Search

BACKGROUND: To evaluate the effects of Helicobacter pylori (HP) eradication on liver function tests (LFT) and fat content (LFC) in non-diabetic non-alcoholic steatohepatitis (NASH). METHODS: This randomized clinical trial included dyspeptic HP infected non-diabetic NASH participants. The intervention arm received HP eradication treatment, while the control arm did not get any HP treatment. In the meantime, the standard management of NASH was performed in both trial arms. Mean alterations in LFT were the primary outcome and the secondary outcomes included the mean changes in LFC and serum metabolic profile. The trial follow-up period was 5 years. RESULTS: 40 participants (female: 20), with a mean age of 41.58 (±12.31) years, were enrolled in the study. The HP eradication arm included 20 participants (female: 11) with a mean age of 40.25 (±10.59) years, and the control arm consisted of 20 individuals (female: 9) with a mean age of 42.90 (±13.97) years. The tests of within-subjects effects showed a significant decrease in mean serum alanine aminotransferase (ALT; P=0.007), triglyceride (TG; P=0.04), cholesterol (P=0.004), and fasting blood sugar (FBS; P

To determine the impact of image binarization and the best thresholding method for conjunctival optical coherence tomography angiography (OCTA).Vessel density (VD) of 14 OCTA conjunctival images (nine nasal and five temporal conjunctivas, and eight right and six left eyes) from normal subjects was analyzed. The binarization of gold-standard images, created by removing pixels that do not represent vessels on ImageJ software, was assessed by three masked graders to determine consistency of VD for images. Various thresholding methods on ImageJ, including manual, 1-, 2- and 3-step processes, were performed on unprocessed images for comparison. Interclass correlation coefficient (ICC) ≥0.750 were classified as good reliability and selected for calculation of the performance of the pixel location in the binarized images of each method.Analysis of the gold-standard threshold method achieved an ICC of 0.816 with excellent agreement (R2 = 0.965, P0.001). From a total 28 different methods and variations performed, only nine methods performed with good reliability, including two 1-step thresholds, six 2-step thresholds, and one 3-step threshold method. Overall, 2-step threshold methods were more reliable than 3-step threshold methods. The 2-step method of Bandpass filter + Phansalkar local threshold (LT) showed the best performance with mean pixel accuracy of 86.9% ± 6.8%, area under the curve of 0.826, sensitivity of 79.0%, and specificity 86.1%.Bandpass filter + Phansalkar LT was the best method for VD measurement in conjunctival OCTA. Most commonly reported threshold methods showed unsatisfactory agreement. There is a need in the OCTA field for a standardized method to allow comparison between different studies.The proposed threshold method using a widely accessible and commonly used software provides an accurate VD measurement for future OCTA studies.

PURPOSE: To evaluate corneal immune dendritiform cell (DC) changes in dry eye disease (DED) using in vivo confocal microscopy (IVCM) and to correlate IVCM parameters with clinical severity. METHODS: This was a retrospective, cross-sectional study including 300 eyes of 150 DED patients and 49 eyes of 49 age-matched controls. Severity of DED was based on the Dry Eye Workshop (DEWS) classification. IVCM images of subbasal layer of the central cornea were analyzed for DC density and morphology (including number of dendrites per DC, DC size and DC field). RESULTS: DC density was significantly higher in DED compared to controls (93.4 ± 6.3 vs. 25.9 ± 3.9 cells/ mm(2); P < 0.001). Morphologically, number of dendrites, DC size and field were significantly larger in DED (3.3 ± 0.1, 106.9 ± 4.7 μm(2), 403.8 ± 20.1 μm(2) than controls (2.3 ± 0.1, 62.5 ± 5.7 μm(2), 241.4 ± 24.4 μm(2), P < 0.001). Significantly higher DC density compared to controls was observed as early as Level 1 DED severity (87 ± 10 cells/mm(2), p < 0.001. Significant morphological changes in DC were detected for Levels 2 to 4 (p= < 0.001, and p = < 0.05) for dendrites and DC field, respectively. Similarly, DC size showed significant increase at DED level 3–4. (p < 0.05). Linear regression analysis showed that both conjunctival and corneal staining were independently associated with DC density, while corneal staining was independently associated with DC morphology. CONCLUSION: DC density and morphology correlated with clinical severity of DED. While, DC density is increased in mild DED, morphological changes are seen only in severe cases. IVCM may be a powerful tool to detect early immune changes and may complement clinical examination in DED.

Purpose Patients with dry eye disease (DED) may suffer from decreased tear break-up time due to meibomian gland (MG) dysfunction. Infrared meibography (IR Meibography) uses infrared wavelength light to visualize meibomian glands in vivo. We aimed to explore the feasibility of using serial IR Meibography imaging to assess morphological changes in MGs as an indirect measure of functionality, following intranasal neurostimulation (ITN). Methods Fifteen DED subjects were prospectively enrolled in a single-center, single-arm study. Changes in MGs were captured using IR meibography (RTVUE-XR, Optovue, Inc. Fremont, CA, USA) on the lower eyelids before and after 3 min of ITN (TrueTear®, Allergan, Dublin, Ireland) use that delivers a microcurrent to sensory neurons of the nasal cavity. The same MGs were selected pre- and post-stimulation, and MG area and perimeter were analyzed by two masked observers. Results Mean (±SD) pre- and post-stimulation MG areas were 2,187.60 ± 635.88 μm2 and 1,933.20 ± 538.55 μm2, respectively. The mean change in area, 254.49 μm2, representing an 11.6% reduction following ITN use, was statistically significant (p = 0.001). Mean (±SD) pre- and post-stimulation MG perimeters were 235.9 ± 51.38 μm and 222.2 ± 47.72 μm, respectively. The mean change in perimeter, 13.7 μm, representing a 5.81% reduction following ITN use, was statistically significant (p = 0.012). Conclusions Our study shows that IR meibography can be used to detect immediate changes in gland area and perimeter, an indirect measure of MG activity following intervention by ITN.

Background: Metabolic-associated fatty liver disease (MAFLD) is a common cause of liver-related mortality and morbidity worldwide. However, there is a paucity of literature on the relationship between cardiovascular disease (CVD) risk factors and quality of life (QoL) in patients with MAFLD. Objectives: This study aimed to examine the association between QoL and CVD risk factors in an Iranian MAFLD population. Methods: This study was conducted on MAFLD patients, referred to the gastroenterology clinic of a general hospital from September 2017 until September 2018. The QoL and Framingham Risk Score (FRS) were determined using the WHOQOL-BREF questionnaire and an online web calculator, respectively. A hierarchical multiple linear regression model was developed to evaluate the association between QoL and FRS after adjusting for the sociodemographic characteristics. Results: This study was performed on 200 participants. All domains of QoL were associated with older age, hypertension, smoking, diabetes mellitus, higher systolic blood pressure, and lower high-density lipoprotein levels in the univariate regression analysis (P < 0.05 for all). Meanwhile, FRS was adversely correlated with the total QoL score (correlation coefficient: -0.49; 95% CI: -0.61, -0.35; P < 0.001). After adjusting for the sociodemographic variables, the results of the hierarchical multiple linear regression model showed that age, smoking, diabetes mellitus, hypertension, and FRS were correlated with the overall QoL score (P < 0.05 for all). Hypertension was the main predictor of the total QoL score (B = -5.51, 95% CI: -7.18, -3.68; P < 0.05). A higher FRS was inversely associated with the physical domain of QoL (B = -0.05, 95% CI: -0.09, -0.01; P < 0.05), the environment domain of QoL (B = -0.04, 95% CI: -0.09, -0.01; P < 0.05), and the total score of QoL (B = -0.04, 95% CI: -0.08, -0.02; P < 0.05). Conclusions: According to the results of this study, a higher risk of developing CVD may reduce QoL in patients with MAFLD. Hypertension, diabetes mellitus, and smoking were the key predictive determinants of QoL in this population. Further studies are suggested to determine if modification of the mentioned risk factors can improve QoL in MAFLD patients.

Background Signs of gastroesophageal reflux disease (GERD) are limited, therefore, follow up of treatment are mainly based on patients’ symptoms. The aims of study were: 1) to compare the prevalence of white tongue (WT) between individuals with GERD and control group, 2) to evaluate the correlation between WT extension and severity of symptoms in GERD. Materials and methods This case-control study consisted of 100 consecutive individuals with GERD who were referred to the gastroenterology clinic of a referral hospital during 2019-2020. The diagnosis of GERD was made by a gastroenterologist if heart burn or regurgitation existed. The same number of healthy accompanies of patients without GERD participated as the control group. A single examiner defined WT if whitish-gray discoloration of tongue surface existed in two separate sessions [Kappa = 0.93; p < 0.01]. WT extension was estimated based on the approximate white discoloration of the tongue surface. Results All participants with GERD showed white tongue in the first observation and 98% in the second observation, while only 5% of the individuals in the control group revealed WT in both observations (p < 0.001). There was a positive correlation between the WT extension and GERD symptom severity (r: 0.44; p < 0.001). Conclusion It seems that WT might be a reliable sign of GERD. Considering the association between GERD symptoms severity and the extent of WT in this observation, further studies may assess the utility of WT extension as a reasonable objective in monitoring treatment response.

Introduction Combined immune checkpoint inhibitor therapy has been successfully used in the treatment of several malignancies. Adverse effects with the combination therapy may be more severe than the ones seen with single immune checkpoint inhibitors. Case presentation We report a unique case of a 59-year-old man of dark skin complexion who underwent treatment with intravenous ipilimumab–nivolumab every 3 weeks for metastatic malignant melanoma. After three cycles of this therapy, he developed extensive skin depigmentation that within 6 weeks, affected nearly the entire skin surface, along with progressive poliosis. Management and outcome Ipilimumab–nivolumab therapy was subsequently discontinued due to grade 3 enterocolitis requiring high-dose steroids and intravenous infliximab. About six months later, imaging studies showed a relapse of malignant melanoma. At that juncture, vitiligo affected the total body surface area, resembling albinism, along with near-total poliosis and significant photosensitivity. Pembrolizumab was tried but had to be stopped after three cycles due to the reoccurrence of grade 3 enterocolitis. Progression of malignant melanoma with new brain, lung, liver, subcutaneous, and colonic metastases led to the patient's demise. Conclusion We report a unique case of severe vitiligo and poliosis that involved total body surface area in a Caucasian man with dark complexion, resembling albinism. Further studies are warranted to evaluate the severity of dermatologic side effects with combination immune checkpoint inhibitor therapy.

Plasmacytoid dendritic cells (pDCs) are crucial for corneal homeostasis through secretion of various anti-angiogenic molecules and growth factors. Due to its avascular nature, only a limited number of adoptively transferred cells home to the cornea, when administered systemically. In addition, local adoptive transfer of cells poses several challenges and the clinical application of commonly used techniques is limited. Herein, we detail a novel approach for local adoptive transfer of pDCs to the cornea for the treatment of corneal wounds. This approach utilizes a commonly used fibrin sealant as a means of transferring previously isolated cells locally on the cornea. The technique is simple, reproducible, and is accompanied with successful transfer and integration of a substantial number of the cells to the cornea. Application of this approach to transfer pDCs promotes corneal wound healing. Furthermore, this technique can be applied for adoptive transfer of any cell of interest to the cornea.

PURPOSE: The diagnosis of neuropathic corneal pain (NCP) is challenging, as it is often difficult to differentiate from conventional dry eye disease (DED). In addition to eye pain, NCP can present with similar signs and symptoms of DED. The purpose of this study is to find an objective diagnostic sign to identify patients with NCP, using in vivo confocal microscopy (IVCM). METHODS: This was a comparative, retrospective, case-control study. Patients with clinical diagnosis of NCP (n=25), DED (n=30), and age and sex-matched healthy controls (n=16), who underwent corneal imaging with IVCM (HRT3/RCM) were included. Central corneal IVCM scans were analyzed by 2 masked observers for nerve density and number, presence of micro-neuromas (terminal enlargements of subbasal corneal nerve) and/or nerve beading (bead-like formation along the nerves), and dendritiform cell (DC) density. RESULTS: There was a decrease in total nerve density in both NCP (14.14±1.03 mm/mm(2)) and DED patients (12.86±1.04 mm/mm(2)), as compared to normal controls (23.90±0.92 mm/mm(2); p

AimsTo evaluate the impact of herpes simplex virus (HSV)-induced scar location on bilateral corneal nerve alterations using laser in vivo confocal microscopy (IVCM).MethodsCentral and peripheral corneal subbasal nerve density (CSND) were assessed bilaterally in 39 patients with unilateral HSV-induced corneal scars (21 central scars (CS), 18 peripheral scars (PS)) using IVCM. Results were compared between patients and 24 age-matched controls. CSND was correlated to corneal sensation for all locations.ResultsOverall patients revealed significant decrease of CSND in the central and peripheral cornea (9.13±0.98 and 6.26±0.53 mm/mm2, p2). CS group showed a decrease in central (8.09±1.30 mm/mm2) and total peripheral nerves (5.15±0.62 mm/mm2) of the affected eyes, whereas PS group demonstrated a decrease in central (10.34±1.48 mm/mm2) and localised peripheral nerves only in the scar area (4.22±0.77 mm/mm2) (all pConclusionsPatients with HSV scar demonstrate bilateral CSND decrease as shown by IVCM. CSND and corneal sensation decrease in both central and peripheral cornea in affected eyes, although only in the scar area in PS group. Interestingly, diminishment of CSND was found locally in the contralateral eyes, corresponding and mirroring the scar location in the affected eyes.

Importance Obstructive meibomian gland dysfunction (MGD) can be refractory to medical therapy. Intraductal meibomian gland (MG) probing may offer a potential therapeutic approach for these patients, but no randomized trials have been conducted to date. Objective To assess clinical changes after intraductal MG probing for patients with refractory obstructive meibomian gland dysfunction. Design Randomized, double-masked, sham-controlled clinical trial. Setting Single-center, tertiary referral center. Participants 42 patients with refractory obstructive MGD associated with lid tenderness. Interventions Enrolled patients received one of the following treatments: 1) MG probing plus post-procedural topical sulfacetamide/prednisolone ointment (Blephamide®), 2) MG probing plus post-procedural lubricating ointment (GenTeal), or 3) sham probing plus GenTeal ointment. The probing was performed on the upper lids of both eyes. Main outcome measures Primary outcome measures were symptoms as measured by Ocular Surface Disease Index (OSDI) and Symptom Assessment iN Dry Eye (SANDE), as well as tear break-up time (TBUT). Secondary outcome measures were other clinical signs. Safety of the procedure was also evaluated by investigating the treatment-related adverse events. At baseline and 4 weeks after the procedure a masked observer evaluated the following outcome measures: symptom questionnaires, including OSDI and SANDE, upper lid tenderness, lid margin telangiectasia, corneal fluorescein staining, conjunctival lissamine green staining, TBUT, Schirmer's test, and meibomian glands yielding liquid secretion (MGYLS). Results Compared to baseline, the MG probing/Blephamide® group showed significant improvements in both OSDI and SANDE scores and the MG probing/GenTeal group demonstrated a significant improvement only in SANDE score. In contrast, the Sham/GenTeal group did not show any statistically significant changes in symptoms. There were no statistically significant changes in clinical signs in any group at the 4-week visit, except for improvement of lid tenderness in the sham probing group. Conclusions MG probing/Blephamide® results in a significant improvement in symptoms in patients with refractory obstructive MGD without any significant effect on clinical signs. Larger studies are warranted to determine the efficacy of MG probing. Trial registration Clinicaltrials.gov (identifier NCT02256969, Filed on 08/13/2014)

Introduction Immune checkpoint inhibitors, such as programmed death (PD)-1 inhibitor nivolumab, are currently widely used in treatment of various malignancies. Due to their widespread application, any new potential adverse effects due to these agents necessitate careful assessment. Case report: We report a case of an 81-year-old man with recurrent high-risk malignant melanoma who underwent a 12-month adjuvant treatment with nivolumab. Shortly after the course of nivolumab, he developed monoclonal B-cell lymphocytosis (MBL) which subsequently progressed to chronic lymphocytic leukemia (CLL). Management and outcome: The patient is currently doing clinically well in Rai stage 0. Malignant melanoma remains in remission. Conclusion: Considering the pathophysiologic plausibility of nivolumab inducing B-cell dysregulation via PD-1 inhibition, we suggest further studies on potential association between nivolumab and B-cell malignancies.

Plasmacytoid dendritic cells (pDCs) constitute a unique population of bone marrow-derived cells that play a pivotal role in linking innate and adaptive immune responses. While peripheral tissues are typically devoid of pDCs during steady state, few tissues do host resident pDCs. In the current study, we aim to assess presence and distribution of pDCs in naive murine limbus and bulbar conjunctiva. Immunofluorescence staining followed by confocal microscopy revealed that the naive bulbar conjunctiva of wild-type mice hosts CD45+ CD11clow PDCA-1+ pDCs. Flow cytometry confirmed the presence of resident pDCs in the bulbar conjunctiva through multiple additional markers, and showed that they express maturation markers, the T cell co-inhibitory molecules PD-L1 and B7-H3, and minor to negligible levels of T cell co-stimulatory molecules CD40, CD86, and ICAM-1. Epi-fluorescent microscopy of DPE-GFP×RAG1-/- transgenic mice with GFP-tagged pDCs indicated lower density of pDCs in the bulbar conjunctiva compared to the limbus. Further, intravital multiphoton microscopy revealed that resident pDCs accompany the limbal vessels and patrol the intravascular space. In vitro multiphoton microscopy showed that pDCs are attracted to human umbilical vein endothelial cells and interact with them during tube formation. In conclusion, our study shows that the limbus and bulbar conjunctiva are endowed with resident pDCs during steady state, which express maturation and classic T cell co-inhibitory molecules, engulf limbal vessels, and patrol intravascular spaces.

SUMMARY The presence and potential functions of resident plasmacytoid dendritic cells (pDCs) in peripheral tissues is unclear. We report that pDCs constitutively populate naïve corneas and are increased during sterile injuries or acute herpes simplex virus 1 (HSV-1) keratitis. Their local depletion leads to severe clinical disease, nerve loss, viral dissemination to the trigeminal ganglion and draining lymph nodes, and mortality, while their local adoptive transfer limits disease. pDCs are the main source of HSV-1-induced IFN-α in the corneal stroma through TLR9, and they prevent re-programming of regulatory T cells (Tregs) to effector ex-Tregs. Clinical signs of infection are observed in pDC-depleted corneas, but not in pDC-sufficient corneas, following low-dose HSV-1 inoculation, suggesting their critical role in corneal antiviral immunity. Our findings demonstrate a vital role for corneal pDCs in the control of local viral infections., Graphical Abstract, In Brief Jamali et al. show that the cornea, as an immune-privileged tissue, hosts resident pDCs, which mediate immunity against HSV-1 by secreting IFN-a via TLR9 and preserving Tregs. pDCs minimize the clinical severity of HSV-1 keratitis, infiltration of immune cells, nerve damage, and viral dissemination to TG and dLNs.

Purpose Diagnosis of graft rejection is based on patient symptoms and on clinical signs detected by slit-lamp biomicroscopy. This study investigated whether laser in vivo confocal microscopy (IVCM) can aid in the diagnosis of corneal graft rejection by detecting cellular corneal changes that take place after transplantation. Design Prospective case-control study. Subjects Thirty-eight eyes of 38 patients with penetrating keratoplasty (15 eyes with corneal graft rejection, 23 eyes without rejection) and 9 age-matched normal controls. Methods Laser IVCM was performed in the corneal grafts centrally. The density of immune cells (IC) was assessed for epithelial, sub-epithelial, stromal, and endothelial layers by 2 masked observers. IC density was compared among different groups and correlated to clinical signs and symptoms of corneal graft rejection. Main Outcome Measurements Outcome measurement was the IC density in the corneal layers and its associations with the presence of clinical signs and symptoms of corneal graft rejection. Results The IC density was significantly different between rejected and non-rejected grafts (P = 0.004) and different from that of normal controls (P = 0.001). Among corneal layers, IC density was significantly higher in rejected grafts than in non-rejected grafts in only the sub-basal (611.54 ± 573.74 vs. 340.61 ± 268.60 cells/mm2, respectively; P = 0.049) and endothelial layers (250.62 ± 267.13 vs. 103.47 ± 81.91 cells/mm2, respectively; P = 0.001). Patients with decreased best corrected visual acuity, Khodadoust line, and anterior chamber cells demonstrated a significant increase in total IC density (P Conclusions Patients with corneal graft rejection demonstrate a significant increase in corneal immune cells, particularly, in the sub-basal and endothelial layers compared to patients with non-rejected grafts and controls. Although symptoms associated with endothelial rejection demonstrate a general increase in IC, pain, irritation, and light sensitivity are associated with increased IC in the sub-basal layer. Assessment of patients with corneal graft rejection by IVCM may serve as an adjunctive tool in the diagnosis and management of corneal graft rejection.

This study evaluated the effects of intravitreal injection of fasudil (IVF), a Rho-kinase inhibitor, in cases of recent-onset nonarteritic anterior ischemic optic neuropathy (NAION). In this interventional case series, 13 eyes of 13 patients diagnosed with NAION within 14 days of onset were included. The affected eyes received a 0.025 mg/0.05 mL IVF. Functional and structural outcomes were assessed 1 and 3 months following treatment. Best corrected visual acuity (BCVA) was the main outcome measured, with mean deviation (MD) index of the VF test and peripapillary retinal nerve fiber layer thickness as secondary measures. There was a statistically significant improvement in the patients' BCVA 1 and 3 months following IVF; BCVA improved from 1.69 ± 0.55 logMAR at baseline to 0.98 ± 0.47 and 0.93 ± 0.51 logMAR at 1 and 3 months, respectively (P = .004). The change in BCVA was not significant between month 1 and month 3 (P = .22). Peripapillary retinal nerve fiber layer thickness decreased from 173.5 ± 29.28 µm in the baseline evaluation to 85.8 ± 8.8 µm at 1 month, and 62.9 ± 5.97 µm at 3 months (P = .003). MD values changed from 24.60 ± 3.80 to 21.0 ± 6.10 and 20.5 ± 6.50 at 1 and 3 months, respectively (P = .007 and .005, respectively). This pilot study suggests that IVF may be an effective treatment for patients with recent-onset NAION. Larger studies are required to establish the therapeutic role of fasudil for NAION.

Purpose To investigate the longitudinal alterations of subbasal corneal nerves in patients with infectious keratitis (IK) during the acute phase, cessation of treatment, and the recovery phase by in vivo confocal microscopy (IVCM). Design Prospective, longitudinal, case-control, single-center study. Participants Fifty-six eyes of 56 patients with the diagnosis of bacterial (n = 28), fungal (n = 15), or Acanthamoeba (n = 13) keratitis were included in the study. Thirty eyes of 30 normal volunteers constituted the control group. Methods Corneal sensation and serial IVCM of the central cornea were performed prospectively using the Heidelberg Retina Tomograph 3/Rostock Cornea Module (Heidelberg Engineering, Heidelberg, Germany). The IVCM images were assessed at 3 time points: at the acute phase (first visit to the cornea service), at cessation of antimicrobial treatment, and up to 6 months after the resolution of infection. Main Outcome Measures Total nerve number and length, main nerve trunks, branching, and corneal sensation were assessed during the follow-up period. Results Corneal nerves were reduced significantly during the acute phase in eyes with IK compared with controls across all subgroups, with total nerve length of 5.47±0.69 mm/mm 2 versus 20.59±1.06 mm/mm 2 ( P 2 ; P = 0.02) and nerve branch length (4.80±0.37 mm/mm 2 ; P = 0.005). During the recovery phase, after resolution of infection, corneal nerves regenerated further, including total nerve length (12.13±1.97 mm/mm 2 ; P = 0.005), main nerve trunk length (5.80±1.00 mm/mm 2 ; P = 0.01), and nerve branch length (6.33±0.76 mm/mm 2 ; P = 0.003) as compared with the acute phase, but were still significantly lower when compared with controls ( P r = 0.47; P = 0.0009). Conclusions Patients with IK who sustain profound loss of corneal nerves during the acute phase of infection demonstrate increased corneal nerve density during the first 6 months after the resolution of infection. However, despite significant nerve regeneration, corneal nerve density does not recover fully and remains low compared to controls. By providing an objective methodology to monitor corneal re-innervation, IVCM adds potentially important findings that may have implications for clinical management and surgical planning.

The avascular cornea is the most densely innervated tissue in the body and is endowed with resident bone marrow-derived cells. We have identified a novel subset of resident corneal plasmacytoid dendritic cells (pDCs). We have shown pDCs support corneal nerves through release of nerve growth factor (NGF). This study was to examine the presence of pDCs in the developing cornea. We examined corneas from E17, P2, and 8 week adult C57BL/6 mice. Corneas were stained for the pan-leukocyte marker CD45, the pDC marker plasmacytoid dendritic cell antigen-1 (PDCA-1), the pan-neuronal marker bIII-tubulin. Corneal CD45+ and PDCA-1+ cells and nerves were quantified. Significance was assigned by ANOVA and post-hoc Tukey test. All data is reported as mean ± standard deviation. Corneal CD45+ leukocyte density increased from E17 (65.4±14 cells/mm2) to P2 pups (301.9±19 cells/mm2, p Our data show pDC density increased from embryonic, to neonatal, and adult corneas. Concurrently corneal nerve density increased during development from embryonic to adult mice.

Protein kinase D2 (PKD2) expression is up-regulated in pancreatic cancer. PKD1 expression is low. Both kinases differentially control pancreatic cancer cell invasion. PKD2 enhances invasion and angiogenesis in 3D ECM, as well as in chorioallantois membrane models, by stimulating expression and secretion of matrix metalloproteinase 7/9., Pancreatic cancer cell invasion, metastasis, and angiogenesis are major challenges for the development of novel therapeutic strategies. Protein kinase D (PKD) isoforms are involved in controlling tumor cell motility, angiogenesis, and metastasis. In particular PKD2 expression is up-regulated in pancreatic cancer, whereas PKD1 expression is lowered. We report that both kinases control pancreatic cancer cell invasive properties in an isoform-specific manner. PKD2 enhances invasion in three-dimensional extracellular matrix (3D-ECM) cultures by stimulating expression and secretion of matrix metalloproteinases 7 and 9 (MMP7/9), by which MMP7 is likely to act upstream of MMP9. Knockdown of MMP7/9 blocks PKD2-mediated invasion in 3D-ECM assays and in vivo using tumors growing on chorioallantois membranes. Furthermore, MMP9 enhances PKD2-mediated tumor angiogenesis by releasing extracellular matrix–bound vascular endothelial growth factor A, increasing its bioavailability and angiogenesis. Of interest, specific knockdown of PKD1 in PKD2-expressing pancreatic cancer cells further enhanced the invasive properties in 3D-ECM systems by generating a high-motility phenotype. Loss of PKD1 thus may be beneficial for tumor cells to enhance their matrix-invading abilities. In conclusion, we define for the first time PKD1 and 2 isoform–selective effects on pancreatic cancer cell invasion and angiogenesis, in vitro and in vivo, addressing PKD isoform specificity as a major factor for future therapeutic strategies.

Objectives The long and demanding course of medical education may be accompanied by distress with serious consequences. This study was conducted to assess the multidimensional health-related quality of life (HR-QoL) in medical students in different stages of medical education and its associations with behavioural and social factors. Methods A cross-sectional study was conducted in medical students at three medical schools at, respectively, Tehran University of Medical Sciences, Aja University of Medical Sciences and Baghiyatalah Medical School, in November and December 2011 using stratified sampling. Data were obtained on participants' characteristics, including gender, current education stage, living situation, smoking status, physical activity, and membership of associations or teams. Health-related QoL was measured using the Persian version of the 36-item Short Form Health Survey (SF-36), which generates a physical component score (PCS) and a mental component score (MCS). Logistic regression was applied to measure the adjusted associations between variables. Results Of the 1350 students invited, 1086 individuals completed the survey to give a response rate of 80.4%. Logistic regression showed male gender (odds ratio [OR] = 2.88, p

We here identify protein kinase D1 (PKD1) as a major regulator of anchorage-dependent and -independent growth of cancer cells controlled via the transcription factor Snail1. Using FRET, we demonstrate that PKD1, but not PKD2, efficiently interacts with Snail1 in nuclei. PKD1 phosphorylates Snail1 at Ser-11. There was no change in the nucleocytoplasmic distribution of Snail1 using wild type Snail1 and Ser-11 phosphosite mutants in different tumor cells. Regardless of its phosphorylation status or following co-expression of constitutively active PKD, Snail1 was predominantly localized to cell nuclei. We also identify a novel mechanism of PKD1-mediated regulation of Snail1 transcriptional activity in tumor cells. The interaction of the co-repressors histone deacetylases 1 and 2 as well as lysyl oxidase-like protein 3 with Snail1 was impaired when Snail1 was not phosphorylated at Ser-11, which led to reduced Snail1-associated histone deacetylase activity. Additionally, lysyl oxidase-like protein 3 expression was up-regulated by ectopic PKD1 expression, implying a synergistic regulation of Snail1-driven transcription. Ectopic expression of PKD1 also up-regulated proliferation markers such as Cyclin D1 and Ajuba. Accordingly, Snail1 and its phosphorylation at Ser-11 were required and sufficient to control PKD1-mediated anchorage-independent growth and anchorage-dependent proliferation of different tumor cells. In conclusion, our data show that PKD1 is crucial to support growth of tumor cells via Snail1.

Background: It is widely acknowledged that research is crucial for development of countries. Despite various studies on the benefits of research, there is no fresh study about students’ familiarity with principles of research methodology in developing countries. Objectives: In this study, we aim to assess undergraduate medical students’ knowledge in principles of research methodology and its contributing factors. Materials and Methods: In this cross sectional study, we investigated 65 randomly selected students who were in their basic science stage of medical studies at Tehran University of Medical Sciences in 2010. To determine knowledge about principles of research, participants filled a validated and reliable questionnaire. The characteristic information of the students and their answers to ten questions on research principles were collected. Linear regression models were applied to predict the score of knowledge of the participants. Results: Median age of participants was 19 ranging from 17-21. 15 (25%) of participants were male and 45 (75%) were female. 45 (75%) of participants had not attended Students’ Scientific Research Center (SSRC) research methodology workshop. The mean of knowledge score was 6.99 ± 3.23 (out of 20). We observed no significant difference in knowledge of the students and also participation in SSRC research methodology workshop between two genders (P = 0.75 and 0.86, respectively). Linear regression model showed participation in research methodology workshop independently predicts 59% of variance of students’ knowledge about principles of research methodology and adding students’ semester to the model increases the prediction to 70%. Conclusions: Despite limitations of this study, our findings highlight low to moderate level of knowledge of undergraduate medical students in principles of research methodology and the important impact of research methodology workshops.

To determine the relationship between serum adenosine deaminase (ADA) and disease activity, and to develop a new disease activity index based on serum ADA in rheumatoid arthritis (RA). Seventy RA patients were included. Disease activity based on Disease Activity Score 28-ESR (DAS28-ESR) and Disease Activity Score 28-CRP (DAS28-CRP) and serum ADA were measured. There were correlations when serum ADA compared with DAS28-ESR and DAS28-CRP. (R2 = 0.014, 0.175, respectively, P values < 0.00). New disease activity index was developed by replacing ADA with ESR and CRP in DAS28-ESR and DAS28-CRP. There were strong correlations when new model compared with DAS28-ESR and DAS28-CRP. (R2 = 0.94 and 0.95, respectively, P values < 0.00) The best new model values corresponding to DAS28-ESR values of 2.6, 3.2, and 5.1 were 2.79, 3.4, and 4.82, respectively; and new model values corresponding to DAS28-CRP values of 2.3, 2.7, and 4.1 were 2.1, 2.9, and 4, respectively. There were agreements when the new model compared with DAS28-ESR and DAS28-CRP for determination of patients in different disease activity categories. (Kappa = 0.81 and 0.71, respectively, P values < 0.00). The new disease activity index that applies serum ADA may help in predicting disease activity in RA.

New in vitro tissue models to mimic in vivo conditions are needed to provide insight into mechanisms involved in peripheral pain responses, potential therapeutic strategies to address these responses, and to replace animal models for such indications. For example, the rabbit cornea Draize test has become the standard method used for decades to screen ophthalmic drug and consumer product toxicity. In vitro tissue models with functional innervation have the potential to replace in vivo animal testing and provide sophisticated bench tools to study ocular nociception and its amelioration. Herein, full thickness, innervated, 3D human corneal tissues are grown under physiologically relevant culture conditions to study nociceptive-related responses, by mimicking ocular environmental cues, including intraocular pressure (IOP) and tear flow (TF). Capsaicin, a chili pepper-derived irritant known to cause a burning sensation in mammalian tissues is utilized as a nociceptive stimulant to induce pain, while subsequent serum treatment is used to mimic healing. Pain mediators released upon capsaicin stimulation and cell regrowth after serum treatment are characterized to assess ocular responses in this new, innervated, human corneal tissue system for comparison of outcomes to established animal and related responses.

Oxidized low-density lipoprotein (ox-LDL) plays a key role in the progression of atherosclerosis and diabetes complications. The aim of this study was first, to evaluate the association between ox-LDL and diabetes duration, and second, to examine serum level of ox-LDL in patients with prolonged diabetes and a desirable LDL-cholesterol level. A total of 36 type-2 diabetic patients with a diabetes duration of more than 5 years, 36 newly diagnosed diabetic patients, and 36 age-, sex- and BMI-matched healthy participants were recruited. Healthy participants and newly diagnosed patients were not receiving any treatment. All patients with prolonged diabetes had desirable LDL-cholesterol levels (100 mg/dL), according to the adult treatment panel-III guidelines. While LDL-cholesterol was significantly lower in patients with diabetes duration5 years, in comparison to newly diagnosed patients (P0.01), ox-LDL was significantly higher in patients with prolonged diabetes (P0.001). The ox-LDL-to-LDL ratio was dramatically higher in patients with diabetes duration5 years in comparison to newly diagnosed patients and healthy participants (P0.001). Ox-LDL was significantly associated with diabetes duration (r = 0.519, P = 0.001). In multivariate analysis, this association remained significant (beta = 0.501, P = 0.003) after adjustment for potential confounders. In conclusion, this study showed that the serum ox-LDL level increases with the length of diabetes, even though the patients' LDL-cholesterol level is maintained at a desirable level. Our findings highlight that possibly more attention should be focused on markers of oxidative stress in the management of lipids in diabetic patients.

The herpes simplex viruses (HSVs) are ubiquitous pathogens, capable of causing either asymptomatic or symptomatic disease. Herpes simplex virus keratitis (HSK) is the most frequent infectious cause of blindness in developed countries.1 Liesegang et al.2 have reported an incidence of 8.4 primary ocular HSV infections per 100,000 person-years. Moreover, further investigation of the natural history of HSK shows a recurrence rate, after the first episode, of 9.6% at 1 year, 22.9% at 2 years, and 63.2% at 20 years.2 The cornea is the most densely innervated tissue of the body, supplied by the terminal branches of the ophthalmic division of the trigeminal nerve as ciliary nerves.3,4 Corneal nerves penetrate the corneal periphery in a radial distribution and form the subbasal nerve plexus between the Bowman's layer and the basal epithelium.3 Corneal innervation provides protective and trophic functions and regulates epithelial integrity, proliferation, and wound healing.5,6 Recently, in vivo confocal microscopy (IVCM) has greatly advanced the microscopic evaluation of ocular structures. Specifically, the corneal subbasal nerve plexus and endothelial layers have been shown to be important indicators of corneal health and disease.7–10 One of the sequelae of HSK is neurotrophic keratopathy, caused by impaired corneal innervation.1,11 The insufficient supply of trophic neural factors and impairment of the tear and blink reflexes are caused by loss of corneal innervation.2,12 More recent studies5,6,13,14 have shown changes in subbasal corneal nerves in patients with early-stage Fuchs' endothelial corneal cell dystrophy (FECD). These findings suggest that corneal nerve alterations may be involved not only in the pathogenesis of FECD, but also potentially in other diseases resulting in decreased endothelial cell density. The embryologic similarities between endothelium and neuronal cells may support the theory that FECD has a neurodegenerative component.7–10,15 Further, Koh et al.16,17 have reported that the neuropeptide vasoactive intestinal peptide (VIP) has a protective effect on the corneal endothelium, playing an active role in maintaining the differentiated state and suppressing apoptosis in endothelial cells. Finally, in a recent preclinical study, we have demonstrated that trigeminal nerve axotomy results in a continuous loss of corneal endothelial cells centrally and peripherally, which correlates with a significant decrease in VIP after axotomy. Loss of endothelial cells is prevented through daily replenishment of the neuropeptide VIP (Yamaguchi T, et al. IOVS 2014;55:ARVO E-Abstract 2077). Thus, in the current study, hypothesizing that corneal nerves may mediate endothelial cell homeostasis, we performed IVCM in patients with a unilateral HSK, in order to analyze bilateral corneal endothelial cell density (ECD), as well as its correlation to subbasal nerve morphology and function.

This study evaluated the effects of intravitreal injection of fasudil (IVF), a Rho-kinase inhibitor, in cases of recent-onset nonarteritic anterior ischemic optic neuropathy (NAION). In this interventional case series, 13 eyes of 13 patients diagnosed with NAION within 14 days of onset were included. The affected eyes received a 0.025 mg/0.05 mL IVF. Functional and structural outcomes were assessed 1 and 3 months following treatment. Best corrected visual acuity (BCVA) was the main outcome measured, with mean deviation (MD) index of the VF test and peripapillary retinal nerve fiber layer thickness as secondary measures. There was a statistically significant improvement in the patients' BCVA 1 and 3 months following IVF; BCVA improved from 1.69 ± 0.55 logMAR at baseline to 0.98 ± 0.47 and 0.93 ± 0.51 logMAR at 1 and 3 months, respectively (P = .004). The change in BCVA was not significant between month 1 and month 3 (P = .22). Peripapillary retinal nerve fiber layer thickness decreased from 173.5 ± 29.28 µm in the baseline evaluation to 85.8 ± 8.8 µm at 1 month, and 62.9 ± 5.97 µm at 3 months (P = .003). MD values changed from 24.60 ± 3.80 to 21.0 ± 6.10 and 20.5 ± 6.50 at 1 and 3 months, respectively (P = .007 and .005, respectively). This pilot study suggests that IVF may be an effective treatment for patients with recent-onset NAION. Larger studies are required to establish the therapeutic role of fasudil for NAION.

Pure small cell carcinoma of the prostate (SCPCa) is a very rare condition usually with poor survival after diagnosis. It seems to show different clinical features compared to other prostate cancer subtypes, specifically adenocarcinoma. Here, we present a 74-year-old man early diagnosed with SCPCa treated with a cisplatine and etoposide regimen. There was no metastasis found in imaging studies and bone scan. The patient mostly complained of obstructive symptoms which were relieved after resection. Interestingly, our patient experienced a disease free condition after chemotherapy and no further progression was found. This could implicate the critical role of early diagnosis in the treatment of SCPCa despite its aggressive nature.

Background Hydrocoeles are common cystic scrotal abnormalities, described as a fluid-filled collection between the visceral and parietal layers of the tunica vaginalis of the scrotum. There are two approaches for treatment of hydrocoeles: surgical open hydrocoelectomy and aspiration followed by sclerotherapy. Objectives We compared the benefits and harms of aspiration and sclerotherapy versus hydrocoelectomy for the management of hydrocoeles. Search methods We searched the Cochrane Renal Group's Specialised Register to 2 August 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Selection criteria Randomised controlled trials (RCTs) and quasi-RCTs comparing aspiration and sclerotherapy versus hydrocoelectomy for the management of hydrocoeles. Data collection and analysis Two authors independently extracted data and assessed risk of bias in the included studies. Random effects meta-analyses were performed using relative risk (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI). Main results We found four small studies that met the inclusion criteria. These studies enrolled 275 patients with 282 hydroceles. Participants were randomised to aspiration and sclerotherapy (155 patients with 159 hydroceles) and surgery (120 patients with 123 hydroceles). All studies were assessed as having low or unclear risk of bias for selection bias, detection bias, attrition bias and selective reporting bias. Blinding was not possible for participants and investigators based on the type of interventions. Blinding for statisticians was not reported in any of included studies. There were no significant difference in clinical cure between the two groups (3 studies, 215 participants: RR 0.45, 95% CI 0.18 to 1.10), however there was significant heterogeneity (I² = 95%). On further investigation one study contributed all of the heterogeneity. This could be due to the agent used or perhaps due to the fact that this is a much older study than the other two studies included in this analysis. When this study was removed from the analysis the heterogeneity was 0% and the result was significant (in favour of surgery) (2 studies, 136 participants: RR 0.74; 95% CI 0.64 to 0.85).There was a significant increase in recurrence in those who received sclerotherapy compared with surgery (3 studies, 196 participants: RR 9.37, 95% CI 1.83 to 48.4). One study reported a non-significant decrease in fever in the sclerotherapy group (60 participants: RR 0.25, 95% CI 0.06 to 1.08). There was an increased number of infections in the surgery group however this increase was not statistically significant (4 studies, 275 participants): RR 0.31, 95% CI 0.09 to 1.05; I² = 0%). Three studies reported the frequency of pain in the surgery group was higher than aspiration and sclerotherapy group but because of different measurement tools applied in these studies, we could not pool the results. Radiological cure was not reported in any of the included studies. There was no significant difference in haematoma formation between the two groups (3 studies, 189 participants: RR 0.57, 95% CI 0.17 to 1.90; I² = 0%). Only one study reported patient satisfaction at three and six months; there was no significant difference between the two groups. Authors' conclusions Postoperative complications as well as cost and time to work resumption were less in the aspiration and sclerotherapy group; however the recurrence rate was higher. The cure rate in short-term follow-up was similar between the groups, however there is significant uncertainty in this result due to the high heterogeneity. There is a great need for further methodologically rigorous RCTs that assess the effectiveness of different type of sclerosant agents, sclerosing solution concentration and injection volume for the treatment of hydrocoeles. It is important that the RCTs have sufficiently large sample size and long follow-up period. Studies should evaluate clinical outcomes such as pain, recurrence, satisfaction, complications and cure using validated instruments. The protocols for all studies should be registered in clinical trial registries and the reports of these studies should conform with international guidelines of trial reporting such as CONSORT. Cost-effectiveness studies should also be undertaken.

To evaluate whether levels of corneal subbasal nerve fiber length (SNFL) in dry eye disease (DED) could prognosticate the level of improvement in signs and symptoms after treatment.Phase IV, double-masked, randomized clinical trial.Sixty patients with meibomian gland dysfunction-associated DED and 27 age-matched controls.Patients with DED were randomized to receive topical artificial tears, loteprednol etabonate 0.5%, or loteprednol etabonate 0.5%/tobramycin 0.3% twice daily for 4 weeks. At baseline, in vivo confocal microscopy of central cornea was performed in both eyes. Patients with DED were divided into 2 subgroups: those with low baseline SNFL and those with near-normal baseline SNFL for this purpose (the cutoff point: the mean SNFL in controls minus 2 standard deviations). Clinical signs and symptoms at baseline and after 4 weeks of treatment were compared between the subgroups with low and near-normal SNFL for all therapeutic groups.Symptom questionnaires, corneal fluorescein staining (CFS), conjunctival staining with lissamine green, tear break-up time, Schirmer's test, and SNFL.In patients with DED, baseline SNFL (17.06±5.78 mm/mm(2)) was significantly lower than in controls (23.68±3.42 mm/mm(2), P = 0.001). In the artificial tear and loteprednol groups, although no significant improvement in any sign or symptom was noted in patients with low baseline SNFL (16.84 mm/mm(2)), subjects with near-normal baseline SNFL (≥16.84 mm/mm(2)) showed significant improvement in both symptoms and CFS score (all P0.05). In the loteprednol/tobramycin group, no significant change was evident for any sign or symptom in either subgroup of low or near-normal baseline SNFL.Significant improvements in CFS and patient symptomatology after DED treatment were evident only in the subgroup with near-normal corneal SNFL. Consideration of SNFL may assist in explaining the variability of patients' response to DED therapy.

1184 www.thelancet.com Vol 381 April 6, 2013 protocol by the research council of the university, students do the research under the supervision of SSRC instructors (senior undergraduate students) and faculty members. Currently, SSRC is running RREs in cancer, radiology, medical education, and osteoporosis. Some RREs have shown promising results: students from the ophthalmology RRE presented four oral presentations at the 28th Congress of the European Society of Cataract and Refractive Surgeons in Paris, France, on Sept 4–8, 2010. RREs thus provide the opportunity for students to learn research by actually doing it.