Microfluidic Microcirculation Mimetic for Exploring Biophysical Mechanisms of Chemotherapy-Induced Metastasis.

There is rapidly emerging evidence from pre-clinical studies, patient samples and patient subpopulations that certain chemotherapeutics inadvertently produce prometastatic effects. Prior to this, we showed that doxorubicin and daunorubicin stiffen cells before causing cell death, predisposing the cells to clogging and extravasation, the latter being a step in metastasis. Here, we investigate which other anti-cancer drugs might have similar prometastatic effects by altering the biophysical properties of cells. We treated myelogenous (K562) leukemic cancer cells with the drugs nocodazole and hydroxyurea and then measured their mechanical properties using a microfluidic microcirculation mimetic (MMM) device, which mimics aspects of blood circulation and enables the measurement of cell mechanical properties via transit times through the device. We also quantified the morphological properties of cells to explore biophysical mechanisms underlying the MMM results. Results from MMM measurements show that nocodazole- and hydroxyurea-treated K562 cells exhibit significantly altered transit times. Nocodazole caused a significant (p < 0.01) increase in transit times, implying a stiffening of cells. This work shows the feasibility of using an MMM to explore possible biophysical mechanisms that might contribute to chemotherapy-induced metastasis. Our work also suggests cell mechanics as a therapeutic target for much needed antimetastatic strategies in general.

Diabetes mellitus prevalence in Northland New Zealand schizophrenia patients on clozapine.

AIMS: Clozapine is a unique atypical anti-psychotic agent with best efficacy for treatment resistant schizophrenia compared to other agents, but with increased metabolic adverse effects. We sought to audit the prevalence of diabetes and pre-diabetes in Northland, New Zealand patients on clozapine. METHOD: We captured all 287 patients in Northland, New Zealand who were prescribed clozapine in September 2021 and obtained demographic, clinical and laboratory data. RESULTS: We discovered that 26.48% had diabetes (one patient type one, 75 type two diabetes) and 14.63% had pre-diabetes that developed after a median of six years' clozapine treatment. Diabetes prevalence is approximately 6% in the general population. NZ Maori made up 65.85% of the entire cohort (35.8% of the general population) and 85.53% of the diabetes patients. NZ Europeans represented most of the remaining 30.66% on clozapine, consistent with the largely bicultural ethnic mix of our region. Maori on clozapine were younger: mean age 42 years, compared to NZ Europeans, mean age 49 years. The average BMI was 37kg/m2 for Maori, 32 for Europeans (range 21-63, SD 8); there was a moderate relationship between clozapine use and increasing BMI (correlation coefficient of 0.74). For the diabetes patients, glycaemic control was overall suboptimal with a mean Hba1c of 66mmol/mol (range 41-117). CONCLUSIONS: Culturally appropriate, flexible and accessible services which integrate both the mental and physical health needs of Northland, New Zealand people with treatment-resistant schizophrenia on clozapine are required to reduce the 41% rate of dysglycaemia in this predominantly Maori group.

Presyncope Is Associated with Intensive Care Unit Admission in Emergency Department Patients with Acute Pulmonary Embolism.

INTRODUCTION: Syncope is common among emergency department (ED) patients with acute pulmonary embolism (PE) and indicates a higher acuity and worse prognosis than in patients without syncope. Whether presyncope carries the same prognostic implications has not been established. We compared incidence of intensive care unit (ICU) admission in three groups of ED PE patients: those with presyncope; syncope; and neither. METHODS: This retrospective cohort study included all adults with acute, objectively confirmed PE in 21 community EDs from January 2013-April 2015. We combined electronic health record extraction with manual chart abstraction. We used chi-square test for univariate comparisons and performed multivariate analysis to evaluate associations between presyncope or syncope and ICU admission from the ED, reported as adjusted odds ratios (aOR) with 95% confidence intervals (CI). RESULTS: Among 2996 PE patients, 82 (2.7%) had presyncope and 109 (3.6%) had syncope. ICU admission was similar between groups (presyncope 18.3% vs syncope 25.7%) and different than their non-syncope counterparts (either 22.5% vs neither 4.7%; p<0.0001). On multivariate analysis, both presyncope and syncope were independently associated with ICU admission, controlling for demographics, higher-risk PE Severity Index (PESI) class, ventilatory support, proximal clot location, and submassive and massive PE classification: presyncope, aOR 2.79 (95% CI, 1.40, 5.56); syncope, aOR 4.44 (95% CI 2.52, 7.80). These associations were only minimally affected when excluding massive PE from the model. There was no significant interaction between either syncope or presyncope and PESI, submassive or massive classification in predicting ICU admission. CONCLUSION: Presyncope appears to carry similar strength of association with ICU admission as syncope in ED patients with acute PE. If this is confirmed, clinicians evaluating patients with acute PE may benefit from including presyncope in their calculus of risk assessment and site-of-care decision-making.

The Detection of Occult Retinal Vasculitis on Fluorescein Angiography in Pediatric Uveitis.

PURPOSE: To evaluate the usefulness of fluorescein angiography (FA) to detect occult retinal vasculitis in children with otherwise apparently quiescent intermediate uveitis, posterior uveitis, and panuveitis based on clinical examination alone. DESIGN: Retrospective chart review. PARTICIPANTS: Pediatric uveitis patients evaluated at the Children's Medical Center in Dallas, Texas. METHODS: Retrospective chart review of pediatric patients treated with immunosuppressive therapy in the uveitis clinic at the Children's Medical Center, Dallas, Texas, between September 2015 and September 2016. Patients with noninfectious uveitis requiring immunosuppressive therapy, in which posterior segment involvement (intermediate uveitis, posterior uveitis, or panuveitis) was known or suspected, and whose disease apparently was quiescent on clinical examination were included. MAIN OUTCOME MEASURES: The incidence of occult retinal vasculitis detected on FA alone. RESULTS: Fourteen pediatric patients met inclusion criteria. Six patients (43%) demonstrated intermediate uveitis, and 8 patients (57%) demonstrated panuveitis. Eleven patients (79%) were found to show additional evidence of occult retinal vasculitis on FA. CONCLUSIONS: Fluorescein angiography can be an important tool in evaluating pediatric uveitis patients with known or suspected posterior involvement for the presence of occult retinal vasculitis. Failure to control occult retinal vasculitis adequately may be a contributing factor to seemingly recalcitrant cases, inability to wean off immunomodulatory therapy, and long-term complications leading to poor prognosis.

Dynamic slow-wave interactions in the rabbit small intestine defined using high-resolution mapping.

BACKGROUND: The motility in the small intestine is governed in part by myogenic bio-electrical events, known as slow waves. High-resolution multi-electrode mapping has improved our understanding of slow-wave propagation in the small intestine but has been applied in a limited number of in vivo animal studies. This study applied high-resolution mapping to investigate slow waves in the rabbit small intestine. METHODS: A high-resolution flexible printed circuit board array (256 electrodes; 4 mm spacing) was applied in vivo to the rabbit intestine. Extracellular slow-wave activity was acquired sequentially along the length of the intestine. KEY RESULTS AND CONCLUSIONS: The majority of the slow waves propagated in the antegrade direction (56%) while retrograde patterns were primarily observed in the distal intestine (29%). Colliding slow-wave events were observed across the length of the small intestine (15%). The interaction of competing pacemakers was mapped in spatiotemporal detail. The frequency and velocity of the slow waves were highest in the duodenum compared to ileum (20.0 ± 1.2 cpm vs 10.5 ± 0.9 cpm, P < 0.001; 14.4 ± 3.4 mm/s vs 12.3 ± 3.4 mm/s; P < 0.05). INFERENCES: In summary, extracellular serosal slow-wave activity was quantified spatiotemporally along the length of the rabbit intestine. In particular, the study provides evidence toward the presence and interaction of slow-wave pacemakers acting along the small intestine and how they may contribute to the slow-wave frequency gradient along the length of the intestine.

Successful treatment with infliximab after adalimumab failure in pediatric noninfectious uveitis.

PURPOSE: To describe the use of infliximab after adalimumab failure in the treatment of pediatric noninfectious uveitis. METHODS: A retrospective analysis was performed on the medical records of pediatric patients with noninfectious uveitis treated with infliximab for a minimum of 6 months after previously failing to achieve steroid-free remission using adalimumab at the University of Texas Medical School and Children's Medical Center between September 2015 and March 2018. Rates of achieving disease activity quiescence and steroid-free remission as well as incidence of adverse events were calculated. RESULTS: A total of 13 patients with noninfectious uveitis refractory to treatment with adalimumab met inclusion criteria. Three (23%) had anterior uveitis, 4 (31%) had pars planitis, and 6 (46%) had panuveitis. Eleven (85%) patients had preexisting ocular comorbidities. Of these, 4 (31%) had retinal vasculitis, and 1 (7.7%) had cystoid macular edema. There was a 100% response rate to treatment with infliximab following failure to achieve disease quiescence on adalimumab. At mean follow-up time of 21 months (range, 8-31) from initiation of infliximab, there was a reduction in steroid dependence from 100% to 15% after transitioning from adalimumab to infliximab (P < 0.001). Nine patients (69%) had achieved steroid-free remission on infliximab therapy. The mean time to steroid-free remission was 8.7 months. CONCLUSIONS: In our study cohort, infliximab was used successfully in all cases of recalcitrant pediatric noninfectious uveitis that previously failed adalimumab therapy.

Uninformative contexts support word learning for high-skill spellers.

The current study investigated how high-skill spellers and low-skill spellers incidentally learn words during reading. The purpose of the study was to determine whether readers can use uninformative contexts to support word learning after forming a lexical representation for a novel word, consistent with instance-based resonance processes. Previous research has found that uninformative contexts damage word learning; however, there may have been insufficient exposure to informative contexts (only one) prior to exposure to uninformative contexts (Webb, 2007; Webb, 2008). In Experiment 1, participants read sentences with one novel word (i.e., blaph, clurge) embedded in them in three different conditions: Informative (six informative contexts to support word learning), Mixed (three informative contexts followed by three uninformative contexts), and Uninformative (six uninformative contexts). Experiment 2 added a new condition with only three informative contexts to further clarify the conclusions of Experiment 1. Results indicated that uninformative contexts can support word learning, but only for high-skill spellers. Further, when participants learned the spelling of the novel word, they were more likely to learn the meaning of that word. This effect was much larger for high-skill spellers than for low-skill spellers. Results are consistent with the Lexical Quality Hypothesis (LQH) in that high-skill spellers form stronger orthographic representations which support word learning (Perfetti, 2007). Results also support an instance-based resonance process of word learning in that prior informative contexts can be reactivated to support word learning in future contexts (Bolger, Balass, Landen, & Perfetti, 2008; Balass, Nelson, & Perfetti, 2010; Reichle & Perfetti, 2003). (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Evaluation of tensile strength of tissue adhesives and sutures for clear corneal incisions using porcine and bovine eyes, with a novel standardized testing platform.

BACKGROUND: Tissue adhesives for ophthalmologic applications were proposed almost 50 years ago, yet to date no adequate tissue glues have been identified that combine strong sealing properties with adequate safety and absence of postsurgical side effects. In recent years, cataract surgeries and Descemet's stripping with endothelial keratoplasty procedures have significantly increased the number of clear corneal incisions performed. One of the obstacles to discovery and development of novel tissue adhesives has been the result of nonstandardized testing of potential tissue glues. METHODS: We developed an instrument capable of controlling intraocular pressure in explanted porcine and bovine eyes in order to evaluate sealants, adhesives, and surgical closure methods used in ophthalmic surgery in a controlled, repeatable, and validated fashion. We herein developed and validated our instrument by testing the adhesive properties of cyanoacrylate glue in both porcine and bovine explant eyes. RESULTS: The instrument applied and maintained intraocular pressure through a broad range of physiological intraocular pressures. Cyanoacrylate-based glues showed significantly enhanced sealing properties of clear corneal incisions compared with sutured wounds. CONCLUSION: This study shows the feasibility of our instrument for reliable and standardized testing of tissue adhesive for ophthalmological surgery.

Syndrome of inappropriate antidiuretic hormone due to multiple myeloma.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been linked to many malignancies. However, literature noting multiple myeloma as a possible cause of SIADH is lacking. Although there is a plethora of literature reporting multiple myeloma induced spurious hyponatremia, our review revealed only one case report, in 1983, describing multiple myeloma induced SIADH. Here we report another case of multiple myeloma induced SIADH, where secondary causes of SIADH, including pseudohyponatremia, were ruled out.