Overexpression of Na ؉ -Dependent Myo-inositol Transporter Gene in Mouse Lens Led to Congenital Cataract

PURPOSE. Maintaining appropriate osmotic pressure is essential for maintaining lens transparency. This study was performed to investigate whether high levels of myo-inositol, one of the major organic osmolytes in the lens, would lead to cataract development. METHODS. Transgenic mouse lines carrying the bovine Na ϩ -dependent myo-inositol transporter (bSMIT) cDNA under the control of the mouse ␣A-crystallin promoter were generated. RESULTS. Increased bSMIT expression was accompanied by increased myo-inositol level in the lens and increased uptake of ( 3 H) myo-inositol by the lens in culture. The transgenic mice developed observable cataract under normal rearing conditions beginning at 2 to 8 weeks of age, and the severity of cataract development was correlated to the level of bSMIT gene expression and lens myo-inositol accumulation. For transgenic mouse line 3352, heterozygous mice did not develop cataract, whereas homozygous ones did. Prenatal feeding of heterozygous 3352 mice with high myo-inositol diet led to cataract development, indicating that cataract development was not merely due to a nonspecific effect of SMIT overexpression. Introducing aldose reductase overexpressing transgene into heterozygous 3352 mice also led to cataract development, indicating that this type of cataract is primarily due to osmotic stress. CONCLUSIONS. The present results indicate that high levels of myo-inositol and sorbitol in the lens contribute to cataract development. This is a useful model to study the role of osmotic stress in cataractogenesis during lens development. (Invest Ophthalmol Vis Sci. 2000;41:1467-1472 C ataract is the most important cause of blindness in the world. Nearly 16 million people are estimated to be blind because of cataract. 1 There are a number of causes for cataract, including congenital cataract, cataract from infection, cataract from UV and X-ray irradiation and oxidation damage, and cataract associated with several diseases, particularly diabetes. The transparency in mammalian lenses is due to the presence of crystallin structures formed by highly ordered association of several proteins. Changes in ionic environment, a reduction in the level of antioxidants such as reduced glutathione and ascorbic acid, and changes in the level of other solutes may lead to random protein aggregation and disruption of the crystallin structures, resulting in lens opacity and cataract. Therefore, the lens needs to stabilize the intracellular osmotic pressure by regulating the influx and efflux of water, osmolytes, and other solutes. Osmotic stress due to the accumulation of sorbitol in the lens is most likely the cause of diabetic cataract. This is based on the fact that sorbitol accumulates to high levels in the lenses of diabetic animals 6 Development of lens opacity in vitro can be prevented by AR inhibitors or if the medium is made hypertonic to balance the increased sorbitol accumulation in the lens, indicating that osmotic stress is the cause of diabetic cataract. 9 To determine whether cataract caused by sorbitol accumulation is a consequence of osmotic stress rather than the toxic effect of sorbitol, we wanted to increase the lens myoinositol (MI) level to see if that also causes cataract. Myoinositol is one of the three major osmolytes in the lens besides sorbitol and taurine. 10 Influx of MI into lens is dependent on the Na ϩ -dependent MI transporter (SMIT). 11 In this study, we produced transgenic mice that overexpress SMIT constitutively in lens cells and found that they developed congenital cataract under normal rearing condition beginning at 2 to 8 weeks of age. These results provide strong evidence that a high level o

Selective Over-Expression of Endothelin-1 in Endothelial Cells Exacerbates Inner Retinal Edema and Neuronal Death in Ischemic Retina

The level of endothelin-1 (ET-1), a potent vasoconstrictor, was associated with retinopathy under ischemia. The effects of endothelial endothelin-1 (ET-1) over-expression in a transgenic mouse model using Tie-1 promoter (TET-1 mice) on pathophysiological changes of retinal ischemia were investigated by intraluminal insertion of a microfilament up to middle cerebral artery (MCA) to transiently block the ophthalmic artery. Two-hour occlusion and twenty-two-hour reperfusion were performed in homozygous (Hm) TET-1 mice and their non-transgenic (NTg) littermates. Presence of pyknotic nuclei in ganglion cell layer (GCL) was investigated in paraffin sections of ipsilateral (ischemic) and contralateral (non-ischemic) retinae, followed by measurement of the thickness of inner retinal layer. Moreover, immunocytochemistry of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS) and aquaporin-4 (AQP4) peptides on retinal sections were performed to study glial cell reactivity, glutamate metabolism and water accumulation, respectively after retinal ischemia. Similar morphology was observed in the contralateral retinae of NTg and Hm TET-1 mice, whereas ipsilateral retina of NTg mice showed slight structural and cellular changes compared with the corresponding contralateral retina. Ipsilateral retinae of Hm TET-1 mice showed more significant changes when compared with ipsilateral retina of NTg mice, including more prominent cell death in GCL characterized by the presence of pyknotic nuclei, elevated GS immunoreactivity in Müller cell bodies and processes, increased AQP-4 immunoreactivity in Müller cell processes, and increased inner retinal thickness. Thus, over-expression of endothelial ET-1 in TET-1 mice may contribute to increased glutamate-induced neurotoxicity on neuronal cells and water accumulation in inner retina leading to edema

Insomnia as an Independent Predictor of Incident Cardiovascular Disease in HIV: Data from the Veterans Aging Cohort Study

Background: Insomnia is associated with increased cardiovascular disease (CVD) risk in the general population and is highly prevalent in people with HIV. The CVD risk conferred by insomnia in the HIV population is unknown. Methods: Using the Veterans Aging Cohort Study-Survey Cohort, insomnia symptoms were measured and dummy coded with the item, “Difficulty falling or staying asleep?” (5-point scale from no difficulty to bothers a lot). Incident CVD event ICD-9 codes (acute myocardial infarction, stroke, or coronary artery revascularization) were identified with VA and Medicare administrative data and VA fee-for-service data. Those with baseline CVD were excluded. Results: HIV-infected (N=3,108) veterans had a median follow-up time of 10.8 years, during which 267 CVD events occurred. Compared to HIV-infected veterans with no difficulty falling or staying asleep, HIV-infected veterans bothered a lot by insomnia symptoms had an increased risk of incident CVD after adjusting for demographics (HR=1.64, 95%CI=1.16-2.31, p=.005), CVD risk factors (HR=1.62, 95%CI=1.14-2.30, p=.007), additional potential confounders (hepatitis C infection, renal disease, anemia, alcohol use, cocaine use; HR=1.70, 95%CI=1.19-2.43, p=.003), and HIV-specific factors (HIV-1 RNA, CD4+ T-cell count, ART; HR=1.66, 95%CI=1.16-2.37, p=.005). Additional adjustment for non-benzodiazepine sleep medication (HR=1.62, 95%CI=1.13-2.32, p=.009) did not attenuate the association; however, it fell short of significance at p < .01 after adjustment for depressive symptoms (HR=1.51, 95%CI=0.98-2.32, p=.060) or antidepressant medication (HR=1.51, 95%CI=1.04-2.19, p=.031). Conclusion: Highly bothersome insomnia symptoms were significantly associated with incident CVD in HIV-infected veterans, suggesting that insomnia may be a novel, modifiable risk factor for CVD in HIV

Inducible Nucleosome Depletion at OREBP-Binding-Sites by Hypertonic Stress

Background: Osmotic Response Element-Binding Protein (OREBP), also known as TonEBP or NFAT5, is a unique transcription factor. It is hitherto the only known mammalian transcription factor that regulates hypertonic stress-induced gene transcription. In addition, unlike other monomeric members of the NFAT family, OREBP exists as a homodimer and it is the only transcription factor known to bind naked DNA targets by complete encirclement in vitro. Nevertheless, how OREBP interacts with target DNA, also known as ORE/TonE, and how it elicits gene transcription in vivo, remains unknown. Methodology: Using hypertonic induction of the aldose reductase (AR) gene activation as a model, we showed that OREs contained dynamic nucleosomes. Hypertonic stress induced a rapid and reversible loss of nucleosome(s) around the OREs. The loss of nucleosome(s) was found to be initiated by an OREBP-independent mechanism, but was significantly potentiated in the presence of OREBP. Furthermore, hypertonic induction of AR gene was associated with an OREBPdependent hyperacetylation of histones that spanned the 59 upstream sequences and at least some exons of the gene. Nevertheless, nucleosome loss was not regulated by the acetylation status of histone. Significance: Our findings offer novel insights into the mechanism of OREBP-dependent transcriptional regulation and provide a basis for understanding how histone eviction and transcription factor recruitment are coupled. © 2009 Tong et al.published_or_final_versio

Quantum Nucleation of Vortex String Loops

We investigate quantum nucleation of vortex string loops in the relativistic quantum field theory of a complex scalar field by using the Euclidean path integral. Our initial metastable homogeneous field dominated by the $O(3)$ symmetric bounce solution. The nucleation rate and the critical vortex loop size are obtained approximately. Gradually the initial current will be reduced to zero as the induced current inside vortex loops is opposite to the initial current. We also discuss a similar process in Maxwell-Higgs systems and possible physical implications.Comment: phyzzx.tex, 13 pages: A correction to the final state of the nucleation of local vortex string

Post-thrombotic Syndrome: Preventative and Risk Reduction Strategies Following Deep Vein Thrombosis

Venous disease is common in the general population, with chronic venous disorders affecting 50–85% of the western population and consuming 2–3% of healthcare funding. It, therefore, represents a significant socioeconomic, physical and psychological burden. Acute deep vein thrombosis, although a well-recognised cause of death through pulmonary embolism, can more commonly lead to post-thrombotic syndrome (PTS). This article summarises the pathophysiology and risk factor profile of PTS, and highlights various strategies that may reduce the risk of PTS, and the endovenous management of iliofemoral deep vein thrombosis. The authors summarise the advances in PTS risk reduction strategies and present the latest evidence for discussion

Quaternionic Spin

We rewrite the standard 4-dimensional Dirac equation in terms of quaternionic 2-component spinors, leading to a formalism which treats both massive and massless particles on an equal footing. The resulting unified description has the correct particle spectrum to be a generation of leptons, with the correct number of spin/helicity states. Furthermore, precisely three such generations naturally combine into an octonionic description of the 10-dimensional massless Dirac equation, as discussed in previous work.Comment: LaTeX2e, 15 pages, 1 PS figure; to appear in Clifford '99 proceeding

Generalized Relativistic Meson Wave Function

We study the most general, relativistic, constituent $q{\overline q}$ meson wave function within a new covariant framework. We find that by including a tensor wave function component, a pure valence quark model is now capable of reproducing not only all static pion data ($f_\pi$, $\langle r_\pi^2 \rangle$) but also the distribution amplitude, form factor $(F_\pi(Q^2))$, and structure functions. Further, our generalized spin wave function provides a much better detailed description of meson properties than models using a simple relativistic extension of the $S=L=0$ nonrelativistic wave function.Comment: 17 pages, REXTeX 3.0 file, (uuencoded postscript files of 8 figures appended

Ultrahigh Energy Cosmic Rays: The state of the art before the Auger Observatory

In this review we discuss the important progress made in recent years towards understanding the experimental data on cosmic rays with energies \agt 10^{19} eV. We begin with a brief survey of the available data, including a description of the energy spectrum, mass composition, and arrival directions. At this point we also give a short overview of experimental techniques. After that, we introduce the fundamentals of acceleration and propagation in order to discuss the conjectured nearby cosmic ray sources. We then turn to theoretical notions of physics beyond the Standard Model where we consider both exotic primaries and exotic physical laws. Particular attention is given to the role that TeV-scale gravity could play in addressing the origin of the highest energy cosmic rays. In the final part of the review we discuss the potential of future cosmic ray experiments for the discovery of tiny black holes that should be produced in the Earth's atmosphere if TeV-scale gravity is realized in Nature.Comment: Final version. To be published in Int. J. Mod. Phys.

Signatures of Short Distance Physics in the Cosmic Microwave Background

We systematically investigate the effect of short distance physics on the spectrum of temperature anistropies in the Cosmic Microwave Background produced during inflation. We present a general argument-assuming only low energy locality-that the size of such effects are of order H^2/M^2, where H is the Hubble parameter during inflation, and M is the scale of the high energy physics. We evaluate the strength of such effects in a number of specific string and M theory models. In weakly coupled field theory and string theory models, the effects are far too small to be observed. In phenomenologically attractive Horava-Witten compactifications, the effects are much larger but still unobservable. In certain M theory models, for which the fundamental Planck scale is several orders of magnitude below the conventional scale of grand unification, the effects may be on the threshold of detectability. However, observations of both the scalar and tensor fluctuation contributions to the Cosmic Microwave Background power spectrum-with a precision near the cosmic variance limit-are necessary in order to unambiguously demonstrate the existence of these signatures of high energy physics. This is a formidable experimental challenge.Comment: 49 pages, 2 figures. References added, minor typos correcte