Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML.

Dysregulation of innate immune signaling is a hallmark of hematologic malignancies. Recent therapeutic efforts to subvert aberrant innate immune signaling in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have focused on the kinase IRAK4. IRAK4 inhibitors have achieved promising, though moderate, responses in preclinical studies and clinical trials for MDS and AML. The reasons underlying the limited responses to IRAK4 inhibitors remain unknown. In this study, we reveal that inhibiting IRAK4 in leukemic cells elicits functional complementation and compensation by its paralog, IRAK1. Using genetic approaches, we demonstrate that cotargeting IRAK1 and IRAK4 is required to suppress leukemic stem/progenitor cell (LSPC) function and induce differentiation in cell lines and patient-derived cells. Although IRAK1 and IRAK4 are presumed to function primarily downstream of the proximal adapter MyD88, we found that complementary and compensatory IRAK1 and IRAK4 dependencies in MDS/AML occur via noncanonical MyD88-independent pathways. Genomic and proteomic analyses revealed that IRAK1 and IRAK4 preserve the undifferentiated state of MDS/AML LSPCs by coordinating a network of pathways, including ones that converge on the polycomb repressive complex 2 complex and JAK-STAT signaling. To translate these findings, we implemented a structure-based design of a potent and selective dual IRAK1 and IRAK4 inhibitor KME-2780. MDS/AML cell lines and patient-derived samples showed significant suppression of LSPCs in xenograft and in vitro studies when treated with KME-2780 as compared with selective IRAK4 inhibitors. Our results provide a mechanistic basis and rationale for cotargeting IRAK1 and IRAK4 for the treatment of cancers, including MDS/AML.

Inactivation of p53 provides a competitive advantage to del(5q) myelodysplastic syndrome hematopoietic stem cells during inflammation.

Inflammation is associated with the pathogenesis of myelodysplastic syndromes (MDS) and emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPC) exhibit an altered response to inflammation. Deletion of chromosome 5 (del(5q)) is the most common chromosomal abnormality in MDS. Although this MDS subtype contains several haploinsufficient genes that impact innate immune signaling, the effects of inflammation on del(5q) MDS HSPC remains undefined. Utilizing a model of del(5q)-like MDS, inhibiting the IRAK1/4-TRAF6 axis improved cytopenias, suggesting that activation of innate immune pathways contributes to certain clinical features underlying the pathogenesis of low-risk MDS. However, low-grade inflammation in the del(5q)-like MDS model did not contribute to more severe disease but instead impaired the del(5q)-like HSPC as indicated by their diminished numbers, premature attrition and increased p53 expression. Del(5q)-like HSPC exposed to inflammation became less quiescent, but without affecting cell viability. Unexpectedly, the reduced cellular quiescence of del(5q) HSPC exposed to inflammation was restored by p53 deletion. These findings uncovered that inflammation confers a competitive advantage of functionally defective del(5q) HSPC upon loss of p53. Since TP53 mutations are enriched in del(5q) AML following an MDS diagnosis, increased p53 activation in del(5q) MDS HSPC due to inflammation may create a selective pressure for genetic inactivation of p53 or expansion of a pre-existing TP53-mutant clone.

Estimation of Time Since Death Using Biochemical Markers in Synovial Fluid.

ABSTRACT: In the field of forensic medicine, estimating time since death plays an important role in helping the investigative organizations unravel the mystery of crime. Presently, many less reliable subjective parameters are being used to measure it, necessitating the need to have more specific and objective parameters. This cross-sectional comparative study was conducted at the Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, Bhopal, India on 60 deceased bodies to determine the correlation between known time since death and biochemical parameters in the synovial fluid specifically sodium, potassium, lactate, and total proteins, analyzed using random access fully automated chemical analyzer (Beckman Coulter Au680) followed by estimation of correlation using Spearman correlation test.All the biochemical parameters that were tested in the synovial fluid except for sodium showed a significant correlation. The potassium and lactate showed a significant positive correlation (P < 0.001), and on the contrary, the total protein level showed a significant negative correlation with time since death (P < 0.001). This study shows usefulness of these markers in estimating the time since death. The smaller sample size and the unavailability of the results of effect of cold storage on these parameters necessitate the need of further similar studies to uncover the real practical application.

Monitoring Misinformation on Twitter During Crisis Events: A Machine Learning Approach.

Social media has been increasingly utilized to spread breaking news and risk communications during disasters of all magnitudes. Unfortunately, due to the unmoderated nature of social media platforms such as Twitter, rumors and misinformation are able to propagate widely. Given this, a surfeit of research has studied false rumor diffusion on Twitter, especially during natural disasters. Within this domain, studies have also focused on the misinformation control efforts from government organizations and other major agencies. A prodigious gap in research exists in studying the monitoring of misinformation on social media platforms in times of disasters and other crisis events. Such studies would offer organizations and agencies new tools and ideologies to monitor misinformation on platforms such as Twitter, and make informed decisions on whether or not to use their resources in order to debunk. In this work, we fill the research gap by developing a machine learning framework to predict the veracity of tweets that are spread during crisis events. The tweets are tracked based on the veracity of their content as either true, false, or neutral. We conduct four separate studies, and the results suggest that our framework is capable of tracking multiple cases of misinformation simultaneously, with F 1 $F_1$ scores exceeding 87%. In the case of tracking a single case of misinformation, our framework reaches an F 1 $F_1$ score of 83%. We collect and drive the algorithms with 15,952 misinformation-related tweets from the Boston Marathon bombing (2013), Manchester Arena bombing (2017), Hurricane Harvey (2017), Hurricane Irma (2017), and the Hawaii ballistic missile false alert (2018). This article provides novel insights on how to efficiently monitor misinformation that is spread during disasters.

A Two-Stage Data-Driven Spatiotemporal Analysis to Predict Failure Risk of Urban Sewer Systems Leveraging Machine Learning Algorithms.

Risk-informed asset management is key to maintaining optimal performance and efficiency of urban sewer systems. Although sewer system failures are spatiotemporal in nature, previous studies analyzed failure risk from a unidimensional aspect (either spatial or temporal), not accounting for bidimensional spatiotemporal complexities. This is owing to the insufficiency of good-quality data, which ultimately leads to under-/overestimation of failure risk. Here, we propose a generalized methodology/framework to facilitate a robust spatiotemporal analysis of urban sewer system failure risk, overcoming the intrinsic challenges of data imperfections-e.g., missing data, outliers, and imbalanced information. The framework includes a two-stage data-driven modeling technique that efficiently models the highly right-skewed sewer system failure data to predict the failure risk, leveraging a bidimensional space-time approach. We implemented our analysis for Bogotá, the capital city of Colombia. We train, test, and validate a battery of machine learning algorithms-logistic regression, decision trees, random forests, and XGBoost-and select the best model in terms of goodness-of-fit and predictive accuracy. Finally, we illustrate the applicability of the framework in planning/scheduling sewer system maintenance operations using state-of-the-art optimization techniques. Our proposed framework can help stakeholders to analyze the failure-risk models' performance under different discrimination thresholds, and provide managerial insights on the model's adequate spatial resolution and appropriateness of decentralized management for sewer system maintenance.

Neuroprotective effects of brain-derived neurotrophic factor against amyloid beta 1-40-induced retinal and optic nerve damage.

Brain-derived neurotrophic factor (BDNF) could be considered a potential neuroprotective therapy in amyloid beta (Aß)-associated retinal and optic nerve degeneration. Hence, in this study we investigated the neuroprotective effect of BDNF against Aß1-40-induced retinal and optic nerve injury. In this study, exposure to Aß1-40 was associated with retinal and optic nerve injury. TUNEL staining showed significant reduction in the apoptotic cell count in the BDNF-treated group compared with Aß1-40 group. H&E-stained retinal sections also showed a striking reduction in neuronal cells in the ganglion cell layer (GCL) of retinas fourteen days after Aß1-40 exposure. By contrast, number of retinal cells was preserved in the retinas of BDNF-treated animals. After Aß1-40 exposure, visible axonal swelling was observed in optic nerve sections. However, the BDNF-treated group showed fewer changes in optic nerve; axonal swelling was less frequent and less marked. In the present study, exposure to Aß was associated with oxidative stress, whereas levels of retinal glutathione (GSH), superoxide dismutase (SOD) and catalase were significantly increased in BDNF-treated than in Aß1-40-treated rats. Both visual object recognition tests using an open-field arena and a Morris water maze showed that BDNF improved rats' ability to recognise visual cues (objects with different shapes) after Aß1-40 exposure, thus demonstrating that the visual performance of rats was relatively preserved following BDNF treatment. In conclusion, intravitreal treatment with BDNF prevents Aß1-40-induced retinal cell apoptosis and axon loss in the optic nerve of rats by reducing retinal oxidative stress and restoring retinal BDNF levels.

Magnesium acetyltaurate protects against endothelin-1 induced RGC loss by reducing neuroinflammation in Sprague dawley rats.

Endothelin-1 (ET-1), a potent vasoconstrictor, plays a significant role in the pathophysiology of ocular conditions like glaucoma. Glaucoma is characterized by apoptotic loss of retinal ganglion cells (RGCs) and loss of visual fields and is a leading cause of irreversible blindness. In glaucomatous eyes, retinal ischemia causes release of pro-inflammatory mediators such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α and promotes activation of transcription factors such as nuclear factor kappa B (NFKB) and c-Jun. Magnesium acetyltaurate (MgAT) has previously been shown to protect against ET-1 induced retinal and optic nerve damage. Current study investigated the mechanisms underlying these effects of MgAT, which so far remain unknown. Sprague dawley rats were intravitreally injected with ET-1 with or without pretreatment with MgAT. Seven days post-injection, retinal expression of IL-1ß, IL-6, TNF-α, NFKB and c-Jun protein and genes was determined using multiplex assay, Western blot and PCR. Animals were subjected to retrograde labeling of RGCs to determine the extent of RGC survival. RGC survival was also examined using Brn3A staining. Furthermore, visual functions of rats were determined using Morris water maze. It was observed that pre-treatment with MgAT protects against ET-1 induced increase in the retinal expression of IL-1ß, IL-6 and TNF-α proteins and genes. It also protected against ET-1 induced activation of NFKB and c-Jun. These effects of MgAT were associated with greater RGC survival and preservation of visual functions in rats. In conclusion, MgAT prevents ET-1 induced RGC loss and loss of visual functions by suppressing neuroinflammatory reaction in rat retinas.

Big Data and Predictive Analytics in Fire Risk Using Weather Data.

The objective of this article is to study the impact of weather on the damage caused by fire incidents across the United States. The article uses two sets of big data--fire incidents data from the National Fire Incident Reporting System (NFIRS) and weather data from the National Oceanic and Atmospheric Administration (NOAA)-to obtain a single comprehensive data set for prediction and analysis of fire risk. In the article, the loss is referred to as "Total Percent Loss," a metric that is calculated based on the content and property loss incurred by an owner over the total value of content and property. Gradient boosting tree (GBT), a machine learning algorithm, is implemented on the processed data to predict the losses due to fire incidents. An R2 value of 0.933 and mean squared error (MSE) of 124.641 out of 10,000 signify the extent of high predictive accuracy obtained by implementing the GBT model. In addition to this, an excellent predictive performance demonstrated by the GBT model is further validated by a strong fitting between the predicted loss and the actual loss for the test data set, with an R2 value of 0.97. While analyzing the influence of each input variable on the output, it is observed that the state in which a fire incident takes place plays a major role in determining fire risk. This article provides useful insights to fire managers and researchers in the form of a detailed framework of big data and predictive analytics for effective management of fire risk.

Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine acyltransferase in combination with TKI.

Tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) has limited efficacy against leukemia stem cells (LSC) responsible for disease propagation, and most CML patients require continued TKI treatment to maintain remission. LSC maintenance is related, at least in part, to signals from the bone marrow microenvironment (BMM). Our previous studies have shown that Wnt signaling from the BMM contributes to preservation of CML LSC following TKI treatment. Secretion of Wnt ligands requires their modification by the O-acyl transferase Porcupine (PORCN). Here we investigated the activity of a potent and selective PORCN inhibitor, WNT974, against CML stem and progenitor cells. WNT974 efficiently antagonized Wnt signaling in human CML CD34+ cells, and in combination with the TKI nilotinib (NIL) significantly enhanced inhibition of proliferation and colony-forming potential of CML stem and progenitor cells and reduced their growth in immunodeficient mice in vivo, in comparison with NIL alone. Treatment of transgenic CML mice in vivo with NIL in combination with WNT974 significantly reduced leukemic stem and progenitor cell numbers, reduced regeneration of leukemic long-term hematopoietic stem cells in secondary transplant recipients, and enhanced survival of mice after discontinuation of treatment, in comparison with NIL alone. CML progenitors demonstrated enhanced sensitivity to Wnt stimulation, associated with increased expression of the FZD4 receptor. FZD4 knockdown inhibited CML progenitor growth. These results support further investigation of PORCN targeting to inhibit Wnt secretion and signaling and enhance targeting of CML stem cells while sparing their normal counterparts.

Taurine protects against NMDA-induced retinal damage by reducing retinal oxidative stress.

This study aimed to evaluate effect of TAU on NMDA-induced changes in retinal redox status, retinal cell apoptosis and retinal morphology in Sprague-Dawley rats. Taurine was injected intravitreally as pre-, co- or post-treatment with NMDA and 7 days post-treatment retinae were processed for estimation of oxidative stress, retinal morphology using H&E staining and retinal cell apoptosis using TUNEL staining. Treatment with TAU, particularly pre-treatment, significantly increased retinal glutathione, superoxide dismutase and catalase levels compared to NMDA-treated rats; whereas, the levels of malondialdehyde reduced significantly. Reduction in retinal oxidative stress in TAU pre-treated group was associated with significantly greater fractional thickness of ganglion cell layer within inner retina and retinal cell density in inner retina. TUNEL staining showed significantly reduced apoptotic cell count in TAU pre-treated group compared to NMDA group. It could be concluded that TAU protects against NMDA-induced retinal injury in rats by reducing retinal oxidative stress.

Protective effect of magnesium acetyltaurate and taurine against NMDA-induced retinal damage involves reduced nitrosative stress.

Purpose: Retinal nitrosative stress associated with altered expression of nitric oxide synthases (NOS) plays an important role in excitotoxic retinal ganglion cell loss in glaucoma. The present study evaluated the effects of magnesium acetyltaurate (MgAT) on changes induced by N-methyl-D-aspartate (NMDA) in the retinal expression of three NOS isoforms, retinal 3-nitrotyrosine (3-NT) levels, and the extent of retinal cell apoptosis in rats. Effects of MgAT with taurine (TAU) alone were compared to understand the benefits of a combined salt of Mg and TAU. Methods: Excitotoxic retinal injury was induced with intravitreal injection of NMDA in Sprague-Dawley rats. All treatments were given as pre-, co-, and post-treatment with NMDA. Seven days post-injection, the retinas were processed for measurement of the expression of NOS isoforms using immunostaining and enzyme-linked immunosorbent assay (ELISA), retinal 3-NT content using ELISA, retinal histopathological changes using hematoxylin and eosin (H&E) staining, and retinal cell apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Results: As observed on immunohistochemistry, the treatment with NMDA caused a 4.53-fold increase in retinal nNOS expression compared to the PBS-treated rats (p<0.001). Among the MgAT-treated groups, only the pretreatment group showed significantly lower nNOS expression than the NMDA-treated group with a 2.00-fold reduction (p<0.001). Among the TAU-treated groups, the pre- and cotreatment groups showed 1.84- and 1.71-fold reduction in nNOS expression compared to the NMDA-treated group (p<0.001), respectively, but remained higher compared to the PBS-treated group (p<0.01). Similarly, iNOS expression in the NMDA-treated group was significantly greater than that for the PBS-treated group (2.68-fold; p<0.001). All MgAT treatment groups showed significantly lower iNOS expression than the NMDA-treated groups (3.58-, 1.51-, and 1.65-folds, respectively). However, in the MgAT co- and post-treatment groups, iNOS expression was significantly greater than in the PBS-treated group (1.77- and 1.62-folds, respectively). Pretreatment with MgAT caused 1.77-fold lower iNOS expression compared to pretreatment with TAU (p<0.05). In contrast, eNOS expression was 1.63-fold higher in the PBS-treated group than in the NMDA-treated group (p<0.001). Among all treatment groups, only pretreatment with MgAT caused restoration of retinal eNOS expression with a 1.39-fold difference from the NMDA-treated group (p<0.05). eNOS expression in the MgAT pretreatment group was also 1.34-fold higher than in the TAU pretreatment group (p<0.05). The retinal NOS expression as measured with ELISA was in accordance with that estimated with immunohistochemistry. Accordingly, among the MgAT treatment groups, only the pretreated group showed 1.47-fold lower retinal 3-NT than the NMDA-treated group, and the difference was significant (p<0.001). The H&E-stained retinal sections in all treatment groups showed statistically significantly greater numbers of retinal cell nuclei than the NMDA-treated group in the inner retina. However, the ganglion cell layer thickness in the TAU pretreatment group remained 1.23-fold lower than that in the MgAT pretreatment group (p<0.05). In line with this observation, the number of apoptotic cells as observed after TUNEL staining was 1.69-fold higher after pretreatment with TAU compared to pretreatment with MgAT (p<0.01). Conclusions: MgAT and TAU, particularly with pretreatment, reduce retinal cell apoptosis by reducing retinal nitrosative stress. Pretreatment with MgAT caused greater improvement in NMDA-induced changes in iNOS and eNOS expression and retinal 3-NT levels than pretreatment with TAU. The greater reduction in retinal nitrosative stress after pretreatment with MgAT was associated with lower retinal cell apoptosis and greater preservation of the ganglion cell layer thickness compared to pretreatment with TAU.

Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor-treated CML stem cells.

Treatment of chronic myelogenous leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKI) fails to eliminate leukemia stem cells (LSC). Patients remain at risk for relapse, and additional approaches to deplete CML LSC are needed to enhance the possibility of discontinuing TKI treatment. We have previously reported that expression of the pivotal proinflammatory cytokine interleukin-1 (IL-1) is increased in CML bone marrow. We show here that CML LSC demonstrated increased expression of the IL-1 receptors, IL-1 receptor accessory protein and IL-1 receptor type 1 (IL-1R1), and enhanced sensitivity to IL-1-induced NF-κB signaling compared with normal stem cells. Treatment with recombinant IL-1 receptor antagonist (IL-1RA) inhibited IL-1 signaling in CML LSC and inhibited growth of CML LSC. Importantly, the combination of IL-1RA with TKI resulted in significantly greater inhibition of CML LSC compared with TKI alone. Our studies also suggest that IL-1 signaling contributes to overexpression of inflammatory mediators in CML LSC, suggesting that blocking IL-1 signaling could modulate the inflammatory milieu. We conclude that IL-1 signaling contributes to maintenance of CML LSC following TKI treatment and that IL-1 blockade with IL-1RA enhances elimination of TKI-treated CML LSC. These results provide a strong rationale for further exploration of anti-IL-1 strategies to enhance LSC elimination in CML.

Time- and dose-related effects of amyloid beta1-40 on retina and optic nerve morphology in rats.

PURPOSE: Amyloid beta (Aß) is known to contribute to the pathophysiology of retinal neurodegenerative diseases such as glaucoma. Effects of intravitreal Aß(1-42) on retinal and optic nerve morphology in animal models have widely been studied but not those of Aß(1-40). Hence, we evaluated the time- and dose-related effects of intravitreal Aß(1-40) on retinal and optic nerve morphology. Since oxidative stress and brain derived neurotrophic factor (BDNF) are associated with Aß-induced neuronal damage, we also studied dose and time-related effects of Aß(1-40) on retinal oxidative stress and BDNF levels. MATERIALS AND METHODS: Five groups of rats were intravitreally administered with vehicle or Aß(1-40) in doses of 1.0, 2.5, 5 and 10 nmol. Animals were sacrificed and eyes were enucleated at weeks 1, 2 and 4 post-injection. The retinae were subjected to morphometric analysis and TUNEL staining. Optic nerve sections were stained with toluidine blue and were graded for neurodegenerative effects. The estimation of BDNF and markers of oxidative stress in retina were done using ELISA technique. RESULTS AND CONCLUSIONS: It was observed that intravitreal Aß(1-40) causes significant retinal and optic nerve damage up to day 14 post-injection and there was increasing damage with increase in dose. However, on day 30 post-injection both the retinal and optic nerve morphology showed a trend towards normalization. The observations made for retinal cell apoptosis, retinal glutathione, superoxide dismutase activity and BDNF were in accordance with those of morphological changes with deterioration till day 14 and recovery by day 30 post-injection. The findings of this study may provide a guide for selection of appropriate experimental conditions for future studies.

Chikungunya infection presenting as mild encephalitis with a reversible lesion in the splenium: a case report.

Chikungunya fever is an Aedes mosquito-transmitted infection caused by chikungunya virus, an RNA virus in the family Togaviridae. The disease is characteristically manifested as fever, arthralgia, and/or rash. Various neurological manifestations like meningoencephalitis, myelitis, and myeloneuropathy have been mentioned in various reports. We present a rare case of chikungunya fever presenting with mild encephalitis with a reversible lesion of the splenium (MERS), which showed complete clinical and radiological recovery.

Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development.

Hematopoietic stem cells (HSCs) reside in regulatory niches in the bone marrow (BM). Although HSC niches have been extensively characterized, the role of endosteal osteoblasts (OBs) in HSC regulation requires further clarification, and the role of OBs in regulating leukemic stem cells (LSCs) is not well studied. We used an OB visualization and ablation mouse model to study the role of OBs in regulating normal HSCs and chronic myelogenous leukemia (CML) LSCs. OB ablation resulted in increase in cells with a LSK Flt3(-)CD150(+)CD48(-) long-term HSC (LTHSC) phenotype but reduction of a more highly selected LSK Flt3(-)CD34(-)CD49b(-)CD229(-) LTHSC subpopulation. LTHSCs from OB-ablated mice demonstrated loss of quiescence and reduced long-term engraftment and self-renewal capacity. Ablation of OB in a transgenic CML mouse model resulted in accelerated leukemia development with reduced survival compared with control mice. The notch ligand Jagged-1 was overexpressed on CML OBs. Normal and CML LTHSCs cultured with Jagged-1 demonstrated reduced cell cycling, consistent with a possible role for loss of Jagged-1 signals in altered HSC and LSC function after OB ablation. These studies support an important role for OBs in regulating quiescence and self-renewal of LTHSCs and a previously unrecognized role in modulating leukemia development in CML.

Mechanism of the anticataract effect of liposomal MgT in galactose-fed rats.

PURPOSE: Increased lenticular oxidative stress and altered calcium/magnesium (Ca/Mg) homeostasis underlie cataractogenesis. We developed a liposomal formulation of magnesium taurate (MgT) and studied its effects on Ca/Mg homeostasis and lenticular oxidative and nitrosative stress in galactose-fed rats. METHODS: The galactose-fed rats were topically treated with liposomal MgT (LMgT), liposomal taurine (LTau), or corresponding vehicles twice daily for 28 days with weekly anterior segment imaging. At the end of the experimental period, the lenses were removed and subjected to analysis for oxidative and nitrosative stress, Ca and Mg levels, ATP content, Ca(2+)-ATPase, Na(+),K(+)-ATPase, and calpain II activities. RESULTS: The LTau and LMgT groups showed significantly lower opacity index values at all time points compared to the corresponding vehicle groups (p<0.001). However, the opacity index in the LMgT group was lower than that in the LTau group (p<0.05). Significantly reduced oxidative and nitrosative stress was observed in the LTau and LMgT groups. The lens Ca/Mg ratio in LMgT group was decreased by 1.15 times compared to that in the LVh group. Calpain II activity in the LMgT group was decreased by 13% compared to the LVh group. The ATP level and Na(+),K(+)-ATPase and Ca(2+)-ATPase activities were significantly increased in the LMgT group compared to the LVh group (p<0.05). CONCLUSIONS: Topical liposomal MgT delays cataractogenesis in galactose-fed rats by maintaining the lens mineral homeostasis and reducing lenticular oxidative and nitrosative stress.

Topical trans-resveratrol ameliorates steroid-induced anterior and posterior segment changes in rats.

Steroid-induced hypertension and glaucoma is associated with increased extracellular meshwork (ECM) deposition in trabecular meshwork (TM). Previous studies have shown that single drop application of trans-resveratrol lowers IOP in steroid-induced ocular hypertensive (SIOH) rats. This IOP lowering is attributed to activation of adenosine A1 receptors, which may lead to increased matrix metalloproteinase (MMP)-2 activity. This study evaluated the effect of repeated topical application of trans-resveratrol for 21 days in SIOH animals on IOP, changes in MMP-2 level in aqueous humor, trabecular meshwork and retinal morphology and retinal redox status. We observed that treatment with trans-resveratrol results in significant and sustained IOP reduction in SIOH rats. This IOP reduction is associated with significantly higher aqueous humor total MMP-2 level; significantly reduced TM thickness and increased number of TM cells. Treatment with trans-resveratrol also significantly increased ganglion cell layer (GCL) thickness, the linear cell density in the GCL and inner retina thickness; and significantly reduced retinal oxidative stress compared to the SIOH vehicle-treated group. In conclusion, repeated dose topical application of trans-resveratrol produces sustained IOP lowering effect, which is associated with increased level of aqueous humor MMP-2, normalization of TM and retinal morphology and restoration of retinal redox status.

Fibroadenoma in the male breast: Truth or Myth?

Truth or myth is seldom encountered in the practice of surgery, especially in cases of breast diseases. Yet, even after thousands of years of treating breast disease by surgeons/healers, fibroadenoma in the male breast seems to be a myth, due to the absence of fibro-glandular tissue. We wish to break this myth by our own experience as well as other studies by others all over the world, and unveil the truth that fibroadenoma in the male breast is a definitive entity and has a prevalence among the vast spectrum of breast diseases.

Aqueous humor TGF-ß2 levels in patients with open-angle glaucoma: A meta-analysis.

INTRODUCTION: Elevated intraocular pressure (IOP) in glaucomatous eyes is often due to increased resistance to aqueous outflow. Previous studies have shown that increased extracellular material deposition in outflow pathways leads to increased resistance to aqueous outflow, and transforming growth factor (TGF)-ß seems to play a role in the deposition of extracellular material. TGF-ß2 is the predominant isoform in ocular tissue. Hence, comparison of the aqueous humor TGF-ß2 level between patients with open-angle glaucoma (OAG) and controls would provide direct evidence for the role of TGF-ß2 in the etiology of OAG. Hence, we performed this meta-analysis to develop an accurate estimate of the changes in aqueous humor TGF-ß2 levels among OAG patients. METHODS: We undertook the meta-analysis of data from all available studies that had a case-control design and investigated the aqueous humor levels of TGF-ß2 (total, active, or both) in OAG patients. OAG included primary OAG (POAG), secondary glaucoma, pseudoexfoliation syndrome, and exfoliation glaucoma (EXG). RESULTS: We selected a total of eight studies that measured TGF-ß2 levels in the aqueous humor of glaucomatous eyes. The studies included in this meta-analysis clearly demonstrated that in OAG eyes, total TGF-ß2 levels are significantly elevated, whereas in POAG eyes, both the total and active TGF-ß2 levels are significantly higher than in controls. CONCLUSIONS: The analysis of pooled data showed that aqueous humor TGF-ß2 levels are elevated in patients with OAG and POAG.

Role of adenosine receptors in resveratrol-induced intraocular pressure lowering in rats with steroid-induced ocular hypertension.

BACKGROUND: Steroid-induced ocular hypertension is currently treated in the same way as primary open-angle glaucoma. However, the treatment is often suboptimal and is associated with adverse effects. We evaluated the oculohypotensive effects of topical trans-resveratrol in rats with steroid-induced ocular hypertension and involvement of adenosine receptors (AR) in intraocular pressure (IOP) lowering effect of trans-resveratrol. METHODS: The oculohypotensive effect of unilateral single-drop application of various concentrations of trans-resveratrol was first studied in oculonormotensive rats. Concentration with maximum effect was similarly studied in rats with steroid-induced ocular hypertension. Involvement of AR was studied by observing the alterations of IOP in response to trans-resveratrol after pretreating animals with AR subtype-specific antagonists. Additionally, we used computational methods, including 3D modelling, 3D structure generation and protein-ligand interaction, to determine the AR-trans-resveratrol interaction. RESULTS: All concentrations of trans-resveratrol produced significant IOP reduction in normotensive rat eyes. Maximum mean IOP reduction of 15.1% was achieved with trans-resveratrol 0.2%. In oculohypertensive rats, trans-resveratrol 0.2% produced peak IOP reduction of 25.2%. Pretreatment with A1 antagonist abolished the oculohypotensive effect of trans-resveratrol. Pretreatment with A3 and A2A AR antagonists produced significant IOP reduction in both treated and control eyes, which was further augmented by trans-resveratrol application in treated eyes. Computational studies showed that trans-resveratrol has highest affinity for A2B and A1, followed by A2A and A3 AR. CONCLUSION: Topically applied trans-resveratrol reduces IOP in rats with steroid-induced ocular hypertension. Trans-resveratrol-induced oculohypotension involves its agonistic activity at the A1 AR.