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CD8 T cell activation prompts extensive transcriptome remodeling underlying effector differentiation and function. Regulation of transcriptome composition by the mitogen-inducible nuclear cap-binding complex (CBC) adaptor protein ARS2 has critical cell type-specific consequences, including thymic T cell survival. Here we show that ARS2 was upregulated by CD28 during activation of peripheral T cells, was essential for anti-tumor immunity, and facilitated T cell activation-induced alternative splicing. The novel splicing function of ARS2 was mediated at least in part by recruitment of splicing factors to nascent transcripts including the M2 isoform of pyruvate kinase (Pkm2), a key determinant of CD8 T cell effector properties. Notably, ARS2-directed Pkm2 splicing occurred days after stimulation of PI3K-indepdendent CD28 signaling and increased glycolysis beyond levels determined by PI3K signaling during T cell priming. Thus, ARS2-directed Pkm2 splicing represents a mechanism by which CD28 drives glycolytic metabolism, allowing for optimal effector cytokine production and T cell anti-tumor immunity.

Humoral immunity is essential for protection against pathogens, emphasized by the prevention of 2-3 million deaths worldwide annually by childhood immunizations. Long-term protective immunity is dependent on the continual production of neutralizing antibodies by the subset of long-lived plasma cells (LLPCs). LLPCs are not intrinsically long-lived, but require interaction with LLPC niche stromal cells for survival. However, it remains unclear which and how these interactions sustain LLPC survival and long-term humoral immunity. We now have found that the immunosuppressive enzyme indoleamine 2,3- dioxygenase 1 (IDO1) is required to sustain antibody responses and LLPC survival. Activation of IDO1 occurs upon the engagement of CD80/CD86 on the niche dendritic cells by CD28 on LLPC. Kynurenine, the product of IDO1 catabolism, activates the aryl hydrocarbon receptor in LLPC, reinforcing CD28 expression and survival signaling. These findings expand the immune function of IDO1 and uncover a novel pathway for sustaining LLPC survival and humoral immunity.

SUMMARY Durable humoral immunity against epidemic infectious disease requires the survival of long-lived plasma cells (LLPCs). LLPC longevity is dependent on metabolic programs distinct from short-lived plasma cells (SLPCs); however, the mechanistic basis for this difference is unclear. We have previously shown that CD28, the prototypic T cell costimulatory receptor, is expressed on both LLPCs and SLPCs but is essential only for LLPC survival. Here we show that CD28 transduces pro-survival signaling specifically in LLPCs through differential SLP76 expression. CD28 signaling in LLPCs increased glucose uptake, mitochondrial mass/respiration, and reactive oxygen species (ROS) production. Unexpectedly, CD28-mediated regulation of mitochondrial respiration, NF-κB activation, and survival was ROS dependent. IRF4, a target of NF-κB, was upregulated by CD28 activation in LLPCs and decreased IRF4 levels correlated with decreased glucose uptake, mitochondrial mass, ROS, and CD28-mediated survival. Altogether, these data demonstrate that CD28 signaling induces a ROS-dependent metabolic program required for LLPC survival., Graphical Abstract, In Brief Long-lived plasma cell survival requires a distinct metabolic program from their short-lived plasma cell counterparts. Utley et al. demonstrate that CD28 signaling through Grb2/Vav/SLP76 regulates LLPC survival and metabolic fitness through IRF4 upregulation and ROS-dependent signaling.

Protective antibodies against diseases such as measles and polio primarily come from bone marrow (BM) resident long lived plasma cells (LLPC) and are a key component of durable humoral immunity. As LLPC are not innately long lived a major question remains about how these cells maintain survival. Our lab has previously demonstrated that the T cell receptor, CD28, is essential for the survival and function of LLPC. Here we further demonstrate that when CD28 on LLPC ligates with CD80/CD86 on DC, it induces upregulation and activation of indoleamine 2,3-dioxygenase (IDO). IDO’s primary action is catabolizing tryptophan into kynurenine, a well-known ligand of the aryl hydrocarbon receptor (AhR). A nuclear transcription factor, AhR is known to modulate immune responses and is expressed in PC. Unexpectedly we observed that IDO KO mice have significantly less long lived antigen specific antibody titers and a decrease in LLPC specifically in the BM post immunization. Specific deletion of IDO+DC also significantly decreases LLPC in vivo. Furthermore, treatment with kynurenine in LLPC causes upregulation of CYP1A1, the downstream target of AhR. Moreover, we see an increase in CD28 expression with kynurenine treatment in murine and human PC. We propose a model where the interaction of CD28 on LLPC with CD80/CD86 on DC activates IDO, producing kynurenine, which activates AhR to further regulate CD28 expression on LLPC. These findings challenge the traditional paradigm of IDO as immunosuppressive and uncover a novel role in promoting immunity. Filling this gap in knowledge furthers our understanding of diseases that involve LLPC, but also has direct implications in future vaccine and therapeutic drug development. Support: T32 CA085183, R01CA121044

Large scale imaging surveys will increase the number of galaxy-scale strong lensing candidates by maybe three orders of magnitudes beyond the number known today. Finding these rare objects will require picking them out of at least tens of millions of images and deriving scientific results from them will require quantifying the efficiency and bias of any search method. To achieve these objectives automated methods must be developed. Because gravitational lenses are rare objects reducing false positives will be particularly important. We present a description and results of an open gravitational lens finding challenge. Participants were asked to classify 100,000 candidate objects as to whether they were gravitational lenses or not with the goal of developing better automated methods for finding lenses in large data sets. A variety of methods were used including visual inspection, arc and ring finders, support vector machines (SVM) and convolutional neural networks (CNN). We find that many of the methods will be easily fast enough to analyse the anticipated data flow. In test data, several methods are able to identify upwards of half the lenses after applying some thresholds on the lens characteristics such as lensed image brightness, size or contrast with the lens galaxy without making a single false-positive identification. This is significantly better than direct inspection by humans was able to do. (abridged), 22 pages, 16 figures, 4 tables, accepted version for A&A

Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.

Long lived plasma cells (LLPC) are a key component of protective humoral immunity. The ability of these cells to maintain longevity and a durable antibody response is largely dependent on the complex nature of the bone marrow (BM) microenvironment in which these cells reside. Our lab has demonstrated that the co-stimulatory receptor, CD28, is essential for the survival and function of LLPC. Furthermore, when CD28 on LLPC ligates with CD80/CD86 expressed on DC, it induces upregulation of the enzyme indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan (Trp) into kynurenine (kyn), a well-known ligand of the aryl hydrocarbon receptor (AhR). AhR is a nuclear transcription factor that can modulate immune responses and is highly expressed in plasma cells (PC). Our preliminary data reveals that IDO knock-out (KO) mice in comparison to wild type (Wt) mice have a decrease in bone marrow resident PCs and a decrease in overall Ig levels. Additionally, 15 weeks post vaccination IDO KO mice have significantly less antigen-specific long lived antibody titers compared to Wt. It was also observed that interaction with DC both in vitro and in vivo is needed for LLPC survival and function. Moreover, AhR activation by kyn causes an increase in CD28 mRNA in LLPC. This leads us to propose a model where CD28 interaction with CD80/CD86 induces IDO production, which through its metabolite kyn activates AhR which can then regulate CD28 expression- thus creating a mechanism that promotes LLPC survival and function. These findings challenge the traditional idea of IDO as an inhibitory molecule and provide the rationale for investigating its essential role in maintaining LLPC survival and sustained antibody responses.

Durable humoral immunity depends upon bone marrow resident long-lived plasma cell (LLPC) survival. We have shown that CD28, the canonical T-cell costimulatory molecule, is required for LLPC survival; however, the mechanistic basis for this is unclear. We have published that of two binding motifs in the CD28 cytoplasmic tail, only the Grb2/Vav moiety, and not the direct PI3k binding motif, supports CD28-mediated survival. CD28 is known to induce glycolysis in T-cells. In contrast, CD28 activation in both LLPCs and human PCs induces glucose metabolism through mitochondrial respiration. A major byproduct of mitochondrial respiration is the production of reactive oxygen species (ROS). Interestingly, the mitochondrial respiration-dependent production of ROS is required for CD28-mediated survival. Previously published data demonstrate the ability of ROS to signal through both NFkB and PI3k. CD28-induced ROS signal through PI3k in LLPCs for increased glucose uptake and the inhibition of PI3k prevents CD28-mediated survival. The ROS-PI3k signal drives the phosphorylation of both S6k and rpS6, downstream targets of mTORC1, and this regulation is independent of Blimp1 expression. Irf4, a critical PC survival factor, is upregulated by CD28-dependent NFkB activation. To our great surprise, ROS inhibition prevented the induction of mitochondrial respiration itself, demonstrating that signals emanating downstream of ROS govern the metabolic program for survival in LLPCs. Taken together, these data suggest a model wherein CD28 signals directly through Grb2/Vav to induce mitochondrial respiration and ROS production. ROS then reinforce signaling through PI3k and NFkB to increase Irf4 expression and metabolic fitness for LLPC survival.

Techniques of evolutionary computing have proven useful for a diverse array of fields in science and engineering. Because of the expected low signal to noise ratio of LIGO data and incomplete knowledge of gravitational waveforms, evolutionary computing is an excellent candidate for LIGO data analysis studies. Using the evolutionary computing methods of genetic algorithms and genetic programming, we have developed, as a proof of principle, search algorithms that are effective at finding sine-gaussian signals hidden in noise while maintaining a small false alarm rate. Because we used realistic LIGO noise as a training ground, the algorithms we have evolved should be well suited to detecting signals in actual LIGO data, as well as in simulated noise. These algorithms have continuously improved during the five days of their evolution and are expected to improve further the more they are evolved. The top performing algorithms from generation 100 and 199 were benchmarked using gaussian white noise to illustrate their performance and the improvement over 100 generations.

A calculation of the ratio of leptonic decay constants ${f}_{{K}^{+}}/{f}_{{\ensuremath{\pi}}^{+}}$ makes possible a precise determination of the ratio of Cabibbo-Kobayashi-Maskawa (CKM) matrix elements $|{V}_{\mathrm{us}}|/|{V}_{\mathrm{ud}}|$ in the standard model, and places a stringent constraint on the scale of new physics that would lead to deviations from unitarity in the first row of the CKM matrix. We compute ${f}_{{K}^{+}}/{f}_{{\ensuremath{\pi}}^{+}}$ numerically in unquenched lattice QCD using gauge-field ensembles recently generated that include four flavors of dynamical quarks: up, down, strange, and charm. We analyze data at four lattice spacings $a\ensuremath{\approx}0.06$, 0.09, 0.12, and 0.15 fm with simulated pion masses down to the physical value 135 MeV. We obtain ${f}_{{K}^{+}}/{f}_{{\ensuremath{\pi}}^{+}}=1.1947(26)(37)$, where the errors are statistical and total systematic, respectively. This is our first physics result from our ${N}_{f}=2+1+1$ ensembles, and the first calculation of ${f}_{{K}^{+}}/{f}_{{\ensuremath{\pi}}^{+}}$ from lattice-QCD simulations at the physical point. Our result is the most precise lattice-QCD determination of ${f}_{{K}^{+}}/{f}_{{\ensuremath{\pi}}^{+}}$, with an error comparable to the current world average. When combined with experimental measurements of the leptonic branching fractions, it leads to a precise determination of $|{V}_{\mathrm{us}}|/|{V}_{\mathrm{ud}}|=0.2309(9)(4)$ where the errors are theoretical and experimental, respectively.

A calculation of the ratio of leptonic decay constants f(K+)/f(π+) makes possible a precise determination of the ratio of Cabibbo-Kobayashi-Maskawa (CKM) matrix elements |V(us)|/|V(ud)| in the standard model, and places a stringent constraint on the scale of new physics that would lead to deviations from unitarity in the first row of the CKM matrix. We compute f(K+)/f(π+) numerically in unquenched lattice QCD using gauge-field ensembles recently generated that include four flavors of dynamical quarks: up, down, strange, and charm. We analyze data at four lattice spacings a ≈ 0.06, 0.09, 0.12, and 0.15 fm with simulated pion masses down to the physical value 135 MeV. We obtain f(K+)/f(π+) = 1.1947(26)(37), where the errors are statistical and total systematic, respectively. This is our first physics result from our N(f) = 2+1+1 ensembles, and the first calculation of f(K+)/f(π+) from lattice-QCD simulations at the physical point. Our result is the most precise lattice-QCD determination of f(K+)/f(π+), with an error comparable to the current world average. When combined with experimental measurements of the leptonic branching fractions, it leads to a precise determination of |V(us)|/|V(ud)| = 0.2309(9)(4) where the errors are theoretical and experimental, respectively.

We present our methods to fit the two point correlators for light, strange, and charmed pseudoscalar meson physics with the highly improved staggered quark (HISQ) action. We make use of the least-squares fit including the full covariance matrix of the correlators and including Gaussian constraints on some parameters. We fit the correlators on a variety of the HISQ ensembles. The lattice spacing ranges from 0.15 fm down to 0.06 fm. The light sea quark mass ranges from 0.2 times the strange quark mass down to the physical light quark mass. The HISQ ensembles also include lattices with different volumes and with unphysical values of the strange quark mass. We use the results from this work to obtain our preliminary results of fD, fDs , fDs = fD, and ratios

We present preliminary results for light, strange and charmed pseudoscalar meson physics from simulations using four flavors of dynamical quarks with the highly improved staggered quark (HISQ) action. These simulations include lattice spacings ranging from 0.15 to 0.06 fm, and sea-quark masses both above and at their physical value. The major results are charm meson decay constants f_D, f_{D_s} and f_{D_s}/f_D and ratios of quark masses. This talk will focus on our procedures for finding the decay constants on each ensemble, the continuum extrapolation, and estimates of systematic error., Proceedings of Lattice 2012 Int. Symposium

We describe the computation of the amplitude ${A}_{2}$ for a kaon to decay into two pions with isospin $I=2$. The results presented in [T. Blum et al., Phys. Rev. Lett. 108, 141601 (2012)] from an analysis of 63 gluon configurations are updated to 146 configurations giving $\mathrm{Re}{A}_{2}=1.381(46{)}_{\mathrm{stat}}(258{)}_{\mathrm{syst}}{10}^{\ensuremath{-}8}\text{ }\text{ }\mathrm{GeV}$ and $\mathrm{Im}{A}_{2}=\ensuremath{-}6.54(46{)}_{\mathrm{stat}}(120{)}_{\mathrm{syst}}{10}^{\ensuremath{-}13}\text{ }\text{ }\mathrm{GeV}$. $\mathrm{Re}{A}_{2}$ is in good agreement with the experimental result, whereas the value of $\mathrm{Im}{A}_{2}$ was hitherto unknown. We are also working toward a direct computation of the $K\ensuremath{\rightarrow}(\ensuremath{\pi}\ensuremath{\pi}{)}_{I=0}$ amplitude ${A}_{0}$ but, within the Standard Model, our result for $\mathrm{Im}{A}_{2}$ can be combined with the experimental results for $\mathrm{Re}{A}_{0}$, $\mathrm{Re}{A}_{2}$ and ${\ensuremath{\epsilon}}^{\ensuremath{'}}/\ensuremath{\epsilon}$ to give $\mathrm{Im}{A}_{0}/\mathrm{Re}{A}_{0}=\ensuremath{-}1.61(28)\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}4}$. Our result for $\mathrm{Im}{A}_{2}$ implies that the electroweak penguin (EWP) contribution to ${\ensuremath{\epsilon}}^{\ensuremath{'}}/\ensuremath{\epsilon}$ is $\mathrm{Re}({\ensuremath{\epsilon}}^{\ensuremath{'}}/\ensuremath{\epsilon}{)}_{\mathrm{EWP}}=\ensuremath{-}(6.25\ifmmode\pm\else\textpm\fi{}{0.44}_{\mathrm{stat}}\ifmmode\pm\else\textpm\fi{}{1.19}_{\mathrm{syst}})\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}4}$.

We fit lattice-QCD data for light-pseudoscalar masses and decay constants, from HISQ configurations generated by MILC, to SU(3) staggered chiral perturbation theory. At present such fits have rather high values of χ2/d.o.f., possibly due to the lack of ensembles with lighter-than-physical sea strange-quark masses. We propose solutions to this problem for future work. We also perform simple linear interpolations near the physical point on two ensembles with different lattice spacings, and obtain the preliminary result ( fK/ fπ) = 1.1872(41) in the continuum limit. XXIX International Symposium on Lattice Field Theory July 10 16 2011 Squaw Valley, Lake Tahoe, California

We report on the first realistic ab initio calculation of a hadronic weak decay, that of the amplitude ${A}_{2}$ for a kaon to decay into two $\ensuremath{\pi}$ mesons with isospin 2. We find $\mathrm{Re}{A}_{2}=(1.436\ifmmode\pm\else\textpm\fi{}{0.063}_{\mathrm{stat}}\ifmmode\pm\else\textpm\fi{}{0.258}_{\mathrm{syst}}){10}^{\ensuremath{-}8}\text{ }\text{ }\mathrm{GeV}$ in good agreement with the experimental result and for the hitherto unknown imaginary part we find $\mathrm{Im}{A}_{2}=\ensuremath{-}(6.83\ifmmode\pm\else\textpm\fi{}{0.51}_{\mathrm{stat}}\ifmmode\pm\else\textpm\fi{}{1.30}_{\mathrm{syst}}){10}^{\ensuremath{-}13}\text{ }\text{ }\mathrm{GeV}$. Moreover combining our result for $\mathrm{Im}{A}_{2}$ with experimental values of $\mathrm{Re}{A}_{2}$, $\mathrm{Re}{A}_{0}$, and ${ϵ}^{\ensuremath{'}}/ϵ$, we obtain the following value for the unknown ratio $\mathrm{Im}{A}_{0}/\mathrm{Re}{A}_{0}$ within the standard model: $\mathrm{Im}{A}_{0}/\mathrm{Re}{A}_{0}=\ensuremath{-}1.63(19{)}_{\mathrm{stat}}(20{)}_{\mathrm{syst}}\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}4}$. One consequence of these results is that the contribution from $\mathrm{Im}{A}_{2}$ to the direct CP violation parameter ${ϵ}^{\ensuremath{'}}$ (the so-called Electroweak Penguin contribution) is $\mathrm{Re}({ϵ}^{\ensuremath{'}}/ϵ{)}_{\mathrm{EWP}}=\ensuremath{-}(6.52\ifmmode\pm\else\textpm\fi{}{0.49}_{\mathrm{stat}}\ifmmode\pm\else\textpm\fi{}{1.24}_{\mathrm{syst}})\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}4}$. We explain why this calculation of ${A}_{2}$ represents a major milestone for lattice QCD and discuss the exciting prospects for a full quantitative understanding of $CP$ violation in kaon decays.

We report on the first realistic ab initio calculation of a hadronic weak decay, that of the amplitude A(2) for a kaon to decay into two π mesons with isospin 2. We find ReA(2)=(1.436±0.063(stat)±0.258(syst))10(-8) GeV in good agreement with the experimental result and for the hitherto unknown imaginary part we find ImA(2)=-(6.83±0.51(stat)±1.30(syst))10(-13) GeV. Moreover combining our result for ImA(2) with experimental values of ReA(2), ReA(0), and ε'/ε, we obtain the following value for the unknown ratio ImA(0)/ReA(0) within the standard model: ImA(0)/ReA(0)=-1.63(19)(stat)(20(syst)×10(-4). One consequence of these results is that the contribution from ImA(2) to the direct CP violation parameter ε' (the so-called Electroweak Penguin contribution) is Re(ε'/ε)(EWP)=-(6.52±0.49(stat)±1.24(syst))×10(-4). We explain why this calculation of A(2) represents a major milestone for lattice QCD and discuss the exciting prospects for a full quantitative understanding of CP violation in kaon decays.

We determine the neutral kaon mixing matrix element BK in the continuum limit with 2+1 flavors of domain wall fermions, using the Iwasaki gauge action at two different lattice spacings. These lattice fermions have near exact chiral symmetry and therefore avoid artificial lattice operator mixing. We introduce a significant improvement to the conventional nonperturbative renormalization (NPR) method in which the bare matrix elements are renormalized nonperturbatively in the regularization invariant momentum scheme (RI-MOM) and are then converted into the MS? scheme using continuum perturbation theory. In addition to RI-MOM, we introduce and implement four nonexceptional intermediate momentum schemes that suppress infrared nonperturbative uncertainties in the renormalization procedure. We compute the conversion factors relating the matrix elements in this family of regularization invariant symmetric momentum schemes (RI-SMOM) and MS? at one-loop order. Comparison of the results obtained using these different intermediate schemes allows for a more reliable estimate of the unknown higher-order contributions and hence for a correspondingly more robust estimate of the systematic error. We also apply a recently proposed approach in which twisted boundary conditions are used to control the Symanzik expansion for off-shell vertex functions leading to a better control of the renormalization in the continuum limit. We control chiral extrapolation errors by considering both the next-to-leading order SU(2) chiral effective theory, and an analytic mass expansion. We obtain BKMS? (3??GeV)=0.529(5)stat(15)?(2)FV(11)NPR. This corresponds to B?KRGI? =0.749(7)stat(21)?(3)FV(15)NPR. Adding all sources of error in quadrature, we obtain B?KRGI? =0.749(27)combined, with an overall combined error of 3.6%.

We present physical results obtained from simulations using 2+1 flavors of domain wall quarks and the Iwasaki gauge action at two values of the lattice spacing $a$, ($a^{-1}$=\,1.73\,(3)\,GeV and $a^{-1}$=\,2.28\,(3)\,GeV). On the coarser lattice, with $24^3\times 64\times 16$ points, the analysis of ref.[1] is extended to approximately twice the number of configurations. The ensembles on the finer $32^3\times 64\times 16$ lattice are new. We explain how we use lattice data obtained at several values of the lattice spacing and for a range of quark masses in combined continuum-chiral fits in order to obtain results in the continuum limit and at physical quark masses. We implement this procedure at two lattice spacings, with unitary pion masses in the approximate range 290--420\,MeV (225--420\,MeV for partially quenched pions). We use the masses of the $\pi$ and $K$ mesons and the $\Omega$ baryon to determine the physical quark masses and the values of the lattice spacing. While our data are consistent with the predictions of NLO SU(2) chiral perturbation theory, they are also consistent with a simple analytic ansatz leading to an inherent uncertainty in how best to perform the chiral extrapolation that we are reluctant to reduce with model-dependent assumptions about higher order corrections. Our main results include $f_\pi=124(2)_{\rm stat}(5)_{\rm syst}$\,MeV, $f_K/f_\pi=1.204(7)(25)$ where $f_K$ is the kaon decay constant, $m_s^{\bar{\textrm{MS}}}(2\,\textrm{GeV})=(96.2\pm 2.7)$\,MeV and $m_{ud}^{\bar{\textrm{MS}}}(2\,\textrm{GeV})=(3.59\pm 0.21)$\,MeV\, ($m_s/m_{ud}=26.8\pm 1.4$) where $m_s$ and $m_{ud}$ are the mass of the strange-quark and the average of the up and down quark masses respectively, $[\Sigma^{\msbar}(2 {\rm GeV})]^{1/3} = 256(6)\; {\rm MeV}$, where $\Sigma$ is the chiral condensate, the Sommer scale $r_0=0.487(9)$\,fm and $r_1=0.333(9)$\,fm., Comment: 129 pages, 59 figures, Published version containing an extended discussion of reweighting and including a new appendix (Appendix C)

Posterior keratoconus is an unusual abnormality of the cornea generally classified as one of the anterior chamber cleavage anomalies. It is characterized clinically by the presence of a circumscribed or generalized corneal thinning with posterior depression of the cornea and is considered distinct from keratoconus. Although patients with posterior keratoconus may have visual complaints clearly related to their abnormal corneas, the surface topography of these corneas has not been studied in detail. Keratometry and photokeratoscopy provide an incomplete picture of the surface geometry of posterior keratoconus. We utilized computer assisted topographic analysis to study the cornea of a patient with posterior keratoconus. The Topographic Modeling System demonstrated that the patient's cornea showed a central steepened "cone" coincident with the area of circumscribed posterior keratoconus as well as paracentral flattening. This report documents the topographic abnormality in this rare disorder.

A national survey of American Optometric Association Low Vision Section members was conducted by the newly formed Geriatrics and Low Vision Committee during the fall of 1989. The "Geriatric Optometry Questionnaire" was designed to establish a greater understanding of the nature of comprehensive professional services for the unique needs of visually impaired older persons. Of the 481 surveys mailed, 289 were returned for a response rate of 60 percent. Seventy-eight percent of the respondents had completed their formal optometric education after 1970. Results indicated that geriatric optometric care is predominantly delivered in private practices and in low vision agencies. Approximately 69 percent of the patients are above the age of 65, with the majority of those being under 85. Although the average initial low vision appointment lasts 60-90 minutes, this generally represents the low vision examination and evaluation of low vision devices only. Complete ocular health assessments combined with low vision evaluations are provided by only 33.5 percent. While 80 percent of the optometrists responding take psychosocial histories, only 60 percent routinely refer patients for social services and rehabilitative training. Similarly, 57 percent of those responding referred patients for independent daily living skills instruction and only 53 percent for orientation and mobility training. These data suggest that optometrists have not yet completely incorporated the multidisciplinary approach to geriatric health care and that continuing education in this area is needed.

Second generation oral hypoglycemic agents, such as glyburide and glipizide, are often the treatment of choice in non-insulin dependent diabetes mellitus. These sulfonylureas are more potent osmotic agents than their predecessors and may give rise to crystalline lens changes and refractive error shifts in the absence of blood glucose variation. Such a case is presented, as is a detailed description of the mechanism of action of commonly prescribed oral hypoglycemic agents.

To the Editor. —The disposable soft contact lens (Acuvue, Vistakon Inc, Jacksonville, Fla), recently licensed for public use by the Food and Drug Administration, has a number of theoretical advantages over the conventional extended-wear soft contact lens. Among these are reduced risks of corneal complications associated with extended-wear soft contact lenses from lens spoilage or poor patient compliance, patient convenience, increased patient comfort, and improved visual acuity.1This lens, made from etafilcon A polymer, is 58% water, and its measurements are 8.8 mm base curve, 14.0 mm diameter, -0.50 to -6.00 diopters power. The manufacturer suggests wearing the lenses for 1 to 2 weeks, after which they are discarded. Between wearing cycles, one night without lenses is recommended. We report two cases of patients with sterile corneal infiltrates associated with disposable extended-wear soft contact lenses. Report of Cases. —Case 1. —A 28-year-old female ophthalmology resident with a 10-year