Sex differences in acute ischemic stroke presentation are a matter of infarct location.

INTRODUCTION: Recognition of stroke by Emergency Medical Services (EMS) is critical to initiate rapid emergency department treatment. Most prehospital stroke screening tools rely heavily on presentation with the classic symptoms of facial droop, speech changes, unilateral weakness. However, women may be less likely to present with classic symptoms and may also have different distributions of stroke by anatomical location. This study seeks to determine the association between biological sex, presentation with classic symptoms, and the location of the infarcted tissue. METHODS: This is a retrospective cohort study. Data from electronic health records were extracted for patients with acute ischemic stroke who presented via EMS to a single Comprehensive Stroke Center between January 1, 2018 and December 31, 2020. We used descriptive statistics characterize the cohort. Multivariable logistic regression identified factors associated with classic symptom presentation (facial droop, speech changes, and/or unilateral weakness). Biological sex, location of the infarct, stroke etiology, age and the interaction between sex and infarct location were assessed as covariates. RESULTS: There were 364 (58.6%) males and 257 (41.1%) females with an acute ischemic stroke included in this study. EMS documented one or more classic symptoms in 125 (72.3%) males and 161 (67.9%) females. There were no baseline differences in infarct location or presentation with classic symptoms as documented by EMS comparing males and females. Multivariate logistic regression found no association between biological sex and presentation with classic symptoms (Odds Ratio 1.08; 95% CI 0.58 to 1.55) after controlling for age, stroke location, etiology of stroke or the interaction between sex and infarct location. Presence of an anterior circulation infarct compared to posterior circulation infarct was positively associated with a classic presentation to EMS (Odds Ratio 3.41; 95% CI 2.15 to 5.41). CONCLUSIONS: This study found no difference in the frequency of patient presentation with classic stroke symptoms based on biological sex alone, nor a significant different in distribution of infarcts between males and females. Infarct location (i.e., involving the anterior circulation) was associated with a classic presentation. This suggests that the likelihood of presenting with classic stroke symptoms is not influenced by sex, but rather the location of the infarct.

Serum biochemical changes in cats with naturally acquired feline cytauxzoonosis.

OBJECTIVE: The geographical distribution of feline cytauxzoonosis is expanding in the US. Clinical signs of feline cytauxzoonosis, including lethargy, anorexia, and icterus, are similar to hepatic lipidosis and cholangiohepatitis. Hematologic and serum biochemical abnormality patterns may assist practitioners in prioritizing feline cytauxzoonosis as a differential diagnosis over hepatic lipidosis and cholangiohepatitis. SAMPLE: Hematology and serum biochemical profiles of cats with naturally acquired feline cytauxzoonosis, hepatic lipidosis, or cholangiohepatitis. PROCEDURES: Retrospective search and analysis of the Kansas State Veterinary Diagnostic Laboratory or Kansas State University Veterinary Health Center records between January 2007 and June 2018 for cats with cytauxzoonosis, hepatic lipidosis, or cholangiohepatitis. RESULTS: Patients with acute feline cytauxzoonosis presented with frequent nonregenerative anemia (20/28 [71%]), leukopenia (23/28 [82%]), thrombocytopenia (23/23 [100%]), hyperbilirubinemia (27/28 [97%]), hypoalbuminemia (26/28 [93%]), reduced (18/28 [64%]) or low normal (10/28 [36%]) serum ALP activity, and hyponatremia (23/28 [82%]). Reduced ALP activity was unique to cats with feline cytauxzoonosis relative to hepatic lipidosis and cholangiohepatitis. No correlation between the severity of anemia and the magnitude of hyperbilirubinemia was identified in feline cytauxzoonosis patients. CLINICAL RELEVANCE: The combination of nonregenerative anemia, leukopenia, thrombocytopenia, hyperbilirubinemia, and reduced serum ALP activity in icteric cats may increase the clinical suspicion, but is not pathognomonic, for acute feline cytauxzoonosis. Hematologic and serum biochemical abnormalities of naturally acquired feline cytauxzoonosis are like those reported with feline bacterial sepsis. Blood smear evaluation for intraerythrocytic Cytauxzoon felis piroplasms, tissue aspirates for schizont-laden macrophages, and/or molecular testing are required to diagnose feline cytauxzoonosis.

Acute Vitiligo Repigmentation in the Setting of Suspected Pulmonary Sarcoidosis.

Background: Sarcoidosis is a noncaseating granulomatous disease that predominately occurs in the lungs. Vitiligo is the most common depigmentation disorder worldwide. Both diseases are autoimmune-mediated, suggesting that one could have implications for the other. However, relatively few reports have been published about patients presenting with coinciding symptoms of the 2 diseases. We report the case of a patient who presented with focal repigmentation of vitiligo with suspected pulmonary sarcoidosis. Case Report: A 63-year-old female with a medical history of diffuse vitiligo reported to the emergency department with the chief complaint of right lower extremity weakness and numbness for 1 week. She reported that she had had a chronic productive cough for the prior 4 to 6 months and had unintentionally lost 50 to 60 pounds in the prior 3 months. At that time, she began to notice numerous hyperpigmented macules and patches on both forearms and her face. Chest x-ray and chest computed tomography demonstrated bilateral hilar and mediastinal lymph node enlargement with multiple bilateral pulmonary nodules. Cytology and flow cytometry were negative for evidence of B- or T-cell lymphoproliferative disorder with evidence of granulomatous inflammation. Conclusion: This clinical presentation suggests a potential interplay between 2 unique disease processes. While both vitiligo and sarcoidosis share common autoimmune etiologies, little data are available about management when they coincide. This case highlights a patient with 2 seemingly distinct clinical manifestations that could yield further clinical information in the management of both diseases separately and together.

Multiple non-catalytic ADAMs are novel integrin α4 ligands.

The ADAM (a disintegrin and metalloprotease) protein family uniquely exhibits both catalytic and adhesive properties. In the well-defined process of ectodomain shedding, ADAMs transform latent, cell-bound substrates into soluble, biologically active derivatives to regulate a spectrum of normal and pathological processes. In contrast, the integrin ligand properties of ADAMs are not fully understood. Emerging models posit that ADAM-integrin interactions regulate shedding activity by localizing or sequestering the ADAM sheddase. Interestingly, 8 of the 21 human ADAMs are predicted to be catalytically inactive. Unlike their catalytically active counterparts, integrin recognition of these "dead" enzymes has not been largely reported. The present study delineates the integrin ligand properties of a group of non-catalytic ADAMs. Here we report that human ADAM11, ADAM23, and ADAM29 selectively support integrin α4-dependent cell adhesion. This is the first demonstration that the disintegrin-like domains of multiple catalytically inactive ADAMs are ligands for a select subset of integrin receptors that also recognize catalytically active ADAMs.

Ultrasound biomicroscopy in chronic pseudophakic ocular inflammation associated with misplaced intraocular lens haptics.

PURPOSE: To evaluate the usefulness of ultrasound biomicroscopy in confirming intraocular lens haptic-induced ocular irritation and in the management of these patients. DESIGN: A retrospective review of patient data. METHODS: Twenty pseudophakic patients who underwent ultrasound biomicroscopy examination between May 2009 and February 2011 to confirm the clinical suspicion of misplacement of intraocular lens haptics were reviewed. Ophthalmic findings at the time of presentation and at each follow-up visit, and management of each patient, were recorded. RESULTS: Intraocular lens haptic misplacement was confirmed by ultrasound biomicroscopy in all suspected cases. In 75% of the eyes 1 haptic was embedded in the iris; it extended into the ciliary body process in 35% and into the pars plana in 10%. Focal iris thinning/atrophy was detected by ultrasound biomicroscopy in 15% of cases and focal angle closure in 25%. Intraocular lens exchange was performed in 40% of patients. The remaining 60% were kept under observation, with the addition of topical steroids and/or cycloplegics in eyes that demonstrated anterior chamber inflammation and intraocular pressure-lowering medications in eyes with persistent elevated intraocular pressure or glaucoma. CONCLUSIONS: Ultrasound biomicroscopy appears to be a valuable tool in confirming the presence of haptic-induced ocular irritation and in assisting the management of these patients.

Astrocytic hamartoma of the optic disc and multiple café-au-lait macules in a child with neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is a heritable syndrome characterized by multifocal proliferation of neural crest-derived cells. The characteristic and diagnostic finding of NF2 is bilateral vestibular nerve schwannomas (acoustic neuromas). In addition to other tumors involving the central and peripheral nervous systems, ophthalmic manifestations, including posterior subcapsular and peripheral cortical cataracts, optic nerve meningiomas, epiretinal membrane, and combined pigment epithelial and retinal hamartomas, are common to NF2. Herein we present an 8-year-old girl with NF2 and astrocytic hamartoma of the optic disc. This patient had been previously diagnosed with NF1 on the basis of multiple CAL macules and suspected subcutaneous neurofibromas. However, neuroimaging revealed bilateral acoustic neuromas, leading to a clinical diagnosis of NF2. Subsequent molecular genetic analysis confirmed the NF2 diagnosis. Multiple CAL macules and astrocytic hamartomas, while associated with NF1, are rarely associated with NF2. Specifically, we are not aware of any reported cases of optic disc astrocytic hamartoma in the setting of NF2.

Scleral thickness following fluocinolone acetonide implant (Retisert).

PURPOSE: To evaluate whether intravitreal fluocinolone acetonide (FA) implantation (Retisert) leads to scleral thinning. METHODS: Scleral thickness was measured at the pars plana region (4 quadrants) with anterior segment OCT (Visante) in FA implanted eyes (18) with noninfectious posterior uveitis in comparison to eyes with prior vitrectomy (8), and normal eyes without prior surgery (30). RESULTS: Mean scleral thickness in normal (nonsurgical) eyes was 0.99/0.93/0.88/0.86, and 0.92 mm in the inferonasal/inferotemporal/superotemporal/superonasal quadrants, and overall, respectively. Sclera was thinner in each quadrant of the FA implanted eyes compared to the fellow or nonsurgical eyes, although none reached statistical significance, as the differences were small. However, a few FA implanted eyes demonstrated more dramatic scleral thinning than others. CONCLUSIONS: FA implant appears to lead to statistically nonsignificant scleral thinning overall with few exceptions. Clinicians should be aware of potential scleral thinning in select cases, important for reimplantation and long-term follow-up.

Generating high peak capacity 2-D maps of complex proteomes using PMMA microchip electrophoresis.

A high peak capacity 2-D protein separation system combining SDS micro-CGE (SDS micro-CGE) with microchip MEKC (micro-MEKC) using a PMMA microfluidic is reported. The utility of the 2-D microchip was demonstrated by generating a 2-D map from a complex biological sample containing a large number of constituent proteins using fetal calf serum (FCS) as the model system. The proteins were labeled with a thiol-reactive AlexaFluor 633 fluorophore (excitation/emission: 633/652 nm) to allow for ultra-sensitive on-chip detection using LIF following the 2-D separation. The high-resolution separation of the proteins was accomplished based on their size in the SDS micro-CGE dimension and their interaction with micelles in the micro-MEKC dimension. A comprehensive 2-D SDS micro-CGE x micro-MEKC separation of the FCS proteins was completed in less than <30 min using this 2-D microchip format, which consisted of 60 mm and 50 mm effective separation lengths for the first and second separation dimensions, respectively. Results obtained from the microchip separation were compared with protein maps acquired using conventional 2-D IEF and SDS-PAGE of a similar FCS sample. The microchip 2-D separation was found to be approximately 60x faster and yielded an average peak capacity of 2600 (+/- 149), nearly three times larger than that obtained using conventional IEF/SDS-PAGE.

A Bacillus subtilis fusion protein system to produce soybean Bowman-Birk protease inhibitor.

A fusion protein based expression system was developed in the Gram-positive bacterium Bacillus subtilis to produce the soybean Bowman-Birk protease inhibitor (sBBI). The N-terminus of the mature sBBI was fused to the C-terminus of the 1st cellulose binding domain linker (CBD linker) of the BCE103 cellulase (from an alkalophilic Bacillus sp.). The strong aprE promoter was used to drive the transcription of the fusion gene and the AprE signal sequence was fused to the mature BCE103 cellulase for efficient secretion of the fusion protein into the culture medium. It was necessary to use a B. subtilis strain deficient in nine protease genes in order to reduce the proteolytic degradation of the fusion protein during growth. The fusion protein was produced in shake flasks at concentrations >1g/L. After growth, the sBBI was activated by treatment with 2-mercaptoethanol to allow the disulfide bonds to form correctly. An economical and scalable purification process was developed to purify sBBI based on acid precipitation of the fusion protein followed by acid/heat cleavage of the fusion protein at labile Asp-Pro bonds in the CBD linker. If necessary, non-native amino acids at the N- and C-termini were trimmed off using glutamyl endopeptidase I. After purification, an average of 72 mg of active sBBI were obtained from 1L of culture broth representing an overall yield of 21% based on the amount of sBBI activated before purification.

Pharmacokinetics of systemic versus focal Carboplatin chemotherapy in the rabbit eye: possible implication in the treatment of retinoblastoma.

PURPOSE: To characterize the pharmacology and toxicity of intravenous versus focal carboplatin delivery in the rabbit eye. METHODS: Pharmacological distribution of carboplatin was examined in New Zealand White Rabbits after a single intravenous infusion of carboplatin (18.7 mg/kg of body weight), a single subconjunctival carboplatin injection (5.0 mg/400 microL), or a single application of carboplatin delivered by Coulomb-controlled iontophoresis (CCI; 14 mg/mL carboplatin, 5.0 mA/cm(2), 20 minutes). After each treatment, animals were euthanatized, and the eyes analyzed at 1, 2, 6, or 24 hours by atomic absorption spectroscopy to determine carboplatin concentration in ocular structures. Potential toxicity of focally delivered carboplatin was assessed by histology after six cycles of 5.0 mg carboplatin delivered by subconjunctival injection or six transscleral carboplatin CCI applications at 72-hour intervals (14.0 mg/mL, 20 minutes at 2.5 mA). RESULTS: Determination of concentrations through atomic absorption spectroscopy in the retina, choroid, vitreous humor, and optic nerve after subconjunctival injection or iontophoretic carboplatin delivery revealed significantly higher levels than those achieved with intravenous administration. Carboplatin concentrations in the blood plasma were found to be significantly higher after intravenous delivery than after focal delivery by subconjunctival injection or CCI. No evidence of ocular toxicity was detected after focally delivered Carboplatin. CONCLUSIONS: Focal administration of carboplatin using subconjunctival or noninvasive CCI safely and effectively transmits this chemotherapeutic drug into the target tissues of the retina, choroid, vitreous, and optic nerve. These results suggest that focal carboplatin delivery may effectively increase intraorbital carboplatin concentrations while decreasing systemic exposure to this cytotoxic drug.

External beam radiation "salvage" therapy in transgenic murine retinoblastoma.

OBJECTIVE: To determine the efficacy of low-dose "salvage" external beam radiation therapy (EBRT) following failed subconjunctival carboplatin chemotherapy in a murine model of heritable retinoblastoma. METHODS: Eighty-four eyes from 8-week-old, simian virus 40, T-antigen-positive mice were treated with 6 serial subconjunctival carboplatin injections (100 microg/25 microL). At 12 weeks of age, 64 eyes received EBRT for a total dose of 480 (4.8 Gy), 1200 (12.0 Gy), 1560 (15.6 Gy), or 3000 (30.0 Gy) rad. Twenty eyes received no additional therapy following subconjunctival carboplatin injections. Ten eyes received a total dose EBRT of only 3000 rad. Eight eyes received subconjuctival injections of only an isotonic sodium chloride solution. Ten eyes served as untreated controls. MAIN OUTCOME MEASURES: Eyes were enucleated at 20 weeks to assess the presence of tumor on histopathological examination. RESULTS: Salvage therapy using low-dose EBRT was able to reestablish tumor control in a dose-dependent manner. Increasing the EBRT dose to 3000 rad resulted in 100% tumor control. The dose-dependent curves were significantly different between the treatment groups-EBRT alone vs salvage EBRT after receiving subconjunctival carboplatin injections (P<.001). CONCLUSION: Low-dose hyperfractionated salvage EBRT following failed primary subconjunctival carboplatin chemotherapy is efficacious in the treatment of retinoblastoma in this animal model. Clinical Relevance Salvage EBRT using a reduced total radiation dose could be associated with a radiation-related treatment enhancement in pediatric retinoblastoma.

Magnetically integrated microporous implant: safety and efficacy of secondary posting.

OBJECTIVE: To evaluate the surgical technique and morbidity related to secondary posting of a previously implanted 12-mm microporous high-density polyethylene implant (MEDPOR) and the enhanced motility associated with magnetic coupling of the prosthesis and the implant in a rabbit model. METHODS: Eight New Zealand rabbits underwent primary evisceration surgery with implantation of a 12-mm microporous high-density polyethylene implant. At 6 weeks, a 4 x 6-mm stainless steel, titanium-coated post was secondarily inserted in 6 rabbit eyes using a bilevel incision. Four weeks after the second surgery, 3 rabbits were fitted with a magnet-embedded prosthesis. Motility was measured by evaluating lateral prosthetic excursion during direct observation. At 3, 6, and 12 months the implants and surrounding tissues were harvested for histopathologic examination. RESULTS: Secondary placement of the post within the implant was accomplished without difficulty. No signs of erosion, dehiscence, or extrusion were found after a12-month follow-up in any of the study eyes. Clinical grading documented increased movement of the magnetically coupled prostheses compared with nonmagnetically integrated control eyes. CONCLUSION: This study establishes the safety of secondary posting and the efficacy of magnetically integrated microporous high-density polyethylene implants in the rabbit model. CLINICAL RELEVANCE: This technique may offer an alternative to patients with previously implanted microporous high-density polyethylene implants seeking enhanced cosmesis and prosthetic motility.

Comparison of retinoblastoma reduction for chemotherapy vs external beam radiotherapy.

OBJECTIVE: To determine the time course and extent of tumor reduction associated with systemic chemotherapy or external beam radiotherapy (EBRT) in the treatment of advanced intraocular retinoblastoma. METHODS: Retrospective review of children with Reese-Ellsworth stages IV and V retinoblastoma undergoing primary globe-conserving therapy with either systemic chemoreduction or EBRT. Study variables were recorded at baseline, at monthly intervals for the first 6 months, and at 12 months after the initiation of treatment. Tumor volumes were calculated using basal area and height values determined by ultrasonography, physical examination, and fundus photographic review. MAIN OUTCOME MEASURES: Outcome measures included tumor volume, tumor reduction, regression pattern, treatment-related complications, metastases, and survival. RESULTS: Twenty-six eyes of 26 patients were evaluated for tumor response; 18 patients were treated with systemic chemotherapy and 8 patients were treated with EBRT. Median follow-up was 36 months. A mean 68% reduction in tumor volume occurred after 1 cycle of chemotherapy compared with a 12% reduction at a similar time point (1 month) after initiation of EBRT (P<.004). There was no statistically significant difference in tumor volume reduction between treatment modalities at the 12-month follow-up visit. Both systemic chemoreduction and EBRT achieved 100% globe conservation and 100% patient survival in this series. CONCLUSIONS: Retinoblastoma reduction exhibits a differential time course based on the applied primary treatment. Systemic chemotherapy is associated with earlier tumor reduction than EBRT.

Ocular delivery of acetylsalicylic acid by repetitive coulomb-controlled iontophoresis.

To investigate the potential of transscleral coulomb-controlled iontophoresis (CCI) for repetitive delivery of acetylsalicylic acid (ASA) into the eye, a total of 50 rabbits was included in this study. Fourteen animals received serial CCI treatment. Fourteen animals underwent CCI with either ASA or balanced salt solution (BSS) for at least 6 days at 24- and 48-hour intervals. Eighteen animals received a single CCI application, while 18 animals were injected with 15 mg ASA/kg body weight intravenously. HPLC analysis was performed to determine the levels of salicylic acid (SA) in ocular tissues. Apart from clinical follow-up, 2 rabbits in the ASA and BSS groups were examined by electroretinography, and 2 animals were examined histologically. Though high concentrations of SA were measured, no alterations were observed clinically, histologically and electrophysiologically. Repetitive CCI demonstrated its potential as a topical drug delivery system for ASA into the eye. This transscleral delivery of ASA resulted in significant and sustained intraocular concentrations of SA without side effects. Iontophoresis may be advantageous in clinical administration maintaining therapeutic levels of ASA while avoiding adverse effects associated with the systemic administration of nonsteroidal anti-inflammatory drugs.

Hyperfractionated external beam radiation therapy in the treatment of murine transgenic retinoblastoma.

OBJECTIVE: To determine the in vivo efficacy of hyperfractionated external beam radiation therapy (EBRT) in comparison with standard daily EBRT in a murine model of heritable retinoblastoma. METHODS: Two hundred twenty eyes from 6-week-old simian virus-40 large T-antigen--positive mice were treated with a total dose of EBRT ranging from 10-76 Gy (1000 to 7600 rad). One hundred ten eyes underwent EBRT administered in 2.0-Gy (200-rad) fractions once per day. Forty-two eyes received hyperfractionated EBRT administered in 1.2-Gy (120-rad) fractions twice per day, while 48 eyes received EBRT twice daily in fractions of 5.0 Gy (500 rad). Twenty eyes served as untreated controls. All eyes were obtained for histopathologic examination and graded positive if any tumor was present. RESULTS: A dose-dependent inhibition of ocular tumor was observed for EBRT in these transgenic retinoblastoma mice. The tumor control dose for 50% of eyes (TCD(50)) treated with 2.0 Gy fractions of EBRT was 45 Gy (4500 rad) when treatments were administered once daily. A significant increase in tumor control was observed when treatments were administered twice per day at fractions of 1.2 Gy, resulting in a TCD(50) of 33 Gy (3300 rad) (P =.003). A further increase in tumor control was observed when twice-daily EBRT was administered in 5.0 Gy fractions resulting in a TCD(50) of 28 Gy (2800 rad). CONCLUSIONS: Hyperfractionated EBRT safely and effectively controls intraocular retinoblastoma in this transgenic animal model. Use of hyperfractionation allows for a reduction in total radiation delivered dose, while shortening the total treatment time. CLINICAL RELEVANCE: This treatment approach may be applicable in the management of pediatric retinoblastoma by maintaining excellent tumor control, while reducing treatment-associated complications.