of proline-glycine-proline.

Several chronic lung diseases have been linked to cigarette smoking (Chronic Obstructive Pulmonary Disease (COPD), and cancer are associated with increased tobacco use). We recently described a collagen fragment, proline-glycine-proline (PGP), chemotactic for neutrophils, that appears to play a role in COPD, cystic fibrosis, and bronchiolitis obliterans syndrome. PGP can exist in either its native or acetylated form (NAcPGP), although the mechanism of N-terminal-acetylation remains unknown. This work investigates the possibility that cigarette smoke (CS) and its components acetylate PGP, describing a possible mechanism for some of the chronic inflammation seen in tobacco-associated disease. CSE and CSC (3.56 and 12.38 ng/ml NAcPGP respectively, p less than 0.01) and its components (acrolein, acetaldehyde, and methyl glyoxal) acetylated PGP (0.51, 1.03, and 0.23 ng/ml NAcPGP, p less than 0.01). Both N-acetyl-cysteine and carbocysteine (scavengers of reactive aldehydes) blocked chemical acetylation of PGP by CS (100 percent and 97 percent inhibition, respectively, p less than 0.01). NAcPGP is more chemoattractive to neutrophils, and less susceptible to degradation by Leukotriene-A4-Hydrolase (detected in the lung). These experiments propose a mechanism for the increased neutrophil recruitment seen in smoking-associated lung diseases.

Molecular recognition theory and sense-antisense interaction: therapeutic applications in autoimmunity.

Perhaps behind only the understanding of the genetic code in importance is the comprehension of protein sequence and structure in its effect on modern scientific investigation. How proteins are structured and interact dictates a considerable amount of the body's processes in maintaining homeostasis. Unfortunately, in diseases of autoimmunity, these processes are directed against the body itself and most of the current clinical responses are severely lacking. This review addresses current therapeutics involved in the treatment of various autoimmune diseases and details potential future therapeutics designed with a more targeted approach. Detailed in this manuscript is the concept of utilizing peptides possessing an inverse hydropathy to the immunogenic region of proteins to generate anti-idiotypic (anti-Id) and anti-clonotypic T cell receptor (TCR) antibodies (Abs). Theoretically, the anti-Id Abs cross react with Id Abs and negate the powerful machinery of the adaptive immune response with little to no side effects. A series of studies by a number of groups have shown this to be an exciting and intriguing concept that will likely play a role in the future treatment of autoimmune diseases.

Proline-glycine-proline as a potential biomarker in chronic obstructive pulmonary disease and cystic fibrosis.

The present review discusses the role of tri-peptide Proline -Glycine -Proline (PGP) as a potential player, biomarker and therapeutic target in this process.