Gender and uveitis in patients with multiple sclerosis.

Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is more commonly seen in women. It has been associated with both anterior and intermediate uveitis as well as retinal vasculitis. Ocular inflammation may develop concurrent with, prior to, or after the development of neurologic signs and symptoms. Patients with MS have an approximately 1% chance of developing intraocular inflammation. Patients with intermediate uveitis have an 8-12% risk of being diagnosed with MS. This risk is higher in females and in those with bilateral disease. This should be kept in mind when evaluating patients with uveitis, particularly in those patients for whom TNF inhibitor therapy is being considered, as these agents may worsen demyelinating disease

Gender-based differences in letters of recommendation written for ophthalmology residency applicants.

BACKGROUND:To determine whether gender-based differences may be present in letters of recommendation written for ophthalmology residency applicants. METHODS:All applications submitted through SF Match to the UCLA Stein Eye Institute Residency Training Program from the 2017-2018 application cycle were analyzed using validated text analysis software (Linguistic Inquiry and Word Count (Austin, TX)). The main outcome measures were differences in language use in letters of recommendation by gender of applicant. RESULTS:Of 440 applicants, 254 (58%) were male and 186 (42%) were female. The two gender groups had similar United States Medical Licensing Exam (USMLE) Step 1 scores, undergraduate grade point averages (uGPA's), proportions of underrepresented minority (URM) applicants and Gold Humanism Honor Society members, numbers of academic and service activities listed, and gender distributions of their letter writers (all P values > 0.05). However, letters written for male applicants were determined to use more "authentic" words than those written for female applicants (mean difference, 0.800; 95% CI, 0.001-1.590; P = 0.047). Letters written for male applicants also contained more "leisure" words (mean difference, 0.056; 95% CI, 0.008-0.104; P = 0.023) and fewer "feel" words (mean difference, 0.033; 95% CI, 0.001-0.065; P = 0.041) and "biological processes" words (mean difference, 0.157; 95% CI, 0.017-0.297; P = 0.028). CONCLUSIONS:There were gender differences detected in recommendation letters in ophthalmology consistent with prior studies from other fields. Awareness of these differences may improve residency selection processes

Positron emission tomography imaging of endometrial cancer using engineered anti-EMP2 antibody fragments.

PurposeAs imaging of the cell surface tetraspan protein epithelial membrane protein-2 (EMP2) expression in malignant tumors may provide important prognostic and predictive diagnostic information, the goal of this study is to determine if antibody fragments to EMP2 may be useful for imaging EMP2 positive tumors.ProceduresThe normal tissue distribution of EMP2 protein expression was evaluated by immunohistochemistry and found to be discretely expressed in both mouse and human tissues. To detect EMP2 in tumors, a recombinant human anti-EMP2 minibody (scFv-hinge-C(H)3 dimer; 80 kDa) was designed to recognize a common epitope in mice and humans and characterized. In human tumor cell lines, the antibody binding induced EMP2 internalization and degradation, prompting the need for a residualizing imaging strategy. Following conjugation to DOTA (1,4,7,10-tetraazacyclododecane-N,N',N',N'″-tetraacetic acid), the minibody was radiolabeled with (64)Cu (t (1/2) = 12.7 h) and evaluated in mice as a positron emission tomography (PET) imaging agent for human EMP2-expressing endometrial tumor xenografts.ResultsThe residualizing agent, (64)Cu-DOTA anti-EMP2 minibody, achieved high uptake in endometrial cancer xenografts overexpressing EMP2 (10.2 ± 2.6, percent injected dose per gram (%ID/g) ± SD) with moderate uptake in wild-type HEC1A tumors (6.0 ± 0.1). In both cases, precise tumor delineation was observed from the PET images. In contrast, low uptake was observed with anti-EMP2 minibodies in EMP2-negative tumors (1.9 ± 0.5).ConclusionsThis new immune-PET agent may be useful for preclinical assessment of anti-EMP2 targeting in vivo. It may also have value for imaging of tumor localization and therapeutic response in patients with EMP2-positive malignancies

Normalization of boutique two-color microarrays with a high proportion of differentially expressed probes

Normalization is critical for removing systematic variation from microarray data. For two-color microarray platforms, intensity-dependent lowess normalization is commonly used to correct relative gene expression values for biases. Here we outline a normalization method for use when the assumptions of lowess normalization fail. Specifically, this can occur when specialized boutique arrays are constructed that contain a subset of genes selected to test particular biological functions

Gender and Uveitis in Patients with Multiple Sclerosis

Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is more commonly seen in women. It has been associated with both anterior and intermediate uveitis as well as retinal vasculitis. Ocular inflammation may develop concurrent with, prior to, or after the development of neurologic signs and symptoms. Patients with MS have an approximately 1% chance of developing intraocular inflammation. Patients with intermediate uveitis have an 8–12% risk of being diagnosed with MS. This risk is higher in females and in those with bilateral disease. This should be kept in mind when evaluating patients with uveitis, particularly in those patients for whom TNF inhibitor therapy is being considered, as these agents may worsen demyelinating disease

Neuro-ophthalmic complications of immune checkpoint inhibitor therapy: Current status and future directions

Since 2011, use of immune checkpoint inhibitors (ICI) in cancer immunotherapy dramatically expanded, both alone and in combination with either a different cancer treatment or with two different ICIs. With this increase in use have come a myriad of adverse effects from enhanced immune activation, including ophthalmic and neurologic immune related adverse events (irAE). Neuro-ophthalmic immune related adverse events (NOirAE) associated with use of ICIs are increasingly recognized and their severity may actually limit use of potentially life-saving immunotherapy. NOirAEs comprise a wide variety of presentations involving both the central and peripheral nervous system. They cause afferent or efferent visual dysfunction, including among them optic neuropathy and edema, orbital inflammatory disease, and ocular myasthenia. While treatment for irAEs typically involves immunosuppression with corticosteroids, there is no expert consensus regarding best practices for treatment of NOirAEs and whether to stop ICI immunotherapy for the cancer or not. This state-of-the-art review explores the pathophysiologic basis for NOirAEs, provides a framework for categorizing them within neuro-ophthalmology, and discusses what is needed to close the current knowledge gaps in diagnosis and management of an increasing population of cancer patients requiring neuro-ophthalmic care

Steroid hormone regulation of EMP2 expression and localization in the endometrium

<p>Abstract</p> <p>Background</p> <p>The tetraspan protein epithelial membrane protein-2 (EMP2), which mediates surface display of diverse proteins, is required for endometrial competence in blastocyst implantation, and is uniquely correlated with poor survival from endometrial adenocarcinoma tumors. Because EMP2 is differentially expressed in the various stages of the murine and human estrous cycle, we tested the hypothesis that the steroid hormones progesterone and estrogen influence EMP2 expression and localization.</p> <p>Methods</p> <p>Frozen human proliferative and secretory endometrium were collected and analyzed for EMP2 expression using SDS-PAGE/Western blot analysis. The response of EMP2 to progesterone and estradiol was determined using a combination of real-time PCR, SDS-PAGE/Western blot analysis, and confocal immunofluorescence in the human endometrial carcinoma cell line RL95-2. To confirm the in vitro results, ovariectomized mice were treated with progesterone or estradiol, and EMP2 expression was analyzed using immunohistochemistry.</p> <p>Results</p> <p>Within normal human endometrium, EMP2 expression is upregulated in the secretory phase relative to the proliferative phase. To understand the role of steroid hormones on EMP2 expression, we utilized RL95-2 cells, which express both estrogen and progesterone receptors. In RL95-2 cells, both estradiol and progesterone induced EMP2 mRNA expression, but only progesterone induced EMP2 protein expression. To compare steroid hormone regulation of EMP2 between humans and mice, we analyzed EMP2 expression in ovarectomized mice. Similar to results observed in humans, progesterone upregulated endometrial EMP2 expression and induced EMP2 translocation to the plasma membrane. Estradiol did not promote translocation to the cell surface, but moderately induced EMP2 expression in cytoplasmic compartments in vivo.</p> <p>Conclusion</p> <p>These findings suggest that targeting of EMP2 to specific locations under the influence of these steroid hormones may be important for integrating the molecular responses required for implantation competence.</p

SANS polarization analysis with nuclear-spin-polarized He-3

A neutron spin filter based on transmission through nuclear-spin-polarized He-3 gas has been applied to polarization analysis of small angle neutron scattering (SANS). Such spin filters, which are based on the large spin dependence of the absorption of neutrons by He-3, make SANS polarization analysis possible because of their large angular acceptance. In the present experiment, a He-3-based analyzer was employed to separate nuclear scattering into its coherent and spin-incoherent components. Polarized He-3 analyzers were prepared by two different optical pumping methods and installed on the NG3 SANS instrument at the NIST Center for Neutron Research (NCNR). Measurements were taken on cellophane tape and silica gel, for which the scattering is almost completely incoherent and coherent, respectively, and on a combined sample. For the combined sample, separation of the coherent part from the incoherent part was successfully demonstrated using polarization analysis

Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium

<p>Abstract</p> <p>Background</p> <p>PMP22, a member of the GAS3 family of tetraspan proteins, is associated with a variety of neurological diseases. Previous studies have shown that PMP22 is expressed in proliferative endometrium, but its function within this tissue is poorly understood. In this study, we first characterized the expression of PMP22 in the human menstrual cycle and began to characterize its function in the endometrium.</p> <p>Methods</p> <p>Using a combination of immunohistochemistry and quantitative PCR, we characterized the expression of PMP22 in both proliferative and secretory endometrium. Differences in PMP22 expression between proliferative and secretory endometrium were determined using a Mann-Whitney U test. In order to investigate the influence of PMP22 on α6 integrin expression, cells were created that ectopically overexpressed PMP22 or expressed a siRNA to inhibit its expression. These cells were analyzed for changes in integrins and binding to extracellular matrices.</p> <p>Results</p> <p>In this study, we show that PMP22 expression is higher in proliferative phase than secretory phase. Functionally, we have begun to characterize the functional significance of this expression. Previous studies have suggested a link between PMP22 and α6 integrin, and therefore we asked whether PMP22 could associate or potentially modulate the expression of α6 integrin. Expression of both PMP22 and α6 integrin were detectable in endometrial epithelial and stromal cells, and we show that both proteins can associate and colocalize with each other. To understand if PMP22 directly altered the expression of a6 integrin, we examined cell lines with modulated levels of the protein. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression.</p> <p>Conclusion</p> <p>These findings suggest a physiologic role for PMP22 on the expression of α6 integrin. We predict that this may be important for the maintainence of endometrial integrity and to the disease biology associated with altered levels of α6 integrin expression in the endometrium.</p

It is Time for Zero Tolerance for Sexual Harassment in Academic Medicine

While there are more women in leadership positions in academic medicine now than ever before in our history, evidence from recent surveys of women and from graduating medical students demonstrates that sexual harassment continues in our institutions. Our ability to change the culture is hampered by fear of reporting episodes of harassment, which is largely due to fear of retaliation. We describe some efforts in scientific societies that are addressing this and working to establish safe environments at national meetings. We must also work at the level of each institution to make it safe for individuals to come forward, to provide training for victims and for bystanders, and to abolish locker room talk that is demeaning to women